REVIEW | doi:10.20944/preprints201910.0296.v1
Subject: Medicine & Pharmacology, Oncology & Oncogenics Keywords: nasal delivery; glioblastoma multiforme; drug delivery; nanoparticles; nose-to-brain delivery; pre-clinical studies; clinical evaluation
Online: 27 October 2019 (09:36:27 CET)
Glioblastoma (GBM) is the most lethal form of brain tumor, characterized by rapid growth and surrounding tissue invasion. The current standard treatment is surgery followed by radiotherapy, and concurrent chemotherapy, typically with temozolomide. Although extensive research has been performed over the past years to develop an effective therapeutic strategy for the treatment of GBM, efforts have not provided major improvements in the overall survival of patients with GBM. Thus, new therapeutic approaches are urgently needed. A major challenge in the development of therapies for central nervous system (CNS) disorders is overcoming the blood–brain barrier (BBB). In this context, the intranasal (IN) route of drug administration has been proposed as a non-invasive alternative route to directly targeting the CNS. In fact, this route of drug administration may bypass the blood-brain barrier and reduce systemic side effects. Recently, formulations have been developed to further enhance nose-to-brain transport, mainly with the use of nano-sized and nanostructured drug delivery systems. The focus of this review will be on the strategies developed to deliver a number of anticancer compounds for the treatment of GBM using the nasal administration. In particular, the specific properties of nanomedicines proposed for the nose-to-brain delivery will be critically evaluated. The number of preclinical and clinical data reviewed support the idea that nasal delivery of anticancer drugs might represent a breakthrough advancement in the fight against GBM.
ARTICLE | doi:10.20944/preprints201810.0697.v1
Subject: Medicine & Pharmacology, Oncology & Oncogenics Keywords: glioma; glioblastoma; pre-clinical drug development; 3D culture systems; radiotherapy
Online: 30 October 2018 (03:38:28 CET)
Glioblastoma (GBM), the most common and aggressive primary brain tumor in adults, remains one of the least treatable cancers. Current standard of care—combining surgical resection, radiation, and alkylating chemotherapy—results in a median survival of only 15 months. Despite decades of investment and research into the development of new therapies, most candidate anti-glioma compounds fail to translate into effective treatments in clinical trials. One key issue underlying this failure of therapies that work in pre-clinical models to generate meaningful improvement in human patients is the profound mismatch between drug discovery systems—cell cultures and mouse models—and the actual tumors they are supposed to imitate. Indeed, current strategies that evaluate the effects of novel treatments on GBM cells in vitro fail to account for a wide range of factors known to influence tumor growth. These include secreted factors, the brain’s unique extracellular matrix, circulatory structures, the presence of non-tumor brain cells, and nutrient sources available for tumor metabolism. While mouse models provide a more realistic testing ground for potential therapies, they still fail to account for the full complexity of tumor-microenvironment interactions, as well as the role of the immune system. Based on the limitations of current models, researchers have begun to develop and implement novel culture systems that better recapitulate the complex reality of brain tumors growing in situ. A rise in the use of patient derived cells, creative combinations of added growth factors and supplements, may provide a more effective proving ground for the development of novel therapies. This review will summarize and analyze these exciting developments in 3D culturing systems. Special attention will be paid to how they enhance the design and identification of compounds that increase the efficacy of radiotherapy, a bedrock of GBM treatment.
REVIEW | doi:10.20944/preprints202102.0405.v1
Subject: Keywords: drug repurposing; antifungal therapy; antifungal mechanism; clinical application; antifungal agents
Online: 18 February 2021 (10:21:38 CET)
The morbidity and mortality caused by invasive fungal infections is increasing across the globe due to developments in transplant surgery, the use of immunosuppressive agents, and the emergence of drug-resistant fungal strains, which has led to a challenge in terms of treatment due to the limitations of three classes of drugs. Hence, it is imperative to establish effective strategies to identify and design new antifungal drugs. Drug repurposing is an effective way of expanding the application of existing drugs. In the last years, various existing drugs have been shown to be useful in the prevention and treatment of the invasive fungi. In this review, we summarize the currently used antifungal agents. In addition, the most up to date information on the effectiveness of existing drugs with antifungal activity is discussed. Moreover, the antifungal mechanisms of existing drugs are highlighted. These data will provide valuable knowledge to stimulate further investigation and clinical application in this field.
ARTICLE | doi:10.20944/preprints201907.0179.v1
Subject: Medicine & Pharmacology, Nutrition Keywords: atherogenesis; passiflora edulis sims; lipid profile; free radicals; pre-clinical trial
Online: 15 July 2019 (05:59:18 CEST)
High oxidative stress in cells due to inflammation process or excessive cell proliferation would produce oxidants or free radicals with biomarkers, one of which is malondialdehyde (MDA). Passion fruit seed’s contain high antioxidant and are expected to decrease the level of cholesterol and MDA. The objective is to identify the effect of passion fruit seed’s ethanol extract in Wistar rats that have been fed with atherogenic feed. The method was preclinical trial (post-test control group design) in rats, by administering passion fruit seed’s ethanol extract for 14 days. This study used 26 male rats aged two months, divided into 5 groups. The result showed significant difference in MDA level which was found in group that was given passion fruit seed extract 10mg/kg BW with positive control group that was given standard feed. Passion fruit seed’s extract showed significant difference in level of triglyceride, which was found in negative control group that was given atherogenic feed with group that was given passion fruit seed’s extract 5mg/kg BW (mean±standard deviation: 1.09±0.30 mg/dL vs 0.77±0.25mg/dL; p=0.048). This study showed that passion fruit seed’s ethanol extract had significant lowering effect in level of MDA, total cholesterol, and triglyceride for 14 days.
REVIEW | doi:10.20944/preprints202004.0367.v1
Subject: Medicine & Pharmacology, Allergology Keywords: COVID-19; drugs; 2019-nCoV; clinical trials; SARS-CoV-2
Online: 20 April 2020 (15:53:56 CEST)
The emergence of new type of viral pneumonia cases in China, on December 31, 2019; identified as the cause of human coronavirus, labeled as "COVID-19," took a heavy toll of death and reported cases of infected people all over the world, with the potential to spread widely and rapidly, achieved worldwide prominence but arose without the procurement guidance. There is an immediate need for active intervention and fast drug discovery against the 2019-nCoV outbreak. Herein, the study provides numerous candidates of drugs (either alone or integrated with another drugs) which could prove to be effective against 2019-nCoV, are under different stages of clinical trials. This review will offer rapid identification of a number of repurposable drugs and potential drug combinations targeting 2019-nCoV and preferentially allow the international research community to evaluate the findings, to validate the efficacy of the proposed drugs in prospective trials and to lead potential clinical practices.
REVIEW | doi:10.20944/preprints202009.0684.v1
Subject: Medicine & Pharmacology, Allergology Keywords: Clinical application; dimethyl fumarate; disease; fumaric acid esters; oxidative stress; inflammation; Nrf2; disease
Online: 28 September 2020 (11:03:25 CEST)
Fumaric acid esters (FAEs) are small molecules with anti-oxidative, anti-inflammatory and immune-modulating effects. Dimethyl fumarate (DMF) is the best characterised FAE and is approved and registered for the treatment of psoriasis and Relapsing-Remitting Multiple Sclerosis (RRMS). Psoriasis and RRMS share an immune-mediated aetiology, driven by severe inflammation and oxidative stress. DMF, as well as monomethyl fumarate and diroximel fumarate, are commonly prescribed first-line agents with favourable safety and efficacy profiles. The potential benefits of FAEs against other diseases that appear pathogenically different but share the pathologies of oxidative stress and inflammation are currently investigated.
ARTICLE | doi:10.20944/preprints202106.0400.v1
Subject: Medicine & Pharmacology, Allergology Keywords: pharmacovigilance; clinical pharmacology; male; female; emergency department.
Online: 15 June 2021 (11:51:17 CEST)
This post-hoc analysis of an Italian active pharmacovigilance study describes pharmacological differences of ADEs leading to emergency department (ED) visit and hospitalization in women and men. During the study period (January 2007 – December 2018), 61,855 reports of ADE leading to ED visit were collected. Overall, 30.6% of ADEs resulted in hospitalization (30% in women and 31% in men). Multivariate logistic regression showed that, among women, drug classes significantly associated with an increased risk of hospitalization were heparins (ROR 1.41, CI 1.13-176), antidepressants (ROR 1.12, CI 1.03-1.23) and antidiabetics (ROR 1.13, CI 1.02-1.24). Among men only vitamin K antagonists (ROR 1.28, CI 1.09-1.50), opioids (ROR 1.30, CI 1.06-1.60) and digitalis glycosides (ROR 1.32, CI 1.09-1.59) were associated with a higher risk of hospitalization. Overall, older age, multiple suspected drugs and the presence of comorbidi-ties were significantly associated with a higher risk of hospitalization. A significantly reduced risk of hospitalization was observed in both women and men experiencing and adverse event following immunization (ROR 0.36, CI 0.27-0.48 and 0.83, 0.42-0.74, respectively) compared to drugs. Results obtained from this real-world analysis highlight important aspects of drug safety between sexes.
REVIEW | doi:10.20944/preprints202005.0477.v1
Subject: Keywords: respiratory syncytial virus vaccine; clinical trial; safety and immunogenicity; RSV promising vaccine
Online: 31 May 2020 (16:07:57 CEST)
Background: Respiratory syncytial virus (RSV) is a leading cause of acute lower respiratory infection globally. There are vaccines in pipeline to prevent it but a systematic review on immunogenicity and safety of vaccine is lacking. Methods: This systematic review of RSV vaccine clinical trials was undertaken using 4 databases. Searches were conducted using both controlled vocabulary terms such as ‘Respiratory Syncytial Virus, Human’, ‘Respiratory Syncytial Virus Infections’, ‘Respiratory Syncytial Virus Vaccines’, ‘Immunization’, ‘Immunization Programs’ and ‘Vaccines’ and corresponding text word terms. The searches for published papers were limited to clinical trials published from January 2000 to August 6th, 2018. RSV infection case was defined as RSV associated medically attended acute respiratory illness (MAARI) or RSV infection by serologically-confirmed test (Western Blot) during the RSV surveillance period. We calculated the relative risk of each vaccine trial with RSV infection case. Results: Of 4395 publications, 24 were included and data were extracted covering 4 major types of RSV vaccine candidates, these being live-attenuated/chimeric (n=9), recombinant-vector (n=10), subunit (n=1) and nanoparticle vaccines (n=4). For RSV infection cases, 7 trials were involved and none of them showed a vaccine-related increased MAARI during RSV surveillance season. Conclusion: LID ∆M2-2, MEDI M2-2, and RSVcps2 (live-attenuated) were considered the most promising vaccine candidates in infant and children. In the elderly, a nanoparticle F vaccine candidate was considered as a potential effective vaccine. Although no promising vaccine was identified from pregnant-women test, RSV F-024 subunit vaccine candidate and an RSV F nanoparticle vaccine showed encouraging results in healthy non-pregnant women.
REVIEW | doi:10.20944/preprints202104.0348.v1
Subject: Medicine & Pharmacology, Allergology Keywords: porous tantalum; clinical application; additive manufacturing; surface modification; bone tissue engineering
Online: 13 April 2021 (11:36:57 CEST)
Porous tantalum (Ta) is a promising biomaterial and has been applied in orthopedics and dentistry for nearly two decades. The high porosity and interconnected pore structure of porous Ta promise fine bone ingrowth and new bone formation within the inner space, which further guarantee rapid osteointegration and bone-implant stability in long term. Porous Ta has high wettability and surface energy that can facilitate adherence, proliferation and mineralization of osteoblasts. Meanwhile, low elastic modulus and high friction coefficient of porous Ta can effectively avoid stress shield effect, minimize marginal bone loss and ensure primary stability. Accordingly, the satisfactory clinical application of porous Ta based implants or prostheses are mainly derived from its excellent biological and mechanical properties. With the advent of additive manufacturing, personalized porous Ta based implants or prostheses have shown their clinical value in the treatment of individual patient who need specially designed implant or prosthesis. In addition, many modification methods have been introduced to enhance the bioactivity and antibacterial property of porous Ta with promising in vitro and in vivo research results. In any case, choosing suitable patients is of great importance to guarantee surgical success after porous Ta insertion.
REVIEW | doi:10.20944/preprints202006.0078.v1
Subject: Life Sciences, Other Keywords: COVID-19; vaccine; vaccine development; vaccine discovery; systems biology; machine learning; platform technologies; adjuvants; smart clinical trials; human genetics; regulatory convergence; real world evidence; vaccines safety
Online: 7 June 2020 (10:11:02 CEST)
The urgency to develop vaccines against Covid-19 is putting pressure on the long and expensive development timelines which are normally required for development of lifesaving vaccines. There is a unique opportunity to take advantage of new technologies, smart and flexible design of clinical trials, and evolving regulatory science to speed up vaccine development against Covid-19 and transform vaccine development altogether.
ARTICLE | doi:10.20944/preprints202010.0530.v1
Subject: Medicine & Pharmacology, Allergology Keywords: KTAS; simulation; clinical decision-making ability; job satisfaction; customer orientation; nurse
Online: 26 October 2020 (14:14:54 CET)
This study focused on the development and implementation of an educational simulation program based on Korean Triage and Acuity Scale (KTAS) for nurses in emergency medical centers who completed KTAS training. We also examined its educational effects based on the evaluation of clinical decision-making ability, job satisfaction, and customer orientation. The study participants were 30 nurses in the emergency medical center of a general hospital. Data were collected from May 3 to 24, 2017, and analyzed using SPSS 22.0. There was a significant difference in the mean scores in clinical decision-making ability, job satisfaction, and customer orientation before and after simulation education. In other words, emergency nurses who received KTAS-based simulation education program improved their clinical decision making ability, job satisfaction, and customer orientation. Based on the results of this study, it is expected that it can be used for KTAS education, and it was found that simulation-based education is a useful learning method for triage nurses in emergency medical center.
ARTICLE | doi:10.20944/preprints202001.0209.v1
Subject: Medicine & Pharmacology, General Medical Research Keywords: good clinical practice; clinical trials; quality; investigator training; clinical investigator
Online: 19 January 2020 (04:46:48 CET)
Background: Good clinical practice (GCP) training is the industry standard for ensuring the quality conduct of registrational clinical trials. However, concerns have been raised about whether the current structure and delivery of GCP training sufficiently prepares clinical investigators and their delegates to conduct clinical trials. Methods: We conducted qualitative semi-structured interviews with 13 clinical investigators and 10 research sponsors to 1) examine characteristics of the quality conduct of sponsored clinical trials, including critical tasks and concerns perceived as essential for trial quality, 2) identify key knowledge and skills required to perform critical tasks, and 3) identify gaps and redundancies in GCP training and areas of improvement to ensure the quality conduct of clinical trials. We used applied thematic analysis to analyze the data. Results: The top three tasks identified as critical for the quality conduct of clinical trials were obtaining informed consent, ensuring protocol compliance, and protecting participants’ health and safety. Respondents acknowledged that GCP principles address each of these critical tasks; however, they described many challenges and burdens of GCP training, including high training frequency and repetitive content. Respondents suggested moving beyond GCP training as a mere check-box activity by making it more effective, engaging, and interactive. They also emphasized that applying GCP principles in a real-world, skills-based environment would increase the relevance of GCP training to investigators and their delegates. Conclusion: Our findings indicate that although investigators and sponsors recognize that GCP training addresses critical tasks necessary to the quality conduct of clinical trials, they articulated the need for significant improvement in the design, content, and presentation of GCP training.
CONCEPT PAPER | doi:10.20944/preprints202005.0298.v1
Online: 18 May 2020 (08:01:52 CEST)
COVID-19 Pandemic management has become the top priority of Government Institutions globally, which is justifiable seeing the high mortality of the disease. In India, Lockdowns by National, State and Local level administrations have greatly reduced the spread of the SARS COV-2 Virus. Some areas with a greater proportion of COVID-19 patients have been declared hotspots with increased restrictions on public activities through law enforcement. But quite often delay in identification of these hotspots leads to community transmission of the Virus thus aggravating the problem. A method to identify the areas which are at risk of becoming the next hotspot for the disease is the need of the hour. In this Research document we will find the probable risk factors and make an appropriate scale to measure the vulnerability of an area, identified by its Postal code. To help with this a Pan India survey by the title of “Survey on General Indian population on the level of preparedness for COVID-19 pandemic” was launched and received around 1250 submissions, with the acquired data we will evaluate the risk factors and make appropriate scale to identify ‘pre-hotspots’.
Subject: Medicine & Pharmacology, Allergology Keywords: Glioblastom; high-grade glioma; convection enhanced delivery; OS2966; CD29; β1 integrin; ITGB1; monoclonal antibody; clinical trial
Online: 2 December 2020 (09:11:37 CET)
Introduction: OS2966 is a fist-in-class, humanized and de-immunized monoclonal antibody which targets the adhesion receptor subunit, CD29/β1 integrin. CD29 expression is highly upregulated in glioblastoma and has been shown to drive tumor progression, invasion, and resistance to multiple modalities of therapy. Here, we present a novel Phase I clinical trial design addressing several factors plaguing effective treatment of high-grade gliomas (HGG). Study Design: This 2-part, ascending-dose, Phase I clinical trial will enroll patients with recurrent/progressive HGG requiring a clinically-indicated resection. In Study Part 1, patients will undergo stereotactic tumor biopsy followed by placement of a purpose-built catheter which will be used for intratumoral, convection-enhanced delivery (CED) of OS2966. Subsequently, patients will undergo their clinically-indicated tumor resection followed by CED of OS2966 to the surrounding tumor-infiltrated brain. Matched pre- and post-infusion tumor specimens will be utilized for biomarker development and validation of target engagement by receptor occupancy. Dose escalation will be achieved using a unique concentration-based accelerated titration design. Discussion: The present study design leverages multiple innovations including: 1) the latest CED technology, 2) 2-part design including neoadjuvant intratumoral administration, 3) a first-in-class investigational therapeutic, and 4) concentration-based dosing. Trial registration: A U.S. Food and Drug Administration (FDA) Investigational New Drug application (IND) for the above protocol is now active. A Phase I trial is registered at clinicialtrials.gov (NCT04608812).
REVIEW | doi:10.20944/preprints202004.0279.v1
Online: 16 April 2020 (13:47:49 CEST)
Objectives: This study aims to identify, report, and analyze registered and published clinical trials and observational studies for the pharmacological treatment of COVID-19 conducted in China. Methods: A strategic search was conducted via the Chinese Clinical Trial Registry to identify and extract clinical trials and observational studies registered and conducted in China for the pharmacological treatment of COVID-2019 between January 1st, 2020 and March 21st, 2020. This was further supplemented by searches conducted via the China National Knowledge Infrastructure (CNKI) database, the MEDLINE database, the World Health Organization (WHO) database, and MedRxiv and BioRxiv electronic platforms for preprint articles, published up until April 8th, 2020. Studies available in Chinese and English were included in the searches and extracted. A primary descriptive analysis was performed for registered clinical trials and observational studies identified in the Chinese Clinical Trial Registry based on the extraction of the following clinical study information: trial ID, planned date of enrollment, recruitment status, study design, population, sample size, intervention/exposure group, control /reference group, dosage, and primary outcomes. A secondary descriptive analysis was performed for published clinical trials and observational studies identified from the supplementary databases based on the extraction of the following published clinical study information: study design, population, intervention/exposure group, control /reference group and main results as appropriate. Results: A total of 221 clinical trials and observational studies were included from all databases searched. From the Chinese Clinical Trial Registry, 195 registered clinical studies including 170 clinical trials and 25 observational studies were identified and included for primary analysis. From the supplementary databases, 26 published clinical studies including 8 clinical trials and 18 observational studies were included for secondary analysis. Of these 26 published clinical studies, 18 studies, including 3 clinical trials and 15 observational studies were identified from CNKI, 2 studies including 1 clinical trial and 1 observational study from MEDLINE, 2 including 1 clinical trials and 1 observational studies from the WHO database, and 4 including 3 clinical trials and 1 observational studies from MedRxiv and BioRxiv platforms. In the primary analysis, among the 170 clinical trials included from the Chinese Clinical Trial Registry, 101 investigated western medicines (WMs), while 15 investigated Traditional Chinese Medicines (TCMs), and 54 investigated a combination of TCMs and WMs. Among the 25 included observational studies from the Chinese Clinical Trial Registry, 2 investigated WMs, 2 investigated TCMs, and 21 investigated a combination of TCMs and WMs. The total number of exposed patients in all 195 clinical studies from the Chinese Clinical Trial Registry amounted to 24,500. In the secondary analysis, treatment with Lopinavir-ritonavir and treatment with Hydroxychloroquine was not associated with a difference from standard of care in the rate of RT-PCR negativity; treatment with a combination of Lopinavir-ritonavir, interferon α, and Lian-Hua-Qing-Wen capsule was found to significantly improve the effective rate of treatment compared with Interferon α combined with Lian-Hua-Qing-Wen capsule. Conclusions: China is generating a massive source of evidence that is critical for defeating the COVID-19 pandemic. Not only the clinical experience, but also the scientific evidence should be shared with the global scientific community.
Subject: Medicine & Pharmacology, General Medical Research Keywords: clinical trials; investigator qualification; good clinical practice; investigator training
Online: 8 October 2019 (05:18:34 CEST)
The Clinical Trials Transformation Initiative (CTTI) Investigator Qualification Project addresses the need for a more efficient and effective means of identifying qualified clinical investigators and delegates. Selection of investigators and delegates who are qualified by training and experience to conduct clinical trials is essential to safeguarding protections for study participants and ensuring data quality and integrity. Sponsors generally document investigator qualification through training on the principles of good clinical practice (GCP), as defined by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH), adopted by regulatory authorities in the US, Japan and the European Union. Although these GCP principles provide an important foundation for promoting the conduct of quality clinical trials, the industry standard “one-size-fits-all” GCP training may not fully prepare investigators and delegates for conducting quality clinical trials. Routine GCP training alone may not be sufficient to prepare an inexperienced member of a site team, while repeating such training is unlikely to enhance the qualifications of an experienced researcher. The CTTI project team used findings from qualitative research activities, as well as input from an expert meeting with multiple stakeholders, to identify gaps and redundancies in the current training of investigators and their delegates and recommend practical, action-based solutions. CTTI provides recommendations on how to implement a more efficient and effective means of qualification for investigators and delegates, determine whether a site team is a good fit for a particular protocol, and improve the quality of clinical trial conduct.
ARTICLE | doi:10.20944/preprints202106.0114.v2
Subject: Engineering, Biomedical & Chemical Engineering Keywords: virtual reality; pre-operative imaging; echocardiography
Online: 18 August 2021 (10:02:51 CEST)
The intricate nature of congenital heart disease requires understanding of complex, patient-specific three-dimensional dynamic anatomy of the heart, from imaging data such as three-dimensional echocardiography for successful outcomes from surgical and interventional procedures. Conventional clinical systems use flat screens and therefore display remains two-dimensional, which undermines the full understanding of the three-dimensional dynamic data. Additionally, control of three-dimensional visualisation with two-dimensional tools is often difficult, so used only by imaging specialists. In this paper we describe a virtual reality system for immersive surgery planning using dynamic three-dimensional echocardiography, which enables fast prototyping for visualisation such as volume rendering, multi-planar reformatting, flow visualisation, and advanced interaction such as three-dimensional cropping, windowing, measurement, haptic feedback, automatic image orientation, and multi-user interactions. The available features were evaluated by imaging and non-imaging clinicians, showing that the virtual reality system can help improve understanding and communication of the three-dimensional echocardiography imaging and potentially benefit congenital heart disease treatment.
ARTICLE | doi:10.20944/preprints202104.0527.v1
Subject: Life Sciences, Biochemistry Keywords: caffeine, pre-pregnancy, pregnancy, intake, quintiles
Online: 20 April 2021 (11:08:10 CEST)
We aimed to assess the caffeine intake before and during pregnancy, compliance with caffeine recommendations during pregnancy (200 mg/day) and factors associated with higher intakes before and in first trimester of pregnancy. Caffeine consumption was collected in a Spanish cohort of pregnant women through a validated food questionnaire, before and in each trimester of gestation (T1, T2 and T3). 463 pregnant women were recruited and follow-up through pregnancy. Compliance with caffeine intake recommendations during pregnancy and quintiles of mg/day of caffeine before and in T1 of pregnancy were calculated. A multivariate logistic regression, comparing extreme quintiles of consumption (Q1 vs Q5) was used. Mean caffeine intake before pregnancy was 120.05 mg/day (SD 117.85), 42.76 mg/day (SD 63.90) at 12th GW, 42.00 mg/day (SD 59.76) at 24th GW and 39.34 mg/day (SD 50.9) at 32nd GW (p<0.001). 86% of women complied with caffeine recommendations during pregnancy. At pregnancy (T1), being an active smoker was associated with Q5 > 100.1 mg/day, aOR = 22.69; 95% CI 4.67- 110.26. igh diet quality, aOR = 0.30; 95% CI, 0.13- 0.68, and moderate physical activity level, aOR= 0.44; 95% CI, 0.19-1.00, were inversely associated with Q5 > 100.1 mg/day. Pregnant women are mostly adhering to current caffeine intake guidelines. Higher caffeine intake at pregnancy is associated with other unhealthy habits during pregnancy.
ARTICLE | doi:10.20944/preprints202301.0136.v1
Subject: Social Sciences, Education Studies Keywords: pre-service teacher education; teacher evaluation; pre-service physical education teacher; class demonstration; teaching behavior analysis
Online: 9 January 2023 (03:09:08 CET)
This study aimed to evaluate the level of skill in observing teaching competency in pre-service physical education (PE) teachers and provide basic data to cultivate teaching competency. A total of 21 third-year pre-service PE teachers were selected as participants. The study derived descriptive statistics to analyze the participants’ observation skills regarding teaching competency in different class stages using evaluation results of class demonstrations by pre-service teachers. Mann–Whitney U test was conducted to verify the statistical significance of the evaluation between in-service and pre-service teachers. Compared with in-service teachers, pre-service teachers reported high agreement with intuitive teaching behaviors. However, pre-service teachers indicated low agreement with skills that required complex teaching behaviors depending on various situations. Based on theories by Schon (1983), pre-service teachers showed high “knowledge for practice” and low “knowledge in practice.” Thus, pre-service education must balance practical knowledge and theory rather than focus on theory-based education. This study provided directions for pre-service teacher education to enhance the competency of pre-service teachers for leading and analyzing classes.
BRIEF REPORT | doi:10.20944/preprints202007.0541.v1
Online: 23 July 2020 (08:24:54 CEST)
Multicompartment compliance aids (MCAs) are devices with each discrete section denoting a single dosing occasion. The purpose of an MCA is to maximize patient adherence and thereby optimize the treatment benefits. These devices are widely employed throughout western Europe and UK and use appears to be rapidly increasing (2) although the RPS as moved away from these devices as a means to improve adherence. We analysed MCAs from various pharmacies over a wide geographic area in England and North Wales. We concluded that most MCA users are elderly patients. Also, most of the patients suffer of combined cardiovascular disease. However, a significant proportion of patients falls in the mental/ neurological disease category. Additionally, most of the externals added to MCAs are inhalers and painkillers. Moreover, SDIs are more frequent in female patients and these SDI are mainly related with mental health medication, cardiovascular disease medication and neurological medication. In conclusion, a directive for dispensing of MCAs in pharmacies by pharmacists through an enhanced service should be elaborated having in consideration PIMs, SDIs, drug stability and use of externals and MCA design and brand.
ARTICLE | doi:10.20944/preprints202206.0026.v1
Subject: Social Sciences, Education Studies Keywords: reflective evaluation tool; pre-service teacher education; teaching competency; pre-service phys-ical education teacher; Delphi survey
Online: 2 June 2022 (04:44:37 CEST)
The purpose of this study was to develop a reflective evaluation tool that can enhance the teaching competency of pre-service physical education teachers. A Delphi survey was conducted to modify the questions based on the evaluation tool for the teaching competency of physical education teachers, and each evaluation standard based on teaching competency was developed. The evaluation tool consisted of 46 questions for class preparation (the creation of the learning environment), the introduction (routine activities, learning goals, and task presentation), development (class strategy, observation and interaction, and the maintenance of the learning environment), and conclusion (routine activities, summary, and closure). It was designed to increase the accuracy of evaluation by developing evaluation criteria for each question. An evaluation tool including quantitative and qualitative methods for use in pre-service physical education teacher education was developed. The significance of this study was the development of an effective evaluation tool that can evaluate the core teaching behaviors in the field of physical education. This evaluation tool should be used as a learning tool that includes planning, operation, evaluation, and seeking improvement measures through reflective activities. If pre-service teacher education institutions apply this evaluation tool in their teacher training programs, it would be a great chance to learn how to develop and sustain teaching abilities and effectiveness.
COMMUNICATION | doi:10.20944/preprints202105.0128.v1
Subject: Life Sciences, Biochemistry Keywords: Chia; Salvia hispanica; nutraceutical; pre-Columbian crop
Online: 7 May 2021 (09:10:35 CEST)
Among the plant resources in pre-Columbian Mexico and Central America, the Chia (Salvia hispanica L.) is unique in being the only member of the Lamiaceae cultivated for the mericarps. Recently the crop has gained considerable attention due to its high of content omega-3 polyunsaturated fatty acid, antioxidants, fibre and protein classifying it as a nutraceutical.
ARTICLE | doi:10.20944/preprints202010.0651.v1
Subject: Medicine & Pharmacology, Allergology Keywords: Pre-exam anxiety; Poor academic performance; GPA
Online: 30 October 2020 (15:49:21 CET)
Introduction: Exams are a relatively stressful period for all students, especially undergraduate medical students. Exams bring anxiety and stress for the students. Some students experience such high stress that it hinders their academic productivity and reduces their exam performance. The aim of this study is to assess the effects of pre-exam anxiety on the academic performance of medical students. Methods: Two hundred and twenty-five final year medical students completed Westside Test Anxiety (WTA) Scale one month before their exams. Grade Point Average (GPA) of these students was noted when the results were announced. Data was processed and analyzed using SPSS v 22.0Results: The mean anxiety score on WTA scale was 3.46 ± 0.87. All students (100%) who scored ≤ 2.50 GPA were highly-extremely highly anxious. In the 2.51-3.00 GPA group, 46% were highly-extremely highly anxious, 32% were moderately anxious, and 21% had low to normal anxiety. In the 3.01-3.50 GPA group, 30% were highly-extremely highly anxious, 30% were moderately anxious, and 39% had low to normal anxiety. In the 3.51-4.00 GPA group, 29% were highly-extremely highly anxious, 23% were moderately anxious, and 47% had low to normal anxiety. The correlation coefficient between GPA and test anxiety of students was -.314 which shows inverse relationship.Conclusion: Pre-exam anxiety and stress imparts negative effects on the exam performance of final year medical students. Poor academic performance was associated with high to extremely high pre-exam anxiety while high achievers had relatively lower anxiety levels.
ARTICLE | doi:10.20944/preprints201907.0333.v1
Subject: Biology, Animal Sciences & Zoology Keywords: correlated response; pre-weaning; survival; weight; welfare
Online: 29 July 2019 (09:40:36 CEST)
A divergent selection experiment on environmental sensitivity was performed in rabbits. The aim of this study was to estimate the correlated response in kits’ weight and its survival, and weight distance from birth to weaning. Weight distance was calculated as the absolute values of the differences between the individual value and the mean value of its litter. Also, relationship between probability of survival at 4 d of age and weight at birth was studied. Environmental sensitivity was measured as litter size variability. A total of 2484 kits from 127 does of the low line (selected for reducing litter size variability) and 1916 kits of 114 does of the high line (selected for increasing litter size variability) of the 12th generation were weighed. Bayesian methodology was used to estimate the correlated response to selection, and LOGISTIC procedure of SAS was used to estimate the relationship between weight and probability of survival. Both lines showed similar individual weight at birth and at weaning, and similar survival at birth and at 4 d of age. Survival at weaning was higher in the low line than in the high line (0.67 and 0.62; P= 0.93). Weight distance was higher at birth but lower at weaning in the low line (47.8 g and 54.1 g; P=0.98). Kit’s weight at birth affected its survival. In conclusion, selection for environmental sensitivity showed correlated response in kits survival and in homogeneity of litter weight at weaning.
Online: 28 June 2020 (19:46:40 CEST)
Objectives: Data sharing has become a requirement of many funding bodies and is becoming a scientific standard in many disciplines. In medical research, however, data sharing can conflict with clinicians’ obligation to protect patients’ privacy. General recommendations on data sharing exist also for clinical research, but so far lack practical and Swiss-specific aspects. The objective of this document is to provide practical recommendations for all relevant aspects of data sharing in agreement with legislation in Switzerland. Methods: This document was written by members of the Swiss CTU Network, a network of academic clinical trial units. The process did not follow a formalized Delphi process. After an internal consensus round, this report is now published as pre-print for external review. A second version will incorporate external comments. We plan to publish this document as a text in progress, as we expect relevant changes in related fields such as the development of further dedicated medical repositories or methodological advances in anonymization techniques. Results: We developed principles and practical recommendations with respect to informed consent, data management plan, anonymization, data structure and format, coding of variables, metadata and documentation, version control, selection of repository, requesting and use of data. We also provide a summary of legal aspects relevant for the Swiss context. Conclusions: The intension to share data has an impact not only after a clinical trial or an observational study is completed, but also during the planning period, the conduct and the analysis phase. Clinical researchers need to be aware at the beginning of a study on how to inform patients and at least the amount of work related to preparing data for sharing, metadata, and any further documentation. This report provides details of aspects to be considered, suggests decision criteria, and provides examples and checklists, in order to support data sharing in practice.
REVIEW | doi:10.20944/preprints202104.0051.v2
Subject: Medicine & Pharmacology, Allergology Keywords: clinical instructor, clinical education, transcultural, intercultural communication, socio-culture and millennial generation
Online: 16 April 2021 (11:20:50 CEST)
Clinical education is a method that is applied to formal nurse education as a step to provide real and direct learning experiences in the nursing environment correctly and effectively. The success of education in a clinical setting certainly requires the support of teaching nurses (clinical instructors) who have credibility and competence in terms of knowledge, attitudes and skills and are actively involved in professional activities. The diversity of backgrounds of nurses and students, including patients, certainly contributes to a shift in paradigms and perspectives for the nursing environment both in education and in clinical settings in health services. Responding to this cultural diversity, it is important to prepare knowledge and understanding related to transcultural nursing issues, intercultural communication and clinical education which explores the socio-cultural elements in the implementation of staff, students and patients. Purpose: The purpose of this literature review is to identify the extent to which nurse educators play a role by including socio-cultural and transcultural aspects in efforts to develop the quality of education in clinical practice environments in the millennium era. Method: The method of writing this article uses 11 literature review, the publication year period 2019,2020 and 2021 with sources from 4 databases such as science Direct, Scopus, ProQues and Elsevier. The review guidelines used are based on Prisma and the Joanna Briggs Institutute. The level of eligibility is identified through the title, abstract, research methodology as well as the type of scholarly journal and full text. Results: The results of the reviews found are presented in a narrative form. The results of the review study found that there were 11 articles explaining the competence of clinical education based on the socio-cultural approach, which is an educational strategy in the clinical area that integrates transcultural elements of nursing, intercultural communication, collaboration, self-directed with the principles of openness, honesty, and mutual respect in the implementation of team interaction and collaboration. The development of interpersonal relationships is also an important role that educators must have in helping to introduce the nurse orientation process to the organizational environment and other professional teams so that the achievement of satisfaction with clinical education is able to improve the performance of nurses and students perfectly. Conclusion: Clinical education which is supported by the competence of nurse educators (clinical instructors) who have individual and professional competences has a role to play in improving clinical learning outcomes by both students and nurses with a socio-cultural and transcultural strategic approach that will create satisfaction with the achievement of clinical competence and performance effectively.
ARTICLE | doi:10.20944/preprints202101.0543.v1
Subject: Biology, Anatomy & Morphology Keywords: Blueberry; Pre-breeding; hybridization; V. elliottii; Fruit quality
Online: 26 January 2021 (15:55:14 CET)
Wild germplasm can be classified as the raw material essential for crop improvement. Introgression of wild germplasm is normally used in breeding to increase crop quality or resilience to evolving biotic and abiotic threats. Here, we explore the potential of introgressing Vaccinium elliottii into commercial blueberry germplasm. Vaccinium elliottii is a wild diploid blueberry species endemic to the southeastern United States that possesses highly desirable and economically important traits for blueberry breeding such as: short bloom to ripe period, adaptation to upland sandy soils, disease resistance, firmness, and pleasant flavor. To examine the potential of hybridization, we evaluated populations of interspecific hybrids across multiples stages of breeding (i.e., F1, F2, and backcrosses) in two crop seasons. We used our extensive pedigree data to generate breeding values for pre-breeding blueberry hybrid populations. Hybrid performance was evaluated considering fitness (i.e., plant vigor and plant height) in addition to evaluating six fruit-quality and marketable-related traits (i.e., size, firmness, acidity, soluble solids, weight, and yield). Overall, F2 and backcrosses rapidly achieved market thresholds, presenting values not significantly different from commercial blueberry germplasm. Our results confirmed the potential of exploiting the high genetic variability contained in V. elliotii for interspecific hybridization. Additionally, we developed germplasm resources that can be further evaluated and utilized in the breeding process, advancing selections for fruit quality and environmental adaptation.
ARTICLE | doi:10.20944/preprints202012.0820.v1
Subject: Life Sciences, Biochemistry Keywords: Sophora japonica; Adipogenesis; AMPK; 3T3-L1 pre-adipocytes
Online: 31 December 2020 (14:24:18 CET)
Background: The world-wide rate of obesity is increasing continuously, representing a serious medical threat since it is associated with a variety of diseases including type 2 diabetes, cardiovascular disease, and numerous cancers. Sophora japonica is used as a traditional herb for medicinal purposes in eastern Asia. However, the anti-obesity effects of S. japonica fruit have not been explored. Objective: The aim of this study is to investigate the inhibition of adipocyte differentiation and adipogenesis by an ethanol extract of S. japonica fruit (EESF) in 3T3-L1 pre-adipocytes. Methods: MTT assay, Oil Red O staining, and Triglyceride contents were used to investigate lipid accumulation in 3T3-L1 cells to clarify adipocyte differentiation. The expression levels of various molecular signals associated with adipogenesis and lipogenesis were examined by western blot analysis. Results: Our results demonstrate that EESF suppressed the terminal differentiation of 3T3-L1 pre-adipocytes in a dose-dependent manner, as confirmed by a decrease in lipid droplet number and lipid content through Oil Red O staining. EESF significantly reduced the accumulation of cellular triglyceride, which was associated with a significant inhibition of the levels of pro-adipogenic transcription factors, downregulated the expression levels of adipocyte-specific proteins. Furthermore, EESF treatment effectively increased the phosphorylation of AMPK and ACC. Conclusions: These results together indicate that EESF has significant effects on the inhibition of adipogenesis and acts by stimulating the AMPK signaling pathway. Further studies will be needed to identify the active compounds in S. japonica.
ARTICLE | doi:10.20944/preprints202008.0339.v1
Subject: Physical Sciences, Astronomy & Astrophysics Keywords: pre-bounce ekpyrotic contraction; f(R) gravity; reconstruction
Online: 15 August 2020 (06:15:05 CEST)
Inspired by the work of S. D. Odintsov and V. K. Oikonomou, Phys. Rev. D 92, 024016 (2015) , the present study reports a reconstruction scheme for f (R) gravity with the scale factor a(t) µ (t * - t) c22describing the pre-bounce ekpyrotic contraction, where t is the big crunch time. The reconstructed f (R) is used to derive expressions for density and pressure contributions and the equation of state parameter resulting from this reconstruction is found to behave like "quintom". It has also been observed that the reconstructed f (R) has satisfied a sufficient condition for a realistic model. In the subsequent phase the reconstructed f (R) is applied to the model of chameleon scalar field and the scalar field f and the potential V(f) are tested for quasi-exponential ex pansion. It has been observed that although the reconstructed f (R) satisfies one of the sufficient conditions for realistic model, the quasi-exponential expansion is not available due to this reconstruction. Finally, the consequences pre-bounce ekpyrotic inflation i n f (R) gravity are compared to the background solution for f (R) matter bounce.
ARTICLE | doi:10.20944/preprints201712.0164.v1
Subject: Medicine & Pharmacology, Other Keywords: pre-hospital emergency; review; qualitative study; patient satisfaction
Online: 25 December 2017 (06:41:26 CET)
Objective. To describe patient satisfaction with pre-hospital emergency knowledge and determine if patients and professionals share a common vision on the satisfaction predictors. Methods. A qualitative study conducted in two phases. First, a systematic review following the PRISMA protocol was carried out searching publications between January 2000 and July 2016 in Medline, Scopus, and Cochrane. Second, three focus groups involving professionals (advisers and healthcare providers) and a total of 79 semi-structured interviews involving patients were conducted to obtain information about what dimensions of care were a priority for patients. Results. Thirty-three relevant studies were identified. A majority conducted in Europe using questionnaires. They pointed out a very high level of satisfaction of callers and patients. Delay with the assistance and the ability for resolution of the case are the elements that overlap in fostering satisfaction. The published studies neither reviewed the overall care process nor related the measurement of the real time in responding to an emergency with the satisfaction. The patients and professionals concurred in their assessments about the most relevant elements for patient satisfaction, although safety was not a predictive factor for patients. Response capacity and perceived capacity for resolving the situation were crucial factors for satisfaction. This qualitative approach yielded assistance targets to be improved. Conclusions. Published studies have assessed similar dimensions of satisfaction. Furthermore, despite the fact that few explanations may be given due to the no face to face attention, taking into account the patient’s emotional needs or maintaining contact with the patient until the emergency services arrive are high predictors of the satisfaction.
ARTICLE | doi:10.20944/preprints202301.0074.v1
Subject: Medicine & Pharmacology, Dentistry Keywords: Clinical Skills; Clinical Training; Competency; Cross-sectional Studies; Dental Education; Dentistry; Self-perception.
Online: 4 January 2023 (08:48:49 CET)
The transition from undergraduate dental student to the actual practicing dentist is a crucial phase and ensuring the preparedness of graduates for the complexity and demands of contempo-rary dental practice is a challenging task. This study aimed to evaluate the self-perceived prepar-edness of undergraduate dental students and house officers in the dental colleges of Pakistan. Cross-sectional national study was planned to collect the information from dental students and new graduates in Pakistan. The pre-validated Dental Undergraduates Preparedness Assessment Scale (DU-PAS) was used. Purposive sampling technique was utilized to recruit house officers and undergraduate dental students from 27 dental schools in Pakistan. The data analysis was car-ried out using the R statistical environment for Windows (R Core Team, 2015). The total of 862 responses with 642 females and 219 males were analyzed in the study. Overall, clinical skills score was 30.56+9.08 and score for soft skills was 30.54+10.6. The mean age of the participants was 23.42+1.28. Deficiencies were reported in various soft skills and clinical skills attributes.The results highlighted the strengths and weaknesses of dental students and new graduates in Pakistani den-tal institutions. The findings may be used to further develop and strengthen teaching and training of dental students in Pakistan.
REVIEW | doi:10.20944/preprints202208.0194.v1
Subject: Medicine & Pharmacology, Pharmacology & Toxicology Keywords: biosimilar; analytical assessment; animal testing; clinical pharmacology; clinical efficacy; FDA; EMA; MHRA; WHO
Online: 10 August 2022 (05:19:49 CEST)
Scientific, technical and bioinformatics advances have made it possible to establish analytics-based molecular biosimilarity for the approval of biosimilars. If the molecular structure and other product- and process-related attributes are comparable within the limits of testing then a biosimilar candidate would have safe safety and efficacy as its reference products. The current model of animal and human testing becomes redundant since all of these studies have much lower sensitivity and reproducibility in confirming biosimilarity. The recent AI-based protein structure prediction model has confirmed that the 3D structure can be predicted from the amino acid sequence, reducing the need for structural analysis; however, the new test methods based on MS are millions of times more sensitive and accurate. While the regulatory agencies have begun waiving animal testing and, in some cases, clinical efficacy testing, removing clinical pharmacology profiling brings a dramatic paradigm shift, reducing development costs without compromising safety and efficacy. Also shared is a list of 160+ products ready to enter as biosimilars. Major actions from regulatory agencies and developers are required to make this paradigm shift.
REVIEW | doi:10.20944/preprints202005.0411.v1
Subject: Medicine & Pharmacology, Other Keywords: COVID-19; Clinical Trials; disruption; non-COVID-19 clinical trials; drugs; therapeutic area
Online: 25 May 2020 (11:17:56 CEST)
COVID-19 is causing major turmoil around the globe, and the clinical trial industry is likely to face unprecedented challenges to health and business sectors. In an effort to find a suitable treatment and prevention options for COVID-19, several COVID-19 clinical trials are being planned and initiated, while a large number of clinical trials for non- COVID-19 indications are suffering delays. With over more than 1000 trials being disrupted and more trials being added to this category daily, there is a direct impact on trial site activation and patient enrolment. This analysis deals with the specific impacts of the COVID-19 pandemic on the clinical trial and pharmaceutical industry. The objective of this study is to provide an updated information of the disrupted clinical trials and its impact on various therapeutic areas and different drugs. Among the severely affected clinical trials, oncology and CNS trials are the hardest hit therapy areas.This article will certainly emphasize the need for advanced and innovative approaches to maintain the health of the clinical trial ecosystem by continuing the existing trials and the start of the new studies. We have to take and follow necessary actions to guarantee that the initiatives will not be locked during the COVID-19 pandemic, both for the treatment of patients and for the researchers to conduct decision-relevant clinical trials.
REVIEW | doi:10.20944/preprints202008.0116.v1
Subject: Medicine & Pharmacology, Gastroenterology Keywords: probiotics; cancer; safety; clinical trials
Online: 5 August 2020 (09:27:01 CEST)
In recent years, the consumption of over-the-counter probiotics used to promote health has grown rapidly worldwide and become an industry. In medicine, various studies have proven that probiotics can help improve the immune system and intestinal health. They are usually safe, but in some rare cases, they may cause concerning adverse reactions. Although the use of probiotics has been widely popularized in the public, the results of many probiotics clinical trials are contradictory. Especially for the cancer patients, the feasibility of probiotics management to provide benefits by targeting cancer and lessening anti-cancer side effects requires further investigations. And this review summarizes the interactions between probiotics and the host and current pros and cons of applying probiotics in the cancer patients.
ARTICLE | doi:10.20944/preprints202211.0310.v2
Subject: Engineering, Civil Engineering Keywords: Dynamic loadings; Inclination angles; Numerical simulation; Pre-cracked concrete
Online: 21 November 2022 (09:06:54 CET)
Dynamic Realistic Failure Process Analysis (DRFPA) is a numerical software based on FEM it is firstly validated by comparing with the experimental test. Such validation is carried out under two consistent concrete specimens under uniaxial compression. After validation, DRFPA is used to study the influence of two parallel pre-existing crack inclination angles on the fracture of concrete under dynamic loads. The evolution of wing cracks and secondary cracks is investigated by observing the initiation, coalescence, and propagation of them. Meanwhile, the relationship between failure mode and inclination angles is discussed via analyzing the acoustic emission events. Finally, it is concluded the relationship between inclination angles of pre-cracks and performance/stability of concrete structure.
ARTICLE | doi:10.20944/preprints202102.0577.v1
Subject: Medicine & Pharmacology, Allergology Keywords: carotid atherosclerosis; pre-diabetes mellitus; microRNAs; inflammation; metformin therapy
Online: 25 February 2021 (11:43:02 CET)
BACKGROUND AND PURPOSE—Atherosclerotic plaque instability and rupture in patients with asymptomatic carotid artery stenosis (ACAS) is a leading cause of major adverse cardiac events (MACE). This could be mainly evidenced in patients with pre-diabetes. Indeed, the altered glucose homeostasis and insulin resistance could cause over-inflammation of atherosclerotic plaque, favoring its conversion to unstable phenotype with rupture and MACE. Notably, the metformin therapy reducing the metabolic distress and the inflammatory burden, could lead to reduction of MACE in ACAS patients with pre-diabetes. In this setting, microRNAs (miRs) could be used as molecular biomarkers of atherosclerosis progression, plaque rupture and worse prognosis in normoglycemics (NG) vs. pre-diabetics metformin users (PDMU) vs. pre-diabetics non metformin users (PDNMU). However, the aim of our study was to investigate a wide miRNA panel in peripheral blood exosomes from patients with ACAS divided in NG vs. PDMU vs. PDNMU, and to associate the circulating miRNA expression profiles with MACE at 2 years of follow-up after endarterectomy. METHODS—The study included 234 patients with ACAS divided in NG (n 125), PDNMU (n 73) and PDMU (n 36). The miRs’ expression profiles of circulating exosomes were determined at baseline and at 2 years of follow-up by Affymetrix microarrays from plasma samples of the patients from any study cohort. Then we collected and analyzed MACE at 2 years of follow-up in NG vs. PDMU vs. PDNMU. RESULTS—prediabetics vs. NG had over-inflammation (p<0.05) and over expressed miR 24 and miR 27 at baseline. At 2 years of follow-up PDNMU vs. NG, PDMU vs. NG and PDNMU vs. PDMU over-expressed inflammatory markers and miR 24, miR 27, miR 100, miR 126 and miR 133 (p<0.05). Finally, at follow-up end we observed a significant difference about MACE comparing PDNMU vs. NG (n 27 (36.9%) vs. n 8 (6.4%); p<0.05), PDNMU vs. PDMU (n 27 (36.9%) vs. n 6 (16.6%); p <0.05), and PDMU vs. NG (n 6 (16.6%) vs. n 8 (6.4%); p<0.05). Admission glucose values (HR 1.020, CI 95% [1.001-1.038], p 0.029), atheromatous carotid plaque (HR 5.373, CI 95% [1.251-11.079], p 0.024), and miR 24 (HR 3.842, CI 95% [1.768-19.222], p 0.011) predicted MACE at 2 years of follow-up. CONCLUSIONS—Specific circulating miRs could be over-expressed in pre-diabetics and specifically in PDNMU vs. PDMU after endarterectomy. MiR24, hyperglycemia and atheromatous plaque could predict MACE at 2 years of follow-up.
ARTICLE | doi:10.20944/preprints201902.0037.v1
Subject: Engineering, Energy & Fuel Technology Keywords: Biomass, valorisation, ionic liquid, crystallinity, enzymatic hydrolysis, pre-treatment
Online: 4 February 2019 (13:57:18 CET)
Ionic liquids have been recognised as interesting solvents applicable in the efficient lignocellulosic biomass valorisation, especially in the biomass fractionation into individual polymeric components or direct hydrolysis some of biomass fractions. Considering the chemical character of ionic liquids, two different approaches, paved the way for a fractionation of biomass. The first strategy integrated a pre-treatment, hydrolysis and conversion of biomass through the employment of hydrogen-bond acidic 1-ethyl-3-methyimidazolim hydrogen sulfate ionic liquid. The second one relied on the use of a three-step fractionation process with hydrogen-bond basic 1-ethyl-3-methylimidazolium acetate to produce high purity cellulose, hemicellulose and lignin fractions. The proposed approaches were scrutinised for wheat straw and eucalyptus residues. Those different biomasses allowed understanding that enzymatic hydrolysis yields are dependent on the crystallinity of pre-treated biomass. The use of acetate based ionic liquid allowed to change crystalline cellulose I to cellulose II and consequently enhanced glucan to glucose yield to 93.14.1 mol% and 82.91.2 mol% for wheat straw and eucalyptus, respectively. Whereas for hydrogen sulfate ionic liquid, the same enzymatic hydrolysis yields were 61.6 0.2 mol% for wheat straw and only 7.90.3 mol% for eucalyptus residues. These results demonstrate the importance of either ionic liquid character or biomass type on the efficient biomass processing.
ARTICLE | doi:10.20944/preprints201810.0290.v1
Subject: Engineering, Civil Engineering Keywords: groundwater model; well field; pre-field investigation; aquitard breach
Online: 15 October 2018 (08:30:00 CEST)
Memphis aquifer is the primary drinking water source in Shelby County (Tennessee, USA) and supplies industrial, commercial, and residential water. Memphis aquifer is separated from the Shallow aquifer by a clayey layer known as Upper Claiborne Confining Unit (UCCU). All of the production wells in the Memphis area are screened in the Memphis aquifer or even deeper in the Fort Pillow aquifer. Traditionally, it was assumed that the UCCU could fully protect the Memphis aquifer from the contaminated Shallow aquifer groundwater. However, recent studies show that at some locations the UCCU is thin or absent which possibly leads to the contribution of Shallow aquifer to the Memphis aquifer. Accurately locating the breaches demands expensive and difficult geological or geochemical investigations, especially within an urban area. Hence, a pre-field investigation to identify the locations where the presence of breaches is likely can significantly reduce the cost of field investigations and improve the their results. In this study, to identify the locations where the presence of breaches in the UCCU is likely we use three different analyses: (1) pilot point calibration (PPC), (2) velocity and flow budget (VFB), and (3) particle tracking (PT) to post-process the developed groundwater results. These pre-field numerical investigations provide relevant and defensible explanations for groundwater flow anomalies in an aquifer system for informed decision-making and future field investigations. In this study, we identify five specific zones within the broad study area which are reasonable candidates for the future field investigations. Finally, we test the results of each analysis against other evidence for breaches to demonstrate that the results of the numerical analyses are reliable and supported by previous studies.
ARTICLE | doi:10.20944/preprints201810.0093.v1
Subject: Earth Sciences, Environmental Sciences Keywords: JPSS; SNPP; VIIRS; Pre-launch; Radiometry; Performance; Calibration; Spectral
Online: 5 October 2018 (09:35:14 CEST)
The Visible Infrared Imaging Radiometer Suite (VIIRS) on-board the second Joint Polar Satellite System (JPSS) completed its sensor level testing in February 2018. The JPSS-2 (J2) mission is scheduled to launch in 2022, and will be very similar to its two predecessor missions, the Suomi National Polar-orbiting Partnership (SNPP) mission, launched on 28 October 2011, and JPSS-1 (renamed NOAA-20) launched on 18 November 2017. VIIRS instrument has 22 spectral bands covering the spectrum between 0.4 and 12.6 mircron: 14 reflective solar bands (RSB), 7 thermal emissive bands (TEB), and one day-night band (DNB). It is a cross-track scanning radiometer capable of providing global measurements through observations at two spatial resolutions, 375 m and 750 m at nadir for the imaging bands and moderate bands, respectively. This paper will provide an overview of J2 VIIRS characterization methodologies and calibration performance during the pre-launch testing phases performed by the National Aeronautics and Space Administration (NASA) VIIRS Characterization Support Team (VCST) to evaluate the at-launch baseline radiometric performance and generate the parameters needed to populate the sensor data record (SDR) Look-Up-Tables (LUTs). Key sensor performance metrics include the signal to noise ratio (SNR), radiance dynamic range, reflective and emissive bands calibration performance, polarization sensitivity, spectral performance, response versus scan-angle (RVS), and scattered light response. A set of performance metrics generated during the pre-launch testing program will be compared to both the SNPP and JPSS-1 VIIRS sensors.
REVIEW | doi:10.20944/preprints201712.0142.v1
Subject: Biology, Plant Sciences Keywords: pre-harvest; ripeness; image analysis; machine learning; fruit phenotyping
Online: 20 December 2017 (09:35:36 CET)
Global food security for the increasing world population not only requires increased sustainable production of food but a significant reduction in pre- and post-harvest waste. The timing of when a fruit is harvested is critical for reducing waste along the supply chain and increasing fruit quality for consumers. The early in field assessment of fruit ripeness and prediction of the harvest date and yield by non-destructive technologies have the potential to revolutionize farming practices and enable the consumer to eat the tastiest and freshest fruit possible. A variety of non-destructive techniques have been applied to estimate the ripeness or maturity but not all of them are applicable for in situ (field or glasshouse) assessment. This review focuses on the non-destructive methods which are promising, or have already been, applied to the pre-harvest in field measurement including colorimetry, visible imaging, spectroscopy and spectroscopic imaging. Machine learning and regression models used in assessing ripeness are also discussed.
REVIEW | doi:10.20944/preprints202202.0242.v1
Subject: Medicine & Pharmacology, Oncology & Oncogenics Keywords: Colorectal cancer; Targeted therapy; Clinical trial
Online: 21 February 2022 (03:05:05 CET)
Colorectal cancer (CRC) is the third most common type of cancer and the second leading cause of cancer deaths worldwide. Surgery or surgery plus radiotherapy and/or chemotherapy for patients with metastatic CRC (mCRC) were accepted as the main therapeutic strategies until the early 2000s, when targeted drugs, like cetuximab and bevacizumab were developed. The use of targeted drugs in clinical practice has significantly increased patients’ overall survival. To date, the emergence of several types of targeted drugs has opened new possibilities and revealed new prospects for mCRC treatment. Therapeutic strategies are continually being updated to select the most suitable targeted drugs based on the results of clinical trials that are currently underway. This review discusses the up-to date molecular evidence of targeted therapy for mCRC and summarizes the Food and Drug Administration-approved targeted drugs including the results of clinical trials. We also explain their mechanisms of action and how these affect the choice of a suitable targeted therapy.
ARTICLE | doi:10.20944/preprints202110.0294.v1
Subject: Medicine & Pharmacology, General Medical Research Keywords: Mucormycosis; Zygomycosis; Epidemiology; Incidence; Clinical; Spain.
Online: 20 October 2021 (15:48:58 CEST)
Background: Mucormycosis is a worldwide angio-invasive fungal infection that is associated with high morbidity and mortality. A few European studies have focused on the epidemiology. Methodology: A retrospective longitudinal descriptive study was performed with inpatients diagnosed with mucormycosis (ICD-9-CM, code 117.7, cases 1997-2015; and ICD-10, code B46, cases 2016-2018; along with length of hospital stay) in Spanish public hospitals between 1 January 1997 and 31 December 2018. Data were obtained from the Minimum Basic Data Set (CMBD in Spanish). Principal findings: A total of 962 patients were recorded; 665 were men. The mean age (±SD) was 55±18.8 years. The annual incidence rate increased from 0.74 to 1.24 cases per million person-years. The lethality rate was 31.3%. Renal failure (41.6%) and hematological malignancy (36.3%) were the main factors involved. Conclusions: Mucormycosis is a rare infectious disease in Spain, but it has had a significantly increased incidence in the last two decades. Being an adult male and having diabetes, neoplasm or renal failure are the main factors associated. High mortality is usually associated mainly with hematological malignancy and renal failure. CMBD studies could be an efficient tool for assessing changes in the epidemiology of mucormycosis.
REVIEW | doi:10.20944/preprints202102.0265.v1
Subject: Life Sciences, Biochemistry Keywords: Peptides; Clinical Practice; Drug Therapy; Therapeutic
Online: 10 February 2021 (15:51:13 CET)
The treatment of peptides has played an important role in clinical practice since the discovery of insulin therapy in the 1920s. Over 60 peptide drugs are approved in the United States (US and other regional mar-kets, and peptides continue to undergo drug discovery steadily. Peptide research and development has lev-eraged a wider range of structures known from other plant sources, via pharmacology and medicinal molecular biology, beyond its conventional focus on individual endogenous peptides. We build a comprehensive database of peptides that have met scientific studies with more than 150 constantly evolving peptides. Here we provide a simple overview of the peptide-based drug therapy environment, comprising evolutionary points of view, structural properties, operational thresholds, and explanation of the therapeutic area.
ARTICLE | doi:10.20944/preprints201902.0187.v1
Subject: Medicine & Pharmacology, Pediatrics Keywords: clinical characteristics; febrile children; Kawasaki disease
Online: 20 February 2019 (09:10:15 CET)
Background: Kawasaki disease (KD) is a form of vasculitis that primarily affects children under the age of 5 years old. Patients may be missed diagnosis when initial clinical symptoms do not fulfill the traditional criteria. We aimed to analyze factors that clinicians could use to differentiate febrile children suspected of KD. Method: We retrospectively enrolled a total of 83 febrile children who were initially suspected of KD, but they did not meet the American Heart Association (AHA) criteria for a diagnosis. However, some of these patients were diagnosed with KD during their second visit. We analyzed patients' characteristics, clinical symptoms, and laboratory data. Results: In total, 50 patients were enrolled in the study. Of those, ten patients were diagnosed with KD on their second visit (group 1), while the other 40 patients still did not fit a KD diagnosis (group 2). A patient with a neutrophil to lymphocyte ratio greater than 1.33 combined with a C-reactive protein more than 33 mg/L was more likely to have KD. Conclusion: Among patients suspected of KD that did not initially meet the criteria, clinicians should pay special attention to elevated neutrophil-to-lymphocyte ratios and CRP levels and closely follow up such patients.
ARTICLE | doi:10.20944/preprints201805.0174.v1
Subject: Medicine & Pharmacology, Other Keywords: e-portfolio; clinical skills; competences; medicine
Online: 11 May 2018 (04:45:11 CEST)
Clinical training in medical schools in Spain is performed by rotations in university hospitals. During these internships, students are expected to acquire and master basic procedural skills. However, the assessment tools available rarely check whether these skills are completely acquired by the students. We have used an e-portfolio to determine the optimal number of times the students need to repeat a procedure to be able to perform it independently. The results were compared with the actual performance during the internships. An e-portfolio collected qualitative information about the internships. Quantitative information was also requested about the number of times each clinical skill was performed. Later, a survey asked these students and their teachers the optimal number of times each skill should be repeated before it could be considered fully acquired. The questionnaire was answered by 98.6% of the students and 70.3% of their teachers. Out of the 21 clinical skills and procedures selected, both students and their tutors agreed in a similar optimal value in 16 of them; only in five of them, teachers thought that students needed a greater number of times than that selected by the students. When these optimal values were compared with the actual values recorded in the portfolio during the internships, it was found that about half of the clinical skills were carried out less frequently than expected, thus providing an important feedback about the internships. Quantitative information collected in portfolios reveals a moderate mismatch between students and tutors perceptions of their training needs.
REVIEW | doi:10.20944/preprints201909.0270.v1
Subject: Medicine & Pharmacology, Clinical Neurology Keywords: Alzheimer’s disease; clinical trial fails; disease-modifying treatments; alzheimer’s disease biomarkers; combination treatment; clinical trial designs
Online: 24 September 2019 (11:23:25 CEST)
Despite all scientific efforts and many protracted and expensive clinical trials, no new drug has been approved by FDA for treatment of Alzheimer disease (AD) since 2003. Indeed, more than 200 investigational programs have failed or have been abandoned in the last decade. The most probable explanations for failures of disease-modifying treatments (DMTs) for AD may include late initiation of treatments during the course of AD development, inappropriate drug dosages, erroneous selection of treatment targets, and mainly an inadequate understanding of the complex pathophysiology of AD, which may necessitate combination treatments rather than monotherapy. Clinical trials’ methodological issues have also been criticized. Current drug-development research for AD is aimed to overcome these drawbacks. Preclinical and prodromal AD populations, as well as traditionally investigated populations representing all the clinical stages of AD, are included in recent trials. Systematic use of biomarkers in staging preclinical and prodromal AD and of a single primary outcome in trials of prodromal AD are regularly integrated. The application of amyloid, tau, and neurodegeneration biomarkers, including new biomarkers—such as Tau positron emission tomography, neurofilament light chain (blood and CSF biomarker of axonal degeneration) and neurogranin (CSF biomarker of synaptic functioning)—to clinical trials allows more precise staging of AD. Additionally, use of the Bayesian statistics, modifiable clinical trial designs, and clinical trial simulators enrich the trial methodology. Besides, combination therapy regimens are currently assessed in clinical trials. The abovementioned diagnostic and statistical advances, which have been recently integrated in clinical trials, are consequential to the recent failures of studies of disease-modifying treatments. Their experiential rather than theoretical origins may better equip potentially successful drug-development strategies.
ARTICLE | doi:10.20944/preprints202212.0306.v1
Subject: Social Sciences, Education Studies Keywords: Empathy; Emotional Education; Emotional Intelligence; Emotional competences; pre-primary Education
Online: 16 December 2022 (14:05:19 CET)
Today, concepts such as Emotional Education and Emotional Intelligence are recognized by many authors and researchers, emphasizing the importance of their development in all people, but especially in schools, specifically in teachers or educators and children. However, we still find many shortcomings within the schools that are needed to continue working. The aim of this study is to investigate the presence of emotional intelligence and empathy in teachers, through a sample of 42 participants. The research was conducted based on two validated and highly reliable assessment tools, called TMMS-24 and TECA. The results of the TMMS-24 indicate that a large percentage of participants have an adequate score of emotional intelligence. The results of the TECA indicate that most of the participants are in the middle, high or extremely high scores in relation to the level of empathy.
REVIEW | doi:10.20944/preprints202205.0051.v1
Subject: Medicine & Pharmacology, Pharmacology & Toxicology Keywords: Tenofovir; Pre-exposure prophylaxis; anti-retroviral therapy; cardiovascular disease; LGBT
Online: 5 May 2022 (16:11:31 CEST)
The introduction of tenofovir-derived prodrugs has revolutionised the prevention and management of HIV, which has coincided with 23% reduction in new HIV incidences globally. To date, there are two formulations of tenofovir-derived nucleoside reverse transcriptase inhibitor (NRTI): tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) and tenofovir alafenamide fumarate/emtricitabine (TAF/FTC). Although these prodrugs have shown favourable safety profile, their effects on cardiovascular health are differ from one another: TDF/FTC exhibits potential lipid-lowering effect, TAF/FTC demonstrates potential lipid-inducing effect, which is a major risk factor for cardiovascular diseases. However, this issue has not been previously elucidated, especially among the marginalised populations [lesbian, gay, bisexual and transgender (LGBT) and men who have sex with men (MSM)] who are likely be the main users of these prodrugs. This is of clinically significance as the cardiovascular health in these populations is often overlooked, in addition to a lack of appropriate cardiovascular risk prediction algorithm. Therefore, this review aims to (1) highlight the cardiovascular risks of tenofovir-derived prodrugs in the marginalized populations, and also to (2) establish the importance of having a cardiovascular risk prediction model that is specific to this particular populations so that their health management could be more comprehensive.
ARTICLE | doi:10.20944/preprints202201.0311.v1
Subject: Social Sciences, Econometrics & Statistics Keywords: Statistical inference; p-hacking; pre-registration; publication bias; replication crisis
Online: 20 January 2022 (15:32:13 CET)
A vivid debate is ongoing in the scientific community about statistical malpractice and the related publication bias. No general consensus exists on the consequences and this is reflected in heterogeneous rules defined by scientific journals on the use and reporting of statistical inference. This paper aims at discussing how the debate is perceived by the agricultural economics community and implications for our roles as researchers, contributors to the scientific publication process, and teachers. We start by summarizing the current state of the p-value debate and the replication crisis, and commonly applied statistical practices in our community. This is followed by motivation, design, results and discussion of a survey on statistical knowledge and practice among the researchers in the agricultural economics community in Austria, Germany and Switzerland. We conclude that beyond short-term measures like changing rules of reporting in publications, a cultural change regarding empirical scientific practices is needed that stretches across all our roles in the scientific process. Acceptance of scientific work should largely be based on the theoretical and methodological rigor and where the perceived relevance arises from the questions asked, the methodology employed, and the data used but not from the results generated. Revised and clear journal guidelines, the creation of resources for teaching and research, and public recognition of good practice are suggested measures to move forward.
ARTICLE | doi:10.20944/preprints202107.0337.v1
Subject: Behavioral Sciences, Social Psychology Keywords: participatory research; pre-intervention; community-based intervention; alcohol use; adolescents
Online: 14 July 2021 (14:04:01 CEST)
This study explores the impact of the ‘pre-intervention effects’ of a community-based interventions. This refers to participatory research processes and parallel publicity in the media on changes in alcohol use and relevant mechanisms (rules and norms about alcohol, accessibility of alcohol in a formal setting) among adolescents before any intervention is implemented. In a quasi-experimental study, adolescent data were collected twice by means of self-report among adolescents living in two municipalities (control and experimental condition). Regression analysis showed pre-intervention main effects on adolescents’ perceived accessibility of alcohol in a formal setting. Moreover, among adolescents aged 15 years and older, the normative decline in strictness of rules and norms was less steep in the experimental condition compared to the control condition. Also, adolescents aged 14 years and younger in the experimental condition reported more weekly drinking compared to their peers in the control condition. No differential effects across gender were found. To conclude, applying a co-creational approach in the development of an intervention, not only contributes to more effective interventions in the end, but involvement of and discussions in the community at the start of intervention planning are contributing to changes in targeted factors. This implies that public discussions about the development of intervention strategies should be considered as an essential feature of co-creation in community-based interventions.
ARTICLE | doi:10.20944/preprints202106.0122.v1
Subject: Earth Sciences, Environmental Sciences Keywords: tree-ring; flow reconstruction; pre-development; estuarine salinity; salinity intrusion
Online: 4 June 2021 (08:11:27 CEST)
This work presents updated reconstructions of watershed runoff to San Francisco Estuary from tree-ring data to AD 903, coupled with models relating runoff to freshwater flow to the estuary and salinity intrusion. We characterize pre-development freshwater flow and salinity conditions in the estuary over the past millennium and compare this characterization with contemporary conditions to better understand the magnitude and seasonality of changes over this time. This work shows that the instrumented flow record spans the range of runoff patterns over the past millennium (averaged over five, ten, twenty and one hundred years), and thus serves as a reasonable basis for planning-level evaluations of historical hydrologic conditions in the estuary. Over annual timescales we show that, although median freshwater flow to the estuary has not changed significantly, it has been more variable over the past century compared to pre-development flow conditions. We further show that the contemporary period is generally associated with greater spring salinity intrusion and lesser summer-fall salinity intrusion relative to the pre-development period. Thus, salinity intrusion in summer and fall months was a common occurrence under pre-development conditions and has been moderated in the contemporary period due to the operations of upstream reservoirs, which were designed to hold winter and spring runoff for release in summer and fall. This work also confirms a dramatic decadal-scale hydrologic shift in the watershed from very wet to very dry conditions during the late 19th and early 20th centuries; while not unprecedented, these shifts have been seen only a few times in the past millennium. This shift resulted in an increase in salinity intrusion in the first three decades of the 20th century, as documented through early records. Population growth and extensive watershed modification during this period exacerbated this underlying hydrologic shift. Putting this shift in the context of other anthropogenic drivers is important in understanding the historical response of the estuary and in setting salinity targets for estuarine restoration. By characterizing the long-term behavior of San Francisco Estuary, this work supports decision-making in the State of California related to flow and salinity management for restoration of the estuarine ecosystem.
REVIEW | doi:10.20944/preprints202008.0233.v1
Subject: Biology, Agricultural Sciences & Agronomy Keywords: lignocellulosic substrate; pre-treatment; microalgae/cyanobacteria; biogas; problems; animal feed
Online: 10 August 2020 (03:46:14 CEST)
Modern day civilization is dependent on energy generation by fossil fuels. But the major drawback of using fossil fuels is environmental pollution. Microalgae are potential candidate for production of various products of interest, such as proteins, mini food, pigments and triglycerides that can be converted into biofuels. Lignocellulosic feedstocks are the most abundantly available raw material of plants that can serve as a promising feedstock for cultivating bacteria, fungi, yeasts and microalgae to produce biofuels and other value-added products. Owing to the abundant availability of these low/no cost substrates, can be utilized as feedstocks for cultivating microalgae to generate biogas/biodiesel. Likewise, there is much room to exploit defatted algal biomass to be used as animal/fish feed and oil producing/accumulating genes knowledge in future to produce high and good quality biodiesel and biogas.
ARTICLE | doi:10.20944/preprints202007.0211.v1
Subject: Life Sciences, Endocrinology & Metabolomics Keywords: Ionotropin; Steroid phosphocholine esters; pre-eclampsia; endogenous ouabain; DLM; PTSD
Online: 10 July 2020 (09:55:05 CEST)
Cardiotonic glycoside toxins, originally isolated from plants or amphibians, have been proposed as mammalian cardiotonic hormones. This paper is a review and update of the discovery of [i] a new class of steroid hormones, [ii] the path for their biosynthesis and [iii] some preliminary data on their function. The compounds are phosphoester conjugates and share a characteristic structural feature, a lactone ring, with [a] one class of synthetic potassium sparing diuretics and with [b] plant and amphibian cardiotonic steroids. Purification was initially monitored by cross reaction with steroid sulfate assays and later with digoxin-specific assays. Six compounds were purified by HPLC to near homogeneity and characterized by Tandem mass spectroscopy (MS-MS) and 31P-NMR. Three were digoxin-like materials (DLM) with 23 carbon atoms. The two extra carbon atoms form a spiral lactone E-ring. Several additional spiral lactones have been identified by MS-MS. In a pilot study, based on MS analysis, we evaluated phosphocholine steroid levels in individual serum samples in patients with pre-eclampsia (n=20). The control group of normotensive pregnant women (n=20) was used to estimate the mean and standard deviation. Twelve of the women with pre-eclampsia had a z-score over 2 for at least one of the four phosphocholine steroids. In contrast, only 1 sample from the normotensive women had a z-score over 2. The observation that there are two patterns, one with elevated phosphocholine steroid levels and one without the elevation, suggests that there may be two different underlying causes of pre-eclampsia. We now need to extend the study to determine which pattern predicts progression to life-threatening hypertension in pregnant women. This pilot study illustrates that it is possible to evaluate individual endogenous cardiotonic hormones without relying on antibodies developed to plant or amphibian toxins.
Subject: Medicine & Pharmacology, Other Keywords: COVID-19; RT-PCR test; pre-test probability; positive rate
Online: 5 May 2020 (06:04:41 CEST)
Several articles have reported that the low number of COVID-19 cases in Japan is attributed to the small number of diagnostic RT-PCR tests performed. The criticism is based on the low number of the tests performed, and they suspected there would be more potential cases in Japan. The use of pre-test probability among tested subjects is proposed in order to evaluate of the sufficiency of test availability instead of the number of the tests. The pre-test probability means the average probability, i.e., ‘suspicion level’, of having coronavirus among the tested subject in a country. The higher pre-test probability is regarded as less sufficient opportunity of the tests, and the test availability could be evaluated by the pre-test probability. Thus, potential problems of underestimation of COVID-19 cases by insufficient amount of the test would be clear by using pre-test probability. The comparison of the pre-test probability could be replaced with that of the positive rate of the test because of the linear relationship between them under the assumption of common sensitivity and specificity. Japan shows the third lowest rate (8.6%), and is considered that the considerably sufficient number of the tests have been performed. In conclusion, the positive rate of the test as a surrogate index of the pre-test probability is useful to evaluate the sufficiency of test amount instead of the number of the tests performed. In present, the potential problem of underestimation by insufficient test availability would be less serious in Japan.
SHORT NOTE | doi:10.20944/preprints202001.0196.v1
Subject: Biology, Entomology Keywords: reproducibility; open access; data curation; data mangement; pre-print servers
Online: 18 January 2020 (09:05:49 CET)
The ability to replicate scientific experiments is a cornerstone of the scientific method. Sharing ideas, workflows, data, and protocols facilitates testing the generalizability of results, increases the speed that science progresses, and enhances quality control of published work. Fields of science such as medicine, the social sciences, and the physical sciences have embraced practices designed to increase replicability. Granting agencies, for example, may require data management plans and journals may require data and code availability statements along with the deposition of data and code in publicly available repositories. While many tools commonly used in replicable workflows such as distributed version control systems (e.g. “git”) or scripted programming languages for data cleaning and analysis may have a steep learning curve, their adoption can increase individual efficiency and facilitate collaborations both within entomology and across disciplines. The open science movement is developing within the discipline of entomology, but practitioners of these concepts or those desiring to work more collaboratively across disciplines may be unsure where or how to embrace these initiatives. This article is meant to introduce some of the tools entomologists can incorporate into their workflows to increase the replicability and openness of their work. We describe these tools and others, recommend additional resources for learning more about these tools, and discuss the benefits to both individuals and the scientific community and potential drawbacks associated with implementing a replicable workflow.
ARTICLE | doi:10.20944/preprints201808.0068.v1
Subject: Earth Sciences, Atmospheric Science Keywords: Harmonie model; radar data assimilation; pre-processing; mesoscale precipitation patterns
Online: 3 August 2018 (12:56:15 CEST)
This study presents a pre-processing approach adopted for the radar reflectivity data assimilation and results of simulations with the Harmonie numerical weather prediction model. The method shows an improvement of precipitation prediction within the radar location area in both the rain rates and spatial pattern presentation. With the assimilation of radar data, the model simulates larger water content in the middle troposphere within the layer from 1 to 6 km, with major variations at 2.5–3 km; it also reproduces better the mesoscale belt and cell patterns of precipitation fields.
ARTICLE | doi:10.20944/preprints201710.0182.v1
Online: 30 October 2017 (10:22:24 CET)
The effect of low cycle fatigue (LCF) pre-damage on the subsequent very high cycle fatigue (VHCF) behavior is investigated in TC21 titanium alloy. LCF pre-damage is applied under 1.8% strain amplitude up to various fractions of the expected life and subsequent VHCF properties are determined using ultrasonic fatigue tests. Results show that 5% of LCF pre-damage insignificantly affects the VHCF limit due to the absent of pre-crack, but decreases the subsequent fatigue crack initiation life estimated by Pairs’ law. Pre-cracks introduced by 10% and 20% of LCF pre-damage significantly reduce the subsequent VHCF limits. The crack initiation site shifts from subsurface-induced fracture for undamaged and 5% of LCF pre-damage specimens to surface pre-crack for 10% and 20% of LCF pre-damage specimens in very high cycle region. The fracture mechanism analysis indicate that LCF pre-crack will re-start to propagate under subsequently low stress amplitude when stress intensity factor of pre-crack is larger than its threshold. Furthermore, the predicted fatigue limits based on EI Haddad model for the LCF pre-damage specimens well agree with the experimental results.
ARTICLE | doi:10.20944/preprints201701.0049.v1
Subject: Behavioral Sciences, Social Psychology Keywords: Afghan, civic engagement, discrimination, distress, ethnic identity, pre-resettlement trauma
Online: 10 January 2017 (10:24:10 CET)
This study investigates the effect of perceived discrimination on the mental health of Afghan refugees, and secondly, tests the distress moderating effects of pre-migration traumatic experiences and post-resettlement adjustment factors. In a cross-sectional design, 259 Afghans completed surveys assessing perceived discrimination and a number of other factors using scales developed through inductive techniques. Multivariate analyses consisted of a series of hierarchical regressions testing the effect of perceived discrimination on distress, followed by a sequential analysis of moderator variables. Perceived discrimination was significantly associated with higher distress, and this relationship was stronger among those with a strong intra-ethnic identity, high civic engagement, and high pre-resettlement traumatic experiences. Discrimination is a significant source of stress for Afghan refugees, which may exacerbate stresses associated with other post-migration stressors. Future research is needed to tailor interventions that can help mitigate the stress associated with discrimination among this highly vulnerable group.
ARTICLE | doi:10.20944/preprints202209.0299.v1
Subject: Medicine & Pharmacology, General Medical Research Keywords: leprosy; ABO/Rh blood group; Clinical; Angola
Online: 20 September 2022 (09:28:22 CEST)
Introduction: Leprosy, caused by Mycobacterium leprae is one of the oldest infectious diseases in human history and its eradication is linked to poverty control, lack of basic sanitation, the fragility of health, and education services. Objective: To evaluate the frequency of blood groups (ABO/Rh) and the sociodemographic and clinical profile of Angolan patients with Leprosy treated at the Anti-Tuberculosis and Leprosy Dispensary in Luanda, the capital city of Angola. Methodology: A descriptive, introspective, cross-sectional study with a quantitative approach was carried out with 102 patients of Luanda, in the second half of 2021. Results: Of the 102 patients included in the study, the majority belonged to the ORh+ group (51.9%), followed by the BRh+ group (27.4%) and ARh+ (18.6%), most were under 51 years of age ( 87.3%), with low education (54.9%), coming from urban areas (44.1%). As for clinical conditions, most had a multibacillary infection (93.1%), diagnosed mainly by smear microscopy (75.5%) without other infection (79.4%), some of them with complications (28.4%) and individuals with non-O blood group showed changes in the blood count. Conclusion: Leprosy seems to be common in ORh+ individuals, it continues to affect especially those residing in areas of population agglomerations and with low education, presenting itself as a multibacillary infection, where changes in the blood count are greater in non-O individuals.
REVIEW | doi:10.20944/preprints202204.0078.v2
Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: digitalization; clinical chemistry; artificial intelligence; interoperability; FAIRification
Online: 15 July 2022 (05:00:44 CEST)
Laboratory medicine is a digital science. Every large hospital produces a wealth of data each day - from simple numerical results from e.g. sodium measurements to highly complex output of “-omics” analyses, as well as quality control results and meta-data. Processing, connecting, storing, and ordering extensive parts of these individual data requires Big Data techniques. Whereas novel technologies such as artificial intelligence and machine learning have exciting application for the augmentation of laboratory medicine, the Big Data concept remains fundamental for any sophisticated data analysis in large databases. To make laboratory medicine data optimally usable for clinical and research purposes, they need to be FAIR: findable, accessible, interoperable, and reusable. This can be achieved for example by automated recording, connection of devices, efficient ETL (Extract, Transform, Load) processes, careful data governance, and modern data security solutions. Enriched with clinical data, laboratory medicine data allow a gain in pathophysiological insights, can improve patient care, or they can be used to develop reference intervals for diagnostic purposes. Nevertheless, Big Data in laboratory medicine do not come without challenges: The growing number of analyses and data derived from them is a demanding task to be taken care of. Laboratory medicine experts are and will be needed to drive this development, take an active role in the ongoing digitalization, and provide guidance for their clinical colleagues engaging with the laboratory data in research.
ARTICLE | doi:10.20944/preprints202205.0175.v1
Subject: Life Sciences, Microbiology Keywords: ESKAPE; heteroaryl-ethylenes; clinical strains; antimicrobial activity
Online: 13 May 2022 (03:30:57 CEST)
The World Health Organization has identified antimicrobial resistance as a public health emergency and developed a global priority pathogens list of antibiotic-resistant bacteria that can be summarized in the acronym ESKAPE (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacterales species), reminding us of their ability to escape the effect of antibacterial drugs. We previously tested new heteroaryl-ethylene compounds in order to define their spectrum of activity and antibacterial capability. Now, we focus our attention on PB4, a compound with promising MIC and MBC values in all conditions tested. In the present study, we evaluate the activity of PB4 on selected samples of ESKAPE isolates from nosocomial infections: 14 S. aureus, 6 E. faecalis, 7 E. faecium, 12 E. coli and 14 A. baumanii. Furthermore, an ATCC control strain was selected for all species tested. MICs were performed according to the standard method, with some modifications. PB4 MIC values were within very low ranges regardless of bacterial species and resistance profiles: from 0,12 to 2 mg/L for S. aureus, E. faecalis, E. faecium and A. baumannii. For E. coli, the MIC values obtained were slightly higher (4-64 mg/L), butstill promising. The PB4 heteroaryl-ethylenic compound was able to counteract the bacterial growth of both high-priority Gram-positive and Gram-negative clinical strains. In the future, it would be interesting to evaluate the activity of PB4 in animal models to test for its toxicity.
ARTICLE | doi:10.20944/preprints202110.0121.v1
Subject: Medicine & Pharmacology, Clinical Neurology Keywords: botulinum toxin; subtype A2; clinical tolerability; safety
Online: 7 October 2021 (15:02:29 CEST)
All the available botulinum type A neurotoxins for clinical uses are of A1 subtype. We developed a subtype A2 low molecular weight (150kD) neurotoxin (A2NTX), with less spread and faster entry into the motor nerve terminal than A1 in vitro and in vivo. Preliminary clinical studies showed its efficacy superior to A1 toxins. We conducted an open study exploring its safety and tolerability profile in comparison with A1LL (onabotulinumtoxinA) and low molecular weight (150kD) A1 neurotoxin (A1NTX). Those who had been using A1LL (n=90; 50-360 mouse LD50 units) or A1NTX (n=30; 50-580 units) were switched to A2NTX (n=120; 25-600 units) from 2010 till 2018 (number of sessions ~ 27, cumulative doses ~11,640 units per patient). Adverse events for A2NTX included weakness (n=1, ascribed to alcoholic polyneuropathy), dysphagia (1), local weakness (4), spread to other muscles (1), whereas those for A1LL or A1NTX comprised weakness (n=2, A1NTX), dysphagia (8), ptosis (6), local weakness (7) and spread to other muscles (15). After injections, 89 out of 120 patients preferred A2NTX to A1 for the successive sessions. The present study demonstrated that A2NTX had the clinical safety up to the dose of 500 units, and was well tolerated compared to A1 toxins.
ARTICLE | doi:10.20944/preprints202105.0387.v1
Subject: Life Sciences, Biochemistry Keywords: Chikungunya; seroprevalence; clinical presentation; febrile outpatient; Malawi
Online: 17 May 2021 (13:19:32 CEST)
Chikungunya is a mosquito-borne viral disease caused by Chikungunya virus (CHIKV. We conducted this study determine the seroprevalence and clinical presentation of Chikungunya infection among outpatients seeking healthcare in Mzuzu City, Malawi. Blood samples were collected from malaria negative and non-septic febrile outpatients with fevers ≥38 °C, for not more than 5 days. The enzyme- linked immunosorbent assay (ELISA) test was used to detect anti-CHIKV IgM antibodies and its results were used to determine seroprevalence of Chikungunya. A total of 119 serum samples were tested, of these, 73 (61.3%) tested positive for anti-CHIKV IgM antibodies by ELISA. Laboratory requisition forms were used to capture demographic information such as age, sex, clinical signs and symptoms presented by the enrolled patients. Age groups of 1-9, 10- 19, 20- 29, 30- 39, 40- 49, and ≥50 years had 17.8% (n= 13), 12.3 %,( n=9), 15.1%) (n=11), 19.2%; (n=14), 17.8% (n=13) and 17.8% (n=13) proportion of seroprevalence respectively. Most of the CHIKV infected individuals presented with fever (52.05%), joint pain (45.21%) and abdominal pain (42.67%). The presence of anti- CHIKV IgM antibodies suggest the presence of recent CHIKV infection and therefore accurate laboratory assays are highly recommended for CHIKV diagnosis and appropriate management of febrile patients.
ARTICLE | doi:10.20944/preprints202103.0445.v1
Subject: Medicine & Pharmacology, Allergology Keywords: Causality; Clinical Predisposing Factors; Delirium; Palliative Care
Online: 17 March 2021 (14:46:06 CET)
Delirium occurs in 50-80% of end-of-life patients but it is often misdiagnosed. Identification of clinical factors potentially associated with delirium onset can lead to a correct early diagnosis. To this aim, we conducted an observational prospective study on patients from an Italian Palliative Care Unit (PCU) in 2018-2019 and evaluated the presence of clinical factors at patients’ admission. We then compared their presence in patients who developed delirium and in those who did not during follow-up. On 503 enrolled patients, 95 (18.9%) developed delirium. In univariate analyses, factors significantly more frequent in patients with delirium were advanced age, care in hospice, very compromised performance status, hypoxia, high number of simultaneous clinical factors, presence of breathlessness, poor well-being, severe drowsiness, and background therapy with haloperidol and drugs acting on CNS. In multivariate analyses, setting of care (odds ratio, OR, 1.68 for hospice versus home care, 95% confidence interval, CI 1.02-2.75; p=0.040), and administration of psychiatric drugs (OR 1.74 for administration versus no administration, 95% CI 1.08-2.81; p=0.023) were significantly associated with the risk of developing delirium, while the associations with age (OR 1.82 for > 80 years versus ≤ 70 years, 95% CI=0.98-3.36; p=0.046) and presence of breathlessness (OR 1.70, 95%, CI 0.99-2.89, p=0.053) were of borderline significance. The study indicates that some clinical factors are associated with the probability of delirium onset. Their evaluation in PC patients could help the healthcare professionals to timely identify the development of delirium in those patients.
ARTICLE | doi:10.20944/preprints202012.0293.v2
Subject: Life Sciences, Biochemistry Keywords: Hsp70; biomarker; glioblastoma; NK cells; clinical study
Online: 26 January 2021 (11:33:34 CET)
Despite rapid progress in the treatment of many cancers, glioblastoma remains a devastating disease with dismal prognosis. The aim of this study was to identify immune-related biomarkers that more effectively predict outcome of glioblastoma. Since heat shock protein 70 (Hsp70) and IL-2 are known to increase the expression of activatory NK cell receptors, recognizing aggressive human tumor cells that present Hsp70 on their cell surface, extracellular Hsp70 levels were determined in glioma patients together with activatory NK cell receptors. All gliomas are membrane Hsp70-positive (mHsp70+) and high grade gliomas more frequently show an overexpression of Hsp70 in the nucleus and cytosol. Significantly increased extracellular Hsp70 levels are detected predominantly in glioblastomas with large necrotic areas. Overall survival (OS) is more favorable in patients with low Hsp70 serum levels indicating that a high Hsp70 expression is associated with an unfavorable prognosis. Elevated frequencies of NK cells are associated with a more favorable outcome. Of caution, a glucocorticoid therapy reduces the prevalence of NK cells. In summary, elevated frequencies of Hsp70-reactive NK cells at diagnosis and lower Hsp70 levels predict a more favorable prognosis in glioblastoma patients.
REVIEW | doi:10.20944/preprints202005.0142.v1
Subject: Medicine & Pharmacology, General Medical Research Keywords: COVID-19; serology; RT-PCR; lab; clinical
Online: 8 May 2020 (12:26:46 CEST)
COVID-19 was identified in Wuhan, China in in December 2019, and rapidly spread worldwide, being declared global pandemic one month later on 30 January 2020. Since its emergence, COVID-19 has raised global concerns associated with drastic measures that were never adopted in any previous outbreak, to contain the situation as early as possible. The 2019 novel corona virus (2019-nCoV) or SARS-CoV-2 is the causative agent of COVID-19. 2019-nCoV genetic sequence was rapidly identified within few days since the first reported cases and RT-PCR kits became available for COVID-19 diagnosis. However, RT-PCR diagnosis carries a risk of false-negative results, therefore additional serologic test are needed. The most important approach in the battle against COVID-19 is rapid diagnosis of suspicious cases, timely therapeutic intervention and isolation to avoid community spread. In this review, we summarize the clinical scenario that raises suspicion of COVID-19 and available laboratory diagnostics.
ARTICLE | doi:10.20944/preprints201906.0179.v2
Subject: Mathematics & Computer Science, Probability And Statistics Keywords: knowledge acquisition; clinical practice guidelines; data driven knowledge acquisition; cancer treatment plan; clinical decision support system; formal verification
Online: 22 July 2019 (06:17:34 CEST)
Validation and verification are the critical requirements in the knowledge acquisition method for the clinical decision support system (CDSS). After acquiring the medical knowledge from diverse sources, the rigorous validation and formal verification process are required before creating the final knowledge model. Previously, we have proposed a hybrid knowledge acquisition method for acquiring medical knowledge from clinical practice guidelines (CPGs) and patient data in the Smart CDSS for treatment of oral cavity cancer. The final knowledge model was created by combining knowledge models obtained from CPGs and patient data after passing through a rigorous validation process. However, detailed analysis shows that due to lack of formal verification process, it involves various inconsistencies in knowledge relevant to the formalism of knowledge, conformance to CPGs, quality of knowledge, and complexities of knowledge acquisition artifacts. Therefore, it is required to enhance a hybrid knowledge acquisition method that thwarts the inconsistencies using formal verification. This paper presents the verification process using the Z formal method and its outcome as an enhanced acquisition method – known as the refined knowledge acquisition (ReKA) method. The ReKA method adopted verification method and explored the mechanism of theorem proving using the Z notation. It enables to identify inconsistencies in the validation process used for hybrid knowledge acquisition. Additionally, it refines the hybrid knowledge acquisition method by discovering the missing steps in the current validation process at the acquisition stage. Consequently, ReKA adds a set of nine additional criteria to be used to have a final valid refined clinical knowledge model. The criteria ensure the validity of final knowledge model concerning formalism of knowledge, conformance to GPGs, quality of the knowledge, usage of stringent conditions and treatment plans, and inconsistencies possibly resulting from the complexities. Evaluation, using four medical knowledge acquisition scenarios, shows that newly added knowledge in CDSS due to the addition of criteria by ReKA method always produces a valid knowledge model. The final knowledge model was also evaluated with 1229 oral cavity patient cases, which outperformed with an accuracy of 72.57\% compared to a similar approach with an accuracy of 69.7\%. Furthermore, ReKA method identified a set of decision paths (about 47.8%) in the existing approach, which results in a final knowledge model with low quality, non-conformed from standard CPGs. In conclusion, ReKA is formally proved method which always yields valid knowledge model having high quality, supporting local practices, and influenced from standard guidelines.
COMMUNICATION | doi:10.20944/preprints202301.0067.v1
Subject: Earth Sciences, Geophysics Keywords: seismic acceleration; Guidonia; earthquake; Benioff cumulative stress; Swarm; pre-earthquake processes
Online: 4 January 2023 (06:08:38 CET)
This communication investigates possible anomalies in the lithosphere atmosphere and ionosphere on the occasion of the ML=3.3 earthquake that occurred on 1st January 2023 close to Guidonia Montecelio (Rome, Italy). This earthquake followed another event on 23 December 2022 of magnitude ML=3.1 with a very close epicentre (distance less than 1km). Seismological investigations clearly show an acceleration of seismicity in the last six months in the area. Two solutions of fitting time to failure power law on the Cumulative Benioff strain curve are the more likelihood: the ML3.3 of 1 January is the mainshock of seismic sequence or incoming earthquakes of a magnitude of about 4.1 provides a slightly better fit of the seismic data. Further investigation are necessary to assess if the accumulated stress have been totally released or not. No atmospheric anomalies related to this seismic activity have been identified even if some SO2 emissions could come from tectonic or volcanic sources in the South-Tyrrhenian Sea. Swarm satellites' magnetic data shows an anomalous track on 16 December 2022, which is temporally compatible with the seismic acceleration but other sources for the anomalous signal are also possible.
ARTICLE | doi:10.20944/preprints202109.0007.v1
Subject: Mathematics & Computer Science, Other Keywords: Social robot; mobile app; e-learning; language education; kindergarden, pre-school
Online: 1 September 2021 (11:46:18 CEST)
We transformed the existing learning program Language Shower, which is used in some Norwegian day-care centers in the Grorud district of Oslo municipality, into a digital solution using an app for smartphone or tablet with the option for further enhancement of presentation by a NAO robot. The solution was tested in several iterations and multiple day-care centers over several weeks. Measurements of the children’s progress across learning sessions indicate a positive impact of the program using a robot as compared to the program without robot. In-situ observations and interviews with day care center staff confirmed the solution’s many advantages, but also revealed some important areas for improvement. In particular, the speech recognition needs to be more flexible and robust, and special measures have to be in place to handle children speaking simultaneously.
REVIEW | doi:10.20944/preprints202010.0406.v1
Subject: Biology, Anatomy & Morphology Keywords: DHA; Brain; MFSD2a; SPM; Fetus; Placenta; infacnts; Neurogenesis; Pregnancy; Pre-term
Online: 20 October 2020 (08:37:41 CEST)
Dietary components are important for the structural and functional development of the brain. Among these, docosahexaenoic acid,22:6n-3 (DHA) is critically required for the structure and development of the growing fetal brain in utero. DHA is the major n-3 long-chain fatty acid in brain gray matter representing about 15% of all fatty acids in the human frontal cortex. DHA affects neurogenesis, neurotransmitter, synaptic plasticity & transmission, and signal transduction in the brain. Studies in animals and humans show that adequate levels of DHA in neural membranes are important for cortical astrocyte maturation and vascular coupling, and helps cortical glucose uptake and metabolism. In addition, specific metabolites of DHA are bioactive molecules that protect tissues from oxidative injury and stress in the brain. A low DHA level in the brain results in behavior changes and is associated with learning problems and memory deficits. In humans, the third trimester-placental supply of maternal DHA to the growing fetus is critically important as the growing brain obligatory requires DHA during this window period. Besides, DHA is also involved in the early placentation process, essential for placental development. This underscores the critical importance of maternal DHA intake for the structural and functional development of the brain. This review describes DHA's multiple roles during gestation, lactation, and the consequences of its lower intake during pregnancy and postnatally on the children's brain development and function.
ARTICLE | doi:10.20944/preprints202003.0178.v3
Subject: Physical Sciences, Other Keywords: consciousness; meta-causation; pre-reflective self-consciousness; physicalism; causal productivity; dynamism; laws of nature; laws of physics; temporal non-locality
Online: 27 August 2020 (08:27:28 CEST)
How, if at all, consciousness can be part of the physical universe remains a baffling problem. This article outlines a new, developing philosophical theory of how it could do so, and offers a preliminary mathematical formulation of a physical grounding for key aspects of the theory. Because the philosophical side has radical elements, so does the physical-theory side. The philosophical side is radical, first, in proposing that the productivity or dynamism in the universe that many believe to be responsible for its systematic regularities is actually itself a physical constituent of the universe, along with more familiar entities. Indeed, it proposes that instances of dynamism can themselves take part in physical interactions with other entities, this interaction then being “meta-dynamism” (a type of meta-causation). Secondly, the theory is radical, and unique, in arguing that consciousness is necessarily partly constituted of meta-dynamic auto-sensitivity, in other words it must react via meta-dynamism to its own dynamism, and also in conjecturing that some specific form of this sensitivity is sufficient for and indeed constitutive of consciousness. The article proposes a way for physical laws to be modified to accommodate meta-dynamism, via the radical step of including elements that explicitly refer to dynamism itself. Additionally, laws become, explicitly, temporally non-local in referring directly to quantity values holding at times prior to a given instant of application of the law. The approach therefore implicitly brings in considerations about what information determines states. Because of the temporal non-locality, and also because of the deep connections between dynamism and time-flow, the approach also implicitly connects to the topic of entropy insofar as this is related to time.
ARTICLE | doi:10.20944/preprints201908.0285.v1
Subject: Medicine & Pharmacology, Dentistry Keywords: oral health , pre-diabetic, diabetic, oral systemic, screening, H1A1c, Findrisk , periodontal
Online: 27 August 2019 (11:58:44 CEST)
Pre-diabetes is a serious health condition where blood sugar levels are higher than normal, but not high enough yet to be diagnosed as type 2 diabetes. Pre-diabetes puts one at an increased risk of developing type 2 diabetes and heart disease Methodology: A cross-sectional study was carried out on 384 patients aged 20-70 years old, attending the dental clinics to assess the risk for diabetes, using the FINDRISC questionnaire, HbA1c blood test and a periodontal examination. Results: The mean age of participants was 38.90±10.74. 32.3% were categorized as no risk, 46.6% low risk, while 19% and 2.1% moderate and high risk of developing diabetes respectively. Tests for serum HbA1c Level showed 46.1 % had normal HbA1c followed by 18.0% and 3.6 % were pre-diabetic and diabetic respectively. 19.3% of participants had periodontal pockets measuring more than 4mm and 15.9% measuring more than 6mm. Conclusion: The study has proven to be useful in identifying patients at high-risk of developing diabetes. Controlling and managing periodontal disease could be a new aspect to include in the standards for diabetes care. Dental settings could be a successful platform to carry out the screening and risk stratification of pre-diabetic patients.
ARTICLE | doi:10.20944/preprints201906.0048.v1
Subject: Medicine & Pharmacology, General Medical Research Keywords: Ambulation, Ischemic stroke, pre-stroke depression, recombinant tissue plasminogen activator (rtPA)
Online: 6 June 2019 (10:37:13 CEST)
Background. Specific clinical risk factors that may be associated with ambulatory outcome following thrombolysis therapy in ischemic stroke patients with pre-stroke depression is not fully understood. This was investigated. Methods. Multivariate analyses were performed to identify predictors of functional ambulatory outcomes. Patient demographics and clinical risk factors served as predictive variables, while improvement or no improvement in ambulatory outcome was considered as the primary outcome. Results. A total of 595 of these patients received rtPA of which 310 patients presented with pre-stroke depression, 217 had no improvement in functional outcome, while 93 patients presented with an improvement in functional outcome. Carotid artery stenosis (OR= 11.577, 95% CI, 1.281 – 104.636, P=0.029) and peripheral vascular disease (OR= 18.040, 95% CI, 2.956-110.086, P=0.002) were more likely to be associated with an improvement in ambulation. Antihypertensive medications (OR= 7.810, 95% CI, 1.401 –43.529, P=0.019),previous TIA (OR= 0.444, 95% CI, 0.517 –0.971, P=0.012), and congestive heart failure (OR= 0.217, 95% CI, 0.318 –0.402, P=0.030) were associated with a no improvement in ambulation. Conclusion. After adjustment for covariates, more clinical risk factors were associated with no improvement when compared with improvement in functional outcome following thrombolysis therapy in an acute ischemic stroke population with pre-stroke depression.
ARTICLE | doi:10.20944/preprints201705.0063.v1
Subject: Medicine & Pharmacology, Other Keywords: economic evaluation; mathematical modeling; HIV vaccines; pre-exposure prophylaxis; cost-effectiveness
Online: 8 May 2017 (12:13:45 CEST)
This economic evaluation aims to support policy-making on the combined use of pre-exposure prophylaxis (PrEP) with HIV vaccines by evaluating the potential cost-effectiveness of implementation that would support the design of clinical trials for assessment of combined product safety and efficacy. The target study population is a cohort of men who have sex with men (MSM) in the United States. Policy strategies considered include standard HIV prevention, daily oral PrEP, HIV vaccine, and their combination. We constructed a Markov model based on clinical trial data and published literature. We used a payer perspective, monthly cycle length, a lifetime horizon, and a 3% discount rate. We assumed a price of $500 per HIV vaccine series in the base case. HIV vaccines dominated standard care and PrEP. At current prices,PrEP was not cost-effective alone or in combination. A combination strategy had the greatest health benefit but was not cost-effective (ICER=$463,448/QALY) as compared to vaccination alone. Sensitivity analyses suggest a combination may be valuable for higher-risk men with good adherence. Vaccine durability and PrEP drug prices were key drivers of cost-effectiveness. Results suggest that boosting potential may be key to HIV vaccine value.
ARTICLE | doi:10.20944/preprints202201.0378.v1
Subject: Medicine & Pharmacology, General Medical Research Keywords: staphylococcus aureus; infective endocarditis; clinical prediction rules; echocardiography
Online: 25 January 2022 (10:41:47 CET)
Background. It is unclear whether the use of clinical prediction rules is sufficient to rule out infective endocarditis (IE) in patients with Staphylococcus aureus bacteremia (SAB) without an echocardiogram evaluation, either transthoracic (TTE) and/or transesophageal (TEE). Our primary purpose was to test the usefulness of PREDICT, POSITIVE and VIRSTA scores to rule out IE without echocardiography. Our secondary purpose was to evaluate whether not performing an echocardiogram evaluation is associated with higher mortality. Methods. We conducted a unicentric retrospective cohort including all patients with a first SAB episode from January 2015 to December 2020. IE was defined according to modified Duke criteria. We predefined threshold cut-off points to consider that IE was ruled out by means of the mentioned scores. To assess 30-day mortality, we used a multivariable regression model considering performing an echocardiogram as covariate. Results. Out of 404 patients, IE was diagnosed in 50 (12.4%). Prevalence of IE within patients with negative PREDICT, POSITIVE and VIRSTA scores was: 3.6% (95% CI 0.1-6.9%), 4.9% (95% CI 2.2-7.7%), and 2.2% (95% CI 0.2-4.3%), respectively. Patients with negative VIRSTA and negative TTE had an IE prevalence of 0.9% (95% CI 0-2.8%). Performing an echocardiogram was independently associated with lower 30-day mortality (OR 0.24 95%CI 0.10-0.54, p=0.001). Conclusion. PREDICT and POSITIVE scores were not sufficient to rule out IE without TEE. In patients with negative VIRSTA score, it was doubtful if IE could be discarded with a negative TTE. Not performing an echocardiogram was associated with worse outcomes, which might be related to presence of occult IE. Further studies are needed to assess the usefulness of clinical prediction rules in avoiding echocardiographic evaluation in SAB patients.
ARTICLE | doi:10.20944/preprints202112.0202.v1
Subject: Medicine & Pharmacology, Other Keywords: helminth; self-treatment; clinical trials; inflammation; dose escalation
Online: 13 December 2021 (12:46:41 CET)
The virtually complete loss of intestinal worms, known as helminths, from Western society has resulted in elimination of a range of helminth-induced morbidities. Unfortunately, that loss has also led to inflammation-associated deficiencies in immune function, ultimately contributing to widespread pandemics of allergies, autoimmunity, and neuropsychiatric disorders. Several socio-medical studies have examined the effects of intentional reworming, or self-treatment with helminths, on a variety of inflammation-related disorders. In this study, the latest results from ongoing socio-medical studies are described. The results point toward two important factors that appear to be overlooked in some if not most clinical trials. Specifically, (a) the method of preparation of the helminth can have a profound effect on its therapeutic efficacy, and (b) variation between individuals in the effective therapeutic dosage apparently covers a 10-fold range, regardless of the helminth used. These results highlight current limits in our understanding of the biology of both hosts and helminths, and suggest that information from self-treatment may be critical for clinical evaluation of the benefits and limits of helminth therapy.
REVIEW | doi:10.20944/preprints202107.0198.v1
Subject: Medicine & Pharmacology, Allergology Keywords: CAR-T; TCR; cancer immunotherapy; immunotherapy clinical trials
Online: 8 July 2021 (11:04:10 CEST)
Chimeric antigen receptor and T-cell receptor (CAR-T/TCR) cellular immunotherapies have shown remarkable success in the treatment of some refractory B-cell malignancies, with potential to provide durable clinical response for other types of cancer. In this paper, we look at all available FDA CAR-T/TCR clinical trials for the treatment of cancer, and analyze them with respect to different disease tissues, targeted antigens, products, and originator locations. We found that 627 of 1,007 registered are currently active and of those 273 (44%) originated in China and 280 (45%) in the US. Our analysis suggests that the rapid increase in the number of clinical trials is driven by the development of different CAR-T products that use a similar therapeutic approach. We coin the term bioparallels to describe such products. Our results suggest that one feature of the CAR-T/TCR industry may be a robust response to success and failure of competitor products.
REVIEW | doi:10.20944/preprints202107.0116.v1
Subject: Medicine & Pharmacology, Allergology Keywords: Parkinson’s disease; Alzheimer’s Disease; Clinical trial; Precision medicine.
Online: 5 July 2021 (16:08:41 CEST)
Concomitant neuropathological hallmarks of Alzheimer’s Disease (AD) are common in the brains of people with Parkinson’s disease (PD). Furthermore, AD biomarkers are associated with cognitive decline and dementia in PD patients during life. Here, we highlight the considerable overlap between AD and PD, emphasizing neuropathological, biomarker, and mechanistic studies. We suggest that precision medicine approaches may successfully identify PD patients most likely to develop concomitant AD. The ability to identify PD patients at high risk for future concomitant AD in turn provides an ideal cohort for trials of AD-directed therapies in PD patients, aimed at delaying or preventing cognitive symptoms.
ARTICLE | doi:10.20944/preprints202104.0130.v1
Subject: Medicine & Pharmacology, Allergology Keywords: nursing student; patient safety; clinical education; educational institutions
Online: 5 April 2021 (12:46:34 CEST)
Students' knowledge of the concept of patient safety in infection prevention and control and treatment safety is still low. Real-life problem-based learning approaches in the area of clinical education assist in patient safety education. This study was designed to identify, evaluate and summarize available evidence on the effectiveness of clinical education on student achievement of patient safety competencies. The Methode that use in this study is systematic review. Search for articles in research journals obtained from Sciencedirect, Ebscohost, Garuda, Proquest and Scopus. As many as 228 articles were obtained consisting of nursing journals and health journals with the keywords clinical education, competence, and patient safety. After that, the screening process was carried out based on the inclusion criteria and obtained 25 articles that met the criteria. The result of this study are the contribution of educational institutions in the achievement of patient safety competencies for nursing students is still low and the achievement of patient safety competencies for students at the professional level is better than for students who are still learning theory in educational institutions. The conclusion of this study is clinical education carried out by educational institutions is considered ineffective in achieving the competence of patient safety for nursing students. Therefore, it is necessary to develop a patient safety model or curriculum that is attached to clinical education in nursing education institutions
REVIEW | doi:10.20944/preprints202012.0455.v1
Subject: Medicine & Pharmacology, Allergology Keywords: Prognosis; prosthodontics; dental implant; clinical performance; risk factor.
Online: 18 December 2020 (11:34:49 CET)
Background: The treatment plan of prosthetic restorations supported by dental implants require comprehensive scientific knowledge to deliver prostheses with good prognosis, even before the implant insertion. This review aims to analyze the main prosthetic determinants of the prognosis of implant-supported prostheses. Methods: A systematic review of the literature was conducted with a PICO question: "For partially or complete edentulous subjects treated with implant-supported prostheses, which prosthetic factors could affect clinical outcomes?". A literature search was performed electronically in PubMed (MEDLINE), Scopus and Cochrane Library with the following equation [PROGNOS* OR RISK] FACTOR IMPLANT DENTAL, and by hand search in relevant journals and throughout the selected papers. Results: This revision was carried out based on 50 papers focused on several prosthodontics-related risk factors that were grouped as follows: implant-connection, loading protocol, transmucosal abutments, prosthetic fit, provisionalization, type of retention, impression technique, fabrication technique, and occlusion. More than a half of the studies were systematic reviews (30%), meta-analysis (16%) or prospective evaluations of prosthesis with various kinds of events (18%). But also narrative reviews of literature (14%) and in vitro/animal studies (16%) were found. Conclusions: The current literature provides insufficient evidence for most of the investigated topics. However, based on the accumulated data, it seems reasonable to defend that the best treatment approach is the use of morse taper implants with transmucosal abutments, recorded by means of rigidly splinted copings through the pick-up technique, and screwed by milled prosthesis occlusally adjusted to minimize functional overloading.
REVIEW | doi:10.20944/preprints202004.0453.v1
Subject: Medicine & Pharmacology, Clinical Neurology Keywords: neurology; clinical features; coronavirus; stroke; encephalitis; headache; delirium
Online: 25 April 2020 (02:36:21 CEST)
The Coronavirus disease due to SARS-CoV-2 emerged in Wuhan city, China in December 2019 and rapidly spread more than 200 countries as a global health pandemic. There are more 3 million confirmed cases and around 207,000 fatalities. The primary manifestation is respiratory and cardiac but neurological manifestations are being reported in the literature as case reports and case series. The most common reported symptoms to include headache and dizziness followed by encephalopathy and delirium. Among the complications noted are Cerebrovascular accident, Guillian barre syndrome, acute transverse myelitis, and acute encephalitis. The most common peripheral manifestation was hyposmia. It is further noted that sometimes the neurological manifestations can precede the typical features like fever and cough and later on typical manifestations develop in these patients. Hence a high index of suspicion is required for timely diagnosis and isolation of cases to prevent the spread in neurology wards. We present a narrative review of the neurological manifestations and complications of COVID-19. Our aim is to update the neurologists and physicians working with suspected cases of COVID-19 about the possible neurological presentations and the probable neurological complications resulting from this novel virus infection.
REVIEW | doi:10.20944/preprints201911.0325.v1
Subject: Medicine & Pharmacology, Dentistry Keywords: dental caries; prevention; clinical trials; herbal; scoping review
Online: 27 November 2019 (03:57:04 CET)
It is currently recognized that an injudicious strategy in the last decades has been not only focusing of research typically on caries in children, but also the narrow focusing on fluoride, because despite sufficient availability of fluoride in water and oral healthcare products, caries levels escalate steadily as people get older and caries remain a main public health issue to be settled. In the last two decades the scientific community intensified efforts of exploring other products for caries prevention, herbal products being one of these approaches. Because preliminary evidence indicated that clinical trials for caries prevention with herbal products are heterogeneous in design, quality and products evaluated, we performed a scoping review intended to explore the main characteristics of such clinical trials. From an initial collection of 1986 unique papers from different literature databases, 56 articles satisfied the inclusion and exclusion criteria. The species investigated, dosage forms, study designs, duration of intervention, controls, endpoints, quality of reporting and risk of bias are discussed. 85.71% of the trials reviewed here reported positive results but given the methodological flaws and biases affecting them, it is difficult to conclude on the efficacy of those products based on the studies published thus far.
ARTICLE | doi:10.20944/preprints201907.0296.v1
Subject: Life Sciences, Biotechnology Keywords: point-of-care; cholesterol; clinical diagnostics; laboratory test
Online: 26 July 2019 (01:13:11 CEST)
Managing blood cholesterol levels is important for the treatment and prevention of diabetes, cardiovascular disease, and obesity. An easy-to-use, portable cholesterol blood test will accelerate more frequent testing by patients and at-risk populations. We aim to evaluate the performance of smartphone-based point-of-care cholesterol blood tests as compared to that of hospital-grade laboratory tests. We used smartphone systems that are already familiar to many people. Because smartphone systems can be carried around everywhere, blood can be measured easily and frequently. We compared the results of cholesterol tests with those of existing clinical diagnostic laboratory methods. We found that smartphone-based point-of-care lipid blood tests are as accurate as hospital-grade laboratory tests (N=116, R>0.97, P<0.001 for all 3 cholesterol blood tests: total cholesterol, high density lipoprotein, and triglyceride). Our system will be useful for those who need to manage blood cholesterol levels to motivate them to track and control their behavior.
TECHNICAL NOTE | doi:10.20944/preprints202203.0095.v1
Subject: Engineering, Other Keywords: pre-processing; image transformation; image enhancement; geometric correction; radiometric correction; Satellite Imagery
Online: 7 March 2022 (09:43:08 CET)
During the few years, various algorithms have been developed to extract features from high-resolution satellite imagery. For the classification of these extracted features, several complex algorithms have been developed. But these algorithms do not possess critical refining stages of processing the data at the preliminary phase. Various satellite sensors have been launched such as LISS3, IKONOS, QUICKBIRD, and WORLDVIEW etc. Before classification and extraction of semantic data, imagery of the high resolution must be refined. The whole refinement process involves several steps of interaction with the data. These steps are pre-processing algorithms that are presented in this paper. Pre-processing steps involves Geometric correction, radiometric correction, Noise removal, Image enhancement etc. Due to these pre-processing algorithms, the accuracy of the data is increased. Various applications of these pre-processing of the data are in meteorology, hydrology, soil science, forest, physical planning etc. This paper also provides a brief description of the local maximum likelihood method, fuzzy method, stretch method and pre-processing methods, which are used before classifying and extracting features from the image.
ARTICLE | doi:10.20944/preprints202201.0217.v1
Subject: Chemistry, Food Chemistry Keywords: Nemipterus virgatus surimi; pre-emulsified safflower seed oil; gel texture; microstructure; flavor
Online: 14 January 2022 (16:12:29 CET)
Surimi-based products occupy an important position in the aquatic product processing industry. To enhance the quality and flavor of surimi-based products, the effects of pre-emulsified safflower seed oil on the texture, water-holding capacity (WHC), microstructure, and flavor of Nemipterus virgatus surimi gel was evaluated. The texture and whiteness of gel were improved, and the WHC increased (P < 0.05) as the content of safflower seed oil increased up to 2 mL per 100 g surimi. Furthermore, the drops of pre-emulsified safflower seed oils with an average diameter of less than 0.10 μm were evenly distributed in gel matrix. Microstructure and infrared spectroscopy analyses indicated that low-content pre-emulsified safflower seed oil acted as filler particles to occupy void spaces, resulting in gel exhibiting a dense network structure. Volatile analysis showed the gel containing pre-emulsified oil enriched volatile compounds, mainly resulting from oxidation and decomposition of oils by the activation of lipoxygenase, which synergistically contributes to unique flavors of gel. Consequently, low-content pre-emulsified safflower seed oil can used to enhance the quality and flavor of N. virgatus surimi-based products. These findings are especially relevant to the current growing interest in low-fat and high-protein diets.
ARTICLE | doi:10.20944/preprints202104.0120.v1
Subject: Earth Sciences, Environmental Sciences Keywords: Pre-COVID-19; Post-COVID-19; Secondary Schools; Water Demand; Groundwater; Nigeria
Online: 5 April 2021 (12:22:37 CEST)
The prevalence of corona virus and the novel COVID-19 disease in the entire globe has exacerbated different impact on socioeconomic spectrum in the world, including water use pattern. Thus a research was conducted to examine the comparative use of water during pre- and post-COVID-19 lockdown pattern among post-primary schools in Iwo, Osun State, Nigeria. A survey was conducted among fifteen schools which were randomly selected, but with eight public and seven private schools for the investigation. Both descriptive and inferential statistical techniques were used in data analysis. The results revealed that the major source of water to the schools investigated is ground water which is obtained through hand-dug wells and boreholes. It was further discovered that there was increase in water use during post-COVID-19 lockdown era as a result of the directive by the government that clean water should be provided for hand-washing by all schools regardless of the owner to curtail the spread of COVID-19 disease in the country. One sample t-test also revealed that there was a significant difference in water use at (p<0.01) level. It is recommended that the government and other stakeholders in water sector to ensure that all-time and non-seasonal dependent source of water be provided rather than ground water source which is susceptible to variations in water yields from seasonal variations. This will enable continuous clean water supply, for all purposes, including COVID-19 protocols.
ARTICLE | doi:10.20944/preprints202103.0617.v1
Subject: Arts & Humanities, Anthropology & Ethnography Keywords: Spondylus shells; archaeomalacology; archaeozoology; pre-Hispanic Ecuador; knowledge representation; formal concept analysis.
Online: 25 March 2021 (13:55:39 CET)
Shells, probably like no other product of nature, have played an important role in the history of mankind. The pre-Hispanic civilizations of Ibero-America also used certain type of shells profusely in their religious ceremonies, in particular, in Ecuador there were two species of main importance, the Spondylus princeps and the Spondylus calcifer broadly employed to manufacture ornaments that possess a strong symbolic, religious and social meaning and that were almost exclusively used by ruling classes. Among these ornaments, the faces carved on the Spondylus shells are little known. In the present study, we chose a total of fifteen (15) pieces from the Pastor Restrepo Lince´s archaeomalacology collection to understand the possible uses of these objects, through the interpretation of the gestures represented on the faces, their dimensions, and their geographical distribution in pre-Hispanic Ecuador. To achieve the proposed objective, we approach the present investigation from the perspective of the formal analysis of concepts, which is a mathematical theory of representation of knowledge, finding that these faces carved in Spondylus, were used daily or in special ceremonial occasions and that its use was common in all the regional cultures of ancient Ecuador, from the oldest such as Valdivia, and for more than 2000 years, indicating a long tradition of the use of Spondylus as an object of great symbolic and economic value until the arrival of the Spanish
ARTICLE | doi:10.20944/preprints201810.0260.v1
Subject: Engineering, Civil Engineering Keywords: tension force; interface damage; CRTSII slab ballastless track; concrete crack; pre-stress
Online: 12 October 2018 (06:34:43 CEST)
There is a confusion in the original design concept for the tensioning of longitudinally connected reinforcement of CRTSII slab ballastless track. In order to clarify the effect of tension value of longitudinal reinforcement on mechanical characteristics of ballastless track, a three dimensional finite element model considering the nonlinear interaction between the track slab and CA mortar of CRTSII slab ballastless track was established. The mechanical characteristics of the track structure under longitudinal tension load and temperature gradient load of the longitudinal joint were calculated. A method of applying pre-stress to post-pouring concrete was proposed according to the concept of pre-stress loss of pretensioning pre-stressed concrete, reasonable tensile force value was proposed after the crack width and the reinforcement stress of the ballastless track in the operation stage were checked and calculated according to the concrete design principle. When the tension force is greater than 300 kN, it’s harmful to the bonding between the slab and mortar layer, which is prone to interlayer damage. In order to adding pre-stress to concrete of wide joints to ensure the longitudinal stability of ballastless track and the reinforcement stress and crack width to meet the design requirements. It is suggested that the tension force value should be 230 kN, and the temperature difference between reinforcement and concrete should be 30 °C before the initial curdle of wide joint concrete.
ARTICLE | doi:10.20944/preprints201703.0081.v1
Subject: Life Sciences, Molecular Biology Keywords: miRNAs; pre-miRNAs sequencing; Abelmoschus esculentus; Next generation sequencing; non-model plant
Online: 14 March 2017 (10:15:14 CET)
MicroRNAs (miRNAs) are crucial regulatory RNAs, originated from hairpin precursors. For the past decade, researchers are focusing extensively on miRNA profiles in various plants. However studies on precursor miRNAs (pre-miRNAs) global profiling stay static even in model plants. Here, for the first time in a non-model plant, Abelmoschus esculentus with negligible genome information, we are reporting the global profiling to characterize the miRNAs and their associated pre-miRNAs by applying next generation sequencing approach. Preliminarily we performed sRNA (small RNA) sequencing with five biological replicates of leaf samples to attain 207,285,863 reads and data analysis using miRPlant keyed out 128 known and 845 novel miRNA candidates. With the objective to seize their associated hairpin precursors, we accomplished pre-miRNA sequencing to attain 83,269,844 reads. The paired end reads are merged, adaptor trimmed and the resulting 40-241 nt (nucleotide) sequences were picked out for analysis by using perl scripts from miRGrep tool and in-house built shell script for Minimum Fold Energy Index (MFEI) calculation. Applying stringent criteria of dicer cleavage pattern and perfect stem loop structure revealed precursors for 57 known miRNAs of 15 families and 18 novel miRNAs. Quantitative Real Time (qRT) PCR was performed to determine the expression of selected miRNAs.
ARTICLE | doi:10.20944/preprints202207.0384.v1
Subject: Medicine & Pharmacology, Pediatrics Keywords: SARS-CoV-2; COVID-19; children; clinical features; comorbidities; male genderSARS-CoV-2, COVID-19, children, clinical features, comorbidities, male gender
Online: 26 July 2022 (04:43:02 CEST)
Background: Given the potential for additional development to clarify a better knowledge of the overall impact of COVID-19 on the pediatric population, the clinical symptoms of SARS-CoV-2 infection in children and adolescents are still being explored. Morbidity in children is characterized by a variable clinical course. Our study's goal was to compare clinical aspects of 230 pediatric patients who tested positive for SARS-CoV-2 and were hospitalized between April 2020 and March 2022. Methods: In a retrospective analysis, we compared two groups hospitalized in the infectious diseases clinical ward IX at the National Institute for Infectious Diseases "Prof. Dr. Matei Bals," Bucharest, Romania. The first group of 88 patients was admitted between (April–December 2020) and their clinical manifestations were compared with the second group of 142 children followed between July 2021 and March 2022. Results: Of 230 children, the median age was 4.5 (interquartile range 0.6-17) years, 53.9% were male. 88 (36.21%) patients (first group) were admitted during the second wave in Romania, mostly aged < 5 years old, and experienced digestive manifestations like fever (p=0.001), and diarrhoea (p=0.004). The second group experienced different clinical signs when compared with the first group, with higher temperature and increased respiratory symptoms analogous to those of acute respiratory viral infections. The proportion in the second group increased, and 64.5% had symptoms for a median interval of 5 days; age (0-4 -years old) and length of stay were both proportionally inversely (p<0.01) and with correlation with hospital admission (p = 0.04). We report two Paediatric Inflammatory Multisystem Syndrome (PIMS) in the second group, with favourable evolution under treatment. Comorbidities were risk factors for complications appear (p < 0.001) in both groups. All paediatric cases admitted to our clinic evolved favourably and no death was recorded. Conclusions: In the first group children experienced digestive symptoms, whereas the second group experienced mild and moderate respiratory symptoms. We confirmed risk factors for severe cases as manifestations across the age spectrum, 0-4 (digestive symptoms) and 5-12 years old (for respiratory symptoms), associated comorbidities, fever, and male gender. The potential effects of COVID-19 infection in children older than 5 years should encourage caregivers to vaccinate and improve the prognosis among pediatric patients at risk.
REVIEW | doi:10.20944/preprints202201.0170.v1
Subject: Mathematics & Computer Science, Other Keywords: significative infrastructure; biological networks; normalized mutual information; recall; pre-cision; modularity; gene ontology
Online: 12 January 2022 (14:17:32 CET)
Abstract: In network science and big data, the concept of finding meaningful infrastructures in networks has emerged as a method of finding groups of entities with similar properties within very complex systems. The whole concept is generally based on finding subnetworks which have more properties (links) amongst nodes belonging to the same cluster than nodes in other groups (A concept presented by Girvan and Newman, 2002). Today meaningful infrastructure identification is applied in all types of networks from computer networks, to social networks to biological networks. In this article we will look at how meaningful infrastructure identification is applied in biological networks. This concept is important in biological networks as it helps scientist discover patterns in proteins or drugs which helps in solving many medical mysteries. This article will encompass the different algorithms that are used for meaningful infrastructure identification in biological networks. These include Genetic Algorithm, Differential Evolution, Water Cycle Algorithm (WCA), Walktrap Algorithm, Connect Intensity Iteration Algorithm (CIIA), Firefly algorithms and Overlapping Multiple Label Propagation Algorithm. These al-gorithms are compared with using performance measurement parameters such as the Mod-ularity, Normalized Mutual Information, Functional Enrichment, Recall and Precision, Re-dundancy, Purity and Surprise, which we will also discuss here.
ARTICLE | doi:10.20944/preprints202007.0746.v1
Subject: Engineering, Electrical & Electronic Engineering Keywords: radio frequency interference detection; deep learning; transfer learning; pre-trained convolutional neural networks
Online: 31 July 2020 (12:06:33 CEST)
Radio Frequency Interference (RFI) detection and characterization play a critical role to in ensuring the security of all wireless communication networks. Advances in Machine Learning (ML) have led to the deployment of many robust techniques dealing with various types of RFI. To sidestep an unavoidable complicated feature extraction step in ML, this paper proposes an efficient end-to-end method using the latest advances in deep learning to extract the appropriate features of the RFI signal. Moreover, this study utilizes the benefits of transfer learning to determine both the type of received RFI signals and their modulation types. To this end, the scalogram of the received signals is used as the input of the pre-trained convolutional neural networks (CNN), followed by a fully-connected classifier. This study considers a digital video stream as the signal of interest (SoI), transmitted in a real-time satellite-to-ground communication using DVB-S2 standards. To create the RFI dataset, the SoI is combined with three well-known jammers namely, continuous-wave interference (CWI), multi- continuous-wave interference (MCWI), and chirp interference (CI). This study investigated four well-known pre-trained CNN architectures, namely, AlexNet, VGG-16, GoogleNet, and ResNet-18, for the feature extraction to recognize the visual RFI patterns directly from pixel images with minimal preprocessing. Moreover, the robustness of the proposed classifiers is evaluated by the data generated at different signal to noise ratios (SNR).
ARTICLE | doi:10.20944/preprints201812.0369.v1
Subject: Biology, Anatomy & Morphology Keywords: serine proteinase inhibitor; Kunitz; bikunin; inter-α-trypsin inhibitor; pre-α-trypsin inhibitor.
Online: 31 December 2018 (11:03:39 CET)
The aim of this study was to assess if the ovine articular cartilage serine proteinase inhibitors (SPIs) were related to the Kunitz inter-α-trypsin inhibitor (ITI) family. Ovine articular cartilage was finely diced and extracted in 6M urea and SPIs isolated by sequential anion exchange, HA affinity and Sephadex G100 gel permeation chromatography. Selected samples were also subjected to chymotrypsin and concanavalin-A affinity chromatography. Eluant fractions from these isolation steps were monitored for protein and trypsin inhibitory activity and pooled fractions assessed by affinity blotting using biotinylated trypsin to detect active SPIs and by Western blotting using antibodies to α1-microglobulin, bikunin, TSG-6 and 2-B-6 (+) CS stub epitope generated by chondroitinase-ABC digestion. This identified 2-B-6 (+) positive 220-250,120, 58 and 36 kDa SPIs. The 58 kDa SPI contained α1-microglobulin, bikunin and chondroitin-4-sulphate stub epitope consistent with its identity as the α1-microglobulin-bikunin (AMBP) precursor and was also isolated by concanavalin-A lectin affinity chromatography indicating it had N-glycosylation. Kunitz protease inhibitor (KPI) species of 36, 26, 12 and 6 kDa could be autolytically generated by prolonged storage of the aforementioned 120 and 58 kDa SPIs; chymotrypsin affinity chromatography also generated the 6kDa SPI. KPI domain 1 and 2 SPIs were separated by concanavalin lectin affinity chromatography, domain 1 displayed affinity for this lectin indicating it had N-glycosylation. KPI 1 and 2 both displayed potent inhibitory activity towards trypsin, chymotrypsin, kallikrein, leucocyte elastase and cathepsin G. Localisation of versican, lubricin and HA in the surface regions of articular cartilage represented probable binding sites for the ITI SPs with likely importance in the preservation of joint function.
REVIEW | doi:10.20944/preprints202210.0289.v1
Subject: Medicine & Pharmacology, Ophthalmology Keywords: Primary Sjögren's Syndrome; dryness; fatigue; depression; anxiety; clinical trials
Online: 19 October 2022 (14:26:01 CEST)
Primary Sjögren's syndrome (pSS) is a chronic, systemic autoimmune disease defined as exocrine gland hypofunction resulting in dry eyes and dry mouth. Recent interest in biological therapies for pSS has been garnered, however achieving FDA-approval has been challenging due to the numerous complications in the trials. Current literature lacks insight and a molecular target-based approach to the development of biological therapies. This review focuses on novel research in newly defined drug targets and latest clinical trials for pSS treatment. A literature search was conducted on ClinicalTrials.gov using the search term “Primary Sjögren's syndrome”. Articles published between 2000 and 2021 in English language were included. Our findings revealed the potential targets for pSS treatment in clinical trials and the most recent advances in understand-ing of molecular mechanisms underlying the pathogenesis of pSS. A prominent gap in current trials is overlooking the treatment of extraglandular symptoms such as fatigue, depression and anxiety which pervade most patients with pSS. Based on dryness and these symptom-directed therapies, emerging biological agents targeting inflammatory cytokines, signal pathways and immune reaction have been studied and proved the efficacy and safety. Novel therapies may complement existing non-pharmacological methods of alleviating symptoms of pSS. Better grad-ing systems adding extraglandular symptoms to gauge disease activity and severity should be created. The future of pSS therapies may lie in gene therapy, stem cell and tissue engineering ther-apy.
REVIEW | doi:10.20944/preprints202208.0316.v1
Subject: Medicine & Pharmacology, General Medical Research Keywords: ANCA-associated vasculitis; Proteinase 3; Myeloperoxidase; Clinical Phenotype; Outcome
Online: 17 August 2022 (09:58:51 CEST)
The traditional nomenclature system for classifying Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV), based on clinical phenotype, described Granulomatosis with Polyangiitis (GPA), Eosinophilic Granulomatosis with Polyangiitis (EGPA) and Microscopic Polyangiitis (MPA) as distinct clinical entities. This classification has proved its expedience in clinical trials and every day clinical practice, yet, a substantial overlap in clinical presentation still exists, and often causes difficulties in prompt definition and clinical distinction. Additionally, new insights into the AAV pathogenesis point out that PR3 and MPO-AAV may not represent expressions of the same disease spectrum but rather two distinct disorders, as they display significant differences. Thus, it is supported that a classification based on ANCA serotype (PR3-ANCA, MPO-ANCA or ANCA-negative), could be more accurate and also closer to the nature of the disease, instead of the phenotype-based one. This review aims to elucidate the major differences between PR3 and MPO-AAV, in terms of epidemiology, pathogenesis, histological and clinical manifestations, and response to therapeutic approaches.
REVIEW | doi:10.20944/preprints202208.0027.v1
Subject: Medicine & Pharmacology, Cardiology Keywords: acute pulmonary embolism; dilemmas; therapeutic treatment; recommendations; clinical application
Online: 2 August 2022 (03:12:56 CEST)
Pulmonary thromboembolism is a very common cardiovascular disease, with a still high mortality rate. Despite the clear guidelines, this disease still represents a great challenge both in diagnosis and treatment. Heterogeneous clinical picture, often without pathognomonic signs and symptoms, represents a huge differential diagnostic problem even for experienced doctors. The decision on the therapeutic regimen also represents a major dilemma in the group of patients who are hemodynamically stable at initial presentation and have signs of right ventricular (RV) dysfunction proven by echocardiography and positive biomarker values (pulmonary embolism of intermediate-high risk). Studies have shown conflicting results about the benefit of using fibrinolytic therapy in this group of patients until hemodynamic decompensation, due to the risk of major bleeding. The latest recommendations give preference to new oral anticoagulants (NOACs) compared to vitamin K antagonists (VKA), except for certain categories of patients (patients with antiphospholipid syndrome, mechanical valves, pregnancy). When using oral anticoagulant therapy, special attention should be paid to drug-drug interactions, which can lead to many complications, even to the death of the patient. Special population groups such as pregnant women, obese patients, patients with antiphospholipid syndrome and cancer represent a great therapeutic challenge in the application of anticoagulant therapy. In these patients, not only the effectiveness of the drugs must be taken into account, but great attention must be paid to their safety and possible side effects, which is why a multidisciplinary approach is emphasized in order to provide the best therapeutic option.
ARTICLE | doi:10.20944/preprints202207.0149.v1
Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: clinical S.aureus; skin carriage; geriatric-MRSA pneumonia; endogenous-S.aureus
Online: 11 July 2022 (04:33:22 CEST)
The changing epidemiology of Staphylococcus aureus has created several gaps in its population structure and emergence of strains. Two global shifts in the aftermath of the past methicil-lin-resistant S. aureus (MRSA) pandemic are: a rise in healthcare-associated infections and evolu-tion of cutaneous and soft tissue infections with high morbidities and mortalities. Furthermore, bitter lessons from COVID-19 showed S. aureus necrotizing-pneumonia and skin conditions ag-gravating Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) and Monkeypox manifestations. Limited data and paucity of high-quality evidence exist for many key clinical questions. Using clinical microbiology, molecular characterization, hospital data on age and in-fection sites, and antibiograms, we have investigated S. aureus infection patterns. We showed that age-specific distribution in both intensive care unit (ICU) and non-ICU revealed highest infection rates (94.7%) in senior-patients >50 years; most were MRSA (81.99%). However, specific distribu-tions of geriatric MRSA and MSSA rates were 46.5% and 4.6% in ICU and 35.48% and 8.065% in non-ICU, respectively. Intriguingly, age groups 0-20 years showed uniquely similar MRSA pat-terns in ICU and non-ICU patients (13.9%, 9.7%, respectively) and MSSA in ICU (11.6%). In age groups 20-50 years, MRSA were 2-fold in non-ICU (35%) than ICU (18.6%). Interestingly, highly significant association was found between infection-site and age-groups (P-value .000). Skin in-fections remained higher in all ages; pediatrics 32.14%, adults 56%, and seniors 25% while res-piratory infections were lower in pediatrics (14.3%) and adult 17%), and highest in seniors (38%). Blood and “other” sites in pediatrics recorded (28.6%; 25%, respectively), slightly lower in adults (18.6%; 8.6%) and seniors (14%); 22.8%), respectively. Further, significant association existed between infection-site and MRSA (Chi-Square Test, P-value .002). The common cutaneous infec-tions across all age-groups and the significant association of MRSA to geriatric-respiratory infec-tions have a high potential for skin-carriage as reservoir for endogenous infection. The similar frequencies of both lineages in youth in all settings imply MSSA-carriage as potential evolutionary origins for MRSA. These findings have important clinical implications for strategic planning in patient management and S. aureus control particularly in age-specific infections and vigilance for potential viral coinfections.
REVIEW | doi:10.20944/preprints202201.0064.v1
Subject: Medicine & Pharmacology, Pharmacology & Toxicology Keywords: combination treatment; monotherapy; clinical trial design; benefit/risk assessment
Online: 6 January 2022 (10:14:10 CET)
Combination treatment, i.e., the use of two or more drugs for the same condition, is frequent in medicine if monotherapy yields an insufficient therapeutic response. We here review and challenge clinical study designs and formats of reporting outcomes for the evaluation of the benefit/risk ratio of combination treatment over monotherapy. We demonstrate that benefits of combination treatment at the group level over-estimate the probability of benefit at the single patient level based on outcome simulations under almost any imaginable setting. Based on these findings we propose that studies testing combination treatment should always report on percentages of responders to monotherapy and combination treatment. We provide equations that allow calculation of the percentage of patients truly benefitting from combination (responders to both monotherapies) and that of patients exposed to risk of harm from adverse effects without a reasonable expectation of individual benefit. These considerations are explained based on real clinical data, mostly from the field of functional urology (male lower urinary tract symptoms).
ARTICLE | doi:10.20944/preprints202110.0241.v1
Subject: Medicine & Pharmacology, Pediatrics Keywords: Juvenile idiopathic arthritis, JIA, Research registry, Clinical trial, DMARD
Online: 18 October 2021 (11:00:57 CEST)
Management of Juvenile idiopathic arthritis (JIA) has improved tremendously in recent years due to the introduction of new drug therapies but remains complex also in terms of non-pharmaceutical issues. In order to determine the direction of scientific progress by characterizing the current spectrum of ongoing clinical research in JIA, we analyzed all ongoing studies in the field of JIA registered in clinicaltrials.gov and clinicaltrialsregister.eu concerning sponsoring, enrollment, duration, localization, and particularly objectives. Close of database was 7 January 2021. After identifying doubled-registered studies, N=72 went into further analysis. Of these, 61.1% were academia-sponsored and 37.5% by pharma industry. The majority of studies was of interventional type (77.8%), while others (22.2%) were observational. Median planned enrollments were 100 participants (interventional studies) and 175 participants (observational studies), respectively. Duration differed remarkably from one month to more than 15 years with a median of 42.5 months. 61.1% of studies were located in a single country, 38.9% were in several. Europe and North America clearly dominated study localizations. Study objectives were DMARDs (56.9%), followed by diagnostics and disease activity measurement (18.1%), and medication other than DMARD (12.5%), besides others. Studies on DMARDs were mainly sponsored by industry, predominantly interventional studies on established and novel biologics, with several on specific issues like systemic JIA and others. The spectrum of registered studies is currently centered on drug therapy and diagnostics, while other issues in JIA play a subordinated role.
Subject: Medicine & Pharmacology, Clinical Neurology Keywords: Alzheimer’s disease; artificial intelligence; clinical trials; eligibility assessment; randomization
Online: 8 October 2021 (11:31:14 CEST)
Clinical trials for Alzheimer’s disease (AD) face multiple challenges, such as the high screen failure rate and even allocation of heterogeneous participants. Artificial intelligence (AI), which has become a potent tool of modern science with the expansion in the volume, variety, and velocity of biological data, offers promising potential to address these issues in AD clinical trials. In this review, we introduce the current status of AD clinical trials and topic of machine learning. Then, a comprehensive review is focused on the potential applications of AI in the steps of AD clinical trials, including the prediction of AD biomarkers and differential diagnosis of AD in the prescreen during eligibility assessment and the likelihood stratification of patients who will progress to AD dementia and fast cognitive decline group from the slow decline group in randomization. Finally, this review provides challenges, developments and the future outlook on the integration of AI into AD clinical trials.