bluuebunny/crossref_metadata_2025 huggingface dataset:
Delving into PubMed Records: Some Terms in Medical Writing Have Drastically Changed after the Arrival of ChatGPT
Authors: Matsui Kentaro
Published: May 2024

It is estimated that ChatGPT is already widely used in academic paper writing. This study aims to investigate whether the usage of specific terminologies has increased, focusing on words and phrases frequently reported as overused by ChatGPT. The list of 118 potentially AI-influenced terms was curated based on posts and comments from anonymous ChatGPT users, and 75 common academic phrases were used as controls. PubMed records from 2000 to 2024 (until April) were analyzed to track the frequency of these terms. Usage trends were normalized using a modified Z-score transformation. A linear mixed-effects model was used to compare the usage of potentially AI-influenced terms to common academic phrases over time. A total of 26,403,493 PubMed records were investigated. Among the potentially AI-influenced terms, 75 displayed a meaningful increase (modified Z-score ≥ 3.5) in usage in 2024. The linear mixed-effects model showed a significant effect of potentially AI-influenced terms on usage frequency compared to common academic phrases (p < 0.001). The usage of potentially AI-influenced terms showed a noticeable increase starting in 2020. This study revealed that certain words and phrases, such as “delve,” “underscore,” “meticulous,” and “commendable,” have been used more frequently in medical and biological fields since the introduction of ChatGPT. The usage rate of these words/phrases has been increasing for several years before the release of ChatGPT, suggesting that ChatGPT might have accelerated the popularity of scientific expressions that were already gaining traction. The identified terms in this study can provide valuable insights for both LLM users, educators, and supervisors in these fields.

Author Summary

Artificial intelligence systems have rapidly integrated into academic writing, particularly in the medical and biological fields. This study investigates changes in the frequency of specific terminologies reported as overused by ChatGPT. By analyzing PubMed records from 2000 to 2024, we tracked 118 potentially AI-influenced terms and compared them with 75 common academic phrases. The study’s findings reveal that terms such as ‘delve,’ ‘underscore,’ ‘meticulous,’ and ‘commendable’ saw a marked increase in usage in 2024. However, this trend actually began around 2020. This suggests that while some of these terms were already gaining popularity before the release of ChatGPT, the large language model may have accelerated their adoption in scientific literature. Furthermore, the analysis highlights that the impact of ChatGPT extends beyond new terminologies to altering the frequency and style of commonly used academic phrases. Understanding these trends can help researchers and educators see how AI tools are shaping academic writing.
The Pediatric Sleep Questionnaire as a screening tool for sleep-related breathing disorders: An Umbrella Review
Authors: Okuji David , Newcity Amanda , Yavari Amir , Shahraki Farnaz , Erhenede Oghenerukevwe , Ahmed Qaiser , Patenaude Rachel , Twi-Yeboah Alberta , McGowan Richard
Published: May 2024

Purpose

The purpose of this umbrella review was to assess available systematic reviews and meta-analyses reporting on the use of the Pediatric Sleep Questionnaire as a screening tool for identifying sleep related breathing disorders in children, with subsequent referral from dentists to physicians.

Methods

A comprehensive literature search was conducted with electronic databases to identify systematic reviews and meta-analyses reporting on the Pediatric Sleep Questionnaire as a screening tool for pediatric sleep related breathing disorders. Eligible reviews were systematically selected and were assessed qualitatively with the AMSTAR 2 tool and quantitatively with meta-analyses methods.

Results

A total of 129 articles for possible inclusion were identified, and five studies were selected for quantitative analysis. Of these five studies, the overall AMSTAR 2 quality assessment showed two with moderate and three with low quality ratings. The five studies showed point-estimate mean values for prevalence, sensitivity, specificity, positive predictive value, positive predictive value, negative predictive value as, respectively, respectively, 50.58, 74.97, 49.68, 58.16, 62.24 percent, and the diagnostic odds ratio as 6.94 percent for the Pediatric Sleep Questionnaire tool.

Conclusions

Dentists should adhere to the American Academy of Pediatric Dentistry guidelines and know that there is low to moderate evidence to support the utilization of the Pediatric Sleep Questionnaire as a sufficiently accurate screening tool for the diagnosis of sleep related breathing disorders in children, followed by an appropriate referral to a physician for comprehensive assessment and management.
Nuclear magnetic resonance-based metabolomics with machine learning for predicting progression from prediabetes to diabetes
Authors: Li Jiang , Yu Yuefeng , Sun Ying , Fu Yanqi , Shen Wenqi , Cai Lingli , Tan Xiao , Cai Yan , Wang Ningjian , Lu Yingli , Wang Bin
Published: May 2024

Background

Identification of individuals with prediabetes who are at high risk of developing diabetes allows for precise interventions. We aimed to determine the role of nuclear magnetic resonance (NMR)-based metabolomic signature in predicting the progression from prediabetes to diabetes.

Methods

This prospective study included 13,489 participants with prediabetes who had metabolomic data from the UK Biobank. Circulating metabolites were quantified via NMR spectroscopy. Cox proportional hazard (CPH) models were performed to estimate the associations between metabolites and diabetes risk. Supporting vector machine, random forest, and extreme gradient boosting were used to select the optimal metabolite panel for prediction. CPH and random survival forest (RSF) models were utilized to validate the predictive ability of the metabolites.

Results

During a median follow-up of 13.6 years, 2,525 participants developed diabetes. After adjusting for covariates, 94 of 168 metabolites were associated with risk of progression to diabetes. A panel of nine metabolites, selected by all three machine learning algorithms, was found to significantly improve diabetes risk prediction beyond conventional risk factors in the CPH model (area under the receiver operating characteristic curve [AUROC], 1-year: 0.823 for risk factors + metabolites vs 0.759 for risk factors, 5-year: 0.830 vs 0.798, 10-year: 0.801 vs 0.776, allP<0.05). Similar results were observed from the RSF model. Categorization of participants according to the predicted value thresholds revealed distinct cumulative risk of diabetes.

Conclusions

Our study lends support for use of the metabolite markers to help determine individuals with prediabetes who are at high risk of progressing to diabetes and inform targeted and efficient interventions.

Funding

Shanghai Municipal Health Commission (2022XD017). Innovative Research Team of High-level Local Universities in Shanghai (SHSMU-ZDCX20212501). Shanghai Municipal Human Resources and Social Security Bureau (2020074). Clinical Research Plan of Shanghai Hospital Development Center (SHDC2020CR4006). Science and Technology Commission of Shanghai Municipality (22015810500).
National Incidence, Outcomes, and Management Strategies for Pre- and Post-Transplant Atrial Fibrillation in Heart Transplant Recipients
Authors: Karius Alexander K , Zhou Alice L , Ruck Jessica M. , Massie Allan B. , Segev Dorry L. , Spragg David , Kilic Ahmet
Published: May 2024

Background

Among heart transplant candidates, atrial fibrillation (AF) is a common comorbidity; however, little is known about the impact of pre-transplant AF on incidence of post-transplant AF or other transplant outcomes.

Methods

Adult heart transplant recipients transplanted from 07/01/2012 to 07/01/2021 with data available in both the Scientific Registry of Transplant Recipients and Symphony Health pharmacy databases were included. Recipients were categorized by presence of pre-transplant AF using prescription fill data. Perioperative outcomes and survival out to 5 years post-transplant were compared between those with and without pre-transplant AF.

Results

Of the 11,789 heart transplant recipients, 2,477 (21.0%) had pre-transplant AF. Pre-transplant AF was associated with an increased likelihood of pre-discharge stroke (aOR 2.13 [95%CI: 1.07-4.26], p=0.03) and dialysis (aOR 1.45 [1.05-2.00], p=0.02), as well as of post-transplant AF at 6 months (aOR 2.42 [1.44-1.48], p=0.001) and 1 year (aOR 2.81 [1.72-4.56], p<0.001). Pre-transplant AF was associated with increased post-transplant mortality at 30 days (aHR 2.39 [1.29-4.44], p=0.006) and 1 year (aHR 1.46 [95% CI: 1.01-2.13], p=0.04), but similar mortality at 5 years (aHR 1.23 [0.96-1.58], p=0.11).

Conclusion

Heart transplant recipients with pre-transplant AF had worse short-term outcomes and increased risk of developing post-transplant AF but comparable survival at 5 years post-transplant. Our findings emphasize the importance of increased monitoring for perioperative complications and highlight the long-term safety of heart transplantation in this population.

What Is New?

Patients with atrial fibrillation who undergo heart transplantation have worse short term survival (30-days and 1-year) but similar long term survival (5-years) compared to recipients without pre-transplant atrial fibrillation.

Pre-transplant atrial fibrillation increases the risk of clinically significant post-transplant atrial fibrillation and peri-operative stroke.

Rate vs rhythm control pharmacotherapy for atrial fibrillation is not associated with differences in survival in heart transplant recipients with pre-transplant atrial fibrillation

What are the Clinical Implications?

Atrial fibrillation should not deter heart transplantation in appropriate candidates, though cardiovascular and stroke risk adjustment may be warranted.

Use of amiodarone at doses ≤ 200 mg/day is not associated with reduced survival in heart transplant recipients with pre-transplant atrial fibrillation.
Sensorimotor faculties bias perceptual decision-making
Authors: Kubanek Jan , Snyder Lawrence H , Abrams Richard A
Published: May 2024

Decision-making is a deliberate process that seemingly evolves under our own volition. Yet, research on embodied cognition has demonstrated that higher-order cognitive processes may be influenced, in unexpected ways, by properties of motor and sensory systems. Here we tested whether and how simple decisions are influenced by handedness and by asymmetries in the auditory system. Right- and left-handed participants performed an auditory decision task. In the task, subjects decided whether they heard more click sounds in the right ear or in the left ear, and pressed a key with either their right or left index finger, according to an instructed stimulus-key assignment (congruent or reversed). On some trials, there was no stimulus and subjects could choose either of the responses freely. When subjects chose freely, their choices were substantially governed by their handedness: Left-handed subjects were significantly biased to make the leftward choice, whereas right-handed subjects showed a substantial rightward bias. When the choice was governed by the sensory stimulus, subjects showed a rightward choice bias under the congruent key assignment, but this effect reversed to a leftward choice bias under the reversed key assignment. This result indicates a bias towards deciding that there were more clicks presented to the right ear. Together, our findings demonstrate that human choices can be considerably influenced by properties of motor and sensory systems.
The main duct of von Ebner’s glands is a source of Sox10+taste bud progenitors and susceptible to pathogen infections
Authors: Yu Wenxin , Kastriti Maria Eleni , Ishan Mohamed , Choudhary Saurav Kumar , Kramer Naomi , Rashid Md Mamunur , Truong Do Hy Gia , Wang Zhonghou , Xu Ting , Schwabe Robert F , Ye Kaixiong , Adameyko Igor , Liu Hong-Xiang
Published: May 2024

We have recently demonstrated thatSox10-expressing (Sox10+) cells give rise to mainly type-III neuronal taste bud cells that are responsible for sour and salt taste. The two tissue compartments containingSox10+cells in the surrounding of taste buds include the connective tissue core of taste papillae and von Ebner’s glands (vEGs) that are connected to the trench of circumvallate and foliate papillae. In this study, we used inducible Cre mouse models to map the cell lineages of connective tissue (including stromal and Schwann cells) and vEGs and performed single cell RNA-sequencing of the epithelium ofSox10-Cre/tdTmouse circumvallate/vEG complex.In vivolineage mapping showed that the distribution of traced cells in circumvallate taste buds was closely linked with that in the vEGs, but not in the connective tissue.Sox10, but not the known stem cells markerLgr5, expression was enriched in the cell clusters of main ducts of vEGs that contained abundant proliferating cells, whileSox10-Cre/tdTexpression was enriched in type-III taste bud cells and excretory ductal cells. Moreover, multiple genes encoding pathogen receptors are enriched in the vEG main ducts. Our data indicate that the main duct of vEGs is a source ofSox10+taste bud progenitors and susceptible to pathogen infections.
eIF2α phosphorylation evokes dystonia-like movements with D2-receptor and cholinergic origin and abnormal neuronal connectivity
Authors: Lewis Sara A. , Forstrom Jacob , Tavani Jennifer , Schafer Robert , Tiede Zach , Padilla-Lopez Sergio R. , Kruer Michael C.
Published: May 2024

Dystonia is the 3rdmost common movement disorder. Dystonia is acquired through either injury or genetic mutations, with poorly understood molecular and cellular mechanisms. Eukaryotic initiation factor alpha (eIF2α) controls cell state including neuronal plasticity via protein translation control and expression of ATF4. Dysregulated eIF2α phosphorylation (eIF2α-P) occurs in dystonia patients and models including DYT1, but the consequences are unknown. We increased/decreased eIF2α-P and tested motor control and neuronal properties in a Drosophila model. Bidirectionally altering eIF2α-P produced dystonia-like abnormal posturing and dyskinetic movements in flies. These movements were also observed with expression of theDYT1risk allele. We identified cholinergic and D2-receptor neuroanatomical origins of these dyskinetic movements caused by genetic manipulations to dystonia molecular candidates eIF2α-P, ATF4, or DYT1, with evidence for decreased cholinergic release.In vivo, increased and decreased eIF2α-P increase synaptic connectivity at the NMJ with increased terminal size and bouton synaptic release sites. Long-term treatment of elevated eIF2α-P with ISRIB restored adult longevity, but not performance in a motor assay. Disrupted eIF2α-P signaling may alter neuronal connectivity, change synaptic release, and drive motor circuit changes in dystonia.
Leeches Predate on Fast-Escaping and Entangling Blackworms by Spiral Entombment
Authors: Tuazon Harry , David Samuel , Ma Kenneth , Bhamla M. Saad
Published: May 2024

We investigate how theHelobdellaspp. freshwater leeches capture and consumeLumbriculus variegatusblackworms despite the blackworm’s ultrafast helical swimming escape reflex and ability to form large tangled ‘blobs’. We describe our discovery of a unique spiral ‘entombment’ strategy used by these leeches to overcome the blackworms’ active and collective defenses. Unlike their approach to less reactive and solitary prey like mollusks, where leeches simply attach and suck,Helobdellaleeches employ this spiral entombment strategy specifically adapted for blackworms. Our findings highlight the complex interactions between predator and prey in freshwater ecosystems, providing insights into ecological adaptability and predator-prey dynamics.
POSTERIOR-SUPERIOR INSULA REPETITIVE TRANSCRANIAL MAGNETIC STIMULATION REDUCES EXPERIMENTAL TONIC PAIN AND PAIN-RELATED CORTICAL INHIBITION IN HUMANS
Authors: Chowdhury Nahian S , Millard Samantha K , de Martino Enrico , Larsen Dennis Boye , Seminowicz David A , Schabrun Siobhan M , Andrade Daniel Ciampi de , Graven-Nielsen Thomas
Published: May 2024

High frequency repetitive transcranial magnetic stimulation (rTMS) to the posterosuperior insula (PSI) may produce analgesic effects. However, the neuroplastic changes behind PSI-rTMS analgesia remain poorly understood. The present study aimed to determine whether tonic capsaicin-induced pain and cortical inhibition (indexed using TMS-electroencephalography) are modulated by PSI-rTMS. Twenty healthy volunteers (10 females) attended two sessions randomized to active or sham rTMS. Experimental pain was induced by capsaicin administered to the forearm for 90 minutes, with pain ratings collected every 5 minutes. Left PSI-rTMS was delivered (10Hz, 100 pulses per train, 15 trains) ∼50 minutes post-capsaicin administration. TMS-evoked potentials (TEPs) and thermal sensitivity were assessed at baseline, during capsaicin pain prior to rTMS and after rTMS. Bayesian evidence of reduced pain scores and increased heat pain thresholds were found following active rTMS, with no changes occurring after sham rTMS. Pain (prior to active rTMS) led to an increase in the frontal negative peak ∼45 ms (N45) TEP relative to baseline. Following active rTMS, there was a decrease in the N45 peak back to baseline levels. In contrast, following sham rTMS, the N45 peak was increased relative to baseline. We also found that the reduction in pain NRS scores following active vs. sham rTMS was partially mediated by decreases in the N45 peak. These findings provide evidence of the analgesic effects of PSI-rTMS and suggest that the TEP N45 peak is a potential marker and mediator of both pain and analgesia.
A novel missense variant in the ATPase domain of ATP8A2 and review of phenotypic variability ofATP8A2-related disorders caused by missense changes
Authors: Flannery Kyle P. , Safwat Sylvia , Matsell Eli , Battula Namarata , Hamed Ahlam A. A. , Mohamed Inaam N. , Elseed Maha A. , Koko Mahmoud , Abubaker Rayan , Abozar Fatima , Elsayed Liena E. O. , Bhise Vikram , Molday Robert S. , Salih Mustafa A. , Yahia Ashraf , Manzini M. Chiara
Published: May 2024

ATPase, class 1, type 8A, member 2 (ATP8A2) is a P4-ATPase with a critical role in phospholipid translocation across the plasma membrane. Pathogenic variants inATP8A2are known to cause cerebellar ataxia, mental retardation, and disequilibrium syndrome 4 (CAMRQ4) which is often associated with encephalopathy, global developmental delay, and severe motor deficits. Here, we present a family with two siblings presenting with global developmental delay, intellectual disability, spasticity, ataxia, nystagmus, and thin corpus callosum. Whole exome sequencing revealed a homozygous missense variant in the nucleotide binding domain of ATP8A2 (p.Leu538Pro) that results in near complete loss of protein expression. This is in line with other missense variants in the same domain leading to protein misfolding and loss of ATPase function. In addition, by performing diffusion-weighted imaging, we identified bilateral hyperintensities in the posterior limbs of the internal capsule suggesting possible microstructural changes in axon tracts that had not been appreciated before and could contribute to the sensorimotor deficits in these individuals.
Identifying barriers to genetic testing in subspecialty cardiac care
Authors: Pond Sierra , Echols Genevie , Tristani-Firouzi Martin M , Etheridge Susan P , Anderson Hannah S , Sawyer Briana L
Published: May 2024

Background

The utility of genetic testing in cardiovascular medicine is well-established in expert consensus statements for optimizing patient care. However, significant genetic testing care gaps persist for patients with inherited cardiovascular conditions.

Objective

This study aimed to understand why genetic testing care gaps in cardiovascular medicine exist by evaluating cardiovascular providers’ opinions and use of genetic testing.

Methods

We developed and administered an anonymous survey to cardiovascular providers delivering direct patient care in the United States. Participants were contacted in collaboration with the Sudden Arrhythmia Death Syndromes (SADS) Foundation.

Results

A total of 111 individuals completed the survey representing the following specialties: electrophysiology (55%, n=61), general cardiology (10.8%, n=12), imaging (7.2%, n=8), heart failure/transplant (6.3%, n=7), interventional cardiology (6.3%, n=7), fetal cardiology (5.4%, n=6), and other (9%, n=10). Eighty-six percent of respondents (n=97) stated genetic testing is ‘very relevant’ in the care of their patients. Eighty percent of electrophysiologists reported ordering genetic testing a few times a month or more. Navigating insurance authorization and billing procedures was an identified area of discomfort by 47.7% of respondents (n=53). Overall, cardiovascular provider specialty was shown to impact how often genetic testing is ordered. Provider work setting was shown to impact opinion of the utility of genetic testing for family screening, opinion of the utility of genetic testing for medication and device management, and how often genetic testing is ordered.

Conclusions

The results of this study support targeted provider education to increase the uptake of genetic testing for patients with inherited cardiovascular conditions.
Correlating hippocampal and amygdala volumes with neuropathological burden in neurodegenerative diseases using 7T postmortem MRI
Authors: Liou Jr-Jiun , Li Jinghang , Berardinelli Jacob , Jin Hecheng , Santini Tales , Noh Jaehoon , Farhat Nadim , Wu Minjie , Aizenstein Howard , Mettenburg Joseph M , Yong William , Head Elizabeth , Ikonomovic Milos , Ibrahim Tamer , Kofler Julia ,   the Alzheimer’s Biomarker Consortium on Down syndrome study
Published: May 2024

Numerous research groups worldwide have focused on postmortem imaging to bridge the resolution gap between clinical neuroimaging and neuropathology data. We developed a standardized protocol for brain embedding, imaging, and processing, facilitating alignment between antemortem MRI, postmortem MRI, and pathology to observe brain atrophy and structural damage progression over time. Using 7T postmortem ex vivo MRI, we explore the potential correlation of amygdala and hippocampal atrophy with neuropathological burden in both Down syndrome (DS) and Alzheimer’s disease (AD) cohorts. Using 7T postmortem ex vivo MRI scans from 66 cases (12 DS and 54 AD) alongside a subset of antemortem scans (n=17), we correlated manually segmented hippocampal and amygdala volumes, adjusted for age, sex, and ApoE4 status, with pathological indicators such as Thal phase, Braak stage, limbic-predominant age-related TDP-43 encephalopathy (LATE) stage, hippocampal sclerosis (HS), and Lewy body (LB) stage. A significant correlation was observed between postmortem and antemortem volumes for the hippocampus, but a similar trend observed for the amygdala did not reach statistical significance. DS individuals exhibited notably smaller hippocampal and amygdala volumes compared to AD subjects. In DS, lower hippocampal and amygdala volumes correlated with more severe Braak stage, without significant associations with Thal phase. LATE and HS pathologies were uncommon in DS cases but trended toward smaller hippocampal volumes. In AD, lower hippocampal volume associated with dementia duration, advanced Thal phase, Braak stage, LATE stage, and HS presence, whereas reduced amygdala volume correlated mainly with severe LATE stage and HS, but not with Thal or Braak stages. No significant LB correlation was detected in either DS or AD cohorts. Hippocampal volume in AD appears influenced by both AD and LATE pathologies, while amygdala volume seems primarily influenced by LATE. In DS, smaller hippocampal volume, relative to AD, appears primarily influenced by tau pathology.
Compartmental Model for Epidemics with Contact Tracing and Isolation under Arbitrary Degree Distribution
Authors: Ocheretner Elan , Leshem Amir
Published: May 2024

The recent COVID-19 epidemic demonstrated the need and importance of epidemic models as a tool for policy-making during times of uncertainty, allowing the decision-makers to test different intervention techniques and scenarios. Furthermore, tools such as large-scale contact tracing became technologically feasible for the first time. While large-scale agent-based simulations are nowadays part of the toolboxes, good analytical models allow for much faster testing of scenarios. Unfortunately, good models that consider contact tracing and quarantine, and allow for different degree distributions do not exist. To overcome these shortcomings of existing models we propose a new simple compartmental model that integrates quarantine and contact tracing into the SIR compartmental models with arbitrary degree distribution of nodes to better understand the dynamics of the disease under various parameters of intervention and contagion. Consequently, we analytically derive the epidemic threshold as a function of the degree distribution and the model parameters when both quarantine and contact tracing are used. Simulation results demonstrate and quantify the benefits of quarantine and contact tracing and show the effectiveness of such measures over a large range of epidemic parameters.
Clinical Course and Factors Associated With Hospital Admission and Mortality among Sars-Cov 2 Patients within Nairobi Metropolitan Area
Authors: Njuguna Augustine Gatimu , Wangombe Ann Wanjiru , Walekhwa Michael N. , Kamondo Davis Kiruki
Published: May 2024

This study aims to investigate the clinical course and factors associated with hospital admission and mortality among SARS-CoV-2 patients within the Nairobi Metropolitan Area. The study utilizes a multicenter retrospective cohort design, collecting clinical characteristics and laboratory parameters of hospitalized patients from March 2020 to May 2022. Data analysis includes percentages, frequencies, chi-square tests, Kaplan-Meier analysis, pairwise comparisons, and multivariate regression models. Ethical considerations are observed throughout the research process.

The study findings highlight significant associations between comorbidities, such as hypertension, and increased mortality risk due to COVID-19. Symptoms including fever, cough, dyspnea, chest pain, sore throat, and loss of smell/taste are also identified as predictors of mortality. Abnormal laboratory parameters, such as oxygen saturation, procalcitonin, glucose levels, serum creatinine, and gamma-glutamyl transpeptidase, are associated with mortality. However, demographic factors and certain vital signs do not exhibit significant associations.

Recommendations based on this study suggest increased monitoring and management of comorbidities, early identification and management of symptoms, regular monitoring of laboratory parameters, continued research and collaboration, and implementation of preventive measures. Overall, a multidisciplinary approach involving healthcare professionals, researchers, policymakers, and the public is crucial to improve COVID-19 outcomes and reduce mortality rates. Adaptation of strategies based on emerging evidence and resource allocation is essential for effective management of the pandemic.
A protocol to assess risk of fractures associated with use of menopausal hormone therapy: nested case-control study using CPRD
Authors: Vinogradova Yana , Iyen Barbara , Masud Tahir , Taylor Lauren , Kai Joe
Published: May 2024

Abstract

Menopausal hormone therapy (MHT) is prescribed to women with severe symptoms of menopause. Various studies have demonstrated increased bone density and decreased fracture risk in women using MHT. The randomised controlled trials were, however, run over only relatively short time periods, and there is no reliable or consistent evidence about fracture risk after MHT discontinuation. The proposed nested case-control study aims to fill this gap. We will use CPRD (GOLD and AURUM) and HES data. Every woman 40 years or over with a diagnosis of first fracture between 1998 and 2022 (a case) will be matched by age and general practice to up to 5 female controls with no previous records of fracture at the time of the case diagnosis (index date). MHT exposure will be assessed using prescriptions for the different types of MHT treatment historically available from the NHS. Conditional logistic regression will estimate fracture risk associated with duration of use and gap after discontinuation of MHT. The findings will be adjusted for smoking status, body mass index, family history of dementia, medical conditions and events, other medications and contraceptive drugs. A number of sensitivity analyses will be run to address the limitations of the study.
Prevalence and work-related risk factors of Musculoskeletal Disorders among miners at Kalumbila Mine, Kalumbila District Zambia
Authors: Kunda Chibuye , Lupenga Joseph , Meki Chisala D.
Published: May 2024

Background

Mining is a hazardous occupation with high injury rates and work-related musculoskeletal disorders. However, few studies have reported on the prevalence and risk factors of work related musculoskeletal disorders among mineworkers in Zambia. Therefore, the study sought to examine risk factors of work-related musculoskeletal disorders among mineworkers at Kalumbila mine in Zambia.

Method

A cross-sectional study was undertaken and data were collected using a selfadministered Cornell Musculoskeletal Discomfort Questionnaire. A total of 357 participants were selected using a systematic random sampling method from among the male and female mine workers at the Kalumbila mine. Stata 17 was used to analyse the data and the descriptive analysis was used to determine the prevalence and types of work-related musculoskeletal disorders. Factors associated with work-related musculoskeletal disorders were identified using simple and multiple logistic regression. The level of significance was set at 0.05 and confidence level at 95%.

Results

The study revealed 274/356 (77%) of the participants reporting pain or discomfort in at least one body location. The highest level of discomfort or pain was reported in the lower back 184 (51.5%), upper back 90 (25.2%) and neck 89 (24.9%), whereas the lowest level of discomfort was reported in the left thigh 10 (2.8%), left forearm 11 (3.1%) and left foot 13 (3.6%). In the multivariable analysis, secondary education (AOR 2.03 CI 95%: 1.02 - 4.05, p=0.044), not taking any breaks while working (AOR 0.10 CI 95%: 0.01 - 0.86, p=0.036), and operating machinery causing whole-body vibration (AOR 3.0 CI 95%: 1.52-5.95, p=0.002) were associated with work-related musculoskeletal disorders.

Conclusion

Self-reported work-related musculoskeletal disorders were common among miners, underscoring the need to invest in worker safety through ergonomic programs and workers’ training on safety measures.
Meta-Reinforcement Learning reconciles surprise, value and control in the anterior cingulate cortex
Authors: Vriens Tim , Vassena Eliana , Pezzulo Giovanni , Baldassarre Gianluca , Silvetti Massimo
Published: May 2024

The role of the dorsal anterior cingulate cortex (dACC) in cognition is a frequently studied yet highly debated topic in neuroscience. Most authors agree that the dACC is involved in either cognitive control (e.g. voluntary inhibition of automatic responses) or monitoring (e.g. comparing expectations with outcomes, detecting errors, tracking surprise). A consensus on which theoretical perspective best explains dACC contribution to behaviour is still lacking. In a recent neuroimaging study, the experimental predictions of two prominent models formalizing the cognitive control hypothesis (Expected Value of Control, EVC) and the monitoring hypothesis (Predicted Response Outcome, PRO) have been tested using a behavioural task involving both monitoring and cognitive control mechanisms. The results indicated that of the two tested models, only the PRO model effectively predicted the dACC activity, indicating surprise tracking for performance monitoring as the key sole underlying mechanism, even when cognitive control was required by the task at hand. These findings challenged the long-standing and established cognitive control hypothesis of dACC function and opened a theory crisis: the proposed surprise-monitoring hypothesis indeed cannot account for a wide array of previous experimental findings evidencing dACC activation in tasks requiring cognitive controlwithoutinvolving monitoring or surprise. Here we propose a novel hypothesis on dACC function that integrates both the monitoring and the cognitive control perspective in a unifying coherent framework, based on meta-Reinforcement Learning. Our model, the Reinforcement Meta Learner (RML), optimizes cognitive control - as in control models like EVC-by meta-learning based on tracking surprise - as in monitoring models like PRO. We tested RML experimental predictions with the same behavioural task used to compare the PRO and EVC models, and showed that RML predictions on dACC activity matched PRO predictions and outperformed EVC predictions. However, crucially, the RML simultaneously accounts for both cognitive control and monitoring functions, resolving the theoretical impasse about dACC function within an integrative framework. In sum, our results suggest that dACC function can be framed as a meta-learning optimiser of cognitive control, providing an integrative perspective on its roles in cognitive control, surprise tracking, and performance monitoring.
Abscisic Acid rescues behavior in adult female mice in Attention Deficit Disorder with Hyperactivity model of dopamine depletion by regulating microglia and vesicular GABA transporter
Authors: Meseguer-Beltrán Maria , Sánchez-Sarasúa Sandra , Kerekes Nóra , Landry Marc , Real-López Matías , Sánchez-Pérez Ana María
Published: May 2024

Background

Attention deficit/hyperactivity disorder (ADHD) is a neurodevelopmental syndrome influenced by both genetic and environmental factors. While genetic studies have highlighted catecholamine dysfunction, emerging epidemiological evidence suggest neuroinflammation as a significant trigger. However, understanding the relative contributions of these alterations to ADHD symptomatology remains elusive.

Method

This study employed 93 female Swiss mice of the ADHD dopamine deficit model. Dopaminergic lesions were induced via 6-hydroxidopamine (6-OHDA) injection on postnatal day 5. The impact of these lesions during development was examined by comparing young and adult mice (at postnatal day 21 and 90, respectively). We sought to mitigate adult symptoms through abscisic acid (ABA) administration during two-months. Postmortem analyses encompassed the evaluation of neuroinflammation (microglia morphology, NLRP3 inflammasome activation, cytokine expression) and excitatory/inhibitory (E/I) ratio in specific brain regions.

Results

Neonatal dopaminergic lesions elicited hyperactivity, impulsivity, hypersensitivity increased social interaction in both one-month and three-month females and induced impaired memory in three-month mice. ABA exposure significantly ameliorated hyperactivity, impulsivity, anxiety, hypersensitivity, and social interaction alterations, but not cognitive impairment. In the anterior cingulate cortex (ACC) of one-month mice dopamine-deficit elevated IL-1β and TNFα expression and reduced Arg1 mRNA levels, along with E/I imbalance. ABA intervention restored microglia morphology, IL-1β, Arg1 expression and enhanced vGAT levels.

Conclusions

This study strongly suggest that dopamine deficit induced alteration of microglia and E/I ratio underling distinct ADHD symptoms. Reinstating healthy microglia by anti-inflammatory agents in specific areas emerges as a promising strategy for managing ADHD.
High-throughput optimisation of protein secretion in yeast via an engineered biosensor
Authors: Williams Alexandra , Luo Runpeng , Smith Oliver B. , Murphy Lydia , Schwessinger Benjamin , Brock Joseph
Published: May 2024

Secretion of high value proteins and enzymes is fundamental to the synthetic biology economy; allowing continuous fermentation during production and protein purification without cell lysis. Most eukaryotic protein secretion is encoded by an N-terminal signal peptide; however, the strong impact of signal peptide sequence variation on the secretion efficiency of a given protein is not well defined. Despite high natural signal peptide sequence diversity, most recombinant protein secretion systems employ only a few well characterised signal peptides. Additionally, the selection of promoters and terminators can significantly affect secretion efficiency, yet screening numerous genetic constructs for optimal sequences remains inefficient. Here, we have adapted a yeast G-protein coupled receptor biosensor, to measure the concentration of a peptide tag that is co-secreted with any protein of interest. Protein secretion efficiency can thus be quantified via the induction of a fluorescent reporter that is upregulated downstream of receptor activation. This enables high-throughput screening of over 6000 combinations of promoters, signal peptides and terminators, assembled using one-pot Combinatorial Golden Gate cloning. We demonstrate this biosensor can quickly identify best combinations for secretion and quantify secretion levels.

Graphical Abstract
Investigating tissue microstructure using steady-state diffusion MRI
Authors: Tendler Benjamin C.
Published: May 2024

Diffusion MRI is a leading method to non-invasively characterise brain tissue microstructure across multiple domains and scales. Diffusion-weighted steady-state free precession (DW-SSFP) is an established imaging sequence for post-mortem MRI, addressing the challenging imaging environment of fixed tissue with short T2and low diffusivities. However, a current limitation of DW-SSFP is signal interpretation: it is not clear what diffusion ‘regime’ the sequence probes and therefore its potential to characterise tissue microstructure. Building on a model of Extended Phase Graphs (EPG), I establish two alternative representations of the DW-SSFP signal in terms of (1) conventional b-values (time-independentdiffusion) and (2) encoding power-spectra (time-dependentdiffusion). The proposed representations provide insights into how different parameter regimes and gradient waveforms impact the diffusion properties of DW-SSFP. Using these representations, I introduce an approach to incorporate existing diffusion models into DW-SSFP without the requirement of extensive derivations. Investigations incorporating free-diffusion and tissue-relevant microscopic restrictions (cylinder of varying radius) give excellent agreement to complementary analytical models and Monte Carlo simulations. Experimentally, the time-independentrepresentation is used to derive Tensor and proof of principle NODDI estimates in a whole human post-mortem brain. A final SNR-efficiency investigation demonstrates the theoretical potential of DW-SSFP for ultra-high field microstructural imaging.
Programming CRISPRi-dCas9 to control the lifecycle of bacteriophage T7
Authors: Bergmiller Tobias
Published: May 2024

CRISPR interference (CRISPRi) based on catalytically dead Cas9 nuclease ofStreptococcus pyogenesis a programmable and highly flexible tool to interrogate gene function and essentiality in bacteria due to its ability to block transcription elongation at nearly any desired DNA target. Here, I assess how CRISPRi-dCas9 can be programmed to control the life cycle and infectivity ofEscherichia colibacteriophage T7, a highly virulent and obligatory lytic phage, by blocking critical host-dependent promoters that are required for host cell entry and life cycle execution. Using fluorescent reporters demonstrates that the efficacy of CRISPRi-dCas9 towardsE. coliRNAP promoters depends on target promoter strength, and that the phage’s own T7 RNAP can be downregulated very efficiently. Effects on the time to lysis were partially dictated by the chronological order of phage DNA and dCas9 target appearance in the cell, suggesting an accessory role ofE. coliRNAP during the early stages of T7 genome ejection. The stringency of the CRISPRi-dCas9 approach was greatly improved when using multiplex sgRNAs to target multiple phage regions simultaneously, resulting in a 25% increase in the time to lysis and up to 8-fold reduction in plaque size. Overall, this work expands CRISPRi-dCas9 as a flexible tool to non-invasively manipulate and probe the lifecycle and infectivity of otherwise native T7 phage.
AARS Online: a collaborative database on the structure, function, and evolution of the aminoacyl-tRNA synthetases
Authors: Douglas Jordan , Cui Haissi , Perona John J. , Vargas-Rodriguez Oscar , Tyynismaa Henna , Alvarez Carreño Claudia , Ling Jiqiang , Ribas-de-Pouplana Lluís , Yang Xiang-Lei , Ibba Michael , Becker Hubert , Fischer Frédéric , Sissler Marie , Carter Charles W. , Wills Peter R.
Published: May 2024

The aminoacyl-tRNA synthetases (aaRS) are a large group of enzymes that implement the genetic code in all known biological systems. They attach amino acids to their cognate tRNAs, moonlight in various non-translational activities, and are linked to many genetic disorders. The aaRS have a subtle ontology characterized by structural and functional idiosyncrasies that vary from organism to organism, and protein to protein. Across the tree of life, the twenty-two coded amino acids are handled by sixteen evolutionary Families of Class I aaRS and twenty-one Families of Class II aaRS. We introduce AARS Online, an interactive Wikipedia-like tool curated by an international consortium of field experts. This platform systematizes existing knowledge about the aaRS by showcasing a taxonomically diverse selection of aaRS sequences and structures. Through its graphical user interface, AARS Online facilitates a seamless exploration between protein sequence and structure, providing a friendly introduction to the material for non-experts and a useful resource for experts. Curated multiple sequence alignments can be extracted for downstream analyses. Accessible atwww.aars.online, AARS Online is a free resource to delve into the world of the aaRS.
Representation of locomotive action affordances in human behavior, brains and deep neural networks
Authors: Bartnik Clemens Georg , Sartzetaki Christina , Puigseslloses Sanchez Abel , Molenkamp Elijah , Bommer Steven , Vuksic Nikolina , Groen Iris Isabelle Anna
Published: May 2024

To decide how to move around the world, we must determine which locomotive actions (e.g., walking, swimming, or climbing) are afforded by the immediate visual environment. The neural basis of our ability to recognize locomotive affordances is unknown. Here, we compare human behavioral annotations, functional magnetic resonance imaging (fMRI) measurements, and deep neural network (DNN) activations to both in-door and outdoor real-world images to demonstrate that human visual cortex represents locomotive action affordances in complex visual scenes. Hierarchical clustering of behavioral annotations of six possible locomotive actions show that humans group environments into distinct affordance clusters using at least three separate dimensions. Representational similarity analysis of multi-voxel fMRI responses in scene-selective visual cortex shows that perceived locomotive affordances are represented independently from other scene properties such as objects, surface materials, scene category or global properties, and independent of the task performed in the scanner. Visual feature activations from DNNs trained on object or scene classification as well as a range of other visual understanding tasks correlate comparatively lower with behavioral and neural representations of locomotive affordances than with object representations. Training DNNs directly on affordance labels or using affordance-centered language embeddings increases alignment with human behavior, but none of the tested models fully captures locomotive action affordance perception. These results uncover a new type of representation in the human brain that reflects locomotive action affordances
Genetic screening and metabolomics identify glial adenosine metabolism as a therapeutic target in Parkinson's disease
Authors: Sodders Maggie J. , Avila-Pacheco Julian , Okorie Ernest C. , Shen Ming , Kumari Namrata , Marathi Archana , Lakhani Mehek , Bullock Kevin , Pierce Kerry , Dennis Courtney , Jeanfavre Sarah , Sarkar Souvarish , Scherzer Clemens R. , Clish Clary , Olsen Abby L.
Published: May 2024

Parkinson's disease (PD) is the second most common neurodegenerative disorder and lacks disease-modifying therapies. We developed a Drosophila model for identifying novel glial-based therapeutic targets for PD. Human alpha-synuclein is expressed in neurons and individual genes are independently knocked down in glia. We performed a forward genetic screen, knocking down the entire Drosophila kinome in glia in alpha-synuclein expressing flies. Among the top hits were five genes (Ak1, Ak6, Adk1, Adk2, and awd) involved in adenosine metabolism. Knockdown of each gene improved locomotor dysfunction, rescued neurodegeneration, and increased brain adenosine levels. We determined that the mechanism of neuroprotection involves adenosine itself, as opposed to a downstream metabolite. We dove deeper into the mechanism for one gene, Ak1, finding rescue of dopaminergic neuron loss, alpha-synuclein aggregation, and bioenergetic dysfunction after glial Ak1 knockdown. We performed metabolomics in Drosophila and in human PD patients, allowing us to comprehensively characterize changes in purine metabolism and identify potential biomarkers of dysfunctional adenosine metabolism in people. These experiments support glial adenosine as a novel therapeutic target in PD.
Reducing neuronal nitric oxide synthase (nNOS) expression in the ventromedial hypothalamus (VMH) increases body weight and blood glucose levels while decreasing physical activity in female mice
Authors: Hirschberg Pamela R. , Siegel Dashiel M. , Teegala Suraj , Rahbe Munir , Sarkar Pallabi , Routh Vanessa H.
Published: May 2024

Glucose-inhibited (GI) neurons of the ventromedial hypothalamus (VMH) depend on neuronal nitric oxide synthase (nNOS) and AMP-activated protein kinase (AMPK) for activation in low glucose. The Lopez laboratory has shown that the effects of estrogen on brown fat thermogenesis and white fat browning require inhibition of VMH AMPK. This effect of estrogen was mediated by downstream lateral hypothalamus (LH) orexin neurons1,2. We previously showed that estrogen inhibits activation of GI neurons in low glucose by inhibiting AMPK3. Thus, we hypothesized that VMH AMPK- and nNOS-dependent GI neurons project to and inhibit orexin neurons. Estrogen inhibition of AMPK in GI neurons would then disinhibit orexin neurons and stimulate brown fat thermogenesis and white fat browning, leading to decreased body weight. To test this hypothesis, we reduced VMH nNOS expression using nNOS shRNA in female mice and measured body weight, adiposity, body temperature, white and brown fat uncoupling protein (UCP1; an index of thermogenesis and browning), locomotor activity, and blood glucose levels. Surprisingly, we saw no effect of reduced VMH nNOS expression on body temperature or UCP1. Instead, body weight and adiposity increased by 30% over 2 weeks post injection of nNOS shRNA. This was associated with increased blood glucose levels and decreased locomotor activity. We also found that VMH nNOS-GI neurons project to the LH. However, stimulation of VMH-LH projections increased excitatory glutamate input onto orexin neurons. Thus, our data do not support our original hypothesis. Excitation of orexin neurons has previously been shown to increase physical activity, leading to decreased blood glucose and body weight4. We now hypothesize that VMH nNOS-GI neurons play a role in this latter function of orexin neurons.