bluuebunny/crossref_metadata_2025 huggingface dataset:
Developing and Validating a Prediction Model For Death or Critical Illness in Hospitalized Adults, an Opportunity for Human-Computer Collaboration
Authors: Verma Amol A. , Pou-Prom Chloe , McCoy Liam G. , Murray Joshua , Nestor Bret , Bell Shirley , Mourad Ophyr , Fralick Michael , Friedrich Jan , Ghassemi Marzyeh , Mamdani Muhammad
Published: May 2023

OBJECTIVES:

Hospital early warning systems that use machine learning (ML) to predict clinical deterioration are increasingly being used to aid clinical decision-making. However, it is not known how ML predictions complement physician and nurse judgment. Our objective was to train and validate a ML model to predict patient deterioration and compare model predictions with real-world physician and nurse predictions.

DESIGN:

Retrospective and prospective cohort study.

SETTING:

Academic tertiary care hospital.

PATIENTS:

Adult general internal medicine hospitalizations.

MEASUREMENTS AND MAIN RESULTS:

We developed and validated a neural network model to predict in-hospital death and ICU admission in 23,528 hospitalizations between April 2011 and April 2019. We then compared model predictions with 3,374 prospectively collected predictions from nurses, residents, and attending physicians about their own patients in 960 hospitalizations between April 30, and August 28, 2019. ML model predictions achieved clinician-level accuracy for predicting ICU admission or death (ML median F1 score 0.32 [interquartile range (IQR) 0.30-0.34], AUC 0.77 [IQ 0.76-0.78]; clinicians median F1-score 0.33 [IQR 0.30–0.35], AUC 0.64 [IQR 0.63–0.66]). ML predictions were more accurate than clinicians for ICU admission. Of all ICU admissions and deaths, 36% occurred in hospitalizations where the model and clinicians disagreed. Combining human and model predictions detected 49% of clinical deterioration events, improving sensitivity by 16% compared with clinicians alone and 24% compared with the model alone while maintaining a positive predictive value of 33%, thus keeping false alarms at a clinically acceptable level.

CONCLUSIONS:

ML models can complement clinician judgment to predict clinical deterioration in hospital. These findings demonstrate important opportunities for human-computer collaboration to improve prognostication and personalized medicine in hospital.
A Novel Method to Detect Copy Number Variation in Melanoma: Droplet Digital PCR for Quantitation of the CDKN2A Gene, a Proof-of-Concept Study
Authors: McFadden Jason R. , Syku Marie , Barney Rachael E. , Stevanovic Mirjana , Chaudhari Advaita S. , O'Hern Keegan J. , Chambers Meagan , Baker Catherine M. , LeBlanc Robert E. , Doan Linda , Tsongalis Gregory J. , Hughes Edward G. , Sriharan Aravindhan
Published: May 2023

A definitive diagnosis of nevus or melanoma is not always possible for histologically ambiguous melanocytic neoplasms. In such cases, ancillary molecular testing can support a diagnosis of melanoma if certain chromosomal aberrations are detected. Current technologies for copy number variation (CNV) detection include chromosomal microarray analysis (CMA) and fluorescence in situ hybridization. Although CMA and fluorescence in situ hybridization are effective, their utilization can be limited by cost, turnaround time, and inaccessibility outside of large reference laboratories. Droplet digital polymerase chain reaction (ddPCR) is a rapid, automated, and relatively inexpensive technology for CNV detection. We investigated the ability of ddPCR to quantify CNV in cyclin-dependent kinase inhibitor 2A (CDKN2A), the most commonly deleted tumor suppressor gene in melanoma. CMA data were used as the gold standard. We analyzed 57 skin samples from 52 patients diagnosed with benign nevi, borderline lesions, primary melanomas, and metastatic melanomas. In a training cohort comprising 29 randomly selected samples, receiver operator characteristic curve analysis revealed an optimal ddPCR cutoff value of 1.73 for calling CDKN2A loss. In a validation cohort comprising the remaining 28 samples, ddPCR detected CDKN2A loss with a sensitivity and specificity of 94% and 90%, respectively. Significantly, ddPCR could also identify whether CDKN2A losses were monoallelic or biallelic. These pilot data suggest that ddPCR can detect CDKN2A deletions in melanocytic tumors with accuracy comparable with CMA. With further validation, ddPCR could provide an additional CNV assay to aid in the diagnosis of challenging melanocytic neoplasms.
Targeting hepatic serine-arginine protein kinase 2 ameliorates alcohol-associated liver disease by alternative splicing control of lipogenesis
Authors: Li Guannan , Chen Hanqing , Shen Feng , Smithson Steven Blake , Shealy Gavyn Lee , Ping Qinggong , Liang Zerong , Han Jingyan , Adams Andrew C. , Li Yu , Feng Dechun , Gao Bin , Morita Masahiro , Han Xianlin , Huang Tim H. , Musi Nicolas , Zang Mengwei
Published: May 2023

Background and Aims:

Lipid accumulation induced by alcohol consumption is not only an early pathophysiological response but also a prerequisite for the progression of alcohol-associated liver disease (ALD). Alternative splicing regulates gene expression and protein diversity; dysregulation of this process is implicated in human liver diseases. However, how the alternative splicing regulation of lipid metabolism contributes to the pathogenesis of ALD remains undefined.

Approach and Results:

Serine-arginine-rich protein kinase 2 (SRPK2), a key kinase controlling alternative splicing, is activated in hepatocytes in response to alcohol, in mice with chronic-plus-binge alcohol feeding, and in patients with ALD. Such induction activates sterol regulatory element-binding protein 1 and promotes lipogenesis in ALD. Overexpression of FGF21 in transgenic mice abolishes alcohol-mediated induction of SRPK2 and its associated steatosis, lipotoxicity, and inflammation; these alcohol-induced pathologies are exacerbated in FGF21 knockout mice. Mechanistically, SRPK2 is required for alcohol-mediated impairment of serine-arginine splicing factor 10, which generates exon 7 inclusion in lipin 1 and triggers concurrent induction of lipogenic regulators—lipin 1β and sterol regulatory element-binding protein 1. FGF21 suppresses alcohol-induced SRPK2 accumulation through mammalian target of rapamycin complex 1 inhibition-dependent degradation of SRPK2. Silencing SRPK2 rescues alcohol-induced splicing dysregulation and liver injury in FGF21 knockout mice.

Conclusions:

These studies reveal that (1) the regulation of alternative splicing by SRPK2 is implicated in lipogenesis in humans with ALD; (2) FGF21 is a key hepatokine that ameliorates ALD pathologies largely by inhibiting SRPK2; and (3) targeting SRPK2 signaling by FGF21 may offer potential therapeutic approaches to combat ALD.
Prognostic factors for high societal costs: a register-based study on 561,665 patients with shoulder disorders
Authors: Sørensen Lotte , van Dongen Johanna Maria , van Tulder Maurits , Oestergaard Lisa Gregersen
Published: May 2023

Shoulder disorders are common and associated with high societal costs, especially for a small group of patients. Prognostic factors can help identify high-cost patients, which is crucial to optimize early identification and develop tailored interventions. We aimed to identify prognostic factors for high societal costs, to examine whether the prognostic factors were similar for high healthcare costs and high costs of sick leave, and to investigate the model's robustness across 4 diagnostic categories. Using national Danish registers, potential prognostic factors (age, sex, educational level, long-term sick leave, admission, visits to general practitioner and physiotherapist, comorbidity, diabetes, low back pain, and neck pain) were included in a logistic regression model with high societal costs, defined by the top 10th percentile, as the main outcome. The model's prognostic accuracy was assessed using the Nagelkerke R
2 and its discriminative ability using area under the receiver operating curve (AUC). Data on 80% of the patients (n = 449,302) were used to develop the model and 20% (n = 112,363) to validate the model. By far the strongest prognostic factor for high societal costs and high costs of sick leave was sick leave at the time of diagnosis (OR: 20.2, 95% CI: 19.5-20.9). Prognostic factors for high healthcare costs were high age, comorbidity, and hospital admission the year before diagnosis. The model was robust across diagnostic categories and sensitivity analyses. In the validation sample, the primary model's discriminative ability was good (AUC = 0.80) and the model explained 28% of the variation in the outcome (Nagelkerke R
2).
Debates as an Active Learning Strategy to Enhance Students' Knowledge of Ethics in Professional Nursing Practice and Health Care
Authors: Napoleon Betty , Kuchenrither Christine
Published: May 2023

Background:

Ethical debates as an active learning strategy encourage students to think critically through complex ethical issues while using evidence-based literature to compare views and support decision-making actions that affect patient outcomes.

Problem:

The current complexity of health care implies that nurses will continue to encounter ethical dilemmas that demand essential knowledge of ethical principles, critical thinking strategies, and practical communication skills.

Approach:

Student groups were assigned a health care–related ethical issue and collaborated to present their pro or con position. The American Nurses Association (ANA) Code of Ethics and the American Association of Colleges of Nursing (AACN) Baccalaureate Essentials guided the structure of the student debates.

Conclusion:

Utilizing the ANA Code and AACN Essentials as supportive frameworks to guide students' ethical debate preparation and execution enhanced students' knowledge and supported their critical thinking about ethical issues in health care.
Development and Validation of an Operational Model for Nursing Academic-Practice Partnerships
Authors: Moss Angela , Cygan Heide , Geis Alice , Bejster Mallory , Ferry-Rooney Raechel , Kalensky Melissa , Delaney Kathleen R. , Cavenagh Yasmin , Gallagher Terry , Garbarz Krzysztof , Rousseau Jennifer
Published: May 2023

Background:

Several definitions and guiding principles for nursing academic-practice partnerships exist.

Problem:

There remains a gap between academic-practice partnership definitions and practical operational models, thereby limiting schools of nursing ability to engage in productive partnerships. This article describes the development and validation of a novel Operational Model for Nursing Academic-Practice Partnerships.

Approach:

An email survey of all nursing faculty (n = 228) identified quantity and types of faculty-led academic-practice partnerships. Quantitative data were analyzed using descriptive statistics. Qualitative data were analyzed via thematic analysis conducted by 2 members of the project team and validated by the full project team.

Outcomes:

The Operational Model for Academic-Practice Partnerships was created and is comprised of 8 partnership strategies: innovation, embedded faculty, joint appointment, consultant, independent practice, volunteer, scholarship, and clinical site development.

Conclusion:

We offer this model as a framework to structure the development, implementation, and evaluation of academic-practice partnerships at nursing schools.
Negative Pressure Wound Therapy for Skin Ulceration and Fistula After Surgery for Oral Cancer
Authors: Nakamura Hideharu , Makiguchi Takaya , Ogawa Masaru , Yokoo Satoshi
Published: May 2023

Oral cancer surgery has a high incidence of wound infection. The anatomy and physiology of the oral and maxillary regions are complex, and wounds often require a long time to heal. Negative pressure wound therapy (NPWT) can accelerate wound healing through the application of negative pressure to the wound. However, there are only a few reports on the use of this therapy in the oral and maxillofacial regions. Herein, the authors report 4 cases of skin ulcers and fistulas after oral cancer surgery treated with NPWT. Negative pressure wound therapy was performed in 4 patients (2 males and 2 females) who underwent resection of oral cancer and flap reconstruction and developed postoperative neck ulcers and fistulas. All 4 cases resulted in the healing of the ulcer and the disappearance of the fistula, and no recurrence was observed. Shortening the duration of treatment with NPWT reduces the patient burden and contributes to the prompt initiation of adjuvant therapy.
HYDROMORPHONE MITIGATES CARDIOPULMONARY BYPASS-INDUCED ACUTE LUNG INJURY BY REPRESSING PYROPTOSIS OF ALVEOLAR MACROPHAGES
Authors: Zhang Jun , Li Jie , An Zhongzhe , Qi Jun
Published: May 2023

Introduction: Acute lung injury (ALI) is a devastating pulmonary illness with diffuse inflammatory responses. Hydromorphone (Hyd) is an opioid agonist used for relieving moderate-to-severe pain. The present work investigated the effect of Hyd on cardiopulmonary bypass (CPB)–induced ALI by regulating pyroptosis of alveolar macrophages (AMs). Methods: Rats were subjected to CPB, followed by Hyd treatment. The lung injury in rat lung tissues was appraised by the ratio of lung wet/dry weight (weight), histological staining, and the total protein concentrations in bronchoalveolar lavage fluid, and lung function was assessed by oxygenation index and respiratory index, and lung macrophage pyroptosis was observed by fluorescence staining. Alveolar macrophages were separated and pyroptosis was determined by western blot assay and enzyme-linked immunosorbent assay. The expression patterns of nuclear factor erythroid 2–related factor 2/heme oxygenase 1 (Nrf2/HO-1), nod-like receptor protein 3 (NLRP3), N-terminal gasdermin-D, and cleaved caspase-1 were examined by real-time quantitative polymerase chain reaction, western blot, and immunohistochemistry assays. The impact of NLRP3 or Nrf2 on pyroptosis of AMs and CPB-induced ALI was observed after treatment of nigericin (NLRP3 agonist) or ML385 (Nrf2 inhibitor). Results: Hyd attenuated CPB-induced lung injury as manifested by reductions in lung inflammation and edema, the scores of lung injury, the ratio of lung wet/dry weight, and the total protein concentrations in bronchoalveolar lavage fluid. Besides, Hyd repressed NLRP3 inflammasome-mediated pyroptosis of AMs after CPB treatment. Hyd upregulated Nrf2/HO-1 expression levels to repress NLRP3 inflammasome-mediated pyroptosis. Treatment of nigericin or ML385 counteracted the role of Hyd in ameliorating pyroptosis of AMs and CPB-induced ALI. Conclusions: Hyd alleviated NLRP3 inflammasome-mediated pyroptosis and CPB-induced ALI via upregulating the Nrf2/HO-1 pathway, which may be achieved by AMs.
Toronto Management of Initially Unresectable Liver Metastases from Colorectal Cancer in a Living Donor Liver Transplant Program
Authors: Rajendran Luckshi , Claasen Marco PAW , McGilvray Ian D , Cattral Mark S , Ghanekar Anand , Selzner Nazia , Burkes Ron , Winter Erin , Gallinger Steven , Sapisochin Gonzalo
Published: May 2023

Introduction:

Living donor liver transplantation (LDLT) is an attractive option for patients with unresectable, bilobar colorectal liver metastases (CRLM). However, it is not available in most centres beyond study protocols. This study describes the interim experience with LDLT for CRLM at a large North American transplant and hepatobiliary centre.

Methods:

Adults with unresectable CRLM, receiving systemic chemotherapy were recruited into a prospective clinical trial. Data on demographics, referral patterns, and clinical characteristics were extracted from October 2016 to February 2023. Patients were divided into three groups: transplanted, resected, and control (excluded, with continuation of systemic chemotherapy). Overall survival (OS) and recurrence-free survival (RFS) were compared.

Results:

81 referred patients were assessed for LDLT. 7 received transplants, 22 underwent resection, and 48 control. All had similar pre-assessment baseline characteristics. Median time from initial assessment to transplantation was 15.4 months. The control population had significantly worse post-assessment OS than the transplanted population (p=0.002) and resected population (p<0.001). The median post-operative follow-up duration was 21.4 months (resection) and 14.8 months (LDLT). There was no difference in OS between the transplanted and resected populations (1-year 100% vs. 93.8%; 3-year 100% vs. 43.3%, p=0.17). However, RFS was superior in the LDLT group (1-year 85.7% vs. 11.4%; 3-year 68.6% vs. 11.4%, p=0.012).

Conclusion:

Most patients with unresectable CRLM referred for LDLT are deemed ineligible for trial inclusion. However, the excellent oncologic outcomes in patients who meet criteria for LDLT supports its role in highly selected populations. Future results after the trial’s completion will inform long-term outcomes.
Widespread mitochondrial DNA haplotypes ofPteroptyxspp. across present–day river systems in Southeast Asia and their historical dispersal through ancient river networks
Authors: Cheng Shawn , Ali Akaram Nur H. , Faidi Mohd A. , Aun Tan Sek , Bhassu Subha , Mat Isa Mohd N.
Published: May 2023

Estuarine fireflies from the genusPteroptyxare widely distributed in Southeast Asia and famous for their nightly displays of bioluminescence by adult fireflies congregating or lekking on mangrove trees.Pteroptyxfireflies also offer insights into the history of the region, as their distribution in many of the isolated rivers they now inhabit are likely a product of dispersal via palaeorivers that formed in Southeast Asia during the Pleistocene. Here, we report the presence of widespread cytochrome oxidase subunit I (cox1) haplotypes among populations ofPteroptyxspp. in estuaries throughout Southeast Asia and suggest possible dispersal routes for these haplotypes vis-à-vis the Siam and Malacca River systems. Separately, reconstruction of the haplotype tree from thecox1gene indicated that the ancestors ofPteroptyx asymmetria, Pteroptyx bearni, Pteroptyx malaccae, Pteroptyx tener, andPteroptyx validaeither had a Thai, Bornean, or Peninsular Malaysian origin. Previous reconstructions of the phylogenetic and network trees ofPteroptyxsp. did not consider the presence of identical mitochondrial DNA haplotypes in their datasets, and the role palaeorivers had on their dispersal. The perspectives reported here aim to guide future taxonomic, phylogenetic and phylogeographic work onPteroptyxfireflies in Southeast Asia.
Investigating causal relationship between smoking behavior and global brain volume
Authors: Chang Yoonhoo , Thornton Vera , Chaloemtoem Ariya , Anokhin Andrey P. , Bijsterbosch Janine , Bogdan Ryan , Hancock Dana B. , Johnson Eric Otto , Bierut Laura J.
Published: May 2023

Background

Previous studies have shown that brain volume is negatively associated with cigarette smoking, but there is an ongoing debate whether smoking causes lowered brain volume or a lower brain volume is a risk factor for smoking. We address this debate through multiple methods that evaluate causality: Bradford Hill’s Criteria to understand a causal relationship in epidemiological studies, mediation analysis, and Mendelian Randomization.

Methods

In 28,404 participants of European descent from the UK Biobank dataset, we examined relationships between a history of daily smoking and brain imaging phenotypes as well as associations of genetic predisposition to smoking initiation with brain volume.

Results

A history of daily smoking is strongly associated with decreased brain volume, and a history of heavier smoking is associated with a greater decrease in brain volume. The strongest association was between total grey matter volume and a history of daily smoking (p-value = 8.28 × 10−33), and there was a dose response relationship with more pack years smoked associated with a greater decrease in brain volume. A polygenic risk score (PRS) for smoking initiation was strongly associated with a history of daily smoking (p-value = 4.09 ×10−72), yet only modestly associated with total grey matter volume (p-value = 0.02). Mediation analysis indicated that a history of daily smoking is a mediator between smoking initiation PRS and total grey matter volume. Mendelian Randomization showed a causal effect of daily smoking on total grey matter volume (p-value = 0.022).

Conclusions

These converging findings strongly support the hypothesis that smoking causes decreased brain volume.
Contribution of rare variants to heritability of a disease is much greater than conventionally estimated: modification of allele distribution model
Authors: Nagao Yoshiro
Published: May 2023

Missing heritability is a current problem in human genetics. I previously reported a method to estimate heritability of a polymorphism (hp2) for a common disease without calculating the genetic variance under dominant and the recessive models. Here, I extended the method to the co-dominant model and carry out trial calculations of hp2. I also calculated hp2applying the allele distribution model originally reported by Pawitan et al. for a comparison. Unexpectedly, hp2calculated for rare variants with high odds ratios was much higher. I noticed that conventional methods use the allele frequency (AF) of a variant in the general population. However, this implicitly assumes that the unaffected are included among the phenotypes: an assumption that is inconsistent with case-control studies in which unaffected individuals belong to the control group. Therefore, I modified the allele distribution model by using the AF in the patient population. Consequently, the hp2of rare variants was quite high. Recalculating hp2of several rare variants reported in the literature with the modified allele distribution model, yielded results were 3.2 - 53.7 times higher than the original model. These results suggest that the contribution of rare variants to heritability of a disease has been considerably underestimated.
ChatGPT and the Clinical Informatics Board Examination: The End of Knowledge-based Medical Board Maintenance?
Authors: Kumah-Crystal Yaa , Mankowitz Scott , Embi Peter , Lehmann Christoph U.
Published: May 2023

Objectives

Assess ChatGPT’s performance on the Clinical Informatics Board Examination (CIBE) and discuss the implications of large language models (LLMs) for board certification and maintenance.

Materials and Methods

We tested ChatGPT using 260 multiple-choice questions from Mankowitz’s Clinical Informatics Board Review book, omitting six image-dependent questions.

Results

ChatGPT answered 190 (74%) of 254 eligible questions correctly. While performance varied across the Clinical Informatics Core Content Areas, differences were not statistically significant.

Discussion

ChatGPT’s performance raises concerns about the potential misuse in medical certification and the future validity of knowledge assessment exams. While ChatGPT is able to answer multiple-choice questions accurately, relying on AI systems for exams will compromise the credibility and validity of at-home assessments and undermine public trust.

Conclusion

The advent of AI and LLMs threatens to upend existing processes to board certification and maintenance and necessitates new approaches to the evaluation of proficiency in medical education.
Temporal Variations in Ischemic and Bleeding Event Risks after Acute Coronary Syndrome during Dual Antiplatelet Therapy
Authors: Fujii Toshiharu , Kasai Satoshi , Kawamura Yota , Yoshimachi Fuminobu , Ikari Yuji
Published: May 2023

Background

This study estimates the temporal risk variations of ischemic and bleeding events during dual antiplatelet therapy (DAPT) and suggests the optimal period for DAPT after acute coronary syndrome (ACS) categorized by the Academic Research Consortium for High Bleeding Risk (ARC-HBR) criteria.

Methods

A total of 1,264 ACS patients receiving either clopidogrel or prasugrel with aspirin were classified by ARC-HBR criteria into HBR (n = 574) and non-HBR groups (n = 690). This study was designed as a multicenter observation to evaluate the primary endpoints of ischemic, including cardiogenic death, myocardial infarction, or ischemic stroke, and bleeding events, defined as Bleeding Academic Research Consortium type 3 or 5. The temporal risk variations were estimated using the Cox hazard and Royston-Parmar models.

Results

Ischemic and bleeding events were observed in 9.4% and 7.4% of patients, respectively, during an average observation period of 313 days. The HBR group had a higher incidence of both events than the non-HBR group (15.3% vs. 4.5%, P < 0.01 for ischemic; 11.9% vs. 3.8%, P < 0.01 for bleeding). The estimated risk curves revealed a peak and steep decline in the first few days, followed by a constant decline. The peak of risk was higher for bleeding than for ischemic events, but this relationship reversed early, with ischemic events displaying a higher risk in both the HBR and non-HBR groups until at least 60 days.

Conclusion

A 60-day period of DAPT is appropriate to balance the risks of adverse events after ACS, regardless of ARC-HBR criteria.
Maternal caffeine consumption during pregnancy and offspring cord blood DNA methylation: a meta-analysis of epigenome-wide association studies
Authors: Schellhas Laura , Monasso Giulietta S , Felix Janine F , Jaddoe Vincent WV , Huang Peiyuan , Fernández-Barrés Sílvia , Vrijheid Martine , Pesce Giancarlo , Annesi-Maesano Isabella , Page Christian M , Brantsæter Anne-Lise , Bekkhus Mona , Håberg Siri E , London Stephanie J , Munafò Marcus R , Zuccolo Luisa , Sharp Gemma C
Published: May 2023

Background

Women are advised to limit caffeine consumption during pregnancy. To uncover the potential epigenetic effects of intrauterine caffeine exposure, we investigated the association of maternal caffeine consumption during pregnancy with genome-wide DNA methylation in cord blood.

Methods

We meta-analysed results from epigenome-wide methylation studies at individual probes and in differentially methylated region (DMR) analysis across 6 European pregnancy and birth cohorts (ALSPAC, BiB, MoBa, Generation R, INMA, EDEN; total n = 3742). Methylation was assessed with lllumina Infinium 450k or EPIC arrays. Maternal caffeine consumption (mg/day) from coffee, tea and cola was derived from questionnaires between weeks 12 - 22 of pregnancy. We investigated associations of methylation with overall and beverage-specific caffeine intake in models adjusted for maternal education, age, BMI, smoking during pregnancy, parity, cord-blood cell proportions and 20 surrogate variables.

Results

One CpG site (cg19370043, nearest genePRRX1) was associated with maternal caffeine consumption after FDR adjustment for multiple testing and one CpG sites (cg14591243, nearest geneSTAG1) was associated with maternal cola consumption. We found evidence for 12-22 DMRs for each of the caffeine models but little overlap between DMRs identified for specific caffeinated beverages.

Conclusions

In models adjusted for maternal smoking and other potential confounders, we found little evidence to support an intrauterine effect of caffeine on offspring DNA methylation. Comparing associations across different sources of caffeine provided no evidence for caffeine being the causal agent. It is possible that our study did not have adequate statistical power to detect very small associations between maternal caffeine and offspring DNA methylation.

Key messages

- This large-scale meta-analysis of epigenomewide association studies across six European cohorts does not support an intrauterine effect of caffeine on offspring cord blood DNA methylation.

- Lack of overlap between associations with different caffeinated drinks suggest that any (weak) associations were driven by diverse confounding structures of different caffeinated drinks, rather than caffeine per se.

- More research is needed to understand the biological mechanisms driving potential effects of caffeine on offspring health.
One side effect – two networks? Lateral and postero-medial stimulation spreads induce dysarthria in subthalamic deep brain stimulation for Parkinson’s Disease
Authors: Jergas Hannah , Petry-Schmelzer Jan Niklas , Hannemann Jonathan , Thies Tabea , Strelow Joshua N. , Rubi-Fessen Ilona , Quinting Jana , Baldermann Juan Carlos , Mücke Doris , Fink Gereon R. , Visser-Vandewalle Veerle , Dembek Till A. , Barbe Michael T.
Published: May 2023

Objective

This study aims to shed light on structural networks associated with stimulation-induced dysarthria (SID) and to derive a data-driven model to predict SID in patients with Parkinson’s Disease (PD) and deep brain stimulation (DBS) of the subthalamic nucleus (STN).

Methods

Randomized, double-blinded monopolar reviews determining SID thresholds were conducted in 25 patients with PD and STN-DBS. A fiber-based mapping approach, based on the calculation of fiber-wise Odds Ratios for SID, was employed to identify the distributional pattern of SID in the STN’s vicinity. The ability of the data-driven model to classify stimulation volumes as “causing SID” or “not causing SID” was validated by calculating receiver operating characteristics (ROC) in an independent out-of-sample cohort comprising 14 patients with PD and STN-DBS.

Results

Local fiber-based stimulation maps showed an involvement of fibers running lateral and postero-medial to the STN in the pathogenesis of SID, independent of the investigated hemisphere. ROC-analysis in the independent out-of-sample cohort resulted in a good fit of the data-driven model for both hemispheres (AUCleft= 0.88, AUCright= 0.88).

Interpretation

This study reveals an involvement of both, cerebello-thalamic fibers, as well as the pyramidal tract, in the pathogenesis of SID in STN-DBS. The results may impact future postoperative programming strategies to avoid SID in patients with PD and STN-DBS.
Normal neurophysiologic parameters of the tibial nerve among adult healthy Sudanese population
Authors: Noury Ahmed O , Elmagzoub Mohammed Salah , Ahmed Ahmed Hassan , Hameed Hussam M A
Published: May 2023

Background

Nerve conductive studies (NCS) are the most informative portion of the electrodiagnostic evaluation for peripheral neuropathy; NCS can be extremely useful both in localizing lesions and determining the pathological processes. Recently, there is increased interest in quality of normative values for each test result and compare should be done between normal and patients regarding specific disease. So, The aim of our study is to help establish NCS normative data of tibial nerve that could be applicable in the Sudanese population and can be used in neurophysiology departments around the country and to compare with those data published in the literature, and to survey the effects of Age, Gender, Height, Weight and Temperature on Nerve Conduction Study Parameters.

Methods

NCSs were performed in 210 tibial nerves of 105 adult healthy Sudanese subjects using standardized techniques.

Results

It was found that the tibial nerve component values as follows; the distal latency is 4.063±1.0533 m/sec, Proximal latency 13.238 ±1.7253 m/sec, Conduction velocity 48.58±5.634 m/sec, F wave 51.509±6.1013 m/sec, Duration of CMAP at ankle 6.199± 1.0254 m/sec, Amplitude of CMAP at ankle 8.528±3.6658 μV, Area of CMAP at ankle 17.569±7.7389μV/ms, Duration of CMAP at popliteal 7.075±1.3173 m/sec, Amplitude of CMAP at popliteal 6.343±3.2871μV and Area at popliteal 14.914±7.8684 μV/ms.

Conclusion

The tibial motor nerve conduction parameters for the tested nerve compared favorably with the existing literature with some discrepancies that were justified

Significance

This is the first study to establish reference values for tibial NCS carried out Sudanese population.
Understanding priorities and needs for child and adolescent mental health in Greece from multiple informants: an open resource
Authors: Koumoula Anastasia , Marchionatti Lauro Estivalete , Karagiorga Vasiliki Eirini , Schafer Julia Luiza , Simioni André , Caye Arthur , Serdari Aspasia , Kotsis Konstantinos , Basta Maria , Athanasopoulou Lilian , Dafoulis Vaios , Tsatsiopoulou Paraskevi , Zilikis Nikos , Vergouli Evangelia , Balikou Panagiota , Kapsimali Efi , Mitropoulou Andromachi , Tzotzi Alexandra , Klavdianou Nikanthi , Zeleni Domna , Mitroulaki Sotiria , Botzaki Anna , Gerostergios Giorgos , Samiotakis Giorgos , Moschos Giorgos , Giannopoulou Ioanna , Papanikolaou Katerina , Angeli Katerina , Scarmeas Nikolaos , Emanuele Jill , Schuster Kenneth , Karyotaki Eirini , Kalikow Lily , Pronoiti Katerina , Merikangas Kathleen R. , Szatmari Peter , Cuijpers Pim , Georgiades Katholiki , Milham Michael P. , Corcoran Mimi , Burke Sarah , Koplewicz Harold , Salum Giovanni Abrahão
Published: May 2023

Background

Evidence-based policymaking is needed so that health systems can address the gap in care for children and adolescents facing mental health challenges. We describe the development of an open-resource dataset providing a comprehensive assessment of the needs for child and adolescent mental health care in Greece.

Methods

This study is a part of the Child and Adolescent Mental Health Initiative (CAMHI), a program aiming to enhance mental health care capacity for children and adolescents across Greece. A comprehensive, mixed-method, community-based research was conducted in 2022/2023 to examine the current state, needs, barriers, and opportunities according to multiple viewpoints. Participants consisted of children, adolescents (including underrepresented minorities), caregivers, schoolteachers, and health professionals. We surveyed geographically distributed samples to assess mental health symptoms, mental health needs, literacy and stigma, service use and access, professional practices, training background, and training needs and preferences. Focus groups were conducted with informants to reach an in-depth understanding of those topics.

Results

We surveyed 1,756 caregivers, 1,201 children/adolescents, 404 schoolteachers, and 475 health professionals. Fourteen focus groups were conducted with the general and professional community. A repository with quantitative and qualitative findings informing multiple topics is now available for researchers, policymakers, and society [https://osf.io/crz6h/].

Discussion

This resource offers valuable data for assessing the needs and priorities for child and adolescent mental health care in Greece. It is now freely available to consult, and is expected to inform upcoming research and evidence-based professional training. This initiative may inspire similar ones in other countries, informing methodological strategies for researching mental health needs.

Funding

The Stavros Niarchos Foundation.
Why are different estimates of the effective reproductive number so different? A case study on COVID-19 in Germany
Authors: Brockhaus Elisabeth K. , Wolffram Daniel , Stadler Tanja , Osthege Michael , Mitra Tanmay , Littek Jonas M. , Krymova Ekaterina , Klesen Anna J. , Huisman Jana S. , Heyder Stefan , Helleckes Laura M. , Heiden Matthias an der , Funk Sebastian , Abbott Sam , Bracher Johannes
Published: May 2023

The effective reproductive numberRthas taken a central role in the scientific, political, and public discussion during the COVID-19 pandemic, with numerous real-time estimates of this quantity routinely published. Disagreement between estimates can be substantial and may lead to confusion among decision-makers and the general public. In this work, we compare different estimates of the national-level effective reproductive number of COVID-19 in Germany in 2020 and 2021. We consider the agreement between estimates from the same method but published at different time points (within-method agreement) as well as retrospective agreement across different approaches (between-method agreement). Concerning the former, estimates from some methods are very stable over time and hardly subject to revisions, while others display considerable fluctuations. To evaluate between-method agreement, we reproduce the estimates generated by different groups using a variety of statistical approaches, standardizing analytical choices to assess how they contribute to the observed disagreement. These analytical choices include the data source, data pre-processing, assumed generation time distribution, statistical tuning parameters, and various delay distributions. We find that in practice, these auxiliary choices in the estimation ofRtmay affect results at least as strongly as the selection of the statistical approach. They should thus be communicated transparently along with the estimates.
Characterization and Resistance to Mutation of a Single-Channel Multiplex PCR Assay for SARS-CoV-2
Authors: Pednault Amy L. , Swalla Brian M.
Published: May 2023

Throughout the COVID-19 pandemic, wastewater surveillance has been used worldwide to provide valuable public health data. RT-qPCR is frequently used as a quantitative methodology for wastewater surveillance but is susceptible to mutations in target regions. These mutations may lead to misinterpretation of surveillance data; a drop in signal could be concluded to be a result of lower viral load, when in fact it is caused by reduced detection efficiency. We describe a novel approach to mitigating the impacts of such mutations: monitoring the cumulative signal from two targets (N1 and N2) via independent amplification reactions using identically labeled probes; a “single-channel multiplex” approach. Using the IDEXX Water SARS-CoV-2 RT-qPCR test, we demonstrate equivalent intra-assay repeatability and quantitative results from the combined N1N2 test when compared to individual N1 and N2 assays. Furthermore, we show that while mutations in B.1.1.529, BA.5.2, and BA.5.2.1 significantly impact the performance of the N1 assay, the impact on the N1N2 assay was negligible, and nearly within acceptable margin of error for technical replicates. These findings demonstrate that a single-channel multiplex approach can be used to improve the robustness of wastewater surveillance and minimize the risk of future mutations leading to unreliable public health data.
Machine Learning-based Clinical Decision Support for Infection Risk Prediction
Authors: Feng Ting , Noren David , Kulkarni Chaitanya , Mariani Sara , Zhao Claire , Ghosh Erina , Swearingen Dennis , Frassica Joseph , McFarlane Daniel , Conroy Bryan
Published: May 2023

Background

Healthcare-associated infection (HAI) remains a significant risk for hospitalized patients and a challenging burden for the healthcare system. This study presents a clinical decision support tool that can be used in clinical workflows to proactively engage secondary assessments of pre-symptomatic and at-risk infection patients, thereby enabling earlier diagnosis and treatment.

Methods

This study applies machine learning, specifically ensemble-based boosted decision trees, on large retrospective hospital datasets to develop an infection risk score that predicts infection before obvious symptoms present. We extracted a stratified machine learning dataset of 36,782 healthcare-associated infection patients. The model leveraged vital signs, laboratory measurements and demographics to predict HAI before clinical suspicion, which is defined as the order of a microbiology test or administration of antibiotics.

Results

We find that our best performing infection risk model achieves a cross-validated AUC of 0.88 at 1-hour before clinical suspicion and maintains an AUC>0.85 for 48-hours before suspicion by aggregating information across demographics and a set of 163 vital signs and laboratory measurements. A second model trained on a reduced feature space comprising demographics and the 36 most frequently measured vital signs and laboratory measurements can still achieve an AUC of 0.86 at 1-hour before clinical suspicion. These results compare favorably against using temperature alone and clinical rules such as the quick Sequential Organ Failure Assessment (qSOFA) score. Along with the performance results, we also provide an analysis on model interpretability via feature importance rankings.

Conclusions

The predictive model aggregates information from multiple physiological parameters such as vital signs and laboratory measurements to provide a continuous risk score of infection that can be deployed in hospitals to provide advance warning of patient deterioration.
DLST—a Cuproptosis-related Gene—is a Potential Diagnostic and Prognostic Factor for Clear Cell Renal Cell Carcinoma
Authors: Wang Haoyuan , Ma Xiaopeng , Li Sijie , Ni Xiaochen
Published: May 2023

Clear cell renal cell carcinoma (ccRCC) accounts for the highest number of renal malignancies and 3% of all adult cancers. The incidence of ccRCC is increasing worldwide, and its prognosis is poor. Approximately 30% of the patients are diagnosed at a late stage and are frequently asymptomatic. Cuproptosis is a new type of cell death that is regulated by Cu ions. As cuproptosis is associated with cancer development, we hypothesized that changes in the expression of cuproptosis-related genes (CRGs) are associated with the prognosis of ccRCC, and that CRGs can serve as biomarkers for the diagnosis and prognosis of ccRCC. In the present study, we explored the correlation between CRGs and ccRCC prognosis by analyzing publicly available data. We analyzed the clinical information and RNA-sequencing data in The Cancer Genome Atlas using bioinformatics tools. Dihydrolipoamide S-succinyltransferase (DLST) was identified as a novel gene with predictive and diagnostic potential. CRGs were under-expressed in ccRCC samples, and downregulation ofDLSTwas highly associated with poor prognosis. Cox univariate and multivariate regression analyses revealed thatDLSTcould serve as an independent prognostic factor for ccRCC. Further, functional enrichment analysis indicated that low expression ofDLSTmay affect immune function. Our results strongly indicate thatDLSTplays an important role in ccRCC progression and may serve as an independent diagnostic and prognostic biomarker for ccRCC. Therefore,DLSTis a potential therapeutic target for patients with ccRCC.
Multi-sector stakeholder consensus on tackling the complex health and social needs of the growing population of people leaving prison in older age
Authors: Hwang Ye In (Jane) , Withall Adrienne , Hampton Stephen , Snoyman Phillip , Forsyth Katrina , Butler Tony
Published: May 2023

As populations age globally, cooperation across multi-sector stakeholders is increasingly important to service older persons, particularly those with high and complex health and social needs. One such population is older people entering society after a period of incarceration in prison. The ‘ageing epidemic’ in prisons worldwide has caught the attention of researchers, governments and community organisations, who identify challenges in servicing this group as they re-enter the community. Challenges lie across multiple sectors, with inadequate support leading to dire consequences for public health, social welfare and recidivism. This is the first study to bring together multi-sector stakeholders from Australia to form recommendations for improving health and social outcomes for older people re-entering community after imprisonment. A modified nominal group technique was used to produce recommendations from N=15 key stakeholders across prison health, corrections, research, advocacy, aged care, community services, via online workshops. The importance and priority of these recommendations was validated by a broader sample of N=44 stakeholders, using an online survey. Thirty-six recommendations for improving outcomes for this population were strongly supported. These recommendations entail two important findings about this population: (1) They are a high-needs, unique, and underserved group at risk of significant health and social inequity in the community, (2) Multi-sector stakeholder cooperation will be crucial to service this growing group.
ARF1 prevents aberrant type I IFN induction by regulating STING activation and recycling
Authors: Hirschenberger Maximilian , Lepelley Alice , Rupp Ulrich , Klute Susanne , Hunszinger Victoria , Koepke Lennart , Merold Veronika , Didry-Barca Blaise , Wondany Fanny , Bergner Tim , Wiese Sebastian , Volpi Stefano , Gattorno Marco , Papa Riccardo , Lynch Sally-Ann , Haug Marte G. , Houge Gunnar , Wigby Kristen M. , Sprague Jessica , Lenberg Jerica , Read Clarissa , Walther Paul , Michaelis Jens , Kirchhoff Frank , de Oliveira Mann Carina C. , Crow Yanick J. , Sparrer Konstantin M.J.
Published: May 2023

Type I interferon (IFN) signalling is tightly controlled. Upon recognition of DNA by cyclic GMP AMP synthase (cGAS), stimulator of interferon genes (STING) translocates along the endoplasmic reticulum (ER)-Golgi axis to induce IFN signalling. Termination is achieved through autophagic degradation or recycling of STING by retrograde Golgi-to-ER transport. Here, we identify the GTPase ARF1 as a crucial negative regulator of cGAS-STING signaling. Heterozygous ARF1 missense mutations cause a novel type I interferonopathy associated with enhanced IFN stimulated gene expression. Disease-associated, GTPase-defective, ARF1 results in increased cGAS-STING dependent type I IFN signalling in cell lines and primary patient cells. Mechanistically, mutated ARF1 perturbs mitochondrial fusion causing cGAS activation by aberrant mitochondrial DNA, and promotes accumulation of active STING at the Golgi/ERGIC due to defective retrograde transport. Our data show that ARF1 has an unexpected dual role in maintaining cGAS-STING homeostasis, through the promotion of mitochondrial fusion and STING recycling.
Interaction between risk SNPs of Developmental Dyslexia and Parental Education on Reading Ability: Evidence for Differential-Susceptibility Theory
Authors: Yang Qing , Cheng Chen , Wang Zhengjun , Belsky Jay , Zhao Jingjing
Published: May 2023

While genetic and environmental factors have been shown as predictors of children’s reading ability, the interaction effects of identified genetic risk susceptibility and specified environmental for reading ability have rarely been investigated. The current study assessed potential gene-environmental (G×E) interactions on reading ability in 1477 school-aged children. The gene-environment interactions on character recognition were investigated by an exploration analysis between the risk single-nucleotide polymorphisms (SNPs) which were discovered by previous genome-wide association studies of developmental dyslexia (DD), and parental education (PE). The re-parameterized regression analysis suggested that this G×E interaction conformed to the strong differential-susceptibility model. Results showed that rs281238 exhibits a significant interaction with PE on character recognition. Children with “T” genotype profited from high PE, whereas they performed worse in low PE environment, but “CC” genotype children were not malleable in different PE environments.

Research Highlights

We calculated the Cumulative Genetic Score (CGS) of 9 SNPs related to developmental dyslexia, and found that the interaction between CGS and parental education on reading ability. The G×E comforted to the differential-susceptibility model that those individuals carrying more plasticity alleles were affected more than those carrying more fewer.

The interaction between rs281238 and parental education conformed to the strong differential-susceptibility model that children with “T” allele would have highest reading ability in positive environment and lowest reading ability in adversity environment, whereas children without “T” allele would not be affected by parental education.