bluuebunny/crossref_metadata_2025 huggingface dataset:
Can polygenic risk scores contribute to cost-effective cancer screening? A systematic review
Authors: Dixon Padraig , Keeney Edna , Taylor Jenny C. , Wordsworth Sarah , Martin Richard M.
Published: November 2021

Polygenic risk is known to influence susceptibility to cancer. The use of data on polygenic risk, in conjunction with other predictors of future disease status, may offer significant potential for preventative care through risk-stratified screening programmes. An important element in the evaluation of screening programmes is their cost-effectiveness.

We undertook a systematic review of papers evaluating the cost-effectiveness of screening interventions informed by polygenic risk scores compared to more conventional screening modalities. We included papers reporting cost-effectiveness outcomes in the English language published as articles or uploaded onto preprint servers with no restriction on date, type of cancer or form of polygenic risk modelled. We excluded papers evaluating screening interventions that did not report cost-effectiveness outcomes or which had a focus on monogenic risk. We evaluated studies using the Quality of Health Economic Studies checklist.

Ten studies were included in the review, which investigated three cancers: prostate (n=5), colorectal (n=3) and breast (n=2). All study designs were cost-utility papers implemented as Markov models (n=6) or microsimulations (n=4). Nine of ten papers scored highly (score >75 on a 0-100) scale) when assessed using the Quality of Health Economic Studies checklist. Eight of ten studies concluded that polygenic risk informed cancer screening was likely to be more cost-effective than alternatives. However, the included studies lacked robust external data on the cost of polygenic risk stratification, did not account for how very large volumes of polygenic risk data on individuals would be collected and used, did not consider ancestry-related differences in polygenic risk, and did not fully account for downstream economic sequalae stemming from the use of polygenic risk data in these ways. These topics merit attention in future research on how polygenic risk data might contribute to cost-effective cancer screening.

Funding

This work was supported by Cancer Research UK under grant number C18281/A29019. PD and RM are members of the MRC Integrative Epidemiology Unit at the University of Bristol which is supported by the Medical Research Council and the University of Bristol (MC_UU_12013/1, MC_UU_12013/9). PD, EK ad RMM received support from a Cancer Research UK (C18281/A29019) programme grant (the Integrative Cancer Epidemiology Programme). SW and JCT receive funding from the Oxford NIHR Biomedical Research Centre.

Registration

Prospectively registered on PROSPERO database before searches commenced. Available at https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=243659
Development of an electronic frailty index for hospitalized geriatric patients in Sweden
Authors: Mak Jonathan K. L. , Hägg Sara , Eriksdotter Maria , Annetorp Martin , Kuja-Halkola Ralf , Kananen Laura , Boström Anne-Marie , Kivipelto Miia , Metzner Carina , Jerlardtz Viktoria Bäck , Engström Malin , Johnson Peter , Lundberg Lars Göran , Åkesson Elisabet , Öberg Carina Sühl , Olsson Maria , Cederholm Tommy , Jylhävä Juulia , Religa Dorota
Published: November 2021

Background

Frailty assessment in the Swedish health system relies on the Clinical Frailty Scale (CFS), but it requires training, in-person evaluation, and is often missing in medical records. We aimed to develop an electronic frailty index (eFI) from routinely collected electronic health records (EHRs) and assess its predictive ability for adverse outcomes in geriatric patients.

Methods

EHRs were extracted for 18,225 geriatric patients with unplanned admissions between 1/3/2020 and 17/6/2021 from nine geriatric clinics in Stockholm, Sweden. A 48-item eFI was constructed using diagnostic codes, functioning and other health indicators, and laboratory data. The CFS, Hospital Frailty Risk Score, and Charlson Comorbidity Index were used for comparative assessment of the eFI. We modelled in-hospital mortality and 30-day readmission using logistic regression; 30-day and 6-month mortality using Cox regression; and length of stay using linear regression.

Results

13,188 patients were included in analyses (mean age 83.1 years). A 10% increment in the eFI was associated with higher risks of in-hospital (odds ratio: 5.34; 95% confidence interval: 4.20-6.82), 30-day (hazard ratio [HR]: 3.28; 2.91-3.69), and 6-month mortality (HR: 2.70; 2.52-2.90) adjusted for age and sex. Of the frailty and comorbidity measures, the eFI had the best predictive accuracy for in-hospital mortality, yielding an area under receiver operating characteristic curve of 0.813. Higher eFI also predicted a longer length of stay, but had a rather poor discrimination for 30-day readmission.

Conclusions

An EHR-based eFI has good predictive accuracy for adverse outcomes, suggesting that it can be used in risk stratification in geriatric patients.
Performance of the Reported and Intended Behavior Scale among Colombian Adolescents
Authors: Campo-Arias A. , Ceballos-Ospino G. A. , Herazo E.
Published: November 2021

Objective

To establish the Reported and Intended Behavior Scale (RIBS) psychometric performance, a mental disorder-related stigma measurement, among Colombian adolescents.

Methods

A validation study was carried out with 350 students aged between 10 and 17, 53.7% of whom were girls. The RIBS has two sub-scales -reported behaviors and intended behaviors, with four items each. Frequencies were estimated for reported behaviors, whereas internal consistency (Cronbach’s alpha and McDonald’s omega) and confirmatory factor analysis (CFA) were measured for intended behaviors.

Results

The reported behavior sub-scale ranged from 10.0 to 24.9%, whereas the intended behavior sub-scale presented a Cronbach’s alpha of 0.88 (CI95% 0.86-0.90) and a McDonald omega of 0.88. For the CFA, KMO was 0.81; Bartlett chi squared, 771.1 (df=6, p=0.01); and Eigen value, 2.95 that explained 73.9% of the total variance. For the goodness-of-fit tests, chi squared was 21.9 (df=2, p=.001); RMSEA, 0.17 (CI90% 0.11-0.24); CFI, 0.97; TLI, 0.92; and SMSR, 0.03.

Conclusions

The RIBS can measure reported behaviors, and the intended behavior sub-scale shows high internal consistency. However, the dimensionality of the intended behavior sub-scale presents modest goodness-of-fit indexes. These findings need further replications.
DEVELOPMENT AND TESTING OF A LOW-COST INACTIVATION BUFFER THAT ALLOWS DIRECT SARS-COV-2 DETECTION IN SALIVA
Authors: Bustos-Garcia Brandon , Garza-Manero Sylvia , Cano-Dominguez Nallely , Lopez Sanchez Dulce Maria , Salgado Montes de Oca Gonzalo , Salgado-Aguayo Alfonso , Recillas-Targa Felix , Avila-Rios Santiago , Valdes Victor Julian
Published: November 2021

Massive testing is a cornerstone in efforts to effectively track infections and stop COVID-19 transmission, including places where good vaccination coverage has been achieved. However, SARS-CoV-2 testing by RT-qPCR requires specialized personnel, protection equipment, commercial kits, and dedicated facilities, which represent significant challenges for massive testing implementation in resource-limited settings. It is therefore important to develop testing protocols that facilitate implementation and are inexpensive, fast, and sufficiently sensitive. In this work, we optimized the composition of a buffer (PKTP) containing a protease, a detergent, and an RNase inhibitor, that is compatible with the RT-qPCR chemistry, allowing for direct testing of SARS-CoV-2 from saliva in an RNA extraction-independent manner. This buffer is compatible with heat-inactivation reducing the biohazard risk of handling the samples. We assessed the PKTP buffer performance in comparison to the RNA-extraction-based protocol of the US Centers for Disease Control and Prevention in saliva samples from 70 COVID-19 patients finding a good sensitivity (82.2% for the N1 and 84.4% for the N2 target, respectively) and correlations (R=0.77, p<0.001 for N1, and R=0.78, p<0.001 for N2). We also propose an auto-collection protocol for saliva samples and a multiplex reaction to reduce the number of PCR reactions per patient and further reduce overall costs while maintaining diagnostic standards in favor of massive testing.
Mural cell SRF controls pericyte migration, vessel patterning and blood flow
Authors: Orlich Michael Martin , Diéguez-Hurtado Rodrigo , Muehlfriedel Regine , Sothilingam Vithiyanjali , Wolburg Hartwig , Oender Cansu Ebru , Woelffing Pascal , Betsholtz Christer , Gaengel Konstantin , Seeliger Mathias , Adams Ralf H. , Nordheim Alfred
Published: November 2021

Rationale

Pericytes (PCs) and vascular smooth muscle cells (vSMCs), collectively known as mural cells (MCs), are recruited through PDGFB-PDGFRB signaling. MCs are essential for vascular integrity, and their loss has been associated with numerous diseases. Most of this knowledge is based on studies in which MCs are insufficiently recruited or fully absent upon inducible ablation. In contrast, little is known about the physiological consequences that result from impairment of specific MC functions.

Objective

Here, we characterize the role of the transcription factor serum response factor (SRF) in MCs and study its function in developmental and pathological contexts.

Methods and Results

We generated a mouse model of MC-specific inducible Srf gene deletion and studied its consequences during retinal angiogenesis. By postnatal day (P)6, PCs lacking SRF were morphologically abnormal and failed to properly co-migrate with angiogenic sprouts. As a consequence, PC-deficient vessels at the retinal sprouting front became dilated and leaky. By P12, also the vSMCs had lost SRF, which coincided with the formation of pathological arteriovenous (AV) shunts. Mechanistically, we show that PDGFB-dependent SRF activation is mediated via MRTF co-factors. We further show that MRTF-SRF signaling promotes pathological PC activation during ischemic retinopathy. RNA-sequencing, immunohistology, in vivo live imaging and in vitro experiments demonstrated that SRF regulates expression of contractile SMC proteins essential to maintain the vascular tone.

Conclusions

SRF is crucial for distinct functions in PCs and vSMCs. SRF directs PC migration downstream of PDGFRB signaling and mediates pathological PC activation during ischemic retinopathy. In vSMCs, SRF is essential for expression of the contractile machinery, and its deletion triggers formation of AV shunts. These essential roles in physiological and pathological contexts provide a rational for novel therapeutic approaches through targeting SRF activity in MCs.
Time course of EEG power during creative problem-solving with insight or remote thinking
Authors: Bieth Théophile , Ovando-Tellez Marcela , Lopez-Persem Alizée , Garcin Beatrice , Hugueville Laurent , Lehongre Katia , Levy Richard , George Nathalie , Volle Emmanuelle
Published: November 2021

Problem-solving often requires creativity and is critical in everyday life. However, the neurocognitive mechanisms underlying creative problem-solving remain poorly understood. Two mechanisms have been highlighted: forming new connections from and between the problem elements and insight solving (with a sudden realization of a solution). We examined EEG activity during an adapted version of a classical insight problem task, the Remote Associates Test, that requires finding a word connecting three words. It allowed us to explore remoteness in semantic connections (by varying the remoteness of the solution word across trials) and insight solving (identified as a “Eurêka” moment reported by the participants). Semantic remoteness was associated with a power increase in alpha band (8-12Hz) in a left parieto-temporal cluster, beta band (13-30Hz) in a right fronto-temporal cluster in the early phase of the task, and theta band (3-7Hz) in frontal cluster before the participants responded. Insight solving was associated with power increase preceding the response in alpha and gamma band (31-60Hz) in left temporal clusters and theta band in a frontal cluster. Source reconstructions show the brain regions associated with these clusters. Overall, our findings shed new light on the dynamic of some of the mechanisms involved in creative problem-solving.
More than meets the Kappa for Antibody Superantigen Protein L (PpL)
Authors: Ling Wei-Li , Yeo Joshua Yi , Ng Yuen-Ling , Wipat Anil , Gan Samuel Ken-En
Published: November 2021

Immunoglobulin superantigens play an important role in the affinity purification of antibodies and underlie the microbiota-immune axis at mucosal areas Focussing on theStaphylococcalProtein A (SpA),StreptococcalProtein G (SpG), and theFinegoldiaProtein L (PpL) that were previously thought to bind to only specific regions of human antibodies, a systematic and holistic analysis of the antibody regions using 63 antibody permutations involving six Vκ and seven VH region IgG1 revealed showed novel PpL-antibody interactions. While SpA and SpG showed relatively consistent interactions with the antibodies, our findings showed PpL binding to certain VH-Vκ2, 5 and 6 interactions had contribution by other antibody regions. The findings of this have implications on PpL-based affinity antibody purifications and antibody design as well as provides novel insights to PpL-based microbiota-immune axis effects.
KRASmutations impact clinical outcome in metastatic non-small cell lung cancer
Authors: Eklund Ella A. , Wiel Clotilde , Fagman Henrik , Akyürek Levent M. , Raghavan Sukanya , Nyman Jan , Hallqvist Andreas , Sayin Volkan I.
Published: November 2021

Purpose

There is an urgent need to identify new predictive biomarkers for treatment response to both platinum doublet chemotherapy (PD) and immune checkpoint blockade (ICB) with pembrolizumab. Here we evaluated whether treatment outcome could be affected byKRASmutational status in patients with metastatic (stage IV) non-small cell lung cancer (NSCLC).

Methods

All consecutive patients molecularly assessed and diagnosed between 2016-2018 with stage IV NSCLC in the region of West Sweden were included in this multi-center retrospective study. Primary study outcome was overall survival (OS).

Results

Out of 580 stage IV NSCLC patients, 35.5% harbored an activating mutation in theKRASgene (KRASMUT). Compared toKRASwild-type (KRASWT), KRASMUTwas a negative factor for OS (p= 0.014). On multivariate analysis, KRASMUTpersisted as a negative factor for OS (HR 1.288, 95% CI 1.091-1.521,p= 0.003). When treated with first-line platinum doublet (n= 195), KRASMUTis a negative factor for survival (p= 0.018) with median OS 9 months vs KRASWT11 months. On multivariate analysis, KRASMUTpersisted as a negative factor for OS (HR 1.564, 95%CI 1.124-2.177,p= 0.008). KRASMUTpatients with high PD-L1 expression (PD-L1high) had better OS than PD-L1highKRASWTpatients (p= 0.036). In response to first-line ICB, KRASMUTpatients had a significant (p= 0.006) better outcome than KRASWTwith a median OS 23 vs 6 months. On multivariable Cox analysis, KRASMUTstatus was an independent prognostic factor for better OS (HR 0.349, 95%CI 0.148-0.822,p= 0.016).

Conclusions

KRASmutations is a positive predictive factor for treatment with pembrolizumab and a negative predictive factor for platinum doublet chemotherapy as well as general OS in stage IV NSCLC.
Deep Learning-Aided Diagnosis of Autoimmune Blistering Diseases
Authors: Cai Daniel , Ardakany Abbas Roayaei , Ay Ferhat
Published: November 2021

Autoimmune blistering diseases (AIBDs) are rare, chronic disorders of the skin and mucous membranes, with a broad spectrum of clinical manifestations and morphological lesions. Considering that 1) diagnosis of AIBDs is a challenging task, owing to their rarity and heterogeneous clinical features, and 2) misdiagnoses are common, and the resulting diagnostic delay is a major factor in their high mortality rate, patient prognosis stands to benefit greatly from the development of a computer-aided diagnostic (CAD) tool for AIBDs. Artificial intelligence (AI) research into rare skin diseases like AIBDs is severely underrepresented, due to a variety of factors, foremost a lack of large-scale, uniformly curated imaging data. A study by Julia S. et al. finds that, as of 2020, there exists no machine learning studies on rare skin diseases [1], despite the demonstrated success of AI in the field of dermatology. Whereas previous research has primarily looked to improve performance through extensive data collection and preprocessing, this approach remains tedious and impractical for rarer, under-documented skin diseases. This study proposes a novel approach in the development of a deep learning based diagnostic aid for AIBDs. Leveraging the visual similarities between our imaging data with pre-existing repositories, we demonstrate automated classification of AIBDs using techniques such as transfer learning and data augmentation over a convolutional neural network (CNN). A three-loop process for training is used, combining feature extraction and fine-tuning to improve performance on our classification task. Our final model retains an accuracy nearly on par with dermatologists’ diagnostic accuracy on more common skin cancers. Given the efficacy of our predictive model despite low amounts of training data, this approach holds the potential to benefit clinical diagnoses of AIBDs. Furthermore, our approach can be extrapolated to the diagnosis of other clinically similar rare diseases.
Variations of the quality of care during the COVID-19 pandemic affected the mortality rate of non-COVID patients with hip fracture
Authors: Golinelli Davide , Sanmarchi Francesco , Capodici Angelo , Gribaudo Giorgia , Altini Mattia , Rosa Simona , Esposito Francesco , Fantini Maria Pia , Lenzi Jacopo
Published: November 2021

Introduction

As COVID-19 roared through the world, governments worldwide enforced containment measures that affected various treatment pathways, including those for hip fracture (HF). This study aimed to measure process and outcome indicators related to the quality of care provided to non-COVID-19 elderly patients affected by HF in Emilia-Romagna, a region of Italy severely hit by the pandemic.

Methods

We collected the hospital discharge records of all patients admitted to the hospitals of Emilia-Romagna with a diagnosis of HF from January to May in the years 2019/2020. We analyzed surgery rate, surgery timeliness, length of hospital stay, timely rehabilitation, and 30-day mortality for each HF patient. We evaluated monthly data (2020 vs. 2019) with the chi-square and t-test, where appropriate. Logistic regression was used to investigate the differences in 30-day mortality.

Results

Our study included 5379 patients with HF. In April and May 2020, there was a significant increase in the proportion of HF patients that did not undergo timely surgery. In March 2020, we found a significant increase in mortality (OR = 2.22). Female sex (OR = 0.52), age ≥90 years (OR = 4.33), surgery after 48 hours (OR = 3.08) and not receiving surgery (OR = 6.19) were significantly associated with increased mortality. After adjusting for the aforementioned factors, patients hospitalized in March 2020 still suffered higher mortality (OR = 2.21).

Conclusions

Our results show a reduction in the overall quality of care provided to non-COVID-19 elderly patients affected by HF. The mortality rate of patients with HF increased significantly in March 2020. Patients’ characteristics and variations in processes of care partially explained this increase. Our analysis reveals the importance of including process and outcomes indicators, for both acute and post-acute care management issues, in emergency preparedness plans, to monitor healthcare systems’ capacities and capabilities.
Alkaline phosphatase variability predicts new onset heart failure, cardiovascular mortality, and all-cause mortality in patients with type-2 diabetes mellitus: a population-based study
Authors: Zhou Jiandong , Lee Sharen , Adhikari Govinda , Wong Wing Tak , Waleed Khalid Bin , Liu Tong , Wong Ian Chi Kei , Cheung Bernard Man Yung , Tse Gary , Zhang Qingpeng
Published: November 2021

Objective

To investigate the associations of alkaline phosphatase (ALP) variability measures with new onset heart failure, cardiovascular mortality, and all-cause mortality in type 2 diabetes mellitus patients with a populational-cohort study.

Method

This study included patients with type 2 diabetes mellitus who presented to ambulatory, outpatient and inpatient facilities managed by the public sector in Hong Kong between January 1st, 2000 to December 31st, 2019. Comprehensive clinical and medical data including demographics, past comorbidities, medications, and laboratory examinations of complete blood, lipid/glycemic profile and their variability were collected. ALP and its variability measures were extracted. Univariable and multiple multivariable Cox regression were used to identify the associations of alkaline phosphatase variability with new onset heart failure and mortality risks. Patients were stratified into three subgroups based on the tertiles of baseline ALP level.

Results

The study cohort consisted of 14289 patients (52.52% males, mean age at initial drug exposure: 74.55 years old [standard deviation (SD): 12.7]). Over a mean follow up of 2513 days [interquartile range (IQR): 1151-4173]), 10182 patients suffered from all-cause mortality (incidence rate [IR]: 71.25%), 1966 patients (IR: 13.75%) died from cardiovascular causes, and 1171 patients (IR: 8.19%) developed with new onset heart failure. Higher cumulative incidences of all three outcomes were observed for the highest tertile of ALP compared to medium/low tertiles. ALP baseline and variability level predicted new onset heart failure, cardiovascular and all-cause mortality before adjusting for subclinical biomarkers (p < 0.01). Amongst the measures of ALP variability, the hazard ratio (HR) of coefficient of variation (CV) was markedly raised in particular (new onset heart failure: HR=2.73, 95% confidence interval [CI]= [1.71-4.37], p <0.0001; all-cause mortality: HR= 5.83, 95% CI= [5.01-6.79], p <0.0001; cardiovascular mortality: HR= 4.81, 95% CI= [3.36-6.88], p <0.0001).

Conclusions

Raised ALP level and variability are associated with increased risks of all-cause mortality, cardiovascular mortality and new onset heart failure amongst patients with type 2 diabetes mellitus.
Dosing interval strategies for two-dose COVID-19 vaccination in 13 low- and middle-income countries of Europe: health impact modelling and benefit-risk analysis
Authors: Liu Yang , Pearson Carl AB , Sandmann Frank G , Barnard Rosanna C , Kim Jong-Hoon ,   CMMID COVID-19 Working Group, Flasche Stefan , Jit Mark , Abbas Kaja
Published: November 2021

Background

In settings where the COVID-19 vaccine supply is constrained, extending the intervals between the first and second doses of the COVID-19 vaccine could let more people receive their first doses earlier. Our aim is to estimate the health impact of COVID-19 vaccination alongside benefit-risk assessment of different dosing intervals for low- and middle-income countries of Europe.

Methods

We fitted a dynamic transmission model to country-level daily reported COVID-19 mortality in 13 low- and middle-income countries in the World Health Organization European Region (Albania, Armenia, Azerbaijan, Belarus, Bosnia and Herzegovina, Bulgaria, Georgia, Republic of Moldova, Russian Federation, Serbia, North Macedonia, Turkey, and Ukraine). A vaccine product with characteristics similar to the Oxford/AstraZeneca COVID-19 (AZD1222) vaccine was used in the base case scenario and was complemented by sensitivity analyses around efficacies related to other COVID-19 vaccines. Both fixed dosing intervals at 4, 8, 12, 16, and 20 weeks and dose-specific intervals that prioritise specific doses for certain age groups were tested. Optimal intervals minimise COVID-19 mortality between March 2021 and December 2022. We incorporated the emergence of variants of concern into the model, and also conducted a benefit-risk assessment to quantify the trade-off between health benefits versus adverse events following immunisation.

Findings

In 12 of the 13 countries, optimal strategies are those that prioritise the first doses among older adults (60+ years) or adults (20-59 years). These strategies lead to dosing intervals longer than six months. In comparison, a four-week fixed dosing interval may incur 10.2% [range: 4.0% - 22.5%; n = 13 (countries)] more deaths. There is generally a negative association between dosing interval and COVID-19 mortality within the range we investigated. Assuming a shorter first dose waning duration of 120 days, as opposed to 360 days in the base case, led to shorter optimal dosing intervals of 8-12 weeks. Benefit-risk ratios were the highest for fixed dosing intervals of 8-12 weeks.

Interpretation

We infer that longer dosing intervals of over six months, which are substantially longer than the current label recommendation for most vaccine products, could reduce COVID-19 mortality in low- and middle-income countries of WHO/Europe. Certain vaccine features, such as fast waning of first doses, significantly shorten the optimal dosing intervals.

Funding

World Health Organization
Similarity in evoked responses does not imply similarity in macroscopic network states across tasks
Authors: Rasero Javier , Betzel Richard , Sentis Amy Isabella , Kraynak Thomas E. , Gianaros Peter J. , Verstynen Timothy
Published: November 2021

There is an ongoing debate as to whether cognitive processes arise from a group of functionally specialized brain modules (modularism) or as the result of distributed nonlinear processes (dynamical systems theory). The former predicts that tasks recruiting similar local brain areas should be equally similar in their network profiles. The latter allows for differential connectivity, even when the areas recruited are largely the same. Here we evaluated both views at the macroscopic level by comparing region-wise activation patterns and functional correlation profiles from a large sample of healthy subjects (N=242) that performed two executive control tasks known to recruit nearly identical brain areas, the color-word Stroop task and the Multi-Source Interference Task (MSIT). Using a measure of instantaneous functional correlations, based on edge time series, we estimated the task-related networks that differed between incongruent and congruent conditions. At the group level, the two tasks were much more different in their network profiles than in their evoked activity patterns. This is found even when matching the degrees of freedom of both activation patterns and functional correlation profiles, when considering subject-level differences, after changing brain parcellations, and if employing alternative methods for defining task-related network profiles. Our results are consistent with the perspective of the brain as a dynamical system, suggesting that task representations should be independently evaluated at both node and edge (connectivity) levels.

Significant Statement

If the brain is strictly modular at the macroscopic scale, then recruiting the same brain regions should result in the same functional interactions between regions. However, if the brain is a dynamical system, with information represented at both the node and edge levels, then two tasks could have the same pattern of activation, but largely different functional correlation profiles. Here we tested this contrastive prediction using two tasks with overlapping cognitive demands, but different sensory signals. Despite being nearly identical in their activation patterns, we found that the tasks produced largely different functional correlation profiles. These findings reinforce the view of the brain as a dynamical system, with task states represented both within and across regions.
Pharmacogenetic variation in Neanderthals and Denisovans and implications for human health and response to medications
Authors: Wroblewski Tadeusz H. , Witt Kelsey E. , Lee Seung-been , Malhi Ripan S. , Huerta-Sanchez Emilia , Villanea Fernando , Claw Katrina G.
Published: November 2021

Modern humans carry both Neanderthal and Denisovan (archaic) genome elements that are part of the human gene pool and affect the life and health of living individuals. The impact of archaic DNA may be particularly evident in pharmacogenes – genes responsible for the processing of exogenous substances such as food, pollutants, and medications. However, the health implications and contribution of archaic ancestry in pharmacogenes of modern humans remains understudied. Here, we explore eleven key cytochrome P450 genes (CYP450) involved in drug metabolizing reactions in three Neanderthal and one Denisovan individuals as well as examine archaic introgression in modern human populations. We infer the metabolizing efficiency of these elevenCYP450genes in archaic individuals and find important phenotypic differences relative to modern human variants. We identify several single nucleotide variants shared between archaic and modern humans in each gene, including some potentially function-altering mutations in archaicCYP450genes, which may result in altered metabolism in living people carrying these variants. We highlight three genes which show evidence for archaic introgression into modern humans, as well as one additional gene that shows evidence for a gene duplication found only in Neanderthals and modern Africans.
Effect of host-switching on the eco-evolutionary patterns of parasites
Authors: D’Bastiani Elvira , Princepe Débora , Marquitti Flavia MD , Boeger Walter A , Campião Karla M , Araujo Sabrina LB
Published: November 2021

Abstract

Increasing empirical evidence has revealed that host-switching are common in the history of parasites. Still, few have explored how the evolutionary histories of hosts might influence such switches and then the evolution of parasites. Here, we investigated how the intensity of host-switching, assumed to depend on the phylogenetic distance between hosts, affects the ecological and evolutionary patterns of parasite species. We developed an individual-based model where parasites can explore and colonise hosts under variable host-switching intensity and have evolution driven by mutation, genetic drift, and mating restriction. We hypothesised that our model can reproduce ecological and evolutionary patterns of empirical communities, characterised by turnover among host species and tree imbalance, respectively. We found an optimum range of host-switching intensity that can predict similar patterns as those observed in the empirical studies, validating our hypothesis. Our results showed that the turnover decreased as the host-switching intensity increased with low variation among the model replications. On the other hand, the tree imbalance had not a monotonic tendency but a wide variation. These results revealed that while the tree imbalance is a sensitive metric to stochastic events, the turnover may be a proxy for host switching. Furthermore, local empirical studies corresponded to higher host-switching intensity when compared to regional studies, highlighting that spatial scale is probably the crucial limitation of host-switching.
Dopamine release in nucleus accumbens is under tonic inhibition by adenosine A1receptors regulated by astrocytic ENT1 and dysregulated by ethanol
Authors: Roberts Bradley M. , Lambert Elizabeth , Livesey Jessica A. , Wu Zhaofa , Li Yulong , Cragg Stephanie J.
Published: November 2021

Striatal adenosine A1receptor (A1R) activation can inhibit dopamine release. A1Rs on other striatal neurons are activated by an adenosine tone that is limited by equilibrative nucleoside transporter 1 (ENT1) that is enriched on astrocytes and is ethanol-sensitive. We explored whether dopamine release in nucleus accumbens core is under tonic inhibition by A1Rs, and is regulated by astrocytic ENT1 and ethanol. Inex vivostriatal slices from male and female mice, A1R agonists inhibited dopamine release evoked electrically or optogenetically and detected using fast-scan cyclic voltammetry, most strongly for lower stimulation frequencies and pulse numbers, thereby enhancing the activity-dependent contrast of dopamine release. Conversely, A1R antagonists reduced activity-dependent contrast but enhanced evoked dopamine release levels, even for single optogenetic pulses indicating an underlying tonic inhibition. The ENT1 inhibitor NBTI reduced dopamine release and promoted A1R-mediated inhibition, and conversely, virally-mediated astrocytic overexpression of ENT1 enhanced dopamine release and relieved A1R-mediated inhibition. By imaging the genetically encoded fluorescent adenosine sensor GRAB-Ado, we identified a striatal extracellular adenosine tone that was elevated by the ENT1 inhibitor and sensitive to gliotoxin fluorocitrate. Finally, we identified that ethanol (50 mM) promoted A1R-mediated inhibition of dopamine release, through diminishing adenosine uptake via ENT1. Together, these data reveal that dopamine output dynamics are gated by a striatal adenosine tone, limiting amplitude but promoting contrast, regulated by ENT1, and promoted by ethanol. These data add to the diverse mechanisms through which ethanol modulates striatal dopamine, and to emerging datasets supporting astrocytic transporters as important regulators of striatal function.

SIGNIFICANCE STATEMENT

Dopamine axons in the mammalian striatum are emerging as strategic sites where neuromodulators can powerfully influence dopamine output in health and disease. We found that ambient levels of the neuromodulator adenosine tonically inhibit dopamine release in nucleus accumbens core via adenosine A1receptors (A1Rs), to a variable level that promotes the contrast in dopamine signals released by different frequencies of activity. We reveal that the equilibrative nucleoside transporter 1 (ENT1) on astrocytes limits this tonic inhibition, and that ethanol promotes it by diminishing adenosine uptake via ENT1. These findings support the hypotheses that A1Rs on dopamine axons inhibit DA release and, furthermore, that astrocytes perform important roles in setting the level of striatal dopamine output, in health and disease.
The population dynamic life histories of the birds and mammals of the world
Authors: Witting Lars
Published: November 2021

With life history traits determining the natural selection fitnesses of individuals and growth of populations, estimates of their variation are essential to advance evolutionary theory and ecological management during times of global change. As quantitative predictions improve with the completeness of models, and as data are usually incomplete or missing for most species, I use published data and inter-specific allometric extrapolations to estimate complete population dynamic life history models for birds and mammals with known body masses. This constructs models for 11,188 species of birds and 4,937 species of mammals, covering 27 life history and ecological traits per species. The estimates are used to illustrate natural selection mechanisms and explain a diverse range of population dynamic trajectories by the inclusion of population dynamic regulation. This provides a first step towards the construction of freely accessible and ready-to-use online population dynamic simulations covering all species of birds and mammals.
Supergene degeneration opposes polymorphism: The curious case of balanced lethals
Authors: Berdan Emma L. , Blanckaert Alexandre , Butlin Roger K. , Flatt Thomas , Slotte Tanja , Wielstra Ben
Published: November 2021

Supergenes offer some of the most spectacular examples of long-term balancing selection in nature but their origin and maintenance remain a mystery. A critical aspect of supergenes is reduced recombination between arrangements. Reduced recombination protects adaptive multi-trait phenotypes, but can also lead to degeneration through mutation accumulation. Mutation accumulation can stabilize the system through the emergence of associative overdominance (AOD), destabilize the system, or lead to new evolutionary outcomes. One such outcome is the formation of balanced lethal systems, a maladaptive system where both supergene arrangements have accumulated deleterious mutations to the extent that both homozygotes are inviable, leaving only heterozygotes to reproduce. Here, we perform a simulation study to understand the conditions under which these different outcomes occur, assuming a scenario of introgression after allopatric divergence. We found that AOD aids the invasion of a new supergene arrangement and the establishment of a polymorphism. However, this polymorphism is easily destabilized by further mutation accumulation. While degradation may strengthen AOD, thereby stabilizing the supergene polymorphism, it is often asymmetric, which is the key disrupter of the quasi-equilibrium state of the polymorphism. Furthermore, mechanisms that accelerate degeneration also tend to amplify asymmetric mutation accumulation between the supergene arrangements and vice versa. As the evolution of a balanced lethal system requires symmetric degradation of both arrangements, this leaves highly restricted conditions under which such a system could evolve. We show that small population size and low dominance coefficients are critical factors, as these reduce the efficacy of selection. The dichotomy between the persistence of a polymorphism and degradation of supergene arrangements likely underlies the rarity of balanced lethal systems in nature.
The effects of weak selection on neutral diversity at linked sites
Authors: Charlesworth Brian
Published: November 2021

The effects of selection on variability at linked sites have an important influence on levels and patterns of within-population variation across the genome. Most theoretical models of these effects have assumed that selection is sufficiently strong that allele frequency changes at the loci concerned are largely deterministic. These models have led to the conclusion that directional selection for selectively favorable mutations, or against recurrent deleterious mutations, reduces nucleotide site diversity at linked neutral sites. Recent work has shown, however, that fixations of weakly selected mutations, accompanied by significant stochastic changes in allele frequencies, can sometimes cause higher diversity at linked sites when compared with the effects of fixations of neutral mutations. The present paper extends this work by deriving approximate expressions for the mean conditional times to fixation and loss of mutations subject to selection, and analysing the conditions under which selection increases rather than reduces these times. Simulations are used to examine the relations between diversity at a neutral site and the fixation and loss times of mutations at a linked site that is subject to selection. It is shown that the long-term level of neutral diversity can be increased over the purely neutral value by recurrent fixations and losses of linked, weakly selected dominant or partially dominant favorable mutations, or linked recessive or partially recessive deleterious mutations. The results are used to examine the conditions under which associative overdominance, as opposed to background selection, is likely to operate.
Population Dynamics of Hybrid State during Adaptive Therapy in Cancer
Authors: Singh Ghanendra
Published: November 2021

Drug resistance emerges due to drug-induced phenotypic switching of drug-sensitive to drug-resistant subpopulations in cancer during therapy. Existing models indicate the competitive advantage of sensitive over resistant population to regulate tumor and reducing the treatment cost with increased time to progression of tumor ultimately benefiting the patient in a clinical setting. Here, we present a Lotka Volterra (LV) based population dynamics (PD) model of the drug-sensitive, drug-resistant, and transient drug-hybrid state along with phenotypic switching during adaptive therapy based on a simple cancer biomarker (CB) to decide the adaptive therapy dosage to regulate cancer. We identified that the strength of intra competition along with phenotypic switching parameters is crucial to mediate the effectiveness of adaptive therapy and also investigated the significance of the initial fraction of subpopulations on AT. We hypothesize and predict the dynamics of drug-induced transient hybrid state playing a key role in the cancer cells undergoing metastasis.
Computational and biochemical analyses reveal that cofilin-2 self assembles into amyloid-like structures and promotes the aggregation of other proteinaceous species: Pathogenic relevance to myopathies
Authors: Kaushik Vibha , Hanschmann Eva-Maria , Brünnert Daniela , Prerna Kumari , Anand Bibin G. , Sharma Phulwanti Kumari , Kar Karunakar , Goyal Pankaj
Published: November 2021

Cofilin-2 is a member of the ADF/cofilin family, expressed extensively in adult muscle cells and involved in muscle maintenance and regeneration. Phosphorylated cofilin-2 is found in pre-fibrillar aggregates formed during idiopathic dilated cardiomyopathy. A recent study shows that phosphorylated cofilin-2, under oxidative distress, forms fibrillar aggregates. However, it remains unknown if cofilin-2 holds an innate propensity to form amyloid-like structures. In the present study, we employed various computational and biochemical techniques to explore the amyloid-forming potential of cofilin-2. We report that cofilin-2 possesses aggregation-prone regions (APRs), and these APRs get exposed to the surface, become solvent-accessible, and are involved in the intermolecular interactions during dimerization, an early stage of aggregation. Furthermore, the cofilin-2 amyloids, formed under physiological conditions, are capable of cross-seeding other monomeric globular proteins and amino acids, thus promoting their aggregation. We further show that Cys-39 and Cys-80 are critical in maintaining the thermodynamic stability of cofilin-2. The destabilizing effect of oxidation at Cys-39 but not that at Cys-80 is mitigated by Ser-3 phosphorylation. Cysteine oxidation leads to partial unfolding and loss of structure, suggesting that cysteine oxidation further induces early events of cofilin-2 aggregation. Overall, our results pose a possibility that cofilin-2 amyloidogenesis might be involved in the pathophysiology of diseases, such as myopathies. We propose that the exposure of APRs to the surface could provide mechanistic insight into the higher-order aggregation and amyloidogenesis of cofilin-2. Moreover, the cross-seeding activity of cofilin-2 amyloids hints towards its involvement in the hetero-aggregation in various amyloid-linked diseases.
Antipsychotic Polypharmacy and Adverse Drug Reactions Among Adults in a London Mental Health Service, 2008-2018
Authors: Yang Justin C. , Thygesen Johan H. , Werbeloff Nomi , Hayes Joseph F. , Osborn David P.J.
Published: November 2021

Background

Antipsychotic polypharmacy (APP) occurs commonly but it is unclear whether it is associated with an increased risk of adverse drug reactions. Electronic health records (EHRs) offer an opportunity to examine APP using real-world data. In this study, we use EHR data to identify periods when patients were prescribed 2+ antipsychotics and compare these with periods of antipsychotic monotherapy. To determine the relationship between APP and subsequent instances of adverse drug reactions: QT interval prolongation, hyperprolactinaemia, and increased body weight (body mass index [BMI] ≥ 25).

Methods

We extracted anonymised EHR data. Patients aged 16+ receiving antipsychotic medication at Camden & Islington NHS Foundation Trust between 1 January 2008 and 31 December 2018 were included. Multilevel mixed-effects logistic regression models were used to elucidate the relationship between APP and the subsequent presence of QT interval prolongation, hyperprolactinaemia, and/or increased BMI following a period of APP within 7, 30, or 180 days respectively.

Results

We identified 35,409 observations of antipsychotic prescribing among 13,391 patients. APP was associated with a subsequent increased risk of hyperprolactinaemia (adjusted odds ratio 2.46; 95% C.I. 1.87-3.24) and of having a BMI > 25 (adjusted odds ratio 1.75; 95% C.I. 1.33-2.31) in the period following the APP prescribing.

Conclusions

Our observations suggest that APP should be carefully managed with attention to hyperprolactinaemia and obesity.
A systematic scoping review on the impact of the COVID-19 quarantine on the psychological wellbeing of medical students
Authors: Vythilingam Divya I. , Atiomo William U.
Published: November 2021

Objectives

The goal of this study was to identify the nature and extent of the available published research on the impact of social isolation, on the psychological wellbeing of medical students, who had to quarantine due to the COVID-19 pandemic.

Design

Scoping review.

Search strategy

The PRISMA-ScR (Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews), guideline, was used to structure this study. A search strategy was carried out across six bibliographic databases. PubMed, Embase, ERIC, Scopus, Cochrane Database of Systematic Reviews and Web of Science. The following search terms were used, “medical student*” AND “impact” AND “quarantine” AND “COVID-19”. Searches were confined to articles published (excluding conference abstracts) between 1 January 2019-21 August 2021. A search of secondary references was conducted. Data from the selected studies were extracted, and the following variables recorded; first author and year of publication, country of study, study design, sample size, focus group, mode of analyzing impact of quarantine from COVID-19 on mental health and results of the studies.

Results

A total of 223 articles were identified across the six databases, from which 69 duplicates were excluded resulting in 154 full-text articles. Of these, 29 met the inclusion criteria. Following a review of the abstracts of these 29, ten full-text articles were identified all of which were cross sectional studies. Sample sizes ranged from 182 to 860 students and all studies used a variety of self-administered questionnaires to measure psychological wellbeing. Eight of the 10 articles showed that quarantine had a negative impact on the psychological well-being of medical students.

Conclusion

The evidence is small but growing. Quarantine because of the COVID-19 pandemic appears to have had a negative impact on the psychological wellbeing of medical students. There is a need for more studies to further evaluate this research question.

Article summary

Strengths and limitations of this study.

This was the first scoping review as far as we know of the literature in this area.

Many of the studies analysed in this review were cross-sectional in nature.

A variety of measurement tools were used to assess psychological wellbeing, preventing comparison of results and data synthesis.

Many of the studies included in the review did not include a control group of medical students, pre-COVID-19 quarantine.

A detailed critical appraisal of the studies included was not conducted, however this is not mandatory for scoping reviews.