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Herbal teas are nutrient, antioxidant, and hydration rich brews made from herbs and spices and taken for various purposes. The objective of this study was to formulate tea from clove (Syzygium aromaticum), leaves of lemongrass (Cymbopogon citratus), guava (Psidium guajava), and moringa (Moringa oleifera), as well as compared with Chinese and yellow Lipton Tea. The samples were analyzed for comparative sensory analysis using the 7 points hedonic scale. The sensory evaluation result demonstrated that the color of the clove tea sample (5.87) was most acceptable by participants, while the lemongrass tea (4.46) sample was least acceptable amongst all the tea samples. The clove remained the most accepted tea for aroma (6.07), taste (5.92), texture (5.76), general appearance (5.74), and general acceptability (5.93), in 7 points hedonic scale. However, all tea samples were had significant acceptable scores above average (p

Background Cerebral arterial thromboses or ischemic strokes may be caused by cumulative or independent effects of a variety of risk factors. High factor VIII level is one of those important but less known risk factors for arterial and venous thrombosis. We hereby provide a comprehensive review of the role of high factor VIII levels as a risk factor of arterial thrombosis. Moreover, we present our views on inclusion of factor VIII testing in the etiology workup protocol of young patients with ischemic strokes and their treatment with anticoagulant therapy. Case presentation We illustrate a case of 32-year-old North Indian female patient with Ischemic stroke whose only identifiable risk factor was revealed to be an elevated factor VIII level. She was treated with oral anticoagulant with an uneventful follow-up of 6 months. Conclusions Elevated factor VIII levels have their independent and additive effects in causation and prognosis of arterial strokes. We herein discuss the mechanism of this association, the feasibility and yield of routine testing, appropriate cut-off levels, and further treatment protocol especially in young stroke patients.

Traditional in-person discussion alone is often used for preoperative education in Mohs micrographic surgery (MMS). The appropriate use of more modern education techniques is not well defined in the MMS literature. The authors aim to evaluate patient education techniques for MMS, address education in special populations, and highlight opportunities for improvement. We performed a PubMed literature search with keywords “Mohs” and “education”, “teaching”, “understanding”, “explanation”, “preoperative”, or “consent” with no restriction on publication time frame due to literature scarcity. Teledermatology consultation, MMS videos, 3D models, pamphlets/online materials, and shared medical appointments appear to be effective techniques (GRADE B). Analogies are also anecdotally helpful when integrated into traditional verbal education (GRADE C). The role of preoperative educational phone calls is more controversial (GRADE C). Regardless of the education technique utilized, no singular technique entirely replaces the traditional in-person discussion. Having access to multiple modalities can be beneficial for patients, allowing them options to choose their preferred method(s) of education. MMS is a difficult topic to conceptualize, and further research into educational techniques is needed to provide clear guidelines for Mohs surgeons.

The risk and determinants of HCC in patients with primary biliary cholangitis (PBC) are unclear. We conducted a systematic review and meta-analysis of the incidence of HCC and risk factors associated with HCC risk among patients with PBC. We searched PubMed, EMBASE, MEDLINE, Cochrane databases and reference lists from relevant articles to identify cohort studies that examined incidence of HCC in patients with PBC from inception through November 2019. A total of 29 studies including 22,615 patients met the eligibility criteria. The median cohort size was 292 patients followed for an average of 76 months. The pooled incidence rate for patients with PBC was 4.17 per 1000 patient-years (95% CI 3.17–5.47). On subgroup analysis, the incidence of HCC in patients with PBC cirrhosis was 15.7 per 1000 patient-years (95% CI 8.73–28.24). The HCC incidence rate was 9.82 per 1000 person-years (95% CI 5.92–16.28) in men and 3.82 per 1000 person-years (95% CI 2.85–5.11) in women. Cirrhosis is the strongest risk factor for HCC in patients with PBC. Male gender was also a risk factor. Our meta-analysis supports current recommendations of HCC surveillance in patients with PBC cirrhosis. Further studies are needed to evaluate risk factors in this population.

It is unclear how hypertrophic cardiomyopathy (HCM) affects cardiac metabolic pathways at rest and with exercise. This case–control study compared 15 cases with HCM to 2 control groups without HCM. Metabolomic profiling of 210 metabolites was carried out at rest and at peak exercise. The 50 most discriminant metabolites differentially regulated during exercise were selected using partial least squares discriminant analysis. Pathway enrichment analysis was also performed. At rest, no significant difference was observed in metabolomic profiling of HCM cases as compared to controls. By contrast, there were significant differences in metabolomic profiling in response to exercise (p

Upper extremity deep vein thrombosis (UEDVT) accounts for ≤10% of DVT and can be associated with morbidity and mortality. Accurate diagnosis and treatment are necessary for safe and effective patient management. We systematically reviewed the accuracy of D-dimer and duplex ultrasonography (US) for the evaluation of suspected first-episode UEDVT. We searched the Cochrane Central Register, OVID MEDLINE, EMBASE, and PubMed for eligible studies, reference lists of relevant reviews, registered trials, and relevant conference proceedings. We included prospective cross-sectional and cohort studies that evaluated test accuracy. Two investigators independently screened and collected data. The risk of bias was assessed using Quality Assessment of Diagnostic Accuracy Studies 2 and certainty of evidence using the Grading of Recommendations Assessment, Development and Evaluation framework. We pooled estimates of sensitivity and specificity. The review included 9 studies. The pooled estimates for D-dimer sensitivity and specificity were 0.96 (95% confidence interval [CI], 0.87-0.99) and 0.47 (95% CI, 0.43-0.52), respectively. The pooled estimates for duplex US sensitivity and specificity were 0.87 (95% CI, 0.73-0.94) and 0.85 (95% CI, 0.72-0.93), respectively. Certainty of evidence was moderate. In this review, we summarized the test accuracy (sensitivity and specificity) of D-dimer and duplex US for this indication. The sensitivity and specificity of the tests found in the present review should be considered in the context of whether they are used alone or in combination, which is dependent on the prevalence of disease in the population, the clinical setting in which the patient is being evaluated, cost, potential harms, and patient outcomes. This study was registered at PROSPERO as Systematic Review Registration Number CRD42018098488.

Background: Nanocarriers improve the efficacy of drugs by facilitating their specific delivery and protecting them from external environment resulting in a better performance against diseases. Objective: In this study, it was aimed to improve the efficacy of capecitabine against colorectal cancer by its entrapment in niosomes. Ether injection method was used to prepare niosomes composed of span 20 and cholesterol. Methods: Niosomes were evaluated by evaluating the entrapment efficiency, in-vitro drug release and cytotoxicity of capecitabine loaded niosomes. Niosomes were characterized by particle size analysis, transmission electron microscopy, Fourier transform infrared spectroscopy and differential scanning calorimetry for surface morphology and drug excipient interactions. Results: High encapsulation efficiency (90.55%) was observed, which is anticipated to resolve the multi-drug resistance problem. Reported particle size was 180.9 + 5 nm with a negative zeta potential - 21 + 0.5 mV and the kinetic study showed a concentration-dependent release of the drug from the niosome. DSC study proved entrapment of the entire drug and its non-covalent bonding with the excipients. Cytotoxicity study of niosomes on CaCO2 cell line showed an improved IC>50 value as compared to the free drug. Conclusion: Enhanced cytotoxicity observed in the results further supports the suitability of niosome as a nanocarrier for pharmaceutical drug delivery.

Deep vein thrombosis (DVT) of the lower extremities can be associated with significant morbidity and may progress to pulmonary embolism and postthrombotic syndrome. Early diagnosis and treatment are important to minimize the risk of these complications. We systematically reviewed the accuracy of diagnostic tests for first-episode and recurrent DVT of the lower extremities, including proximal compression ultrasonography (US), whole leg US, serial US, and high-sensitivity quantitative D-dimer assays. We searched Cochrane Central, MEDLINE, and EMBASE for eligible studies, reference lists of relevant reviews, registered trials, and relevant conference proceedings. Two investigators screened and abstracted data. Risk of bias was assessed using Quality Assessment of Diagnostic Accuracy Studies-2 and certainty of evidence using the Grading of Recommendations Assessment, Development and Evaluation framework. We pooled estimates of sensitivity and specificity. The review included 43 studies. For any suspected DVT, the pooled estimates for sensitivity and specificity of proximal compression US were 90.1% (95% confidence interval [CI], 86.5-92.8) and 98.5% (95% CI, 97.6-99.1), respectively. For whole-leg US, pooled estimates were 94.0% (95% CI, 91.3-95.9) and 97.3% (95% CI, 94.8-98.6); for serial US pooled estimates were 97.9% (95% CI, 96.0-98.9) and 99.8% (95% CI, 99.3-99.9). For D-dimer, pooled estimates were 96.1% (95% CI, 92.6-98.0) and 35.7% (95% CI, 29.5-42.4). Recurrent DVT studies were not pooled. Certainty of evidence varied from low to high. This systematic review of current diagnostic tests for DVT of the lower extremities provides accuracy estimates. The tests are evaluated when performed in a stand-alone fashion, and in a diagnostic pathway. The pretest probability of DVT often assessed by a clinical decision rule will influence how, together with sensitivity and specificity estimates, patients will be managed.

Background:Respiratory protective equipment recommended in the UK for healthcare workers (HCWs) caring for patients with COVID-19 comprises a fluid-resistant surgical mask (FRSM), except in the context of aerosol generating procedures (AGPs). We previously demonstrated frequent pauci- and asymptomatic severe acute respiratory syndrome coronavirus 2 infection HCWs during the first wave of the COVID-19 pandemic in the UK, using a comprehensive PCR-based HCW screening programme (Rivett et al., 2020; Jones et al., 2020).Methods:Here, we use observational data and mathematical modelling to analyse infection rates amongst HCWs working on ‘red’ (coronavirus disease 2019, COVID-19) and ‘green’ (non-COVID-19) wards during the second wave of the pandemic, before and after the substitution of filtering face piece 3 (FFP3) respirators for FRSMs.Results:Whilst using FRSMs, HCWs working on red wards faced an approximately 31-fold (and at least fivefold) increased risk of direct, ward-based infection. Conversely, after changing to FFP3 respirators, this risk was significantly reduced (52–100% protection).Conclusions:FFP3 respirators may therefore provide more effective protection than FRSMs for HCWs caring for patients with COVID-19, whether or not AGPs are undertaken.Funding:Wellcome Trust, Medical Research Council, Addenbrooke’s Charitable Trust, NIHR Cambridge Biomedical Research Centre, NHS Blood and Transfusion, UKRI.

IntroductionThe Coronavirus (COVID-19) Pandemic has caused significant global mortality and impacted lives around the world. Virus Watch aims to provide evidence on which public health approaches are most likely to be effective in reducing transmission and impact of the virus, and will investigate community incidence, symptom profiles, and transmission of COVID-19 in relation to population movement and behaviours.Methods and analysisVirus Watch is a household community cohort study of acute respiratory infections in England & Wales and will run from June 2020 to August 2021. The study aims to recruit 50,000 people, including 12,500 from minority ethnic backgrounds, for an online survey cohort and monthly antibody testing using home finger prick kits. Nested within this larger study will be a sub-cohort of 10,000 individuals, including 3,000 people from minority ethnic backgrounds. This cohort of 10,000 people will have full blood serology taken between October 2020 and January 2021 and repeat serology between May 2021 and August 2021. Participants will also post self-administered nasal swabs for PCR assays of SARS-CoV-2 and will follow one of three different PCR testing schedules based upon symptoms.Ethics and disseminationThis study has been approved by the Hampstead NHS Health Research Authority Ethics Committee. Ethics approval number – 20/HRA/2320. We are monitoring participant queries and using these to refine methodology where necessary, and are providing summaries and policy briefings of our preliminary findings to inform public health action by working through our partnerships with our study advisory group, Public Health England, NHS and Government Scientific Advisory panels.Strengths and limitations of this studyVirus Watch is a large national household community cohort study of the occurrence and risk factors for COVID-19 infection that aims to recruit 50,000 people, including 12,500 from minority ethnic backgrounds.Virus Watch is designed to estimate incidence of PCR confirmed COVID-19 in those with respiratory and non-respiratory presentations and the incidence of hospitalisation among PCR confirmed COVID-19 cases.Virus Watch will measure effectiveness and impact of recommended COVID-19 control measures including testing, isolation, social distancing, respiratory and hand hygiene measures on risk of respiratory infection.Only households with a lead householder able to speak English were able to take part in the study up until March 2021.Only households of up to six people were eligible for inclusion and they were also required to have access to an internet connection. These restrictions will limit the generalisability to large or multigenerational households, and those without access to the internet.

Before the coronavirus disease 2019 (COVID-19) pandemic, use of telehealth services had been limited in cardiovascular care. Potential benefits of telehealth include improved access to care, more efficient care management, reduced costs, the ability to assess patients within their homes while involving key caretakers in medical decisions, maintaining social distance, and increased patient satisfaction. Challenges include changes in payment models, issues with data security and privacy, potential depersonalization of the patient-clinician relationship, limitations in the use of digital health technologies, and the potential impact on disparities, including socioeconomic, gender, and age-related issues and access to technology and broadband. Implementation and expansion of telehealth from a policy and reimbursement practice standpoint are filled with difficult decisions, yet addressing these are critical to the future of health care.

Pulmonary embolism (PE) is a common, potentially life-threatening yet treatable condition. Prompt diagnosis and expeditious therapeutic intervention is of paramount importance for optimal patient management. Our objective was to systematically review the accuracy of D-dimer assay, compression ultrasonography (CUS), computed tomography pulmonary angiography (CTPA), and ventilation-perfusion (V/Q) scanning for the diagnosis of suspected first and recurrent PE. We searched Cochrane Central, MEDLINE, and EMBASE for eligible studies, reference lists of relevant reviews, registered trials, and relevant conference proceedings. 2 investigators screened and abstracted data. Risk of bias was assessed using Quality Assessment of Diagnostic Accuracy Studies-2 and certainty of evidence using the Grading of Recommendations Assessment, Development and Evaluation framework. We pooled estimates of sensitivity and specificity. The review included 61 studies. The pooled estimates for D-dimer sensitivity and specificity were 0.97 (95% confidence interval [CI], 0.96-0.98) and 0.41 (95% CI, 0.36-0.46) respectively, whereas CTPA sensitivity and specificity were 0.94 (95% CI, 0.89-0.97) and 0.98 (95% CI, 0.97-0.99), respectively, and CUS sensitivity and specificity were 0.49 (95% CI, 0.31-0.66) and 0.96 (95% CI, 0.95-0.98), respectively. Three variations of pooled estimates for sensitivity and specificity of V/Q scan were carried out, based on interpretation of test results. D-dimer had the highest sensitivity when compared with imaging. CTPA and V/Q scans (high probability scan as a positive and low/non-diagnostic/normal scan as negative) both had the highest specificity. This systematic review was registered on PROSPERO as CRD42018084669.

Small noncoding microRNAs (miRNAs) are important regulators of skeletal muscle size, and circulating miRNAs within extracellular vesicles (EVs) may contribute to atrophy and its associated systemic effects. The purpose of this study was to understand how muscle atrophy and regrowth alter in vivo serum EV miRNA content. We also associated changes in serum EV miRNA with protein synthesis, protein degradation, and miRNA within muscle, kidney, and liver. We subjected adult (10 mo) F344/BN rats to three conditions: weight bearing (WB), hindlimb suspension (HS) for 7 days to induce muscle atrophy, and HS for 7 days followed by 7 days of reloading (HSR). Microarray analysis of EV miRNA content showed that the overall changes in serum EV miRNA were predicted to target major anabolic, catabolic, and mechanosensitive pathways. MiR-203a-3p was the only miRNA demonstrating substantial differences in HS EVs compared with WB. There was a limited association of EV miRNA content to the corresponding miRNA content within the muscle, kidney, or liver. Stepwise linear regression demonstrated that EV miR-203a-3p was correlated with muscle mass and muscle protein synthesis and degradation across all conditions. Finally, EV miR-203a-3p expression was significantly decreased in human subjects who underwent unilateral lower limb suspension (ULLS) to induce muscle atrophy. Altogether, we show that serum EV miR-203a-3p expression is related to skeletal muscle protein turnover and atrophy. We suggest that serum EV miR-203a-3p content may be a useful biomarker and future work should investigate whether serum EV miR-203a-3p content is mechanistically linked to protein synthesis and degradation.

Trichoblastoma is a rare, slow-growing, benign cutaneous tumor derived from follicular germinative cells. Trichoblastoma commonly appears as an asymptomatic, symmetrical, well-circumscribed, skin-colored to brown or blue-black papule or nodule. It may appear clinically and histologically similar to basal cell carcinoma, making its diagnosis challenging. Even on dermoscopy, it is challenging to differentiate trichoblastoma from basal cell carcinoma. In practice, it is important to differentiate the two, because the choice of treatment and resulting prognosis differ between the lesions. Surgical biopsy to analyze histopathological and immunohistochemical differences is the gold standard for diagnosing and differentiating trichoblastoma from basal cell carcinoma. Trichoblastoma typically has a favorable prognosis, with a low incidence of recurrence, progression or association with malignancy. This paper provides a review of the epidemiology, clinical presentation, dermoscopy, histology, immunochemistry, treatment, and prognosis of trichoblastoma.

In monocots other than maize (Zea mays) and rice (Oryza sativa), the repertoire and diversity of microRNAs (miRNAs) and the populations of phased, secondary, small interfering RNAs (phasiRNAs) are poorly characterized. To remedy this, we sequenced small RNAs (sRNA) from vegetative and dissected inflorescence tissue in 28 phylogenetically diverse monocots and from several early-diverging angiosperm lineages, as well as publicly available data from 10 additional monocot species. We annotated miRNAs, small interfering RNAs (siRNAs) and phasiRNAs across the monocot phylogeny, identifying miRNAs apparently lost or gained in the grasses relative to other monocot families, as well as a number of transfer RNA fragments misannotated as miRNAs. Using our miRNA database cleaned of these misannotations, we identified conservation at the 8th, 9th, 19th, and 3′-end positions that we hypothesize are signatures of selection for processing, targeting, or Argonaute sorting. We show that 21-nucleotide (nt) reproductive phasiRNAs are far more numerous in grass genomes than other monocots. Based on sequenced monocot genomes and transcriptomes, DICER-LIKE5, important to 24-nt phasiRNA biogenesis, likely originated via gene duplication before the diversification of the grasses. This curated database of phylogenetically diverse monocot miRNAs, siRNAs, and phasiRNAs represents a large collection of data that should facilitate continued exploration of sRNA diversification in flowering plants.

Introduction: COVID-19 is a global public health threat that Africa faces including the country Malawi. With an already burdened health system and an economically challenged population due to the poverty level, Malawi is suddenly faced by a pandemic that will test the country’s healthcare systems. Its government has already instituted an array of initiatives and plans and funding efforts toward the effective containment of the pandemic. Some of these efforts include reorientation and training for health workers, securing funding to procure and distribute needed personal protective equipment, medicine supply, health promotion, surveillance and case management. These efforts are being done in the context of an already heavy burden of diseases such as HIV/AIDS, malnutrition and poor health literacy. Whether efforts of the government and other stakeholders are enough, these remain to be seen in containing the virus and its aftermath. Until an effective treatment or vaccine is available, Malawi has to remain vigilant and needs to continue all its efforts to address its COVID-19 epidemic.

Prompt evaluation and therapeutic intervention of suspected pulmonary embolism (PE) are of paramount importance for improvement in outcomes. We systematically reviewed outcomes in patients with suspected PE, including mortality, incidence of recurrent PE, major bleeding, intracranial hemorrhage, and postthrombotic sequelae. We searched the Cochrane Central Register of Controlled Trials, MEDLINE, and Embase for eligible studies, reference lists of relevant reviews, registered trials, and relevant conference proceedings. We included 22 studies with 15 865 patients. Among patients who were diagnosed with PE and discharged with anticoagulation, 3-month follow-up revealed that all-cause mortality was 5.69% (91/1599; 95% confidence interval [CI], 4.56-6.83), mortality from PE was 1.19% (19/1597; 95% CI, 0.66-1.72), recurrent venous thromboembolism (VTE) occurred in 1.38% (22/1597; 95% CI: 0.81-1.95), and major bleeding occurred in 0.90% (2/221%; 95% CI, 0-2.15). In patients with a low pretest probability (PTP) and negative D-dimer, 3-month follow-up revealed mortality from PE was 0% (0/808) and incidence of VTE was 0.37% (4/1094; 95% CI: 0.007-0.72). In patients with intermediate PTP and negative D-dimer, 3-month follow-up revealed that mortality from PE was 0% (0/2747) and incidence of VTE was 0.46% (14/3015; 95% CI: 0.22-0.71). In patients with high PTP and negative computed tomography (CT) scan, 3-month follow-up revealed mortality from PE was 0% (0/651) and incidence of VTE was 0.84% (11/1302; 95% CI: 0.35-1.34). We further summarize outcomes evaluated by various diagnostic tests and diagnostic pathways (ie, D-dimer followed by CT scan).

A previously healthy 53-year-old male with primary membranous nephropathy (positive anti phospholipase A2 antibody) presented to our hospital with worsening cough, shortness of breath, hypotension, and malaise. During his hospital stay, he quickly progressed to overt respiratory failure requiring mechanical ventilation. Upon further workup, he met clinical criteria for tumor lysis syndrome due to an unknown diffuse large B-cell lymphoma, who underwent rapid cytolysis after starting stress dose steroids.

Conceptions of acute public health events typically assume that they are tackled exclusively or principally through technical and medical solutions. Yet health and politics are inexorably linked. To better understand this link, this paper adopts a disaster diplomacy perspective for analysing and assessing the impacts of acute public health events on diplomatic outcomes. Two gaps in understanding disaster-health-politics connections are addressed: (i) how health interventions can impact diplomatic endeavours, especially for (ii) acute public health events. Three diverse case studies are interpreted from a disaster diplomacy perspective: Cuba's medical diplomacy, China and Severe Acute Respiratory Syndrome (SARS), and polio vaccination. Disaster diplomacy permits deeper investigation and analysis of connections amongst health, disaster, and diplomatic activities by viewing efforts on acute public health events as being political through disaster risk reduction (beforehand) and disaster response (during and afterwards). Understanding improves how health interventions affect diplomacy and on disaster diplomacy's limitations.

Summary and keywordsLittle is known about the characteristics and function of reproductive phased, secondary, small interfering RNAs (phasiRNAs) in the Poaceae, despite the availability of significant genomic resources, experimental data, and a growing number of computational tools. We utilized machine-learning methods to identify sequence-based and structural features that distinguish phasiRNAs in rice and maize from other small RNAs (sRNAs).We developed Random Forest classifiers that can distinguish reproductive phasiRNAs from other sRNAs in complex sets of sequencing data, utilizing sequence-based (k-mers) and features describing position-specific sequence biases.The classification performance attained is >80% in accuracy, sensitivity, specificity, and positive predicted value. Feature selection identified important features in both ends of phasiRNAs. We demonstrated that phasiRNAs have strand specificity and position-specific nucleotide biases potentially influencing AGO sorting; we also predicted targets to infer functions of phasiRNAs, and computationally-assessed their sequence characteristics relative to other sRNAs.Our results demonstrate that machine-learning methods effectively identify phasiRNAs despite the lack of characteristic features typically present in precursor loci of other small RNAs, such as sequence conservation or structural motifs. The 5’-end features we identified provide insights into AGO-phasiRNA interactions; we describe a hypothetical model of competition for AGO loading between phasiRNAs of different nucleotide compositions.

In grasses, two pathways that generate diverse and numerous 21-nt (premeiotic) and 24-nt (meiotic) phased siRNAs are highly enriched in anthers, the male reproductive organs. These “phasiRNAs” are analogous to mammalian piRNAs, yet their functions and evolutionary origins remain largely unknown. The 24-nt meiotic phasiRNAs have only been described in grasses, wherein their biogenesis is dependent on a specialized Dicer (DCL5). To assess how evolution gave rise to this pathway, we examined reproductive phasiRNA pathways in nongrass monocots: garden asparagus, daylily, and lily. The common ancestors of these species diverged approximately 115–117 million years ago (MYA). We found that premeiotic 21-nt and meiotic 24-nt phasiRNAs were abundant in all three species and displayed spatial localization and temporal dynamics similar to grasses. The miR2275-triggered pathway was also present, yielding 24-nt reproductive phasiRNAs, and thus originated more than 117 MYA. In asparagus, unlike in grasses, these siRNAs are largely derived from inverted repeats (IRs); analyses in lily identified thousands of precursor loci, and many were also predicted to form foldback substrates for Dicer processing. Additionally, reproductive phasiRNAs were present in female reproductive organs and thus may function in both male and female germinal development. These data describe several distinct mechanisms of production for 24-nt meiotic phasiRNAs and provide new insights into the evolution of reproductive phasiRNA pathways in monocots.

Background: Cumulative data on radiation monotherapy for Merkel cell carcinoma (MCC) is lacking. Objective: We sought to synthesize all available data on treatment outcomes for radiation monotherapy for inoperable stage I-III MCC. Methods: We performed a systematic review of the current literature. Articles published in English in the PUBMED database up to July 29, 2016 were evaluated. Results: Eight case reports, 4 case series, and 6 retrospective studies, yielding 68 patients, were included in our analysis. Of the 24 stage I/II patients treated with local irradiation, 6 (25%) relapsed and 1 (4%) died from MCC. Of the 24 stage I/II patients treated with local and regional nodal irradiation, 5 (21%) relapsed and 2 (8%) died from MCC. Of the 20 stage III patients treated with local and regional nodal irradiation, 12 (60%) relapsed and 7 (35%) died from MCC. Conclusions: Radiation monotherapy appears to be a reasonable treatment modality for patients with inoperable stage I-III MCC. Further investigation with prospective studies is needed to draw definitive conclusions.

Backgroud Modern day cataract surgery aims at a spectacle free vision which becomes difficult in cases with pre-operative astigmatism more than 1.5 D. Implantation of toric intra-ocular lenses (IOL) after phacoemulsification in such eyes is one of the ways to counteract this problem. Methods Thirty eyes with pre-operative astigmatism between 1.5 D and 4.5 D were implanted with toric IOLs following uneventful phaco-emulsification. The estimation of the axis of implantation of this toric IOL included calculating the surgically induced astigmatism (SIA) of the surgeon. Results Post-operatively, 20 (66.67%) patients had a visual acuity 6/9 or better and 17 (57%) had a visual acuity of 6/6 at 12 weeks. The mean postoperative uncorrected visual acuity (UCVA) was 0.12 ± 0.15 at 12 weeks. The difference between means of preoperative best corrected visual acuity (BCVA) LogMAR and postoperative UCVA at 12 wk LogMAR was found to be statistically significant at p = 0.001. Mean (SD) scores of pre-op astigmatism of study group was −2.20 (0.67) and residual astigmatism was −0.32 (0.44). Conclusions The difference between means of pre-op astigmatism and residual astigmatism in the study group was significant at p = 0.001 with 95% CI −2.22 to −1.50. This significant difference was because of the toric IOL implantation.

Patients commonly report difficulty kneeling after total knee arthroplasty (TKA) as it is one of the most neglected activities postop due to a variety of reasons. Data and research have suggested that there is little to no association between range of motion and kneeling ability. This suggests that patients are able to kneel but elect not to. Reasons for patients not electing to kneel seems to be varied which include pain or discomfort in knee fear of harming the implant or hearsay advice from others. There is currently no evidence on whether patients should kneel or not on their replaced knee, and reasons for not kneeling could be addressed through education and rehabilitation. The purpose of this study was to retrospectively assess patients' ability to kneel after TKR after 6 months follow-up duration.

Guillain-Barre syndrome (GBS) is the most common cause of flaccid paralysis in affected patients. Here we present a case of GBS presenting with flaccid paralysis as well as hyponatremia. The association of hyponatremia in GBS is discussed, as well as other potential causes and risk factors.

Background and Objectives: While the impact of maternal factors on birth outcomes are widely reported, the extent to which paternal involvement and varying cultural family dynamics influence birth outcomes particularly in an international context, remain understudied. The purpose of this study was to assess the relationship between paternal involvement and adverse birth outcomes in South Gujarat, India. Methods: An in-person questionnaire was administered to adult women at delivery or during the one-month postpartum visit at New Civil Hospital, in South Gujarat, India between May and June 2016 to assess level of paternal support and attendance at prenatal appointments and household structure. Pregnancy variables including birthweight and gestational age at delivery were collected from maternal and newborn record/chart review. Chi-square and t-test were used to assess demographics, as appropriate. Logistic regression was used to examine the association between paternal involvement and pregnancy birth outcomes. Results: Of the 404 infants born during the study period, 26.7% were premature (

After deep vein thrombosis (DVT) is diagnosed, prompt evaluation and therapeutic intervention are of paramount importance for improvement in patient-important outcomes. We systematically reviewed patient-important outcomes in patients with suspected DVT, including mortality, incidence of pulmonary embolism (PE) and DVT, major bleeding, intracranial hemorrhage, and postthrombotic sequelae. We searched the Cochrane Central Register of Controlled Trials, Ovid Medline, Embase for eligible studies, references lists of relevant reviews, registered trials, and relevant conference proceedings. Two investigators screened and abstracted data. Nine studies with 5126 patients were included for lower extremity DVT. Three studies with 500 patients were included for upper extremity DVT. Among patients with lower extremity DVT, 0.85% (95% confidence interval [CI], 0% to 2.10%) and 0% developed recurrent DVT and PE, respectively, at 3 months. Among patients with upper extremity DVT, 0.49% (95% CI, 0% to 1.16%) and 1.98% (95% CI, 0.62% to 3.33%) developed recurrent DVT and PE, respectively, at 3 months. No major bleeding events were reported for those anticoagulated, which is lower than in other systematic reviews. For both upper and lower extremity DVT, low pretest probability patients with a negative D-dimer had a comparable incidence of VTE at 3 months (∼1%) as patients with a negative ultrasound (US). At higher pretest probabilities, negative US testing with or without serial US appears to be the safer option. In this review, we summarized the outcomes of patients evaluated by various diagnostic pathways. In most instances, there was significant limitation due to small population size or lack of direct evidence of effects of using a specific pathway. This systematic review was registered at PROSPERO as CRD42018100502.

Over the past few years, there has been a considerable spread of microarray technology in many biological patterns, particularly in those pertaining to cancer diseases like leukemia, prostate, colon cancer, etc. The primary bottleneck that one experiences in the proper understanding of such datasets lies in their dimensionality, and thus for an efficient and effective means of studying the same, a reduction in their dimension to a large extent is deemed necessary. This study is a bid to suggesting different algorithms and approaches for the reduction of dimensionality of such microarray datasets. This study exploits the matrix-like structure of such microarray data and uses a popular technique called Non-Negative Matrix Factorization (NMF) to reduce the dimensionality, primarily in the field of biological data. Classification accuracies are then compared for these algorithms. This technique gives an accuracy of 98%., Comment: 9th International Conference on Data Mining & Knowledge Management Process (CDKP 2020)

With the long-standing controversy surrounding the use of prostate-specific antigen (PSA) for the detection, evaluation, and surveillance of prostate cancer, there is a need for a minimally invasive technique to identify and risk-stratify these patients. Additionally, in an effort to reduce the number of unnecessary biopsies and identify clinically significant prostate cancer (csPCa), there has been a shift in practice towards the use of multiparametric magnetic resonance imaging (mpMRI) in conjunction with decision-making regarding prostate cancer diagnosis and management. In the current review, we summarize the data regarding the use of mpMRI in the detection, evaluation, and surveillance of csPCa. Recent prospective clinical trials have determined that a pre-biopsy mpMRI may rule out insignificant prostate cancers, thereby reducing the number of patients who require a biopsy. The anatomic information gathered from these pre-biopsy mpMRI performed during MRI fusion biopsy in csPCa increases the accuracy of pathologic staging in terms of Gleason scores. In regard to active surveillance, prospective trials suggest little to no clinical utility for mpMRI and fusion biopsy in the surveillance of prostate cancer despite conflicting findings from retrospective studies. Recent trials suggest that mpMRI can play an important role in the detection and evaluation of csPCa. The ideal role for mpMRI in active surveillance remains limited.

An estimated 14.2% (9.34 million people) of people living in the UK in 2019 were international migrants. Despite this, there are no large-scale national studies of their healthcare resource utilisation and little is known about how migrants access and use healthcare services. One ongoing study of migration health in the UK, the Million Migrants study, links electronic health records (EHRs) from hospital-based data, national death records and Public Health England migrant and refugee data. However, the Million Migrants study cannot provide a complete picture of migration health resource utilisation as it lacks data on migrants from Europe and utilisation of primary care for all international migrants. Our study seeks to address this limitation by using primary care EHR data linked to hospital-based EHRs and national death records. Our study is split into a feasibility study and a main study. The feasibility study will assess the validity of a migration phenotype, a transparent reproducible algorithm using clinical terminology codes to determine migration status in Clinical Practice Research Datalink (CPRD), the largest UK primary care EHR. If the migration phenotype is found to be valid, the main study will involve using the phenotype in the linked dataset to describe primary care and hospital-based healthcare resource utilisation and mortality in migrants compared to non-migrants. All outcomes will be explored according to sub-conditions identified as research priorities through patient and public involvement, including preventable causes of inpatient admission, sexual and reproductive health conditions/interventions and mental health conditions. The results will generate evidence to inform policies that aim to improve migration health and universal health coverage.

Treatment of cancer is a furtive problem in the current era in spite of significant advancement in drug delivery systems and identification of new therapeutic molecules. The ration of lab to market translation of therapeutic research is quite low in anticancer therapy due to hidden and unnameable disease causing and disease progression mechanisms. Oncogene activation disturbs normal cell processes such as cell growth and apoptosis, which ultimately leads to cancer. Different ways, such as RNAi, antisense oligonucleotides, Translation suppressing oligonucleotide and external guide sequences which silences oncogenes are key techniques under investigation currently. The emerging way of formulating nanoparticles containing antisense oligonucleotides and the targeting approaches is illustrated with the brief information on key materials used for the same purpose. Gene targets identified and investigated by various companies and research groups are enumerated and reviewed for their potential to consider antisense gene therapy. Nanocarrier systems which have been reported to enhance feasibility of selective antisense oligonucleotides to treat the disease are assessed for their pros and cons.

Background While the overall incidence rate of colorectal cancer (CRC) in Canada has been decreasing, some countries show an increasing incidence in those under the age of 50. We examined the trends in CRC incidence and associated lifestyle risk factors in Canadians aged 15⿿49. Methods Incidence data for colorectal, colon and rectum/rectosigmoid cancers were obtained for 1969⿿2010 from the Canadian Cancer Registry, and trends in age-standardized incidence rates (ASIRs) were examined by Joinpoint regression for three age groups (15⿿29, 30⿿39, 40⿿49 years) and by sex. Trends in the prevalence of some CRC risk factors were similarly examined from national health surveys for various periods ranging from 1970 to 2012. Results In both sexes combined, ASIRs rose by 6.7%/year (1997⿿2010) for 15⿿29-year-olds, 2.4%/year (1996⿿2010) for 30⿿39-year-olds, and 0.8%/year (1997⿿2010) for 40⿿49-year-olds. Similar trends were observed by sex. The rise in ASIR was more rapid for cancers of the rectum/rectosigmoid compared to colon for all age groups. Risk factor trends varied: excess weight rose substantially, vegetables and fruit consumption increased slightly, physical inactivity rates declined but remained high, alcohol consumption changed little, and smoking rates declined. Data on red/processed meat consumption were unavailable. Conclusion The ASIR of CRC in young Canadians has increased since about the mid-1990s. The rising prevalence of excess weight in younger generations has likely played a role in the CRC trend, but more research is needed.

Since its clinical inception, tamoxifen (TAM) has proved to be a powerful tool in treating estrogen receptor-positive breast cancers while exhibiting manageable side effects. Although TAM was synthesized as an estrogen receptor antagonist, reports have found that a significant fraction of women with estrogen receptor-negative cancers have benefitted from TAM treatment, suggesting the possibility of an alternate anti-cancer mechanism. In this paper, we present a review of recent and past literature in an attempt to clarify how TAM inhibits cell proliferation and induces apoptosis in cells lacking the estrogen receptor. Our analysis indicates that micromolar concentrations of TAM selectively elevate intracellular calcium concentrations in malignant cells, possibly by inversely agonizing cannabinoid receptors, producing considerable mitochondrial distress followed by the rapid production of reactive oxygen species. In response, cytoplasmic proteins such as JNK1 are activated, which mediates the activation of caspase-8. Fyn kinase auto phosphorylates in response to increased reactive oxygen species and directs the ubiquitin ligase c-Cbl to tag growth factor receptors for ubiquitination, potentially abrogating constitutively active survival pathways that are hallmarks of cancer progression. We attempt to differentiate the effect that TAM has on purified Protein Kinase C (PKC) compared to that in an intact cell, suggesting that low micromolar concentrations of TAM indirectly inhibit PKC by inducing EGFR destruction and high micromolar concentrations of TAM inhibits PKC through a direct binding mechanism.

Assessing the extent of absorption of topical drugs into the various skin layers has been one of the biggest challenges of recent dermatological research. Although skin biopsy samples can be used to directly measure topical drug absorption, biopsies are invasive and not practical for obtaining kinetic data. Common alternative techniques used to assess the bioavailability of topical drugs include in vitro (Franz cell chamber), ex vivo (isolated perfused skin models), and in vivo (vasoconstrictor assay, tape stripping/dermatopharmacokinetics, and microdialysis) techniques. Despite the popularity of these techniques, each technique has its own advantages and disadvantages that limit its use. Consideration of each technique requires that there is a rational linkage to the drug's clinical endpoint and/or site of action. In this article, we review these in vitro, ex vivo, and in vivo techniques, focusing on the basic concepts and the advantages and disadvantages of each technique.

The increasing prevalence of carbon nanotubes (CNTs) as components of new functional materials has the unintended consequence of causing increases in CNT concentrations in aqueous environments. Aqueous systems are reservoirs for bacteria, including human and animal pathogens, that can form biofilms. At high concentrations, CNTs have been shown to display biocidal effects; however, at low concentrations, the interaction between CNTs and bacteria is more complicated, and antimicrobial action is highly dependent upon the properties of the CNTs in suspension. Here, impact of low concentrations of multiwalled CNTs (MWCNTs) on the biofilm-forming opportunistic human pathogen Pseudomonas aeruginosa is studied. Using phase contrast and confocal microscopy, flow cytometry, and antibiotic tolerance assays, it is found that sub-lethal concentrations (2 mg/L) of MWCNTs promote aggregation of P. aeruginosa into multicellular clusters. However, the antibiotic tolerance of these “young” bacterial-CNT aggregates is similar to that of CNT-free cultures. Overall, our results indicate that the co-occurrence of MWCNTs and P. aeruginosa in aqueous systems, which promotes the increased number and size of bacterial aggregates, could increase the dose to which humans or animals are exposed.

An estimated 14.2% (9.34 million people) of people living in the UK in 2019 were international migrants. Despite this, there are no large-scale national studies of their healthcare resource utilisation and little is known about how migrants access and use healthcare services. One ongoing study of migration health in the UK, the Million Migrants study, links electronic health records (EHRs) from hospital-based data, national death records and Public Health England migrant and refugee data. However, the Million Migrants study cannot provide a complete picture of migration health resource utilisation as it lacks data on migrants from Europe and utilisation of primary care for all international migrants. Our study seeks to address this limitation by using primary care EHR data linked to hospital-based EHRs and national death records. Our study is split into a feasibility study and a main study. The feasibility study will assess the validity of a migration phenotype, a transparent reproducible algorithm using clinical terminology codes to determine migration status in Clinical Practice Research Datalink (CPRD), the largest UK primary care EHR. If the migration phenotype is found to be valid, the main study will involve using the phenotype in the linked dataset to describe primary care and hospital-based healthcare resource utilisation and mortality in migrants compared to non-migrants. All outcomes will be explored according to sub-conditions identified as research priorities through patient and public involvement, including preventable causes of inpatient admission, sexual and reproductive health conditions/interventions and mental health conditions. The results will generate evidence to inform policies that aim to improve migration health and universal health coverage.

Background: Modern diagnostic strategies for venous thromboembolism (VTE) incorporate pretest probability (PTP; prevalence) assessment. The ability of diagnostic tests to correctly identify or exclude VTE is influenced by VTE prevalence and test accuracy characteristics. Objective: These evidence-based guidelines are intended to support patients, clinicians, and health care professionals in VTE diagnosis. Diagnostic strategies were evaluated for pulmonary embolism (PE), deep vein thrombosis (DVT) of the lower and upper extremity, and recurrent VTE. Methods: The American Society of Hematology (ASH) formed a multidisciplinary panel including patient representatives. The McMaster University GRADE Centre completed systematic reviews up to 1 October 2017. The panel prioritized questions and outcomes and used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to assess evidence and make recommendations. Test accuracy estimates and VTE population prevalence were used to model expected outcomes in diagnostic pathways. Where modeling was not feasible, management and accuracy studies were used to formulate recommendations. Results: Ten recommendations are presented, by PTP for patients with suspected PE and lower extremity DVT, and for recurrent VTE and upper extremity DVT. Conclusions: For patients at low (unlikely) VTE risk, using D-dimer as the initial test reduces the need for diagnostic imaging. For patients at high (likely) VTE risk, imaging is warranted. For PE diagnosis, ventilation-perfusion scanning and computed tomography pulmonary angiography are the most validated tests, whereas lower or upper extremity DVT diagnosis uses ultrasonography. Research is needed on new diagnostic modalities and to validate clinical decision rules for patients with suspected recurrent VTE.

The aim of this study was to compare hospital outcomes for patients in a motorcycle collision with and without helmet use. The study was conducted as a retrospective analysis of the National Trauma Data Bank's 2013 data set, which included reported data from 100 hospitals across the United States.Inclusion criterion for this study is a motorcycle crash involving a driver or passenger. The total number of patients in motorcycle crashes as reported by the National Trauma Data Bank in 2013 was 10,345. Helmet use, hospital stay, ICU and ventilation days, mortality, Glasgow Coma Score, Injury Severity Score, patient payer mix, and complication data were obtained.Patients were divided into two groups: those wearing a helmet (n = 6250) and those without (n = 4095). Patients not wearing a helmet had an increased risk of admission to the ICU (OR = 1.36, P 0.001, CI 1.25-1.48), requiring ventilation support (OR = 1.55, P 0.001, CI 1.39-1.72), presenting with a Glasgow Coma Score of eight or below (OR = 2.15, P 0.001), and in-patient mortality (OR = 2.00, P 0.001, CI 1.58-2.54). Unhelmeted patients were more likely to have government insurance or be uninsured than those patients wearing a helmet (P 0.001).It is not well understood why many states are repealing or have repealed universal helmet laws. Lack of helmet use increases the severity of injury in traumatized patients leading to a substantial financial impact on health care costs. Our analysis suggests the need to revisit the issue regarding laws that require protective headwear while riding motorcycles because of the individual and societal impact.III.

Small RNAs are key regulators in plant growth and development. One subclass, phased siRNAs (phasiRNAs) require a trigger microRNA for their biogenesis. In grasses, two pathways yield abundant phasiRNAs during anther development; miR2275 triggers one class, 24-nt phasiRNAs, coincident with meiosis, while a second class of 21-nt phasiRNAs are present in premeiotic anthers. Here we report that the 24-nt phasiRNA pathway is widely present in flowering plants, indicating that 24-nt reproductive phasiRNAs likely originated with the evolutionary emergence of anthers. Deep comparative genomic analyses demonstrated that this miR2275/24-nt phasiRNA pathway is widely present in eudicots plants, however, it is absent in legumes and in the model plant Arabidopsis, demonstrating a dynamic evolutionary history of this pathway. In Solanaceae species, 24-nt phasiRNAs were observed, but the miR2275 trigger is missing and some loci displaying 12-nt phasing. Both the miR2275-triggered and Solanaceae 24-nt phasiRNAs are enriched in meiotic stages, implicating these phasiRNAs in anther and/or pollen development, a spatiotemporal pattern consistent in all angiosperm lineages that deploy them., 24-nt phased siRNA (phasiRNA) regulate reproduction in grasses, yet are absent from Arabidopsis, and were thought to be monocot-specific. Here, Xia et al. show that 24-nt phasiRNAs are in fact broadly distributed among eudicots and are consistently enriched during meiosis, despite possibly arising from distinct biogenesis pathways.

Langerhans cell histocytosis (LCH) and Erdheim-Chester disease are two rare histiocytic disorders. Their occurrence in the same patient is more infrequent, but has been described. We report a case of a 38-year-old woman who presented with a diagnosis of single system cutaneous LCH. Subsequently, she developed multiple papules on her extremities consistent with a non-LCH xanthogranuloma type lesion. BRAF(V600E) mutation immunostain, VE1 was positive in the skin lesion, which was confirmed by molecular polymerase chain reaction (PCR) studies, initiating a complete systemic workup for Erdheim-Chester disease. Systemic involvement was confirmed with bilateral sclerotic bone lesions and retroperitoneal and pelvic fibrosing disease. She was also found to have a BRAF(V600E) mutation positive papillary thyroid carcinoma. New suspicious cutaneous lesions presenting in patients with a history of LCH need to be biopsied. A BRAF(V600E) mutation in a non-LCH histiocytic lesion with a xanthogranuloma phenotype (CD163/CD68/CD14/fascin/Factor 13a) should prompt an Erdheim-Chester disease workup. This is a unique case of a woman with BRAF(V600E) mutation positive Erdheim-Chester disease and cutaneous LCH, while also being, to our knowledge, the first reported case in the English literature of it occurring in a patient with a BRAF(V600E) mutation positive papillary thyroid carcinoma.

The trabecular bone score (TBS) is a novel tool using grayscale variograms of the lumbar spine bone mineral density (BMD) to assess trabecular bone microarchitecture. Studies in patients with chronic kidney disease (CKD) suggest it may be helpful in assessing fracture risk. However, TBS has not been validated as a measure of trabecular architecture against transiliac bone biopsy with histomorphometry in CKD patients. We hypothesized that TBS would reflect trabecular architecture at the iliac crest in CKD patients. We obtained tetracycline double labeled transiliac crest bone biopsy, areal BMD of the spine, total hip, femoral neck (FN) and spine TBS by dual energy X-ray absorptiometry (DXA), and cortical and trabecular volumetric density and microarchitecture by high resolution peripheral quantitative computed tomography (HR-pQCT) in CKD patients from two centers: twenty-two patients from Columbia University Medical Center, USA and thirty patients from Hospital das Clinicas - Universidade de São Paulo, Brazil. Two patients were excluded for outlier status. Univariate and multivariate relationships between TBS and measures from DXA, HR-pQCT and histomorphometry were determined. Patients were 50.2 ± 15.8 years old, 23 (46%) were men, and 33 (66%) were on dialysis. TBS was1.31 in 21 (42%) patients and 22%, 14% and 10% had T-scores ≤ -2.5 at spine, FN and total hip respectively. In univariate regression, TBS was significantly associated with trabecular bone volume (BV/TV), trabecular width (Tb.Wi), trabecular spacing, cortical width but not with trabecular number or cortical porosity. FN Z-score and height were also associated with cancellous BV/TV and Tb.Wi, In multivariate analysis, TBS remained an independent predictor of BV/TV and Tb.Wi. There were no relationships between TBS and dynamic parameters from histomorphometry. These data suggest that TBS reflected trabecular microarchitecture and cortical width measured by bone biopsy in CKD patients. Future studies should address its utility in the identification of CKD patients who may benefit from fracture prevention strategies.

Background: 258 million people - 3% of the world's adult population - reside outside of their country of birth, yet there has been no previous global systematic review and meta-analysis of mortality data for these international migrants. We undertook a systematic review and meta-analysis to investigate current knowledge about mortality in international migrants. Methods: The review was carried out in line with PRISMA guidelines and was registered on Prospero (CRD42017073608). We searched the MEDLINE, EMBASE, and Global Health databases for studies on international migrants published between 1 Jan 2001 and 31 March 2017. Primary outcomes were standardised mortality ratios (SMRs) and absolute mortality rates. Meta-analyses were conducted using random effects models. Findings: We identified 12480 articles, of which 106 met our inclusion criteria. Data were included from all global regions and for 92 countries. 5498 SMR or absolute mortality estimates on more than 15.2 million migrants were included. The summary estimate of all-cause SMR for international migrants was lower than one (indicating lower mortality) when compared to the general population in host countries to which they migrate 0·70 (95%CI: 0·65-0·76;I2=99·8%). We estimated that all-cause SMR was lower in both male (0·72 [0·63-0·81]; I2=99·8%) and female (0·75 [0·66-0·84]; I2=99·8%) international migrants compared to the host population. The mortality advantage was evident for refugees (0.50 [0.46-0.56];I2=89·8%), but not for asylum seekers (1.05 [0.89-1.24];I2=54·4%), though there were limited data on these groups. SMRs for all causes of mortality were lower in migrants compared to the host population in the destination country with only two exceptions - infectious diseases and external causes - out of 13 ICD-10 categories. Heterogeneity was high across analyses. Point estimates of age-standardised mortality ranged from 488 in women to 874 in men per 100,000 population. Interpretation: Our analyses found that international migrants experience a mortality advantage compared to host populations, and this advantage persisted across the majority of ICD-10 disease categories. This finding is in contrast to the portrayal of migrants as a health burden and demonstrates that international migrants provide a major health benefit for host countries. Our research also highlights the need for better data on underrepresented and potentially more marginalised groups such as asylum seekers and undocumented migrants. Funding Statement: Wellcome Trust, NIHR, MRC, Alliance for Health Policy and Systems Research, DFID, Fogarty International Center, Grand Challenges Canada, International Development Research Center Canada, Inter-American Institute for Global Change Research, National Cancer Institute, National Heart, Lung and Blood Institute, National Institute of Mental Health, Swiss National Science Foundation, World Diabetes Foundation, UK National Institute for Health Research Imperial Biomedical Research Centre and the the Imperial College Healthcare Charity. Declaration of Interests: RWA and IA undertook paid consultancy work in support of the Doctors of the World 2017 Observatory report - Falling through the cracks: The Failure of Universal Healthcare Coverage in Europe. JSF, LBN, and SH have collaborated on research projects with Doctors of the World UK, which includes research commissioned by the Equality and Human Rights Commission on barriers and enablers to care for asylum seekers and refused asylum seekers in the UK. RWA is supported by a Wellcome Trust Clinical Research Career Development Fellowship (206602/Z/17/Z). SB is supported by an NIHR research methods fellowship. JJM acknowledges receiving additional support from the Alliance for Health Policy and Systems Research (HQHSR1206660), DFID/MRC/Wellcome Global Health Trials (MR/M007405/1), Fogarty International Center (R21TW009982, D71TW010877), Grand Challenges Canada (0335-04), International Development Research Center Canada (106887, 108167), Inter-American Institute for Global Change Research (IAI CRN3036), Medical Research Council (MR/P008984/1, MR/P024408/1, MR/P02386X/1), National Cancer Institute (1P20CA217231), National Heart, Lung and Blood Institute (HHSN268200900033C, 5U01HL114180, 1UM1HL134590), National Institute of Mental Health (1U19MH098780), Swiss National Science Foundation (40P740-160366), Wellcome Trust (074833/Z/04/Z, 205177/Z/16/Z) and the World Diabetes Foundation (WDF15-1224). LBN, SH, and JSF receive funding from the UK National Institute for Health Research Imperial Biomedical Research Centre and the Imperial College Healthcare Charity; SH and LN are funded by the Wellcome Trust (Grant number 209993/Z/17/Z) with co-applicants of RWA, JSF and IA for this work. The views expressed are those of the authors and not those of the Wellcome Trust, NIHR, NHS, NHS Research Scotland, Medical Research Council, Chief Scientist’s Office. Ethics Approval Statement: The review was carried out in line with PRISMA guidelines and was registered on Prospero (CRD42017073608).

Hereditary Nonpolyposis Colorectal Cancer (HNPCC), also known as Lynch Syndrome, is an autosomal dominant, tumor predisposing disorder usuallycaused by germline mutations in mismatch repair (MMR) genes. A subset of HNPCC, Muir-Torre Syndrome (MTS) also involves MMR gene defects and is generally accepted as a variant of HNPCC. MTS is typicallycharacterized by at least one visceral malignancy and one cutaneous neoplasm of sebaceous differentiation, with or without keratoacanthomas. In either version of the disorder, nonfunctional MMR systems lead tothe loss of genomic integrity, marked commonly by mismatches in repetitive DNA sequences, resulting in microsatellite instabilities. Deleterious nucleotide alterations ultimately drive the process of tumorigenesis in both HNPCC and MTS. The following article reviews the epidemiology, genetics, clinical presentation, and management of HNPCC and its MTS variant.

Angiotensin-I-converting enzyme (ACE) inhibitors have been very effective in treating cardiac hypertension since their clinical inception over four decades ago. Since then, it has been established that angiotensin II, the product of ACE, has oncogenic and pro-proliferative qualities, which begs the question as to whether ACE inhibitors may have oncolytic characteristics. In fact, scattered reports suggest that ACE inhibitors are oncolytic and oncopreventive, but the available literature has yet to be thoroughly examined. In the present review, we examine the available literature and determine that ACE inhibitors would have great utility in the prevention and treatment of cancer. At the same time, they would augment the efficacy of chemo- and radiotherapy as well as mitigating damage to healthy tissue by standard chemotherapeutic regimens. We review some of the mounting clinical evidence and show that ACE inhibitors have oncolytic activity in multiple types of cancer and discuss the ability of ACE inhibitors to prevent cardiotoxicity of multiple chemotherapies. Our analysis demonstrates that the actions of ACE inhibitors converge on vascular endolthelial growth factor to reduce its levels in tumors and prevent construction of blood vessels to masses, leaving them nutrient-depleted and subsequently hindering their growth. Given that ACE inhibitors are approved by the Federal Drug Administration and the therapeutic dose for hypertension treatment also slows the growth of multiple cancers types, ACE inhibitors are in a perfect position to be repurposed as oncolytic agents, that would widely increase their utility in the clinic.

Neurotrophins are a family of growth factors that are vital to the proper development of the central nervous system. Their effects on cells are governed by the expression and activation of the tyrosine kinase receptors TrkA, TrkB and TrkC. TrkB has been immensely implicated in mediating neuronal migration, development and differentiation. It has also been shown to protect several neuronal cell types from an array of cytotoxic stressors after activation by its conjugate ligand brain-derived neurotrophic factor (BDNF). Over the past two decades, it has been shown that TrkB and BDNF are up-regulated in many types of cancers, conferring aggressive phenotypes underpinned by their resistance to several standard chemotherapeutic agents. This resistance to chemotherapy is modulated by the downstream targets of the TrkB receptor which include the well-characterized PI3K /Akt growth pathway, a hallmark of uncontrolled cancer cell growth and proliferation. Pre-clinical efforts to develop inhibitors of this receptor are promising, and such inhibitors also seem to sensitize cancer cells to standard chemotherapies. However, new evidence suggests that BDNF overexpression in the hypothalamus has immunoaugmenting properties, eliciting an increased anti-tumor immune response and reducing the activity of several proteins that would normally confer resistance to chemotherapeutic agents. In the current work, we provide a global analysis of the physiological consequences of TrkB receptor activation in vitro and discuss the dynamic consequences of TrkB activation in vivo. Finally, we propose a clinically-feasible option for increasing BDNF expression in the hypothalamus to more readily utilize the oncolytic effects of BDNF.

Breast cancer (BC) is the second largest diagnosed cancer among women, with approximately 266,120 new cases of BC in the United States. Thus far BC is understood as a disease driven by genetic abnormalities. Specifically, recent studies provide evidence that epigenetic modifications, such as methylation profiles, play a critical role in BC development regarding tumor suppressor genes. Despite there being many DNMT inhibitors, such as 5- azacytidine (Vidaza), they are ineffective versus solid tumors and they elicit a cytotoxic response. Thus, it is vital that a drug that is able to halt BC growth and progression is investigated. This project hopes to test the anti-tumor potential and therapeutic potential of Hydralazine (HDZ) because of its ability to act as a DNA methylation inhibitor, specifically DNMT1 and DNMT3A. In addition, despite HDZ being currently tested in clinical cancer trials for its antihypertensive effect, its mechanism of antitumor action remains undefined.We analyzed the anti-cancer potential of HDZ on two human BC cell lines and a mouse mammary tumor cell line (AT3). Cells were treated with different doses of HDZ (0, 1, 10, 25, and 50 M) for different time points (1, 2, 3, 7, and 14 days) and cell viability was measured by MTT assay. From these experiments, we optimized the time and concentration of HDZ in BC cells. Finally, we treated the cells with the appropriate concentration and time and then prepared RNA and protein for gene expression analysis, measured DNMT1 activity, and analyzed stem cells status using cell surface markers (CD24/CD44). We also tested the anti-tumor potential of HDZ in a mouse model using AT3 cells. AT3 cells were implanted in the mammary fat pads and grown to the tumor size of 250 mm3. Then, we treated the mice with HDZ and monitored the tumor growth. Tumor tissues harvested from these mice will be used for gene expression analysis, measure DNMT1 activity, histological analysis and analyze the stem cell status such as Oct4, Nanog, Gata4, Slug, and Sox2.All 4 BC cell lines demonstrated a slightly lower cell viability from the MTT when treated for 3 days and used at the highest dosage. In addition, through the use of RT-PCR, it has been shown that the levels of DNMT1 and CD24 expressions have been slightly downregulated. Western Blot analysis showed, the protein levels of DNMT1 and CD24 also decreased slightly. We also found that HDZ treatment significantly reduced tumor growth and volume in the mouse model. These findings suggest that the drug HDZ has a slight anti-tumor property on breast cancer growth and progression in the cell and mouse models. Although not as significant as we originally thought, the future implications of this project would be to complement HDZ with another drug such as a stem cell inhibitor. We believe that this dual therapy would synergistically work to halt BC progression and growth much more efficiently than any monotherapy for the treatment of triple-negative breast cancer. Citation Format: Parth B. Patel. Anti-tumor potential of Hydralazine, a DNMT1 inhibitor, on breast cancer growth and progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3845.

Summary: We describe miTRATA, the first web-based tool for microRNA Truncation and Tailing Analysis—the analysis of 3′ modifications of microRNAs including the loss or gain of nucleotides relative to the canonical sequence. miTRATA is implemented in Python (version 3) and employs parallel processing modules to enhance its scalability when analyzing multiple small RNA (sRNA) sequencing datasets. It utilizes miRBase, currently version 21, as a source of known microRNAs for analysis. miTRATA notifies user(s) via email to download as well as visualize the results online. miTRATA’s strengths lie in (i) its biologist-focused web interface, (ii) improved scalability via parallel processing and (iii) its uniqueness as a webtool to perform microRNA truncation and tailing analysis. Availability and implementation: miTRATA is developed in Python and PHP. It is available as a web-based application from https://wasabi.dbi.udel.edu/∼apps/ta/. Contact: meyers@dbi.udel.edu Supplementary information: Supplementary data are available at Bioinformatics online.

BACKGROUND Randomized controlled trials are the gold standard for comparing safety and effectiveness of surgical interventions. Reporting guidelines are available for conveying the results of such trials. OBJECTIVE To assess adherence to standard reporting guidelines among randomized controlled trials in dermatologic surgery. MATERIALS AND METHODS Systematic review. Data source was randomized controlled trials in the journal Dermatologic Surgery, per PubMed search, 1995 to 2014. Studies were appraised for the number of the 37 CONSORT 2010 Checklist criteria reported in each. Analysis included comparison of reporting across 4 consecutive periods. RESULTS Three hundred sixty-three studies were eligible. The mean number of items reported per study increased monotonically from 14.5 in 1995 to 1999 to 16.2 in 2002 to 2004, 17.7 in 2005 to 2009, and 18.0 in 2010 to 2014 (p < .0001). A limitation was that study procedures may have been performed without being reported. CONCLUSION Completeness of reporting in randomized controlled trials in dermatologic surgery has improved significantly during the preceding 2 decades. Some elements are still reported at lower rates.

Current cancer research strongly focuses on identifying novel pathways that can be selectively exploited in the clinic and identifying drugs capable of exploiting cancer vulnerabilities. Occasionally, drugs identified to exploit a cancer-specific vulnerability are on the market for clinical indications in another disease area. Rebranding them as anti-cancer drugs is a process commonly referred to as drug repurposing and is typically a faster method than bringing a novel drug to market. Selective serotonin reuptake inhibitors (SSRIs) are primarily used for treating several types of depression, but over the past two decades mounting evidence suggests that drugs in this class have oncolytic properties and reduce the risk of certain cancers. In the current work, we discuss how the secondary mechanisms of action associated with these drugs mediate their oncolytic effect. In particular, sertraline limits tumor growth by abrogating the PI3K/akt signaling pathway, a growth pathway shown to be constitutively active in multiple cancers. Fluoxetine has been shown to activate the AMPA-type glutamate receptor, induce massive calcium influx and mitochondrial calcium overload and induce caspase-9-dependent apoptosis. This receptor being highly overexpressed in cancer stem cells may explain why SSRIs lower the risk of multiple types of cancer. Fluoxetine has also been shown to inhibit multidrug resistance pumps, increasing the efficacy of several standard chemotherapies. Given the vast potential of SSRIs in treating cancer, these drugs should be more heavily used not only in treating cancer-related depression, but in combating cancer and increasing the efficacy of standard of care chemotherapies.