The purpose of this Individually Randomized Group Treatment Trial was to compare an Acceptance and Commitment Therapy-based (ACT) group intervention and a Cog-nitive Behavioral Therapy-based (CBT) group intervention for weight loss maintenance in a sample of adult patients with obesity seeking treatment for weight loss. 155 over-weight adults (BMI: Kg/m2= 43.8[6.8]) attending a multidisciplinary rehabilitation program for weight loss were randomized into two conditions: ACT and CBT. Demo-graphical, physical, and clinical data were assessed at the beginning of the program (t0), at discharge (t1), and at 6-month follow-up (t2). The following measures were ad-ministered: The Acceptance and Action Questionnaire-II (AAQ-II) and the Clinical Outcome in Routine Evaluation-Outcome Measure (CORE-OM). Generalized linear mixed models were performed to assess differences between groups. Moderation ef-fects for gender and eating disorders (ED) have been considered. From baseline to dis-charge no significant differences between interventions were found, with the only ex-ception of an improvement in the CORE-OM total score and in the CORE-OM subjective well-being subscale for those in the CBT condition. From discharge to follow-up ACT group participants showed significant results in terms of weight loss maintenance, CORE-OM total score, and CORE-OM and AAQ-II’s wellbeing, symptoms, and psy-chological problems subscales. Gender moderated the effects of time and intervention on the CORE-OM’ subscale reporting the risk for self-harm or harm others. The pres-ence of an eating disorder moderated the effect of time and intervention on the CORE-OM total score, on the CORE-Om’ symptoms and psychological problems sub-scales, and on the AAQ-II. Patients who received the ACT intervention were more likely to achieve a ≥5% weight loss from baseline to follow-up and to maintain the weight loss after discharge. The ACT intervention was thus effective in maintaining weight loss over time.

Comorbidities can have a cumulative effect on hospital outcomes of care, such as the length of stay (LOS), and hospital mortality. This study examines patients hospitalized with Congestive Heart Failure (CHF), a life-threatening condition, which, when it coexists with a burdened disease profile, the risk for negative hospital outcomes increases. Since coexisting conditions co-interact, with a variable effect on outcomes, clinicians should be able to recognize these joint effects. In order to study CHF comorbidities, we used medical claims data from CMS. After extracting the most frequent cluster of CHF comorbidities, we: (i) Calculated, step-by-step, the conditional probabilities for each disease combination inside this cluster (ii) Estimated the cumulative effect of each comorbidity combination on the LOS and hospital mortality (iii) Constructed (a) Bayesian, scenario-based graphs and (b) Bayes-networks to visualize results. Results show that, for CHF patients, different comorbidity constructs have variable effect on the LOS and hospital mortality. Therefore, dynamic comorbidity risk assessment methods should be implemented for informed clinical decision making in any ongoing effort for quality of care improvements.

As exemplified by the global response to the SARS-CoV-2 pandemic, whole genome sequencing played an important role in monitoring the evolution of novel viral variants and provided guidance on potential antiviral treatments. The recent rapid and extensive introduction and spread of highly pathogenic avian influenza virus in Europe, North America and elsewhere raises the need for similarly rapid sequencing to aid in appropriate response and mitigation activities. To facilitate this objective, we investigated a next generation sequencing platform that uses a portable nanopore sequencing device to generate and present data in real time. This platform offers the potential to extend in-house sequencing capacities to laboratories that may otherwise lack resources to adopt sequencing technologies requiring large benchtop instruments. We evaluated this platform for routine use in a diagnostic laboratory. In this study we evaluated different primer sets for the whole genome amplification of influenza A virus and evaluated five different library preparation approaches for sequencing on the nanopore platform using the MinION flow-cell. A limited amplification procedure and a rapid procedure were found to be best among the approaches taken.

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.

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.

We describe how clinical researchers can exploit the Android cell phone as an economic platform for the gathering of data from clinical trial participants. The aim was to provide a solution with the shortest possible learning curve for researchers who are comfortable with setting up web pages. The additional requirement is that they extend their skills to the installation of a local webserver on the cell phone and then use four simple PHP templates to construct the clinical research data collection and processing forms. Data so collected is automatically written to local csv files on the cell phone. These csv phones can be retrieved from the device by the researcher simply by plugging the cell phone into their desktop PC and accessing the cell phone memory in just the same way as they would a USB memory stick. The results are presented as a list of recommended Android Apps along with settings that have proved to provide a stable combination likely to be easily used by clinical research participants. We have made a limited ‘user trial’ of this approach with satisfactory feedback received. We have concluded that this approach will reward researchers with a solution that is user friendly, will provide transcription free data and that is more than cost competitive with the conventional error prone/poor compliance ‘paper based participant form – researcher transcription’ cycle.

As new treatment modalities are being explored in neuro-oncology, viruses are emerging as a promising class of therapeutics. Virotherapy consists of introduction of either wild-type or engineered viruses to the site of disease, where they exert anti-tumor effect. These viruses can either be non-lytic, in which case they are used to deliver gene therapy, or lytic, which induce tumor cell lysis and subsequent host immunologic response. Replication-competent viruses can then go on to further infect and lyse neighboring glioma cells. This treatment paradigm is being explored extensively in both preclinical and clinical studies for a variety of indications. Virus-based therapies are advantageous due to the natural susceptibility of glioma cells to viral infection, which improves therapeutic selectivity. Furthermore, lytic viruses expose glioma antigens to the host immune system and subsequently stimulate an immune response that specifically targets tumor cells. This review surveys the current landscape of oncolytic virotherapy clinical trials in high-grade glioma, summarizes preclinical experiences, identifies challenges associated with this modality across multiple trials, and highlights potential to integrate this therapeutic strategy into promising combinatory approaches.

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.

Scrub typhus is a neglected tropical disease predominantly occurring in Asia. The causative agent is a bacterium transmitted by the larval stage of mites found in rural vegetation in endemic regions. Cases of scrub typhus frequently present as acute undifferentiated febrile illness, and without early diagnosis and treatment, the disease can develop fatal complications. We retrospectively reviewed de-identified data from a 23-year-old woman who presented to an emergency department with complaints of worsening abdominal pain. On presentation, she appeared jaundiced and toxic-looking. Other positive findings on abdominal examination were a positive Murphey’s sign, abdominal guarding and hepatosplenomegaly. Magnetic resonance cholangiopancreatography demonstrated acalculous cholecystitis. Additional findings included eschar on the medial aspect of the left thigh with inguinal regional lymphadenopathy. Further, positive results were obtained for immunoglobulins M and G, confirming scrub typhus. Workups for other infectious causes of acute acalculous cholecystitis detected human herpesvirus 4 (Epstein-Barr virus). Whether that represented acute infection or re-activation of the Epstein-Barr virus could not be determined. As other reports have described acute acalculous cholecystitis in adult scrub typhus patients, we recommend doxycycline to treat acute acalculous cholecystitis in endemic regions while awaiting serological confirmation.

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.

Protein phosphatase 2A (PP2A) is a ubiquitous serine/threonine phosphatase implicated in a wide variety of regulatory cellular functions. PP2A is abundant in the mammalian nervous system and dysregulation of its cellular functions are associated with myriad neurodegenerative disorders. Additionally, PP2A has oncologic implications, recently garnering attention and emerging as a therapeutic target because of the antitumor effects of a potent PP2A inhibitor, LB100. LB100 abrogation of PP2A is believed to exert its inhibitory effects on tumor progression through cellular chemo- and radio-sensitization to adjuvant agents. An updated and unifying review of PP2A biology and inhibition with LB100 as a therapeutic strategy for targeting cancers of the nervous system is needed, as other reviews have mainly covered broader applications of LB100. In this review, we discuss the role of PP2A in normal cells and tumor cells of the nervous system. Further, we summarize current evidence regarding the therapeutic potential of LB100 for treating solid tumors of the nervous system.

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.

The videofluorographic study is indicated for diseases potentially causing dysphagia and aspiration, such as gastrointestinal reflux disease, cancers of the oropharynx and esophagus, and certain neurologic diseases needing swallowing assessment. The study is designed to survey the anatomy and physiology of swallowing to diagnose any swallowing impairment and is standardized using scales such as the Modified Barium Swallow Impairment Profile (MBSImP). The procedure requires the patient to swallow a barium contrasted bolus which helps to visualize and obtain a real-time result. There are certain complications of the procedure including radiation exposure which requires necessary safety protocols to be followed.

There is a growing number of evidence-based indications for pharmacogenetic (PGx) testing. We aimed to evaluate clinical relevance of a 16-gene panel test for PGx-guided pharmacotherapy. In an observational cohort study we included subjects tested with a PGx panel for variants of ABCB1, COMT, CYP1A2, CYP2B6, CYP3A4, CYP3A5, CYP2C9, CYP2C19, CYP2D6, CYP4F2, DPYD, OPRM1, POR, SLCO1B1, TPMT and VKORC1. PGx-guided pharmacotherapy management was supported by the PGx expert system SONOGEN XP. The primary study outcome was PGx-based changes and recommendations regarding current and potential future medication. PGx-testing was triggered by specific drug-gene pairs in 102 subjects, and by screening in 33. Based on PharmGKB expert guidelines we identified at least one “actionable” variant in all 135 (100%) tested patients. Drugs that triggered PGx-testing were clopidogrel in 60, tamoxifen in 15, polypsychopharmacotherapy in 9, opioids in 7, and other in 11 patients. Among those, PGx variants resulted in clinical recommendations to change PGx-triggering drugs in 33 (32.4 %), and other current pharmacotherapy in 23 (22.5%). Additional costs of panel vs. single gene tests are moderate, and the efficiency of PGx panel testing challenges traditional cost-benefit calculations for single drug-gene pairs. However, PGx-guided pharmacotherapy requires specialized expert consultations with interdisciplinary collaborations.

Objective: To analyze the clinical and economic impact of community-onset urinary tract infections (UTI) caused by extended-spectrum beta-lactamase (ESBL)-producing Klebsiella pneumoniae requiring hospitalization. Methods: A retrospective cohort study included all adults with UTI caused by K. pneumoniae admitted to a tertiary care hospital in Barcelona, Spain, between 2011 and 2015. Demographic, clinical and economic data were analyzed. Results: One hundred and seventy-three episodes of UTI caused by K. pneumoniae were studied; 112 were non-ESBL-producing and 61 ESBL-producing. Multivariate analysis identified ESBL production, acute confusional state associated with UTI, shock, and time to adequate treatment as risk factors for clinical failure during the first 7 days. Economic analysis showed differences between ESBL-producing and non-ESBL-producing K. pneumoniae for the total cost of hospitalization per episode (mean 6,718 € vs 3,688 € respectively). Multivariate analysis of the higher costs of UTI episodes found statistically significant differences for ESBL production and time to adequate treatment. Conclusion: UTI caused by ESBL-producing K. pneumoniae requiring hospitalization, and time to adequate antimicrobial therapy are associated with worse clinical and economic outcomes.

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.

The premutation of the fragile X messenger ribonucleoprotein 1 (FMR1) gene is characterized by an expansion of the CGG trinucleotide repeats (55 to 200 CGGs) in the 5' untranslated region, and increased levels of FMR1 mRNA. Molecular mechanisms leading to fragile X premutation-associated conditions (FXPAC) include co-transcriptional R loop formations, FMR1 mRNA toxicity through both RNA gelation into nuclear foci, and sequestration of various CGG re-peat-binding proteins, and repeat-associated non-AUG (RAN) initiated translation of potentially toxic proteins. Such molecular mechanisms contribute to subsequent consequences, including mitochondrial dysfunction and neuronal death. Clinically, premutation carriers may exhibit a wide range of symptoms and phenotypes. Any of the problems associated with the premutation, can appropriately be called FXPAC. Fragile X-associated tremor/ataxia syndrome (FXTAS), fragile X-associated primary ovarian insufficiency (FXPOI), and fragile X-associated neuropsychiatric disorders (FXAND) can fall under FXPAC. Understanding the molecular and clinical aspects of the premutation of the FMR1 gene is crucial for accurate diagnosis, genetic counseling, and appropriate management of affected individuals and families. This paper summarizes all the known problems associated with the premutation and documents the presentations and discussions that occurred at the International Premutation Conference, which took place in New Zealand in 2023.

Background: The purpose of this article is to update the diagnostic assessment, therapeutic approach, and 12-18 month follow up of patients added in the Italian Lombardy ADHD Register. Methods: Data on patients evaluated by the 18 Regional ADHD Reference Centres in the ten year period from 2011 to April 2021 were analysed. Results: 4091 of 5934 added patients received a diagnosis of ADHD. In 20.3% of cases, there was a family history of ADHD. 2879 children (70.4%) had at least one comorbidity disorder, the most common of which was learning disorder (39%). Nearly all (95.9%) received at least one psychological prescription, 17.9% of them almost one pharmacological treatment, and 15.6% a combination of both. Values of ≥5 of the Clinical Global Impressions- Severity (CGI-S) are more commonly presented by patients with a pharmacological prescription than with a psychological treatment (p < .0001). A significant improvement was reported in half of the patients followed after 1 year, with Clinical Global Impressions- Improvement (CGI-I ≤ 3). In all, 233 of 4091 are 18 year old patients. Conclusion: A ten year systematic monitoring of models of care was a fruitful shared and collaborative initiative in order to promote significant improvement in clinical practice, providing effective and continuous quality of care. The unique experience here reported should spread.

Since the effects of renin–angiotensin–aldosterone system (RAAS) inhibitors on the clinical outcomes of coronavirus disease-19 (COVID-19) have been conflicting in different studies, we performed this meta-analysis. A systematic search of published articles was performed in PubMed and EMBASE from January-May 5, 2020. Studies that reported the clinical outcomes of patients with COVID-19, stratified by the class of concomitant antihypertensive drug therapy, were included. The Mantel-Haenszel random effects model was used to estimate pooled odds ratio (OR). A total of 6,997 hypertensive patients with COVID-19 were included. The overall risk of poor patient outcomes (severe COVID-19 or death) was lower in patients taking RAAS inhibitors (OR=0.84, 95% CI: [0.73, 0.96]; P=0.017) compared with those receiving non-RAAS inhibitor antihypertensives. Patients taking angiotensin-I-converting enzyme inhibitors (ACEIs) were less likely to experience poor clinical outcomes (OR=0.73, 95% CI: [0.58-0.92]; P=0.01) compared with those receiving angiotensin-II receptor blockers (ARBs). Compared to all other antihypertensives, ACEIs decreases the risk poor COVID-19 outcomes (OR=0.77, 95% CI: [0.63-0.93]) while ARBs did not (OR=1.13, 95% CI: [0.95-1.35]). The risk of poor patient outcomes from COVID-19 was lower in patients who received RAAS inhibitors compared with those who took non-RAAS inhibitors. Unlike ARBs, ACEIs might help in decreasing the severity and mortality of COVID-19.

The coronavirus disease 2019 (COVID-19) pandemic has caused considerable global disruption to clinical practice. This article will review the impact that the pandemic has had on oncology clinical trials. It will assess the effect of the COVID-19 situation on the initial presentation and investigation of patients with suspected cancer. It will also discuss the impact of the pandemic on the subsequent management of cancer patients and how clinical trial approval, recruitment and conduct were affected during the pandemic. An intriguing aspect of the pandemic is that clinical trials investigating treatments for COVID-19 and vaccinations against the causative virus, SARS-CoV-2, have been approved and conducted at unprecedented speed. In light of this, this re-view will also discuss the potential that this enhanced regulatory environment could have on the running of oncology clinical trials in the future.

Background: Laryngopharyngeal reflux (LPR) is a common disease in otolaryngology characterized by an inflammatory reaction of the mucosa of the upper aerodigestive tract caused by digestive refluxate enzymes. LPR has been identified as etiological or favoring factor of laryngeal, oral, sinonasal or otological diseases. In this case-series, we reported atypical clinical presentation of LPR in patients presenting in our clinic with reflux. Methods: A retrospective medical chart review of 351 patients with LPR treated in the European Reflux Clinic in Brussels, Poitiers and Paris was performed. In order to be included, patients had to report atypical clinical presentation of LPR, consisting of symptoms or findings that are not described in reflux symptom score and reflux sign assessment. The LPR diagnosis was confirmed with 24-hour hypopharyngeal-esophageal impedance pH-study and patients were treated with a combination of diet, proton pump inhibitors and alginates. The atypical symptoms or findings had to be resolved from pre- to posttreatment Results: From 2017 to 2021, 21 patients with atypical LPR were treated in our center. The clinical presentation consisted of recurrent aphthosis or burning mouth (N=9), recurrent burps and abdominal disorders (N=2), posterior nasal obstruction (N=2), recurrent acute suppurative otitis media (N=2), severe vocal fold dysplasia (N=2), and recurrent acute rhinopharyngitis (N=1), tearing (N=1), aspirations (N=1) or tracheobronchitis (N=1). Abnormal upper aerodigestive tract reflux events were identified in all of these patients. Atypical clinical findings resolved and did not recur after an adequate anti-reflux treatment. Conclusion: LPR may present with various clinical presentations including mouth, eye, tracheobronchial, nasal or laryngeal findings, which may all regress with an adequate treatment. Future studies are needed to better specify the relationship between LPR and these atypical findings through analyses identifying gastroduodenal enzyme in the enflamed tissue.

This study aimed to explore how Indonesian clinical psychologists (CPs) address aspects of spirituality and religion (SR), particularly their attitudes towards and experience of it, on the mental health context. Semi-structured interviews were conducted with 43 CPs in public health centres in Yogyakarta Province, Indonesia. Data were anyalsed using deductive thematic analysis and they generated ten sub-themes which were merged into three central themes. The first theme was experiences related to SR, particularly in Indonesian sociocultural context. The second theme concentrated on participants’ clinical experience related to SR integration into clinical practice. The last theme highlighted the effort made by participants to create holistic mental health services. The originality of this study was represented by the interview quote in the title, “Doing my profession is also part of worship”. It was found that SR is part of culture and belief among Indonesian people, including CPs and mental health treatment clients. In summary, participants genuinely acknowledged that they were not able to completely detach SR from their professional practice. However, participants also pointed out that they were different with spiritual-religious healers (SRHs) and favourably welcomed future collaboration with credible SRHs. This positive attitude embodied a holistic care approach that recognises the diverse biopsycho-social-spiritual needs of clients. Therefore, professional organisations and psychology faculties should establish regulations and education of SR in psychology curricula and conventional psychotherapy to achieve this holistic mental health services in Indonesia.

Background: Absolute uterine factor infertility (AUFI) is a kind of infertility that is completely attributable to uterine absence (surgical or congenital for women with Mayer-Rokitansky-Küster-Hauser syndrome: MRKH) or anatomic or functional abnormality that prevents embryo implantation or completion of pregnancy to term. Until recently, the only viable option to parenthood for couples with AUFI were adoption or surrogacy. Since a first attempt of uterus transplant (UTx) in 2000, nine babies were born from women with a transplanted uterus from 2014, eight of which in Sweden, and one in the United States. These promising results are raising immense hopes for the women with AUFI and there is optimism about the possibility for UTx to become part of clinical care even though, besides encouraging results, the procedure has also resulted in increased risks and harms for both the donors and recipients and increased risks of premature birth for the fetus. At present UTx is still considered as experimental and requiring more research and safety assessment before becoming a therapeutic option for AUFI. The transition from experimental procedure to therapeutic care would result in less strict ethical scrutiny for UTx and in the possibility for patients to get reimbursement for the procedure by the relevant healthcare insurance or public healthcare providers. In turn, an increase in the number of UTx performed yearly by specialized surgical teams would result in a general improvement of the “field strength”. However, at present it is difficult to establish the amount of evidence that we need in order to consider UTx as no longer experimental but routine clinical practice. The literature on UTx provides recommendations on the different outcomes that should be monitored in this experimental phase but no study is anticipating the number of subjects that should be followed and for how long. Conclusion: As for other transplants that have become routine practice, like renal transplant and heart transplant, it is likely that the decision on “routine practice readiness” will result from available cumulated evidences, from expert capacity to find a consensus on best practices and on political considerations as well, including pressures form patients and patient groups.

A nutritional approach could be a promising strategy to prevent or slow the progression of neurodegenerative diseases such as Parkinson’s and Alzheimer’s disease, since there is no effective therapy for these diseases so far. The beneficial effects of omega-3 fatty acids are now well established by a plethora of studies through their involvement in multiple biochemical functions, including synthesis of antinflammatory mediators, cell membrane fluidity, intracellular signalling and gene expression. This systematic review will consider epidemiological studies and clinical trials that assessed the impact of supplementation or dietary intake of omega-3 polyunsaturated fatty acids on neurodegenerative diseases such as Parkinson’s and Alzheimer’s diseases. Indeed, treatment with omega-3 fatty acids, being safe and well tolerated, represent a valuable and biologically plausible tool in the management of neurodegenerative diseases in their early stages.

Background: About 10% of Wilms Tumor (WT) patients have a malformation or cancer predisposition syndrome (CPS) with causative germline genetic or epigenetic variants. Knowledge on CPS is essential for genetic counselling. Methods: This retrospective analysis focused on 2927 consecutive patients with WTs registered between 1989 and 2017 in the SIOP/GPOH studies. Results: (GU, N=66, 2,3%), Beckwith-Wiedemann spectrum (BWS, N=32, 1,1%), isolated hemihypertrophy (IHH, N=29, 1,0%), Denys-Drash syndrome (DDS, N=24, 0,8%) and WAGR syndrome (N=20, 0,7%) were reported most frequently. Compared to others, these patients were younger at WT diagnosis (median age 24,5 months vs. 39,0 months), had smaller tumors (334,8mL vs. 496,9mL), less often metastasis (8,2% vs. 18%), but more often nephroblastomatosis (12,9% vs. 1,9%). WT with IHH was associated with blastemal WT and DDS with stromal subtype. Bilateral WTs were common in WAGR (30%), DDS (29%) and BWS (31%). Chemotherapy induced reduction in tumor volume was poor in DDS (7,7% increase) and favorable in BWS (84,6% reduction). The event-free survival (EFS) of patients with BWS was significantly (p=0,002) worse than in others. Conclusions: CPS should be considered in WTs with specific clinical features resulting in referral to a geneticist. Their outcome was not always favorable.

Admission and discharge diagnoses of in-hospital patients are often in discord. Incorrect admission diagnoses are related to increased cost of care and patient safety. Additionally, due to the seasonality of many conditions, this discord may vary across the year. In this paper, we used medical claims data to develop a methodological framework that examines these differences, for Medicare beneficiaries. We provide examples for pneumonia, a condition with seasonal implications, and aneurysm, where early detection can be life-saving. Following a Bayesian approach, our work quantifies and visualizes with time series plots the degree that any clinical condition is correctly diagnosed upon admission. We examined differences in weekly intervals, during a calendar year. The mean length of stay and hospital charges were furthermore compared between matching and non-matching {admission, discharge Dx} pairs, and 95% confidence intervals of the difference of means were estimated. We applied Statistical Process Control methods and then visualized differences, for the hospital charges and the length of stay, per week, with time series plots. Our methodology and the visualizations underline the importance of a rigorous and non-delayed diagnostic process upon admission since there are significant implications in terms of hospital outcomes and cost of care.

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).

Background. Until now, cost of allergy treatment in insured public health care system and non-insured self-financing private health care system in Indonesia has not been well documented and published, as well as the cost of allergy treatment with subcutaneous immunotherapy. Objective. To evaluate the clinical and cost benefits of allergic rhinitis treatment in children with subcutaneous immunotherapy in non-insured self-financing private health care system. Methods. A retrospective cohort study conducted from 2015 until 2020, compared clinical improvement and health care costs over 18 months in newly diagnosed AR children who received SCIT versus matched AR control subjects who did not receive SCIT, with each group consisting of 1,098 subjects Results. Decrease of sp-HDM-IgE level (kU/ml) from 20.5 + 8.75 kU/ml to 12.1 + 3.07 kU/ml had been observed in the SCIT group. To reduce the symptom score of allergic rhinitis by 1.0 with SCIT it costs IDR 21,753,062.7 per child, for non SCIT it costs IDR 104,147,878.0 per child. Meanwhile, to reduce the medication score (MS) by 1.0 with SCIT it costs Rp. 17,024,138.8 while with non SCIT it costs Rp. 104,147,878.0. Meanwhile, to lower combination symptoms and medication score (CSMS) by 1.0, with SCIT it costs IDR 9,550,126.6, while with non SCIT it costs IDR 52,073,938.9. Conclusion. In conclusion, this first Indonesia-based study demonstrates substantial health care cost savings associated with SCIT for children with AR in an uninsured private health care system and provides strong evidence for the clinical benefits and cost-savings benefits of AR treatment in children.

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.

ABSTRACT Background It is important to be able to predict, for each individual patient, the likelihood of later metastatic occurrence, because the prediction can guide treatment plans tailored to a specific patient to prevent metastasis and to help avoid under- or over-treatment. Deep Neural Network (DNN) learning, commonly referred to as deep learning, has become popular due to its success in image detection and prediction, but questions such as whether deep learning outperforms other machine learning methods when using non-image clinical data remain unanswered. Grid search has been introduced to deep learning hyperparameter tunning for the purpose of improving its prediction performance, but the effect of grid search on other machine learning methods are under-studied. In this research, we take the empirical approach to study the performance of deep learning and other machine learning methods when using non-image clinical data to predict the occurrence of breast cancer metastasis (BCM) 5, 10, or 15-years after the initial treatment. We developed DNN models as well as models using 9 other machine learning methods including Naive Bayes (NB), Logistic Regression (LR), Support Vector Machine (SVM), LASSO, Decision Tree (DT), k-Nearest Neighbors (KNN), Random Forrest (RF), AdaBoost (ADB), and XGBoost (XGB). We used grid search to tune hyperparameters for all methods. We then compared the deep learning models to the models trained using the 9 other machine learning methods. Results Based on the mean test AUC results, DNN ranks 6th, 4th, and 3rd when predicting 5-year, 10-year, and 15-year BCM respectively, out of 10 machine learning methods. The top performing methods in predicting 5-year BCM are XGB(1^st), RF(2^nd), and KNN(3^rd). For predicting 10-year BCM the top performers are XGB (1^st), RF(2^nd), and NB(3^rd) . Finally, for 15-year BCM the top performers are SVM (1^st), LR and LASSO (tied for 2^nd), and DNN (3^rd). The ensemble methods RF and XGB outperform other methods when data are less balanced, while SVM, LR, LASSO, and DNN outperform other methods when data are more balanced. Our statistical testing results show that at a significance level of 0.05 DNN overall performs no worse than other machine learning methods when predicting 5-year, 10-year, and 15-year BCM. Conclusions Our results show that deep learning with grid search overall performs at least as well as other machine learning methods when using non-image clinical data. It is interesting to note that some of the other machine learning methods such as XGB, RF, and SVM are very strong competitors of DNN when incorporating grid search. It is also worth noting that the computation time required to do grid search with DNN is way more than that required to do grid search with the other 9 machine learning methods.

Open domain question answering (OpenQA) tasks have been recently attracting more and more attention from the natural language processing (NLP) community. In this work, we present the first free-form multiple-choice OpenQA dataset for solving medical problems, MedQA, collected from the professional medical board exams. It covers three languages: English, simplified Chinese, and traditional Chinese, and contains 12,723, 34,251, and 14,123 questions for the three languages, respectively. We implement both rule-based and popular neural methods by sequentially combining a document retriever and a machine comprehension model. Through experiments, we find that even the current best method can only achieve 36.7%, 42.0%, and 70.1% of test accuracy on the English, traditional Chinese, and simplified Chinese questions, respectively. We expect MedQA to present great challenges to existing OpenQA systems and hope that it can serve as a platform to promote much stronger OpenQA models from the NLP community in the future.

Next Generation Sequencing based cancer risk screening with multigene panels has become the most successful method for programming cancer prevention strategies. ATM germ-line heterozygosity has been described as able to increase tumor susceptibility. In particular, families that carry heterozygous germ-line variants of ATM gene show a 5- to 9-fold risk of developing breast cancer. Recent studies identified ATM as the second most mutated gene after CHEK2 in BRCA-negative patients. Nowadays, more than 170 potential missense variants and several truncating mutations have been identified in ATM gene. Here we present the molecular characterization a new ATM deletion, identified thanks to the CNV algorithm implemented in the NGS analysis pipeline. An automated workflow implementing the SOPHiA Genetics’ Hereditary Cancer Solution (HCS) protocol was used to generate NGS libraries that were sequenced on Illumina MiSeq Platform. NGS data analysis allowed to identify a new inactivating deletion of exons 19-27 of ATM gene. DNA breakpoint was characterized both at DNA and RNA level

Exercise can be hypothesized to play an important role in NAFLD treatment by changing the oral bacterial flora and in the mechanism underlying periodontal disease. We performed salivary component analysis before and after an exercise regimen, and genome analysis of the oral bacterial flora to elucidate the underlying mechanism. Obese middle-aged men with NAFLD and periodontal disease were allocated to 12-week exercise (n=49) or dietary restriction (n=21) groups. We collected saliva to compare the oral microflora; performed predictive analysis of metagenomic functions; and measured the salivary immunoglobulin A, cytokine, bacterial lipopolysaccharide (LPS), and lactoferrin concentrations. The exercise group showed improvements in clinical indices of oral environment. Salivary component analysis revealed significant reductions in LPS, and lactoferrin during the exercise regimen. Diversity analysis of oral bacterial flora revealed higher alpha- and beta-diversity after the exercise regimen. Analysis of the microbial composition revealed that the numbers of Campylobacter (+83.9%), Corynebacterium (+142.3%), Actinomyces (+75.9%), and Lautropia (+172.9%) were significantly higher and that of Prevotella (−28.3%) was significantly lower. The findings suggest that an exercise regimen improves the oral environment of NAFLD patients by increasing the diversity of the oral microflora and reducing the number of periodontal bacteria that produce LPS and its capability.

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.

The purpose of the study was to investigate the bacterial viability of the initial biofilm on the surface of experimental modified dental resin composites. Twenty-five healthy individuals with good oral hygiene were included in this study. In a split-mouth design, they received acrylic splints with five experimental composite resin specimens. Four of them were modified with either a novel polymeric hollow beads delivery system or methacrylated polymerizable Irgasan (Antibacterial B), while one specimen served as unmodified control (ST). The delivery system based on Poly-Pore® was loaded with one of the active agents Tego® Protect 5000 (Antiadhesive A), Dimethicone (Antiadhesive B) or Irgasan (Antibacterial A). All study subjects refrained from toothbrushing during the study period. Specimens were detached from the splints after 8h and given a live/dead staining before fluorescence microscopy. Friedman test and post-hoc Nemenyi test were applied with significance level at p &lt; 0.05. In summary all materials but Antibacterial B showed a significant antibacterial effect compared to ST. In conclusion dental resin composites with Poly-Pore loaded active agents show antibacterial effectiveness in situ.

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.

Succinic semialdehyde dehydrogenase deficiency (SSADH-D) is a genetic disorder that results from the aberrant metabolism of the neurotransmitter γ-amino butyric acid (GABA). The disease is caused by the impaired activity of the mitochondrial enzyme succinic semialdehyde dehydrogenase. SSADH-D manifests as varying degree of mental retardation, autism, ataxia and epileptic seizures, but the clinical picture is highly heterogeneous. So far, there is no approved therapy for this disease. In this review, we briefly summarize the molecular genetics of SSADH-D, the past and ongoing clinical trials and the emerging features of the molecular pathogenesis, including redox imbalance and mitochondrial dysfunction. The main aim of this review is to discuss the potential use of further therapy approaches that have so far not been tested in SSADH-D, such as pharmacological chaperones, read-through drugs and gene therapy. Special attention will also be paid to elucidating the role of patient advocacy organizations in facilitating research and in the communication between the researchers and the patients.

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.

Severe Acute Respiratory Syndrome Coronavirus - 2 (SARS-CoV-2), later renamed Coronavirus Disease 2019 (COVID-19) was first identified in Wuhan, China, in early December 2019. Initially, the China office of the World Health Organization was informed of numerous cases of pneumonia of unidentified etiology in Wuhan, Hubei Province on December 31, 2019. This would subsequently result in a global pandemic with over 76 million confirmed cases of COVID-19 and 6.9 million deaths reported to the WHO. We have analyzed most of the data published since the beginning of the pandemic to compile this comprehensive review of SARS-CoV-2. We look at the core ideas, such as the etiology, epidemiology, pathogenesis, clinical symptoms, diagnostics, histopathologic findings, consequences, therapies, and vaccines. We have also included the long-term effects and myths associated with some therapeutics of COVID-19. This study comprehensively assesses of the SARS-CoV-2 virology, vaccines, medicines, and significant variants identified during the pandemic. Our review article is intended to provide medical practitioners with a better understanding of the fundamental sciences, clinical treatment, and prevention of COVID-19. As of June 2023, this paper contains the most recent data made accessible.

Many clinical trials end uninformatively. Informativeness, in the context of clinical trials, defines whether a study’s results definitively answer its research questions with meaningful next steps. One subset of these trials are those focused on global health set in low-resource settings. Global health clinical trials benefitting people in low-resource settings are funded primarily by a limited number of large foundations, pharmaceutical firms (“industry”), and national governments. While clinical trial protocols are required to go through reviews in regulatory and ethical domains, outside of industry-funded trials, funders rarely require focused scientific design reviews. There are no documented standards and processes, or even best practices, for funders to perform scientific reviews after the funding commitment. Considering the investment in and standardization of ethical and regulatory reviews, and the prevalence of studies ending without clarity or never finishing, it may be that scientific reviews of trial designs with a focus on informativeness offer the best chance for improved outcomes and return on investments in clinical trials. A maturity model is a helpful tool for knowledge transfer to help grow capabilities in a new area, or for those looking to perform a self-assessment in an existing area. Such a model is offered for scientific design reviews of clinical trial protocols: a valuable and often-neglected governance step for funders or sponsors, among others. This maturity model includes 11 process areas and 5 maturity levels. Each of the 55 process area levels is populated with descriptions on a continuum toward an optimal state to improve trial protocols in the area of risk of failure. This tool allows for prescriptive guidance on next investments to improve attributes of post-funding reviews of trials, with a focus on informativeness.

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.

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).

African swine fever (ASF) is one of the most important and devastating viral diseases in wild boar and domestic pigs worldwide. In the absence of vaccines or treatment options, early clinical detection is key and requires sound knowledge of disease characteristics. To provide practitioners and state veterinarians with detailed information, the objective of the present study was to characterize the ASF virus (ASFV) isolate “Belgium 2018/1” in subadult and weaning domestic pigs. To this end, two animal trials were performed. Trial A included eight subadult domestic pigs and trial B five weaner pigs. In general, clinical signs and pathological lesions were in line with previous studies utilizing highly virulent ASF genotype II viruses. However, in trial A, four subadult domestic pigs survived and recovered pointing to an age dependent outcome. The long-term fate of those survivors remains under discussion and would need further investigations.

Some of the European countries affected by COVID-19 have not learned from previous experience in China. Italy did not learn from China and Spain did neither learn from China nor from Italy. Confinement in Spain was postponed due to pressure from economic interests and traveling of infected people, especially from Madrid to the beaches in South-East Spain, was allowed. Strict confinement and border closure came late, when the curve of infected people and the death toll already had the worse trend worldwide. Tests to SARS-CoV-2 RNA detection by PCR, were first unavailable and, later, faulty and/or detecting antibodies and not the virus itself. Instead of mobilizing research laboratories for making tests, and instead of making masks and ventilators, mediatic scientists asked for money for controversial clinical trials and for obtaining a vaccine. In this scenario, common sense indicates that ad hoc measures should be taken at the end of confinement in order to minimize pain. The chain of errors should be avoided in the management of next pandemics by designing Good Practice Rules (GPRs). In addition, post-confinement measures should be implemented as soon as possible to be ready for SARS-CoV-2 return next season. In this sense a longitudinal study in the most affected cities (Madrid, Barcelona, Vitoria and Pamplona) should be performed with the primary objective of detecting carriers with no symptoms, to stratify patients according to symptoms, and to early detection of virus reappearance. Also relevant is to sequence as many viruses as possible to detect possible variants; there are still patients that are PCR positive.

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.

Malignant gliomas are heterogeneous neoplasms. Glioma stem-like cells (GSCs) are undifferentiated and self-renewing cells that develop and maintain these tumors. These cells are the main population that resist current therapies. Genomic and epigenomic analyses has identified various molecular subtypes. Bone morphogenetic protein 4 (BMP4) reduces the number of GSCs through differentiation and induction of apoptosis, thus increasing therapeutic sensitivity. However, the short half-life of BMP4 impedes its clinical application. We have previously reviewed BMP4 signaling in central nervous system development and glioma tumorigenesis and its’ potential as a treatment target in human gliomas. Recent advances in understanding both adult and pediatric malignant gliomas highlight critical roles of BMP4 signaling pathways in the regulation of tumor biology, and indicate its’ potential as a therapeutic molecule. Furthermore, significant progress has been made on synthesizing BMP4 biocompatible delivery materials, which can bind to and markedly extend BMP4 half-life. Here, we review current research associated with BMP4 in brain tumors, especially in pediatric malignant gliomas. We also summarize BMP4 delivery strategies, with a focus on biocompatible BMP4 binding peptide amphiphile nanostructures as promising novel delivery platforms for treatment of these devastating tumors.

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex and debilitating disease with a significant global prevalence of over 65 million individuals. It affects various systems, including the immune, neurological, gastrointestinal, and circulatory systems. Studies have shown abnormalities in immune cell types, increased inflammatory cytokines, and brain abnormalities. Further research is needed to identify consistent biomarkers and develop targeted therapies. A multidisciplinary approach is essential for diagnosing, treating, and managing this complex disease. The current study aims at employing explainable artificial intelligence (XAI) and machine learning (ML) techniques to identify discriminative metabolites for ME/CFS. Material and Methods: The present study used a metabolomics dataset of CFS patients and healthy controls, including 26 healthy controls and 26 ME/CFS patients aged 22-72. The dataset encapsulated 768 metabolites, classified into nine metabolic super-pathways: amino acids, carbohydrates, cofactors, vitamins, energy, lipids, nucleotides, peptides, and xenobiotics. Random forest-based feature selection and Bayesian Approach based-hyperparameter optimization were implemented on the target data. Four different ML algorithms [Gaussian Naive Bayes (GNB), Gradient Boosting Classifier (GBC), Logistic regression (LR) and Random Forest Classifier (RFC)] were used to classify individuals as ME/CFS patients and healthy individuals. XAI approaches were applied to clinically explain the prediction decisions of the optimum model. Performance evaluation was performed using the indices of accuracy, precision, recall, F1 score, Brier score, and AUC. Results: The metabolomics of C-glycosyltryptophan, oleoylcholine, cortisone, and 3-hydroxydecanoate were determined to be crucial for ME/CFS diagnosis. The RFC learning model outperformed GNB, GBC, and LR in ME/CFS prediction using the 1000 iteration bootstrapping method, achieving 98% accuracy, precision, recall, F1 score, 0.01 Brier score, and 99% AUC. Conclusion: RFC model proposed in this study correctly classified and evaluated ME/CFS patients through the selected biomarker candidate metabolites. The methodology combining ML and XAI can provide a clear interpretation of risk estimation for ME/CFS, helping physicians intuitively understand the impact of key metabolomics features in the model.

Deep learning has shown remarkable results in every field, especially in the biomedical field, due to its ability to exploit large-scale datasets. A convolutional neural network (CNN) is a widely used deep learning approach to solve medical imaging problems. Over the past few years, many studies have focused on CNN-based techniques for brain tumor diagnosis. There are, however, still some critical challenges that CNNs face towards clinic application. This study presents a comprehensive review of current literature that involves CNN architectures for brain tumor classification. We compare the key achievements in the performance evaluation metrics of the applied classification algorithms. In addition, this review assesses the clinical effectiveness of the included studies to elaborate on the limitations and directions of this area for future work. No review focusing on the clinical effectiveness of previous works in this field has been published. We believe that this study has the potential to elevate the application of CNN-based deep learning methods in clinical practice and also can be a quick reference for biomedical researchers who are interested in this field.

(1) Background: The aim of this work was to systematically review existing studies on whether hysteroscopy improves the reproductive outcomes of women with infertility even in the absence of intrauterine pathologies when compared to women who did not receive a hysteroscopy. (2) Methods: We established the Participant-Intervention-Comparison-Outcome strategy and used the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement to conduct a systematic review of 11 studies which were retrieved from 3 electronic databases: Ovid-Medline, Ovid-Embase, and the Cochrane Library. Two independent investigators extracted the data from the included studies and used the Cochrane risk-of-bias tool to assess their quality. (3) Results: The primary outcome measures were the clinical pregnancy rates (CPRs) and live birth rates (LBRs) in the in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) cycles. Hysteroscopy in infertile women without intrauterine pathologies showed higher CPRs and LBRs than those in the same population who did not receive hysteroscopy in cases of recurrent implantation failure and IVF (odds ratio: 1.79 and 1.46, 95% confidence interval: 1.46-2.30 and 1.08-1.97 for CPR and LBR, respectively); however, the degree of significance was not as high for LBR. (4) Conclusions: Hysteroscopy before IVF/ICSI in infertile women without intrauterine pathologies may potentially be effective in improving the CPRs and LBRs in patients with RIF. Robust and high-quality randomized trials are warranted to confirm this finding.

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.

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.

Lung cancer, globally recognized as the leading cause of cancer-related mortality, presents a pressing need for innovative treatment strategies. Increasing evidence points towards the potential of monoamine oxidase (MAO) inhibitors in modulating cancer progression, primarily due to their role in regulating cellular metabolism and apoptotic pathways. This extraordinary study delves into the multifaceted therapeutic implications of MAO inhibitors in lung cancer management, elucidating their ability to pave the way for clinical advancement via novel targets and pathways. Capitalizing on recent advances in molecular biology, this research explores the molecular mechanisms underlying the anticancer actions of MAO inhibitors. By examining their impact on cell proliferation, migration, invasion, and apoptosis in lung cancer cell lines, we provide insight into the intricate signaling pathways and biochemical processes modulated by these compounds. The study also investigates the synergistic effects of MAO inhibitors in combination with established chemotherapeutic agents, elucidating their potential to enhance treatment efficacy and reduce cytotoxicity. Furthermore, we delve into the implications of MAO inhibitors on the tumor microenvironment, evaluating their influence on angiogenesis, immune regulation, and the epithelial-mesenchymal transition. This comprehensive analysis enables the identification of novel molecular targets, which hold promise for the development of advanced therapeutics tailored for specific lung cancer subtypes. To substantiate our findings, in this review, we thoroughly analyze the existing literature using state-of-the-art bioinformatics tools." in vivo orthotopic lung cancer models, and clinical patient cohorts. This robust and multidisciplinary approach permits the generation of clinical evidence supporting the integration of MAO inhibitors in lung cancer management. Conclusion: This ground-breaking study establishes the therapeutic potential of monoamine oxidase inhibitors in lung cancer management by unearthing novel pathways and targets for clinical advancement. The outcomes open doors for the development of innovative treatment strategies and inspire continued research efforts to combat the global burden of lung cancer.

The rapid evolution of Next Generation Sequencing in clinical settings and the resulting challenge of variants interpretation in the light of constantly updated information, requires robust data management systems and organized approaches to variant reinterpretation. In this paper, we present iVar: a freely available and highly customizable tool provided with a user-friendly web interface. It represents a platform for the unified management of variants identified by different sequencing technologies. iVar accepts, as input, VCF files and text annotation files and elaborates them, optimizing data organization and avoiding redundancies. Updated annotations can be periodically re-uploaded and associated to variants as historicize attributes. Data can be visualized through variant-centered and sample-centered interfaces. A customizable search functionality can be exploited to periodically check if pathogenicity related data of a variant are changed over time. Patient recontacting ensuing from variant reinterpretation is made easier by iVar through the effective identification of all patients present in the database and carrying a specific variant. We tested iVar by uploading 4171 VCF files and 1463 annotation files, obtaining a database of 4166 samples and 22569 unique variants. iVar has proven to be a useful tool with good performances for collecting and managing data from medium-throughput

Objective: The objective of this study is to determine the epidemic dynamics and clinical features of COVID-19 in southern Hainan Island, China, and provide experience for other tropical areas of the world. Methods: This retrospective study included confirmed cases of COVID-19 in southern Hainan. All enrolled patients were treated in Sanya, and data on epidemiological and clinical features of the disease and infection prevention and control measures adopted by the local government during the epidemic were collected. Results: Of the 74 cases, 71 (95.95%) were imported from Wuhan, Hubei Province (47, 63.51%), other cities in Hubei Province (11, 14.86%), or provinces other than Hubei and Hainan (13, 17.57%). Three (4.06%) patients were infected in southern Hainan, including one autochthonous case in Sanya. Fifty-four cases (72.97%) were detected in Sanya, and 27 cases (27.03%) were diagnosed in other cities. The rate of severe or critical cases was 28.38% (21/74), and mortality was 2.7% (2/74). The serum lactate levels and base excess of severe-critical patients were higher than those of patients with mild-moderate disease. Multivariate logistic regression analysis showed that chronic conditions were risk factors for severe and critical COVID-19. Seventy-four patients were diagnosed with COVID-19 over a 22-day period in Sanya, and the epidemic period in the city was 48 days. The outbreak was controlled rapidly because the local government adopted strict infection prevention and control measures. Conclusions: The clinical characteristics of COVID-19 in Hainan Island were similar to those reported in other regions. In Sanya, the rate of severe and very severe cases was higher than in other regions; however, most cases were imported, and there was only one autochthonous case. The rapid control of the outbreak in Sanya may be related to the tropical climate, adoption of strict infection prevention and control measures, daily reporting of new cases, increased public awareness about the epidemic, and other emergency actions implemented by the local government.

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.

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.

Financial capacity instruments are psychometric tools designed to evaluate individual decisional capacity based on financial decisions. As tests are complex and need special conditions for administration and evaluation, it is difficult to use them in daily geriatric clinics. Our scoping review objective was to evaluate existing financial capacity instruments from the perspective of simplicity and portability. We evaluated one English speaking knowledge database (Medline) using a dedicated MeSH terminology. The review yielded one independent instrument, The Semi-Structured Clinical Interview for Financial Capacity, that can be easy adapted for every-day clinical use. It is simple to understand and perform and do not need trained personnel for administration. It can be finalized in 15 minutes. Initially validated on 261 subjects (with different forms of cognitive impairment), it showed good accuracy and precision mainly in subjects with cognitive impairment. The test is less apt to detect early or fluctuating cognitive impairment. Simplicity, the main advantage of the test, allows gamification fact that increases portability. Familiar images (coins, money) that are used for performing simple tasks does not need complex translation and adaptation. In form of a game, the test is suitable for serial administration, increasing the chance for early capacity reduction detection. Results reflect a physician judgement related to the subjects’ capacity to understand and execute simple financial instructions and not financial proficiency scores. The main limitation of our review is that we investigated only one, English speaking, knowledge database. The scoping strategy generated a financial capacity instrument that can be used in geriatric clinics for early diagnostic of decisional capacity reduction. Further studies are needed to evaluate the reliability and validity of the test in conditions of serial administration and in populations having various financial experience.

In order to harness the potential of mobile technologies to enhance the quality of clinical research, it is critical to first understand how to engage patients and research sites when planning and conducting mobile clinical trials. The Clinical Trials Transformation Initiative has developed the first comprehensive, evidence-based set of recommendations for incorporating patient and site perspectives in mobile clinical trials, which can aid in engaging stakeholders, addressing site challenges, and maximizing value for participants.

We have previously reported that a single test measuring oVEMP n10 to 4000Hz stimuli (either bone-conducted vibration (BCV) or air-conducted sound (ACS)) provides a definitive diagnosis of semicircular canal dehiscence (SCD) in 22 CT-verified patients with a sensitivity of 1.0 and specificity of 1.0. Such a single short screening test has great advantages of speed, minimizing testing time and the exposure of patients to stimulation. However some studies of the 4000Hz test for SCD have reported sensitivity and sensitivity values somewhat less that what we reported.

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.

Background: There is a high bureaucratic and administrative burden associated with health care tasks (test requesting, visits scheduling, supporting documents provision) that has historically largely fallen on health care professionals, which is one among the factors contributing to low job satisfaction and lower productivity. Incorporating new professional roles that help to better respond to the needs of both patients and professionals can increase the quality and efficiency of service provision. Objective: To evaluate the impact of the clinical assistant’s introduction in the Sant Joan de Déu Barcelona Children’s Hospital’s pediatric oncology department, in terms of displacement of activity loads carried out by this new professional role and the consequent time freed up for physicians. Methodology: Observational and retrospective study using administrative data based on the analysis of the type of activity performed by clinical assistants and the measurement of the time freed up in favor of the physicians, based on in situ timekeeping, to approximate the potential skill mix productivity increase. Results: Since its implementation in the pediatric oncology department, clinical assistants have performed 13,553 requests (69.93% of the total), representing a total saving of 266.83 hours or 6.67 workweeks of 40 hours. They performed 74.25% of outpatient surgical requests in the oncology department, 87.5% of day hospital requests and 54.13% of total requests in the outpatient consultations area. Conclusion: The introduction of clinical assistants in the oncology department could be efficient to the extent that it displaces a good part of the bureaucratic and administrative tasks previously performed by health care professionals. This delegation allows them to work more closely to the maximum of their competences and the physicians to have more time for higher added value clinical tasks. In terms of efficiency, this role change enables to optimize the clinical process, reducing the cost by 56% compared to the conventional model.

Thrombosis has threatened human health in past decades. Bacillus nattokinase is a potential thrombolytic drug without side-effect and low cost and has been introduced into the consumer market as a functional food or dietary supplement. This review firstly summarizes the biodiversity sources and fermentation process of nattokinase, and systematically expounds the structure, cata-lytic mechanism and enzymatic properties of nattokinase; In view of the problems of low fermen-tation yield, insufficient activity and stability of nattokinase, this review discusses the heterologous expression of nattokinase in different microbial hosts, and summarizes the protein and genetic en-gineering progress of nattokinase-producing strains; Finally, this review summarizes the clinical application of nattokinase.

Predicting change from multivariate time series has relevant applications ranging from medical to engineering fields. Multisensory stimulation therapy in patients with dementia aims to change the patient’s behavioral state. For example, patients who exhibit a baseline of agitation may be paced to change their behavioral state to relaxed. This study aims to predict changes in behavioral state from the analysis of the physiological and neurovegetative parameters to support the therapist during the stimulation session. In order to extract valuable indicators for predicting changes, both handcrafted and learned features were evaluated and compared. The handcrafted features were defined starting from the CATCH22 feature collection, while the learned ones were extracted using a Temporal Convolutional Network, and the behavioral state was predicted through Bidirectional Long Short-Term Memory Auto-Encoder, operating jointly. From the comparison with the state-of-the-art, the learned features-based approach exhibits superior performance with accuracy rates of up to 99.42% with a time window of 70 seconds and up to 98.44% with a time window of 10 seconds.

Objective: The purpose of this study was to determine if Porphyra tenera extract (PTE) has immune-enhancing effects and is safe in healthy adults. Methods: Subjects (3x10³ ≤ peripheral blood leukocyte levels < 8x10³ cells/μl) who met the inclusion criteria were recruited for this study. Enrolled subjects (n=120) were randomly assigned to either the PTE group (n=60) who were given 2.5 g/day of PTE (as Porphyra tenera extract) in capsule form or the placebo group (n=60) who were given crystal cellulose capsules with the identical appearance, weight, and flavor as the PTE capsules for 8 weeks. Outcomes were assessed by measuring natural killer cell (NK-cell) activity, cytokines, and upper respiratory infection (URI), and safety parameters were assessed at baseline and 8 weeks. Results: Compared to baseline, NK cell activity (%) increased for all effector cell to target cell ratios in the PTE group after 8 weeks, but there were no changes in the placebo group (p<0.1). Subgroup analysis of 101 subjects without an URI revealed that NK-cell activity in the PTE group tended to be increased for all E:T ratios (E:T=12.5:1 p=0.068; E:T=25:1 p=0.036; E:T=50:1 p=0.081) compared to the placebo group. There was a significant difference between these two groups for the E:T=25:1 ratio, which increased from 20.3±12.0% at baseline to 23.2±12.4% after 8 weeks in the PTE group (p=0.036). There was no significant difference in levels of cytokines between these two groups. Conclusions: PTE supplementation appears to enhance immune function by improving NK-cell activity without adverse effects in healthy adults.

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.

Pathological vessel growth harms vision and may finally lead to vision loss. Anti-angiogenic gene therapy with viral vectors for ocular neovascularization has shown great promise in pre-clinical studies. Most of the studies has conducted with different adeno-associate serotype vectors. In addition, Adeno and lentivirus vectors have been used. Therapy has targeted to block vascular endothelial growth factors or other pro-angiogenic factors. Clinical trials of intraocular gene therapy for neovascularization have shown the treatment to be safe without severe adverse events or systemic effects. Nevertheless, clinical studies have not proceeded phase 2 trials further.

Background: Media coverage of Lyme disease (LD) has led to an increase in consultations for presumed LD in Europe. However, LD is confirmed in only 10-20% of patients, with a significant number remaining in a diagnostic dead-end. Objectives: To reach a deeper understanding of how patients themselves contribute to the diagnostic process. To describe the genesis of the LD hypothesis in care pathways. Methods: In 2019, 30 patients from a prospective cohort consulting in the infectious diseases department at University Hospital in Marseille for presumed LD were recruited for semi-structured interviews. The inclusion criteria were : suffering from subjective symptoms for 6 months, no clinical or paraclinical argument suggesting current LD. The patients’ medical trajectories were collected using a biographical approach. Results: The diagnosis of Lyme disease was primarily triggered by identification with personal testimonies found on the internet. Most of patients were leading their own diagnostic investigation. The majority of participants were convinced they had LD despite the lack of medical evidence and the scepticism of their referring GP. Conclusion: GPs should first systematically explore patients’ etiologic representations in order to improve adherence to the diagnosis especially in the management of medically unexplained symptoms. Long COVID-19 syndrome challenge offers an opportunity to promote active patient involvement in diagnosis.

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.

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.

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.

The 2019 COVID-19 pandemic caused by SARS-CoV-2 has resulted in many fatalities worldwide. Despite various types of supportive care, mortality rates for patients with comorbidities remain high. To explore alternative treatment options, interferons (IFNs) have emerged as promising therapeutic drugs for SARS-CoV-2. This review aims to investigate the potential of IFNs as a drug with details on their mechanisms of action, and available data on their use with ongoing clinical trials, results, potential limitations, and challenges. Recently published research articles, which were systematically searched through online databases, have been selected and found that IFNs have colossal potential in treating SARS-CoV-2 infection by modulating the host's immune response and inhibiting viral replication and decreasing the severity of disease and hospitalization (p = 0.03, ±0.05) and (p = 0.04, ±0.05) respectively. However, due to less available data, more controlled and randomized trials are needed to confirm the efficacy and safety of IFN therapy. The optimal dosing and duration of IFN therapy also remain to be determined. Although further research is needed the wait for ongoing clinical trial results under investigation is also important for a better understanding of IFN therapy.

Background and Objectives: Clinical trials are a critical step in the development of new medicines and medical devices, testing the efficacy and safety of new treatment regimens. However, if the results of clinical trials are not made public, the evidence base on interventions is incomplete and possibly distorted, which lead to suboptimal treatment choices and negatively affect public health. This study analyses and contrasts the laws and regulations governing clinical trial registration and reporting in China and the United States. Methods: We used desk research to compile, assess and compare current laws, regulations, compliance patterns, and enforcement mechanisms and actions in China and the United States (U.S.). Policy documents were downloaded from Chinese and U.S. government websites. A spreadsheet analysis was utilized for direct comparison. Results: Both China and the U.S. have laws and regulations governing clinical trial registration and reporting. Chinese legislation covers a broader range of trials. In the U.S. trial results must be disclosed to both the national regulator and the public, while Chinese law mandates disclosure to the regulator alone. Cross-country comparisons of regulatory compliance by trial sponsors are impossible due to the opacity of the Chinese data platform. Neither country effectively ensures that all clinical trial results are made public as required by the Declaration of Helsinki and recommended by the WHO. Interpretation: While neither country is perfect, both may be able to learn from each other. There is a major gap in the literature regarding the extent of non-publication of clinical trial results by sponsors operating in China.

Background: In 2014 the World Health Organization (WHO) warned of an emerging world-wide crisis of antibiotic resistant microorganisms. In response, government and professional organizations recommended that health care systems adopt antimicrobial stewardship programs (ASPs). In the United States, the Centers for Medicare Services (CMS) mandated antimicrobial stewardship in the hospital inpatient setting. Effective January 1, 2020, the Joint Commission required ambulatory centers that prescribe antibiotics, such as wound centers, to institute an ASP. Chronic wounds often remain open for months, during which time patients may receive multiple courses of antibiotics and numerous antimicrobial topical treatments. The wound clinician plays an integral role in reducing antimicrobial resistance in the outpatient setting: antibiotics prescribed for skin and soft tissue infections are among the most common in an outpatient setting. One of the most challenging aspects of antimicrobial stewardship in treating chronic wounds is the inaccuracy of bacterial and infection diagnosis. Methods: Joint Commission lists five elements of performance (EP): (1) Identifying an antimicrobial stewardship leader, (2) establishing an annual antimicrobial stewardship goal, (3) implementing evidence-based practice guidelines related to the antimicrobial stewardship goal, (4) providing clinical staff with educational resources related to the antimicrobial stewardship goal, and (5) collecting, analyzing, and reporting data related to the antimicrobial stewardship goal. This article focuses on choosing and implementing an evidence-based ASP goal for 2020. Discussion: Clinical trials have demonstrated the ability of fluorescence imaging (MLiX) to detect clinically significant levels of bacteria in chronic wounds. Combined with clinical examination of signs and symptoms of infection, the MLiX procedure improves the clinician’s ability to diagnose infection and can guide antimicrobial use. In order to satisfy the elements of performance, the MLiX procedure was incorporated into the annual ASP goal for several wound care centers. Clinicians were educated on the fluorescence imaging device and guidelines were instituted. Collection of antimicrobial utilization data is underway.

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

Predicting Length of Stay (LoS) and understanding its underlying factors is essential to minimize the risk of hospital-acquired conditions, improve financial, operational, and clinical outcomes, and to better manage future pandemics. The purpose of this study is to forecast patients’ LoS using a deep learning model and analyze cohorts of risk factors minimizing or maximizing LoS. We employed various pre-processing techniques, SMOTE-N to balance data, and Tab-Transformer model to forecast LoS. Finally, Apriori algorithm was applied to analyze cohorts of risk factors influencing LoS at hospital. The Tab-Transformer outperformed the base Machine Learning models with an F1-score (.92), precision (.83), recall (.93), and accuracy (.73) for discharge dataset, and F1-score (.84), precision (.75), recall (.98), and accuracy (.77) for deceased dataset. The association mining algorithm was able to identify significant risk factors/indicators belonging to lab, X-Ray, and clinical data such as elevated LDH, and D-Dimer, lymphocytes count, and comorbidities such as hypertension and diabetes responsible for extending patients LoS. It also reveals what treatments has reduced the symptoms of COVID-19 patients leading to reduction in LoS particularly when no vaccines or medication such as Paxlovid were available.

Comparing to males, females require much more morphine to produce comparable levels of analgesia, suggesting a difference in the endogenous hyperalgesia and analgesia modulation between sexes. Aside from hormones, emerging evidence suggests sex-differential intrinsic neural regulation of pain generation and maintenance. According to the International Association for the Study of Pain (IASP) and American College of Gastroenterology (ACG), up to 25 % of the population having visceral pain at any one time, and in the United States 10-15 percent of adults suffering from irritable bowel syndrome (IBS). Here we analyzed literatures on clinical reports of sex differences in visceral pain focusing on IBS, other form of bowel dysfunction and comorbidities, and summarized animal models that provided means to investigate the underlying molecular mechanisms in sexual dimorphism of visceral pain. Neurons and nonneuronal cells (glia and immune cells) in the peripheral and central nervous systems all contribute to sex-dependent nociception and nociplasticity in the painful signal processing. Emotion is another factor in pain perception and appears to have sexual dimorphism.

Panoramic and periapical radiograph tools help dentists diagnose the most common dental diseases. Generally, dentists identify dental caries manually by inspecting X-ray images. However, due to their heavy workload, or poor image quality, dentists may sometimes overlook some unnoticeable dental caries, which may ultimately hinder the patient treatment. The purpose of this study was to develop an algorithm that classifies the teeth X-Ray images into three categories of “Normal”, “Caries”, and “Filled”. Our study used a dataset of 116 patients and 3712 single teeth images for training, validation and testing. Images were pre-processed using a sharpening filter and an intensity color map. We used a pre-trained transfer learning model, the NASNetMobile, which served as the feature extractor and the Convolutional Neural Network (CNN) model served as the classifier. The training dataset had a “Recall” of 0.92, 0.90 and 0.91 for “Normal”, “Caries” and “Filled” respectively and the test dataset had a “Recall” of 0.86, 0.81 and 0.85 for “Normal”, “Caries” and “Filled” respectively. The classification of the teeth X-Rays was successful and can be valuable for dentist as the artificial intelligence algorithm can serve as a decision support tool to aid dentists when they need to diagnose dental treatment.

Scrub typhus (ST) is one of the most neglected tropical diseases, a leading cause of acute undifferentiated febrile illness in areas of the ‘tsutsugamushi triangle’, diagnosed frequently in South Asian countries. The bacteria Orientia tsutsugamushi is the causative agent of the disease, which enters to human body through the bite of trombiculid mite (Chigger) of the genus Leptotrombidium deliense.The diagnosis of the disease becomes challenging as its early symptoms mimic other febrile illnesses like dengue, influenza, and corona viruses. Lack of rapid, reliable, and cost-effective diagnostic methods further complicates the identification process. Northeast India, a mountainous region with a predominantly rural tribal population, has witnessed a resurgence of scrub typhus cases in recent years. Various ecological factors, including rodent population, habitat characteristics, and climatic conditions, influence its prevalence. Entomological investigations have confirmed the abundance of vector mites, highlighting the importance of understanding their distribution and the probability of transmission of scrub typhus in the region. Proper diagnosis, awareness campaigns, and behavioral interventions are essential for controlling scrub typhus outbreaks and reducing its impact on public health in Northeast India. Further research and community-based studies are necessary to accurately assess the disease burden and implement effective prevention strategies.

The use of inertial measurement units (IMUs) to compute gait outputs such as the 3D lower limb kinematics is of huge potential, but no consensus on the procedures and algorithms exists. This study aimed at evaluating the validity of a 7-IMUs system against the optoelectronic system. Ten asymptomatic subjects were included. They wore IMUs on their feet, shanks, thighs and pelvis. The IMUs were embedded in clusters with reflective markers. Reference kinematics was computed from anatomical markers. Gait kinematics was obtained from accelerometer and gyroscope data after sensor orientation estimation and sensor-to-segment (S2S) calibration steps. The S2S calibration steps were also applied to the cluster data. IMU-based and cluster-based kinematics were compared to the reference through root mean square errors (RMSEs), centered RMSEs (after mean removal), correlation coefficients (CCs) and differences of amplitude. The mean RMSE and centered RMSE were respectively 7.5° and 4.0° for IMU-kinematics, and 7.9° and 3.8° for cluster-kinematics. Very good CCs were found in the sagittal plane for both IMUs and cluster-based kinematics at the hip, knee and ankle levels (CCs&gt;0.85). The overall mean amplitude difference was about 7°. These results reflected good accordance of our system with the reference, especially in the sagittal plane, but the presence of offsets requires caution for clinical use.

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.

In a wide range of lymphoid neoplasms, the process of malignant transformation is associated to somatic mutations in B cells that affect the epigenetic machinery. Consequential alterations in histone modifications contribute to disease-specific changes in the transcriptional program. Affected genes commonly play important roles in cell cycle regulation, apoptosis-inducing signal transduction and DNA damage response, thus facilitating the emergence of malignant traits that impair immune surveillance and favor the emergence of different B-cell lymphoma subtypes. In the last two decades, the field has made a major effort to develop therapies that target these epigenetic alterations. In this review, we discuss which epigenetic alterations occur in non-Hodgkin B-cell lymphoma. Furthermore, we aim to present in close to comprehensive manner the current state-of-the-art in the preclinical and clinical development of epigenetic drugs. We focus on therapeutic strategies interfering with histone methylation and acetylation as these are most advanced in being deployed from the bench-to-bedside and have greatest potential to improve the prognosis of lymphoma patients.

Cyclic vomiting syndrome (CVS) is a frequently disabling condition defined by severe, discrete, stereotypical episodes of nausea and vomiting. In our previous report [1], a candidate gene list was evaluated in a group of 80 unrelated participants with CVS with extensive genetic sequencing (whole exome/genome). Twenty-two good candidate genes for CVS association were identified, from which a cellular model of aberrant cation transport and energy metabolism was proposed. Herein, we present additional clinical information on those 80 participants, including eight case reports to highlight general principles and clinical practices. Our participants demonstrate substantial phenotypic and genotypic heterogeneity in CVS, including a propensity for specific co-morbidities in the participants and relatives, evolution towards episodes in which vomiting is less apparent, labeling with “non-organic” diagnoses, multiple genes, polygenic inheritance, and association with variants not designated as Pathogenic. Our case reports illustrate how genetic information can guide clinical management and argue to the high clinical utility of appropriate genetic testing and analysis in CVS. Expression profiling of our 22 candidate genes suggests an anatomical model in a unit defined by vagal afferents and adjacent cells. Our models are consistent with multiple current hypotheses of CVS and the efficacy of commonly-recommended treatments.

The study comprehensively evaluated the prognostic roles of PLR, NLR, MLR, BLR, and ELR in patients with acute exacerbation chronic obstructive pulmonary disease (AECOPD). 619 patients with AECOPD and 300 healthy volunteers were retrospectively included into the study. The clinical characteristics containing laboratory findings of the AECOPD patients and the blood cell counts (CBCs) of the healthy volunteers were collected. Compared with the healthy volunteers, PLR, NLR, and MLR were elevated in COPD patients in stable condition, and were further ele-vated during exacerbation. ELR showed the opposite trend. PLR, NLR, and MLR were all posi-tively correlated with hospital LOS as well as CRP. In contrast, ELR was negatively correlated with hospital LOS as well as CRP. Elevated PLR, NLR, and MLR were all associated with more serious airflow limitation in AECOPD. Elevated PLR, NLR, and MLR were all associated with increased in-hospital mortality while Elevated ELR was associated with decreased in-hospital mortality in AECOPD. A nomogram was construct to predict in-hospital mortality in AECOPD. The nomo-gram had a C-index of 0.850 (95% CI: 0.799 – 0.901) with good predictive value and clinical ap-plicability. In summary, PLR, NLR, MLR, and ELR served as predictors for clinical outcomes in patients with AECOPD.

The awareness of the existence in plants of bioactive compounds namely phytochemicals (PHYs), having health properties is progressively expanding. Therefore, their massive introduction in the normal diet, in food supplements, and their use as natural therapeutics to treat several diseases are increasingly emphasized by several sectors. Particularly, most PHYs possessing antifungal, antiviral, anti-inflammatory, antibacterial, antiulcer, anti-cholesterol, hypoglycemic, immunomodulatory, and antioxidant properties have been isolated from plants. Additionally, their secondary modification with new functionalities, to further improve their intrinsic beneficial effects, is extensively investigated. Unfortunately, although the idea of exploiting PHYs as therapeutics is amazing, its realization is far from simple, and the possibility of exploiting them as effective orally administrable drugs is almost utopic. Most PHYs are insoluble in water and, when introduced orally, they scarcely reach the site of action in therapeutic concentrations. Degradation by enzymatic and microbial digestion, occurring in the mouth, stomach, and intestine, as well as fast metabolism and rapid excretion via the kidney, biliary, or lung, strongly limit their in vivo activity. To overcome these drawbacks, several nanotechnological approaches have been used and many PHYs-loaded delivery systems with dimensions of nanometers have been developed. This paper, also by reporting various recent case studies, reviews the foremost nano-suspension and nano-emulsion-based techniques developed for formulating the most relevant PHYs in more bioavailable nanoparticles (NPs), suitable or promising for clinical application. Also, the acute and chronic toxic effects due to the exposure to NPs reported so far, the possible nanotoxicity which could derive by their massive employment, as well as the ongoing actions to improve the knowledge in the field were discussed. The state of the art concerning the actual clinical application of both PHYs and the nanotechnologically engineered PHYs was also reviewed.

A multicenter, prospective cohort study conducted in 5 physiotherapy clinics in the UAE from January 2021 to March 2023 to assess coronal lumbar spine radiographic parameters as a predictor of conservative therapy outcomes in patients suffering from low back and leg pain due to lumbar disc herniation (HNP). Ninety patients (mean age 44 yrs., 54% male) with lumbar HNP underwent conservative therapy. All participants received lumbar spine MRI and radiography to assess spine alignment. Interventions included specific exercises, diathermy, traction, education, a home-based exercise pro-gram, and medications. Detailed demographic data was collected. Follow-up was 6-months after discharge. A successful outcome was based on a minimum of the following four outcomes: (1) reduction of pain by 17.5 points (0–100 NRS); (2) fatigue reduction by 7.5 points; (3) distress reduction by 5 points; and (4) interference reduction by 9.5 points. At 6-month follow-up it was found that patient age, education, and radio-graphic determined lumbosacral angle measures significantly affected the odds of a successful outcome. Increasing age 1-year significantly decreased the odds of success of improving pain, fatigue (OR = 0.85, p = 0.016) and interference scores (OR = 0.89, p = 0.042) by 15%, 15%, and 11% respectively. Lower education significantly increased the odds of success for improving pain, fatigue, and interference by 26.18, 26.18, and 7.5 (p = 0.006, = 0.006, and = 0.029 respectively). Increasing (worsening) the radiographic lumbosacral angle by each 1° significantly reduced the odds of success for improving pain, fatigue, distress, and interference by 3.52, 3.52, 27.99, and 2.55, respectively (p < 0.001, < 0.001, = 0.003, = 0.001). Our findings indicate that younger age, less education, and better coronal radiological lumbar spine alignment all had a substantial impact on the likelihood of success of 6-month outcomes in patients suffering from chronic lower back pain and radiculopathy due to HNP.

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.

Objectives: Human herpes viruses can cause life-threatening diseases in immunocompromised children, especially leukemic patients. Therefore, the aim of this study is to detect the human herpes viruses (HHV1-7) and to investigate its clinical significance in Middle Eastern Pediatric Leukemia Patients by using 2 Independent PCR assays. Methods: Detection of human herpes virus DNA has been done in blood samples of 200 pediatric leukemia patients in addition to 90 blood donors as a control group using multiplex PCR assays. When a ‘‘positive’’ result was observed, real-time PCR was performed to measure the viral load. Results: The most frequent herpes virus infection in Middle Eastern Pediatric Leukemia cases was CMV, followed by EBV, then HHV6, VZV, HHV7, HSV1, and HSV2, where they were 92/200 (46%), 76/200 (38%), 72/200 (36%), 48/200 (24%), 12/200 (6%), 8/200 (4%), and 2/200 (1%) respectively. Also, there was a statistically significance difference between leukemic patients and their controls regarding CMV, EBV, HHV6, and VZV (P <0.05). Correlation between percentage of co-infection, and clinical parameters for the 7 herpes viruses has been studied, and there is an increase in absolute neutrophilic count (ANC), total leukocyte count (TLC) and duration of fever and neutropenia in age group 6-11 years for HHV6/CMV, then in age group 12-18 years especially for EBV/CMV and CMV/HHV6. Also, our results show that multiplex PCR assay is close to single PCR assay in relation to specificity and sensitivity which in turn prove its validity for early diagnosis of herpes viral infection. Conclusions: Adopting multiplex PCR technique is helpful in screening of virus infections. It will save time, effort, cost effective and will assist in rapid diagnosis. However, the clinical relevance of the virus infection needs to be evaluated by quantitative real-time PCR which in turn will help patient's management by using appropriate antiviral treatment.

Lung cancer is the leading cause of global cancer-related mortality resulting in ~1.8 million deaths annually. Systemic, molecular targeted, and immune therapies have provided significant improvements of survival outcomes for patients. However, drug resistance usually arises and there is an urgent need for novel therapy screening and personalized medicine. 3D patient-derived organoid (PDO) models have emerged as a more effective and efficient alternative for ex vivo drug screening than 2D cell culture and patient-derived xenograft (PDX) models. In this review, we performed an extensive search of lung cancer PDO-based ex vivo drug screening studies. Lung cancer PDOs were successfully established from fresh or biobanked sections/biopsy of lung tumors, PDXs, and pleural affusion. PDOs were subject to ex vivo drug screening with chemotherapy, targeted therapy and immune therapy agents. PDOs mainly recapitulated the genomic alterations, transcriptomic landscape and drug sensitivity of primary tumors. Although sample sizes of the previous studies were limited and some technical challenges remained, PDOs showed promise to screen novel therapy drugs. With the technical advance of high throughput, tumor-on-chip, combined microenvironment, and air-liquid interface (ALI), the drug screening using PDOs would serve better for precision care of lung cancer patients.

Gene therapy has seen major progress in recent years. Viral vectors have made a significant contribution through efficient engineering for improved delivery and safety. A large variety of indications such as cancer, cardiovascular, metabolic, hematological, neurological, muscular, ophthalmological, infectious diseases, and immunodeficiency have been targeted. Viral vectors based on adenoviruses, adeno-associated viruses, herpes simplex viruses, retroviruses including lentiviruses, alphaviruses, flaviviruses, measles viruses, rhabdoviruses, Newcastle disease virus, poxviruses, picornaviruses, reoviruses, and polyomaviruses have been used. Proof-of-concept has been demonstrated for different indications in animal models. Therapeutic efficacy has also been achieved in clinical trials. Several viral vector-based drugs have been approved for the treatment of cancer, and hematological, metabolic, and neurological diseases. Moreover, viral vector-based vaccines have been approved against COVID-19 and Ebola virus disease.

Background: Aluminum phosphide (AlP), also known as “rice tablet,” is widely used as an effective pesticide. However, AlP poisoning is a common cause of mortality in many countries, such as Iran. Unfortunately, there is no specific antidote for AlP toxicity to date. AlP releases phosphine gas when it is exposed to moisture and acid. Phosphine is a robust mitochondrial toxin that could significantly inhibit cellular energy metabolism. AlP poisoning is an emergency condition that needs instant and effective intervention. Dihydroxyacetone (DHA) is a simple saccharide used for several pharmacological as well as cosmetic purposes. Previously, we found that DHA could significantly prevent mitochondrial impairment induced by toxic agents such as cyanide and phosphine in various in vitro and in vivo experimental models.Methods: Hospitalized patients (n = 111) were evaluated for eligibility criteria. Among these patients, n = 35 cases were excluded due to incomplete data (n = 11) and suspicion of poisoning rather than AlP (n = 24). Meanwhile, n = 76 cases with confirmed AlP poisoning were included in the study. AlP-poisoned patients who did not receive DHA (n =18) were used as the control group.Patients (n = 58) received at least one dose of DHA (500 ml of 5% DHA solution w/v, i.v.) in addition to routine treatment of AlP poisoning. Arterial blood gas (ABG), blood pH, bicarbonate levels, and other vital signs and biochemical measurements were monitored. Moreover, the mortality rate and time of hospitalization were evaluated in both DHA-treated (n = 58) and AlP-poisoned patients without DHA administration (n = 18). Several biomarkers were assessed before (upon hospitalization) and after DHA treatment. The routine tests for AlP-poisoned patients in this study were the measurement of electrolytes (K+ and Na+), WBC, RBC, hemoglobin, INR, carbonate (HCO3), blood pH, PaCO2, and PaO2 and SGPT, SGOT, BUN, Cr. Results: Upon patients' admission, significant decreases in blood pH (acidosis), blood PaO₂, and HCO₃ levels were the hallmarks of AlP poisoning. It was found that DHA significantly alleviated biomarkers of AlP poisoning and tremendously enhanced patients’ survival rate compared to patients treated based on hospital routine AlP poisoning protocols (no DHA). No significant adverse effects were evident in DHA-treated patients in the current study.Interpretation: These data suggest that parenteral DHA is a novel and effective antidote against AlP poisoning.Trial registration: IR.SUMS.REC.1394.102

Surgical neurolysis is a procedure designed to liberate an injured nerve from scar tissue or adjacent structure, thereby facilitating nerve regeneration in cases of brachial plexus neuropathy (BPN). This study presents a case series of patients diagnosed with BPN who underwent surgical neurolysis. The primary focus was on the clinical assessment of recovery using the British Medical Research Council motor grading scale (BMRC). Additionally, a comprehensive literature review was conducted to analyze motor recovery outcomes related to surgical neurolysis for BPN. 18 patients with BPN who underwent surgical neurolysis where included. The results experienced a notable increase of 58% in muscle strength as assessed by the BMRC. The average preoperative state of 2.17±1.15 improved significantly to a postoperative condition of 3.44±1.34 (p = 0.003, d= 0.913) The systematic review identified 2298 articles which were selected for qualitative analysis, demonstrated that surgical neurolysis was associated with favorable motor recovery outcomes in 75.82% of the patients. Both the case series and the literature review reveal significant motor recovery following surgical neurolysis. It is crucial to conduct well-designed, adequately powered, randomized, and blinded clinical trials. Such studies will provide robust evidence to support or refute the utility of this approach in motor recovery.

Background: The ageing process starts in the center of the face, in the periocular region and around the mouth, with a combination of volume loss and tissue descent, wrinkles deepen, and loss of skin structure and quality. Recently, several studies proved the efficacy of therapies based on the autologous adipose tissue grafting that leverages the properties of stromal vascular fraction (SVF) and adipose derived mesenchymal stem cells (ADSCs) to accelerate the regenerative processes of the skin. This study aimed to verify the ability of the guided Superficial Enhanced Fluid Fat Injection (SEFFI) in the facial area to correct volume loss and skin aging and proved the very low rate of complications of this standardized procedure . Methods: we retrospectively collected data from 2,365 procedures performed in Italian centers between 2019 and 2021. Guided SEFFI was performed alone or combined with cosmetic treatments, including the use of hyaluronic acid filler, suspension threads, synthetic calcium hydroxylapatite, botulin toxin, and microneedling. Results: SEFFI was used alone in more than 60% of the patients, and in all face areas. In about one tenth of patients SEFFI was combined with botulin toxin treatment or hyaluronic acid filling. Other procedures were used more rarely. Ecchymosis in the donor or injection sites was the most frequent event, and yet observed in only 14.2% and 38.6% of patients, respectively. Conclusions: The SEFFI technique is standardized and minimally invasive, leading to very few complications. It can be a promising antiaging medical treatment that combines effectiveness, safety, and simplicity.

Cardiovascular diseases remain the leading cause of mortality worldwide. Although new therapies are actively being developed and used for cardiovascular pathologies, these attempts have not significantly decreased mortality rates. Regenerative medicine has made enormous progress and set promising approaches over the past half-century. However, since autologous (donor-derived) vascular grafts are lacking, an alternative prosthesis must be constructed for cardiovascular disease patients. In vascular tissue manufacturing and regenerative medicine, scientists seek to improve this significant clinical challenge using bio-fabrication techniques combining additive manufacturing, biomaterials science, and advanced cellular biology. In the last few decades, many improvements and changes in various approaches have helped develop bioengineered concepts that reflect native blood vessels’ structure and function. However, numerous challenges must be overcome to clinically translate the next generation of tissue-engineered vascular transplants. This review provides update on the cell sources, scaffold essential for cardiovascular tissue engineering, and tissue engineering approaches as prospective options for curative therapy for blood vessel disease.

Background: Infections of Coronavirus Disease-2019 (COVID-19) can cause long-term effects known as long COVID. This pilot study aimed to evaluate the feasibility of a clinical study as well as the efficacy and safety of traditional East Asian herbal medicines in alleviating fatigue and cognitive dysfunction “brain fog” in patients with long COVID. Methods: This prospective pilot study investigated the use of three types of herbal medicines, Bojungikki-tang (BIT), Kyungok-go (KOG), and Cheonwangbosim-dan (CBD), for a 12-week period as potential treatments for fatigue and cognitive dysfunction in patients with long COVID. Forty-five patients with long COVID were recruited, and one of three drugs was given based on the patient’s symptoms and pattern identification. The effect of herbal medications on fatigue and cognitive function outcomes was assessed over a 36-week period, with patient adherence closely monitored. Results: After 12 weeks of herbal drug administration, fatigue symptoms improved significantly across all groups, with treatment success rates of 80%, 53.33%, and 46.67% in the BIT, KOG, and CBD groups, respectively. However, “brain fog” symptoms showed less improvement, with treatment success rates of 40%, 46.67%, and 13.33% in the BIT, KOG, and CBD groups, respectively. All adverse events reported were mild and unrelated to the medication. The study design was found to be feasible with high medication adherence. Conclusions: This study demonstrated the feasibility of conducting a clinical trial with three herbal medicines to treat long COVID symptoms like fatigue and “brain fog.”

This study was aimed to examine the recent trends of antibiotic resistance (AR) prevalence in Staphylococcus aureus isolated from milk of animals with clinical mastitis in areas of the Abruzzo and Molise regions in central Italy. Fifty-four S. aureus isolates could be obtained from routine testing for clinical mastitis agents carried out in the author institution in years 2021 and 2022. These were analyzed for phenotypic resistance to eight antibiotics recommended for testing by European norms and belonging to the antibiotic classes used for mastitis treatment in milk producing animals. Moreover, the presence of 14 transferable genetic determinants encoding resistance to the same antibiotics was analyzed by qPCR tests developed in this study. Phenotypic resistance to non-β-lactams was infrequent, with only one 2022 isolate resistant to clindamycin. However, low level resistance to the β-lactam cefoxitin was observed in 59.2% isolates in both years making these isolates classifiable as methicillin resistant. The AR genotypes detected were blaZ gene (50% 2021 isolates and 44.4% 2022 isolates), ermC/T- aphA3-blaZ (one 2021 isolate), ant6-ermC/T-aphA3-blaZ (one 2021 isolate), ermB-blaZ (one 2022 isolate) and mecA-mph (one 2022 isolate). An interview to the veterinarians who conferred the samples, regarding antimicrobials prescribed for mastitis treatment and criteria of usage, indicated a possible causal relation with the AR test results. The low prevalence of AR genotypes, not increasing in time, most probably reflecting the reported management of antibiotic therapies in farms. However, the frequently observed cefoxitin resistance needs to be explained genotypically, further monitored and limited by modifying antibiotic usage practices. The identification of a mecA positive isolate in 2022 suggests to investigate further if this genotype is emerging locally.

Cisplatin (CDDP), carboplatin (CP), and oxaliplatin (OXP) are three platinating agents clinically approved worldwide for use against a variety of cancers. They are canonically known as DNA damage inducers; however, that is only one of their mechanisms of cytotoxicity. CDDP mediates its effects through DNA damage-induced transcription inhibition and apoptotic signalling. In addition, CDDP targets the endoplasmic reticulum (ER) to induce ER-stress, the mitochondria via mitochondrial DNA damage leading to ROS production, and the plasma membrane and cytoskeletal components. CP acts in a similar fashion to CDDP by inducing DNA damage, mitochondrial damage, and ER stress. Additionally, CP is also able to upregulate micro-RNA activity, enhancing intrinsic apoptosis. OXP, on the other hand, at first induces damage to all the same targets as CDDP and CP, yet it is also capable of inducing immunogenic cell death via ER stress and can decrease ribosome biogenesis through its nucleolar effects. In this comprehensive review, we provide detailed mechanisms of action for the three platinating agents, going beyond their nuclear effects to include their cytoplasmic impact within cancer cells. In addition, we cover their current clinical use and limitations, including side effects and mechanisms of resistance.

Biological drugs are inaccessible to more than 80% of the world population due mainly to their high costs; this is a significant concern of the World Health Organization. Biosimilars are supposed to reduce the cost burden, but their approval process is complex, including expensive and irrelevant studies. While the Stringent Regulatory Authorities (SRAs) have adopted the guidance of the FDA or EMA, such adoptions are neither necessary nor practical for the rest of the world (ROW). We present a science-driven, rational approach to formulate regulatory guidelines that will enable faster biosimilars' entry into the ROW without compromising their safety and efficacy. The key recommendations include removing animal and safety efficacy testing, making analytical assessment more robust, and cGMP compliance assured through third-party audits. The ROW countries are also recommended to initiate a rapporteur system available in the EU, to overcome the biases and assure state-of-the-science evaluation as the common understanding of the critical quality attributes evolves. It is anticipated that stronger regional agencies like those in the MENA region, with the leadership of the Kingdom of Saudi Arabia, will help propel the idea faster across the globe.

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.

The primary focus of this review is to explore the application and significance of coping strategies within the domains of clinical psychology and neuropsychology. These strategies consist of a variety of techniques, behaviors, and cognitive interventions, and their critical role in reinforcing resilience and facilitating adaptive responses to stressors has been highlighted. At the core of this exploration, the intricate neuropsychological relationship between brain stress pathways and the application of coping mechanisms has been analyzed. The neural aspects of stress, and how they can be influenced by adaptive strategies, are detailed, illustrating the profound impact these coping mechanisms have at a neurobiological level. Delving into the neuropsychological underpinnings, this review will shed light on how stress response pathways in the brain interact with, and can be modulated by, various coping strategies. These mechanisms are particularly salient when addressing the multifaceted challenges faced by individuals with neuropsychological or mental health issues. While these strategies span a broad spectrum, from introspection and cognitive reframing to behavioral activation and social support seeking, their integration and application remain diverse within clinical contexts. This review endeavors to elucidate the theoretical underpinnings of these strategies, their empirical support, and their practical implications within therapeutic interventions. Furthermore, the intricate interplay between individualized coping techniques and structured therapeutic methodologies will be examined, emphasizing the potential for a holistic treatment paradigm, thereby enhancing therapeutic outcomes and fostering individual resilience.

Background: Transient Hypogammaglobulinemia of Infancy (THI) is a primary immunodeficiency caused by a temporary decline of serum levels of immunoglobulin G (IgG) greater than 2 standard deviations below the mean age-specific reference values in an infant between 5 and 24 months of age. Preterm infants are particularly susceptible to THI, as, in the third trimester of pregnancy, IgG is transferred across the placenta from mother to infant.Objective: To systematically review the diagnostic criteria of Transient Hypogammaglobulinemia of infants.Design & Methods: Systematic Review. Manual searching of 3 electronic databases (PubMed, Medline, & Google Scholar) from September 2021 – April 2022. Abstracts were screened to assess fit to the inclusion criteria. Data was extracted from the selected studies by using an adapted extraction tool from Cochrane.org. Studies were then assessed for bias by using an assessment tool also adapted from Cochrane.org.Results: Of the 215 articles identified, 16 were eligible for examining the diagnostic criteria of THI. These studies were also assessed for bias in 6 domains. 5 studies (31%) had a low risk of bias, while 4 studies (25%) had a high risk of bias, & 7 studies (44%) were unclear for bias.Conclusion: We can conclude that THI is only definitively diagnosed after the abnormal IgG levels have normalized, hence THI is mostly a benign condition, but must be monitored for subsequent recurrent infections. The diagnostic criterion also includes vaccine & isohaemagglutinin responses to differentiate against other immunological disorders in infants.