bluuebunny/crossref_metadata_2025 huggingface dataset:
The Clustered Gamma Protocadherin Pcdhγc4 Isoform Regulates Cortical Interneuron Programmed Cell Death in the Mouse Cortex
Authors: Mancia Leon Walter R , Steffen David M , Dale-Huang Fiona , Rakela Benjamin , Breevoort Arnar , Romero-Rodriguez Ricardo , Hasenstaub Andrea R , Stryker Michael P , Weiner Joshua A , Alvarez-Buylla Arturo
Published: February 2023

Cortical function critically depends on inhibitory/excitatory balance. Cortical inhibitory interneurons (cINs) are born in the ventral forebrain and migrate into cortex, where their numbers are adjusted by programmed cell death. Previously, we showed that loss of clustered gamma protocadherins (Pcdhγ), but not of genes in the alpha or beta clusters, increased dramatically cIN BAX-dependent cell death in mice. Here we show that the sole deletion of the Pcdhγc4 isoform, but not of the other 21 isoforms in the Pcdhγ gene cluster, increased cIN cell death in mice during the normal period of programmed cell death. Viral expression of thePcdhγc4isoform rescued transplanted cINs lackingPcdhγfrom cell death. We conclude thatPcdhγ, specificallyPcdhγc4, plays a critical role in regulating the survival of cINs during their normal period of cell death. This demonstrates a novel specificity in the role ofPcdhγisoforms in cortical development.
Combined multiphoton microscopy and somatostatin receptor type 2 imaging of pancreatic neuroendocrine tumors
Authors: Daigle Noelle , Knapp Thomas , Duan Suzann , Jones David W. , Azhdarinia Ali , Ghosh Sukhen C. , AghaAmiri Solmaz , Ikoma Naruhiko , Estrella Jeannelyn , Schnermann Martin J. , Merchant Juanita L. , Sawyer Travis W.
Published: February 2023

Pancreatic neuroendocrine tumors (PNETs) are a rare but increasingly more prevalent cancer with heterogeneous clinical and pathological presentation. Surgery is the preferred treatment for all hormone-expressing PNETs and any PNET greater than 2 cm, but difficulties arise when tumors are multifocal, metastatic, or small in size due to lack of effective surgical localization. Existing techniques such as intraoperative ultrasound provide poor contrast and resolution, resulting in low sensitivity for such tumors.

Somatostatin receptor type 2 (SSTR2) is commonly overexpressed in PNETs and presents an avenue for targeted tumor localization. SSTR2 is often used for pre-operative imaging and therapeutic treatment, with recent studies demonstrating that somatostatin receptor imaging (SRI) can be applied in radioguided surgery to aid in removal of metastatic lymph nodes and achieving negative surgical margins. However not all PNETs express SSTR2, indicating labeled SRI could benefit from using a supplemental label-free technique such as multiphoton microscopy (MPM), which has proven useful in improving the accuracy of diagnosing more common exocrine pancreatic cancers.

Our work tests the suitability of combined SRI and MPM for localizing PNETs by imaging and comparing samples of PNETs and normal pancreatic tissue. Specimens were labeled with a novel SSTR2-targeted contrast agent and imaged using fluorescence microscopy, and subsequently imaged using MPM to collect four autofluo-rescent channels and second harmonic generation. Our results show that a combination of both SRI and MPM provides enhanced contrast and sensitivity for localizing diseased tissue, suggesting that this approach could be a valuable clinical tool for surgical localization and treatment of PNETs.
The tyrosine phosphatase LAR acts as a receptor of the nidogen-tetanus toxin complex
Authors: Surana Sunaina , Villarroel-Campos David , Panzi Chiara , Novoselov Sergey S. , Richter Sandy , Zanotti Giuseppe , Schiavo Giampietro
Published: February 2023

Tetanus toxin is one of the most potent neurotoxins and is the causative agent of tetanus. This neurotoxin binds to the neuromuscular junction and, after internalisation into motor neurons, undergoes long-distance axonal transport and transcytosis into spinal cord inhibitory interneurons. Inside the cytoplasm of interneurons, the catalytic chain of the toxin blocks neurotransmitter release, leading to spastic paralysis. Whilst the effects of tetanus toxin intoxication have been extensively studied, the molecular composition of its receptor complex is still poorly understood. We have previously shown that the extracellular matrix proteins nidogens are essential for binding of the toxin to the neuromuscular junction. In this study, we show that the tyrosine phosphatase LAR interacts with the nidogen-tetanus toxin complex and enables its uptake into motor neurons. Binding of LAR to the toxin complex is mediated by its fibronectin III domains, which we have harnessed to inhibit tetanus toxin entry into motor neurons. Surprisingly, this function of LAR is independent of its role in regulating the neurotrophic activity of the TrkB receptor, which has previously been shown to augment the axonal transport of signalling endosomes containing tetanus neurotoxin. These findings identify a multi-subunit complex acting as a protein receptor for tetanus neurotoxin, and demonstrate a novel endocytic trafficking route for extracellular matrix proteins in neurons. Our study paves the way for dissecting the molecular mechanisms that control the recognition and uptake of physiological ligands and pathological proteins at the neuronal plasma membrane, as well as their targeting to the axonal retrograde pathway for long-distance transport within the nervous system.
VO2maxprediction based on submaximal cardiorespiratory relationships and body composition in male runners and cyclists: a population study
Authors: Wiecha Szczepan , Kasiak Przemysław Seweryn , Szwed Piotr , Kowalski Tomasz , Cieśliński Igor , Postuła Marek , Klusiewicz Andrzej
Published: February 2023

Objectives

Oxygen uptake (VO2) is one of the most important measures of fitness and critical vital sign. CPET is a valuable method of assessing fitness in sport and clinical settings. This study aimed to: (1) derive prediction models for maximal VO2(VO2max) based on exercise variables at anaerobic threshold (AT) or respiratory compensation point (RCP) or only somatic and (2) internally validate provided equations.

Methods

4424 male endurance athletes (EA) underwent maximal symptom-limited CPET on a treadmill (n=3330) or cycle ergometer (n=1094). The cohort was randomly divided between: variables selection (nrunners=1998; ncyclist=656), model building (nrunners=666; ncyclist=219) and validation (nrunners=666; ncyclist=219). Random Forest was used to select the most significant variables. Models were derived and internally validated with Multiple Linear Regression.

Results

Runners were 36.24±8.45 yrs.; BMI=23.94±2.43 kg·m−2; VO2max=53.81±6.67 mL·min−1·kg−1. Cyclists were 37.33±9.13 yr.; BMI=24.34±2.63 kg·m−2; VO2max=51.74±7.99 mL·min−1·kg−1. VO2at AT and RCP were the most contributing variables to exercise equations. Body mass and body fat had the highest impact on the somatic equation. Model performance for VO2maxbased on variables at AT was R2=0.81, at RCP was R2=0.91, at AT&RCP was R2=0.91 and for somatic-only was R2=0.43.

Conclusions

Derived prediction models were highly accurate and fairly replicable. Formulae allow for precise estimation of VO2maxbased on submaximal exercise performance or somatic variables. Presented models are applicable for sport and clinical settling. They are a valuable supplementary method for fitness practitioners to adjust individualised training recommendations.

Funding

The author(s) received no specific funding for this work.
The BAF chromatin complex component SMARCC1 does not mediate GLI transcriptional repression of Hedgehog target genes in limb buds
Authors: Ramachandran Janani , Chen Wanlu , Lex Rachel K. , Windsor Kathryn E. , Lee Hyunji , Wang Tingchang , Zhou Weiqiang , Ji Hongkai , Vokes Steven A.
Published: February 2023

Transcriptional responses to the Hedgehog (HH) signaling pathway are primarily modulated by GLI repression in the mouse limb. Previous studies suggested a role for the BAF chromatin remodeling complex in mediating GLI repression. Consistent with this possibility, the core BAF complex protein SMARCC1 is present at most active limb enhancers including the majority of GLI enhancers. However, in contrast to GLI repression which reduces chromatin accessibility, SMARCC1 maintains chromatin accessibility at most enhancers, including those bound by GLI. Moreover, SMARCC1 binding at GLI-regulated enhancers occurs independently of GLI3. Consistent with previous studies, some individual GLI target genes are mis-regulated inSmarcc1conditional knockouts, though most GLI target genes are unaffected. Moreover, SMARCC1 is not necessary for mediating constitutive GLI repression in HH mutant limb buds. We conclude that SMARCC1 does not mediate GLI3 repression, which we propose utilizes alternative chromatin remodeling complexes.
Dopamine Dynamics Underlying Alloparental Behavioral Acquisition Facilitated by Top-down Orbitofrontal Inputs in Female Mice
Authors: Tasaka Gen-ichi , Hagihara Mitsue , Irie Satsuki , Kobayashi Haruna , Inada Kengo , Kobayashi Kenta , Kato Shigeki , Kobayashi Kazuto , Miyamichi Kazunari
Published: February 2023

Maternal behaviors, which are crucial for the survival of mammalian infants, require the coordinated operation of multiple brain regions to process infant cues, make decisions, and execute motor plans. Although these processes likely demand higher cognitive functions, the top-down regulation of limbic parental programs remains poorly understood. Here, we show that the orbitofrontal cortex (OFC) excitatory projection neurons promote alloparental caregiving behaviors in female mice. By chronic microendoscopy, we observed robust yet adaptable representations of pup-directed anticipatory and motor-related activities within the OFC that significantly overlapped with those related to nonsocial reward signals. The inactivation of OFC output reduced the phasic activities of midbrain dopamine (DA) neurons specifically tied to pup retrieval and impaired the modulation of DA release to the ventral striatum during the acquisition of alloparental behaviors. Collectively, our study identifies top-down signals from the OFC that modulate the plasticity of the DA system, thereby promoting alloparental behaviors.

Teaser

Orbitofrontal cortex neurons facilitate alloparental behaviors in virgin female mice by modulating the dopamine system.
Rapid prototyping of models for COVID-19 outbreak detection in workplaces
Authors: Abell Isobel , Zachreson Cameron , Conway Eamon , Geard Nicholas , McVernon Jodie , Waring Thomas , Baker Christopher
Published: February 2023

Early case detection is critical to preventing onward transmission of COVID-19 by enabling prompt isolation of index infections, and identification and quarantining of contacts. Timeliness and completeness of ascertainment depend on the surveillance strategy employed. We use rapid prototype modelling to quickly investigate the effectiveness of testing strategies, to aid decision making. Models are developed with a focus on providing relevant results to policy makers, and these models are continually updated and improved as new questions are posed. The implementation of testing strategies in high risk settings in Australia was supported using models to explore the effects of test frequency and sensitivity on outbreak detection. An exponential growth model is firstly used to demonstrate how outbreak detection changes with varying growth rate, test frequency and sensitivity. From this model we see that low sensitivity tests can be compensated for by high frequency testing. This model is then updated to an Agent Based Model, which was used to test the robustness of the results from the exponential model, and to extend it to include intermittent workplace scheduling. These models help our fundamental understanding of disease detectability through routine surveillance in workplaces and evaluate the impact of testing strategies and workplace characteristics on the effectiveness of surveillance. This analysis highlights the risks of particular work patterns while also identifying key testing strategies to best improve outbreak detection in high risk workplaces.
Characteristics and Long-term Mortality in Patients with ST-Segment Elevation Myocardial Infarction with Non-Obstructive Coronary Arteries (STE-MINOCA): A High Risk Cohort
Authors: Quesada Odayme , Yildiz Mehmet , Henry Timothy D. , Okeson Brynn K. , Chambers Jenny , Shah Ananya , Stanberry Larissa , Volpenhein Lucas , Aziz Dalia , Lantz Rebekah , Palmer Cassady , Ugwu Justin , Ahsan Muhammad J. , Garberich Ross F. , Rohm Heather S. , Aguirre Frank V. , Garcia Santiago , Sharkey Scott W.
Published: February 2023

Background

The prognosis of ST-segment elevation myocardial infarction with non-obstructive coronaries (STE-MINOCA) is largely unknown.

Methods

The objective of this study is to evaluate the prevalence, characteristics, and 5-year mortality of patients with STE-MINOCA compared to STEMI with coronary artery obstruction (STEMI-Obstruction) using a multicenter cohort of consecutive STEMI patients at 3 regional Midwest STEMI programs from 2003 to 2020. STE-MINOCA was defined based on (1) coronary stenosis < 60% by visual estimation, (2) ischemia with elevated troponin, and (3) no alternative diagnosis. STE-MINOCA was further classified based on American Heart Association (AHA) definition as AHA STE-MINOCA and AHA STE-MINOCA Mimicker.

Results

8,566 STEMI patients, including 420 (4.9%) STE-MINOCA (26.9% AHA STE-MINOCA and 73.1% AHA STE-MINOCA Mimicker) were followed for a median of 7.1 years. Compared to STEMI-Obstruction, STE-MINOCA were younger, more often female, had fewer cardiovascular risk factors, and were less likely to be discharged on cardiac medications. At five years, mortality was higher in STE-MINOCA compared with STEMI-Obstruction (18% vs. 15%, p=0.033). In propensity score-matched analysis, STE-MINOCA had a 1.4-fold (95% CI: 1.04-1.89, p=0.028) higher risk of 5-year all-cause mortality compared with STEMI-Obstruction. Furthermore, 5-year mortality risk was significantly higher in AHA STE-MINOCA Mimicker (19% vs. 15%, p=0.043) but similar in AHA STE-MINOCA (17% vs. 15%, p=0.42) compared with STEMI-Obstruction.

Conclusions

In this large multicenter STEMI cohort, nearly 5% of patients presented with STE-MINOCA. At five years, mortality approached 20% among patients with STE-MINOCA. Despite the lower risk profile, STE-MINOCA patients were at 40% higher risk of 5-year all-cause mortality compared with STEMI-Obstruction. Additionally, 5-year all-cause mortality risk was higher in AHA STE-MINOCA Mimicker but similar in AHA STE-MINOCA compared to STEMI-Obstruction.
Harmonized US National Health and Nutrition Examination Survey 1988-2018 for high throughput exposome-health discovery
Authors: Nguyen Vy Kim , Middleton Lauren Y. M. , Huang Lei , Zhao Neil , Verly Eliseu , Kvasnicka Jacob , Sagers Luke , Patel Chirag J , Colacino Justin , Jolliet Olivier
Published: February 2023

The National Health and Nutrition Examination Survey (NHANES) provides data on the health and environmental exposure of the non-institutionalized US population. Such data have considerable potential to understand how the environment and behaviors impact human health. These data are also currently leveraged to answer public health questions such as prevalence of disease. However, these data need to first be processed before new insights can be derived through large-scale analyses. NHANES data are stored across hundreds of files with multiple inconsistencies. Correcting such inconsistencies takes systematic cross examination and considerable efforts but is required for accurately and reproducibly characterizing the associations between the exposome and diseases. Thus, we developed a set of curated and unified datasets and accompanied code by merging 614 separate files and harmonizing unrestricted data across NHANES III (1988-1994) and Continuous (1999-2018), totaling 134,310 participants and 4,740 variables. The variables convey 1) demographic information, 2) dietary consumption, 3) physical examination results, 4) occupation, 5) questionnaire items (e.g., physical activity, general health status, medical conditions), 6) medications, 7) mortality status linked from the National Death Index, 8) survey weights, 9) environmental exposure biomarker measurements, and 10) chemical comments that indicate which measurements are below or above the lower limit of detection. We also provide a data dictionary listing the variables and their descriptions to help researchers browse the data. We also provide R markdown files to show example codes on calculating summary statistics and running regression models to help accelerate high-throughput analysis and secular trends of the exposome.
Contributions of rare and common variation to early-onset and atypical dementia risk
Authors: Wright Carter A. , Taylor Jared W. , Cochran Meagan , Lawlor James M.J. , Moyers Belle A. , Amaral Michelle D. , Bonnstetter Zachary T. , Carter Princess , Solomon Veronika , Myers Richard M. , Love Marissa Natelson , Geldmacher David S. , Cooper Sara J. , Roberson Erik D. , Cochran J. Nicholas
Published: February 2023

We collected and analyzed genomic sequencing data from individuals with clinician- diagnosed early-onset or atypical dementia. Thirty-two patients were previously described, with sixty-eight newly described in this report. Of those sixty-eight, sixty-two patients reported Caucasian, non-Hispanic ethnicity and six reported as African American, non-Hispanic. Fifty-three percent of patients had a returnable variant. Five patients harbored a pathogenic variant as defined by the American College of Medical Genetics criteria for pathogenicity. A polygenic risk score was calculated for Alzheimer’s patients in the total cohort and compared to the scores of a late-onset Alzheimer’s cohort and a control set. Patients with early-onset Alzheimer’s had higher non-APOEpolygenic risk scores than patients with late onset Alzheimer’s, supporting the conclusion that both rare and common genetic variation associate with early-onset neurodegenerative disease risk.
Mental distress among Norwegian adults during the Covid-19 pandemic: predictors of initial response and subsequent trajectories
Authors: Lu Li , Hannigan Laurie J. , Brandlistuen Ragnhild E , Nesvåg Ragnar , Trogstad Lill , Magnus Per , Unnarsdóttir Anna Bára , Valdimarsdóttir Unnur A. , Andreassen Ole A , Ask Helga
Published: February 2023

Background

Understanding factors associated with mental distress during a pandemic is imperative for planning interventions to reduce the negative mental health impact of future crises. Our aim was to identify factors associated with change in levels of mental distress in the Norwegian adult population at the onset of the Covid-19 pandemic, relative to pre-pandemic levels, and with longitudinal changes in mental distress until vaccination against Covid-19 became widespread in Norway (the first 1.5 years of the pandemic).

Methods

The Norwegian Mother, Father and Child Cohort Study (MoBa) is a prospective longitudinal study with baseline recruitment from 1999-2009. Baseline characteristics and eight waves of data collection during the pandemic (between March 2020 and September 2021) were used for this analysis. Mental distress was measured with the 5-item version of Hopkins Symptoms Checklist (HSCL-5). A piecewise latent growth model was fitted to identify initial change in mental distress (March-early April 2020, adjusting for pre-pandemic mental distress measured during prior years of data collection) and longitudinal changes across the pandemic in three distinct periods.

Findings

Our sample consisted of 105 972 adult participants (59.6% females). Mental distress levels peaked at the beginning of the pandemic. Several factors were associated with initial increases in distress: chronic medical conditions, living alone, history of psychiatric disorders, relatively lower educational background, female sex, younger age, and obesity. Several of these factors were also associated with long-term change. Being quarantined or having to isolate was associated with the likelihood of increasing distress during the pandemic. We observed a reduction in distress associated with Covid-19 vaccination status, while being infected with SARS-CoV-2 was associated with increasing distress late in the pandemic.

Interpretation

Pre-pandemic vulnerability factors – like having a chronic disease – as well as Covid-19-related factors – like being quarantined or infected by SARS-CoV-2 – were associated with increased mental distress during the pandemic. This knowledge is important for planning of interventions to support vulnerable individuals during pandemics and other health crises.

Funding

The Norwegian Ministry of Health, and Care Services and the Ministry of Education and Research. NordForsk, The Research Council of Norway, The South-Eastern Norway Regional Health Authority.
Systemic administration of the antisense oligonucleotide NS-089/NCNP-02 for skipping of exon 44 in patients with Duchenne muscular dystrophy: study protocol for a phase I/II clinical trial
Authors: Ishizuka Takami , Komaki Hirofumi , Asahina Yasuko , Nakamura Harumasa , Motohashi Norio , Takeshita Eri , Shimizu-Motohashi Yuko , Ishiyama Akihiko , Yonee Chihiro , Maruyama Shinsuke , Hida Eisuke , Aoki Yoshitsugu
Published: February 2023

Aim

The purpose of this study is to evaluate the safety and pharmacokinetics of the novel morpholino oligomer NS-089/NCNP-02 which can induce exon 44 skipping, in patients with DMD. Additionally, we aimed to identify markers predictive of therapeutic efficacy and determine the optimal dosing for future studies.

Methods

This is an open-label, dose-escalation, two-center phase I/II trial in ambulant patients with DMD, presence of an out-of-frame deletion, and a mutation amenable to exon 44 skipping. Part 1 is a stepwise dose-finding stage (4 weeks) during which NS-089/NCNP-02 will be administered intravenously at four dose levels once weekly (1.62, 10, 40, and 80 mg/kg); Part 2 is a 24-week evaluation period based on the dosages determined during Part 1. The primary (safety) endpoints are the results of physical examinations, vital signs, 12-lead electrocardiogram and echocardiography tests, and adverse event reporting. Secondary endpoints include expression of dystrophin protein, motor function assessment, exon 44 skipping efficiency, plasma and urinary NS-089/NCNP-02 concentrations, and changes in blood creatine kinase levels.

Discussion

Exon-skipping therapy using ASOs shows promise in selected patients, and this first-in-human study is expected to provide critical information for subsequent clinical development of NS-089/NCNP-02.
Are metastatic tumours histologically similar to the primary? Result of a blinded experiment
Authors: Singh Akshita , Jambhekar Nirmala , Shet Tanuja , Ramadwar Mukta , Dikshit Rajesh , Mittra Indraneel
Published: February 2023

There is an entrenched belief among pathologists, biologists and clinicians alike that metastatic tumours are histologically similar to the primary. Although this belief has never been scientifically tested, it forms the conceptual foundation upon which metastasis research has been based for decades. In order to scientifically test this dogma, we conducted a blinded experiment in which three highly experienced professor grade cancer pathologists were asked to predict the site of origin of 298 metastatic tumours arising at nine different sites. The accuracy of prediction of all three examiners was just under 50%. However, there was very little inter-observer agreement, and Kappa statistic generated the value of 0.27 which is much below the figure of 0.4 required to detect even a moderate level of concordance. In only 56 / 298 (18.8%) cases did the examiners agree with each other’s diagnosis. Thus the possibility cannot be excluded that the correct diagnoses made by the examiners had happened by play of chance. Our finding suggests that histological relationship between primary and metastatic tumours requires further investigation.
Genome-wide association study of blood mercury in European pregnant women and children
Authors: Dack Kyle , Bustamante Mariona , Taylor Caroline M. , Llop Sabrina , Lozano Manuel , Yousefi Paul D , Grazuleviciene Regina , Gutzkow Kristine Bjerve , Brantsæter Anne Lise , Mason Dan , Escaramís Georgia , Lewis Sarah J
Published: February 2023

Background

Mercury (Hg) is a toxic heavy metal which humans are most commonly exposed to through food chain contamination, especially via fish consumption. Even low-level exposure can be harmful because of the poor clearance rate, particularly for methylmercury. It is likely that genetic variation modifies exposure through changes in the absorption, metabolism, and/or removal of mercury. Associations have been reported between Hg and variants at multiple genetic loci, but in many cases these results are not yet replicated.

Methods

This study included two populations: pregnant women from the Avon Longitudinal Study of Parents and Children (ALSPAC, n=2,893) and children from the Human Early Life Exposome (HELIX, n=1,042). Genome-wide testing by cohort was performed by fitting linear regressions models on whole blood Hg levels and Haplotype Reference Consortium imputed single-nucleotide polymorphisms (SNPs). SNP heritability was estimated using linkage disequilibrium (LD)-score regression, and the biological functions of the top variants were investigated using resources which aggregate prior literature.

Results

Hg SNP heritability was estimated to be 24.0% (95% CI: 16.9% to 46.4%) for pregnant women. The number of genetic variants independently associated with whole blood mercury levels above a suggestive p-value threshold (P < 1×10−5) was 16 for pregnant women and 21 for children. However, none were replicated in both populations, nor did any pass a stronger genome-wide significant threshold (P < 5×10−8). Several suggestive variants had possible biological links to Hg such as rs146099921 in metal transporterSLC39A14, and two variants (rs28618224, rs7154700) in potassium voltage-gated channels genes.

Discussion

There was evidence for a considerable proportion of Hg variance being attributed to genome-wide variation in pregnant women. However, results between pregnant women and children were highly discordant which could reflect differences in metabolism and a gene-age interaction with Hg levels. There were a large number of SNPs suggestively associated with Hg levels, which likely include both true associations and false positives. These interim findings will be expanded following collaboration with additional study groups.
Prioritization of risk genes for Alzheimer’s disease: an analysis framework using spatial and temporal gene expression data in the human brain based on support vector machine
Authors: Wang Shiyu , Fang Xixian , Wen Xiang , Yang Congying , Yang Ying , Zhang Tianxiao
Published: February 2023

Background

Alzheimer’s disease (AD) is a complex disorder, and its risk is influenced by multiple genetic and environmental factors. In this study, an AD risk gene prediction framework based on spatial and temporal features of gene expression data (STGE) was proposed.

Methods

We proposed an AD risk gene prediction framework based on spatial and temporal features of gene expression data. The gene expression data of providers of different tissues and ages were used as model features. Human genes were classified as AD risk or non-risk sets based on information extracted from relevant databases. Support vector machine (SVM) models were constructed to capture the expression patterns of genes believed to contribute to the risk of AD.

Results

The recursive feature elimination (RFE) method was utilized for feature selection. Data for 64 tissue-age features were obtained before feature selection, and this number was reduced to 19 after RFE was performed. The SVM models were built and evaluated using 19 selected and full features. The area under curve (AUC) values for the SVM model based on 19 selected features (0.740 [0.690–0.790]) and full feature sets (0.730 [0.678–0.769]) were very similar. Fifteen genes predicted to be risk genes for AD with a probability greater than 90% were obtained.

Conclusion

The newly proposed framework performed comparably to previous prediction methods based on protein-protein interaction (PPI) network properties. A list of 15 candidate genes for AD risk was also generated to provide data support for further studies on the genetic etiology of AD.
Trials underestimate the impact of preventive treatment for household contacts exposed to multidrug-resistant tuberculosis: a simulation study
Authors: Kasaie Parastu , Pennington Jeff , Gupta Amita , Dowdy David W. , Kendall Emily A.
Published: February 2023

Background

Several clinical trials of tuberculosis preventive treatment (TPT) for household contacts of patients with multidrug-resistant tuberculosis (MDR-TB) are nearing completion. The potential benefits of TPT for MDR-TB contacts extend beyond the outcomes that clinical trials can measure.

Methods

We developed an agent-based, household-structured TB and MDR-TB transmission model, calibrated to an illustrative setting in India, the country accounting for 26% of global MDR-TB burden. We simulated household contact investigation for contacts of patients with MDR-TB, comparing an MDR-TPT regimen against alternatives of isoniazid preventive treatment, household contact investigation without TPT, or no household contact intervention. We simulated outcomes of a clinical trial and estimated the patient-level and population-level effects over a longer time horizon.

Findings

During two years of follow-up per recipient, a simulated 6-month MDR-TPT regimen with 70% efficacy against both DS- and MDR-TB infection could prevent 72% [Interquartile range (IQR): 45 – 100%] of incident MDR-TB among TPT recipients (number needed to treat (NNT) 73 [44 – 176] to prevent one MDR-TB case), compared to household contact investigation without TPT. This NNT decreased to 54 [30 – 183] when median follow-up was increased from two to 16 years, to 27 [11 – Inf] when downstream transmission effects were also considered, and to 12 [8 – 22] when these effects were compared to a scenario of no household contact intervention.

Interpretation

If forthcoming trial results demonstrate efficacy, the long-term population impact of MDR-TPT implementation could be much greater than suggested by trial outcomes alone.

Funding

NIH K01AI138853 and K08AI127908; Johns Hopkins Catalyst Award.
A population-based serological survey ofVibrio choleraeantibody titers in Ouest Department, Haiti in the year prior to the 2022 cholera outbreak
Authors: Clutter Christy H. , Klarman Molly B. , Cajusma Youseline , Cato Emilie T. , Sayeed Md. Abu , Brinkley Lindsey , Jensen Owen , Baril Chantale , Beau De Rochars V. Madsen , Azman Andrew S. , Long Maureen T. , Cummings Derek , Leung Daniel T. , Nelson Eric J.
Published: February 2023

After three years with no confirmed cholera cases in Haiti, an outbreak ofVibrio choleraeO1 emerged in October 2022. Levels of pre-existing antibodies provide an estimate of prior immunologic exposure, reveal potentially relevant immune responses, and set a baseline for future serosurveillance. We analyzed dried blood spots collected in 2021 from a population-weighted representative cross-sectional serosurvey in two communes in the Ouest Department of Haiti. We found lower levels of circulating IgG and IgA antibodies againstV. choleraelipopolysaccharide (LPS, IgG and IgA p<0.0001) in those below 5 years of age compared to those five years and older. Among a subset of patients with higher titers of antibodies, we were unable to detect any functional (vibriocidal) antibodies. In conclusion, the lack of detectable functional antibodies, and age-discordant levels ofV. choleraeLPS IgG, suggest that populations in Haiti may be highly susceptible to cholera disease, especially among young children.
Effects of joint mobilization combined with acupuncture on pain, physical function, and depression in stroke patients with chronic neuropathic pain: a randomized controlled trial
Authors: Lee Ji-Eun , Akimoto Takayuki , Lee Ho-Seong
Published: February 2023

Objective

To investigate the effectiveness of joint mobilization (JM) combined with acupuncture (AC) for treatment pain, physical function and depression in poststroke patients.

Methods

A total of 69 poststroke patients were randomly assigned to the JM+AC group (n = 23), the JM group (n = 23), and the control group (n = 23). Patients in the JM+AC group and the JM group received JM for 30 minutes, twice a week for 12 weeks, and the JM+AC group received AC for 30 minutes separately once a week. The control group did not receive JM or AC. Pain (visual analog scale, shoulder pain and disability index, Western Ontario and McMaster universities osteoarthritis index), physical function (range of motion, 10-m walking speed test, functional gait assessment, manual function test, activities of daily living scale, instrumental activities of daily living scale), and depression (center for epidemiologic studies depression scale, Beck depression inventory) were assessed for each patient before and after the 12 weeks of intervention.

Results

Pain and physical function were improved significantly in the JM+AC group compared with the JM and control groups. Physical function and depression were improved significantly in the JM+AC and JM groups compared with the control group.

Conclusion

The treatment of JM combined with AC improved pain, depression, and physical function of poststroke patients with chronic neuropathic pain in this study. This valuable finding provides empirical evidence for the designing therapeutic interventions and identifying potential therapeutic targets.
Heavy Metals Induced Health Risk Assessment Through Consumption of Selected Commercially Available Spices in Noakhali District of Bangladesh
Authors: Islam Md Shahedul , Chowdhury Akibul Islam , Shill Lincon Chandra , Reza Sompa , Alam Mohammad Rahanur
Published: February 2023

There are growing concerns for food safety due to the risks associated with heavy metal contamination of culinary herbs and spices in developing countries like Bangladesh. The objective of the present cross-sectional study is to determine the concentrations of the heavy metals Lead (Pb), Cadmium (Cd), Chromium (Cr), Copper (Cu), and Iron (Fe) in the branded and non-branded spices collected from the Noakhali district by Atomic absorption spectrophotometry method, as well as to assess the health hazard risk associated with heavy metal intake via consumption of spices. The findings revealed that the greatest concentrations of Pb (15.47 ± 1.93), Cd (1.65 ± 0.011), Cr (31.99 ± 3.97), Cu (18.84 ± 1.97), and Fe (9.29 ± 1.71) were found in Cardamom, Coriander leaf, Bay leaf, Dried chili, and Black pepper respectively. Around 37% of Cr and 5% of Fe Estimated Daily Values (EDI) were greater than reference doses (RfD). All spices had Total Hazard Quotient (THQ) values for Pb, Cd, Cu, and Fe that were below acceptable, and 37% of all spices had TTHQ values for Pb, Cd, Cu, and Fe that were over the standard range, suggesting adverse health impacts for consumers. Green chili, ginger, coriander leaf, and all kinds of chili powder and turmeric powder have been reported to have exceptionally high TTHQ levels of Cr. The estimated carcinogenic risk for unbranded chili, green chili, and coriander leaf was found to be higher than safe levels.
Analysis of electronic health records from three distinct and large populations reveals high prevalence and biases in the co-administration of drugs known to interact
Authors: Sánchez-Valle Jon , Correia Rion Brattig , Camacho-Artacho Marta , Lepore Rosalba , Mattos Mauro M. , Rocha Luis M. , Valencia Alfonso
Published: February 2023

The co-administration of drugs known to interact has a high impact on morbidity, mortality, and health economics. We study the drug-drug interaction (DDI) phenomenon by analyzing drug administrations from population-wide Electronic Health Records (EHR) in Blumenau (Brazil), Catalonia (Spain), and Indianapolis (USA). Despite very different health care systems and drug availability, we find a common large risk of DDI administration that affected 13 to 20% of patients in these populations. In addition, the increasing risk of DDI as patients age is very similar across all three populations but is not explained solely by higher co-administration rates in the elderly. We also find that women are at higher risk of DDI overall— except for men over 50 years old in Indianapolis. Finally, we show that PPI alternatives to Omeprazole can reduce the number of patients affected by known DDIs by up to 21% in both Blumenau and Catalonia, and 2% in Indianapolis, exemplifying how analysis of EHR data can lead to a significant reduction of DDI and its associated human and economic costs. Although the risk of DDIs increases with age, administration patterns point to a complex phenomenon that cannot be solely explained by polypharmacy and multimorbidity. The lack of safer drug alternatives, particularly for chronic conditions, further overburdens health systems, thus highlighting the need for disruptive drug research.
Human dorsal root ganglia after plexus injury: either preservation or loss of the multicellular unit
Authors: Schulte Annemarie , Degenbeck Johannes , Aue Annemarie , Schindehütte Magnus , Schlott Felicitas , Schneider Max , Monoranu Camelia Maria , Bohnert Michael , Pham Mirko , Antoniadis Gregor , Blum Robert , Rittner Heike L
Published: February 2023

Objective

Plexus injury results in lifelong suffering of flaccid paralysis, sensory loss, and intractable pain. For this clinical problem, regenerative medicine concepts, such as cell replacement for restoring dorsal root ganglion (DRG) function, set high expectations. However, it is completely unclear which DRG cell types are affected by plexus injury.

Methods

We investigated the cellular composition of human DRG in a clinically characterized cohort of patients with plexus injury. Avulsed DRG of 13 patients were collected during reconstructive nerve surgery. Then, we analyzed the cellular composition of the DRG with a human-adapted objective deep learning-based analysis of large-scale microscopy images.

Results

Surprisingly, in about half of the patients, the injury-affected DRG no longer contained DRG cells. The complete entity of neurons, satellite glial cells, and microglia was lost and replaced by mesodermal/connective tissue. In the other half of patients, the cellular entity of the DRG was well preserved. We found no loss of neurons, no gliosis, and macrophages close to single sensory neuron/satellite glial cell entities. Patients with ‘neuronal preservation’ had less pain than patients with ‘neuronal loss’.

Interpretation

The findings classify plexus injury patients in two categories: type I (neuronal preservation) and type II (neuronal loss). We call for early, post-accidental interventions to protect the entire DRG and improved MRI diagnostics to detect ‘neuronal loss’. Regenerative medicine to restore DRG function will need at least two translational directions: reafferentation of existing DRG units for type I injuries; or replacement of the entire DRG structure for type II patients.
Odor imagery but not perception drives risk for food cue reactivity and increased adiposity
Authors: Perszyk Emily E. , Davis Xue S. , Djordjevic Jelena , Jones-Gotman Marilyn , Trinh Jessica , Hutelin Zach , Veldhuizen Maria G. , Koban Leonie , Wager Tor D. , Kober Hedy , Small Dana M.
Published: February 2023

Mental imagery has been proposed to play a critical role in the amplification of cravings. Here we tested whether olfactory imagery drives food cue reactivity strength to promote adiposity in 45 healthy individuals. We measured odor perception, odor imagery ability, and food cue reactivity using self-report, perceptual testing, and neuroimaging. Adiposity was assessed at baseline and one year later. Brain responses to real and imagined odors were analyzed with univariate and multivariate decoding methods to identify pattern-based olfactory codes. We found that the accuracy of decoding imagined, but not real, odor quality correlated with a perceptual measure of odor imagery ability and with greater adiposity changes. This latter relationship was mediated by cue-potentiated craving and intake. Collectively, these findings establish odor imagery ability as a risk factor for weight gain and more specifically as a mechanism by which exposure to food cues promotes craving and overeating.
Altered IL-6 signalling and risk of tuberculosis disease: a meta-analysis and Mendelian randomisation study
Authors: Hamilton Fergus , Schurz Haiko , Yates Tom A. , Gilchrist James J. , Möller Marlo , Naranbhai Vivek , Ghazal Peter , Timpson Nicholas J ,   International Host TB Genetics Consortium, Parks Tom , Pollara Gabriele
Published: February 2023

IL-6 responses are ubiquitous inMycobacterium tuberculosis (Mtb)infections, but their role in determining human tuberculosis (TB) disease risk is unknown. We used single nucleotide polymorphisms (SNPs) in and near the IL-6 receptor(IL6R)gene, focusing on the non-synonymous variant, rs2228145, associated with reduced classical IL-6 signalling, to assess the effect of altered IL-6 activity on TB disease risk. We identified 16 genome wide association studies (GWAS) of TB disease collating 17,982 cases of TB disease and 972,389 controls across 4 continents. Meta-analyses and Mendelian randomisation analyses revealed that reduced classical IL-6 signalling was associated with lower odds of TB disease, a finding replicated using multiple, independent SNP instruments and 2 separate exposure variables. Our findings establish a causal relationship between IL-6 signalling and the outcome ofMtbinfection, suggesting IL-6 antagonists do not increase the risk of TB disease and should be investigated as adjuncts in treatment.
Month-to-month all-cause mortality forecasting: A method to rapidly detect changes in seasonal patterns
Authors: Léger Ainhoa-Elena , Silvia Rizzi
Published: February 2023

Background

Short-term forecasts of all-cause mortality are used retrospectively to estimate the baseline mortality and to obtain excess death after mortality shocks, such as heatwaves and pandemics, have occurred. In this study we propose a flexible method to forecast all-cause mortality in real-time and to rapidly identify short-term changes in all-cause mortality seasonal patterns within an epidemiological year.

Methods

We use all-cause monthly death counts and ratios of death counts between adjacent months as inputs. The ratio between one month (earlier month) and the consecutive month (later month) is called later/earlier ratio. We forecast the deaths one-month-ahead based on their proportion to the previous month, defined by the average later/earlier ratio over the preceding years. We provide forecasting intervals by way of a bootstrapping procedure.

Results

The method is applied to monthly mortality data for Denmark, France, Spain, and Sweden from 2012 through 2022. Over the epidemiological years before COVID-19, the method captures the variations in winter and summer mortality peaks. The results reflect the synchrony of COVID-19 waves and the corresponding mortality burdens in the four analyzed countries. The forecasts show a higher level of accuracy compared to traditional models for short-term forecasting, i.e., 5-year-average method and Serfling model.

Conclusion

The method proposed is attractive for health researchers and governmental offices to aid public health responses, because it uses minimal input data, i.e., monthly all-cause mortality data, which are timely available and comparable across countries.

Keymessages

What is already known on this topic: There is a lack of methods to forecast all-cause mortality in the short-term in a timely or near real-time manner.

What this study adds: The method that we propose forecasts all-cause mortality one month ahead assuming a seasonal mortality structure and adjusting it to the level of mortality of the epidemic year. These aspects make the method suitable for forecasting in a timely manner also during mortality shocks, such as the current COVID-19 pandemic.

How this study might affect research, practice or policy: The forecasts obtained with the proposed method detects changes in all-cause mortality patterns in a timely manner and can be used to aid public health responses.
Should bionic limb control mimic the human body? Impact of control strategy on bionic hand skill learning
Authors: Schone Hunter R. , Udeozor Malcolm , Moninghoff Mae , Rispoli Beth , Vandersea James , Lock Blair , Hargrove Levi , Makin Tamar R , Baker Chris I.
Published: February 2023

A longstanding engineering ambition has been to design anthropomorphic bionic limbs: devices that look like and are controlled in the same way as the biological body (biomimetic). The untested assumption is that biomimetic motor control enhances device embodiment, learning, generalization, and automaticity. To test this, we compared biomimetic and non-biomimetic control strategies for able-bodied participants when learning to operate a wearable myoelectric bionic hand. We compared motor learning across days and behavioural tasks for two training groups: Biomimetic (mimicking the desired bionic hand gesture with biological hand) and Arbitrary control (mapping an unrelated biological hand gesture with the desired bionic gesture). For both trained groups, training improved bionic limb control, reduced cognitive reliance, and increased embodiment over the bionic hand. Biomimetic users had more intuitive and faster control early in training. Arbitrary users matched biomimetic performance later in training. Further, arbitrary users showed increased generalization to a novel control strategy. Collectively, our findings suggest that biomimetic and arbitrary control strategies provide different benefits. The optimal strategy is likely not strictly biomimetic, but rather a flexible strategy within the biomimetic to arbitrary spectrum, depending on the user, available training opportunities and user requirements.
Corticosterone enhances formation of non-fear but not fear memory during infectious illness
Authors: Hill Alice , Johnston Colin , Agranoff Isaac , Gavade Swapnil , Spencer-Segal Joanna
Published: February 2023

Survivors of critical illness are at high risk of developing post-traumatic stress disorder (PTSD) but administration of glucocorticoids during the illness can lower that risk. The mechanism is not known but may involve glucocorticoid modulation of hippocampal- and amygdalar-dependent memory formation. In this study, we sought to determine whether glucocorticoids given during an acute illness influence the formation and persistence of fear and non-fear memories from the time of the illness. We performed cecal ligation and puncture in male and female mice to induce an acute infectious illness. During the illness, mice were introduced to a neutral object in their home cage and separately underwent contextual fear conditioning. We then tested the persistence of object and fear memories after recovery. Glucocorticoid treatment enhanced object discrimination but did not alter the expression of contextual fear memory. During context re-exposure, neural activity was elevated in the dentate gyrus irrespective of fear conditioning. Our results suggest that glucocorticoids given during illness enhance hippocampal-dependent non-fear memory processes. This indicates that PTSD outcomes in critically ill patients may be improved by enhancing non-fear memories from the time of their illness.