bluuebunny/crossref_metadata_2025 huggingface dataset:
Modeling islet enhancers using deep learning identifies candidate causal variants at loci associated with T2D and glycemic traits
Authors: Hudaiberdiev Sanjarbek , Taylor D. Leland , Song Wei , Narisu Narisu , Bhuiyan Redwan M. , Taylor Henry J. , Yan Tingfen , Swift Amy J. , Bonnycastle Lori L. ,   DIAMANTE Consortium, Stitzel Michael L. , Erdos Michael R. , Ovcharenko Ivan , Collins Francis S.
Published: May 2022

Genetic association studies have identified hundreds of independent signals associated with type 2 diabetes (T2D) and related traits. Despite these successes, the identification of specific causal variants underlying a genetic association signal remains challenging. In this study, we describe a deep learning method to analyze the impact of sequence variants on enhancers. Focusing on pancreatic islets, a T2D relevant tissue, we show that our model learns islet-specific transcription factor (TF) regulatory patterns and can be used to prioritize candidate causal variants. At 101 genetic signals associated with T2D and related glycemic traits where multiple variants occur in linkage disequilibrium, our method nominates a single causal variant for each association signal, including three variants previously shown to alter reporter activity in islet-relevant cell types. For another signal associated with blood glucose levels, we biochemically test all candidate causal variants from statistical fine-mapping using a pancreatic islet beta cell line and show biochemical evidence of allelic effects on TF binding for the model-prioritized variant. To aid in future research, we publicly distribute our model and islet enhancer perturbation scores across ∼67 million genetic variants. We anticipate that deep learning methods like the one presented in this study will enhance the prioritization of candidate causal variants for functional studies.
A homozygous p.(Arg371Ser) mutation in FICD de-regulates AMPylation of the human endoplasmic reticulum chaperone BiP causing infancy-onset diabetes and severe neurodevelopmental delay
Authors: Perera Luke A. , Hattersley Andrew T. , Harding Heather P. , Wakeling Matthew N. , Flanagan Sarah E. , Moshina Ibrahim , Raza Jamal , Gardham Alice , Ron David , De Franco Elisa
Published: May 2022

Dysfunction of the endoplasmic reticulum (ER) in insulin-producing beta cells results in cell loss and diabetes mellitus. Here we report on 5 individuals from three different consanguineous families with infancy-onset diabetes mellitus and severe neurodevelopmental delay caused by a homozygous p.(Arg371Ser) mutation in FICD. The FICD gene encodes a bifunctional Fic domain-containing enzyme that regulates the ER Hsp70 chaperone, BiP, via catalysis of two antagonistic reactions: inhibitory AMPylation and stimulatory deAMPylation of BiP. Arg371 is a conserved residue in the Fic domain active site. The FICDR371S mutation partially compromises BiP AMPylation in vitro but eliminates all detectable deAMPylation activity. Overexpression of FICDR371S or knock-in of the mutation at the FICD locus of stressed CHO cells result in inappropriately elevated levels of AMPylated BiP. These findings, guided by human genetics, highlight the destructive consequences of de-regulated BiP AMPylation and raise the prospect of tuning FICD’s antagonistic activities towards therapeutic ends.
Self-medication practices and associated factors among COVID-19 recovered patients to prevent future infections: A web-based survey in Bangladesh
Authors: Sujan Md. Safaet Hossain , Haghighathoseini Atefehsadat , Tasnim Rafia , Islam Md. Saiful , Salauddin Sarif Mahammad , Hasan Mohammad Mohiuddin , Uddin Muhammad Ramiz
Published: May 2022

Background

Human health is largely affected by self-medication in both ways, adversely and favorably, as evidenced by the COVID-19 pandemic. The fear of spreading COVID-19 among health workers and hospital environments has led many Bangladeshi people to practice self-medicate for as a preventive strategy against this disease. Consequently, this practice entails an improper and injudicious use of medicine to cure self-recognized symptoms. To date, the COVID-19 has no effective treatment. The lack of a cure for COVID-19 and the continual progression of the diseases in educational settings induce a substantial population to practice self-medication. Therefore a study of self-medication practices is necessary for the framework of the pandemic. This study aimed to estimate the prevalence and factors associated with self-medication to prevent or manage future COVID-19 infections among recovered COVID-19 patients.

Methods

This cross-sectional study was conducted from September 2020 to February 2021 using an e-survey along with 360 participants. Data were collected using a pre-tested self-reported questionnaire. Descriptive statistics and correlations analysis were performed in the study.

Results

Among 360 participants, males were 69.7%, and females 30.3%. The prevalence of self-medication is 11%, and monthly family income, residence, education, occupation, and previous history of SM are the associated factors. Among the participants, 29.7% use antibiotics, and 30% use herbal products or drugs as medication.

Conclusion

The present study found SMP is moderately prevalent among COVID-19 recovered patients. To minimize the rate of SMP, adequate health care access systems and public education should be introduced, and media & community should be engaged in rational use of medication.
Dynamics of corticocortical brain functional connectivity relevant to therapeutic response to biologics in inflammatory arthritis
Authors: Abe Nobuya , Sakiyama Kodai , Fujieda Yuichiro , Tha Khin K. , Narita Hisashi , Karino Kohei , Kanda Masatoshi , Kono Michihito , Kato Masaru , Atsumi Tatsuya
Published: May 2022

Aberrant resting-state static functional connectivity of the brain regions, which could be evaluated by functional magnetic resonance imaging (fMRI), affects clinical courses in inflammatory arthritis (IA) including rheumatoid arthritis and spondyloarthritis. This static methods for assessing brain functional connections would be too simple to estimate the whole picture of resting-state brain function because it fluctuates over time. The effects of resting-state brain connectivity dynamics for clinical course are unknown in patients with IA. Therefore, we aimed to evaluate dynamic functional connectivity for clinical courses of IA in the context of therapeutic responsiveness to biologics using resting-state fMRI data of 64 patients with IA consisting of two cohorts. We determined representative whole-brain dynamic functional connectivity patterns by k-means++ cluster analysis, and evaluated the association of their occurrence probability and therapeutic outcomes with biologics. We determined four distinct clusters of dynamic functional connectivity in IA patients. In the first cohort, occurrence probability of the distinct cluster was associated with favorable therapeutic response in disease activity and patients’ global assessment. This finding was validated by the second cohort. The whole-brain functional coordination of the cluster indicated significantly increased corticocortical connectivity, and probabilistically decreased after therapy in treatment-effective patients compared to -ineffective patients. In conclusion, dynamic functional connectivity, in particular, frequent emergence of corticocortical connections was associated with clinical outcomes in patients with IA. The coherence of corticocortical interactions might affect modulation of pain, which would be relevant to therapeutic satisfaction.

Effects of resting-state dynamic connectivity on clinical course of inflammatory arthritis regarding therapeutic responsiveness to biologics were assessed by functional magnetic resonance.

Occurrence probability of corticocortical functional connectivity pattern was associated with favorable therapeutic response in disease activity and patients’ global assessment in inflammatory arthritis.
Multi-omic comparative analysis of COVID-19 and bacterial sepsis-induced ARDS
Authors: Batra Richa , Whalen William , Alvarez-Mulett Sergio , Gómez-Escobar Luis G. , Hoffman Katherine L. , Simmons Will , Harrington John , Chetnik Kelsey , Buyukozkan Mustafa , Benedetti Elisa , Choi Mary E. , Suhre Karsten , Schenck Edward , Choi Augustine M.K. , Schmidt Frank , Cho Soo Jung , Krumsiek Jan
Published: May 2022

Background

Acute respiratory distress syndrome (ARDS), a life-threatening condition characterized by hypoxemia and poor lung compliance, is associated with high mortality. ARDS induced by COVID-19 has similar clinical presentations and pathological manifestations as non-COVID-19 ARDS. However, COVID-19 ARDS is associated with a more protracted inflammatory respiratory failure compared to traditional ARDS. Therefore, a comprehensive molecular comparison of ARDS of different etiologies groups may pave the way for more specific clinical interventions.

Methods and Findings

In this study, we compared COVID-19 ARDS (n=43) and bacterial sepsis-induced (non-COVID-19) ARDS (n=24) using multi-omic plasma profiles covering 663 metabolites, 1,051 lipids, and 266 proteins. To address both between- and within-ARDS group variabilities we followed two approaches. First, we identified 706 molecules differently abundant between the two ARDS etiologies, revealing more than 40 biological processes differently regulated between the two groups. From these processes, we assembled a cascade of therapeutically relevant pathways downstream of sphingosine metabolism. The analysis suggests a possible overactivation of arginine metabolism involved in long-term sequelae of ARDS and highlights the potential of JAK inhibitors to improve outcomes in bacterial sepsis-induced ARDS. The second part of our study involved the comparison of the two ARDS groups with respect to clinical manifestations. Using a data-driven multi-omic network, we identified signatures of acute kidney injury (AKI) and thrombocytosis within each ARDS group. The AKI-associated network implicated mitochondrial dysregulation which might lead to post-ARDS renal-sequalae. The thrombocytosis-associated network hinted at a synergy between prothrombotic processes, namely IL-17, MAPK, TNF signaling pathways, and cell adhesion molecules. Thus, we speculate that combination therapy targeting two or more of these processes may ameliorate thrombocytosis-mediated hypercoagulation.

Conclusion

We present a first comprehensive molecular characterization of differences between two ARDS etiologies – COVID-19 and bacterial sepsis. Further investigation into the identified pathways will lead to a better understanding of the pathophysiological processes, potentially enabling novel therapeutic interventions.
Population-based analysis ofPOT1variants in a cutaneous melanoma case-control cohort
Authors: Simonin-Wilmer Irving , Ossio Raul , Leddin Emmett , Harland Mark , Pooley Karen A. , Martil de la Garza Mauricio Gerardo , Obolenski Sofia , Hewinson James , Wong Chi C. , Iyer Vivek , Taylor John C. , Newton-Bishop Julia A. , Bishop D. Timothy , Cisneros G. Andrés , Iles Mark M. , Adams David J. , Robles-Espinoza Carla Daniela
Published: May 2022

Pathogenic germline variants in the protection of telomeres 1 gene (POT1) have been associated with predisposition to a range of tumor types, including melanoma, glioma, leukemia and cardioangiosarcoma. We sequenced all coding exons of thePOT1gene in 2,929 European-descent melanoma cases and 3,298 controls, identifying 43 protein-changing genetic variants. We performed POT1-telomere binding assays for all missense and stop gained variants, finding nine variants that impair or disrupt protein-telomere complex formation, and we further define the role of variants in the regulation of telomere length and complex formation through molecular dynamics simulations. We determine thatPOT1variants are a minor contributor to melanoma burden in the general population, with only about 0.5% of melanoma cases carrying germline pathogenic variants in this gene, but should be screened in individuals with a strong family history of melanoma and/or multiple malignancies.
Jinhua Qinggan Granules for Nonhospitalized COVID-19 Patients: a Double-Blind, Placebo-Controlled, Randomized Controlled Trial
Authors: Shah Muhammad Raza , Fatima Samreen , Khan Sehrosh Naz , Shafiullah  , Himani Gulshan , Wan Kelvin , Lin Timothy , Lau Johnson Y.N. , Liu Qingquan , Lam Dennis S.C.
Published: May 2022

Background

Key findings from the World Health Organization Expert Meeting on Evaluation of Traditional Chinese Medicine in treating COVID-19 reported that TCMs are beneficial, particularly for mild-to-moderate cases. The efficacy of Jinhua Qinggan Granules (JHQG) in COVID-19 patients with mild symptoms has yet to be clearly defined.

Methods

We conducted a phase 2/3, double-blind, randomized, placebo-controlled trial to evaluate the efficacy and safety of treatment with JHQG in mild, nonhospitalized, laboratory-confirmed COVID-19 patients. Participants were randomly assigned to receive 5g/sacket of JHQG or placebo granules orally thrice daily for 10 days. The primary outcomes were the improvement in clinical symptoms and proportion tested negative on viral PCR after treatment. Secondary outcomes were the time to recovery from clinical symptoms and changes in white blood cells (WBC) and acute phase reactants (C-reactive protein (CRP) and ferritin) 10-15 days after treatment.

Results

A total of 300 patients were randomly assigned to receive JHQG (150 patients) and placebo (150 patients). Baseline characteristics were similar in the two groups. In the modified intention-to-treat analysis, JHQG showed greater clinical efficacy (82.67%) after 10 days of treatment compared with the placebo group (10.74%) (rate difference: 71.93%; 95% CI 64.09 - 79.76). The proportion of patients with a negative PCR after treatment were comparable (rate difference: -4.67%; 95% CI -15.76 - 6.42). While all changes in WBC, ferritin, and CRP levels showed a statistically significant decline in JHQG (P≤0.044) after treatment, but not the latter in placebo (P=0.077). The median time to recovery of COVID-19 related symptoms including cough, sputum, sore throat, dyspnea, headache, nasal obstruction, fatigue, and myalgia were shorter in the JHQG group compared to the placebo group (P<0.001 for all). 3 patients experienced mild to moderate adverse events during the treatment period in the JHQG group. Findings were similar between the modified intention-to-treat and the per-protocol analysis that included only patients who reported 100% adherence to the assigned regimen.

Conclusions

JHQG is a safe and effective TCM for the treatment of mild COVID-19 patients.

Clinical Trial Registration

The Trial was prospectively registered on www.clinicaltrials.gov with registration number: NCT04723524.
School Reopening Simulations with COVID-19 Agent-based Model for the Philippine Regions
Authors: Bongolan Vena Pearl , Francisco Nico Andrew G. , Saliba Martin Thomas D. , Celeste Jimuel
Published: May 2022

Schools have been closed in the Philippines since March 2020 due to the COVID-19 pandemic. In 2022, the government already allowed a pilot run of limited in-person classes in low-risk areas. With such development, the present paper aims to explore the question “Is it safe to reopen schools with the current vaccination coverage?” We used an age-stratified COVID-19 agent-based model coupled with social contact probabilities to simulate school reopening and vaccination scenarios in the 17 regions of the country. Through these simulations, we found downtick points for infections and deaths—the vaccination coverage at which we do not expect increases in infections and deaths should schools reopen. We then calculated the School Reopening Viability (SRV) of the regions and visualized these scores with a stop-go map for school reopening. Simulation results suggest that all regions except Regions 7, 9, BARMM, and 13 can already reopen schools without the fear of upticks in infections nor deaths. These regions have lower vaccination coverages relative to the rest of the country, especially against the case of Luzon which has the highest vaccination coverage. We recommend that the areas of concern ramp up their vaccination efforts before reopening schools. At the same time, behavioral factors (mask-wearing, physical distancing, hand-washing) and disease resistance factors (healthy living habits) shall be enforced once schools reopen. Finally, school reopening shall be gradual to ensure the crafting of data-driven (hospital utilization, positivity rate) policies.
Modelling long-term COVID-19 hospital admission dynamics using empirical immune protection waning data
Authors: Reyné Bastien , Sofonea Mircea T. , Alizon Samuel
Published: May 2022

Immune waning is key to the timely anticipation of COVID-19 long-term dynamics. We assess the impact of periodic vaccination campaigns using a compartmental epidemiological model with embedded multiple age structures and empiric time-dependent vaccine protection kinetics. Despite the uncertainty inherent to such scenarios, we show that vaccination campaigns decreases the yearly number of COVID-19 admissions. However, especially if restricted to individuals over 60 years old, vaccination on its own seems insufficient to prevent thousands of hospital admissions and it suffers the comparison with non-pharmaceutical interventions aimed at decreasing infection transmission. The combination of such interventions and vaccination campaigns appear to provide the greatest reduction in hospital admissions.
Quantifying the information in noisy epidemic curves
Authors: Parag Kris V , Donnelly Christl A , Zarebski Alexander E
Published: May 2022

Reliably estimating the dynamics of transmissible diseases from noisy surveillance data is an enduring problem in modern epidemiology. Key parameters, such as the instantaneous reproduction number, Rt at time t, are often inferred from incident time series, with the aim of informing policymakers on the growth rate of outbreaks or testing hypotheses about the effectiveness of public health interventions. However, the reliability of these inferences depends critically on reporting errors and latencies innate to those time series. While studies have proposed corrections for these issues, methodology for formally assessing how these sources of noise degrade Rt estimate quality is lacking. By adapting Fisher information and experimental design theory, we develop an analytical framework to quantify the uncertainty induced by under-reporting and delays in reporting infections. This yields a novel metric, defined by the geometric means of reporting and cumulative delay probabilities, for ranking surveillance data informativeness. We apply this metric to two primary data sources for inferring Rt: epidemic case and death curves. We find that the assumption of death curves as more reliable, commonly made for acute infectious diseases such as COVID-19 and influenza, is not obvious and possibly untrue in many settings. Our framework clarifies and quantifies how actionable information about pathogen transmissibility is lost due to surveillance limitations.
Evaluating specialist intensive support teams for adults with intellectual disabilities who display behaviours that challenge: The IST-ID mixed methods study
Authors: Hassiotis Angela , Kouroupa Athanasia , Hamza Leila , Marston Louise , Romeo Renee , Yaziji Nahel , Hall Ian , Langdon Peter E , Courtenay Ken , Taggart Laurence , Morant Nicola , Crossey Vicky , Lloyd-Evans Brynmor
Published: May 2022

Background

Intensive Support Teams (ISTs) are recommended for individuals with intellectual disabilities who display behaviours that challenge. However, there is currently little evidence about the clinical and cost effectiveness of IST models operating in England.

Aims

To investigate the clinical and cost effectiveness of IST models.

Methods

We carried out a cohort study to evaluate the clinical and cost-effectiveness of two previously identified IST models (independent and enhanced) in England. Adult participants (n=226) from 21 ISTs (10 independent and 11 enhanced) were enrolled. The primary outcome was change in challenging behaviour between baseline and 9 months measured by the Aberrant Behaviour Checklist-Community 2.

Results

We found no statistically significant differences between models for the primary outcome (adjusted β: 4.27; 95% CI: -6.34 to 14.87; p=0.430) or any secondary outcomes. Quality Adjusted Life Years (0.0158; 95% CI: -0.0088 to 0.0508) and costs (£3409.95; 95% CI: -£9957.92 to £4039.89) of the two models were comparable.

Conclusions

The study provides evidence that both models were associated with clinical improvement for similar costs at follow-up. We recommend that the choice of service model should rest with local services. Further research should investigate the critical components of IST care to inform the development of fidelity criteria, and policy makers should consider whether roll out of such teams should be mandated.

Study registration number

ClinicalTrials.govNCT03586375; IRAS 239820; National Institute for Health Research (NIHR) Central Portfolio Management System (CPMS) 38554.
Deep learning for subtypes identification of pure seminoma of the testis
Authors: Medvedev Kirill E. , Acosta Paul H. , Jia Liwei , Grishin Nick V.
Published: May 2022

The most critical step in the clinical diagnosis workflow is the pathological evaluation of each tumor sample. Deep learning is a powerful approach that is widely used to enhance diagnostic accuracy and streamline the diagnosis process. In our previous study using omics data, we identified two distinct subtypes of pure seminoma. Seminoma is the most common histological type of testicular germ cell tumors (TGCTs). Here we developed a deep learning decision making tool for the identification of seminoma subtypes using histopathological slides. We used all available slides for pure seminoma samples from The Cancer Genome Atlas (TCGA). The developed model showed an area under the ROC curve of 0.896. Our model not only confirms the presence of two distinct subtypes within pure seminoma but also unveils the presence of morphological differences between them that are imperceptible to the human eye.
United States’ political climates and the spread of SARS-2-COVID-19 during 2020
Authors: Pratto Felicia , Cortopassi Andrew , Marrouch Natasza
Published: May 2022

We tested whether the political climate in each U.S. state and Washington, DC determined the nature of the spread of COVID-19 cases and deaths in those polities during 2020. Political climate for each polity was indexed as a weighted average of the proportion of Republicans in legislatures in 2018 and the degree of public trust in both the White House and President Trump to handle COVID-19 in April, 2020. We found that polities higher on the political climate index had faster increases in per capita COVID-19 cases and deaths. Such Republican-trusting polities also had lower access to health care and less public engagement in prevention behavior, both of which mediated the influence of political climate on COVID- 19 cases and deaths. Further, the relationship between incidence of COVID-19 cases and deaths was weaker in more Republican-trusting polities. Political climate can be seen as contributing to more cases and deaths due to lower access to health care and to lower public adherence to public health guidelines in polities led by Republicans and which trusted the Trump White House to handle the pandemic.
Evaluation of a disease-specific mHealth-based exercise self-tracking measure
Authors: Ensari Ipek , Horan Emma , Elhadad Noémie , Bakken Suzanne R.
Published: May 2022

Objectives

This study investigates the concurrent and construct validity of a brief, customizable exercise self-tracking item from a research mHealth App (“Phendo”) for use as a measure of day-level and habitual exercise behavior in endometriosis.

Study Sample

Study 1 included 52 participants who were recruited online and provided data for up to 14 days. Study 2 included 359 Phendo users who had retrospectively-collected data on the study measures.

Methods

In Study 1, we evaluated the responses on the self-tracking exercise item as estimates of day-level moderate-to-vigorous intensity exercise (MVE) and total step counts. Comparison measures included recall-based MVE minutes and accelerometry-based step counts, which were self-reported through daily surveys. In Study 2, we derived a measure of habitual exercise using each individual’s longitudinal self-tracked responses. We assessed its concurrent validity using the Nurses’ Health Study II Physical Activity Scale (NHS-II) as the comparison measure. We assessed its discriminant validity through known-group differences analysis where the sample was dichotomized based on Health Survey Short Form-36 (SF-36) and body mass index (BMI).

Data Analysis

We assessed bivariate associations between the scores on the self-tracking and comparison measures using Kendall’s rank correlations. We estimated daily MVE and step counts (Study 1), and weekly exercise (Study 2) from the self-tracking item scores through adjusted linear and polynomial regression models. We used t-tests and linear regression to conduct known-group differences analyses.

Results

In Study 1, self-tracked exercise responses were moderately correlated with survey based MVE and step counts. Regression analyses indicated that overall exercise responses were associated with ∼17 minutes of MVE for the average participant (B=16.09, t=3.11, p=0.045). Self-tracked aerobic-type exercise was a stronger predictor of MVE minutes and step counts (B=27.561, t=5.561, p<0.0001). In Study 2, each self-tracked exercise instance corresponded to ∼19 minutes of exercise per week on the NHS-II Scale (B=19.80, t=2.1, p=0.028). Finally, there were statistically significant differences between the groups dichotomized based on SF-36 subscale scores and BMI.

Conclusion

This study presents preliminary evidence on the concurrent and discriminant validity of a brief mHealth App measure for exercise self-tracking among individuals with endometriosis. These findings have implications in the context of large-scale studies that involve monitoring a diverse group of participants over long durations of time, as well as engaging and retaining research participants.
Allergen recognition by specific effector Th2 cells enables IL-2-dependent activation of regulatory T cell responses in humans
Authors: Lozano-Ojalvo Daniel , Tyler Scott R. , Aranda Carlos J. , Wang Julie , Sicherer Scott , Sampson Hugh A. , Wood Robert A. , Burks A. Wesley , Jones Stacie M. , Leung Donald Y. M. , Curotto de Lafaille Maria , Berin M. Cecilia
Published: May 2022

Type 2 allergen-specific T cells are essential for the induction and maintenance of allergies to foods, and Tregs specific for these allergens are assumed to be involved in their resolution. However, it has not been convincingly demonstrated whether allergen-specific Treg responses are responsible for the generation of oral tolerance in humans. We observed that sustained food allergen exposure in the form of oral immunotherapy resulted in increased frequency of Tregs only in individuals with lasting clinical tolerance. We sought to identify regulatory components of the CD4+ T cell response to food allergens by studying their functional activation over time in vitro and in vivo. Two subsets of Tregs expressing CD137 or CD25/OX40 were identified with a delayed kinetics of activation compared to clonally enriched pathogenic effector Th2 cells. Treg activation was dependent on IL-2 derived from effector T cells. In vivo exposure to peanut in the form of an oral food challenge of allergic subjects induced a delayed and persistent activation of Tregs after initiation of the allergen-specific Th2 response. Our results reveal a dependency of Tregs on effector Th2 cells for their activation and highlight the important role of IL-2 in the generation of a regulatory response to food allergens.

One Sentence Summary

Initiation of allergen-specific Th2 cell responses induces an IL-2-mediated activation of Tregs with suppressive properties.
Mitochondrial DNA heteroplasmy distinguishes disease manifestation in PINK1- and PRKN-linked Parkinson’s disease
Authors: Trinh Joanne , Hicks Andrew A. , König Inke R. , Delcambre Sylvie , Lüth Theresa , Schaake Susen , Wasner Kobi , Ghelfi Jenny , Borsche Max , Vilariño-Güell Carles , Hentati Faycel , Germer Elisabeth L. , Bauer Peter , Takanashi Masashi , Kostić Vladimir , Lang Anthony E. , Brüggemann Norbert , Pramstaller Peter P. , Pichler Irene , Rajput Alex , Hattori Nobutaka , Farrer Matthew J. , Lohmann Katja , Weissensteiner Hansi , May Patrick , Klein Christine , Grünewald Anne
Published: May 2022

Biallelic mutations in PINK1 and PRKN cause recessively inherited Parkinson’s disease (PD). Though some studies suggest that PINK1/PRKN monoallelic mutations may not contribute to risk, deep phenotyping assessment showed that PINK1 or PRKN monoallelic pathogenic variants were at a significantly higher rate in PD compared to controls. Given the established role of PINK1 and Parkin in regulating mitochondrial dynamics, we explored mitochondrial DNA (mtDNA) integrity and inflammation as potential disease modifiers in carriers of mutations in these genes. MtDNA integrity, global gene expression and serum cytokine levels were investigated in a large collection of biallelic (n=84) and monoallelic (n=170) carriers of PINK1/PRKN mutations, iPD patients (n=67) and controls (n=90). Affected and unaffected PINK1/PRKN monoallelic mutation carriers can be distinguished by heteroplasmic mtDNA variant load (AUC=0.83, CI:0.74-0.93). Biallelic PINK1/PRKN mutation carriers harbor more heteroplasmic mtDNA variants in blood (p=0.0006, Z=3.63) compared to monoallelic mutation carriers. This enrichment was confirmed in iPSC-derived and postmortem midbrain neurons from biallelic PRKN-PD patients. Lastly, the heteroplasmic mtDNA variant load was found to correlate with IL6 levels in PINK1/PRKN mutation carriers (r=0.57, p=0.0074). PINK1/PRKN mutations predispose individuals to mtDNA variant accumulation in a dose- and disease-dependent manner. MtDNA variant load over time is a potential marker of disease manifestation in PINK1/PRKN mutation carriers.
HUMAN PAPILLOMAVIRUS SEROTYPES IN ABNORMAL CERVICAL SMEARS IN CALABAR CROSS RIVER STATE A CROSS SECTIONAL STUDY
Authors: Orji Ocheze Chinwendu , Eyong Edu Michael , Nnoli Martins Anadozo , Ugbem Theophilus Ipeh , Samaila Modupeola , Rotimi Solomon Oladapo , Ekanem Ima-obong Asuquo
Published: May 2022

Background

Human Papillomavirus (HPV) is sexually transmitted and constitutes the major cause of cancer of the cervix and could be detected using cervical smear screening test.

Aim and objective

To determine the frequency of high risk HPV serotypes (16,18,33,45)in abnormal cervical smears in women aged 18-65 years in Calabar, Cross River State using cytological method over a period of one year from 1stMarch, 2017 to 28thFebruary, 2018 in Cross River State, Nigeria.

Materials and method

The study was a cross sectional study carried out in University of Calabar Teaching Hospital, Calabar on women aged 18-65 years who met the study inclusion criteria and were consecutively selected for conventional cervical screening test from the three provinces of Efik, Efut and Qua provinces. Females who were positive for squamous intraepithelial lesion after screening results were subjected to Human papillomavirus deoxyribonucleic acid (HPV DNA) testing.

Results

304 women aged 18-65 years were recruited into the study. Of these only 30 had intraepithelial lesions. Low grade squamous lntraepithelial lesions (LSIL) predominated with 63.3%(19) as compared with High grade squamous lntraepithelial lesion of 36.6%(11). HPV DNA was observed in all the abnormal cytology subjected to HPV DNA test. The prevalence rate of high risk HPV in this study was 9.9 %. The commonest serotypes found among study participants were HPV 16,33,and 45 with prevalence of 4.7%, 100% and 61.9% respectively.

Among participants infected with HPV 33 and HPV 45, 13(61.9%) and 8(38.1%) had low grade squamous Intraepithelial lesion respectively while 8(38.1%) and 5(23.8%) had high grade squamous Intraepithelial lesion respectivelyIn this study,66.67%(14) out of 21 participants had HPV DNA co – infection.

Conclusion

The prevalent HPV serotypes were 16,33 and 45 from this study with serotypes 33 being the commonest. Advocacy for HPV vaccine for reproductive age females should be encouraged and this should be included with established cervical cancer screening programs in government hospitals.
Antibody response to SARS-CoV2 among COVID-19 confirmed cases, and correlates with neutralizing assay in a subgroup of patients in Delhi National Capital Region, India
Authors: Misra Puneet , Kant Shashi , Guleria Randeep , Rai Sanjay , Jaiswal Abhishek , Mandal Suprakash , Medigeshi Guruprasad R , Ahmad Mohammad , Rahman Anisur , Sangral Meenu , Yadav Kapil , Bairwa Mohan , Haldar Partha , Kumar Parveen
Published: May 2022

Background

Plaque reduction neutralization test (PRNT) is the gold standard to detect neutralizing capacity of the serum antibodies. Neutralizing antibody confers protection against further infection. The present study was done with the objective to measure the antibody level against SARS-CoV2 among laboratory confirmed COVID-19 cases and to evaluate whether the presence of anti-SARS-CoV2 antibodies indicate virus neutralizing capacity.

Methods

One hundred COVID-19 confirmed cases were recruited. Sociodemographic details and history of COVID-19 vaccination, contact with positive COVID-19 cases, and symptoms were ascertained using a self-developed semi-structured interview schedule. Serum samples of the participants were collected within three months from date of the positive report of COVID-19. The presence of anti-SARS-CoV-2 antibodies (IgA, IgG and IgM antibodies), receptor binding domain antibodies (anti-RBD), and neutralizing antibodies were measured.

Findings

Almost all participants had Anti-SARS-CoV2 antibodies (IgA, IgG and IgM) (99%) and Anti-RBD IgG antibodies (97%). However, only 69% had neutralizing antibodies against SARS-CoV2. Anti-RBD antibody levels were significantly higher among participants having neutralizing antibodies compared to those who didn’t.

Interpretation

The present study highlights that presence of antibodies against SARS-CoV2, or presence of anti-RBD antibody doesn’t necessarily imply presence of neutralizing antibodies.

Funding

World Health Organisation
How might postprandial ‘extras’ fatten? Simulation of a gastric mixing hypothesis
Authors: Booth David A.
Published: May 2022

It was suggested that the ingestion of extra calories towards the end of or shortly after a meal might be especially fattening. That hypothesis was based on the intuition that mixing of the sugared drink and accompaniments while the stomach was emptying rapidly would delay the release of hunger less than the same intake in the hour before the next meal. This paper presents an examination of that mechanism by calculating the time course of gastric emptying with extra intake at different times after the meal. The output from these simulations confirmed that early further energy would delay the end of emptying less than later. However, within the parameters tested, the effect is not large. Fattening effects of calories after meals could arise by a variety of mechanisms that remain to be tested without disrupting daily life.

“Highlights”

Extra intake may be more fattening shortly after meals than later.

That proposal was supported by theoretical calculations of gastric emptying.

Hence the timing of energy intake well before a meal seems critical to its effect on weight.

The eater’s own concepts of meal, snacks and drinks are key to research on weight control.
‘Self-Management Intervention through Lifestyle Education for Kidney health’ (the SMILE-K study): protocol for a single-blind longitudinal randomised control trial with nested pilot study
Authors: Lightfoot Courtney J. , Wilkinson Thomas J. , Yates Thomas , Davies Melanie J , Smith Alice C.
Published: May 2022

Introduction

Many people living with chronic kidney disease (CKD) are expected to self-manage their condition. Patient activation is the term given to describe the knowledge, skills, and confidence a person has in managing their own health and is closely related to the engagement in preventive health behaviors. Self-management interventions have the potential to improve remote disease management and health outcomes. We are testing an evidence- and theory-based digital self-management structured 10-week programme developed for CKD patients called ‘My Kidneys & Me’. The primary aim of the study (SMILE-K) is to assess the effect on patient activation levels.

Methods and analysis

A single-blind randomised control trial (RCT) with a nested pilot study will assess the feasibility of the intervention and study design before continuation to a full RCT. Individuals aged 18 years or older, with established CKD stage 3-4 (eGFR of 15-59 ml/min/1.73m2) will be recruited through both primary and secondary care pathways. Participants will be randomised into two groups: intervention group and control group. The primary outcome is the Patient Activation Measure (PAM-13). The full RCT will assess the effect of the programme on online self-reported outcomes which will be assessed at baseline, after 10-weeks, and then after 20-weeks in both groups. A total sample size of n=432 participants are required based on a 2:1 randomisation. A sub-study will measure physiological changes (e.g., muscle mass, physical function) and patient experience (qualitative semi-structured interviews).

Ethics and dissemination

This study was fully approved by the Research Ethics Committee-Leicester South on the 19/11/2020 (reference: 17/EM/0357). All participants are required to provide informed consent obtained online. The results are expected to be published in scientific journals and presented at clinical research conferences. This is protocol version 1.0 dated 27/01/2021.

Trial registration number

The study was prospectively registered as ISRCTN18314195 in December 2020.
Kidney stone prevalence based on self-report and Electronic Health Records: insight into the prevalence of active medical care for kidney stones
Authors: Forbes Connor M. , Nimmagadda Naren , Kavoussi Nicholas L. , Xu Yaomin , Bejan Cosmin A. , Miller Nicole L. , Hsi Ryan S.
Published: May 2022

Introduction

Kidney stone prevalence estimates vary depending on sampling methodology. We compared rates of patient-reported kidney stone disease to Electronic Health Records (EHR) kidney stone diagnosis using a common dataset to evaluate for socio-demographic differences in these populations, including between those with and without active care for kidney stones.

Methods

From the All of Us research database, we identified 21,687 adult participants with both patient-reported medical history and EHR data. We extracted patient-reported kidney stone history and medical encounters for kidney stones from EHR. We compared differences in age, sex, race, education, employment status and healthcare access between patients with self-reported kidney stone history without EHR data to those with EHR-based diagnoses.

Results

In this population, the self-reported prevalence of kidney stones was 8.6% overall (n=1877), including 4.6% (n=1004) who had self-reported diagnoses but no EHR data. Among those with self-reported kidney stone diagnoses only, the median age was 66, 43% were male, and 92% were Non-Hispanic Whites, compared 120,623 (53.9%) in the entire All of Us cohort. The EHR-based prevalence of kidney stones was 5.7% (n=1231), median age 67, of whom 45% were male and 92% were Non-Hispanic White. No differences were observed in age, sex, education, employment status, rural/urban status, or ability to afford healthcare between groups with EHR diagnosis or self-reported diagnosis only. Of patients who had a self-reported history of kidney stones, 24% reported actively seeing a provider for kidney stones.

Conclusions

Kidney stone prevalence by self-report is higher than EHR-based prevalence in this national dataset. Using either method alone to estimate kidney stone prevalence may exclude some patients with the condition, although the demographic profile of both groups is similar. Approximately one in four patients report actively seeing a provider for stone disease.
Convolutional Encoder-Decoder Networks for Volumetric Computed Tomography Surviews from Single- and Dual-View Topograms
Authors: Shapira Nadav , Bharthulwar Siddharth , Noël Peter B.
Published: May 2022

Computed tomography (CT) is an extensively used imaging modality capable of generating detailed images of a patient’s internal anatomy for diagnostic and interventional procedures. High-resolution volumes are created by measuring and combining information along many radiographic projection angles. In current medical practice, single and dual-view two-dimensional (2D) topograms are utilized for planning the proceeding diagnostic scans and for selecting favorable acquisition parameters, either manually or automatically, as well as for dose modulation calculations. In this study, we develop modified 2D to three-dimensional (3D) encoder-decoder neural network architectures to generate CT-like volumes from single and dual-view topograms. We validate the developed neural networks on synthesized topograms from publicly available thoracic CT datasets. Finally, we assess the viability of the proposed transformational encoder-decoder architecture on both common image similarity metrics and quantitative clinical use case metrics, a first for 2D-to-3D CT reconstruction research. According to our findings, both single-input and dual-input neural networks are able to provide accurate volumetric anatomical estimates. The proposed technology will allow for improved (i) planning of diagnostic CT acquisitions, (ii) input for various dose modulation techniques, and (iii) recommendations for acquisition parameters and/or automatic parameter selection. It may also provide for an accurate attenuation correction map for positron emission tomography (PET) with only a small fraction of the radiation dose utilized.
Variational and phase response analysis for limit cycles with hard boundaries, with applications to neuromechanical control problems
Authors: Wang Yangyang , Gill Jeffrey P. , Chiel Hillel J. , Thomas Peter J.
Published: May 2022

Motor systems show an overall robustness, but because they are highly nonlinear, understanding how they achieve robustness is difficult. In many rhythmic systems, robustness against perturbations involves response of both the shape and the timing of the trajectory. This makes the study of robustness even more challenging.

To understand how a motor system produces robust behaviors in a variable environment, we consider a neuromechanical model of motor patterns in the feeding apparatus of the marine molluskAplysia californica(Shaw et al., 2015; Lyttle et al., 2017). We established in (Wang et al., 2021) the tools for studying combined shape and timing responses of limit cycle systems under sustained perturbations and here apply them to study robustness of the neuromechanical model against increased mechanical load during swallowing. Interestingly, we discover that nonlinear biomechanical properties confer resilience by immediately increasing resistance to applied loads. In contrast, the effect of changed sensory feedback signal is significantly delayed by the firing rates’ hard boundary properties. Our analysis suggests that sensory feedback contributes to robustness in swallowing primarily by shifting the timing of neural activation involved in the power stroke of the motor cycle (retraction). This effect enables the system to generate stronger retractor muscle forces to compensate for the increased load, and hence achieve strong robustness.

The approaches that we are applying to understanding a neuromechanical model inAplysia, and the results that we have obtained, are likely to provide insights into the function of other motor systems that encounter changing mechanical loads and hard boundaries, both due to mechanical and neuronal firing properties.
Assessment of glucocorticoid-induced enhancer activity of eSNP regions using STARR-seq reveals novel molecular mechanisms in psychiatric disorders
Authors: Penner-Goeke Signe , Bothe Melissa , Kappelmann Nils , Kreitmaier Peter , Kaya Ezgi , Pöhlchen Dorothee , Kühnel Anne , Czamara Darina ,   BeCOME working group, Glaser Laura V. , Roeh Simone , Ködel Maik , Monteserin-Garcia Jose , Rummel Christine , Arloth-Knauer Janine , Diener-Hölzl Laura , Woelfel Barbara , Sauer Susann , Riesenberg Stephan , Ziller Michael J. , Labeur Marta , Meijsing Sebastiaan H. , Binder Elisabeth B.
Published: May 2022

Exposure to stressful events increases risk for psychiatric disorders. Mechanistic insight into genetic factors moderating the impact of stress can increase our understanding of disease processes. Here, we test 3662 SNPs from preselected expression quantitative trait loci in massively parallel reporter assays to identify genetic variants that modulate the activity of regulatory elements sensitive to glucocorticoids, important mediators of the stress response. Of the tested SNP sequences, 547 were located in glucocorticoid-responsive regulatory elements of which 233 showed allele-dependent activity. Transcripts regulated by these variants were enriched for those differentially expressed in psychiatric disorders in postmortem brain. Phenome-wide Mendelian randomization analysis in 4,439 phenotypes revealed potentially causal associations specifically in neuro-behavioral traits, including psychiatric disorders. Finally, functional gene scores derived from these variants were significantly associated with differences in physiological stress measures, suggesting that these may alter disease risk by moderating the individual set point of the stress response.
Prevalence and determinants of mental well-being and satisfaction with life among university students amidst COVID-19 pandemic
Authors: Hossain Sujan Md. Safaet , Haghighathoseini Atefehsadat , Tasnim Rafia , Ripon Rezaul Karim , Ripon Sayem Ahmed , Hasan Mohammad Mohiuddin , Uddin Muhammad Ramiz , Ferdous Most. Zannatul
Published: May 2022

Background

The COVID-19 pandemic has caused a slew of mental illnesses due to a lack of cures and vaccinations, as well as concerns about students’ well-being and satisfaction with life, resulting in psychological symptoms and dissatisfaction with their lives. As students are highly susceptible to mental health issues, researchers discovered that perceived SWL and MWB decreased. The present study investigated the prevalence and determinants of mental well-being and satisfaction with life among university students in Bangladesh.

Methods

An e-survey based cross-sectional study was carried out from February to April 2021 among 660 students. A purposive sampling technique was utilized in the study. Self-reported mental well-being and satisfaction with life psychological tools were also used. The e-questionnaire survey was conducted with informed consent and questions were related to socio-demographics, satisfaction with life, and mental well-being scales. Descriptive statistics and multiple regression analysis were performed. The data were rechecked and analyzed with the R programming language

Results

The prevalence estimates of mental well-being and satisfaction with life were 27% and 13%, respectively. In a total of 660 participants, 58.2% of them were male and the rest of them were female (41.8%). Among the participants, 22.5% suffer the worst conditions regarding their financial conditions, and 16.5% badly seek a job for livelihood.

Conclusion

The present findings revealed that the COVID-19 pandemic and longtime educational institution closure significantly affect the students mental health. Students’ mental well-being was in vulnerable conditions and their satisfaction with life was extremely poor. A comprehensive student psychological support service should be expanded to help students’ mental health.