bluuebunny/crossref_metadata_2025 huggingface dataset:
Anti-Gephyrin antibodies: A novel specificity in patients with systemic sclerosis and lower bowel dysfunction
Authors: McMahan ZH , Kulkarni S , Andrade F , Perin J , Zhang C , Hooper JE , Wigley FM , Rosen A , Pasricha PJ , Casciola-Rosen L
Published: September 2022

Objective

Autoantibodies are clinically useful in phenotyping patients with systemic sclerosis (SSc). GI function is regulated by the enteric nervous system (ENS) and commonly impaired in SSc suggesting that the SSc autoimmune response may target ENS antigens. We sought to identify novel anti-ENS autoantibodies with an aim to clinically phenotype SSc GI dysfunction.

Methods

Serum from a SSc patient with GI dysfunction but without defined SSc-associated autoantibodies was used for autoantibody discovery. Immunoprecipitations performed with murine myenteric plexus lysates were on-bead digested and autoantigens were identified by mass spectrometry. Prevalence and clinical features associated with novel autoantibodies were evaluated in a SSc cohort using regression analyses. Expression of gephyrin in human GI tract tissue was examined by immunohistochemistry.

Results

We identified gephyrin as a novel SSc autoantigen. Anti-gephyrin antibodies were present in 9% of SSc patients (16/188) and absent in healthy controls (0/46). Anti-gephyrin antibody-positive patients had higher constipation scores [1.00 vs. 0.50;p=0.02] and were more likely to have severe constipation and severe distention/bloating [46% vs. 15%;p=0.005; 54% vs. 25%;p=0.023, respectively]. Anti-gephyrin antibody levels were significantly higher among patients with severe constipation [0.04 vs. 0.00;p=0.001] and severe distention and bloating [0.03 vs. 0.004;p=0.010]. Severe constipation was associated with anti-gephyrin antibodies even in the adjusted model. Importantly, gephyrin was expressed in the ENS, which regulates gut motility.

Conclusion

Gephyrin is a novel ENS autoantigen that is expressed in human myenteric ganglia. Anti-gephyrin autoantibodies are associated with the presence and severity of constipation in SSc patients.
Is acetazolamide a potential intervention for people with bipolar disorders? A scoping review protocol
Authors: Strawbridge Rebecca , Orfanos Stelios , Yalin Nefize , Young Allan H
Published: September 2022

Acetazolamide is a carbonic anhydrase inhibitor whose primary indication is to alleviate altitude sickness, but it is also used in the treatment of glaucoma, seizures and oedema. Although it has not been repurposed for psychiatric illnesses, acetazolamide has been advocated for its putative benefits in those with a bipolar disorder (BD). Because current treatment options for BD bring a variety of challenges, it is important to examine the current evidence to date in a formal synthesis. This article describes a protocol for a scoping review to do so, in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for scoping reviews (PRISMA-ScR). PubMed, Embase and PsycInfo will be searched for all available publications focusing on the intervention acetazolamide for people with BD. This will include non-primary and primary research of any design, focusing on any outcome, in order to comprehensively bring together the work that has been undertaken to date on this topic. Relevant data from included articles will be subject to a narrative synthesis. It is anticipated that the results from the review will help to ascertain the potential for acetazolamide to benefit people with bipolar affective disorders in the future and aid the planning of future primary research to establish this.
Longitudinal Associations Between White Matter Microstructure and Psychiatric Symptoms in Adolescence
Authors: Dall’Aglio Lorenza , Xu Bing , Tiemeier Henning , Muetzel Ryan L.
Published: September 2022

Objective

Associations between psychiatric problems and white matter (WM) microstructure have been reported in childhood and adolescence. Yet, a deeper understanding of this relation has been hampered by a dearth of well-powered longitudinal studies and a lack of explicit examination of the bidirectional associations between brain and behavior. We investigated the temporal directionality of WM microstructure and psychiatric symptom associations from late childhood to early adolescence.

Methods

In this observational study, we leveraged the world’s largest single- and multi-site cohorts of neurodevelopment: the Generation R and Adolescent Brain Cognitive Development Studies (total n scans = 11,400). We assessed psychiatric symptoms with the Child Behavioral Checklist as broad-band Internalizing and Externalizing scales, and as syndrome scales (e.g., Anxious/Depressed). We quantified WM with Diffusion Tensor Imaging, globally and at a tract level. We used cross-lagged panel models to test bidirectional associations of global and specific measures of psychopathology and WM microstructure, meta-analyzed results across cohorts, and used linear mixed-effects models for validation.

Results

We did not identify any robust longitudinal associations of global WM microstructure with internalizing or externalizing problems across cohorts (confirmatory analyses). We observed similar findings for longitudinal associations between tract-based microstructure with internalizing and externalizing symptoms, and for global WM microstructure with specific syndromes (exploratory analyses).

Conclusion

Uni- or bi-directionality of longitudinal associations between WM and psychiatric symptoms was not robustly identified. We propose several explanations for these findings, including interindividual differences, the use of longitudinal approaches, and smaller effects than expected.
Restoring the True Form of the Gigantic Blue Whale for the First Time, and Mass Estimation
Authors: Paul Gregory S.
Published: September 2022

Using photographs of swimming blue whales and mounted skeletons, the body form of the largest known animal is correctly restored, no previous effort having been entirely accurate in part because of the absence of rigorous technical efforts prior to this study. The maximum total length/depth ratio is about 7.5-8.1, with the greatest depth in the chest forward of midlength. There is a subtle ventral concavity between the chest and abdomen. The chest is broader than deep, contradicting mounted skeletons in which the ribs are articulated too vertically so that the chest is falsely deeper than broad. The tip of the mandible is fairly blunt, although the throat pouch is streamlined when cruising, the head is very large. The result is an elongated, tear drop, hydrodynamically optimized shape. A volume based mass estimate based on the restoration is close to that observed in harvested blue whales relative to length, and indicates that the largest individuals reach ~200 tonnes.
Impact of HLA divergence on humoral response to SARS-CoV-2 and HBV vaccines in the liver transplantation setting
Authors: Féray Cyrille , Allain Vincent , Taupin Jean Luc , Roche Bruno , Desterke Christophe , Kounis Ilias , Demir Zeynep , Roque-Afonso Anne-Marie , Coilly Audrey , Samuel Didier , Caillat-Zucman Sophie
Published: September 2022

Background

Organ transplant recipients are at high risk of viral infections but show lower humoral vaccine responsiveness than immunocompetent individuals. HLA evolutionary divergence (HED) quantifies the sequence differences between homologous HLA alleles and reflects the breadth of the immunopeptidome presented to T lymphocytes.

Methods

We retrospectively investigated the impact of HED on humoral response to SARS-CoV-2 mRNA vaccine in 310 liver transplant recipients (undetectable anti-spike IgG titers considered as no response, ≤250 BAU/mL as moderate response, >250 BAU/mL as strong response) and to Hepatitis B virus (HBV) vaccine in 424 liver transplant candidates (anti-HBs IgG <10 mIU/mL considered as no response, 10-100 mIU/mL as moderate reponse, ≥100 mIU/mL as strong response). HED between aligned allele pairs at HLA-A, -B, -DRB1 and- DQB1 loci were measured as a continuous metric using the Grantham distance. The impact of HED on vaccine responses was analyzed through ordinal logistic regression and inverse probability weighting approach based on generalised propensity scores.

Findings

For both vaccines, HED at the DQB1 locus, but not at other loci, was significantly higher in responders than in others, independent of covariates associated to the response (age, time since transplant, hemoglobin levels, combined graft, immunosuppression with steroids or mycophenolate for SARS-CoV-2 vaccine; age, gender, and liver disease for HBV vaccine).

Interpretation

DQB1 HED is a critical determinant of humoral response to vaccines in liver transplant recipients. This metric could guide the design of future vaccines as it predicts the magnitude of the repertoire of vaccine-derived peptides presented to CD4 helper T cells.

Funding

Institut National de la Sante et de la Recherche Medicale (INSERM)
Simplification of free-running cardiac magnetic resonance by respiratory phase using principal component analysis
Authors: Shammi Ummul Afia , Luan Zhijian , Xu Jia , Hamid Aws , Flors Lucia , Cassani Joanne , Altes Talissa A. , Thomen Robert P. , Van Doren Steven R.
Published: September 2022

Cardiac magnetic resonance imaging (CMR) provides many cardiac functional insights. The reliance of standard cine CMR upon breath holds is not feasible for some patients. Its process of combining multiple heartbeats is unsuited to arrhythmias. Real-time cine methods sidestep these problems but can introduce respiratory displacement of the heart. To aid CMR acquisitions during breathing, we developed post-processing software to diminish the effects of respiratory displacement of the heart. It uses principal component analysis to resolve respiratory motions from cardiac cycles in the dynamic image. The software groups heartbeats from expiration and inspiration to decrease the appearance of respiratory motion. The effects of respiratory motion and such motion correction were evaluated on short-axis views (acquired with compressed sensing) of 11 healthy subjects and 8 cardiac patients. The smallest correlation coefficients between end-systolic frames of the original dynamic scans averaged 0.79. After segregation of cardiac cycles by respiratory phase, the mean correlation coefficients between cardiac cycles were 0.94 ± 0.03 at end-expiration and 0.90 ± 0.08 at end-inspiration. The improvements in correlation coefficients were significant in paired t-tests, i.e., P ≤ 0.01 for healthy subjects and P ≤ 0.001 for heart patients at end-expiration. Two expert cardiothoracic radiologists, blinded to the processing, assessed the dynamic images in terms of blood-myocardial contrast, endocardial interface definition, and motion artifacts. Clinical assessment preferred cardiac cycles during end-expiration, which maintained or enhanced scores in 90% of healthy subjects and 83% of the heart patients. Performance remained high in a case of arrhythmia and irregular breathing. Heartbeats collected from end-expiration reliably mitigated respiratory motion when the new software was applied to DICOM files from real-time acquisitions.
Effects of cardiovascular disease risk factors on cardiorespiratory fitness in firefighters – a protocol for a systematic review and meta-analysis
Authors: Ras Jaron , Soteriades Elpidoforos S. , Kengne Andre P. , Smith Denise , Leach Lloyd
Published: September 2022

Introduction

Globally, firefighting is recognized as among the most physically demanding professions. In addition, because of the hazardous nature of firefighting, firefighters are required to wear heavy insulated personnel protective equipment that protects them from exposures to hazardous chemicals and fumes and severe temperatures. This requires that, throughout their careers, firefighters maintain their cardiovascular health and maintain a satisfactory cardiovascular fitness to manage these stressors and perform their duties sufficient vigour. The aim of this systematic is to determine the effects of cardiovascular disease risk factors on cardiorespiratory fitness of firefighters.

Methods

Using the comprehensive search terms, a detailed literature search, with no limitation to publication year, will be conducted to identify relevant studies from PubMed/Medline, Web of Science, EBSCOHost, ScienceDirect and SCOPUS. Data-extraction will be extracted using a researcher-generated data extraction form. Data will be imported into Zotero® version 6.0.9, and duplicates removed. The article screening will be conducted using the Rayyan® intelligent systematic review tool. Thereafter, information from the included studies will be captured on the researcher-generated data extraction form. For the methodological assessment, the Appraisal Tool for Cross Sectional Studies (AXIS) checklist and the Critical Appraisal Skills Programme (CASP) toolkit will be used. For the meta-analysis, Review Manager 5.3 will be used to determine the exposure effects and MedCalc® statistical software Ltd. to determine the pooled correlation effects.

Discussion

This systematic review arose from the global cardiovascular health concerns that firefighters face, and how the development and progression of CVD risk factors effect cardiorespiratory fitness in firefighters. Cardiorespiratory has been shown to be an essential factor in optimal occupational performance in firefighters but understudied related to CVD risk factors. It is anticipated that this review will make a considerable contribution to the international scientific literature on the effect that CVD risk factors will have on cardiorespiratory fitness.

Systematic review protocol registration

PROSPERO (CRD42021258898)
Effectiveness of endurance training rehabilitation after hospitalisation in intensive care for COVID-19-related acute respiratory distress syndrome on dyspnoea (RECOVER): a randomised controlled, open-label multicentre trial
Authors: Romanet Christophe , Wormser Johan , Fels Audrey , Lucas Pauline , Prudat Camille , Sacco Emmanuelle , Bruel Cédric , Plantefève Gaëtan , Pene Frédéric , Chatellier Gilles , Philippart François
Published: September 2022

Background

COVID-19-related Acute Respiratory Distress Syndrome (CARDS) is the severe evolution of the Sars-Cov-2 infection leading to an intensive care unit (ICU) stay. Its onset is associated with “long-covid” including persisting respiratory disorders up to one year. Rehabilitation is suggested by most guidelines in the treatment of “long-covid”. As no randomised controlled trial did support its use in “long-covid” we aimed to evaluate the effects of endurance training rehabilitation (ETR) on dyspnoea in “long-covid” following CARDS.

Methods

In this multicentre, two-arm, parallel, open, assessor-blinded, randomised, controlled trial performed in three French ICU, we enrolled adults previously admitted for CARDS, discharged for at least three months and presenting an mMRC dyspnea scale score > 1. Eligible patients were randomly allocated (1:1) to receive either ETR or standard physiotherapy (SP), both for three months. Outcomes assessors were masked to treatment assignment. Primary outcome was dyspnoea’s evolution, measured by Multidimensional Dyspnea Profile (MDP) at inclusion and after 90 days.

Results

Between August 7, 2020 and January 26, 2022, 871 COVID-19 patients were screened, of whom 60 were randomly assigned to ETR (n=27) or SP (n=33). Mean MDP score after treatment was significantly lower in the ETR group than in the SP group (26.15 [SD 15.48] vs. 44.76 [SD 19.25]; mean difference -18.61 [95% CI -27.78 to -9.44]; p<0.0001).

Conclusion

CARDS patients suffering from breathlessness three months after discharge improved their dyspnoea significantly more when treated with ETR for three months rather than with SP.
Predictive value ofSLCO1B1c.521T>C polymorphism on observed changes in the treatment of 1136 statin-users
Authors: Jansen ME , Rigter T , Fleur TMC , Souverein PC , Verschuren WMM , Vijverberg SJ , Swen JJ , Rodenburg W , Cornel MC
Published: September 2022

Purpose

Pharmacogenomic testing is a method to prevent adverse drug reactions. Pharmacogenomics could be relevant to optimize statin treatment, by identifying patients at high risk for adverse drug reactions. We aim to investigate the clinical validity and utility of pre-emptive pharmacogenomics screening in primary care, withSLCO1B1c.521T>C as a risk factor for statin induced adverse drug reactions.

Methods

The focus was on changes in therapy as a proxy for adverse drug reactions observed in statin-users in a population-based Dutch cohort. In total 1136 statin users were retrospectively genotyped for theSLCO1B1c.521T>C polymorphism (rs4149056) and information on their statin dispensing was evaluated as a cross-sectional research.

Results

Approximately half of the included participants discontinued or switched their statin treatment within three years. In our analyses we could not confirm an association between theSLCO1B1c.521T>C genotype and any change in statin therapy or arriving at a stable dose sooner in primary care.

Conclusion

To be able to evaluate the predictive values ofSLCO1B1c.521T>C genotype on adverse drug reactions from statins, prospective data collection of actual adverse drug reactions and reasons to change statin treatment should be facilitated.
Buprenorphine treatment receipt characteristics and retention among people who inject drugs at Integrated Care Centers in India
Authors: Ganapathi Lakshmi , McFall Allison M. , Greco Kimberly F. , Srikrishnan Aylur , Mayer Kenneth H. , O’Cleirigh Conall , Mehta Shruti H. , Lucas Gregory M. , Solomon Sunil S.
Published: September 2022

Background

India is facing an alarming rise in the injection of opioids leading to burgeoning HIV epidemics among people who inject drugs (PWID) in several cities. Integrated Care Centers (ICCs) provide free single-venue HIV services and substance use treatment to PWID and have been established across 8 Indian cities. We evaluated engagement of PWID in buprenorphine treatment at ICCs to inform interventions.

Methods

We retrospectively analyzed 1-year follow-up data for PWID initiating buprenorphine between 1 January – 31 December 2018 across 7 ICCs. We used descriptive statistics to evaluate buprenorphine uptake, receipt frequency, treatment interruptions (no buprenorphine receipt for 60 consecutive days but with subsequent re-engagement in treatment), and treatment drop-out (no buprenorphine receipt for 60 consecutive days without subsequent re-engagement), and explore differences between historical opioid epidemic regions (i.e., Northeast cities (NEC)) and emerging opioid epidemic regions (i.e., North/Central/Northwest cities (NCC)). We used a multivariable logistic regression model to determine predictors of treatment drop-out by 6 months.

Results

1312 PWID initiated buprenorphine (76% NCC vs. 24% NEC). 31% of PWID in NCC, and 25% in NEC experienced ≥ 1 treatment interruption. About a third (34%) of PWID in NCC vs. half (50%) in NEC dropped-out by 6 months (p<0.0001). Over 6 months, 48% of PWID in NCC vs. 60% in NEC received buprenorphine ≤2 times/week on average (p<0.0001). In multivariable models, living in NEC was associated with increased odds of treatment drop-out while receipt of counseling was associated with decreased odds of treatment drop-out.

Conclusions

PWID at ICCs, particularly those in NEC have low buprenorphine receipt and retention. Patient-centered interventions adapted to regional contexts are urgently needed to ameliorate these gaps.
Insights into COVID-19 epidemiology and control from temporal changes in serial interval distributions in Hong Kong
Authors: Ali Sheikh Taslim , Chen Dongxuan , Lim Wey Wen , Yeung Amy , Adam Dillon C. , Lau Yiu Chung , Lau Eric H. Y. , Wong Jessica Y. , Xiao Jingyi , Ho Faith , Gao Huizhi , Wang Lin , Xu Xiao-Ke , Du Zhanwei , Wu Peng , Leung Gabriel M. , Cowling Benjamin J.
Published: September 2022

The serial interval distribution is used to approximate the generation time distribution, an essential parameter to predict the effective reproductive number “Rt”, a measure of transmissibility. However, serial interval distributions may change as an epidemic progresses rather than remaining constant. Here we show that serial intervals in Hong Kong varied over time, closely associated with the temporal variation in COVID-19 case profiles and public health and social measures that were implemented in response to surges in community transmission. Quantification of the variation over time in serial intervals led to improved estimation of Rt, and provided additional insights into the impact of public health measures on transmission of infections.

One-Sentence Summary

Real-time estimates of serial interval distributions can improve assessment of COVID-19 transmission dynamics and control.
Optimized Monophasic Pulses with Equivalent Electric Field for Rapid-Rate Transcranial Magnetic Stimulation
Authors: Wang Boshuo , Zhang Jinshui , Li Zhongxi , Grill Warren M. , Peterchev Angel V. , Goetz Stefan M.
Published: September 2022

Objective

Transcranial magnetic stimulation (TMS) with monophasic pulses achieves greater changes in neuronal excitability but requires higher energy and generates more coil heating than TMS with biphasic pulses, and this limits the use of monophasic pulses in rapid-rate protocols. We sought to design a stimulation waveform that retains the characteristics of monophasic TMS but significantly reduces coil heating, thereby enabling higher pulse rates and increased neuromodulation effectiveness.

Approach

A two-step optimization method was developed that uses the temporal relationship between the electric field (E-field) and coil current waveforms. The model-free optimization step reduced the ohmic losses of the coil current and constrained the error of the E-field waveform compared to a template monophasic pulse, with pulse duration as a second constraint. The second, amplitude adjustment step scaled the candidate waveforms based on simulated neural activation to account for differences in stimulation thresholds. The optimized waveforms were implemented to validate the changes in coil heating.

Main results

Depending on the pulse duration and E-field matching constraints, the optimized waveforms produced 12% to 75% less heating than the original monophasic pulse. The reduction in coil heating was robust across a range of neural models. The changes in the measured ohmic losses of the optimized pulses compared to the original pulse agreed with numeric predictions.

Significance

The first step of the optimization approach was independent of any potentially inaccurate or incorrect model and exhibited robust performance by avoiding the highly nonlinear behavior of neural responses, whereas neural simulations were only run once for amplitude scaling in the second step. This significantly reduced computational cost compared to iterative methods using large populations of candidate solutions and more importantly reduced the sensitivity to the choice of neural model. The reduced coil heating and power losses of the optimized pulses can enable rapid-rate monophasic TMS protocols.
Host network-based discovery of critical regulators of innate immunity, virus growth, and pathogenesis in influenza virus infection
Authors: Eisfeld Amie J. , Fan Shufang , Rao Hongyu , Venkatachalam Backiyalakshmi Ammayappan , Smith Danielle Westhoff , Halfmann Peter J. , Walters Kevin B. , Nair Sharmila , Thackray Larissa B. , Kocher Jacob F. , Sims Amy C. , Mitchell Hugh D. , Neumann Gabriele , Blank Volker , Waters Katrina M. , Baric Ralph S. , Diamond Michael S. , Kawaoka Yoshihiro
Published: September 2022

Innate immunity is protective against viruses, but also can facilitate pathological infection responses. Despite intensive research, our understanding of the mechanisms that regulate innate immunity in virus infection remains incomplete. Systems biology-based data-driven modeling approaches hold substantial promise toward discovery of crucial innate immune signaling regulators, yet model-derived predictions are almost completely unexplored. Here, we carried out systematic experimental validation of candidate regulators predicted by a transcriptional association network model of influenza virus-infected cells. We identified dozens of novel innate immune signaling regulators with potent effects on the replication of influenza and other viruses, and importantly, we established the biological relevance of a validated regulator in vivo. Collectively, these findings aid in clarifying mechanisms of influenza virus pathogenicity and might lead to innovative approaches for treating influenza virus disease. Similar data-driven modeling strategies may be applicable for the study of other pathogen systems or immunological disorders.
Mosquito invasion via the global shipping network is slowed in high-risk areas by on-shore and ship-board monitoring
Authors: Willoughby Janna R. , McKenzie Benjamin A. , Ahn Jordan , Steury Todd D. , Lepzcyk Christopher A. , Zohdy Sarah
Published: September 2022

The global shipping network (GSN) has been suggested as a pathway for the establishment and reintroduction of Aedes aegypti and Aedes albopictus primarily via the tire trade. We used historical maritime movement data in combination with an agent-based model to understand invasion risk in the United States Gulf Coast and how the risk of these invasions could be reduced. We found a strong correlation between the total number of cargo ship arrivals at each port and likelihood of arrival by both Ae. aegypti and Ae. albopictus. Additionally, in 2012, 99.2% of the arrivals into target ports had most recently visited ports occupied by both Ae. aegypti and Ae. albopictus, increasing risk of Aedes invasion. Model results indicated that detection and removal of mosquitoes from containers when they are unloaded at a port may be more effective in reducing the establishment of mosquito populations compared to eradication efforts that occur while onboard the vessel, suggesting detection efforts should be focused on unloaded containers. To reduce the risk of invasion and reintroduction of Ae. aegypti and Ae. albopictus, surveillance and control efforts should be employed when containers leave high risk locations and when they arrive in ports at high risk of establishment.
NBS-SNI, an extension of the Network-based statistic: Abnormal functional connections between important structural actors
Authors: Normand Francis , Gajwani Mehul , Côté Daniel C. , Allard Antoine
Published: September 2022

Elucidating the coupling between the structure and the function of the brain and its development across maturation has attracted a lot of interest in the field of network neuroscience in the last fifteen years. Mounting evidence support the hypothesis that the onset of certain brain disorders is linked with the interplay between the structural architecture of the brain and its functional processes, often accompanied with unusual connectivity features. This paper introduces a method called the Network-based statistic–simultaneous node investigation (NBS-SNI) that integrates both representations into a single framework, and identifies connectivity abnormalities in case-control studies. With this method, significance is given to the properties of the nodes, as well as to their connections. This approach builds on the well-established Network-based statistic (NBS) proposed in 2010. We uncover and identify the regimes in which NBS-SNI offers a gain in statistical resolution to identify a contrast of interest using synthetic data. We also apply our method on two real case-control studies, one consisting of individuals diagnosed with autism and the other consisting of individuals diagnosed with early-psychosis. Using NBS-SNI and node properties such as the closeness centrality and local information dimension, we found hypo and hyperconnected subnetworks and show that our method can offer a 9 percentage points gain in prediction power over the standard NBS.

AUTHOR SUMMARY

We propose an extension to the well-known Network-based statistic (NBS) dubbed NBS-SNI, where the extension SNI stands for simultaneous node investigation. The goal of this approach is to integrate nodal properties such as centrality measures into the statistical network-based framework of NBS to probe for abnormal connectivity between important nodes in case-control studies. We expose the regimes where NBS-SNI offers greater statistical resolution for identifying a contrast of interest using synthetic data and test the approach with a real autism-healthy dataset which contains both the structural (DTI) and functional (fMRI) brain networks of each individual. We also tested our approach on a second dataset of individuals diagnosed with early-psychosis. In the second case, our framework is supplemented by incorporating the anatomically derived measures of intrinsic curvature index and gray matter volume directly as a node property, rather than the structural networks, thereby illustrating the versatility of our approach.
Relictual Hybridization and Biogeography of Massasauga Rattlesnakes (Sistrurusspp.)
Authors: Martin Bradley T. , Douglas Marlis R. , Chafin Tyler K. , Placyk John S. , Mackessy Stephen P. , Briggler Jeffrey T. , Douglas Michael E.
Published: September 2022

Climate change inevitably leaves behind a genetic footprint within phylogeographic legacies of affected species, as individuals are driven to either disperse to track suitable conditions or adaptin situ. One potential consequence is the possibility of hybridization among species, as both geographic ranges and adaptive landscapes shift. The admixture resulting from these newly formed ‘contact zones’ has various outcomes, to include the creation of new lineages. Interpreting these within the context of historic climate change provides clues necessary to predict biotic responses (and thus evolutionary trajectories) as a function of contemporary shifts. Herein, we dissect historic contact zones for Massasaugas (Viperidae;Sistrurusspp.) within two distinct North American regions (southwestern United States and Central Great Plains) using ddRAD sequencing. We identified fine-scale but previously unrecognized population structure within the southwestern contact zone, where we detected contemporary intergradation between Prairie and Desert massasaugas (S. tergeminus tergeminus, andS. t. edwardsii,respectively), with primary divergence indicated by demographic model selection. Within the Central Great Plains, we found evidence for historic secondary contact via Quaternary climatic cycles, subsequently followed by range expansion at the suture zone separatingS. tergeminusandS. catenatus. Extant Missouri populations represent ancestral/relictual vestiges of this earlier hybridization, isolated between the eastern terminus ofS. t. tergeminusand the western edge ofS. catenatus. Our results illustrate how abrupt climate change has driven ancestral hybridization, cryptic diversity, and range dynamism withinSistrurus.
Can SARS-CoV-2 transmit from a dead body?
Authors: Iwatsuki-Horimoto Kiyoko , Ueki Hiroshi , Ito Mutsumi , Nagasawa Sayaka , Hirata Yuichiro , Hashizume Kenichiro , Ushiwata Kazuho , Iwase Hirotaro , Makino Yohsuke , Ushiku Tetsuo , Akitomi Shinji , Imai Masaki , Saitoh Hisako , Kawaoka Yoshihiro
Published: September 2022

Although it has been 2.5 years since the COVID-19 pandemic began, the transmissibility of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) from a dead infected body remains unclear, and often, in Japan bereaved family members are not allowed to view in-person a loved one who has died from COVID-19. In this study, we analyzed the possibility of SARS-CoV-2 transmission from a dead body by using the hamster model. We also analyzed the effect of Angel-care––in which the pharynx, nostril, and rectum are plugged––and embalming on reducing transmissibility from dead bodies. We found that SARS-CoV-2 could be transmitted from the body of animals that died within a few days of infection; however, Angel-care and embalming were effective in preventing transmission from the dead body. These results suggest that protection from infection is essential when in contact with a SARS-CoV-2-infected dead body, and that sealing the cavities of a dead body is an important infection control step if embalming is not done.

Importance

We found that SARS-CoV-2 could be transmitted from a dead body presumably via postmortem gases. However, we also found that postmortem care, such as plugging the pharynx, nostrils, and rectum, or embalming could prevent transmission from the dead body. These results indicate that protection from infection is essential when handling infected corpses, and that appropriate care of SARS-CoV-2-infected corpses is important.
Resting-state alterations in behavioral variant frontotemporal dementia are related to the distribution of monoamine and GABA neurotransmitter systems
Authors: Hahn Lisa , Eickhoff Simon B. , Mueller Karsten , Schilbach Leonhard , Barthel Henryk , Fassbender Klaus , Fliessbach Klaus , Kornhuber Johannes , Prudlo Johannes , Synofzik Matthis , Wiltfang Jens , Diehl-Schmid Janine , Otto Markus ,   FTLD consortium, Dukart Juergen , Schroeter Matthias L.
Published: September 2022

Aside to clinical changes, behavioral variant frontotemporal dementia (bvFTD) is characterized by progressive structural and functional alterations in frontal and temporal regions. We examined if there is a selective vulnerability of specific neurotransmitter systems in bvFTD by evaluating the link between disease-related functional alterations and the spatial distribution of specific neurotransmitter systems and their underlying gene expression levels.

Maps of fractional amplitude of low frequency fluctuations (fALFF) were derived as a measure of local activity from resting-state functional magnetic resonance imaging for 52 bvFTD patients (mean age = 61.5 ± 10.0 years; 14 female) and 22 healthy controls (HC) (mean age = 63.6 ± 11.9 years; 13 female). We tested if alterations of fALFF in patients co-localize with the non-pathological distribution of specific neurotransmitter systems and their coding mRNA gene expression. Further, we evaluated if the strength of co-localization is associated with the observed clinical symptoms.

Patients displayed significantly reduced fALFF in fronto-temporal and fronto-parietal regions. These alterations co-localized with the distribution of serotonin (5-HT1b, 5-HT2a), dopamine (D2), and γ-aminobutyric acid (GABAa) receptors, the norepinephrine transporter (NET), and their encoding mRNA gene expression. The strength of co-localization with D2 and NET was associated with cognitive symptoms and disease severity of bvFTD.

Local brain functional activity reductions in bvFTD followed the distribution of specific neurotransmitter systems indicating a selective vulnerability. These findings provide novel insight into the disease mechanisms underlying functional alterations. Our data-driven method opens the road to generate new hypotheses for pharmacological interventions in neurodegenerative diseases even beyond bvFTD.
A novel immunotherapy prognostic score for patients with pretreated advanced urinary tract carcinoma from the subgroup analysis of the SAUL study. The urInary TrAct CArcinoma score (ITACA)
Authors: Fornarini Giuseppe , Rebuzzi Sara Elena , Buti Sebastiano , Rescigno Pasquale , Merseburger Axel , de Giorgi Ugo , Basso Umberto , Maruzzo Marco , Giannatempo Patrizia , Ponzano Marta , Giunta Emilio Francesco , Catalano Fabio , Murianni Veronica , Damassi Alessandra , Cremante Malvina , Gandini Annalice , Puglisi Silvia , Obispo Miguel Angel Llaja , Signori Alessio , Banna Giuseppe Luigi
Published: September 2022

Background
The current prognostic models for patients with advanced urinary tract cancers were developed and validated in the chemotherapy setting. As immunotherapy has become the backbone of novel treatments, updated prognostic scores are needed.

Methods
A comprehensive analysis of inflammatory indexes from peripheral blood and clinical factors was planned on the entire real-world cohort of pretreated patients with advanced urinary tract carcinoma receiving atezolizumab in the prospective, single-arm, phase IIIb SAUL study. Univariable and multivariable analyses with overall survival as the primary endpoint, bootstrap internal validation, Schneeweiss scoring system and calibration test were performed to develop a novel immunotherapy prognostic score.

Results
Thirteen clinical variables from 1001 patients were analysed. The following eight prognostic factors were included in a model: ECOG PS, liver and bone metastases, histology, pre-treatment steroids, systemic immune-inflammatory index (i.e., neutrophils-to-lymphocytes ratio times platelets count), haemoglobin and lactate dehydrogenase.

The prognostic model was able to stratify patients into five risk groups with significantly different (p < 0.001) median overall survival of NR, 18.0, 8.7, 4.6 and 2.4 months, respectively. The c-index for OS was higher than the Bellmunt score one (0.702 vs 0.672).

Conclusions
A novel 5-class prognostic model contemporary to immunotherapy provides robust prognostic discrimination of patients with advanced urinary tract carcinoma homogeneously treated with immunotherapy through baseline affordable and reproducible clinical and laboratory factors. It couls be quickly adopted in clinical practice to inform patients about prognosis with immunotherapy and assess the benefit of novel immunotherapy combinations in clinical trials.
Quantitative Mass Spectrometry Analysis of Cerebrospinal Fluid Protein Biomarkers in Alzheimer’s Disease
Authors: Watson Caroline M. , Dammer Eric B. , Ping Lingyan , Duong Duc M. , Modeste Erica , Carter E. Kathleen , Johnson Erik C. B. , Levey Allan I. , Lah James J. , Roberts Blaine R. , Seyfried Nicholas T.
Published: September 2022

Alzheimer’s disease (AD) is the most common form of dementia, with cerebrospinal fluid (CSF) β-amyloid (Aβ), total Tau, and phosphorylated Tau providing the most sensitive and specific biomarkers for diagnosis. However, these diagnostic biomarkers do not reflect the complex changes in AD brain beyond amyloid (A) and Tau (T) pathologies. Here, we report a selected reaction monitoring mass spectrometry (SRM-MS) method with isotopically labeled standards for relative protein quantification in CSF. Biomarker positive (AT+) and negative (AT-) CSF pools were used as quality controls (QCs) to assess assay precision. We detected 62 peptides (51 proteins) with an average CV of ∼13% across 30 QCs and 133 controls (cognitively normal, AT), 127 asymptomatic (cognitively normal, AT+) and 130 symptomatic AD (cognitively impaired, AT+). Proteins that could distinguish AT+ from AT-individuals included SMOC1, GDA, 14-3-3 proteins, and those involved in glycolysis. Proteins that could distinguish cognitive impairment were mainly neuronal proteins (VGF, NPTX2, NPTXR, and SCG2). This demonstrates the utility of SRM-MS to quantify CSF protein biomarkers across stages of AD.
Early-life exposure to persistent organic pollutants, gut microbiota diversity and metabolites, and respiratory health in Norwegian children
Authors: Lenters Virissa , Portengen Lützen , Eggesbø Merete , Vermeulen Roel
Published: September 2022

Background

Evidence suggests that early-life exposure to certain environmental chemicals increases the risk of allergic diseases, while gut microbiota diversity and microbiota-derived short-chain fatty acid (SCFA) metabolites may be protective.

Objectives

We assessed associations between persistent organic pollutants (POPs), microbial markers, and subsequent risk of asthma and lower respiratory tract infection (LRTI).

Methods

We studied a Norwegian birth cohort (HUMIS). Twenty-six POPs [polychlorinated biphenyls (PCBs), polybrominated diphenyl ethers (PBDEs), perfluoroalkyl substances (PFASs), and organochlorine pesticides (OCPs)] were quantified in maternal breastmilk (n=993). Shannon diversity and SCFAs were assessed at multiple time points before 2 years of age in a subset of children. We evaluated registry-based diagnosis of asthma when children were a median age of 10 years, along with maternal-reported asthma and LRTI by 2 years of age.

Results

∑14PCBs was associated with decreased odds and ∑4OCPs with increased odds of asthma; associations between β-HCH (OR=2.99 per 2-SD increase; 95% CI: 1.66, 5.43) and PCB-138 (OR=0.43; 95% CI: 0.20, 0.91) and asthma by age 10 years were most robust. PBDEs and PFASs were not consistently associated with asthma and no POPs were associated with LRTI. There were both inverse and positive associations between diversity and respiratory outcomes, and generally imprecise associations for SCFAs. There was limited evidence that POP exposures perturbed diversity or production of SCFAs, except for an association between ∑14PCBs and reduced diversity at 2 years, and there was no clear evidence of mediation effects.

Conclusions

This study provides support for associations between some POPs and risk of childhood asthma, and indications of a potential independent role of gut microbiota.
Circulating B Cells in Relapsing-Remitting Multiple Sclerosis Show Markedly Different Patterns of Regulatory Marker Expression Compared with Healthy Controls
Authors: Mielcarz Daniel W. , Bergeron Alan J. , DeLong John K. , Dias Alexandra , Smith Kathleen M. , Mack Karen L. , Kasper Lloyd H. , Channon Jacqueline Y.
Published: September 2022

Recent evidence has shown that B cells may play a key role in the pathogenesis of relapsing-remitting multiple sclerosis. Studies in our laboratory have shown a difference in the production of IL-6 and IL-10 by B cells isolated from RRMS patients compared with healthy controls. In order to further characterize the nature of the B cells in RRMS patients, we analyzed samples from patients on no disease modifying treatment for B cell expression of multiple phenotypic and regulatory markers. We observed an increased frequency in the number of circulating B cells, an increase in B1 B cells and a decrease in memory B cells in RRMS patients. These B1 cells showed a significantly higher frequency of CD5 expression and the memory B cells a significant increase in the class-switched IgD-phenotype. We also examined death receptors involved in apoptotic pathways. CD95 frequency was significantly lower in RRMS patients tan healthy controls in all B cell subsets. Conversely, frequency of PD-1 was elevated in both the naïve and memory B cell subsets, and PD-L1 was elevated in B1 cells from RRMS patients. Finally, we examined a series of immunoreceptor tyrosine-based inhibition motif (ITIM)-containing inhibitory receptors, including members of the SIGLEC family. Significantly higher levels of CD22, CD305 and CD307d were seen in RRMS patients, while significantly lower levels of SIGLEC-10 were observed. Taken together, these results indicate a potential for differential regulation of B cells in RRMS patients that may provide an avenue for B cell directed therapies for the disease.
Glycemic challenge is associated with the rapid cellular activation of the locus ceruleus and nucleus of solitary tract: Circumscribed spatial analysis of phosphorylated MAP kinase immunoreactivity
Authors: Tapia Geronimo P. , Agostinelli Lindsay J. , Chenausky Sarah D. , Salcido Padilla Jessica V. , Navarro Vanessa I. , Alagh Amy , Si Gabriel , Thompson Richard H. , Balivada Sivasai , Khan Arshad M.
Published: September 2022

Rodent studies indicate that impaired glucose utilization or hypoglycemia is associated with cellular activation of neurons in themedulla(Winslow, 1733) (MY) believed to control feeding behavior and glucose counterregulation. However, such activation has been tracked primarily within hours of the challenge, rather than sooner, and has been poorly mapped within standardized brain atlases. Here, we report that within 15 min of receiving 2-deoxy-D-glucose (2-DG; 250 mg/kg, i.v.), which can trigger glucoprivic feeding behavior, marked elevations were observed in the numbers ofrhombic brain(His, 1893) (RB) neuronal cell profiles immunoreactive for the cellular activation marker(s), phosphorylated p44/42 MAP kinases (phospho-ERK1/2), some of which were also catecholaminergic. We mapped their distributions within an open-access rat brain atlas and found that 2-DG-treated rats (compared to their saline-treated controls) displayed greater numbers of phospho-ERK1/2+neurons in thelocus ceruleus(Wenzel & Wenzel, 1812) (LC) and thenucleus of solitary tract (>1840)(NTS). Thus, 2-DG-activation of certain RB neurons is more rapid than perhaps previously realized, engaging neurons that serve multiple functional systems and are of varying cellular phenotypes. Mapping these populations within standardized brain atlas maps streamlines their targeting and/or comparable mapping in preclinical rodent models of disease.
Dynamic Adaptation of Default Mode Network in Resting state and Autobiographical Episodic Memory Retrieval State
Authors: Jeong Garam , Paolini Marco
Published: September 2022

The default mode network is a brain network processing mental states featuring an internal representation of subjective experiences like autobiographical episodic memory retrieval and a resting state. If the default mode network is the common spatial domain processing such mental states, then the temporal domain might present the differences in the mental states. To detect adaptations in dynamics of a single brain network dependent on the mental states it processes, we suggested a novel analysis method called one-to-many dynamic functional connectivity analysis for fMRI. The analysis method assesses the variance in the partial correlations of a center that are time-windowed functional correlations of a brain region (a center) to the rest of the regions in a brain network, then compares the similarities in the directions of their major variance from the same or distinct mental states. We applied one-to-many dynamic functional connectivity analysis to the default mode network and measured the similarity between the major variances of the partial correlations from three autobiographical episodic memory retrieval states and a resting state. If the major direction of the variance is a configuration presenting the mental states of the brain network, we expect to see the high similarity for the same mental states and less similarity for the distinct mental states. To test our hypothesis with the new analysis method, we chose a single subject who is a late blind with advanced mental imagery ability. The results showed that the dynamic adaption in the default mode network in the two mental states could be well depicted when the posterior cingulate cortex is the center in this single case. Furthermore, we could observe that the weight of the correlation between the posterior cingulate cortex and the right parahippocampal cortex varied mostly and therefore its contribution to the dynamic adaptation was relatively higher than the other correlations.