bluuebunny/crossref_metadata_2025 huggingface dataset:
Severe Upper Lid Fornix Prolapse After a Ptosis Repair in Floppy Eyelid Syndrome
Authors: Radulovich Nicholas P. , Michels Kevin S.
Published: October 2023

Patients with profound floppy eyelid syndrome (FES) may experience challenges achieving eyelid and tarsal stability in the setting of severe ptosis. A 43-year-old woman with sleep apnea presented to clinic with difficulties driving because of droopy eyelids. She also experienced chronic tearing, crusting, and discharge of the eyes. She was diagnosed with severe FES and significant ptosis. She underwent a wedge excision of the upper lid in the medial and lateral aspect of the upper lid. This was followed by a ptosis repair that resulted in complete upper lid fornix obliteration causing the conjunctiva to obstruct the patient's pupils. The patient's symptoms ultimately improved after a definitive fornix reconstruction. Her visual field symptoms were improved with 1-year follow-up. To our knowledge, this is the first report in the literature of a prolapsed fornix resulting in vision obstruction after floppy eyelid repair via a wedge excision followed by a ptosis repair via an external levator advancement. Given these unusual findings for the patient's age, further investigations into treatment management may be necessary to mitigate eyelid reconstruction complications in younger patients with FES.
Technical and Clinical Differences Between Transgender and Cisgender Females Undergoing Breast Augmentation
Authors: Torres Perez-Iglesias Carolina A. , Heyman Annie , Koh Daniel J. , Medina Nilton , Roh Daniel S. , Slama Jaromir
Published: October 2023

Background

Gender-affirming surgery is a quickly expanding field. However, it is facing a shortage of specialized surgeons for a population exceeding 1.4 million individuals. Many studies comparing outcomes between cisgender and transgender patients fail to describe the technical differences of the operation. Breast augmentation in the transgender female patient involves important anatomical, technical, and clinical features that differ from the cisgender female. In this study, we aimed to describe and compare these characteristics between these 2 groups to better inform the new generation of gender-affirming surgeons.

Methods

A retrospective cohort study of patients who underwent primary breast augmentation between 2009 and 2019 at a specialized tertiary center for transgender care was performed. Mastopexy, secondary augmentation, and reconstructive procedures were excluded. Demographic, operative, and clinical data were collected from medical records. All patients had a minimum of 1 year of follow-up after the initial surgery. Bivariate analysis was performed.

Results

A total of 250 cisgender females and 153 transgender females were included. The transgender group showed higher rates of smoking (P < 0.0001), immunosuppression (P < 0.0001), obesity (P < 0.0001), mental health disorders (P < 0.0001), and hypertension (P = 0.002). Median base width (P < 0.0001), sternal notch to nipple distance (P < 0.0001), and implant size (500 mL [interquartile range, 425–600 mL] vs 350 mL [interquartile range, 325–385 mL]; P < 0.0001) were larger in transgender patients. Transgender patients also demonstrated a stronger correlation between implant size and body surface area (r = 0.71, P < 0.0001). Readmission, reoperation, and complication rates were similar between the groups; however, transgender females had a higher incidence of surgical site infections (3.9% vs 0.4%, P < 0.013). Capsular contracture was the most common complication and indication for reoperation in both groups.

Conclusions

There are important anatomical, clinical, and technical differences between reconstructive gender-affirming breast augmentation in transgender female patients and cosmetic breast augmentation in the cisgender female. The gender-affirming surgeon must know these differences to provide the best quality of care and help patients achieve better congruence between their gender identity and body image.
Effects of virtual reality working memory task difficulty on the passive processing of irrelevant auditory stimuli
Authors: Kamal Farooq , Segado Melanie , Shaigetz Vincent Gagnon , Perron Maxime , Lau Brian , Alain Claude , Choudhury Nusrat
Published: October 2023

The virtual reality (VR) environment is claimed to be highly immersive. Participants may thus be potentially unaware of their real, external world. The present study presented irrelevant auditory stimuli while participants were engaged in an easy or difficult visual working memory (WM) task within the VR environment. The difficult WM task should be immersive and require many cognitive resources, thus few will be available for the processing of task-irrelevant auditory stimuli. Sixteen young adults wore a 3D head-mounted VR device. In the easy WM task, the stimuli were nameable objects. In the difficult WM task, the stimuli were abstract objects that could not be easily named. A novel paradigm using event-related potentials (ERPs) was implemented to examine the feasibility of quantifying the extent of processing of task-irrelevant stimuli occurring outside of the VR environment. Auditory stimuli irrelevant to the WM task were presented concurrently at every 1.5 or 12 s in separate conditions. Performance on the WM task varied with task difficulty, with accuracy significantly lower during the difficult task. The auditory ERPs consisted of N1 and a later P2/P3a deflection which were larger when the auditory stimuli were presented slowly. ERPs were unaffected by task difficulty, but significant correlations were found. N1 and P2/P3a amplitudes were smallest when performance on the Easy WM task was highest. It is possible that even the easy WM task was so immersive and required many processing resources that few were available for the co-processing of the task-irrelevant auditory stimuli.
Efficacy and safety of clozapine in treatment-resistant psychotic patients with DiGeorge syndrome (22q11.2 deletion syndrome): a case series
Authors: Berardelli Isabella , Cifrodelli Mariarosaria , Giuliani Carlotta , Antonelli Giulia , Putotto Carolina , Pulvirenti Federica , Pompili Maurizio
Published: October 2023

Neuropsychiatric disorders are common manifestations in 22q11.2 deletion syndrome (22q11.2DS-DiGeorge Syndrome). Although many patients with 22q11.2DS receive antipsychotic treatment for psychotic disorders, little is known about the safety and tolerability of antipsychotics in 22q11.2DS and resistant psychosis. The aim of this case series is to describe the effectiveness as well as safety and tolerability profile coming from the real-world observation of three clinical cases affected by 22q11.2DS and treatment-resistant psychosis. We administered the following tests: the Columbia Suicide Severity Rating Scale, the Hamilton Rating Scale for Anxiety, the Positive and Negative Severity Scale, the Clinical Global Impression-Severity Scale, the Yale-Brown Obsessive-Compulsive Scale, the Beck Depression Inventory and the Beck Hopelessness Scale. All these questionnaires were administered at the first visit (T0), and then 3 (T1) 6 (T2) and 12 months after (T3). We observed a clinical improvement that remained stable at 12 months. Furthermore, in our patients, the clinical effectiveness was achieved with a very low dose of clozapine (<150 mg/day) concerning the standard dose used in idiopathic schizophrenia (>300 mg/day to 600 mg/day).
Integrating large-scale meta-GWAS and PigGTEx resources to decipher the genetic basis of complex traits in pig
Authors: Xu Zhiting , Lin Qing , Cai Xiaodian , Zhong Zhanming , Li Bingjie , Teng Jinyan , Zeng Haonan , Gao Yahui , Cai Zexi , Wang Xiaoqing , Shi Liangyu , Wang Xue , Wang Yi , Zhang Zipeng , Lin Yu , Liu Shuli , Yin Hongwei , Bai Zhonghao , Wei Chen , Zhou Jun , Zhang Wenjing , Zhang Xiaoke , Shi Shaolei , Wu Jun , Diao Shuqi , Liu Yuqiang , Pan Xiangchun , Feng Xueyan , Liu Ruiqi , Su Zhanqin , Chang Chengjie , Zhu Qianghui , Wu Yuwei ,   The PigGTEx Consortium, Zhou Zhongyin , Bai Lijing , Li Kui , Wang Qishan , Pan Yuchun , Xu Zhong , Peng Xianwen , Mei Shuqi , Mo Delin , Liu Xiaohong , Zhang Hao , Yuan Xiaolong , Liu Yang , Liu George E. , Su Guosheng , Sahana Goutam , Lund Mogens Sandø , Ma Li , Xiang Ruidong , Shen Xia , Li Pinghua , Huang Ruihuang , Ballester Maria , Crespo-Piazuelo Daniel , Amills Marcel , Clop Alex , Karlskov-Mortensen Peter , Fredholm Merete , Tang Guoqing , Li Mingzhou , Li Xuewei , Ding Xiangdong , Li Jiaqi , Chen Yaosheng , Zhang Qin , Zhao Yunxiang , Zhao Fuping , Fang Lingzhao , Zhang Zhe
Published: October 2023

Understanding the molecular and cellular mechanisms that underlie complex traits in pigs is crucial for enhancing their genetic improvement program and unleashing their substantial potentials in human biomedicine research. Here, we conducted a meta-GWAS analysis for 232 complex traits with 28.3 million imputed whole-genome sequence variants in 70,328 individuals from 14 pig breeds. We identified a total of 6,878 genomic regions associated with 139 complex traits. By integrating with the Pig Genotype-Tissue Expression (PigGTEx) resource, we systemically explored the biological context and regulatory circuits through which these trait-associated variants act and finally prioritized 16,664 variant-gene-tissue-trait circuits. For instance, rs344053754 regulates the expression ofUGT2B31in the liver by affecting the activity of regulatory elements and ultimately influences litter weight at weaning. Furthermore, we investigated the conservation of genetic and regulatory mechanisms underlying 136 human traits and 232 pig traits. Overall, our multi-breed meta-GWAS in pigs provides invaluable resources and novel insights for understanding the regulatory and evolutionary mechanisms of complex traits in both pigs and humans.
Double-strand break repair-associated intragenic deletions and tandem duplications suggest the architecture of the repair replication fork
Authors: Dalin Simona , Webster Sophie , Sugawara Neal , Zhang Shu , Wu Qiuqin , Cui Tracy , Liang Victoria , Beroukhim Rameen , Haber James E.
Published: October 2023

Double-strand break (DSB) repair is associated with a 1000-fold increase in mutations compared to normal replication of the same sequences. In budding yeast, repair of an HO endonuclease-induced DSB at theMATα locus can be repaired by using a homologous, heterochromaticHMR::Kl-URA3donor harboring a transcriptionally silencedURA3gene, resulting in aMAT::URA3(Ura+) repair product whereURA3is expressed. Repair-associatedura3-mutations can be selected by resistance to 5-fluoroorotic acid (FOA). Using this system, we find that a major class of mutations are -1 deletions, almost always in homonucleotide runs, but there are few +1 insertions. In contrast, +1 and -1 insertions in homonucleotide runs are nearly equal among spontaneous mutations. Approximately 10% of repair-associated mutations are interchromosomal template switches (ICTS), even though theK. lactis URA3sequence embedded inHMRis only 72% identical withS. cerevisiae ura3-52sequences on a different chromosome. ICTS events begin and end in regions of short microhomology, averaging 7 bp. Long microhomologies are favored, but some ICTS junctions are as short as 2 bp. Both repair-associated intragenic deletions (IDs) and tandem duplications (TDs) are recovered, with junctions sharing short stretches of, on average, 6 bp of microhomology. Intragenic deletions are more than 5 times more frequent than TDs. IDs have a mean length of 60 bp, but, surprisingly there are almost no deletions shorter than 25 bp. In contrast, TDs average only 12 bp. The usage of microhomologies among intragenic deletions is not strongly influenced by the degree of adjacent homeology. Together, these data provide a picture of the structure of the repair replication fork. We suggest that IDs and TDs occur within the migrating D-loop in which DNA polymerase δ copies the template, where the 3’ end of a partly copied new DNA strand can dissociate and anneal with a single-stranded region of microhomology that lies either in front or behind the 3’ end, within the open structure of a migrating D-loop. Our data suggest that ∼100 bp ahead of the polymerase is “open,” but that part of the repair replication apparatus remains bound in the 25 bp ahead of the newly copied DNA, preventing annealing. In contrast, the template region behind the polymerase appears to be rapidly reannealed, limiting template switching to a very short region.
CUDASW++4.0: Ultra-fast GPU-based Smith-Waterman Protein Sequence Database Search
Authors: Schmidt Bertil , Kallenborn Felix , Chacon Alejandro , Hundt Christian
Published: October 2023

Background

The maximal sensitivity for local pairwise alignment makes the Smith-Waterman algorithm a popular choice for protein sequence database search. However, its quadratic time complexity makes it compute-intensive. Unfortunately, current state-of-the-art software tools are not able to leverage the massively parallel processing capabilities of modern GPUs with close-to-peak performance. This motivates the need for more efficient implementations.

Results

CUDASW++4.0 is a fast software tool for scanning protein sequence databases with the Smith-Waterman algorithm on CUDA-enabled GPUs. Our approach achieves high efficiency for dynamic programming-based alignment computation by minimizing memory accesses and instructions. We provide both efficient matrix tiling, and sequence database partitioning schemes, and exploit next generation floating point arithmetic and novel DPX instructions. This leads to close-to-peak performance on modern GPU generations (Ampere, Ada, Hopper) with throughput rates of up to 1.94 TCUPS, 5.01 TCUPS, 5.71 TCUPS on an A100, L40S, and H100, respectively. Evaluation on the Swiss-Prot, UniRef50, and TrEMBL databases shows that CUDASW++4.0 gains over an order-of-magnitude performance improvements over previous GPU-based approaches (CUDASW++3.0, ADEPT). In addition, our algorithm demonstrates significant speedups over top-performing CPU-based tools (BLASTP, SWIPE, SWIMM2.0), can exploit multi-GPU nodes with linear scaling, and features an impressive energy efficiency of up to 15.7 GCUPS/Watt.

Conclusion

CUDASW++4.0 changes the standing of GPUs in protein sequence database search with Smith-Waterman alignment by providing close-to-peak performance on modern GPUs. It is freely available athttps://github.com/asbschmidt/CUDASW4.
Enhancing Disease Risk Gene Discovery by Integrating Transcription Factor-Linked Trans-located Variants into Transcriptome-Wide Association Analyses
Authors: He Jingni , Perera Deshan , Wen Wanqing , Ping Jie , Li Qing , Lyu Linshuoshuo , Chen Zhishan , Shu Xiang , Long Jirong , Cai Qiuyin , Shu Xiao-Ou , Zheng Wei , Long Quan , Guo Xingyi
Published: October 2023

Transcriptome-wide association studies (TWAS) have been successful in identifying disease susceptibility genes by integrating cis-variants predicted gene expression with genome-wide association studies (GWAS) data. However, trans-located variants for predicting gene expression remain largely unexplored. Here, we introduce transTF-TWAS, which incorporates transcription factor (TF)-linked trans-located variants to enhance model building. Using data from the Genotype-Tissue Expression project, we predict gene expression and alternative splicing and applied these models to large GWAS datasets for breast, prostate, and lung cancers. We demonstrate that transTF-TWAS outperforms other existing TWAS approaches in both constructing gene prediction models and identifying disease-associated genes, as evidenced by simulations and real data analysis. Our transTF-TWAS approach significantly contributes to the discovery of disease risk genes. Findings from this study have shed new light on several genetically driven key regulators and their associated regulatory networks underlying disease susceptibility.
Limited overlap between genetic effects on disease susceptibility and disease survival
Authors: Yang Zhiyu , Pajuste Fanny-Dhelia , Zguro Kristina , Cheng Yipeng , Kurant Danielle E. , Eoli Andrea , Wanner Julian , Jermy Bradley ,   FinnGen,   Estonian Biobank research team, Kanoni Stavroula , van Heel David A. ,   Genes & Health Research Team, Hayward Caroline , Marioni Riccardo E , McCartney Daniel L. , Renieri Alessandra , Furini Simone ,   Genomics England Research Consortium, Mägi Reedik , Gusev Alexander , Drineas Petros , Paschou Peristera , Heyne Henrike , Ripatti Samuli , Mars Nina , Ganna Andrea
Published: October 2023

Understanding disease progression is of a high biological and clinical interest. Unlike disease susceptibility whose genetic basis has been abundantly studied, less is known about the genetics of disease progression and its overlap with disease susceptibility. Considering ten common diseases (N cases ranging from 17,152 to 99,666) across seven biobanks, we systematically compared the genetic architecture of susceptibility and progression, defined as disease-specific mortality. We identified only one locus significantly associated with disease-specific mortality and show that, at a similar sample size, more genome-wide significant loci can be identified in a GWAS of disease susceptibility. Variants that were significantly affecting disease susceptibility were weakly or not associated with disease-specific mortality. Moreover, susceptibility polygenic scores (PGSs) were weak predictor of disease-specific mortality while a PGS for general lifespan was significantly associated with disease-specific mortality for five out of ten diseases. We used theoretical derivation and simulation to propose plausible explanations for our empirical observations and account for potential index-event bias. Overall, our findings point to little similarity in genetic effects between disease susceptibility and disease-specific mortality and suggest that either larger sample sizes or different measures of progression are needed to identify the genetic underpinning of disease progression.
People who identify as trans, non-binary or gender diverse can experience inclusive, culturally sensitive physical therapy while attending a gender-affirming clinic: qualitative study
Authors: Aird Madelaine , Walters Julie L , Ker Alex , Ross Megan H
Published: October 2023

Objective

To explore physical therapy experiences and identify barriers and facilitators of access to physical therapy for people who identify as trans, non-binary, or gender diverse (TGD).

Methods

A qualitative descriptive design was employed using semi-structured interviews conducted in New Zealand. Participants were individuals aged 12 years or older, who self-identified as TGD, and had accessed physical therapy at a New Zealand clinic that provided a gender-affirming service. Participants were recruited via email invitation to the clinic database. Interview data were analysed using reflexive thematic analysis.

Demographics are reported descriptively.

Results

Seventeen individuals participated. Four themes identified during analysis. Barriers to and facilitators of care were identified at policy, environmental, clinic and therapist levels. All participants reported physical therapy experiences relating to one or more of the following themes:challenging cisnormativityat policy, environmental, clinic and therapist levels;safety and trustthroughout the clinical experience-including clinic credibility for being a safe provider, clinic displays of TGD-inclusivity, implementation of safe clinic processes, and respectful therapist interactions;inclusive experiencesin a clinic which provided affordable care and took active steps to understand and affirm TGD identities, and physical therapists with a high level of knowledge of TGD-specific health issues and a biopsychosocial approach to care; and sensitivity tobody discomfort or dysphoriatriggers.

Conclusions

People who identify as TGD face challenges to accessing safe and culturally sensitive physical therapy. However, there are achievable areas for improvement at policy, environmental, clinic and physical therapist level to gain trust and engagement in care for the TGD-community.

Impact Statement

This study provides nuanced exploration of TGD physical therapy experiences and identifies specific areas of improvement for TGD physical therapy care to provide clinicians and physical therapy clinics insights into the provision of safe and culturally sensitive physical therapy.
Availability of Essential Medicines During the COVID-19 Pandemic: A Qualitative Study Examining Experiences and Level of Preparedness in Kenya
Authors: Onyango Joseph Odhiambo , Ogira Dosila , Kokwaro Gilbert
Published: October 2023

This study investigated the impact of the COVID-19 pandemic on essential medicine availability in Kenya’s health system. Key informant interviews were conducted, and the data were analyzed using NVIVO software. Six themes emerged, aligning with the WHO health system building blocks. These themes provided insights into the experiences, challenges, and opportunities regarding essential medicine availability during the pandemic. The initial response involved reallocating resources, affecting the procurement of essential medicines at national and county levels. To enhance preparedness, investments are crucial in strengthening financial systems and policies, improving supply chain resilience, and promoting local production through regulatory enhancements. These strategies aim to build resilient health systems and self-reliance, particularly for countries transitioning from donor aid. The findings underscore the importance of effective preparedness to ensure the availability of essential medicines during emergencies like the COVID-19 pandemic
Cohort Profile: ReCoDID Consortium’s Harmonized Acute Febrile Illness Arbovirus Meta-Cohort
Authors: Gómez Gustavo , Hufstedler Heather , Montenegro Carlos , Roell Yannik , Lozano Anyela , Tami Adriana , Magalhaes Tereza , Marques Ernesto T.A. , Balmaseda Angel , Calvet Guilherme , Harris Eva , Brasil Patricia , Herrera Victor , Villar Luis , Maxwell Lauren , Jaenisch Thomas ,   ReCoDID Arbovirus harmonization study group
Published: October 2023

Infectious disease (ID) cohorts are key to advancing public health surveillance, public policies and pandemic responses. Unfortunately, ID cohorts often lack funding to store and share clinical-epidemiological data (CE) and high-dimensional laboratory (HDL) data long-term, which is evident when the link between these data elements is not kept up to date. This becomes particularly apparent when smaller cohorts fail to successfully address the initial scientific objectives due to limited case numbers, which also limits the potential of pooling for these studies to monitor long-term cross-disease interactions within and across populations. To facilitate advancements in cross-population inference and reuse of cohort data, the European Commission (EC) and the Canadian Institutes of Health Research, Institute of Genetics (CIHR-IG) funded the ReCoDID (Reconciliation of Cohort Data for Infectious Diseases) Consortium to store and share harmonized and standardized CE and HDL data on a federated platform and also provide innovative statistical tools to conduct meta-analyses of the individual patient data. Here we describe the harmonization of CE data from nine arbovirus (arthropod-borne viruses) cohorts in Latin America, which serve as a starting point for the ReCoDID meta-cohort. CE data was retrospectively harmonized using Maelstrom’s methodology and standardized to Clinical Data Interchange Standards Consortium (CDISC).

This meta-cohort will facilitate various joint research projects, e.g., on immunological interactions between sequential flavivirus infections and for the evaluation of potential biomarkers for severe arboviral disease.
USe of Diagnostic sUbtraction angiography in The isCHemic stroke setting (US DUTCH study)
Authors: Mulder Maxim J.H.L. , Dippel Diederik W.J. , Burke James
Published: October 2023

Introduction

There are no recommendations for DSA in the ischemic stroke work-up according to current guidelines. We studied the rate of DSA in ischemic stroke, the recent time-trend (given the recent rapid increase in mechanical thrombectomy), hospital variation and associated factors.

Methods

This is a retrospective cross-sectional study among Medicare fee-for-service beneficiaries with ischemic stroke admitted between 2016 and 2020 in the United States. ICD-10 codes were used to determine ischemic stroke diagnosis and procedure codes for thrombectomy and DSA. Hospital trends and factors associated with DSA performance were analyzed in hospitals with DSA capacity.

Results

7.373 (0.7%) of the 1,085,644 ischemic stroke patients, had a DSA for diagnostic purposes. In the patients that were admitted to a hospital with DSA facility, the following factors showed the strongest association with DSA: younger age (aOR=0.81 [95% confidence interval (CI):0.81-0.83]), thrombectomy rate in that hospital (aOR=2549 [95%CI:610-10663]), transfer (aOR=1.41[95%CI:1.34-1.50]) and carotid disease (aOR=5.8 [95%CI:5.6-6.1]). There was large variation in the hospital DSA rate, varying from 0.07% to 11.1%. Of the variance of DSA rates, 15% was attributed to the residual effect hospital propensity to perform DSA. The top decile of hospitals with the highest DSA rate, performed DSA’s in >2.3% of patients, compared to the 0.6% median. There was no change in DSA rates over time.

Conclusion

DSA is used infrequently in acute ischemic stroke patients and did not change between 2016 to 2020. Hospital variation in DSA use was however large, and not solely explained by patient and facility factors.
An interactive cellular ecosystem blocks epithelial transformation in naked mole-rat
Authors: Behm Mikaela , Baeza Centurión Pablo , Penso-Dolfin Luca , Botey Bataller Francisco Javier , Hirschmüller Nick , Delaunay Sylvain , Koch Marie-Luise , Del Prete Stefania , Sohn Daniela , Reifenberg Celine , Schopp Meike , Lammers Fritjof , Solé-Boldo Llorenç , Dutton Jeleana , Begall Sabine , Khaled Walid T. , Smith Ewan St. J. , Odom Duncan T. , Frye Michaela , Goncalves Angela
Published: October 2023

The mechanisms underlying cancer resistance in long-lived organisms are largely unexplored. Here, we report how naked mole-rats (Heterocephalus glaber) resist tumorigenesis when exposed to potent skin carcinogens. Single-cell transcriptional analysis of homeostatic full-thickness naked mole-rat skin revealed higher epidermal turn-over, a distinct composition of dermal extracellular matrix (ECM) and fewer resident T-cells, when compared to mouse and human. Carcinogenic treatment of skin generated the expected mutational landscape, but unlike in the mouse, failed to stimulate T-cells or generate tumours. Instead, naked mole-rat accelerated epidermal turnover to shed mutant cells. At the same time, the ECM was extensively remodelled via enhanced anti-inflammatory communication among fibroblasts and between fibroblasts and epidermal cells, creating a tumour-suppressive microenvironment. We demonstrate that, in contrast to mouse, naked mole-rat dermal fibroblasts lack intrinsic tumour-promoting capabilitiesin vitroandin vivo. Our results demonstrate that the cellular ecosystem of naked mole-rat skin actively suppresses epithelial transformation.
AMBERff at scale: Multimillion-atom simulations with AMBER force fields in NAMD
Authors: Antolínez Santiago , Jones Peter Eugene , Phillips James C. , Hadden-Perilla Jodi A.
Published: October 2023

All-atom molecular dynamics (MD) simulations are an essential structural biology technique with increasing application to multimillion-atom systems, including viruses and cellular machinery. Classical MD simulations rely on parameter sets, such as the AMBER family of force fields (AMBERff), to accurately describe molecular motion. Here, we present an implementation of AMBERff for use in NAMD that overcomes previous limitations to enable high-performance, massively-parallel simulations encompassing up to two billion atoms. Single-point potential energy comparisons and case studies on model systems demonstrate that the implementation produces results that are as accurate as running AMBERff in its native engine.
GPN-MSA: an alignment-based DNA language model for genome-wide variant effect prediction
Authors: Benegas Gonzalo , Albors Carlos , Aw Alan J. , Ye Chengzhong , Song Yun S.
Published: October 2023

Whereas protein language models have demonstrated remarkable efficacy in predicting the effects of missense variants, DNA counterparts have not yet achieved a similar competitive edge for genome-wide variant effect predictions, especially in complex genomes such as that of humans. To address this challenge, we here introduce GPN-MSA, a novel framework for DNA language models that leverages whole-genome sequence alignments across multiple species and takes only a few hours to train. Across several benchmarks on clinical databases (ClinVar, COSMIC, OMIM), experimental functional assays (DMS, DepMap), and population genomic data (gnomAD), our model for the human genome achieves outstanding performance on deleteriousness prediction for both coding and non-coding variants.
Multioviz: an interactive platform forin silicoperturbation and interrogation of gene regulatory networks
Authors: Xie Helen , Crawford Lorin , Conard Ashley Mae
Published: October 2023

In this paper, we aim to build a tool that will help bridge the gap between high-dimensional computation and wet-lab experimentation by allowing users to interrogate genomic signatures at multiple molecular levels and identify best next actionable steps for downstream decision making. We introduceMultioviz: a publicly accessibleRpackage and web application platform to easily performin silicohypothesis testing of generated gene regulatory networks. We demonstrate the utility ofMultiovizby conducting an end-to-end analysis in a statistical genetics application focused on measuring the effect ofin silicoperturbations of complex trait architecture. By using a real data set from the Wellcome Trust Centre for Human Genetics, we both recapitulate previous findings and propose hypotheses about the genes involved in the percentage of immune CD8+ cells found in heterogeneous stocks of mice. Source code for theMultioviz Rpackage is available athttps://github.com/lcrawlab/multio-vizand an interactive version of the platform is available atmultioviz.ccv.brown.edu.
MagSlice - Ultra Low-cost, modular and rapid 3D printed anatomical models for preoperative planning and patient education
Authors: Tucker Harrison , Pickering Edmund , Fysh Corey , Chen Michael Y. , Rukin Nicholas J , Woodruff Maria A
Published: October 2023

3D printed, patient-specific anatomical models have been demonstrated as effective tools for preoperative training, especially in complex surgeries involving rare cases or unique anatomy. Current, state-of-the-art solutions are expensive, requiring 3D printers with large capital and operating costs, making them impractical for common usage and less likely to be adopted in healthcare settings. Alternatively, models fabricated using low-cost printing techniques, like fused filament fabrication (FFF), fail to achieve the utility of their more expensive counterparts. To overcome this challenge, we have developed an innovative approach using FFF that is able to partition the model into separate segments, held together with magnetic fasteners, to unveil the internal anatomy of the model thereby overcoming the challenges of low-cost printing methods and providing equivalent efficacy to the state-of-the-art. Notably, our models can be printed significantly faster and cheaper than other published models and can be viewed holistically as one model, or can be physically expanded into slices (like a deck of cards) whilst maintaining the entire model integrity. By dramatically reducing cost and time, our solution unlocks the potential of 3D printed patient specific models, making these practical for hospital usage.
Generalisability of AI-based scoring systems in the ICU: a systematic review and meta-analysis
Authors: Rockenschaub Patrick , Akay Ela Marie , Carlisle Benjamin Gregory , Hilbert Adam , Meyer-Eschenbach Falk , Näher Anatol-Fiete , Frey Dietmar , Madai Vince Istvan
Published: October 2023

Background

Machine learning (ML) is increasingly used to predict clinical deterioration in intensive care unit (ICU) patients through scoring systems. Although promising, such algorithms often overfit their training cohort and perform worse at new hospitals. Thus, external validation is a critical – but frequently overlooked – step to establish the reliability of predicted risk scores to translate them into clinical practice. We systematically reviewed how regularly external validation of ML-based risk scores is performed and how their performance changed in external data.

Methods

We searched MEDLINE, Web of Science, and arXiv for studies using ML to predict deterioration of ICU patients from routine data. We included primary research published in English before April 2022. We summarised how many studies were externally validated, assessing differences over time, by outcome, and by data source. For validated studies, we evaluated the change in area under the receiver operating characteristic (AUROC) attributable to external validation using linear mixed-effects models.

Results

We included 355 studies, of which 39 (11.0%) were externally validated, increasing to 17.9% by 2022. Validated studies made disproportionate use of open-source data, with two well-known US datasets (MIMIC and eICU) accounting for 79.5% of studies. On average, AUROC was reduced by -0.037 (95% CI -0.064 to -0.017) in external data, with >0.05 reduction in 38.6% of studies.

Discussion

External validation, although increasing, remains uncommon. Performance was generally lower in external data, questioning the reliability of some recently proposed ML-based scores. Interpretation of the results was challenged by an overreliance on the same few datasets, implicit differences in case mix, and exclusive use of AUROC.
SARS-CoV-2, influenza A/B and respiratory syncytial virus positivity and association with influenza-like illness and self-reported symptoms, over the 2022/23 winter season in the UK: a longitudinal surveillance cohort
Authors: Dietz Elisabeth , Pritchard Emma , Pouwels Koen , Ehsaan Muhammad , Blake Joshua , Gaughan Charlotte , Haduli Eric , Boothe Hugh , Vihta Karina-Doris , Peto Tim , Stoesser Nicole , Matthews Philippa , Taylor Nick , Diamond Ian , Studley Ruth , Rourke Emma , Birrell Paul , De Angelis Daniela , Fowler Tom , Watson Conall , Eyre David , House Thomas , Walker Ann Sarah
Published: October 2023

Background

Syndromic surveillance often relies on patients presenting to healthcare. Community cohorts, although more challenging to recruit, could provide additional population-wide insights, particularly with SARS-CoV-2 co-circulating with other respiratory viruses.

Methods

We estimated positivity and incidence of SARS-CoV-2, influenza A/B, and RSV, and trends in self-reported symptoms including influenza-like illness (ILI), over the 2022/23 winter season in a broadly representative UK community cohort (COVID-19 Infection Survey), using negative-binomial generalised additive models. We estimated associations between test positivity and each of symptoms and influenza vaccination, using adjusted logistic and multinomial models.

Findings

Swabs taken at 32,937/1,352,979 (2.4%) assessments tested positive for SARS-CoV-2, 181/14,939 (1.2%) for RSV and 130/14,939 (0.9%) for influenza A/B, varying by age over time. Positivity and incidence peaks were earliest for RSV, then influenza A/B, then SARS-CoV-2, and were highest for RSV in the youngest and for SARS-CoV-2 in the oldest age-groups. Many test-positives did not report key symptoms: middle-aged participants were generally more symptomatic than older or younger participants, but still only ∼25% reported ILI-WHO and ∼60% ILI-ECDC. Most symptomatic participants did not test positive for any of the three viruses. Influenza A/B-positivity was lower in participants reporting influenza vaccination in the current and previous seasons (odds ratio=0.55 (95% CI 0.32,0.95)) versus neither season.

Interpretation

Symptom profiles varied little by aetiology, making distinguishing SARS-CoV-2, influenza and RSV using symptoms challenging. Most symptoms were not explained by these viruses, indicating the importance of other pathogens in syndromic surveillance. Influenza vaccination was associated with lower rates of community influenza test positivity.

Funding

UK Health Security Agency, Department of Health and Social Care, National Institute for Health Research.
Molecular Epidemiology of DiarrhoeagenicEscherichia coliin Africa: A Systematic Review and Meta-Analysis
Authors: Kalule John Bosco , Bester Linda A. , Banda Daniel L. , Derra Firehiwot Abera , Chikuse Francis , Tessema Sofonias K. ,   Africa PGI Foodborne Diseases Genomic Surveillance Focus Group, Foster-Nyarko Ebenezer
Published: October 2023

Introduction

DiarrhoeagenicEscherichia coli(DEC) persistently challenges public health in Africa, contributing substantially to the diarrhoeal disease burden. This systematic review and meta-analysis illuminate the distribution and antimicrobial resistance (AMR) patterns of DEC pathotypes across the continent.

Methods

The review selectively focused on studies reporting prevalence and/or AMR of human-derived DEC pathotypes from African nations, excluding data from extra-intestinal, animal, and environmental sources, and studies focused on drug and mechanism experiments. Employing a robust search strategy, pertinent studies were retrieved from SCOPUS, PubMed, and EBSCOhost, processed with Covidence, and screened in alignment with PRISMA guidelines.

Results

The reviewed studies were predominantly hospital-based (80%) and paediatric-focused (91%), with a meagre 4.4% documenting DEC outbreaks. Seven DEC pathotypes were discerned, with EnteroaggregativeE. coli(EAEC) being notably prevalent (43%, 95% CI: 30% – 55%) and EnteroinvasiveE. coli(EIEC) least prevalent (24%, 95%CI: 17% – 32%). Identified non-susceptibilities were noted against essential antibiotics, including ciprofloxacin, ceftriaxone, and ampicillin, while instances of carbapenem and Extended-Spectrum Beta-Lactamase (ESBL) resistance were scarce.

Conclusion

Despite sporadic data on DEC prevalence and AMR in Africa, particularly in community settings, a palpable gap remains in real-time outbreak surveillance and comprehensive data documentation. Augmenting surveillance and embracing advancements in molecular/genomic characterisation techniques are crucial to precisely discerning the actual impact and resistance continuum of DEC in Africa.
Transcriptomics profiling of Parkinson’s disease progression subtypes reveals distinctive patterns of gene expression
Authors: Fabrizio Carlo , Termine Andrea , Caltagirone Carlo
Published: October 2023

Parkinson’s Disease (PD) exhibits significant individual variability, and recent Artificial Intelligence advancements have identified three distinct progression subtypes, each with known clinical features but unexplored gene expression profiles. This study aimed to identify the transcriptomics characteristics of PD progression subtypes, and assess the utility of gene expression data in subtype prediction at baseline. Differentially expressed genes were subtype-specific, and not typically found in other PD studies. Pathway analysis showed distinct and shared features among subtypes. Two had opposing expression patterns for shared pathways, and the third had a more unique profile with respect to the others. Machine Learning revealed that the progression subtype with the worst prognosis can be predicted at baseline with 0.877 AUROC, yet the contribution of gene expression was marginal for the prediction of the subtypes. This study offers insights into PD subtypes transcriptomics, fostering precision medicine for improved diagnosis and prognosis.
Scenario Design for Infectious Disease Projections: Integrating Concepts from Decision Analysis and Experimental Design
Authors: Runge Michael C. , Shea Katriona , Howerton Emily , Yan Katie , Hochheiser Harry , Rosenstrom Erik , Probert William J.M. , Borchering Rebecca , Marathe Madhav V. , Lewis Bryan , Venkatramanan Srinivasan , Truelove Shaun , Lessler Justin , Viboud Cécile
Published: October 2023

Across many fields, scenario modeling has become an important tool for exploring long-term projections and how they might depend on potential interventions and critical uncertainties, with relevance to both decision makers and scientists. In the past decade, and especially during the COVID-19 pandemic, the field of epidemiology has seen substantial growth in the use of scenario projections. Multiple scenarios are often projected at the same time, allowing important comparisons that can guide the choice of intervention, the prioritization of research topics, or public communication. The design of the scenarios is central to their ability to inform important questions. In this paper, we draw on the fields of decision analysis and statistical design of experiments to propose a framework for scenario design in epidemiology, with relevance also to other fields. We identify six different fundamental purposes for scenario designs (decision making, sensitivity analysis, value of information, situational awareness, horizon scanning, and forecasting) and discuss how those purposes guide the structure of scenarios. We discuss other aspects of the content and process of scenario design, broadly for all settings and specifically for multi-model ensemble projections. As an illustrative case study, we examine the first 17 rounds of scenarios from the U.S. COVID-19 Scenario Modeling Hub, then reflect on future advancements that could improve the design of scenarios in epidemiological settings.
Light exposure during sleep is associated with irregular sleep timing: the Multi-Ethnic Study of Atherosclerosis (MESA)
Authors: Wallace Danielle A , Qiu Xinye , Schwartz Joel , Huang Tianyi , Scheer Frank A.J.L. , Redline Susan , Sofer Tamar
Published: October 2023

Objective

Exposure to light at night (LAN) may influence sleep timing and regularity. Here, we test whether greater light exposure during sleep (LEDS) associates with greater irregularity in sleep onset timing in a large cohort of older adults.

Methods

Light exposure and activity patterns, measured via wrist-worn actigraphy (ActiWatch Spectrum), were analyzed in 1,933 participants with 6+ valid days of data in the Multi-Ethnic Study of Atherosclerosis (MESA) Exam 5 Sleep Study. Summary measures of LEDS averaged across nights were evaluated in linear and logistic regression analyses to test the association with standard deviation (SD) in sleep onset timing (continuous variable) and irregular sleep onset timing (SD≥1.36 hours, binary). Night-to-night associations between LEDS and absolute differences in nightly sleep onset timing were also evaluated with distributed lag non-linear models and mixed models.

Results

In between-individual linear and logistic models adjusted for demographic, health, and seasonal factors, every 5-lux unit increase in LEDS was associated with an increase of 7.8 minutes in sleep onset SD (β=0.13 hours, 95%CI:0.09-0.17) and 40% greater odds (OR=1.40, 95%CI:1.24-1.60) of irregular sleep onset. In within-individual night-to-night mixed model analyses, every 5-lux unit increase in LEDS the night prior (lag0) was associated with a 2.2-minute greater deviation of sleep onset the next night (β=0.036 hours, p<0.05). Conversely, every 1-hour increase in sleep deviation (lag0) was associated with a 0.35-lux increase in future LEDS (β=0.347 lux, p<0.05).

Conclusion

LEDS was associated with greater irregularity in sleep onset in between-individual analyses and subsequent deviation in sleep timing in within-individual analyses, supporting a role for LEDS in exacerbating irregular sleep onset timing. Greater deviation in sleep onset was also associated with greater future LEDS, suggesting a bidirectional relationship. Maintaining a dark sleeping environment and preventing LEDS may promote sleep regularity and following a regular sleep schedule may limit LEDS.
What do Iranians value most when choosing a hospital? Evidence from a discrete choice experiment
Authors: Ranjbar Mohammad , Bazyar Mohammad , Pahlevanshamsi Fatemeh , Angell Blake , Assefa Yibeltal
Published: October 2023

Background

Individual preferences have preceded the use of health care services, and it has been affected by different hospital attributes. This study aimed to elicit the Iranians’ preferences in choosing hospitals using a discrete choice experiment.

Methods

A discrete choice experiment (DCE) was conducted through face to face interviews with 301 respondents. The DCE was constructed by six attributes were included based on a literature review, qualitative interviews, Focus Group Discussion (FGD) and stakeholder consultation: waiting time, quality of care, travel time, hospital type, provider competency, and hospital facilities. individuals’ preferences for hospital attributes were analyzed using a mixed logit model, and interaction terms were used to assess preference heterogeneity among individuals with different sociodemographic characteristics.

Results

Participants had strong and significant preferences for care delivered in hospitals with ‘full’ (β=0.6052, p<0.001) or ‘moderate’ (β=0.5882, p<0.001) hospital equipment and with ‘excellent’ provider competency (β=0.2637, p<0.001). The estimated coefficients for the “waiting time of 120 minutes” (β=−0.1625, p<0.001) and the “travel time of 30 minutes” (β=−0.1157, p<0.001) were negative and significant. The results also show that the personal characteristics such as age, education level, and income significantly affected individual preferences in choosing a hospital.

Conclusion

Considering people’s preferences can be important given the more active role of today’s patients in decision-making about their treatment processes. The results of this study should be taken into consideration by health policymakers and all stakeholders to be aware of differences in preferences of people and maximize their satisfaction. In this case, it is important to continuously involve people and consider their preferences in the design, topology, construction, and equipment of hospitals.