Epistasis not needed to explain low dN/dS

An important question in molecular evolution is whether an amino acid that occurs at a given position makes an independent contribution to fitness, or whether its effect depends on the state of other loci in the organism's genome, a phenomenon known as epistasis. In a recent letter to Nature, Breen et al. (2012) argued that epistasis must be "pervasive throughout protein evolution" because the observed ratio between the per-site rates of non-synonymous and synonymous substitutions (dN/dS) is much lower than would be expected in the absence of epistasis. However, when calculating the expected dN/dS ratio in the absence of epistasis, Breen et al. assumed that all amino acids observed in a protein alignment at any particular position have equal fitness. Here, we relax this unrealistic assumption and show that any dN/dS value can in principle be achieved at a site, without epistasis. Furthermore, for all nuclear and chloroplast genes in the Breen et al. dataset, we show that the observed dN/dS values and the observed patterns of amino acid diversity at each site are jointly consistent with a non-epistatic model of protein evolution.Comment: This manuscript is in response to "Epistasis as the primary factor in molecular evolution" by Breen et al. Nature 490, 535-538 (2012

Evaluation of two high-throughput proteomic technologies for plasma biomarker discovery in immunotherapy-treated melanoma patients

Background: Selective kinase and immune checkpoint inhibitors, and their combinations, have significantly improved the survival of patients with advanced metastatic melanoma. Not all patients will respond to treatment however, and some patients will present with significant toxicities. Hence, the identification of biomarkers is critical for the selection and management of patients receiving treatment. Biomarker discovery often involves proteomic techniques that simultaneously profile multiple proteins but few studies have compared these platforms. Methods: In this study, we used the multiplex bead-based Eve Technologies Discovery assay and the aptamer-based SomaLogic SOMAscan assay to identify circulating proteins predictive of response to immunotherapy in melanoma patients treated with combination immune checkpoint inhibitors. Expression of four plasma proteins were further validated using the bead-based Millipore Milliplex assay. Results: Both the Discovery and the SOMAscan assays detected circulating plasma proteins in immunotherapy-treated melanoma patients. However, these widely used assays showed limited correlation in relative protein quantification, due to differences in specificity and the dynamic range of protein detection. Protein data derived from the Discovery and Milliplex bead-based assays were highly correlated. Conclusions: Our study highlights significant limitations imposed by inconsistent sensitivity and specificity due to differences in the detection antibodies or aptamers of these widespread biomarker discovery approaches. Our findings emphasize the need to improve these technologies for the accurate identification of biomarkers

How did the latest increase in fees in England affect student enrolment and inequality?

This paper presents a first analysis of the increase of undergraduate tuition fees to £9,000 (€11.000) in English higher education in 2012. I use a semi-experimental research design to estimate the effect of the reforms, based on student enrolment data drawn from the Higher Education Statistics Agency (HESA). Taking into account possible anticipation effects of the fee increase, I find that enrolment declined by 15 % in the treated groups as a result of the tuition fee increase. This number is almost three times higher than what previous studies have found, and may represent a serious long term cost for the English economy. The decline in enrolments is particularly pronounced for students in older age groups and students from the service class and the middle class. No effect is visible for students from the working class, indicating that the reforms did not lead to a much-feared increase in class bias in higher education enrolment. The reforms also seem not to have exacerbated ethnic inequality in higher education, as all ethnic groups were negatively affected by the reforms. These results are consistent with earlier research in the United States and the United Kingdom, although they expand our understanding of student price responsiveness in other important ways. The paper argues that younger and older students face different costs and benefits. Older students may be less certain about their benefits, and therefore be more sensitive towards price increases. The strong decrease in mature learners may require a policy response, taking into account these differing incentives

Gene expression analysis of TIL rich HPV-driven head and neck tumors reveals a distinct B-cell signature when compared to HPV independent tumors

Human papilloma virus (HPV)-associated head and neck squamous cell carcinoma (HNSCC) has a better prognosis than it's HPV negative (HPV(-)) counterpart. This may be due to the higher numbers of tumor-infiltrating lymphocytes (TILs) in HPV positive (HPV(+)) tumors. RNA-Sequencing (RNA-Seq) was used to evaluate whether the differences in clinical behaviour simply reflect a numerical difference in TILs or whether there is a fundamental behavioural difference between TILs in these two settings. Thirty-nine HNSCC tumors were scored for TIL density by immunohistochemistry. After the removal of 16 TILlow tumors, RNA-Seq analysis was performed on 23 TILhigh/med tumors (HPV(+) n=10 and HPV(-) n=13). Using EdgeR, differentially expressed genes (DEG) were identified. Immune subset analysis was performed using Functional Analysis of Individual RNA-Seq/ Microarray Expression (FAIME) and immune gene RNA transcript count analysis. In total, 1,634 DEGs were identified, with a dominant immune signature observed in HPV(+) tumors. After normalizing the expression profiles to account for differences in B- and T-cell number, 437 significantly DEGs remained. A B-cell associated signature distinguished HPV(+) from HPV(-) tumors, and included the DEGs CD200, GGA2, ADAM28, STAG3, SPIB, VCAM1, BCL2 and ICOSLG; the immune signal relative to T-cells was qualitatively similar between TILs of both tumor cohorts. Our findings were validated and confirmed in two independent cohorts using TCGA data and tumor-infiltrating B-cells from additional HPV(+) HNSCC patients. A B-cell associated signal segregated tumors relative to HPV status. Our data suggests that the role of B-cells in the adaptive immune response to HPV(+) HNSCC requires re-assessment

Proportional lumbar spine inter-vertebral motion patterns: a comparison of patients with chronic, non-specific low back pain and healthy controls

Introduction: Identifying biomechanical subgroups in chronic, non-specific low back pain (CNSLBP) populations from inter-vertebral displacements has proven elusive. Quantitative fluoroscopy (QF) has excellent repeatability and provides continuous standardised inter-vertebral kinematic data from fluoroscopic sequences allowing assessment of mid-range motion. The aim of this study was to determine whether proportional continuous IV rotational patterns were different in patients and controls. A secondary aim was to update the repeatability of QF measurement of range of motion (RoM) for inter-vertebral (IV) rotation

Addressing ethnic disparities in neurological research in the United Kingdom: An example from the prospective multicentre COVID-19 Clinical Neuroscience Study

\ua9 2024 The Author(s). Background: Minority ethnic groups have often been underrepresented in research, posing a problem in relation to external validity and extrapolation of findings. Here, we aimed to assess recruitment and retainment strategies in a large observational study assessing neurological complications following SARS-CoV-2 infection. Methods: Participants were recruited following confirmed infection with SARS-CoV-2 and hospitalisation. Self-reported ethnicity was recorded alongside other demographic data to identify potential barriers to recruitment. Results: 807 participants were recruited to COVID-CNS, and ethnicity data were available for 93.2%. We identified a proportionate representation of self-reported ethnicity categories, and distribution of broad ethnicity categories mirrored individual centres’ catchment areas. White ethnicity within individual centres ranged between 44.5% and 89.1%, with highest percentage of participants with non-White ethnicity in London-based centres. Examples are provided how to reach potentially underrepresented minority ethnic groups. Conclusions: Recruitment barriers in relation to potentially underrepresented ethnic groups may be overcome with strategies identified here

Mailed Outreach Invitations Significantly Improve HCC Surveillance Rates in Patients With Cirrhosis: A Randomized Clinical Trial

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/147207/1/hep30129-sup-0001-Appendix.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/147207/2/hep30129_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/147207/3/hep30129.pd

UK-Wide Surveillance of Neurological and Neuropsychiatric Complications of COVID-19: The First 153 Patients

Background: Increasingly neurological complications of COVID-19 are identified, mostly in small series. Larger studies have been limited by both geography and specialty.Consequently, the breadth of complications is not represented. Comprehensive characterization of clinical syndromes is critical to rationally select and evaluate potential therapies.Methods: During the exponential pandemic phase, we developed coordinated online portals for rapid notification across the spectrum of major UK neuroscience bodies, representing neurology, stroke, psychiatry, and intensive care. Evidence of infection and clinical case definitions were applied prospectively. Cases were compared to overall Government Public Health COVID-19 reporting.Findings: Within three weeks, 153 cases were notified, both geographically and temporally representative of overall COVID-19 Public Health reports. Median (range) age was 71 (23-94) years. 77 (62%) had a cerebrovascular event: 57 (74%) ischemic strokes, nine (12%) intracerebral hemorrhages, and one CNS vasculitis.The second most common group were 39 (31%) who had altered mental status, including 16 (41%) with encephalopathy of whom seven (44%) had encephalitis. The remaining 23 (59%) had a psychiatric diagnosis of whom 21 (92%) were new diagnoses; including ten (43%) with psychosis, six (26%) neurocognitive (dementia-like) syndrome, and 4 (17%) an affective disorder. Cerebrovascular events predominated in older patients. Conversely, altered mental status, whilst present in all ages, had disproportionate representation in the young.Interpretation: This is the first nationwide, cross-specialty surveillance study of acute complications of COVID-19 in the nervous system. Alteration in mental status was common, reflecting encephalopathy/encephalitis and primary psychiatric diagnoses, often in young patients.These data provide valuable and timely information urgently needed by clinicians, researchers, and funders to inform immediate steps in COVID-19 neuroscience research and health policy throughout the areas of neurology and neuropsychiatry

Duration of temporary catheter use for hemodialysis: an observational, prospective evaluation of renal units in Brazil

<p>Abstract</p> <p>Background</p> <p>For chronic hemodialysis, the ideal permanent vascular access is the arteriovenous fistula (AVF). Temporary catheters should be reserved for acute dialysis needs. The AVF is associated with lower infection rates, better clinical results, and a higher quality of life and survival when compared to temporary catheters. In Brazil, the proportion of patients with temporary catheters for more than 3 months from the beginning of therapy is used as an evaluation of the quality of renal units. The aim of this study is to evaluate factors associated with the time between the beginning of hemodialysis with temporary catheters and the placement of the first arteriovenous fistula in Brazil.</p> <p>Methods</p> <p>This is an observational, prospective non-concurrent study using national administrative registries of all patients financed by the public health system who began renal replacement therapy (RRT) between 2000 and 2004 in Brazil. Incident patients were eligible who had hemodialysis for the first time. Patients were excluded who: had hemodialysis reportedly started after the date of death (inconsistent database); were younger than 18 years old; had HIV; had no record of the first dialysis unit; and were dialyzed in units with less than twenty patients. To evaluate individual and renal unit factors associated with the event of interest, the frailty model was used (N = 55,589).</p> <p>Results</p> <p>Among the 23,824 patients (42.9%) who underwent fistula placement in the period of the study, 18.2% maintained the temporary catheter for more than three months until the fistula creation. The analysis identified five statistically significant factors associated with longer time until first fistula: higher age (Hazard-risk - HR 0.99, 95% CI 0.99-1.00); having hypertension and cardiovascular diseases (HR 0.94, 95% CI 0.9-0.98) as the cause of chronic renal disease; residing in capitals cities (HR 0.92, 95% CI 0.9-0.95) and certain regions in Brazil - South (HR 0.83, 95% CI 0.8-0.87), Midwest (HR 0.88, 95% CI 0.83-0.94), Northeast (HR 0.91, 95% CI 0.88-0.94), or North (HR 0.88, 95% CI 0.83-0.94) and the type of renal unit (public or private).</p> <p>Conclusion</p> <p>Monitoring the provision of arteriovenous fistulas in renal units could improve the care given to patients with end stage renal disease.</p

Physicians' messages in problematic sickness certification: a narrative analysis of case reports

<p>Abstract</p> <p>Background</p> <p>Many physicians find sickness certification tasks problematic. There is some knowledge about situations that are experienced as problematic, whereas less is understood about how physicians respond to the problems they face. One way to acquire such knowledge is to consider "reflection-in-action", aspects of which are expressed in the physician's interpretation of the patient's story. The aim of this study was to gain knowledge about the meaning content of case reports about problematic sickness certification. Specifically, we looked for possible messages to the colleagues intended to read the reports.</p> <p>Methods</p> <p>A narrative approach was used to analyse reports about problematic sickness certification cases that had been written by GPs and occupational health service physicians as part of a sickness insurance course. The analysis included elements from both thematic and structural analysis. Nineteen case reports were used in the actual analysis and 25 in the validation of the results. Main narrative qualities and structural features of the written case reports were explored.</p> <p>Results</p> <p>Five types of messages were identified in the case reports, here classified as "a call for help", "a call for understanding", "hidden worries", "in my opinion", and "appearing neutral". In the reports, the physicians tried to achieve neutrality in their writing, and the patients' stories tended to be interpreted within a traditional biomedical framework. In some cases there was an open request for help, in others it was not obvious that the physician had any problems. Overall, the messages were about having problems as such, rather than the specific features of the problems.</p> <p>Conclusions</p> <p>The case reports clearly demonstrated different ways of writing about problems that arise during sickness certification, from being neutral and not mentioning the problems to being emotionally involved and asking for help. The general character of the messages suggests that they are also relevant for case reports in problematic areas other than sickness certification. If pertinent relationships can be found between reflection-in-practice and the narrative writing about practice, they will provide an approach to further research concerning consultations perceived as problematic and also to medical education.</p