REVIEW Download: 100| View: 329| Comments: 0 | doi:10.20944/preprints201904.0037.v1
Subject: Medicine & Pharmacology, Cardiology Keywords: second-hand smoke; cardiovascular disease; third-hand smoke; passive vaping; electronic cigarettes; heated tobacco; water pipe; myocardial infarction; stroke; diabetes
Online: 3 April 2019 (10:07:13 CEST)
In deaths and diseases attributed to tobacco smoke cardiovascular events exceed cancer and respiratory diseases. Second hand smoke (SHS) promotes the development of arteriosclerosis and can also trigger acute changes of endothelial function and of blood coagulability. Indoor smoking bans reduced coronary syndrome and myocardial infarction 10-20% within one year and were followed by sustainable decreases of stroke and diabetes. With a smoke-free hospitality industry people recognized tobacco smoke as an air pollutant, smoking in public was denormalized and social acceptance of smoking in front of children and pregnant women decreased also in homes and in cars. Combined effects with ambient air pollution are proven for active smoking and suspected for SHS. Contamination with third hand smoke (THS, “cold smoke”) persists for months in homes and cars, creating secondary pollutants that in some cases are more toxic (e.g., tobacco-specific nitrosamines). Remnants found in air, dust, and on surfaces (carpets, wallpapers, upholstery, soft toys) were associated with their metabolites in saliva and urine of children and with elevated levels of nicotine on hands and cotinine in urine of nonsmokers residing in homes previously occupied by smokers. In animal experiments effects of THS were found on thrombogenesis, insulin resistance through oxidative stress, on the developing immune system, lipid metabolism and alterations in liver, lung, skin and behavior. Much less is known about health effects for bystanders from the aerosols exhaled during “vaping” of e-cigarettes, but nicotine and other toxins from e-cigarettes are certainly a hazard, which should be prevented by the use of dermal and oral nicotine products, which are safer for nicotine replacement and without risk for bystanders.
Tue, 2 April 2019
REVIEW Download: 44| View: 213| Comments: 0
Subject: Medicine & Pharmacology, General Medical Research Keywords: consumer health informatics; E-health; mobile Apps; outpatient follow-up; patient portal; patient-reported outcomes
Online: 2 April 2019 (12:32:10 CEST)
Replacement of fee-for-service with capitation arrangements, forces physicians and institutions to minimize health care costs, while maintaining high-quality care. In this report we describe how patients, their families (and caregivers) can work with members of the medical care team to achieve these twin goals of maintaining (and perhaps improving) high-quality care and minimizing costs. We describe how increased self-management enables patients and their families/caregivers to provide electronic patient-reported outcomes (i.e., symptoms, events) (ePROs) as frequently as the patient or the medical care team consider appropriate. These capabilities also allow greater reliance on the use of mobile technologies (mHealth) to provide ongoing assessments of physiologic measurements/phenomena. Remote surveillance of these communications allows longer intervals between (fewer) visits of patients to the medical-care team when this is appropriate and earlier interventions when that is appropriate. Systems are now available that alert medical care providers to situations when interventions might be needed.
ARTICLE Download: 63| View: 222| Comments: 0 | doi:10.20944/preprints201904.0030.v1
Subject: Medicine & Pharmacology, Anesthesiology Keywords: Brody effect; electrocardiographic variation; R-wave amplitude; hemodynamic monitoring; pulse pressure variation
Online: 2 April 2019 (12:19:31 CEST)
The aim of this study was to analyze whether the respiratory variation in ECG standard lead II R-wave amplitude (ΔRDII) could be used to assess intravascular volume status following inferior vena cava (IVC) clamping. This clamping causes an acute decrease in cardiac output during liver transplantation (LT). We retrospectively compared ΔRDII and related variables before and after IVC clamping in 34 recipients. Receiver operating characteristic (ROC) curve and area under the curve (AUC) analyses were used to derive a cutoff value of ΔRDII for predicting pulse pressure variation (PPV). After IVC clamping, cardiac output significantly decreased while ΔRDII significantly increased (P = 0.002). The cutoff value of ΔRDII for predicting a PPV >13% was 16.9% (AUC: 0.685) with a sensitivity of 57.9% and specificity of 77.6% (95% confidence interval 0.561 – 0.793, P = 0.015). Frequency analysis of ECG also significantly increased in the respiratory frequency band (P = 0.016). Although significant changes in ΔRDII during vena cava clamping were found at norepinephrine doses < 0.1 μg/kg/min (P = 0.014), such changes were not significant at norepinephrine doses > 0.1 μg/kg/minP = 0.093). ΔRDII could be a noninvasive dynamic parameter in LT recipients presenting with hemodynamic fluctuation. Based on our data, we recommended cautious interpretation of ΔRDII may be requisite according to vasopressor administration status.
ARTICLE Download: 71| View: 212| Comments: 0 | doi:10.20944/preprints201809.0028.v2
Subject: Medicine & Pharmacology, Nursing & Health Studies Keywords: photovoice; chronic illness; physical activity; barriers; facilitator
Online: 2 April 2019 (07:48:28 CEST)
Aims: A community-based multi-component intervention (increasing awareness of the importance of physical activity in chronic illness management through reading comic books, training regarding warm-up stretching exercises, identifying facilitators and barriers to exercise through photosharing, supporting self-reflection and development of action plans) was developed to promote physical activity (PA) among patients with diabetes and hypertension. This study aimed to evaluate the efficacy of this intervention on health behaviour (walking) and health outcomes. Design: A non-randomized controlled trial with waitlisted control and pre- and post-measures. Setting: Community centres for the elderly. Participants: A total of 204 older adults with diabetes and/or hypertension were recruited. They were assigned to either the intervention group (IG) or waitlisted to the control group (CG). Intervention: Under the supervision of a nurse, six weekly group meetings were arranged in community centres for the elderly in which the participants freely exchanged their views regarding the barriers and facilitators of regular physical activity. Participants were encouraged to take photos in their neighbourhood or at home and brought these photos to share at the group meetings. The photos showed both the barriers and the facilitators to PA. In the last meeting, each participant worked out a plan to perform PA in the coming four weeks. Measures: PA referred to the number of steps taken per day and it was measured by a Garmin Accelerometer at baseline, Week 6 and Week 10. Other measures included the nine-item Self-Efficacy Scale for Exercise - Chinese version (SEE-C), the 23-item Chinese Barriers to Exercise Scale and Senior Fitness Tests. Generalised Estimating Equations (GEE) models compared the outcomes over time between IG and CG. Results: A statistically significant difference in the changes in the average number of steps taken daily between the two groups at Week 10 (mean difference = 965.4; 95% confidence interval: 92.2, 1838.6, p = 0.030) was observed, although the difference at Week 6 was non-significant (mean difference = 777.6; 95% confidence interval: −35.3, 1590.5, p = 0.061). IG participants also showed significant improvements in lower body strength (mean difference = 0.967; 95% confidence interval: 0.029, 1.904, p = 0.043) and lower limb flexibility (mean difference = 2.068; 95% confidence interval: 0.404, 3.731, p = 0.015) at Week 10 compared to CG participants. Conclusion: This multi-component intervention improved the participants’ physical activity level and physical fitness, particularly in lower limb flexibility and body strength.
Mon, 1 April 2019
ARTICLE Download: 62| View: 147| Comments: 0 | doi:10.20944/preprints201904.0019.v1
Subject: Medicine & Pharmacology, Gastroenterology Keywords: Castor oil; Ascorbic acid; Bowel preparation; Polyethylene glycol
Online: 1 April 2019 (13:42:38 CEST)
Our aim was to evaluate efficacy and safety of 30mL CaO alone or plus Asc in bowel preparation before colonoscopy. Two hundred and forty six patients were allocated randomly to ingest 2L PEG with 30mL CaO, 1L PEG with 30mL CaO plus 5g Asc, or 3L PEG. We used Boston Bowel Preparation Scale (BBPS) to evaluate bowel preparation efficacy. We also determined other outcomes such as procedure time, polyp or adenoma detection rate and adverse events (AEs). Of 282 patients recruited, 36 were excluded. Groups were matched for baseline characteristics except weight (P = 0.020) and body mass index (BMI) (P = 0.003). Patient’s satisfaction were higher in 2L PEG-CaO (P = 0.016) and 1L PEG-CaO-Asc groups (P = 0·017). Patients’ compliance was 67.5%, 71.4% and 80.5% in 3L PEG, 2L PEG-CaO and 1L PEG-CaO-Asc groups (P = 0.014). Adequate bowel preparation rate was 75%, 78.57% and 53.66% in 3L PEG, 2L PEG-CaO and 1L PEG-CaO-Asc groups (P = 0.021). There were no differences in terms of remaining outcomes. Despite an increase in patients’ satisfaction and compliance, 1L PEG-CaO-Asc significantly decreased adequate bowel preparation rate. However, 2L PEG-CaO improved the patients' satisfaction and compliance and increased adequate bowel preparation rate.
CASE REPORT Download: 52| View: 145| Comments: 0 | doi:10.20944/preprints201904.0017.v1
Subject: Medicine & Pharmacology, Other Keywords: marginal ridge staining; enamel crack; detecting cracks in teeth; PTR-LUM
Online: 1 April 2019 (13:38:50 CEST)
Detecting cracks in teeth is a clinical challenge. Patients may complain of diffuse pain on chewing, no pain on temperature change and pain that occurs episodically. Common diagnostic tools such as radiographs and visual examination may not detect cracks. This case study shows how PTR-LUM in The Canary System can detect cracks in teeth not seen with other devices. In this clinical situation, the crack involved a large part of the mesial and distal surfaces of a mandibular second molar.
ARTICLE Download: 61| View: 170| Comments: 0 | doi:10.20944/preprints201904.0015.v1
Subject: Medicine & Pharmacology, Clinical Neurology Keywords: dysphagia; FEES; Parkinson’s disease; swallowing speed; screening; water test
Online: 1 April 2019 (13:32:41 CEST)
There is still a lack of a clinical test to reliably identify patients with Parkinson’s disease (PD) being at risk for aspiration. In this prospective, controlled, cross-sectional study we assessed if swallowing speed for water is a useful clinical test to predict aspiration proven by flexible endoscopic evaluation of swallowing (FEES). Due to this we measured the swallowing speed for 90 ml water in 115 consecutive and unselected PD outpatients of all clinical stages and 32 healthy controls. Average swallowing speed was lower in patients compared with controls (6.5 ± 3.9 ml/s vs. 8.5 ± 3.2 ml/s; p < 0.01). The disease-independent widely used threshold of < 10 ml/s showed insufficient sensitivity of 88% and specificity of 19% with unacceptable false-positive rates of 63% for patients and 69% for controls. Receiver operating characteristic (ROC) analysis was carried out to define a suitable cut-off value for detection of aspiration of water (area under the curve 0.72, p < 0.001) in PD patients. The optimized cut-off value was 5.5 ml/s with a sensitivity of 69% and a specificity of 64%. Overall, measuring swallowing speed is prone to methodological errors and not suitable as a screening instrument to predict aspiration in PD patients.
Sat, 30 March 2019
REVIEW Download: 98| View: 306| Comments: 0 | doi:10.20944/preprints201903.0288.v1
Subject: Medicine & Pharmacology, Oncology & Oncogenics Keywords: Enhancers; BET inhibitors; CDK7 inhibitors; HDAC inhibitors; Transcription factors; eRNAs; cancer
Online: 30 March 2019 (08:33:07 CET)
Tight regulation of gene transcription is essential for normal development, tissue homeostasis and disease-free survival. Enhancers are distal regulatory elements in the genome that provide specificity to gene expression programs and are frequently misregulated in cancer. Recent studies examined various enhancer-driven malignant dependencies and identified different approaches to specifically target these programs. In this review, we describe numerous features that make enhancers good transcriptional targets in cancer therapy and discuss different approaches to overcome enhancer perturbation. Interestingly, a number of approved therapeutic agents such as cyclosporine, steroid hormones, and thiazolidinediones actually function by affecting enhancer landscapes by directly targeting very specific transcription factor programs. More recently, a broader approach to targeting deregulated enhancer programs has been achieved via Bromodomain and Extraterminal (BET) inhibition or perturbation of transcription-related cyclin-dependent kinases (CDK). One challenge to enhancer-targeted therapy is proper patient stratification. We suggest that monitoring of enhancer RNA (eRNA) expression may serve as a unique biomarker of enhancer activity that can help to predict and monitor responsiveness to enhancer-targeted therapies. A more thorough investigation of cancer-specific enhancers and the underlying mechanisms of deregulation will pave the road for an effective utilization of enhancer modulators in a precision oncology approach to cancer treatment.
ARTICLE Download: 51| View: 170| Comments: 0 | doi:10.20944/preprints201903.0287.v1
Subject: Medicine & Pharmacology, Oncology & Oncogenics Keywords: resistant; microRNA-21; doxorubicin; PTEN; MCF-7/Dox cell line
Online: 30 March 2019 (06:46:35 CET)
Background: Breast cancer is the leading cause of cancer mortality and morbidity among Indonesian women. Identification of biological pathways leading into therapeutic resistance through in vitro model is an important step to develop alternative effective therapy in breast cancer. Loss of PTEN expression has been associated with resistance to chemotherapy by involving PI3K/PTEN- dependent apoptosis pathway. We conducted in vitro experiment to investigate the association of hsa-miR-21 and PTEN expression in Doxorubicin-resistant MCF-7 cell line. Methods: Parental MCF-7 cells were periodically incubated with Doxorubicin to obtain specific Dox-resistant variant determined by IC50 using MTT assay. PTEN protein expression was analyzed using immunocytochemistry. Expression of mature has-miR-21 was measured using qRT-PCR. Results: The IC50 of Doxorubicin in parental MCF-7 and Doxorubicin-resistant MCF-7 cells (MCF-7/Dox) was 0.68 and 5.78 µg/ml, respectively. Hsa-miR-21 was significantly overexpressed in MCF-7/Dox cells compared to parental MCF cells (7.94 fold changes). Conclusion: PTEN and hsa-miR-21 expression levels were negatively correlated in Doxorubicin resistant-MCF cells. Further study to confirm the causal relationship of miR-21 overexpression and PTEN downregulation in MCF-7/Dox is required.
Fri, 29 March 2019
REVIEW Download: 85| View: 207| Comments: 0 | doi:10.20944/preprints201903.0282.v1
Subject: Medicine & Pharmacology, Gastroenterology Keywords: pancreatitis; epidemiology; diagnosis; complications; treatment; prognosis.
Online: 29 March 2019 (12:13:17 CET)
Acute pancreatitis (AP) is an inflammatory condition of the pancreas and is one of the most common ailments of the gastrointestinal system that results in significant morbidity and mortality. The main etiologic causes of AP are alcohol consumption, gallstones, hypertriglyceridemia, and biliary stones. The clinical signs and symptoms, and diagnostic criteria of AP are well established in the literature and multiple studies. Multiple scoring systems have been used to predict the severity, prognosis, and mortality associated with AP. The present review of the literature brings to light the significant and recent contributions in the etiology, risk factors, epidemiology, diagnosis, complications, prognosis and newest modalities in treatment that could be beneficial in the management of AP.
Thu, 28 March 2019
ARTICLE Download: 119| View: 337| Comments: 0 | doi:10.20944/preprints201903.0271.v1
Subject: Medicine & Pharmacology, Obstetrics & Gynaecology Keywords: glucocorticoid receptor; 11HSD; mitochondria; NFκB; inflammation; ovary; uterus; polycystic ovary syndrome
Online: 28 March 2019 (14:05:40 CET)
Hyperandrogenism and insulin resistance are co-pathologies of polycystic ovary syndrome (PCOS). Recent evidence has suggested that elevated local cortisol levels are associated with ovarian and endometrial insulin resistance in hyperandrogenic PCOS patients, but the molecular mechanisms underlying these clinical findings remain unclear. We and others have used chronic treatment with human chorionic gonadotropin (hCG) and insulin to create an in vivo rodent model for the onset and development of PCOS-like phenotypes. Here, we aimed to determine whether the molecular mechanisms of glucocorticoid receptor (GR) signaling, mitochondrial function, and local inflammation in the ovary and uterus are intrinsically different in PCOS-like rats compared to controls. In both the ovary and the uterus, decreased expression of two GR protein isoforms was concurrent with increased expression of Fkbp51 but not Fkbp52 mRNA in PCOS-like rats compared to controls. However, PCOS-like rats exhibited an opposite regulation of Hsd11b1 or Hsd11b2 mRNAs in the two tissues. Further, the expression of several oxidative phosphorylation-related protein components was decreased in the PCOS-like ovary and uterus, but surprisingly the expression of many genes involved in mitochondrial function and homeostasis was increased in the same tissues and animals. Additionally, PCOS-like rats showed the increased expression of ovarian and uterine NFκB signaling proteins and Tnfaip3 mRNA. In PCOS-like rats, while similar decreased expression of Il1b, Il6, and Mmp2 mRNAs was seen in the ovary and uterus, the opposite regulation of Tnfa, Ccl2, Ccl5, and Mmp3 mRNA expression was observed in the two tissues. Both ovaries and uteri from PCOS-like animals showed increased collagen deposition compared to controls. Collectively, our observations suggest that hyperandrogenism and insulin resistance disrupt ovarian and uterine GR activation and trigger compensatory or adaptive effects for mitochondrial homeostasis, allowing tissue-level maintenance of mitochondrial function in order to limit ovarian and uterine dysfunction. Our study also suggests that hyperandrogenism and insulin resistance-induced activation of NFκB signaling resulting in aberrant regulation of inflammation-related gene expression might be tissue specific in female reproductive tissues.
REVIEW Download: 60| View: 180| Comments: 0 | doi:10.20944/preprints201903.0267.v1
Subject: Medicine & Pharmacology, Gastroenterology Keywords: hepatocellular carcinoma, gut microbiota, gut-liver axis, intestinal dysbiosis
Online: 28 March 2019 (13:43:07 CET)
Hepatocellular carcinoma (HCC), one of the leading causes of death worldwide, has a causal nexus with liver injury, inflammation, and regeneration that accumulate over decades. Observations from recent studies have accounted for the involvement of the gut-liver axis in the pathophysiological mechanism responsible for HCC. The human intestine nurtures a diversified colony of microorganisms residing in the host ecosystem. The intestinal barrier is critical for conserving the normal physiology of the gut microbiome. Therefore, a rupture of this barrier or dysbiosis cause the intestinal microbiome to serve as the main source of portal-vein endotoxins such as lipopolysaccharide, in the progression of hepatic diseases. Indeed, increased bacterial translocation is a key sign of HCC. Considering the limited number of clinical studies on HCC with respect to the microbiome, we focus on the clinical as well as animal studies involving the gut microbiota with the current understandings of the mechanism by which the intestinal dysbiosis promotes hepatocarcinogenesis. Future research might offer mechanistic insights into the specific phyla targeting the leaky gut, as well as microbial dysbiosis, and their metabolites, as key pathways that drive HCC-promoting microbiome-mediated liver inflammation and fibrosis, thereby restoring the gut barrier function.
ARTICLE Download: 43| View: 171| Comments: 0 | doi:10.20944/preprints201903.0266.v1
Subject: Medicine & Pharmacology, Other Keywords: Chronic hepatitis B; Risk Factors; Prevalence; Iran
Online: 28 March 2019 (11:35:53 CET)
Background: Hepatitis B virus infection and its complications are major health problems. The aim of this study were to investigate risk factors in patients with chronic hepatitis B. Methods: This cross-sectional study was performed on 174 patients with chronic hepatitis B who referred to the Shahid Mohammadi hospital in the city of Bandar Abbas, Iran. Information was collected through a questionnaire. Results: 174 persons (97 males, 77 females) with a mean age of 42.96 years. There was no significant relationship between the risk of having disease with gender, age, weight, height, waist circumference, hip circumference, BMI and WHR (P> 0.05). The frequency of exposure to risk factors are as follows: such as history of hairdressers, vaccination, contact with suspected HBV persons, Family history of HBV positive in patients had higher prevalence than other groups. Conclusion: It seems to be more important to pay attention to lifestyles, jobs, and cultural themes of Iranian people that predispose people to risk factors so as to implement measures to control HBV spread. Also, awareness and social-health education in order to avoid unprotected sexual contact with an infected partner can be highly effective according to the high levels of hepatitis B infection among married persons. Despite existence of a long list of risk factors, various epidemiological studies with alternative methodologies along with meta-analysis of risk factors in each separate area seems to be helpful in collecting information about transmission.
ARTICLE Download: 50| View: 183| Comments: 0 | doi:10.20944/preprints201903.0265.v1
Subject: Medicine & Pharmacology, Other Keywords: Chronic hepatitis B; Epidemiology; Heoatocellular Carcinoma (HCC); cirrhosis; microRNA , HBV, Treatment
Online: 28 March 2019 (11:30:39 CET)
Introduction: Due to lack of unique method with high accurate and repeatable, assessment and even treatment of HBV infection and it,s complications such as cirrhosis and HCC has been with limitations. MicroRNAs (miRNAs) are small 19-24 nucleotide-long molecules with up-regulated and down-regulated Expression.The present research provides a narrative review expression profiling biomarkers miRNAs in diagnosis, treatment and differnciated CHB from cirrhosis or HCC.Methods: We search database google scholar, pubmed, scopus, SID on English Languish article and also assess EASL and AASLD (2002-2016).Results: Some of miRNAs are specifically more abundant in specific tissues, such as miR-122 in the liver. MiRNAs such as miRNA125a, miRNA141, miRNA1, miRNA197, miRNA122 and miRNA372, 373 have a major role in CBH and miRNA29a/b/c, miRNA200, miRNA199, miRNA133a, miRNA214 andmiRNA181b have a major role in fibrosis/cirrhosis. miR-106b and miR-181b, have a significant clinical diagnostic value in liver cirrhosis, especially at its early stages. miR-122, miR-192, miR-92, miR-223, miR-26a, miR-27a and miR-801, has a highly accurate diagnostic power that can differentiate HCC from CHB and cirrhosis and from healthy people as well as.Conclusion: In the future, the miRNAs biomarkers provide researchers with a golden opportunity and can be used as early diagnostic and miRNAs based-therapeutic panels and current knowledge between miRNAs profiling biomarkers and progressive stage of HBV related diseases. Panels of miRNAs will play a significant role in decision-making about their proper course in both of treatment and diagnosis of diseases such as hepatitis B virus infection.
ARTICLE Download: 41| View: 173| Comments: 0
Subject: Medicine & Pharmacology, Dentistry Keywords: hyaluronic acid; biphasic bone substitute; biocompatibility; tissue reaction; inflammation; macrophage; M1; M2; multinucleated giant cells
Online: 28 March 2019 (06:54:57 CET)
Biphasic bone substitutes (BBS) are nowadays established biomaterials. Through their constant development even natural components like hyaluronic acid (HY) are added to improve both their handling and also their regenerative properties. However, low knowledge exists regarding the consequences of the HY addition for their biocompatibility and the inflammatory tissue reactions. Thus, the present study was conducted aiming to analyze the influence of two different amounts of high molecular weight HY (HMWHY) combined with a BBS on the in vitro biocompatibility and the in vivo tissue reaction. Established in vitro procedures using L929 cells were used for cytocompatibility analyses under the test conditions of DIN EN:ISO 10993-5. For the in vivo study part, calvarial defects were created in 20 Wistar rats and subsequently filled with the BBS and the BBS combined with two different HMWHY amounts, i.e., BBS+HY(L) and BBS+HY(H). As controls empty defects were used. Established histological, immunohistochemical and histomorphometrical methods were applied to analyze the tissue reactions to the three different materials, including the induction of pro- and anti-inflammatory macrophages and multinucleated giant cells (BMGCs). The in vitro results showed that none of the materials or compositions caused biological damages to the L929 cells and can considered to be non-toxic. The in vivo results showed that only the addition of high doses of HY to a biphasic bone substitute significantly decreases the occurrence of proinflammatory macrophages (* p < 0.05) comparable to the numbers found in the control group, while no significant differences within the three study groups for M2-macrophages nor BMGCs were detected. In conclusion, the addition of different amounts of HMWHY does not seem to affect the inflammation response to the BBS while improving the material handling properties.
REVIEW Download: 109| View: 208| Comments: 0 | doi:10.20944/preprints201903.0256.v1
Subject: Medicine & Pharmacology, Oncology & Oncogenics Keywords: immunocheckpoint inhibitors; chemotherapy; tirosin kinase inhibitors; angiogenesis
Online: 28 March 2019 (06:48:37 CET)
Despite the impact of immune checkpoint inhibitors on malignancies treatment is unprecedented, a lack of response to these molecules is observed in several cases. Differently from melanoma and non-small cell lung cancer, where the use of immune checkpoint inhibitors results in a high efficacy, the response rate in other tumors, such as gastrointestinal cancers, breast cancer, sarcomas, and part of genitor-urinary cancers remains low. The first strategy evaluated to improve the response rate to immune checkpoint inhibitors is the use of predictive factors for the response as PD-L1 expression, tumor mutational burden, and clinical features. In addition to the identification of the patients with a high sensibility to immune checkpoint inhibitors, another approach currently under intensive investigation is the use of therapeutics in a combinatory manner with immune checkpoint inhibitors to obtain an enhancement of efficacy through the modification of the tumor immune microenvironment. In addition to the abscopal effect induced by radiotherapy, a lot of studies are evaluating several drugs able to improve response rate to immune checkpoint inhibitors, including microbiota modifiers, drugs targeting co-inhibitors receptors, anti-angiogenic therapeutics, small molecules, and oncolytic viruses. In view of the rapid and extensive development of this research field, we conducted a systematic review of the literature identifying which of these drugs are closer to achieving validation in the clinical practice.
Wed, 27 March 2019
ARTICLE Download: 35| View: 190| Comments: 0 | doi:10.20944/preprints201903.0249.v1
Subject: Medicine & Pharmacology, Oncology & Oncogenics Keywords: N3, head and neck cancer, radiation, upfront neck dissection, concurrent chemoradiotherapy
Online: 27 March 2019 (08:46:58 CET)
Currently, data regarding optimal treatment modality, response, and outcome specifically for N3 head and neck cancer are lacking. This study aimed to compare the treatment outcomes between definitive concurrent chemoradiotherapy (CCRT) to the neck and upfront neck dissection followed by adjuvant CCRT. 93 N3 squamous cell carcinoma head and neck cancer patients were included. Primary tumor treatment was divided to definitive CCRT (CCRT group) or curative surgery followed by adjuvant CCRT (surgery group). Neck treatment was also classified into two treatment modalities: definitive CCRT to the neck (CCRT group) or curative neck dissection followed by adjuvant CCRT (neck dissection group). Overall, the 2-year overall survival (OS), local recurrence-free survival (LRFS), regional recurrence-free survival (RRFS), and distant metastasis-free survival (DMFS) were 51.8%, 47.3%, 45.6%, and 43.6%, respectively. In both oropharyngeal cancer and nonoropharyngeal cancer patients, in terms of OS, LRFS, RRFS or DMFS no difference was noted regarding primary tumor treatment (CCRT vs. surgery) or neck treatment (CCRT vs. neck dissection). In summary, N3 neck patients treated with definitive CCRT can achieve similar outcomes to those treated with upfront neck dissection followed by adjuvant CCRT. Cautions should be made to avoid overtreatment for this group of patients.
Tue, 26 March 2019
REVIEW Download: 82| View: 157| Comments: 0
Subject: Medicine & Pharmacology, Nutrition Keywords: Colon; high-sulfur foods; inflammation; metagenomics; microbiota; sulfur reducing bacteria.
Online: 26 March 2019 (10:45:11 CET)
The biogeography of inflammation in ulcerative colitis (UC) suggests a proximal to distal concentration gradient of a toxin. Hydrogen sulfide (H2S) has long been considered one such toxin candidate, and dietary sulfur along with the abundance of sulfate reducing bacteria (SRB) were considered the primary determinants of H2S production and clinical course of UC. The metabolic milieu in the lumen of the colon, however, is the result of a multitude of factors beyond dietary sulfur intake and SRB abundance. Here we present an updated formulation of the H2S toxin hypothesis for UC pathogenesis, which strives to incorporate the interdependency of diet composition and the metabolic activity of the entire colon microbial community. Specifically, we suggest that the increasing severity of inflammation along the proximal-to-distal axis in UC is due to dilution of beneficial factors, concentration of toxic factors, and changing detoxification capacity of the host, all of which are intimately linked to the nutrient flow from the diet.
Mon, 25 March 2019
ARTICLE Download: 45| View: 124| Comments: 0
Subject: Medicine & Pharmacology, Psychiatry & Mental Health Studies Keywords: physical activity; depression; elderly people living alone; Patient Health Questionnaire-10; flexibility exercise; muscular strength exercise; complex sample logistic regression
Online: 25 March 2019 (11:10:17 CET)
Background and objectives: Only a few studies analyzed the physical activity level of elderly people living alone in local communities and evaluated the relationship between it and mental health. The purpose of this study was to investigate the relationship between physical activity and depression in the elderly living alone and to provide basic data for the prevention of depression in the elderly. Materials and Methods: We analyzed 256 elderly people living alone aged 65 years or older who completed the 2014 Korea National Health and Nutrition Examination Survey. Depression was defined as a score of 10 or higher using Patient Health Questionnaire-10(PHQ-9). This study investigated walking per week, days of muscular strength exercise performance in the past one week, days of flexibility exercise in the past one week, mean hours in a sitting position per day, the numbers of days and hours conducting a high intensity physical activity in the past one week, and numbers of days and hours conducting a medium intensity physical activity in the past one week to define physical activity. Our study presented prevalence odds ratios (pOR) and 95% confidence interval (CI) by using complex sample logistic regression analysis in order to identify the relationship between physical activity and depression. Results: The results of complex sample logistic regression analysis showed that flexibility exercise was significantly related to depression (p <0.05). On the other hand, the mean hours in a sitting position per day, aerobic physical activity, walking, and muscular strength exercise were not significantly related to geriatric depression. Conclusions: The results of our study implied that persistent flexibility exercise might be more effective to maintain a healthy mental status than muscular strength exercise. A longitudinal study is required to prove the causal relationship between physical activity and depression in the old age.
ARTICLE Download: 58| View: 134| Comments: 0
Subject: Medicine & Pharmacology, Other Keywords: Validation; communication; questionnaire; healthcare attention; patient satisfaction; nursing.
Online: 25 March 2019 (10:40:45 CET)
Background: Healthcare attention is sometimes considered purely technical, but communication has proven to be closely related to clinical results and patient satisfaction. Therefore, evaluation of communication in the scope of healthcare is a priority. The purpose of this study was to validate and adapt, if necessary, the Spanish version of the Communication Styles Inventory (CSI) in a sample of nursing professionals. (2) Methods: The sample was made up of 2313 nursing professionals selected at random from various medical centers in Spain, and is therefore a sample actively employed at the time data were acquired. We started out from the Communication Style Inventory, a questionnaire for evaluating the predominance of certain individual communication behaviors on six scales (expressiveness, preciseness, verbal aggressiveness, questioningness, emotionality and impression manipulativeness). (3) Results: Confirmatory Factor Analysis of the model proposed showed god fit indices. The reliability of the model shown by the Cronbach’s alpha of α=.81 was adequate, and so was single-level and aggregate consistency. Finally, in the analysis of variance by type of contract, configural, metric and scalar invariance was acceptable, but not strict invariance. (4) Conclusions: This instrument progresses in measuring non-technical attributes, such as communication styles, in nursing personnel.
ARTICLE Download: 80| View: 142| Comments: 0
Subject: Medicine & Pharmacology, Psychiatry & Mental Health Studies Keywords: supervised learning, major depression, cytokines, inflammation, neuro-immune, opioids
Online: 25 March 2019 (10:14:02 CET)
Rationale: Major depressive disorder (MDD) is characterized by signaling aberrations in interleukin (IL)-6, IL-10, beta-endorphins as well as mu (MOR) and kappa (KOR) opioid receptors. Here we examined whether these biomarkers may aid in the classification of unknown subjects into the target class MDD.Methods: The aforementioned biomarkers were assayed in 60 first-episode, drug-naïve depressed patients and 30 controls. We analyzed the data using joint principal component analysis (PCA) performed on all subjects to check whether subjects cluster by classes; support vector machine (SVM) with 10-fold validation; and linear discriminant analysis (LDA) and SIMCA performed on calibration and validation sets and we computed the figures of merit and learnt from the data. Results: PCA shows that both groups were well separated using the first three PCs, while correlation loadings show that all 5 biomarkers have discriminatory value. SVM and LDA yielded an accuracy of 100% in validation samples. Using SIMCA there was a highly significant discrimination of both groups (model-to-model distance=87.5); all biomarkers showed a significant discrimination and modeling power, while 10% of the patients were identified as outsiders and no aliens could be identified.Discussion: We have delineated that MDD is a distinct class with respect to neuro-immune and opioid biomarkers and that future unknown subjects can be authenticated as having MDD using this SIMCA fingerprint. Precision psychiatry should employ SIMCA a) to authenticate patients as belonging to the claimed target class and identify other subjects as outsiders, members of another class or aliens; and b) to acquire knowledge through learning from the data by constructing a biomarker fingerprint of the target class.
Fri, 22 March 2019
ARTICLE Download: 44| View: 231| Comments: 0 | doi:10.20944/preprints201903.0207.v1
Subject: Medicine & Pharmacology, Ophthalmology Keywords: myopia,photon-electron theory,high-frequency electromagnetic radiation
Online: 22 March 2019 (09:51:48 CET)
The exact etiology of myopia remains elusive. The author proposes the particle property of photon in living tissue and the photon-electron theory in living tissue, if the frequency of the photon beyond the threshold, the photon has enough energy to strike the electron away and forms a hole of a diameter in photon diameter scale in living tissue include the eye.The visual light which passes through the radiation hole in the eye cannot be refracted on the macula. Longer time of high-frequency electromagnetic radiation will cause more holes and a larger radius of holes, which lead to high myopia, this is in accordance with the investigation results that high myopic eyes have macular holes (micron scale). According to the particle property of the photon model, the eye elongated by the striking of high-frequency photons.
Thu, 21 March 2019
ARTICLE Download: 70| View: 230| Comments: 0
Subject: Medicine & Pharmacology, Psychiatry & Mental Health Studies Keywords: premenstrual syndrome; depression; anxiety; fatigue; neuro-immune; progesterone
Online: 21 March 2019 (04:13:21 CET)
Objective: To examine associations between IgA responses to Gram-negative gut-commensal bacteria and peri-menstrual symptoms and sex hormone levels during the menstrual cycle in women with and without premenstrual symptoms. Methods: Forty women aged 18-45 years completed the Daily Record of Severity of Problems (DRSP) during all 28 consecutive days of the menstrual cycle. We assayed, in plasma,, IgA responses to 6 Gram-negative bacteria, i.e. Hafnei alvei, Pseudomonas aeruginosa, Morganella morganii, Klebsiella pneumoniae, Pseudomonas putida and Citrobacter pylori, progesterone and oestradiol at days 7, 14, 21 and 28 of the menstrual cycle. Results: Significant changes in Δ (actual minus one week earlier) IgA to LPS of the 6 Gram-negative bacteria during the menstrual cycle were observed with peak IgA levels at T4 (day 28) and lows at T1 or T2 (day 7 or 14). The Δ IgA changes in H. alvei, M. Morganii, P. putida during the menstrual cycle were significantly and positively associated with changes in the total DRSP score, and severity of physio-somatic, anxiety and breast-craving, but not depressive, symptoms. The changes in IgA responses to LPS were largely predicted by changes in progesterone and steady-state levels of progesterone averaged over the luteal phase. Discussion: Menstrual cycle-associated changes in IgA directed against LPS and by inference bacterial translocation may be driven by effects of progesterone on transcellular, paracellular and vascular pathways thereby contributing to the severity of physio-somatic and anxiety symptoms as well as fatigue, breast swelling and food cravings.
Wed, 20 March 2019
ARTICLE Download: 58| View: 272| Comments: 0
Subject: Medicine & Pharmacology, General Medical Research Keywords: KIT assay; chronic kidney disease; biomarker; non-invasive; urine; eGFR; cfDNA
Online: 20 March 2019 (02:12:19 CET)
The standard of care measures for kidney function, proteinuria, and serum creatinine (SCr) are poor predictors of early stage kidney disease. Measures that can detect chronic kidney disease in its earlier stages are needed to enable therapeutic intervention and reduce adverse outcomes of chronic kidney disease. We have developed the Kidney Injury Test (KIT) and a novel KIT Score based on the composite measurement and validation of multiple biomarkers across a unique set of 397 urine samples. The test is performed on urine samples that require no processing at the site of collection and without target sequencing or amplification. We sought to verify that the pre-defined KIT test, KIT Score, and clinical thresholds correlate with established chronic kidney disease (CKD) and may provide predictive information of early kidney injury status above and beyond proteinuria and renal function measurements alone. Statistical analyses across six DNA, protein, and metabolite markers were performed on a subset of residual spot urine samples with CKD that met assay performance quality controls from patients attending the clinical labs at the University of California, San Francisco (UCSF) as part of an ongoing IRB approved prospective study. Inclusion criteria included selection of patients with confirmed CKD and normal healthy controls; exclusion criteria included incomplete or missing information for sample classification, logistical delays in transport/processing of urine samples or low sample volume, and acute kidney injury. Multivariate logistic regression of kidney injury status and likelihood ratio statistics were used to assess the contribution of the KIT Score for prediction of kidney injury status and stage of CKD as well as assess the potential contribution of the KIT Score for detection of early stage CKD above and beyond traditional measures of renal function. Urine samples were processed by a proprietary immunoprobe for measuring cfDNA, methylated cfDNA, clusterin, CXCL10, total protein, and creatinine. The KIT Score and stratified KIT Score Risk Group (High versus Low) had a sensitivity and specificity for detection of kidney injury status (healthy or CKD) of 97.3% (95% CI: 94.6%–99.3%) and 94.1% (95% CI: 82.3%–100%). In addition, in patients with normal renal function [eGFR ≥ 90], the KIT Score clearly identifies those with predisposing risk factors for CKD, which could not be picked up by eGFR or proteinuria (p < 0.001). The KIT Score uncovers a burden of kidney injury that may yet be incompletely recognized, opening the door for earlier detection, intervention and preservation of renal function.
Tue, 19 March 2019
ARTICLE Download: 64| View: 254| Comments: 0
Subject: Medicine & Pharmacology, Oncology & Oncogenics Keywords: Oral cancer; Oropharyngeal cancer; Tumor-suppressor genes; Promoter hypermethylation
Online: 19 March 2019 (12:56:24 CET)
Silencing of tumor suppressor genes (TSGs) by DNA promoter hypermethylation is an earlyevent in carcinogenesis; Hence TSGs may serve as early tumor biomarkers. We determinedthe promoter methylation levels of p16INK4a, RASSF1A, TIMP3 and PCQAP/MED15 TSGs in salivary DNA from oral cancer (OC), and oropharyngeal cancer (OPC) patients, using methylation specific PCR coupled with densitometry analysis. We assessed the association between DNA methylation of individual TSGs with OC and OPC risk factors. We evaluated the performance and the clinical validity of this quadruple methylation marker panel in discriminating OC and OPC patients from healthy controls using CombiROC web tool. Our study reported that RASSF1A, TIMP3 and PCQAP/MED15 TSGs were significantly hypermethylated in OC and OPC cases compared to healthy controls. We found that DNA methylation levels of TSGs were significantly augmented by smoking, alcohol use and betel quid chewing by indicating that the fact that frequent exposure to risk factors may drive oral and oropharyngeal carcinogenesis through TSG promoter hypermethylation. Also, this quadruple-methylation marker panel of p16INK4a, RASSF1A, TIMP3 and PCQAP/MED15 TSGs demonstrated excellent diagnostic accuracy in the early detection of OC at 91.7% sensitivity and 92.3% specificity, and OPC at 99.8% sensitivity and 92.1% specificity, from healthy controls.
ARTICLE Download: 74| View: 243| Comments: 0
Subject: Medicine & Pharmacology, Pharmacology & Toxicology Keywords: necroptosis; cisplatin; ototoxicity; organ of corti; spiral ganglion neuron
Online: 19 March 2019 (10:40:20 CET)
Cisplatin induces early-onset ototoxicity, resulting in hearing loss. The exact mechanism by which cisplatin causes ototoxicity remains unclear. The purpose of this study was to identify the involvement of receptor-interacting protein kinase(RIP)3-dependent necroptosis in cisplatin-induced ototoxicity in animal models. Sprague–Dawley rats (SD, 8 week) were treated via intraperitoneal (i.p) injection with cisplatin (16 mg/kg for 1 day), and their hearing thresholds were was measured by the auditory brainstem response (ABR) method. Hematoxylin and eosin (H-E) staining, immunohistochemistry, and western blots were performed to determine the effect of cisplatin-induced ototoxicity on cochlear morphology. H-E stains outlined necroptotic changes in the organ of Cortis (OCs) and spiral ganglion neurons (SGNs). Additionally, immunohistochemistry and western blot analysis showed overexpression of RIP3 in the OCs and SGNs that were treated with cisplatin. These results suggest that RIP3-dependent necroptosis was substantial in cisplatin-induced ototoxicity; inner cochlear regions, the OCs, and SGNs were especially sensitive to necroptosis.
Mon, 18 March 2019
ARTICLE Download: 60| View: 270| Comments: 0
Subject: Medicine & Pharmacology, Nutrition Keywords: Dietary diversity; nutrient adequacy; metabolic syndrome; aging; PREDIMED-Plus study
Online: 18 March 2019 (09:25:48 CET)
Dietary guidelines emphasizes the importance of a varied diet to provide an adequate nutrient intake. However, the aging is often associated with consumption of monotonous diets that can be nutritionally inadequate, increasing the risk for the development or progression of diet-related chronic diseases such as the metabolic syndrome (MetS). To assess the relationship between dietary diversity (DD) and nutrient adequacy and to identify associated demographic variables related with DD. We analysed cross-sectional baseline data from the PREDIMED-Plus study: 6587 Spanish adults, aged 55–75 years, with overweight/obesity and MetS. Using a 143-item validated semi-quantitative food frequency questionnaire (FFQ), we calculated an energy-adjusted score of DD (DDS). Nutrient inadequacy was defined as an intake below 2/3 of the recommended dietary intake at least of ≥4 of 17 nutrients. Logistic regression models were used to evaluate the relationship between nutritional inadequate intakes and DDS. In the higher DDS quartile there were more women and less current smokers. Compared with subjects in the highest DDS quartile, those in the lowest DDS quartile had a higher risk of inadequate nutrient intake OR=28.56 (95% C.I. 20.80-39.21). When we estimated diversity for each one of the food groups, participants in the first quartile of diversity had a higher risk of nutrient deficiency: for vegetables, OR= 14.03 (IC 95% 10.55-18.65), fruits OR=11.62 (IC 95% 6.81-19.81), dairy products OR= 6.54 (IC 95% 4.64-9.22) and protein foods OR=6.60 (IC 95% 1.96-22.24). As DDS decreases, the risk of inadequate nutrients intake rises. Given the impact of nutrient intake adequacy on the prevention of non-communicable diseases, health policies should focus on the promotion of a healthy varied diet, specifically promoting the intake of vegetables and fruit among population groups with lower DDS such as men, smokers or widow people.
ARTICLE Download: 76| View: 256| Comments: 0
Subject: Medicine & Pharmacology, Sport Sciences & Therapy Keywords: training loads; monitoring; illness; fatigue; training intensity distribution; threshold training; polarized training;
Online: 18 March 2019 (09:22:29 CET)
Despite the continued growth of the sport, particularly among recreational athletes, very little is known about how triathletes prepare for an event. The aim of this study was to identify the training characteristics of recreational-level triathletes and assess how their preparation for a triathlon influences their health and fatigue. During the 6 weeks prior to an Olympic distance triathlon, and the 2 weeks after the event, ten (5 males, 5 females) recreational athletes completed a daily training log to provide information on every training session. In addition, participants answered the Daily Analysis of Life Demands Questionnaire (DALDA), the Training Distress Scale (TDS), and the Alberta Swim Health Questionnaire weekly. Training loads were calculated using session-based rating of perceived exertion (sRPE) and training impulse (TRIMP). Every week of training was compared to week 1 to determine how athletes’ training and health changed throughout the study. In the 6 weeks leading up to the event, training loads, total minutes trained, and time spent in each training zone did not differ significantly. Significant reductions in training duration (Z=2.39, p=0.017, ES = 0.90), training strain (Z=2.59, p=0.009, 0.98), and number of sessions (Z=2.49, p=0.012, ES = 0.94) were seen on week 6. Training intensity distribution favored a threshold approach with athletes spending 56% of their training time at zone 1, 40% at zone 2, and 4% at zone 3. No significant changes were seen in the DALDA or TDS questionnaires. The results show that while the training intensity distribution of recreational-level triathletes does not follow a polarized model, these athletes were able to maintain their health while preparing for an Olympic distance triathlon.
Fri, 15 March 2019
ARTICLE Download: 56| View: 242| Comments: 0 | doi:10.20944/preprints201903.0165.v1
Subject: Medicine & Pharmacology, Other Keywords: Environmental Tobacco Smoke (ETS); pregnant women; questionnaire; urinary cotinine; oxidative stress parameters
Online: 15 March 2019 (14:03:35 CET)
Abstract: Background: Exposure to ETS (Environmental Tobacco Smoke) is one of the most toxic environmental exposures. Objective: To investigate the impact of ETS on physiological, biochemical, psychological indicators, on the urine antioxidant capacity (AC) and oxidative damage to lipids in a pilot sample of healthy pregnant women. Methods: The exposure to ETS was investigated by a validated questionnaire, urine cotinine and the marker of oxidative damage to lipids - 8-isoprostane concentrations using an ELISA kit. Urine AC was determined by the spectrophotometric TEAC method. From the sample of pregnant women (n=319, average age 30.84 ± 5.09 years) in 80 the levels of cotinine and oxidative stress markers were analyzed. Results: From our sample, 5 % individuals (7.4 % objectified by cotinine) were current smokers and 25 % reported passive smoking in the household (18.8 % objectified by cotinine). The Kappa was 0.78 for smokers and 0.22 for ETS exposed non-smokers. Smokers as well as non-smokers had significantly higher (p<0.05) urine AC than ETS exposed non-smokers. Non-smokers had significantly lower levels of 8-isoprostane than smokers (p<0.01) and ETS-exposed non-smokers (p<0.05). Correlations between urine levels of cotinine and AC were positive in ETS exposed non-smokers. Conclusion: The harmful effect of active and passive smoking on oxidative stress parameters has been indicated.
Thu, 14 March 2019
ARTICLE Download: 118| View: 355| Comments: 0 | doi:10.20944/preprints201903.0146.v1
Subject: Medicine & Pharmacology, General Medical Research Keywords: antimicrobial stewardship; resistance; infections; antibiotic utilization; peer-reviewed literature
Online: 14 March 2019 (06:57:30 CET)
Antimicrobial stewardship efforts are an emphasis among many institutions around the world to combat inappropriate antimicrobial utilization, rising healthcare costs and emerging antimicrobial resistance. Implementation of new innovative strategies may be challenging for many institutions with limited or constrained resources. Using proven effective methods as evidenced by other institutions in the peer-reviewed literature may offer an opportunity to evaluate institution-specific practices, which may be implemented locally. A structured examination and survey of the peer-reviewed, stewardship literature by an expert group of clinicians, scholars and educators determined the most influential publications from 2016. Herein, the top thirteen manuscripts are reviewed to aid clinicians identify potential stewardship opportunities and serve as an educational tool for trainees and others.
Tue, 12 March 2019
CASE REPORT Download: 73| View: 237| Comments: 0 | doi:10.20944/preprints201903.0136.v1
Subject: Medicine & Pharmacology, Pharmacology & Toxicology Keywords: cricket glycosaminoglycan; N-glycan; homo db mice; anti-oxidant enzyme
Online: 12 March 2019 (10:28:47 CET)
Field cricket (Gryllus bimaculatus) is newly emerged as an edible insect in several countries. Anti-inflammatory effect of glycosaminoglycan derived this cricket was not fully investigated on chronic disease animal model such as diabetic mouse. For potential therapeutic agents, anti-diabetic activities of field cricket glycosaminoglycan (GbG) was evaluated in diabetic mice based on their abilities to reduce glucose, ALT, AST, LDL-cholesterol, and BUN levels, compared with dung beetle (Catharsius molossus) glycosaminoglycan (CaG) as a positive control glycosaminoglycan. Db mice were orally administered for one month according to their groups: Db Hetero (normal), Db Homo (type-2 diabetic), CaG (5 mg/kg), GbG (5 mg/kg), and metformin (10 mg/kg). Blood glucose level was decreased after 1st week treatment with GbG. It also inhibited LDL-cholesterol and alkaline phosphatase levels. Regarding oxidative damage of diabetic state, levels of hepatocellular biomarkers levels and protein carbonyl content were reduced in db mice treated with GbG. Especially anti-oxidative activities of catalase, superoxide dismutase, and glutathione peroxidase were significantly increased in GbG treated group compared to those in the control. GbG was composed of heparin disaccharides and main N-glycan was identified as Hex9GlcNAc2 (m/z 1905.7) of with neutral mono-sugar mainly comprising of hexose, L (+) rhamnose by mass spectroscopy. These results from sero-biochemical, hepatocellular anti-oxidant assay in db mice data suggest cricket (G. bimaculatus) glycosaminoglycan might play a role in its anti-diabetic action.
REVIEW Download: 69| View: 240| Comments: 0 | doi:10.20944/preprints201903.0133.v1
Subject: Medicine & Pharmacology, Oncology & Oncogenics Keywords: Pancreatic cancer; PDAC (Pancreatic Ductal Adenocarcinoma); immune microenvironment; immune biomarkers; personalized cancer care; inflammation; PD1; CTLA-4
Online: 12 March 2019 (03:15:16 CET)
It is estimated that pancreatic cancer will be the 2nd leading cause of cancer-related deaths globally by 2030, highlighting the ongoing lack of effective treatment options in this devastating condition. There is a lack of reliable prognostic or predictive markers in pancreatic cancer to guide management decisions, whether for systemic chemotherapy, molecularly targeted therapies, or immunotherapies. To date, the results for targeted agents and immunotherapies in unselected populations of chemo-refractory pancreatic cancer have not met expectations. The reasons for this lack of efficacy of immunotherapy in pancreatic cancer are incompletely understood. The challenges in pancreatic cancer include the physical barrier created by the dense desmoplastic stroma surrounding the tumor, chemokine-mediated exclusion of T cells, poor antigenicity, paucity of infiltrating T cells within the tumor, ultimately leading to an immunosuppressive microenvironment. A better understanding of the role of inflammation in pancreatic cancer, its tumor microenvironment and individualized patient-related features, be they molecular, clinical or histopathological would enable a more effective tailored approach to the management of pancreatic cancer. In this review, the role of inflammation, the immune tumor microenvironment and potential immune biomarkers in pancreatic cancer are explored.
Mon, 11 March 2019
ARTICLE Download: 95| View: 250| Comments: 0 | doi:10.20944/preprints201903.0128.v1
Subject: Medicine & Pharmacology, Gastroenterology Keywords: Liver cirrhosis; epidemiology; etiology; risk factors; pathophysiology; diagnosis.
Online: 11 March 2019 (09:44:18 CET)
Liver cirrhosis is a chronic disease that is characterized by the presence of fibrosis and regeneration of nodules in the liver whose consequences are the development of portal hypertension and liver failure. Cirrhosis arises from a wide variety of chronic diseases, which progresses slowly after years or decades. Liver cirrhosis is a public health problem. It is usually associated with viral hepatitis, consumption of alcohol, metabolic syndrome, autoimmune processes, storage diseases, toxic substances, and medications. Cirrhosis is the fourteenth most common cause of death in adults throughout the world, the fourth in Europe and the ninth in the United States. The prevalence of this disease is underestimated because it is symptomatic it is not diagnosed in initial stages, and it usually goes to the decompensated stage at a rate of 5 to 7% per year. We review here the epidemiology, pathophysiology, etiology, and diagnosis of liver cirrhosis.
REVIEW Download: 112| View: 226| Comments: 0 | doi:10.20944/preprints201903.0116.v1
Subject: Medicine & Pharmacology, Oncology & Oncogenics Keywords: beetroot; betanins; cancer chemoprevention; anti-oxidant; inflammation; apoptosis
Online: 11 March 2019 (08:00:34 CET)
Carcinogenesis is the process whereby a normal cell is transformed into a neoplastic cell. This action involves several steps starting with initiation and followed by promotion and progression. Driving these stages are oxidative stress and inflammation, which in turn encompasses a myriad of aberrant gene expressions, both within the transforming cell population and the cells within the surrounding lesion. Chemoprevention of cancer with bioreactive foods or their extracted/purified components occurs via normalizing these inappropriate gene activities. Various foods/agents have been shown to affect different gene expressions. In this review we discuss whereby the chemoprevention activities of the red beetroot itself may disrupt carcinogenesis and the activities of the water soluble betalains extracted from the plant.
ARTICLE Download: 59| View: 157| Comments: 0 | doi:10.20944/preprints201903.0113.v1
Subject: Medicine & Pharmacology, General Medical Research Keywords: biosurfactant; Rhodotorula glutinis; antifungal activity; saprophytic fungi
Online: 11 March 2019 (07:50:52 CET)
Background: Biosurfactants are amphiphilic surface active compounds that produced by several microorganisms, including, bacteria and fungi. Biodegradability, low toxicity, applications diversity and functionality under extreme conditions are characterized them from chemically biosurfactants. It is found that, Rhodotorula species, read yeasts, have high potency for biosurfactant producing. Recently, antimicrobial activities of biosurfactants have been subjected for new antibiotic therapy. The aim of the present study was to evaluate biosurfactant production by the different strains of Rhodotorula species in laboratory conditions. In addition, antifungal activity of produced biosurfactant was assessed against several saprophytic fungi. In the present study 54 strains of Rhodotorula including, R. glutinis (48 strains), R. minuta (2 strains), R. mucilaginosa (2 strains) and Rhodotorula species (2 strains) were screened for biosurfactant production. The biosurfactant was produced using the Sabouraud dextrose broth medium and confirmed by specific tests. Antifungal assay was also evaluated by disk diffusion method and the serial dilutions of biosurfactant. In the present study, although all tested strains were capable to produce biosurfactant in vitro, the degree of biosurfactant production was varied among stains. 7.4% strains had the highest (+5) biosurfactant activity followed by 16.7%, 29.5%, 25.8% and 20.4% had +4, +3, +2 and +1, respectively. In the present study, all tested fungi were inhibited at 40 µl of biosurfactant. Rhodotorula species are appropriate organisms for the production of biosurfactants and R. glutinis strains have the greatest ability to producing biosurfactant than another species. Furthermore, our results were demonstrated that the produced biosurfactant by R. glutinis presented a valuable potential for biopharmaceutical applications.
Fri, 8 March 2019
ARTICLE Download: 53| View: 234| Comments: 0 | doi:10.20944/preprints201903.0105.v1
Subject: Medicine & Pharmacology, Psychiatry & Mental Health Studies Keywords: depression, bipolar disorder, oxidative and nitrosative stress, neuro-immune, inflammation, cytokines
Online: 8 March 2019 (09:13:40 CET)
Objective: Major depression (MDD) and a lifetime history of MDD are characterized by increased nitrosylation, while bipolar disorder type 1 (BP1), but not BP2, is accompanied by highly increased levels of oxidative stress and nitric oxide (NO) production. Nevertheless, it is unknown whether nitrosylation is involved in BP and whether there are differences in nitrosylation between BP1 and BP2.Methods: Serum IgM antibodies directed against nitroso (NO)-adducts were examined in MDD, BP1, BP2 and healthy controls, namely IgM responses to NO-cysteine, NO-tryptophan (NOW), NO-arginine and NO-albumin (SBA) in association with IgA/IgM responses to Gram-negative bacteria, IgG responses to oxidized low-density lipoprotein (oxLDL) and serum peroxides.Results: Serum IgM levels against NO adducts were significantly higher in BP1 and MDD as compared with healthy controls, whereas BP2 patients occupied an intermediate position. IgM responses to NO-albumin were significantly higher in BP1 and MDD than in BP2 patients. There were highly significant associations between the IgM responses to NO-adducts and IgG responses to oxLDL and IgA/IgM responses to Gram-negative bacteria.Conclusions: BP1 and MDD are characterized by an upregulation of the nitrosylome (the proteome of nitrosylated proteins), and increased IgM responses to nitrosylated conjugates. Increased nitrosylation may be driven by increased bacterial translocation and is associated with lipid peroxidation processes. Innate like (B1 and marginal zone) B cells and increased nitrosylation may play a key role in the major affective disorders through activation of immune-inflammatory and oxidative pathways, cardiovascular comorbidity and impairments in antioxidant defenses, neuro-glial interactions, synaptic plasticity, neuroprotection, neurogenesis, etc.
Thu, 7 March 2019
ARTICLE Download: 81| View: 260| Comments: 0 | doi:10.20944/preprints201903.0087.v1
Subject: Medicine & Pharmacology, Other Keywords: Tissue hypoxia; sleep disordered breathing; primary snoring; molecular tissue oximeter; tissue hyperoxia
Online: 7 March 2019 (10:19:48 CET)
Snoring gets no respect. It also gets little to no medical therapy. Why is this? How can something that is clearly pathological based on epidemiologic research not be diagnosed and treated with effective therapy? The problem is the lack of a credible, objective index of pathology during snoring. Pulse oximetry detects drops in arterial blood oxygen saturation (SpO2) associated with obstructive sleep apnea and hypopnea events in polysomnographic (PSG) testing. When no desaturation is present, evidence of sleep disturbance is required to indicate the presence of pathology. However, obstruction at the mild end of the continuum of sleep disordered breathing (SDB) can occur without producing a drop in SpO2 or sleep disturbance; in which case it is referred to as ‘primary snoring.’ Although statistically associated with co-morbidities of SDB, without there being a drop in SpO2 or sleep disturbance, primary snoring is not thought to be pathologic enough to warrant diagnosis or treatment. One promising means of detecting the pathological processes associated with primary snoring is molecular tissue oximetry, which detects skin tissue oxygen need, vs. oxygen supply. In cases of hypoxic challenge, regulatory mechanisms restrict blood flow to the skin to preferentially maintain blood oxygen supply to more vital organs. As a result, molecular tissue oximetry of the skin is a more sensitive measure of inadequate breathing than pulse oximetry measuring blood oxygen saturation. In this article we review molecular tissue oximetry technology and methodology and make the case that it is a promising tool for identifying pathology occurring in association with primary snoring.
REVIEW Download: 91| View: 239| Comments: 0 | doi:10.20944/preprints201903.0085.v1
Subject: Medicine & Pharmacology, Nutrition Keywords: fluid overload; resistance; reactance; bioelectrical impedance vector analysis; bioelectrical impedance spectroscopy; malnutrition
Online: 7 March 2019 (06:52:39 CET)
Although the need to assess hydration is well recognized, laboratory tests and clinical impressions are impractical and lack sensitivity to be clinically meaningful. Different approaches use bioelectrical impedance measurements to overcome some of these limitations and aid in classification of hydration status. One indirect approach utilizes single or multiple frequency bioimpedance in regression equations and theoretical models, respectively, with anthropometric measurements to predict fluid volumes (bioelectrical impedance spectroscopy; BIS) and estimate fluid overload based on deviation of calculated to reference extracellular fluid volume. Alternatively, bioimpedance vector analysis (BIVA) uses direct phase-sensitive measurements of resistance and reactance, measured at 50 kHz, normalized for height, then plotted on a bivariate graph, resulting in a vector with length related to fluid content normalized by standing height, and direction with phase angle that indexes hydration status. Comparison with healthy population norms enables BIVA to classify (normal, under- and over-) and rank (change relative to pre-treatment) hydration independent of body weight. Each approach has wide-ranging uses in evaluation and management of clinical groups with overhydration with an evolving emphasis on prognosis. This review discusses the advantages and limitations of BIS and BIVA for hydration assessment with comments on future applications.
Wed, 6 March 2019
ARTICLE Download: 82| View: 207| Comments: 0 | doi:10.20944/preprints201903.0082.v1
Subject: Medicine & Pharmacology, Veterinary Medicine Keywords: RAAS; Canine Congestive Heart Failure; Therapeutics
Online: 6 March 2019 (13:33:08 CET)
Congestive heart failure (CHF) is a major cause of morbidity and mortality with an increasing prevalence in human and canine populations. Similar to humans, overactivation of the renin-angiotensin aldosterone system is involved in the pathophysiology of CHF in dogs. Current therapeutic strategies for the management of canine CHF include the use of RAAS inhibitors, diuretics and inodilators. The present review summarizes data from our own research on the modulation of the renin-angiotensin cascade in dogs in dogs, together with new findings (including novel therapeutic targets) from the veterinary and the human literature.
Tue, 5 March 2019
REVIEW Download: 189| View: 503| Comments: 0 | doi:10.20944/preprints201812.0187.v2
Subject: Medicine & Pharmacology, Nutrition Keywords: Diabetes, eating patterns, DASH, Mediterranean, plant-based, low-carbohydrate
Online: 5 March 2019 (11:07:03 CET)
Over half of adult Americans now have diabetes or prediabetes and worse, this epidemic is now world-wide and shows no signs of slowing, with rates of both diabetes and diabetes-related health complications still rising. When advising patients with diabetes on food choices, many providers rely on nutrition guidelines provided by the American Diabetes Association (ADA), and these guidelines influence other recommendations across the globe. Given the alarming trends in diabetes, it is paramount to review the treatment guidelines to ensure they are based on rigorous and accepted scientific methods. Our review included the evidence cited by the ADA in support of its claims and recommendations for eating patterns to combat diabetes (see Description of Eating Patterns, Supplemental Appendix), as presented in the most current edition of the annual ADA’s Standards of Medical Care in Diabetes (2018 Standards). Our review also includes sources cited in the latest edition of the ADA’s Nutrition Therapy Recommendations for Adults with Diabetes (2014 Recommendations), which also informed the 2018 Standards. In October 2018 low carbohydrate was named as a recommended eating pattern by the ADA and European Association for the Study of Diabetes (EASD)5but only citations from the 2014 and early 2018 ADA documents were reviewed.
Mon, 4 March 2019
ARTICLE Download: 82| View: 177| Comments: 0 | doi:10.20944/preprints201903.0045.v1
Subject: Medicine & Pharmacology, Oncology & Oncogenics Keywords: Thienopyrimidines, RP-010, Prostate cancer, Metastasis, Wnt/β-catenin, Apoptosis.
Online: 4 March 2019 (13:37:02 CET)
Thienopyrimidines are a versatile group of compounds that contain a biologically active pharmacophore and reported to have anticancer efficacy in vitro. Here, we report for the first time, that thieno[3,2-d]pyrimidine - based compounds, designated the RP series, have efficacy in prostate cancer cells. The lead compound, RP-010, was efficacious in PC3 and DU-145 prostate cancer (PC) cells (IC50< 1µM). The cytotoxicity of RP-010 was significantly lower in normal cells. RP-010 (0.5, 1, 2, and 4 µM) arrested prostate cancer cells in the G2 phase of the cell cycle, induced mitotic catastrophe and apoptotic signaling in both PC cell lines. Mechanistic studies suggested that RP-010 (1 and 2 µM) inhibits the wingless-type MMTV (Wnt)/β-catenin signaling pathway, mainly by inducing β-catenin fragmentation, while down regulating important proteins in the pathway, i.e. LRP-6, DVL3, and c-Myc. Interestingly, RP-010 (1 and 2 µM) induced the nuclear translocation of the negative feedback proteins, Naked 1 and Naked 2, in the signaling pathway. In addition, RP-010 (0.5, 1, 2, and 4 µM) significantly decreased the migration and invasiveness of PC cells in vitro. Finally, RP-010 did not produce significant toxic effects in zebrafish at concentrations up to 6 µM. In conclusion, RP-10 is a promising anticancer compound in metastatic prostate cancer and did not produce overt toxicity in an in vivo zebrafish model. Future mechanistic and efficacy studies are needed in-vivo to optimize the lead compound RP-010 for clinical use.
ARTICLE Download: 62| View: 155| Comments: 0 | doi:10.20944/preprints201903.0042.v1
Subject: Medicine & Pharmacology, Oncology & Oncogenics Keywords: pancreatic cancer, T cells, cancer stem cells, CD8, PD-L1, CD44, CD133, immunotherapy
Online: 4 March 2019 (13:28:43 CET)
Cancer immunotherapy targeting immune checkpoints has exhibited promising clinical outcomes in many cancers, but it offers only limited benefits for pancreatic cancer (PC). Cancer stem cells (CSCs), a minor subpopulation of cancer cells, play important roles in tumor initiation, progression, and drug resistance. Accumulating evidence suggests that CSCs employ immunosuppressive effect to evade the immune recognition. However, clinical implications of the associations among CD8+ T cells infiltration, programmed death receptor ligand-1 (PD-L1) expression, and CSCs existence are poorly understood in PC. Immunostaining and quantitative analysis were performed to assess CD8+ T cells infiltration, PD-L1 expression, and their relationship with CD44+/CD133+ CSCs and disease progression in PC. CD8+ T cells infiltration was associated with better survival while PD-L1 expression was correlated with PC recurrence. Both the low CD8+ T cells infiltration/high PD-L1 expression group and the high CD8+ T cells infiltration/high PD-L1 expression group show high levels of CD44+/CD133+ CSCs, but patients with low CD8+ T cells infiltration/high PD-L1 expression had worse survival and higher recurrence risk than those with high CD8+ T cells infiltration/high PD-L1 expression. Moreover, CD8+ T cells infiltration could reduce unfavorable prognostic effect of high co-expression of PD-L1 and CD44/CD133. Our study highlights an interaction among CD8+ T cells infiltration, PD-L1 expression, and CD44+/CD133+ CSCs existence, which contributes to PC progression and immune evasion.
ARTICLE Download: 87| View: 150| Comments: 0 | doi:10.20944/preprints201903.0036.v1
Subject: Medicine & Pharmacology, Oncology & Oncogenics Keywords: breast neoplasms, ductal carcinoma in situ (DCIS), gene expression profiling, high-throughput nucleotide sequencing, infiltrating ductal carcinoma (IDC), paraffin embedding, sequence alignment, transcriptome
Online: 4 March 2019 (10:23:25 CET)
The rapid expansion of transcriptomics from increased affordability of next-generation sequencing (NGS) technologies generates rocketing amounts of gene expression data across biology and medicine, and notably in cancer research. Concomitantly, many bioinformatics tools were developed to streamline gene expression analysis and quantification. We tested the concordance of NGS RNA sequencing (RNA-seq) analysis outcomes between the two predominant programs for reads alignment, HISAT2 and STAR, and the two most popular programs for quantifying gene expression in NGS experiments, edgeR and DESeq2, using RNA-seq data from a series of breast cancer progression specimens, which include histologically confirmed normal, early neoplasia, ductal carcinoma in situ and infiltrating ductal carcinoma samples microdissected from formalin fixed, paraffin embedded (FFPE) breast tissue blocks. We identified significant differences in aligners’ performance: HISAT2 was prone to misalign reads to retrogene genomic loci, STAR generated more precise alignments, especially for early neoplasia samples. edgeR and DESeq2 produced similar lists of differentially expressed genes in stage comparisons, with edgeR producing more conservative, though shorter, lists of genes. Albeit, Gene Ontology (GO) enrichment analysis revealed no skewness in significant GO categories identified among differentially expressed genes by edgeR vs DESeq2. As transcriptome analysis of archived FFPE samples becomes a vanguard of precision medicine, identification and fine-tuning of bioinformatics tools becomes critical for clinical research. Our results indicate that STAR and edgeR are well-suited tools for differential gene expression analysis from FFPE samples.
Fri, 1 March 2019
ARTICLE Download: 51| View: 163| Comments: 0 | doi:10.20944/preprints201903.0016.v1
Subject: Medicine & Pharmacology, Obstetrics & Gynaecology Keywords: Costs, delivery, cesarean section, ethnicity, maternal morbidity
Online: 1 March 2019 (14:33:15 CET)
Recent policy and service provision recommends a woman-centered approach to maternity care and encourages the development of personalized models of clinical assistance. As ethnicity has been recognized as determinant in the risk calculation of some obstetric complication, our aim was to assess costs for birth assistance according to the maternal ethnicities. In a five-year period (2012-16) all women admitted for delivery at the Department of Obstetrics and Gynaecology, Fondazione Policlinico Universitario ‘A. Gemelli’ IRCCS, Rome, Italy were investigated. Economic evaluations were performed by using the ‘diagnosis-related group’ (DRG) approach. Cost analysis was completed by including maternal ethnicity, delivery mode and perinatal complications. A total of 18,093 patients were involved in the analysis. An overall care expense of €42.663.481 was calculated. Caucasian was the main ethnicity (90.7%), leaving the minority groups to 9.3%. Vaginal delivery (VD) was the most common mode of delivery in all ethnic clusters, with a global rate of 59.6%. Not including Asiatic women, increased CS rates were recorded in all minority ethnic groups (Maghreb (51.5%) and Afro-Caribbean (47.8%)). A double incidence of complicated VD was observed in the minority groups, primarily among Afro-Caribbean (69.9%), followed by Asiatic (64.1%), Maghreb (63.2%) and Latin-America (62.7%) patients. By logistic regression, Afro-Caribbean delivering women had a significant increased risk of complicated CS among all subgroups. Minority groups (Afro-Caribbean, in particular) increase the health care cost for birth assistance due to higher incidence of adverse perinatal outcomes.
ARTICLE Download: 48| View: 164| Comments: 0 | doi:10.20944/preprints201902.0266.v1
Subject: Medicine & Pharmacology, Pharmacology & Toxicology Keywords: β2-adrenergic receptor; cAMP; cardiac myocytes; CRISPR; Epac1; fibrosis; osteopontin; signal transduction
Online: 1 March 2019 (05:15:17 CET)
Cardiac β2-adrenergic receptors (ARs) are known to inhibit collagen production and fibrosis in cardiac fibroblasts and myocytes. The β2AR is a Gs protein-coupled receptor (GPCR) and, upon its activation, stimulates generation of cyclic 3', 5'-adenosine monophosphate (cAMP). cAMP has two effectors: protein kinase A (PKA) and the exchange protein directly activated by cAMP (Epac). Epac1 has been shown to inhibit cardiac fibroblast activation and fibrosis. Osteopontin (OPN) is a ubiquitous pro-inﬂammatory cytokine, mediating also fibrosis in several tissues, including the heart. OPN underlies several cardiovascular pathologies, including atherosclerosis and cardiac adverse remodeling. We have found that the cardiotoxic hormone aldosterone transcriptionally upregulates OPN in H9c2 rat cardiac myoblasts, an effect prevented by endogenous β2AR activation. Additionally, CRISPR-mediated OPN deletion enhances cAMP generation in response to both b1AR and β2AR activation in H9c2 cardiomyocytes, leading to upregulation of Epac1 protein levels. These effects render β2AR stimulation capable of completely abrogating transforming growth factor (TGF)-β-dependent fibrosis in OPN-lacking H9c2 cardiomyocytes. Finally, OPN interacts constitutively with Gas subunits in H9c2 cardiac cells. Thus, we have uncovered a direct inhibitory role of OPN in cardiac β2AR anti-fibrotic signaling via cAMP/Epac1. OPN blockade could be of value in the treatment and/or prevention of cardiac fibrosis.
Wed, 27 February 2019
ARTICLE Download: 70| View: 235| Comments: 0 | doi:10.20944/preprints201902.0258.v1
Subject: Medicine & Pharmacology, Nutrition Keywords: alcohol; natural wine; blood alcohol content; breathalyzer; pesticides
Online: 27 February 2019 (12:17:33 CET)
Background When equalized for alcohol content by volume, however, not all alcoholic beverages have the same effect on blood alcohol concentration (BAC) or neurotoxicity. The aim of this study was to investigate differences between metabolism of a natural wine and of a conventional wine. Methods Fifty-five healthy male volunteers were randomly administered the equivalent of 2 units of alcohol (24 g of ethanol) of a natural or of a conventional wine, and one week later received the same dose of the other wine. At each of the two sessions, a breathalyzer was used to estimate BAC levels before the intake of the wine and then every twenty-minute for 2 hours. The entire study was conducted in triple-blind conditions. Results The blood alcohol curves after consumption of the two different wines diverged significantly at the twenty-minute mark (T20) and then again at their peak values. In both cases, the BAC induced by the natural wine was lower than the one corresponding to the conventional wine (T20 0.44 vs. 0.49 [p<0.012], peak 0.56 vs. 0.60 [p<0.032]). Conclusions The results of the study suggest that natural and conventional wines have a different effect on BAC. The alcohol in the natural wine seems to be absorbed more slowly. Different techniques applied in the production chain likely lead to the development of different amino acids and different types and amounts of antioxidants in the two wines. These compounds, in turn, may affect the kinetics of alcohol absorption and metabolism. The presence or absence of residues of pesticides and other agrochemicals, differences in sugar and fiber content, and the use of either indigenous or selected yeasts, are additional factors that may contribute to the differences observed. If this hypothesis is confirmed, it could have important public health and policy implications.
ARTICLE Download: 43| View: 55| Comments: 0 | doi:10.20944/preprints201902.0251.v1
Subject: Medicine & Pharmacology, Other Keywords: Addis Ababa; living place; market place; packaged water; perception
Online: 27 February 2019 (10:49:22 CET)
Descriptive research design was used to select 200 respondents (i.e., 100 from each study places) following purposive sampling technique on two study areas (Market; Living). Personal observation and interview with retailers were done to triangulate the collected data from the formal survey. The collected data was analyzed using SPSS version 20 software program. Descriptive statistical measurements, Index and multinomial regression model was calculated to assess the relationship between customers point of emphasis during packaged water buying and respondents demographic variables. Majority of the respondent who frequently purchase packaged water generated a monthly income between 5000 and 10000 Birr. Television and radio was ranked first compare to other Media. Living place customers were more health concerned as compared to market place customers. Market place customer’s primarily give emphasis to price of packaged water. Almost all (97%) customers did not have the awareness towards packaged water standards. Only 86(43%) of the total respondents checked the chemical composition, of which 74(85%) of the respondents did not understand it. Customers sex, educational level and health status showed significant relationship with choice of packaged water quality -1.42(p<0.05), price -2.45(P<0.01) and health status -1.80(P<0.05) in market place and living places, respectively.
REVIEW Download: 117| View: 161| Comments: 0 | doi:10.20944/preprints201902.0245.v1
Subject: Medicine & Pharmacology, Oncology & Oncogenics Keywords: cyclin-dependent kinases; cyclin-dependent kinase 4 and 6 inhibitors; targeted therapies; breast cancer
Online: 27 February 2019 (04:48:54 CET)
Breast Cancer (BC) is the second most common type of cancer worldwide and displays the highest cancer-related mortality among women worldwide. Targeted therapies have revolutionized the way BC has been treated in the last decades improving life expectancies of millions of women. Among the different molecular pathways that have been of interest for the development of targeted therapies are the Cyclin-Dependent Kinases (CDK). CDK inhibitors are a class of molecules that already exist in nature and those belonging to the INK4 protein family specifically inhibit the CDK4/6 proteins. CDK4/6 inhibitors specifically block the transition from the G1 to the S phase of the cell cycle by dephosphorylation of the retinoblastoma tumor suppressor protein. In the past four years CDK4/6 inhibitors palbociclib, ribociclib, and abemaciclib received their first FDA approval for the treatment of Hormone Receptor (HR)-positive and Human Epidermal growth factor Receptor 2 (HER2)-negative breast cancer after showing significant improvements in progression-free survival in the PALOMA-1, MONALEESA-2 and the MONARCH-2 randomized clinical trials, respectively. After the encouraging results from these clinical trials, CDK4/6 inhibitors have also been investigated in the other BC subtypes. In HER2-positive BC, combination of CDK4/6 inhibitors with HER2-targeted therapies showed promise in preclinical studies and their clinical evaluation is ongoing. Moreover, in triple-negative BC, CDK4/6 inhibitors efficacy has been investigated in combination with other targeted therapies or immunotherapies. This review summarizes the molecular background and clinical efficacy of CDK4/6 inhibitors as single agents or in combination with other targeted therapies for the treatment of BC. Future directions of ongoing clinical trials and predictive biomarkers will be further debated.
Tue, 26 February 2019
ARTICLE Download: 90| View: 166| Comments: 0 | doi:10.20944/preprints201902.0236.v1
Subject: Medicine & Pharmacology, Psychiatry & Mental Health Studies Keywords: depression; neuro-immune; cytokines; inflammation; indoleamine 2,3-dioxygenase
Online: 26 February 2019 (11:05:49 CET)
Major depressive disorder (MDD) is associated with changes in the levels of the cations calcium (Ca) and magnesium (Mg) as well as circulating pro- and anti-inflammatory cytokines. The immune-inflammatory nature of MDD has encouraged researchers to use anti-inflammatory drugs as an adjuvant treatment for MDD. However, the effect of this treatment on cation levels has not been studied. The present study examined a) differences in both cations between drug-naïve MDD patients and controls, and b) the effects of a combination of sertraline and ketoprofen, an anti-inflammatory drug, on Ca and Mg (both total and ionized). In the same patients we also examined the associations between both cations and IL-1β, IL-4, IL-6, IL-18, IFN-γ, TGF-β1, zinc and indoleamine 2,3-dioxygenase (IDO). Clinical improvement was estimated using the Beck Depression Inventory-II (BDI-II) at baseline and after follow up for two months. Serum Ca and Mg (total and ionized) were significantly lower in MDD patients as compared with controls, while treatment significantly increased calcium but decreased magnesium levels. There were significant and inverse correlations between the BDI-II scores from baseline to endpoint and Ca (both total and ionized), but not Mg, levels. The effects of calcium on the BDI-II score remained significant after considering the effects of zinc, IDO and an immune activation z unit weighted composite score based on the sum of all cytokines. There was a significant and inverse association between this immune activation index and calcium levels from baseline to endpoint. In conclusion, reduced levels of both cations play a role in the pathophysiology of major depression. Increased calcium levels are coupled to the clinical efficacy of antidepressants and attenuation of immune activation. The suppressant effect of antidepressants on Mg levels may be a side effect of those drugs. New antidepressant treatments should be developed that increase the levels both Ca and Mg.
Mon, 25 February 2019
ARTICLE Download: 69| View: 143| Comments: 0 | doi:10.20944/preprints201902.0224.v1
Subject: Medicine & Pharmacology, Sport Sciences & Therapy Keywords: WHOQOL; Senior Fitness Test; exercises; actigraph; accelerometry; elderly; older adults; physical fitness
Online: 25 February 2019 (14:21:58 CET)
The aim of this study was to identify the differences in functional fitness and quality of life among women over 60 years of age depending on their level of objectively measured physical activity (PA) according to Global Recommendations on Physical Activity for health. The study used cross-sectional design with 213 volunteered women over 60 years of age. Physical activity was monitored for 7 days of the week using Actigraph Gt3x monitor. The Senior Fitness Test battery and Hand-grip strength tests were performed to assess functional fitness. Quality of life was self-reported using short version of WHOQOL-brief questionnaire. Women who met the PA recommendations achieved slightly better results in most functional tests and all domain of quality of life. The significant differences were found in upper body strength, dynamic balance and social relationships domain of quality of life. Physical activity programs developed on the basis of WHO recommendations have the potential to improve functional capacity and quality of life. However, further experimental studies in this area are required.
REVIEW Download: 105| View: 180| Comments: 0 | doi:10.20944/preprints201902.0220.v1
Subject: Medicine & Pharmacology, Gastroenterology Keywords: Acute pancreatitis; Etiology; Biliary pancreatitis; Systematic review; Meta-analysis
Online: 25 February 2019 (08:58:59 CET)
Introduction: Cholelithiasis and consumption of alcohol are the most frequent causes of acute pancreatitis (AP), accounting for about 30 to 40% of the cases, respectively. The frequency of acute biliary pancreatitis is high in a certain population in Brazil. Objective: To estimate the global frequencies of acute biliary pancreatitis (ABP), acute alcoholic pancreatitis (AAP) and the cases considered as acute idiopathic pancreatitis (AIP) in studies published from October 2006 to December 31, 2018. Methods: A systematic review of observational studies was performed from October 2006 to December 31, 2018. A meta-analysis by the random effects model was used to calculate the frequencies of global ABP, AIP and AAP and subgroups. Results: Forty-six studies representing 2,341,007 AP cases were included in 36 countries. The overall estimate for acute biliary pancreatitis (ABP) was 41.6% (95% CI 39.2-44.1), followed by acute alcoholic pancreatitis (AAP) with 20.5% (95% CI) 16.6- 24.6) and acute idiopathic pancreatitis (AIP) in 18.3% (95% CI 15.1-27.7). Conclusion: ABP is the most prevalent etiology of AP, being two times more frequent than second-placed pancreatitis. Latin America has a frequency for ABP much higher than the rest of the world. The importance of the etiologic diagnosis is the treatment of the cause for prevention of recurrence.
Thu, 21 February 2019
ARTICLE Download: 52| View: 229| Comments: 0 | doi:10.20944/preprints201902.0199.v1
Subject: Medicine & Pharmacology, Other Keywords: polymyalgia rheumatica; elderly-onset rheumatoid arthritis; sleep impairment; seronegative rheumatoid arthritis; elderly patients
Online: 21 February 2019 (09:55:22 CET)
Background: Differential diagnosis between polymyalgia rheumatica (PMR) and seronegative elderly-onset rheumatoid arthritis (SEORA) is not easy, to the point that in the past they were considered the same entity. In these patients, sleep disorders have been scarcely assessed, and considered as expression of mood disorders such as depression and anxiety. Methods: In 38 Caucasian elderly patients (median age: 73.9 ± 8.06 years) consecutively referred to two outpatient clinics from January to May 2018 with diagnosis of PMR and SEORA, sleep impairment was assessed using the Medical Outcomes Study-Sleep scale (MOS-SS). Depression and anxiety were assessed using the Neuropsychiatric Inventory (NPI) score, with point 0 for absent and point 3 for severe. Comorbidities were assessed using the Cumulative Illness Rating Scale (CIRS). Patients taking medications used to treat sleep disturbance or that could favor sleep disturbances were excluded. The study was approved by the local ethics committee and carried out in accordance with the Helsinki Declaration, revised 2013. Every patient signed an informed consent form at the time of the first visit. Results: MOS-SS total point in PMR patients was significantly higher than in SEORA patients (47.60 ± 8.4 vs 28.26 ± 12.4; P = 0.000). After six-month therapy with prednisone (12.5–15 mg/day, followed after 4 weeks by gradual tapering), MOS-SS total point improved in the two groups of patients, with no significant difference (17.0 ± 6.2 vs 17.8 ± 4.2; P = 0.644). No correlation was found between MOS-SS and comorbidities, and between MOS-SS, anxiety or depression. Conclusions: Our data suggest that the assessment of sleep impairment could be very useful in the differential diagnosis between PMR and SEORA. Up today, the reasons why patients with PMR have—at the time of diagnosis—a sleep impairment higher than SEORA are speculative. Further ad hoc complementary studies in multicenter cohorts are needed.
ARTICLE Download: 36| View: 223| Comments: 0 | doi:10.20944/preprints201901.0082.v3
Subject: Medicine & Pharmacology, Oncology & Oncogenics Keywords: dog; prostatic tissue; extracellular matrix; picrosirius; immunohistochemistry
Online: 21 February 2019 (06:52:00 CET)
This study aimed to investigate Coll-I, III, IV and elastin in canine normal prostate and PC, using Picrosirius red (PSR) and Immunohistochemical (IHC) analysis. Eight normal prostates and 10 PC from formalin-fixed, paraffin-embedded samples were used. Collagen fibers area was analyzed with ImageJ software. The distribution of Coll-I and Coll-III was approximately 80% around prostatic ducts and acini, 15% among smooth muscle and 5% surrounding blood vessels, in both normal prostate and PC. There was a higher median area of Coll-III in PC, when compared to normal prostatic tissue (p=0.001 for PSR and p= 0.05 for IHC). Immunostaining for Coll-IV was observed in the basal membrane of prostate acini, smooth muscle, blood vessels, and nerve fibers of normal and PC samples. Although there was no difference in Coll-IV area between normal tissue and PC, tumors with Gleason score 10 showed absence of Coll-IV, when compared to scores 6 and 8 (p=0.0095). Elastic fibers were found in the septa dividing the lobules and around the prostatic acini of normal samples, and was statistically higher in PC, compared to normal tissue (p=0.00229). Investigation of ECM components brings new information and should be correlated with prognosis in future studies.
Wed, 20 February 2019
ARTICLE Download: 61| View: 222| Comments: 0 | doi:10.20944/preprints201902.0187.v1
Subject: Medicine & Pharmacology, Pediatrics Keywords: clinical characteristics; febrile children; Kawasaki disease
Online: 20 February 2019 (09:10:15 CET)
Background: Kawasaki disease (KD) is a form of vasculitis that primarily affects children under the age of 5 years old. Patients may be missed diagnosis when initial clinical symptoms do not fulfill the traditional criteria. We aimed to analyze factors that clinicians could use to differentiate febrile children suspected of KD. Method: We retrospectively enrolled a total of 83 febrile children who were initially suspected of KD, but they did not meet the American Heart Association (AHA) criteria for a diagnosis. However, some of these patients were diagnosed with KD during their second visit. We analyzed patients' characteristics, clinical symptoms, and laboratory data. Results: In total, 50 patients were enrolled in the study. Of those, ten patients were diagnosed with KD on their second visit (group 1), while the other 40 patients still did not fit a KD diagnosis (group 2). A patient with a neutrophil to lymphocyte ratio greater than 1.33 combined with a C-reactive protein more than 33 mg/L was more likely to have KD. Conclusion: Among patients suspected of KD that did not initially meet the criteria, clinicians should pay special attention to elevated neutrophil-to-lymphocyte ratios and CRP levels and closely follow up such patients.
Tue, 19 February 2019
ARTICLE Download: 75| View: 280| Comments: 0 | doi:10.20944/preprints201902.0182.v1
Subject: Medicine & Pharmacology, Psychiatry & Mental Health Studies Keywords: schizophrenia; inflammation; neuro-immune; oxidative stress; TRYCATs; leaky gut
Online: 19 February 2019 (12:14:29 CET)
Deficit schizophrenia is characterized by leaky tight and adherens junctions and bacterial translocation. Here we examine whether (deficit) schizophrenia is accompanied by leaky paracellular, transcellular and vascular barriers in the gut and blood brain barriers. We measured IgA responses to occludin, claudin-5, E-cadherin and β-catenin (paracellular pathway, PARA), talin, actin, vinculin and epithelial intermediate filament (transcellular pathway, TRANS) and plasmalemma vesicle-associated protein (PLVAP, vascular pathway) in 78 schizophrenia patients and 40 controls. IgA responses to claudin-5, E-cadherin and β-catenin, the sum of the four PARA proteins and the ratio PARA/TRANS were significantly higher in deficit schizophrenia than in non-deficit schizophrenia and controls. A large part of the variance in PHEMN (psychosis, hostility, excitation, mannerism and negative) symptoms, psychomotor retardation, formal thought disorders, verbal fluency, word list memory, word list recall and executive functions was explained by the PARA/TRANS ratio coupled with plasma IgA responses to Gram-negative bacteria, IgM to malondialdehyde, CCL-11 (eotaxin), IgA levels of the ratio of noxious to more protective tryptophan catabolites (NOX/PRO TRYCATs) and a plasma immune activation index. Moreover, IgA levels to Gram-negative bacteria were significantly associated with IgA to E-cadherin, β-catenin and PLVAP, while IgA levels to claudin-5 were significantly predicted by IgA to E-cadherin, NOX/PRO TRYCAT ratio, Gram-negative bacteria and CCL11. The phenomenology of the deficit syndrome is to a large extent explained by the cumulative effects of lowered natural IgM, breakdown of the paracellular and vascular pathways, increased bacterial translocation, peripheral immune-inflammatory responses and indices of BBB breakdown.
Mon, 18 February 2019
ARTICLE Download: 77| View: 238| Comments: 0 | doi:10.20944/preprints201902.0169.v1
Subject: Medicine & Pharmacology, Dentistry Keywords: Tooth size; Tooth size discrepancy; Bolton ratios; Meta-analysis; Systematic review
Online: 18 February 2019 (17:17:20 CET)
Introduction: The purposes of this study were to seek for overall ratio (OR) and anterior ratio (AR) patients data in normal occlusion and Angle’s malocclusion studies, and to assess if such results support Bolton’s standards as general references. Methods: Pubmed, Medline, CENTRAL and Scholar databases were searched up to February 2018 (CRD42018088438). Gray literature was explored through OpenGray. Non-randomized clinical studies, published in English and assessing Bolton’s OR and AR in normal occlusion and Angle’s malocclusion groups (Class I, Class II, Class II division 1, Class 2 division 2, Class III) patients were included. OR and AR means and standard deviations (SD) were collected. Potential covariates (study design, publication year, country where the study was conducted, number of cases, gender, mesiodistal measurement method, and calibration method) were also extracted. The National Health Heart Lung, and Blood Institute’s Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies was used to assess each included studies quality. Pairwise Random-Effects and Multilevel Bayesian Network Meta-Analyses were used to synthesize available data. Results: Fifty-two observational studies were included (8872 participants; male/females 2674/3272; 16 studies lacked gender information). For normal occlusion, global pooled estimates for OR and AR means were 91.74% (95% CI: 91.37-92.10) and 78.24% (95% CI: 77.85-78.63), respectively. We could identify on Angle’s Class III patients meaningful OR and AR mean deviations from normal occlusion (0.89, 95% credible interval [CrI], 0.66-1.12, and 0.66, 95% CrI, 0.38-0.94, respectively), while on Class I patients we found a meaningful mean deviation from normal occlusion only for OR (0.25, 95% CrI, 0.03-0.47). Concerning gender impact, male patients presented higher OR (0.30, 95% CI 0.00-0.59) and AR (0.41, 95% CI 0.00-0.83) mean values than females in Class I. Conclusions: The results show that global pooled OR and AR mean values for normal occlusion patients are slightly above Bolton’s original values. Class I, for OR mean values, and Class III, for both OR and AR, are proportionally larger than normal occlusion patients. Gender had almost no impact on teeth mesiodistal proportion.
ARTICLE Download: 54| View: 217| Comments: 0 | doi:10.20944/preprints201902.0161.v1
Subject: Medicine & Pharmacology, Other Keywords: Climate variability; dengue hemorrhagic fever incidence; average temperature; humidity; rainfall; Surabaya
Online: 18 February 2019 (10:52:46 CET)
Dengue hemorrhagic fever is an arboviral infectious disease that has occurred frequently as an extraordinary event due to its fast spread and lethal potential in Indonesia. The vector Aedes aegypti is sensitive to climate variability. This study determines the relationship between climate variability and dengue hemorrhagic fever in Surabaya, East Java, Indonesia from 2009 to 2017. This study used the monthly dengue hemorrhagic fever incidence obtained from the Surabaya Health Office and the monthly climate variability parameters (average temperature, rainfall, humidity) obtained from the Indonesian Agency for Meteorology, Climatology and Geophysics and website www.worldweatheronline.com. Data analysis was done using One-Sample Kolmogorov Smirnov Test and Spearman non-parametric correlation test. The results showed a correlation between all three climate variability parameters with dengue hemorrhagic fever incidence (average temperature p<0.05, r=-0.603; rainfall p<0.05, r=0.407; humidity p<0.05, r=0.7). Average temperature is negatively correlated to dengue hemorrhagic fever incidence, while rainfall and humidity are positively correlated to dengue hemorrhagic fever incidence. This study shows preliminary evidence on the correlation of climate variability and dengue hemorrhagic fever in Surabaya, East Java, Indonesia.
ARTICLE Download: 79| View: 205| Comments: 0 | doi:10.20944/preprints201902.0149.v1
Subject: Medicine & Pharmacology, Pharmacology & Toxicology Keywords: tacrolimus; CYP3A5; liver transplant; pharmacokinetics
Online: 18 February 2019 (09:14:34 CET)
The body of evidence available in paediatrics population is limited for making clinical decisions regarding pharmacotherapy optimization of tacrolimus. The objective of this study was to estimate the frequency of CYP3A5 genetic polymorphisms and their relationship with tacrolimus requirements in paediatric population. This was a longitudinal cohort study, with two-year follow-up of 77 patients under 18 who had liver transplant over the period 2009-2012 at the Paediatric Hospital J. P Garrahan. Tacrolimus levels from day 5 to 2-year post-transplant were obtained from hospital records of routine therapeutic drug monitoring. The genotyping of CYP3A5 (CYP3A5*1/*3 or *3/*3) were performed in liver biopsies of both the donor and the recipient. Recipients frequency of CYP3A5 *1 expression was 37.1% and 32.2% for Donors. Patient who received an organ expresser showed lower Co/dose especially after 90 days post-surgery. The role of each polymorphism is different according to days after transplantation proceeds and it must be taken into account to optimize the benefits of TAC therapy during the post-transplant induction and maintenance phase.
ARTICLE Download: 49| View: 199| Comments: 0 | doi:10.20944/preprints201902.0145.v1
Subject: Medicine & Pharmacology, Dentistry Keywords: multilevel analysis; periodontal disease; nonsurgical periodontal therapy; risk factor; modelling; periodontal healing
Online: 18 February 2019 (07:31:01 CET)
This retrospective study aimed to investigate the effect of known risk factors on nonsurgical periodontal treatment (NSPT) response using a pocket depth fine-tuning multilevel linear model (MLM). Thirty-seven patients (24 males and 13 females) with moderate to severe chronic periodontitis were treated with nonsurgical periodontal therapy. Follow-up visits at 3, 6, and 12 months included measurement of several clinical periodontal parameters. Data were extracted from a database system. Probing depth (PD) and Clinical Attachment Loss (CAL) reductions after NSPT in an overall of 1416 initially affected sites (baseline PD ≥ 4 mm), distributed on 536 teeth, were analyzed against known risk factors at three hierarchical levels (patient, tooth and site). The variance component models fitted to assess the three-level variance of PD and CAL decrease for each post-treatment follow-up showed that all levels contributed significantly to the overall variance (P < 0.001). Patients that underwent NSPT and were continually monitored had very curative results. All three hierarchical levels included risk factors who had impact on the to influence the magnitude of PD and CAL reduction. Specifically, the tooth’s type, surfaces involved and teeth mobility site-level risk factors showed the highest influence on these reductions, being highly relevant factors for the NSPT success.
Fri, 15 February 2019
ARTICLE Download: 71| View: 452| Comments: 0 | doi:10.20944/preprints201902.0142.v1
Subject: Medicine & Pharmacology, Psychiatry & Mental Health Studies Keywords: CIDER; post-traumatic stress disorder; trauma; adolescent; trauma-focused group psychotherapy
Online: 15 February 2019 (15:04:13 CET)
We aimed to evaluate the feasibility and preliminary efficacy of trauma-focused group psychotherapy in adolescents who experienced traumatic events in Korea. Participants were assigned and recruited from two sites in Korea. Children in Disaster: Evaluation and Recovery (CIDER) V1.0 is a trauma-focused group psychotherapy approach consisting of psychoeducation, normalization, stabilization, and techniques of managing the traumatic memory. The CIDER intervention consists of eight 50-minute-long sessions. The effectiveness of the intervention was evaluated using the Korean version of the Children’s Response to Traumatic Events Scale-Revised (K-CRTES-R), the Beck Depression Inventory (BDI), the State Anxiety Inventory for Children (SAIC), and the Pediatric Quality of Life Inventory (PedQL). Data were analyzed by Wilcoxon signed-rank test. We recruited 22 traumatized adolescents (mean age 16 years; SD 1.43; range 13–18 years old; 71.4% boys) in this pilot study. The K-CRTES-R scores were significantly improved (Z = −2.85, p < 0.01). The BDI demonstrated the effectiveness of the therapy (Z = −2.35, p < 0.05). The assessment of the PedQL supported the effect of CIDER (Z = −3.08, p < 0.01). However, there was no statistically significant differences in the SAIC scores (Z = −1.90, p > 0.05). The results show that there is preliminary evidence that CIDER intervention reduces post-traumatic stress and depressive symptoms and improves quality of life. Our findings indicate that CIDER is feasible for treating adolescents exposed to traumatic events. Larger controlled trials are needed to establish the efficacy of this trauma-focused group psychotherapy and examine its impact on post-traumatic stress disorder.
Thu, 14 February 2019
ARTICLE Download: 499| View: 1446| Comments: 0 | doi:10.20944/preprints201902.0139.v1
Subject: Medicine & Pharmacology, Oncology & Oncogenics Keywords: Cancer; Turbulence; Navier-Stokes; Chaos; Complexity; Fractals; Fluid Dynamics; Reprogramming
Online: 14 February 2019 (14:04:51 CET)
As we transition towards an era of Computational Medicine and Deep Learning Healthcare, our mathematical models of cancer dynamics must be revised. As such, recent evidences support the perspective that cancer-microenvironment interactions consist of turbulent flows and strange attractor dynamics. Using a systems biology approach, cancer pattern formation, energy flow, protein folding kinetics, stem cell fate bifurcations and metastatic invasion are hereby discussed within the context of hydrodynamical turbulence. Cancer is presented as a three-dimensional Navier-Stokes equations global regularity, smoothness and existence problem.
ARTICLE Download: 62| View: 516| Comments: 0 | doi:10.20944/preprints201902.0131.v1
Subject: Medicine & Pharmacology, Dentistry Keywords: Platelet-rich fibrin, A-PRF, Gingival graft harvesting, Healing, Periodontal plastic surgery
Online: 14 February 2019 (10:29:29 CET)
This study aimed to investigate the healing effect of advanced platelet-rich fibrin (A-PRF) clot membranes in the reduction of palatal wounds resulting from free gingival graft (FGG) harvesting, in the re-epithelization rate and in the pain experience after surgery. Twenty-five patients requiring soft tissue augmentation (gingival recession coverage or keratinized gingiva augmentation) participated in this prospective randomized clinical study. After FGG harvesting, the test group (n=14) received A-PRF clot membranes at the palatal wound and the control group (n=11) a gelatin sponge. Epithelialization rate of the palatal wound, wound healing area, correspondent percentage of reduction and post-surgical pain experience were assessed. The follow-up period was 90 days. There was a significantly higher reduction of the palatal wound area in the A-PRF group vs. the control group, at 7 (p<0.001), 14 (p=0.009) and 30 days (p<0.001) follow-up. The maximum difference between groups was attained at 30 days (91.5% for A-PRF vs. 59.0% for the control group). At 14 days a significant difference in the proportion of patients showing total epithelization was found: 64.3% for A-PRF vs. 9.1% for the control group (p=0.012). At 90 days, both groups showed total recovery. Overall, the control group experienced a higher level of pain and discomfort until the 14th day, being significantly higher on the second day (p=0.013). The results suggest that A-PRF membranes haste the healing process by promoting a greater reduction along the recovery period and an apparent less painful postoperative period.
Wed, 13 February 2019
ARTICLE Download: 74| View: 510| Comments: 0 | doi:10.20944/preprints201902.0123.v1
Subject: Medicine & Pharmacology, Dentistry Keywords: Medical Illiteracy, Public Awareness, Periodontal Diseases, Global Burden of Disease, Google Trends
Online: 13 February 2019 (15:54:04 CET)
Background: The progression of periodontal diseases at national Portuguese level and its public awareness are of great interest, mainly due to the high burden of periodontitis. Objectives: To evaluate the prevalence progression of periodontal diseases in Portugal and correspondent public awareness, between 2004 and 2017, by using data from the Global Burden of Disease (GBD), Directorate-General of Health (DGH) and Google® Trends (GT). Methods: For the period 2004-2017, Portuguese national data of periodontal diseases prevalence were searched in the Institute for Health Metrics and Evaluation of GBD and DGH and for public awareness, GT comparison tool between Portuguese words for “Periodontitis”, “Gingivitis”, “Gums” and “Periodontal disease” trends was used. Results: For the period 2004-2017, the overall prevalence of periodontitis slightly increased from 11.3% to 11.7%. During that period the GT search term “Gums” (“Gengivas”) was the most relevant. It increased steadily over time while the search term “Periodontal disease” (“Doença periodontal”) decreased, being these search trends significantly correlated (
ARTICLE Download: 64| View: 463| Comments: 0 | doi:10.20944/preprints201902.0116.v1
Subject: Medicine & Pharmacology, Other Keywords: Flos chrysanthemum; Bud Chrysanthemum; Fetal Chrysanthemum; Hongxinju; GC-MS based metabolomics; violate components
Online: 13 February 2019 (13:08:09 CET)
Hang-ju was one of five officinal varieties of Flos chrysanthemum for its edible and potable usage. Besides Flos Chrysanthemum (FL), there were also Bud Chrysanthemum (BC) and Fetal Chrysanthemum (FC) at the early and late stage of buds, respectively, in the consumption market of Hang-ju with higher prices. Whether the quality and efficiency of BC and FC was superior to FL or merely consumption misunderstandings? Three commercial products of Hongxinju, a representive cultivar of Hang-ju were studied with a GC-MS based metabolomics approach, complemented with morphology, contents of moisture and protein and the anti-oxidant activity, to reveal the metabolic alterations of violate components in Hongxinju in different flowering stage and at different processing periods. It revealed that most of the violate components were increased from fresh FC to FL, and the low-boiling fractions, inflammatory methyl arachidonate and air-polluting component of ethylbenzene were declined while the representative components with pungent flavor and cool nature of a-curcumene and (Z,Z,Z)-9,12,15-octadecatrienoic acid, vision improving carotenol of rhodopin and high-boiling fractions were elevated after processed in final FL compared with that in BC and/or FC. Though the content of protein and anti-oxidative capacity of final BC and FC were nearly equal to those of FL, in comprehensive consideration of the representative components related with the efficiency in heat cooling and vision improving, as well as the representative components related with inflammation and air-pollution, final FL was recommended other than BC and FC in the practice of medicine with the yield and quality integrated into account.
ARTICLE Download: 58| View: 455| Comments: 0 | doi:10.20944/preprints201902.0109.v1
Subject: Medicine & Pharmacology, Oncology & Oncogenics Keywords: connexins; Cx43; gap junctions; lung cancer; immunohistochemistry; prognosis; nuclear
Online: 13 February 2019 (10:30:49 CET)
Direct intercellular communication, mediated by gap junctions formed by the connexin transmembrane protein family, is frequently dysregulated in cancer. Connexins have been described as tumour suppressors, but emerging evidence suggests that they can also act as tumour promoters. This feature is connexin- and tissue-specific and may be mediated by complex signalling pathways through gap junctions or hemichannels or by completely junction-independent events. Lung cancer is the number one cancer in terms of mortality worldwide, and novel biomarkers and therapeutic targets are urgently needed. Our objective was to gain a better understanding of connexins in this setting. We used several in silico tools to analyse TCGA data in order to compare connexin mRNA expression between healthy lung tissue and lung tumours and correlated these results with gene methylation patterns. Using Kaplan-Meier plotter tools, we analysed a microarray dataset and an RNA-seq dataset of non-small cell lung tumours in order to correlate connexin expression with patient prognosis. We found that connexin mRNA expression is frequently either upregulated or downregulated in lung tumours. This correlated with both good and poor prognosis (overall survival) in a clear connexin isoform-dependent manner. These associations were strongly influenced by the histological subtype (adenocarcinoma versus squamous cell carcinoma). We present an overview of all connexins but particularly focus on four isoforms implicated in lung cancer: Cx26, Cx30.3, Cx32 and Cx43. We further analysed the protein expression and localization of Cx43 in a series of 72 human lung tumours. We identified a subset of tumours that exhibited a unique strong nuclear Cx43 expression pattern that predicted worse overall survival (p=0.014). Upon sub-stratification, the prognostic value remained highly significant in the adenocarcinoma subtype (p=0.002) but not in the squamous carcinoma subtype (p=0.578). This finding highlights the importance of analysis of connexin expression at the protein level, particularly the subcellular localization. Elucidation of the underlying pathways regulating Cx43 localization may provide for novel therapeutic opportunities.
ARTICLE Download: 23| View: 429| Comments: 0 | doi:10.20944/preprints201901.0082.v2
Subject: Medicine & Pharmacology, Oncology & Oncogenics Keywords: dog; prostatic tissue; extracellular matrix; picrosirius; immunohistochemistry
Online: 13 February 2019 (10:07:11 CET)
Collagen (Coll) is the most common protein in the extracellular matrix, responsible for providing tissue structure and support. In some types of cancer, including prostate cancer (PC) Coll deregulation was described and related to tumor progression and metastasis. This study aimed to investigate Coll-I, III, IV and elastin in canine normal prostate and PC, using Picrosirius red (PSR) and Immunohistochemical (IHC) analysis. Eight normal prostates and 10 PC from formalin-fixed, paraffin-embedded samples were used. Collagen fibers area was analyzed with ImageJ software. The distribution of Coll-I and Coll-III was approximately 80% around prostatic ducts and acini, 15% among smooth muscle and 5% around in blood vessels, in both normal prostate and PC. Immunostaining for Coll-IV was observed in the basal membrane of prostate acini, smooth muscle, blood vessels, and never fibers of normal and PC samples. Elastic fibers were found in the septa dividing the lobules and around the prostatic acini of normal samples. A high amount of elastic fibers was observed around the ducts and the urethra in normal and PC. The distribution and area percentage of staining for collagen are similar in normal and neoplastic canine prostate when analyzed with PSR and IHC.
Tue, 12 February 2019
ARTICLE Download: 104| View: 562| Comments: 0 | doi:10.20944/preprints201902.0103.v1
Subject: Medicine & Pharmacology, General Medical Research Keywords: Patient Safety Climate Attitudes, Hospital Emergency Department, Qualitative
Online: 12 February 2019 (11:36:02 CET)
Introduction: The attitudes of doctors and nurses toward patient safety is a significant factor in hospital safety climates and medical error rates. Yet, there are very few studies of patient safety attitudes in Saudi hospitals and none conducted in hospital emergency departments. Aims: The current study aims to investigate the discrepancy between the patient safety attitudes of doctors and nurses in a Saudi hospital emergency department. Materials and Method: The study employed a qualitative research designvia semi-structured interviews with Saudi and non-Saudi doctors and nurses working in a Saudi hospital emergency department to determine their attitudes and experiences about the patient safety climate. Results: The findings showed doctors and nurse held some similar safety attitudes, however, nurses reported issues with doctors with respect to their teamwork, communication, and patient safety attitudes. Moreover, several barriers to the patient safety climate were identified such as limits to resources, teamwork, communication, and incident reporting. Conclusion: The findings provide one of the few research contributions to knowledge on the differential patient safety attitudes of Saudi and non-Saudi doctors and nurses and suggest the application of such knowledge would enhance positive patient outcomes in emergency departments.
REVIEW Download: 109| View: 580| Comments: 0 | doi:10.20944/preprints201902.0101.v1
Subject: Medicine & Pharmacology, Ophthalmology Keywords: age-related macular degeneration; anti-inflammatory agents; dry AMD; geographic atrophy; intravitreal injection; complement inhibitors; neuroprotective agents; non-exudative AMD
Online: 12 February 2019 (11:00:52 CET)
The present review focuses on recent clinical trials that analyze the efficacy of intravitreal therapeutic agents for the treatment of dry age-related macular degeneration (AMD), such as neuroprotective drugs, and complement inhibitors, also called immunomodulatory or anti-inflammatory. A systematic literature search was performed to identify randomized controlled trials published prior to January 2019. Patients affected by dry AMD treated with intravitreal therapeutic agents were included. The changes in the correct visual acuity and the reduction in geographic atrophy progression were evaluated. Several new drugs have shown some promising results, including those targeting the complement cascade and agents called neuroprotective. The action potential of the two groups of drugs is to block the complement cascade model for immunomodulating agents, and prevent the degeneration and apoptosis of ganglion cells for the neuroprotectors, respectively. To the best of knowledge, and after extensive studies on the matter, there are still many investigations to be carried out on dry AMD in collaboration between researchers. They will have to identify truly effective molecules, understand the practical potential of pluripotent stem cells, and refine gene therapies. Only in-depth clinical trials will be able to allow the most appropriate and personalized treatments for each dry AMD patient.
ARTICLE Download: 45| View: 551| Comments: 0 | doi:10.20944/preprints201902.0100.v1
Subject: Medicine & Pharmacology, Gastroenterology Keywords: obesity; diabetes; body weight; body composition; glucose tolerance; insulin tolerance; incretin; energy expenditure
Online: 12 February 2019 (10:37:42 CET)
Background/Goals: The gut hormone PYY secreted from intestinal L-cells has been implicated in the mechanisms of satiation via Y2-receptor (Y2R) signaling in the brain and periphery and is a major candidate for mediating the beneficial effects of bariatric surgery on appetite and body weight. Methods: Here we assessed the role of Y2R signaling in the response to low- and high-fat diets and its role in the effects of Roux-en-Y gastric bypass (RYGB) surgery on body weight, body composition, food intake, energy expenditure and glucose handling, in global Y2R-deficient (Y2RKO) and wildtype mice made obese on high-fat diet. Results: Both male and female Y2RKO mice responded normally to low- and high-fat diet in terms of body weight, body composition, fasting levels of glucose and insulin, as well as glucose and insulin tolerance for up to 30 weeks of age. Contrary to expectations, obese Y2RKO mice also responded similarly to RYGB compared to WT mice for up to 20 weeks after surgery, with initial hypophagia, sustained body weight loss, and significant improvements in fasting insulin, glucose tolerance, HOMA-IR, and liver weight compared to sham-operated mice. Furthermore, non-surgical Y2RKO mice weight-matched to RYGB showed the same improvements in glycemic control as Y2RKO mice with RYGB that were similar to WT mice. Conclusions: PYY signaling through Y2R is not required for the normal appetite-suppressing and body weight-lowering effects of RYGB in this global knockout mouse model. Potential compensatory adaptations of PYY signaling through other receptor subtypes or other gut satiety hormones such as GLP-1 remain to be investigated.
Fri, 8 February 2019
ARTICLE Download: 77| View: 575| Comments: 0 | doi:10.20944/preprints201902.0078.v1
Subject: Medicine & Pharmacology, Psychiatry & Mental Health Studies Keywords: major depressive disorder, bipolar disorder, structural MRI, grey matter volume, voxel-based morphometry
Online: 8 February 2019 (09:30:12 CET)
Objective: The aim of the current study was to examine whether and to what extent mood disorders, comprising major depression and bipolar disorder, are accompanied by structural changes in the brain as measured using voxel-based morphometry (VBM). Methods: We have performed a VBM study using a 3Т MRI system (GE Discovery 750w) in patients with mood disorders (n=50), namely 39 with major depression and 11 with bipolar disorder, compared to 42 age, sex and education matched healthy controls. Results: Our results show that depression was associated with significant decreases in grey matter (GM) volume restricted to regions located in medial frontal and anterior cingulate cortex on the left side and middle frontal gyrus, medial orbital gyrus, inferior frontal gyrus (triangular and orbital parts), and middle temporal gyrus (extending to the superior temporal gyrus) on the right side. When the patient group was separated into bipolar disorder and major depression the reductions remained significant only for the patients with major depressive disorder. Conclusions: Using VBM the present study was able to replicate decreases in GM volume restricted to frontal and temporal regions in patients with mood disorders mainly major depression, as compared with healthy controls.
Thu, 7 February 2019
ARTICLE Download: 54| View: 612| Comments: 0 | doi:10.20944/preprints201902.0070.v1
Subject: Medicine & Pharmacology, Gastroenterology Keywords: Helicobacter pylori, aspirin, atrophic gastritis, intestinal metaplasia, microRNA, methylation
Online: 7 February 2019 (11:30:17 CET)
The risk of gastric cancer (GC) declines after Helicobacter pylori (H. pylori) eradication and long-term aspirin use. We evaluated the effects of H. pylori eradication (Cohort 1) and aspirin use (Cohort 2) on the methylation of microRNAs (miRNAs) such as miR-34c, miR-124a-3, miR-129-2, and miR-137 in the gastric mucosa with and without GC, i.e., atrophic mucosa (AM) and intestinal metaplasia (IM). DNA was isolated from AM and IM separately using laser caption microdissection. In Cohort 1, H. pylori eradication was associated with a significant reduction of miR-124a-3 methylation only in AM, but not in IM. miR-129-2 methylation in AM may be a surrogate marker of GC in H. pylori-infected patients. In Cohort 2, aspirin did not reverse miRNA methylation in either AM or IM irrespective of H. pylori infection. miR-129-2 methylation in AM was an independent predictive marker of GC in H. pylori-infected but not -eradicated patients. These results indicate that H. pylori eradication and aspirin use were less effective in improving methylation in IM compared with AM; thus, these interventions are recommended at an early stage prior to the development of IM to prevent GC development.
Wed, 6 February 2019
ARTICLE Download: 100| View: 644| Comments: 0 | doi:10.20944/preprints201902.0020.v1
Subject: Medicine & Pharmacology, Ophthalmology Keywords: Moraxella; keratitis; conjunctivitis; endophthalmitis; DNA sequencing; MALDI TOF MS; Biolog ID system
Online: 6 February 2019 (06:27:07 CET)
Purpose. Moraxella is an ocular bacterial pathogen isolated in cases of keratitis, conjunctivitis, and endophthalmitis. Gram-negative brick-shaped diplobacilli from ocular specimens, and slow growth in culture, are early indications of Moraxella ocular infection; however, identifying Moraxella to species can be complex and inconsistent. Methods. In this study, bacteria consistent with Moraxella were identified to species using: 1) DNA sequencing coupled with vancomycin susceptibility, 2) MALDI-TOF Mass Spectrometry, and 3) Biolog ID System. Study samples consisted of 9 ATCC Moraxella controls, 82 isolates from keratitis, 21 isolates from conjunctivitis, and 4 isolates from endophthalmitis. Results. The ATCC controls were correctly identified. For keratitis, 66 (80.5%) were identified as M. nonliquefaciens, 7 (9.0%) as M. lacunata, 5 (6%) as M. osloensis, 2 (2.5%) as Acinetobacter lwoffi, 1 (1.0%) as M. bovis/nonliquefaciens, and 1 (1.0%) as M. osloensis/nonliquefaciens. For conjunctivitis, 9 (43.0%) were identified as M. osloensis, 6 (29.0%) as M. nonliquefaciens, 3 (14.3%) as Roseomonas, 2 (9.5%) as Acinetobacter (parvus, junii), and 1 (4.5%) as M. catarrhalis/M. nonliquefaciens. From endophthalmitis, 3 of 4 of the isolates were M. nonliquefaciens. Overall, M. nonliquefaciens and M. osloensis were identified in 70% (75 of 107) and 13% (14 of 107) of cases, respectively, totaling 83% (89 of 107). Conclusions. M. nonliquefaciens and M. osloensis are important bacterial pathogens of the eye as determined by DNA sequencing, MALDI-TOF MS, and Biolog. Although Moraxella catarrhalis is a clinical pathogen, other species of Moraxella appear to have a prominent role in eye infections.
Mon, 4 February 2019
REVIEW Download: 273| View: 753| Comments: 0 | doi:10.20944/preprints201902.0043.v1
Subject: Medicine & Pharmacology, Oncology & Oncogenics Keywords: ADC; HM2-MMAE; (vic-)trastuzumab duocarmazine; Trastuzumab deruxtecan; TAK-522; Trastuzumab emtansine; anti-HER2/PBD-MA; HER2 low; HER2-low; mode of action
Online: 4 February 2019 (17:01:31 CET)
Since the discovery of the human epidermal growth factor receptor 2 (HER2) as an oncogenic driver in a subset of breast cancers and the development of HER2 directed therapies, the prognosis of HER2 amplified breast cancers has increased meaningfully. Next to monoclonal anti-HER2 antibodies and tyrosine kinase inhibitors, the antibody-drug conjugate T-DM1 is a pillar of targeted treatment of advanced HER2-positive breast cancers. Currently, several HER2 directed antibody-drug conjugates are under clinical investigation for HER2 amplified but also HER2 expressing but not amplified breast tumors. In this article, we review the current preclinical and clinical evidence of the investigational drugs A166, ALT-P7, ARX788, DHES0815A, DS-8201a, RC48, SYD985, MEDI4276 and XMT-1522.
REVIEW Download: 52| View: 398| Comments: 0 | doi:10.20944/preprints201902.0030.v1
Subject: Medicine & Pharmacology, Cardiology Keywords: biomarkers; miRNAs; heart failure; system biology
Online: 4 February 2019 (11:44:17 CET)
Heart failure (HF) has several etiologies including myocardial infarction (MI) and left ventricular remodeling (LVR), but its progression remains difficult to predict in clinical practice. Systems biology analyses of LVR after MI predict molecular insights of this event such as modulation of microRNA (miRNA) that could be used as a signature of HF progression. To define a miRNA signature of LVR after MI, we use 2 systems biology approaches integrating either proteomic data generated from LV of post-MI rat induced by left coronary artery ligation or multi-omics data (proteins and non-coding RNAs) generated from plasma of post-MI patients from the REVE-2 study. The first approach predicts 13 miRNAs and 3 of these miRNAs were validated to be associated with LVR in vivo: miR-21-5p, miR-23a-3p and miR-222-3p. The second approach predicts 24 miRNAs among 1310 molecules and 6 of these miRNAs were selected to be associated with LVR in silico: miR-17-5p, miR-21-5p, miR-26b-5p, miR-222-3p, miR-335-5p and miR-375. We identified a signature of 7 microRNAs associated with LVR after MI that support the interest of integrative systems biology analyses to define a miRNA signature of HF progression.
ARTICLE Download: 140| View: 469| Comments: 0 | doi:10.20944/preprints201902.0029.v1
Subject: Medicine & Pharmacology, Psychiatry & Mental Health Studies Keywords: major depressive disorder, microglia, cytokines, neuro-immune, chronic fatigue, oxidative stress
Online: 4 February 2019 (11:41:22 CET)
In 2011, it was reviewed that there is a strong co-occurrence between major depression and chronic fatigue syndrome (CFS), with fatigue and physio-somatic symptoms being key symptoms of depression, and depressive symptoms appearing during the course of CFS. Moreover, the comorbidity between both conditions may in part be explained by activated immune-inflammatory pathways, including increased translocation of Gram-negative bacteria and increased levels of pro-inflammatory cytokines, such as interleukin (IL)-1. Nevertheless, the possible involvement of activated microglia in this comorbidity has remained unclear. This paper aims to review microglial disturbances in major depression, CFS and their comorbidity. A comprehensive literature search was conducted using the PubMed / MEDLINE database to identify studies that are relevant to this current review. Depressed patients present neuroinflammatory alterations, probably related to microglial activation, while animal models show that a microglial response to immune challenges including lipopolysaccharides is accompanied by depressive-like behaviors. Recent evidence from preclinical studies indicate that activated microglia have a key role in the onset of fatigue. In chronic inflammatory conditions, such as infections and senescence, microglia orchestrate an inflammatory microenvironment thereby causing fatigue. In conclusion, based on our review we may posit that shared immune-inflammatory pathways and activated microglia underpin comorbid depression and CFS and that activated microglia are the main orchestrators of this comorbidity. As such, microglial activation and neuro-inflammation may be promising targets to treat the overlapping manifestations of both depression and CFS.
Fri, 1 February 2019
ARTICLE Download: 136| View: 604| Comments: 0 | doi:10.20944/preprints201902.0011.v1
Subject: Medicine & Pharmacology, Oncology & Oncogenics Keywords: Cancer treatment, resistance to treatment, evolution of resistance, background extinctions
Online: 1 February 2019 (10:29:06 CET)
We propose the traditional goal of cancer therapists to develop a single drug or drug combination that can, by itself, eliminate all cancer cells within a host has neglected potential treatments that may achieve curative outcomes by strategically combining agents that are individually effective but non-curative. We derive basic principles for such an approach from the eco-evolutionary dynamics of background extinctions in which a “first strike” reduces the size and heterogeneity of the initial population and is followed immediately by demographic and ecological “second strikes” that push the population below an extinction threshold. This proposed strategy appears identical to the empirically-derived curative therapy in childhood Acute Lymphocytic Leukemia.
ARTICLE Download: 65| View: 463| Comments: 0 | doi:10.20944/preprints201811.0621.v2
Subject: Medicine & Pharmacology, General Medical Research Keywords: Zika virus (ZIKV); geographical information systems (GIS); public health; travelers; arboviruses; infectious diseases epidemiology; Honduras
Online: 1 February 2019 (09:44:12 CET)
Background: Zika virus (ZIKV) infection has significantly affected Latin America in 2015–2017. Most studies have been reported from Brazil and Colombia, and only a few from Central America. For these reasons we analyzed the incidence, incidence rates and evolution of cases in Honduras from 2016–2017. Methods: Using epidemiological weeks (EW) surveillance data on the ZIKV epidemics in Honduras, we estimated incidence rates (cases/100,000 population), and developed maps at national, departmental and municipal levels. Results: From 1 January 2016 to 31 December 2017, a total of 32,607 cases of ZIKV were reported (98.5% in 2016 for an incidence rate of 36.85 cases/100,000 pop; 1% confirmed by RT-PCR). The highest peak was reached on the EW 6°, 2016 (2,559 cases; 29.34 cases/100,000 pop). The department with the highest number of cases and incidence rate was Cortés (13,128 cases, 791.08 cases/100,000 pop in 2016). Discussion: The pattern and evolution of ZIKV infection in Honduras has been similar to that which occurred for chikungunya in 2015. As previously reported, infection with chikungunya involved predominantly the central and capital area of the country, reaching incidences there >750 cases/100,000 pop. Studies using geographical information systems linked with clinical disease characteristics are necessary to attain accurate epidemiological data for public health systems. Such information is also useful for assessment of risk for travelers who visit specific areas in a destination country.
ARTICLE Download: 79| View: 530| Comments: 0 | doi:10.20944/preprints201902.0006.v1
Subject: Medicine & Pharmacology, Clinical Neurology Keywords: APOE gene; Apolipoprotein E; DNA methylation; Mild cognitive impairment; Hispanics.
Online: 1 February 2019 (09:22:48 CET)
Background: Biomarkers are essential for identification of individuals at high risk of mild cognitive impairment (MCI) for potential prevention of dementia. We investigated DNA methylation in the ApoE gene and plasmatic apolipoprotein E (ApoE) levels as MCI biomarkers in Colombian subjects with MCI and controls. Methods: 100 participants were included (71% women, average age, 70 yrs., range 43-91). MCI was diagnosed by neuropsychological testing, medical and social history, activities of daily living, cognitive symptoms and neuroimaging. Multivariate logistic regression models adjusted by age and gender were performed to examine the risk association of MCI with plasma ApoE and APOE methylation Results: MCI was diagnosed in 41 subjects (average age, 66.5±9.6 yrs.) and compared with 59 controls. Elevated plasma ApoE and APOE methylation of CpGs 165, 190, and 198 were risk factors for MCI (P<0.05). Higher CpG-227 methylation correlated with lower risk for MCI (P=0.002). Only CpG-227 was significantly correlated with plasmatic ApoE levels (correlation coefficient=-0.665; P=0.008). Conclusion: Differential APOE methylation and increased plasma ApoE levels were correlated with MCI. These epigenetic patterns can be used as potential biomarkers to identify early stages of MCI.
Thu, 31 January 2019
ARTICLE Download: 64| View: 506| Comments: 0 | doi:10.20944/preprints201901.0324.v1
Online: 31 January 2019 (08:56:46 CET)
Introduction: Type 2 diabetes (T2D) is a major driver of health care costs, thus treatments enabling T2D reversal may reduce expenditures. We examined the impact of a T2D continuous care intervention (CCI) on health care utilization. Previous research documented that CCI, including individualized nutrition supported by remote care, simultaneously reduced hemoglobin A1c and medication use and improved cardiovascular status after two years; however, the impact on utilization is unknown. Methods: This study used four years of data (two years pre-intervention, two years post-intervention) from the Indiana Network for Patient Care (INPC) health record. Two methods estimated the impact of CCI on utilization. First, an interrupted time series (ITS) including only CCI participants (n=193) compared post-intervention utilization to expected utilization had the pre-intervention trend persisted. Deviation from the trend was estimated non-parametrically for each 6-month interval after the implementation of CCI . Second, a 1:3 matched comparator group (n=579) was constructed and used for a difference-in-differences (DiD) analysis. The primary outcome was annualized outpatient encounters. Secondary outcomes included emergency encounters and hospitalizations. Results: In two years prior to intervention, CCI participants had a mean of 5.77 annualized encounters (5.62 outpatient, 0.04 hospitalizations, 0.11 emergency). The CCI group showed a reduction in outpatient utilization after intervention. In ITS analysis, 1.6 to 1.9 fewer annualized outpatient encounters occurred in each 6-month interval post-intervention relative to expected utilization based on pre-intervention trends (p<0.01 each 6-month period; 28-33% reduction). The DiD analysis suggested a larger reduction; 5 fewer annualized outpatient encounters in the quarter after intervention, diminishing to 2.5 fewer after 2 years (p<0.01 each quarter). The study was underpowered to draw conclusions about hospitalization and emergency encounters due to the limited number of CCI patients and the rarity of encounters. Conclusions: Outpatient encounters were significantly reduced for a T2D patient population up to 2 years after receiving an individualized intervention supporting nutrition and behavior change through remote care.
ARTICLE Download: 77| View: 469| Comments: 0 | doi:10.20944/preprints201901.0320.v1
Subject: Medicine & Pharmacology, Other Keywords: Acanthamoeba sp.; eyes; toll-like receptor 2 (TLR2); toll-like receptor 4 (TLR4)
Online: 31 January 2019 (07:00:38 CET)
Toll-like receptors (TLRs) play a key role in the innate immune response to numerous pathogens, including Acanthamoeba sp. The aim of this study was to determine the expression of TLR2 and TLR4 in the eyes of mice following intranasal infection with Acanthamoeba sp. Amoebae used in this study were isolated from the bronchial aspirate of a patient with acute myeloid leukemia (AML) and atypical symptoms of pneumonia. We found statistically significant differences in the expression of TLR2 and TLR4 in the eyes of immunocompetent mice at 8, 16, and 24 days post Acanthamoeba sp. infection (dpi) compared to control. Immunosuppressed mice showed significant differences in the expression of TLR2 at 16 and 24 dpi compared to uninfected animals. Our results indicate that TLR2 and TLR4 are upregulated in the eyes of mice in response to Acanthamoeba sp. We suggest that it is possible for trophozoites to migrate through the optic nerve from the brain to the eyes.
ARTICLE Download: 88| View: 487| Comments: 0 | doi:10.20944/preprints201901.0317.v1
Subject: Medicine & Pharmacology, Veterinary Medicine Keywords: Crimean-Congo hemorrhagic fever; nucleocapsid; Bovine herpesvirus type 4; IFNAR-/- mice; lethal dose
Online: 31 January 2019 (05:26:35 CET)
Crimean-Congo hemorrhagic fever virus (CCHFV) is the causative agent of a tick-borne infection with significant mortality rate of up to 40% in the endemic areas, with evidence for geographical expansion. Lacking effective therapeutics and control measures, the development of protective CCHFV vaccine remains a crucial public health task. This manuscript describes, for the first time, a Bovine herpesvirus type 4 (BoHV-4) based viral vector (BoHV4-∆TK-CCHFV-N) and its immunogenicity and protection potential in BALB/c and IFNAR-/- mice models in comparison with Adenovirus type 5 (Ad5-N) and pCDNA3.1 myc/His A (pCD-N1), two widely used vaccine platforms. All constructs expressing viral nucleocapsid (N) protein successfully elicited cytokine and total/specific antibody responses in BALB/c mice. BoHV4-∆TK-CCHFV-N and Ad5-N constructs further produced 100% protection in IFNAR-/- mice during CCHFV Ank-2 strain lethal challenge. Despite elevated specific antibody responses in both animal models, the produced antibodies were unable to neutralize the virus in vitro. A comparison of delivery platforms was not possible, due to similar protection rates in IFNAR-/- mice. In conclusion, vector-based CCHFV N protein expression proved to constitute an effective approach for the vaccine development pipeline and BoHV-4 emerged as a strong alternative to previously-used virus vectors.
Wed, 30 January 2019
ARTICLE Download: 59| View: 506| Comments: 0 | doi:10.20944/preprints201901.0315.v1
Subject: Medicine & Pharmacology, Oncology & Oncogenics Keywords: glioblastoma; p53; apoptosis; doxorubicin; bortezomib; vorinostat.
Online: 30 January 2019 (13:03:22 CET)
In prostate cancer, p53 maximizes apoptosis in response to severe DNA damage, not DNA replication stress. Here, we examined the apoptotic response of two glioblastoma cells, p53-wild type U87 and a p53-mutated T98G cell, for the same stresses. We ascertained that p53 intensified apoptosis in response to severe DNA damage, not DNA replication stress in glioblastoma. We further asked if p53-mediated apoptosis can be induced by cellular stress other than severe DNA damage. We analyzed two compounds, bortezomib and vorinostat, respective inhibitors of 26S proteasome and histone deacetylase, to evaluate their capacity to activate p53-mediated apoptosis. The cellular stress incited by bortezomib, not vorinostat, activated p53-mediated apoptosis. Next, we asked if the cellular stress generated by combining the two compounds had a synergistic effect on apoptosis. Our results demonstrated that doxorubicin with bortezomib or CFS-1686, or bortezomib with vorinostat have a significant synergistic effect on apoptosis only in p53-wild type cell. Under high stress, p53 translocates from cytosol into the nucleus to cause apoptosis possibly. Together, p53 maximizes apoptosis for cellular stress caused by severe DNA damage, disruption of protein turnover, and for the stress induced by drug combination including doxorubicin with bortezomib or CFS-1686, and bortezomib with vorinostat.
ARTICLE Download: 98| View: 394| Comments: 0 | doi:10.20944/preprints201901.0306.v1
Subject: Medicine & Pharmacology, Psychiatry & Mental Health Studies Keywords: Mental disorder, treatment gap, health system, Madhya Pradesh.
Online: 30 January 2019 (09:25:43 CET)
Background: India has one-fifth of the world's population and the number of people suffering from mental illness is assumed to be huge considering the contribution of mental disorders to the overall burden of the disease being 13.9 %. Objectives of Study: To estimate prevalence and patterns of mental illnesses to assess the current mental health services and systems in the Madhya Pradesh. Material and Methods: Multi-stage, stratified, random cluster sampling technique, with random selection based on probability proportionate to size at each stage. A total of 3240 individuals aged 18 years and above were interviewed. Both quantitative and qualitative methods were employed. A set of 10 instruments including Mini International Neuro-psychiatric Interview were utilized. Results: The overall weighted prevalence for any mental illness was 16.7% lifetime and 13.9% current. Treatment-gap for all mental health problems is as high as 91% in the state along with huge socioeconomic impact of mental illness. Conclusions: This huge burden of mental, behavioural and substance use disorders, in Madhya Pradesh, calls for immediate attention of political leaders, policy makers, health professionals, opinion-makers and society at large. It is hoped that the data from the study will inform mental health policy and legislation and help shape mental health care delivery systems in the country.
ARTICLE Download: 55| View: 302| Comments: 0 | doi:10.20944/preprints201901.0300.v1
Subject: Medicine & Pharmacology, Pediatrics Keywords: infant; newborn; Cambodia; child mortality; perinatal mortality; case reports
Online: 30 January 2019 (05:15:16 CET)
Introduction: Neonatal mortality has declined in Cambodia but remains a key contributor to under-five deaths. The aim of this study was to further understanding of potential factors contributing to high neonatal mortality rates in Cambodia through assessment of verbal autopsies collected following newborn deaths. The study team analyzed verbal autopsies of perinatal deaths in order to describe timing and causes of neonatal deaths, demographic data, and factors potentially related to mortality. Methods: The case series data derive from 13 verbal autopsy reports collected in rural southern Cambodia. The mortality review was nested within a trial of a behavioral intervention to improve newborn survival, and was conducted after the close of the trial. The study examined all neonatal deaths occurring to infants born at 16 health centers between in the study site of Takeo province. The World Health Organization standardized definition of neonatal mortality was employed, and two pediatricians independently reviewed data collected from each event to assign a cause of death. Results: Thirteen newborn deaths of infants born at a health facility were reported during the time period February 2015–November 2016. Ten out of the 13 deaths (76.92%) were early neonatal deaths, two (15.38%) were late neonatal deaths, and one was a stillbirth. Five out of 13 deaths (38.46%) occurred within the first day of life, indicating death was likely due to an intrapartum event. The largest single contributor to mortality was neonatal sepsis; six of 13 deaths (46.15%) were attributed to some form of sepsis. Twenty-three percent of the deaths were attributed to asphyxia. Other causes of death included stillbirth and prematurity. Eight deaths (61.54%) occurred within the control group of the larger intervention study. Conclusion: The study highlights the continuing need to improve both intrapartum and postnatal quality of care and infection prevention and control, and to fully address causes of sepsis, in order to effectively reduce mortality in the newborn period.
Tue, 29 January 2019
ARTICLE Download: 54| View: 350| Comments: 0 | doi:10.20944/preprints201901.0296.v1
Subject: Medicine & Pharmacology, Behavioral Neuroscience Keywords: episodic memory, apolipoprotein, dementia, biomarkers, anion gap, inflammation
Online: 29 January 2019 (16:52:14 CET)
Background: The Apolipoprotein E4 (ApoE4) genotype is strongly associated with Alzheimer’s disease (AD), although the presence of the ApoE4 allele alone is not sufficient to explain AD. The pathophysiology of amnestic mild cognitive impairment (aMCI) remains unclear. This study aims to examine associations between peripheral blood biomarkers coupled with ApoE4 and episodic and semantic memory. Methods: The CERAD battery was completed and various biomarkers were assayed in 60 subjects with aMCI, 60 with AD and 62 healthy controls. Results: Deficits in semantic and episodic memory were significantly predicted by anion gap and bicarbonate, albumin and glucose coupled with Apo E4. Furthermore, these peripheral biomarkers interacted with ApoE to predict greater memory impairments. Conclusions: Peripheral blood biomarkers may interact with pathways related to ApoE4 to predict greater semantic and episodic memory impairments, thus contributing to the pathophysiology of aMCI and AD. Our data suggest that the transition from aMCI to AD could at least in some cases be associated with significant interactions between ApoE4 and those peripheral blood biomarkers.
ARTICLE Download: 70| View: 351| Comments: 0 | doi:10.20944/preprints201901.0291.v1
Subject: Medicine & Pharmacology, Dentistry Keywords: Membranes; Polymer; Biocompatibility; Inflammatory cells; Calcium Phosphate
Online: 29 January 2019 (09:38:04 CET)
This study aimed to evaluate the physico-chemical properties, biocompatibility and bioabsorption of 3 different new membranes for bone guided regeneration (PLGA associated with hydroxyapatite and beta-TCP) with three thicknesses (200, 500 and 700 µm) implanted in mice subcutaneously. Scanning electron microscopy (SEM), X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR) and the quantification of Carbon, Hidrogen and Nitrogen were used to characterize the physico-chemical properties. One hundred Balb-C mice were divided into 5 experimental groups: Group 1 - Sham (without implantation); Group 2 - 200 μm; Group 3 - 500 μm; Group 4 - 700 μm; and Group 5 - Pratix®. Each group was subdivided into four experimental periods (7, 30, 60 and 90 days). Samples were collected and processed for histological and histomorphometrical evaluation. The membranes showed no moderate or severe tissue reactions in the experimental periods studied. The 500 μm membrane did not show tissue reaction for any experimental periods studied. The 200 μm membrane membranes began to exhibit fragmentation after 30- day, while the 500 and 700 µm membranes started the fragmentation at 90-day. All membranes studied were biocompatible, and the 500µm membrane showed the best results being a promissory membrane for bone guided regeneration.
ARTICLE Download: 65| View: 352| Comments: 0 | doi:10.20944/preprints201901.0288.v1
Subject: Medicine & Pharmacology, General Medical Research Keywords: HbA1c; point-of-care; diabetes; glycosylated haemoglobin
Online: 29 January 2019 (08:06:18 CET)
Background: Measurement of glycosylated hemoglobin (HbA1c) levels is standard of care in assessment of glycemic control among diabetes mellitus patients. Traditional high performance liquid chromatography (HPLC) based tests are expensive, need specialized equipment, and have a longer turn-around-time. Point-of-care tests to estimate HbA1c levels are now commercially available but with only limited studies from developed nations. We performed this study to understand diagnostic accuracy of two commercially available HbA1c point-of-care test. Methods: The study was conducted in an urban and a rural outpatient clinic in central India. We compared HbA1c estimated from two index tests (Hemocue Hb501, Sweden; SD Biosensor, South Korea) from capillary blood samples and compared it with HPLC, as a reference standard in an independent and a blinded manner. We estimated diagnostic accuracy of the index tests as compared to the reference standard. Results: The area under Reciever Operating Curve (ROC) for SDBiosensor device was 0.935 (95% CI = 0.886–0.983), and for HemocueHb501 device was 0.938 (95% CI = 0.893–0.984). A SDBiosensor device HbA1c value of above 7.0% = 53 mmol/mol (positive test) correctly predicted poor glycemic control 92% times (vs. 81.58% for HemocueHb501divice). A HemocueHb501device HbA1c value of less than 7.0% = 53 mmol/mol (negative test) correctly predicted optimal glycemic control 91% times (vs. 85% by SDBiosensor device). There were 4, and 11 device failures, and 14 and 12 test failures with SDBiosensor device and HemocueHb501 device respectively. Ambient air temperatures were no different for the test failure rates as compared to the test success events. Conclusion: Commercially available point-of-care tests evaluated in this study are comparable and an acceptable alternative to HPLC based measurements for assessment of glycemic control. Tests and device failure rates of both the index tests were similar.
Mon, 28 January 2019
ARTICLE Download: 89| View: 350| Comments: 0 | doi:10.20944/preprints201901.0277.v1
Subject: Medicine & Pharmacology, Nursing & Health Studies Keywords: personality; burnout; engagement; Big Five; healthcare personnel
Online: 28 January 2019 (12:00:59 CET)
The burnout syndrome, which affects so many healthcare workers, has recently awakened wide interest due to the severe repercussions related to its appearance. Even though job factors are determinant to its development, not all individuals exposed to the same work conditions show burnout, which demonstrates the importance of individual variables such as personality. The purpose of this study was to determine personality characteristics of a sample of nursing professionals based on the Big Five model, and then, having determined the personality profiles, analyze the differences in burnout and engagement based on those profiles. The sample was made up of 1236 nurses. An ad hoc questionnaire was prepared to collect the sociodemographic data, and the Brief Burnout Questionnaire, the Utrecht Work Engagement Scale and the Big Five Inventory-10 were used. The results showed that the existence of burnout in this group of workers, is associated negatively with extraversion, agreeableness, conscientiousness and openness to experience, and positively with the neuroticism personality trait. These personality factors showed the opposite pattern with regard to engagement. Three different personality profiles were also found in nursing personnel, in which professionals who had a profile marked by strong neuroticism and low scores on the rest of the personality traits where those who were most affected by burnout.
REVIEW Download: 127| View: 374| Comments: 0 | doi:10.20944/preprints201901.0275.v1
Subject: Medicine & Pharmacology, Other Keywords: canine enteroid/colonoids; gut-on-a-chip; translational medicine; Alzheimer’s disease; canine cognitive disfunction
Online: 28 January 2019 (10:30:57 CET)
Identifying appropriate animal models is critical in developing translatable in vitro and in vivo systems for therapeutic development and investigating disease pathophysiology. These animal models should have direct biological and translational relevance to the underlying disease they are supposed to mimic. Aging dogs naturally develop a cognitive decline in many aspects including learning and memory, but also exhibit human-like individual variability in the aging process. Neurodegenerative processes that can be observed in both human and canine brains include the progressive accumulation of β-amyloid (Aβ) found as diffuse plaques in the prefrontal cortex, including the gyrus proreus, the hippocampus, and in the cerebral vasculature. A growing body of epidemiological data shows that human patients with neurodegenerative diseases have concurrent intestinal lesions, and histopathological changes in the gastrointestinal (GI) tract occurs decades that evolve before neurodegenerative changes. Gut microbiome alterations also have been observed in many neurodegenerative diseases including Alzheimer’s and Parkinson’s diseases, and inflammatory CNS diseases. Interestingly, only recently has the dog gut microbiome been recognized to more closely resemble in composition and in functional overlap with the human gut microbiome as compared to rodent models. This article aims to review the physiology of the gut-brain axis (GBA), and its involvement with neurodegenerative diseases in dogs and humans. Additionally, we outline the advantages and disadvantages of traditional in vitro and in vivo models and discuss future research directions investigating major human neurodegenerative diseases such as Alzheimer’s and Parkinson’s diseases using dogs.
ARTICLE Download: 101| View: 372| Comments: 2 | doi:10.20944/preprints201901.0274.v1
Subject: Medicine & Pharmacology, General Medical Research Keywords: musculoskeletal disorders; lower back pain; female artisanal fisher; shellfish gatherers
Online: 28 January 2019 (10:19:59 CET)
Lower back musculoskeletal disorders (MSD) are an important public health problem and the leading cause of disability worldwide, but with prevalence yet unknown among shellfish gatherers. To investigate the prevalence and work-related factors associated with lower back MSD in a population of female shellfish gatherers, an epidemiological cross-sectional study was carried out in Saubara, Bahia – Brazil, in 2013. The Brazilian version of the Job Content Questionnaire (JCQ) and the Nordic Musculoskeletal Questionnaire (NMQ), in addition to a questionnaire containing the physical demands adapted to the artisanal work, were applied to a random sample of 209 female shellfish gatherers. The prevalence of lower back MSD was 72.7%. Using multivariate logistic regression, the shellfish gatherers who had worked for more than 26 years in the activity showed a prevalence of 1.22 (95% CI: 1.04-1.44) times higher compared to those unexposed. Lower back MSD was 1.24 (95%CI: 1.08-1.42) times higher among those more exposed to work sitting with trunk flexion. Those performed manual handling and muscle force with the arms had a prevalence ratio of 1.18 (95%CI: 1.01-1.39). These results show the need for greater awareness of health and social welfare factors impacting workers in small-scale fisheries and will promote the elaboration of health care policies for this occupational class.
Thu, 24 January 2019
ARTICLE Download: 55| View: 535| Comments: 0 | doi:10.20944/preprints201901.0250.v1
Subject: Medicine & Pharmacology, Pharmacology & Toxicology Keywords: drug delivery system, muscle atrophy, nanoparticle, prostaglandin E1, sciatic nerve injury
Online: 24 January 2019 (08:51:02 CET)
The effect of prostaglandin E1 (PGE1) encapsulated in nanoparticles (Nano PGE1) on motor dysfunction and muscle atrophy induced by sciatic nerve injury (SNI) was investigated in rats, and was compared with PGE1 encapsulated in lipid microspheres (Lipo PGE1) or PGE1 clathrated in cyclodextrin (PGE1-CD). The hind limb muscle weight ratio decreased until 2 weeks after SNI. All 3 PGE1 formulations significantly improved SNI-induced motor dysfunction. Nano PGE1 significantly promoted recovery from muscle atrophy at 2 and 3 weeks after SNI. Lipo PGE1 was also effective, but multiple doses were required. Compared with the SNI control group, the Nano PGE1 group showed upregulation of vascular endothelial growth factor (VEGF) and agrin expression in the injured sciatic nerve and atrophic muscles. Nano PGE1 accumulated prominently at the site of nerve injury and persisted for longer than Lipo PGE1 or PGE1-CD. Expression of all EP receptors was detected in the normal sciatic nerve, and EP2 expression increased after SNI. Finally, Nano PGE1 promoted ERK1/2 and Akt phosphorylation. These findings suggest that PGE1 released from nanoparticles accumulates at sites of nerve injury and increases VEGF production by augmenting ERK1/2 phosphorylation via EP receptor signaling, thus promoting tissue repair and regeneration.
ARTICLE Download: 71| View: 578| Comments: 0 | doi:10.20944/preprints201901.0249.v1
Subject: Medicine & Pharmacology, Psychiatry & Mental Health Studies Keywords: mental health; psychedelics; psychopharmacology; psychiatry; innovative
Online: 24 January 2019 (08:46:50 CET)
The current crisis in ps