bluuebunny/crossref_metadata_2025 huggingface dataset:
Associations of Infant Sleep Characteristics with Childhood Cognitive Outcomes
Authors: Finkel Morgan A. , Duong Ngoc , Hernandez Amanda , Goldsmith Jeff , Rifas-Shiman Sheryl L. , Dumitriu Dani , Oken Emily , Shechter Ari , Woo Baidal Jennifer A.
Published: August 2024

Objective:

The objective of this study was to quantify associations of infant 24-hour sleep duration and nighttime sleep consolidation with later child cognition.

Methods:

This study included children from Project Viva, a prospective cohort in Massachusetts with (1) sleep measures in infancy (median age 6.4 months) and (2) child cognition in early childhood (median age 3.2 years) or mid-childhood (median age 7.7 years). Main exposures were parental reports of infant 24-hour sleep duration and nighttime sleep consolidation (% of total daily sleep occurring at nighttime). Cognitive outcomes were (1) early childhood vocabulary and visual-motor abilities and (2) mid-childhood verbal and nonverbal intelligence quotient (IQ), memory, and visual-motor abilities. We examined associations of infant sleep with childhood cognition using linear regression models adjusted for child sex, age, and race or ethnicity; maternal age, education, and parity; and household income.

Results:

Early and mid-childhood analyses included 1102 and 969 children, respectively. Most mothers reported infant race or ethnicity as White (69%) and were college graduates (71%). The mean infant 24-hour sleep duration was 12.2 ± 2.0 hours, and the mean nighttime sleep consolidation was 76.8% ± 8.8%. Infant 24-hour sleep duration was not associated with any early or mid-childhood outcomes. Higher infant nighttime sleep consolidation was associated with higher mid-childhood verbal intelligence (β: 0.12 points per % nighttime sleep; 95% CI, 0.01–0.22), but not with any early childhood cognitive measures.

Conclusion:

In this cohort, higher infant nighttime sleep consolidation was associated with higher verbal IQ in mid-childhood. Future studies should investigate causal relationships of infant sleep consolidation with child cognition among diverse populations.
Toward More Equitable Care: A Closer Look at Autism Clinic Intake Practices and Paperwork
Authors: Srinivasan Anisha P. , Nishiguchi Erika Phelps , Gonzalez Cassandra , Jimenez Manuel E. , Zuckerman Katharine E. , Lion Katherine C.
Published: August 2024

Objective:

To describe intake requirements among autism clinics and to assess how well intake paperwork aligns with national standards for enhancing language and literacy accessibility.

Methods:

This was a survey of 126 autism clinics in the Children's Hospital Association, assessing intake processes and intake paperwork readability conducted between November 2021 and August 2022. Descriptive analyses characterized intake requirements and paperwork components. Free-text responses about intake support strategies were categorized into themes. Logistic regression models examined associations between clinic patient demographics and odds of requiring intake paperwork. Intake packet length, content, and reading grade level were examined.

Results:

Of the invited clinics, 73% completed the survey. Among the participating clinics, 55% required intake paperwork before scheduling appointments, 34% offered English forms only, and 89% had no plain language forms. Clinic patient demographics were not associated with intake paperwork requirements. Analyzed intake packets (n = 67) averaged 11 pages long, and most were written above the fifth-grade reading level. Most packets solicited medical, developmental, and educational/therapy history. Many also requested psychoeducational evaluations and teacher rating forms. Reported intake support strategies for families with language or literacy needs included making ad hoc exceptions to the usual process, task shifting to outside organizations, providing support at family's request, and delegating to support staff.

Conclusion:

Many autism clinics nationwide require intake paperwork before diagnostic evaluation. Many clinics offer intake paperwork in English only, and paperwork often does not meet health literacy standards. Reducing paperwork requirements and providing more routine and robust intake support may facilitate equitable access to autism diagnostic evaluations.
Evaluating Binary Outcome Classifiers Estimated from Survey Data
Authors: Wadekar Adway S. , Reiter Jerome P.
Published: August 2024

Surveys are commonly used to facilitate research in epidemiology, health, and the social and behavioral sciences. Often, these surveys are not simple random samples, and respondents are given weights reflecting their probability of selection into the survey. We show that using survey weights can be beneficial for evaluating the quality of predictive models when splitting data into training and test sets. In particular, we characterize model assessment statistics, such as sensitivity and specificity, as finite population quantities and compute survey-weighted estimates of these quantities with test data comprising a random subset of the original data. Using simulations with data from the National Survey on Drug Use and Health and the National Comorbidity Survey, we show that unweighted metrics estimated with sample test data can misrepresent population performance, but weighted metrics appropriately adjust for the complex sampling design. We also show that this conclusion holds for models trained using upsampling for mitigating class imbalance. The results suggest that weighted metrics should be used when evaluating performance on test data derived from complex surveys.
Evidence of Mitophagy in Lens Capsule Epithelial Cells of Patients With Pseudoexfoliation Syndrome
Authors: Aydemir Dilara , Sonmez Sadi Can , Kisakurek Zeynep Busra , Gozel Merve , Karslioglu Melisa Zisan , Guleser Umit Yasar , Sahin Afsun , Hasanreisoglu Murat
Published: August 2024

Précis:

Alterations in the PTEN-induced kinase 1 (PINK)-mediated mitophagy pathway play an important role in pseudoexfoliation syndrome (PEX) disease.

Purpose:

PEX is a condition in which aberrant fibrillary protein builds up in various components of the eye and other extraocular tissues. In this study, we aim to investigate the functionality of intracellular auto-degradative machinery—especially mitophagy—and related genes and proteins in PEX.

Materials and Methods:

Anterior lens capsules were obtained from cataract patients with and without PEX to constitute the PEX group and age-matched controls during microincision cataract surgery. PINK1-mediated mitophagy markers were evaluated on the transcriptional and translational level via reverse transcriptionquantitative polymerase chain reaction and immunohistochemistry analysis, respectively.

Results:

The lens epithelial cells of PEX patients were characterized by significantly higher PINK1 gene expression compared with that of the controls (P<0.05). In terms of intensity of staining of expressed proteins, PINK1 (P<0.05), Parkin (P<0.01), and microtubule-associated protein 1A/1B-light chain 3 B (P<0.01) were all statistically higher in PEX, compared with the controls.

Conclusion:

Altered auto-degradative response—specifically mitophagy—is a component of increased oxidative stress in PEX patients. The role of this mechanism in emerging complications warrants further research.
Implications of Requiring the Physician Assistant College Admissions Test on Physician Assistant Program Applicant Pool: Lessons Learned
Authors: Fogelgren Lauren
Published: August 2024

Introduction

To present a physician assistant (PA) program's experience and lessons learned by requiring a new standardized test as an admissions requirement. A state academic PA program changed an admission requirement by requiring the Physician Assistant College Admissions Test (PA-CAT) instead of the Graduate Record Examination. The admissions requirement change correlated with a 72% drop in the applicant pool.

Methods

Data from previous literature present background information on standardized testing and predictors of student success. The program-specific data retrospectively evaluate changes in application numbers.

Results

Several studies have evaluated various preadmission metrics and their correlation to student success. However, the PA-CAT and its predictor of student success in the program and passing the Physician Assistant National Certifying Exam still need to be evaluated.

Discussion

Requiring standardized testing increases the barrier to applicant PA school admissions. Despite its potential, the PA-CAT has yet to be extensively studied to predict success in matriculated PA students and should be used cautiously. The implications of using the PA-CAT as an admissions requirement are a potential decrease in the strength of applicants, the number of total applicants, and the overall decline in the quality of graduating PAs. This cautionary note is crucial for maintaining the quality and integrity of our PA programs.
Breastfeeding may reduce the effects of maternal smoking on lung cancer mortality in adult offspring: a prospective cohort study
Authors: Yin Hang , Wang Yixue , Wang Siyu , Zhang Shijie , Ling Xiaodong , Han Tianshu , Sun Changhao , Ma Jianqun , Wei Wei , Zhu Jinhong , Wang Xiaoyuan
Published: August 2024

Background:

Although previous research has indicated a correlation between smoking and the mortality rate in patients with lung cancer, the impact of early life factors on this relationship remains unclear and requires further investigation. This study aimed to investigate the hypothesis that breastfeeding reduces the risk of lung cancer-related death.

Methods

The authors conducted a prospective cohort study involving 501 859 participants recruited from the United Kingdom Biobank to explore the potential association between breastfeeding and the risk of lung cancer mortality using a Cox proportional hazards model. Subsequently, the polygenic risk score for lung cancer was calculated to detect interactions between genes and the environment.

Results:

Over a median follow-up duration of 11.8 years, encompassing a total of 501 859 participants, breastfeeding was found to reduce the risk of lung cancer-related death and the impact of maternal smoking on lung cancer mortality in adult offspring. This association remained consistent after stratification. Furthermore, the influence of maternal smoking and breastfeeding on the risk of lung cancer mortality was significant at a high genetic risk level.

Conclusion:

Breastfeeding can reduce the risk of lung cancer-related death and the impact of maternal smoking on lung cancer mortality in adult offspring. This correlation has the potential to reduce the probability of lung-cancer-related deaths in subsequent generations.
Research hotspots and frontiers of neoadjuvant therapy in triple-negative breast cancer: a bibliometric analysis of publications between 2002 and 2023
Authors: Yang Chuang , Liu Hui , Feng Xing , Shi Han , Jiang Yuchan , Li Junfeng , Tan Jinxiang
Published: August 2024

Triple-negative breast cancer (TNBC) is a highly aggressive type of breast cancer with poor prognosis, and neoadjuvant therapy (NAT) has emerged as an important component in managing advanced-stage patients by providing surgical opportunities and improving survival outcomes. A search of publications on NAT for TNBC from 2002 to 2023 was conducted through the Web of Science core collection. A comprehensive bibliometric analysis was conducted on the data using CiteSpace, VOSviewer, and Bibliometrix. The analysis revealed a continuous and steady growth in the number of articles published in this field over the past 20 years. The United States has made significant contributions to this field, with The University of Texas MD Anderson Cancer Center publishing the most articles. Loibl, S. from Germany was found to be the most published author with 54 articles. Analysis of the journals showed that the Journal of Clinical Oncology is the most cited journal. Combined with the keyword co-occurrence analysis and clustering analysis, current research topic focuses on treatment regimens and disease prognosis. Dual-map overlay of the journals indicates that the research trend is gradually shifting from molecular biology and genetics to immunology and clinical research. Combination therapy, including immunotherapy, may be the future direction for NAT treatment of TNBC. Overall, this study provides valuable insights into the current research status, latest advancements, and emerging development trend of NAT for TNBC.
Efficacy of HA380 hemoperfusion in the treatment of septic shock
Authors: Chen Li , Zhou Shenglin , Wang Chao , Qie Guoqiang , Tai Zijian , Wang Feng , Ding Ruiqi , Liu Guangyun , Liu Yan , Bai Xue , Zhang Jicheng
Published: August 2024

Background:

To evaluate the clinical efficacy of HA380 hemoperfusion (HP) in the treatment of septic shock.

Methods:

This study retrospectively analyzed the clinical data of patients with septic shock admitted to Ward II of the Department of Critical Care Medicine at the Shandong Provincial Hospital Affiliated to Shandong First Medical University from January 2022 to December 2023. These data included general information, temperature, heart rate (HR), mean arterial pressure (MAP), oxygenation index, norepinephrine (NE) dose, lactic acid, white blood cell count, neutrophil percentage, lymphocyte absolute value, procalcitonin (PCT), interleukin-6 (IL-6), acute physiology and chronic health evaluation II (APACHE II), sequential organ failure assessment (SOFA) before and after each blood perfusion (HA380), total hospital stay, intensive care unit (ICU) stay, and 28-day survival.

Results:

A total of 41 patients with septic shock were included in this study, consisting of 38 males and 3 females. According to their primary diseases, there were 18 cases of severe pneumonia, 16 cases of abdominal infection, 4 cases of bloodstream infection, 2 cases of urinary infection, and 1 case of soft tissue infection. At the time of inclusion, 33 patients underwent mechanical ventilation for respiratory support, and 4 patients were treated with extracorporeal membrane oxygenation. Statistically significant differences (all P < 0.05) were observed in body temperature, HR, MAP, oxygenation index, norepinephrine dose, lactic acid, PCT, IL-6, creatinine (Cr), APACHE II, and SOFA before and after HP (HA380) treatment. According to the 28-day survival status of patients, patients were allocated into survival and death groups. The total hospital stay and ICU stay were statistically significantly different between the two groups (all P < 0.05). Additionally, there were also statistically significant differences in APACHE II and SOFA before and after treatment (all P < 0.05). Based on the severity stratification of IL-6 and PCT levels, it was observed that following HP (HA380) treatment, all subgroups showed varying degrees of improvement in SOFA and APACHE II scores (P < 0.05).

Conclusion:

HP (HA380) can improve the clinical efficacy of patients with septic shock. In addition, this method improves hemodynamics, effectively reduces lactic acid levels and infection indexes, and alleviates organ function damage in patients with septic shock, which can strive for more time for subsequent treatment.
Evaluation of the Clinical and Paraclinical Symptoms of Children Intoxicated With Amphetamines in Akbar Hospital of Mashhad, Iran 2021–2022
Authors: Aria Arsalan , Pourbadakhshan Nafiseh , Alizadeh Anahita
Published: August 2024

Introduction

Amphetamine poisoning in children is a significant public health concern due to its potential for severe adverse effects on physical and mental health. In this article, we describe a case series of 29 children under the age of 14 presenting with sympathomimetic toxidrome due to confirmed amphetamine poisoning.

Material and Method

In this cross-sectional study, children (1 month to 14 years old) who were hospitalized in the emergency and pediatric departments of Imam Reza and Akbar Hospital in Mashhad from the beginning of April 2021 to September 2022 were identified with the diagnosis of amphetamine poisoning. Their demographic, clinical, and paraclinical (laboratory and electrocardiogram) information, which was included in the relevant checklists, were analyzed and reported.

Findings

Out of 29 children included in the study, 18 (62%) were male and the rest were female. The average age of children was 44.75 ±43.9 months; most of them were less than 4 years old. In all patients, glasgow coma scale (GCS) was 15. In 25.92% of cases (8 patients) blood pressure was above the 90% percentile for age and sex, 82.60% (24 cases) were tachycardia, 72.41% crying (21 cases), 86.20% were restless (25 cases), 10.34% tremor (3 cases), 10.34% had body pain (3 cases), and 6.89% (2 cases) had delusions. None of the subjects had a seizure. The serum level of creatine phosphokinase was on average 771.99 ± 966 units/L. All children had an increase in creatine phosphokinase (CPK) and 25.9% of children had an increase in CPK to more than 1000 units/L.

Conclusion

Based on the results, in children with symptoms such as restlessness, crying, and tachycardia, poisoning with amphetamine group substances should be included in the differential diagnosis list, and also measuring CPK and investigating the possible occurrence of rhabdomyolysis in cases of poisoning of children with amphetamine seems necessary.
Central Venous Oxygen Saturation in Children With Cancer
Authors: Vissing Nadja Hawwa , Dungu Kia Hee Schultz , Andersen Frederik Mølkjær , Mønster Mette Bondo , Hjalgrim Lisa Lyngsie , Schmiegelow Kjeld , Nygaard Ulrikka
Published: August 2024

Objective

Central venous saturation (ScvO2) can guide resuscitation of children with septic shock. The normal range of ScvO2 is typically considered as 0.70–0.80, but has not been established in children with cancer. Children with cancer are particularly prone to develop sepsis due to their immunosuppressive therapy, and usually have a permanent central venous catheter, making ScvO2 readily available. We aimed to investigate normal values of ScvO2 in clinically stable children with cancer, and the association between ScvO2, hemoglobin, and lactate.

Methods

We conducted a prospective clinical study at the outpatient clinic of a tertiary pediatric hematology/oncology unit. Blood samples were collected from stable children aged 0–17.9 years who were treated for cancer between January 1 and November 30, 2019, during their routine outpatient clinic visits.

Results

A total of 183 blood samples were collected from 68 patients (24 girls and 44 boys). The predicted mean level of ScvO2 with a 95% confidence interval was 0.67 (0.56–0.78). The ScvO2 value was below the expected lower normal limit of 0.70 in 126 (69%) of the samples and in 48 patients (71%) at least once. ScvO2 was significantly associated with hemoglobin (β1 = 0.012 per g/L hemoglobin, P < 0.001), but not with age, sex, underlying diagnosis, or lactate.

Conclusions

The study revealed that a substantial portion of clinically stable childhood cancer patients exhibited ScvO2 levels below the typical reference value of 0.70, suggesting that these children may have inherently lower baseline ScvO2 levels. This should be kept in mind when evaluating children with cancer for septic shock, emphasizing the importance of tailored assessments in this population. Further understanding of baseline ScvO2 abnormalities may be helpful if ScvO2 is used to guide resuscitation.
Comparison of Ligament Z-Plasty and Conventional Surgery for the Treatment of Carpal Tunnel Syndrome: A Randomized Clinical Trial
Authors: Calzado-Alvarez Irene , Camacho-Sanchez Maria R. , Carpintero-Lluch Rocio , Muñoz-Luna Francisco , Lopez-Medina Clementina , Minarro Jose Carlos , Izquierdo-Fernandez Alberto
Published: August 2024

Background:

Conventional surgery performed to treat carpal tunnel syndrome (CTS) is associated with complications such as pillar pain or loss of strength. This study aimed to compare the incidence of pillar pain between 2 techniques at the 3-week and 6-month follow-up and to determine differences in the recovery of grip strength (GS), pinch strength (PS), and Boston Carpal Tunnel Questionnaire scores.

Methods:

This randomized clinical trial included 109 patients, 55 of whom underwent ligament Z-plasty and 54, conventional surgery (longitudinal section of the transverse carpal ligament without posterior closure). GS, PS, pillar pain, and Boston Carpal Tunnel Questionnaire scores were assessed preoperatively and 3 weeks and 6 months after surgery.

Results:

The incidence of pillar pain 3 weeks after surgery was lower in patients undergoing Z-plasty than in those undergoing conventional surgery (25.5% versus 44.4%; P = 0.04). Moreover, the absolute change in PS 3 weeks after surgery (P = 0.01) and GS 6 months after surgery (P = 0.05) and the absolute and relative changes in PS after 6 months (P = 0.008 and P = 0.01, respectively) were significantly higher in the Z-plasty group than in the conventional surgery group.

Conclusions:

Z-plasty is a valid surgical procedure for treating CTS. It is associated with a lower incidence of pillar pain and better recovery of postoperative strength compared with the conventional surgical technique, with both techniques showing similar results in CTS recovery.

CLINICAL QUESTION/LEVEL OF EVIDENCE:

Therapeutic, II.
Evaluation of Minimum Axial Airway Area and Airway Volume in Orthognathic Surgery Patients
Authors: Yey Özkeskin Sabahat Zeynep , Ersan Nilüfer , Öztürk Muhtar Merve , Cansiz Erol , Ramazanoğlu Mustafa
Published: August 2024

The aim of this study was to compare preoperative and postoperative linear, planar, and volumetric measurements in the pharyngeal airway in orthognathic surgery patients. Preoperative and postoperative cone beam computed tomography (CBCT) images of 60 patients, who underwent maxillary advancement with mandibular setback (Group I, n=25) and bimaxillary advancement (Group II, n=35), were compared. The airway was divided into 3 regions as nasopharynx, oropharynx, and hypopharynx. Linear and planar measurements were made on the reference sections of each region. The minimum axial airway area, the volume of 3 regions, and total airway volume were also measured. Regarding the linear, planar, and volumetric measurements, while there was a statistically significant increase in the measurements for all three regions in Group II, in Group I only the measurements in the nasopharyngeal region demonstrated a statistically significant increase postoperatively (P<0.05). There was an increase in minimum axial airway areas in both groups; however, it was only statistically significant in Group II (P<0.05). There was a statistically significant increase in total airway volumes in both groups (P<0.05). A positive and good correlation was found between the percent increase in the minimum axial area and the percent increase in the total volume (P<0.05). While bimaxillary advancement surgery results in a significant increase in the pharyngeal airway, mandibular setback with maxillary advancement caused an increase in the total airway. Changes that may occur in the airway should be considered while planning orthognathic surgery.
Mechanistic Understanding of EBV+Lymphoproliferative Disease Development After Transplantation
Authors: Furlano Philippe L. , Böhmig Georg A. , Puchhammer-Stöckl Elisabeth , Vietzen Hannes
Published: August 2024

Posttransplant lymphoproliferative disorders (PTLDs) are among the most common malignant complications after transplantation, leading to a drastic reduction in patient survival rates. The majority of PTLDs are tightly linked to Epstein-Barr virus (EBV+PTLDs) and are the result of an uncontrolled proliferation of EBV-infected cells. However, although EBV infections are a common finding in transplant recipients, most patients with high EBV loads will never develop EBV+PTLD. Natural killer cells and EBV-specific CD8+ T lymphocytes are critical for controlling EBV-infected cells, and the impairment of these cytotoxic immune responses facilitates the unfettered proliferation of EBV-infected cells. Recent years have seen a considerable increase in available literature aiming to describe novel risk factors associated with the development of EBV+PTLD, which may critically relate to the strength of EBV-specific natural killer cell and EBV-CD8+ T lymphocyte responses. The accumulation of risk factors and the increased risk of developing EBV+PTLD go hand in hand. On the one hand, most of these risk factors, such as the level of immunosuppression or the EBV donor and recipient serologic mismatch, and distinct genetic risk factors are host related and affect cytotoxic EBV-specific immune responses. On the other hand, there is growing evidence that distinct EBV variants may have an increased malignant potential and are thus more likely to induce EBV+PTLD. Here, we aim to review, from a mechanistic point of view, the risk factors for EBV+PTLD in the host and the infecting EBV variants that may explain why only a minority of transplant recipients develop EBV+PTLD.
Establishing species boundaries in Bornean geckos
Authors: Davis Hayden R. , Sanford Henry T. , Das Indraneil , Nashriq Izneil , Leaché Adam D.
Published: August 2024

Species delimitation using mitochondrial DNA (mtDNA) remains an important and accessible approach for discovering and delimiting species. However, delimiting species with a single locus (e.g. DNA barcoding) is biased towards overestimating species diversity. The highly diverse gecko genus
Cyrtodactylus
is one such group where delimitation using mtDNA remains the paradigm. In this study, we use genomic data to test putative species boundaries established using mtDNA within three recognized species of
Cyrtodactylus
on the island of Borneo. We predict that multi-locus genomic data will estimate fewer species than mtDNA, which could have important ramifications for the species diversity within the genus. We aim to (i) investigate the correspondence between species delimitations using mtDNA and genomic data, (ii) infer species trees for each target species, and (iii) quantify gene flow and identify migration patterns to assess population connectivity. We find that species diversity is overestimated and that species boundaries differ between mtDNA and nuclear data. This underscores the value of using genomic data to reassess mtDNA-based species delimitations for taxa lacking clear species boundaries. We expect the number of recognized species within
Cyrtodactylus
to continue increasing, but, when possible, genomic data should be included to inform more accurate species boundaries.
The academic Great Gatsby Curve
Authors: Sun Ye , Caccioli Fabio , Li Xiancheng , Livan Giacomo
Published: August 2024

The Great Gatsby Curve measures the relationship between income inequality and intergenerational income persistence. By using genealogical data of over 245 000 mentor–mentee pairs and their academic publications from 22 different disciplines, this study demonstrates that an academic Great Gatsby Curve exists as well, in the form of a positive correlation between academic impact inequality and the persistence of impact across academic generations. We also provide a detailed breakdown of academic persistence, showing that the correlation between the impact of mentors and that of their mentees has increased over time, indicating an overall decrease in academic intergenerational mobility. We analyse such persistence across a variety of dimensions, including mentorship types, gender and institutional prestige.
A mechanical analogue of electromagnetic induction for waves in a chiral elastic structure
Authors: Allison Finn J. P. , Selsil Özgür , Haslinger Stewart G. , Movchan Alexander B.
Published: August 2024

Classical Faraday’s law on electromagnetic induction states that a change of magnetic field through a coil wire induces a current in the wire. A mechanical analogue of the Lorentz force, induced by a magnetic field on an electric charge, is the gyroscopic force. Here, we demonstrate a mechanical analogy with a chiral elastic waveguide subjected to gyroscopic forcing. We study waves in an infinite mass-spring ‘gyrocore helix’, which consists of a helix and a central line (gyroscopic elastic core). The helicoidal geometric chirality is considered in conjunction with a physical chirality, induced by gyroscopic forces. It is shown that the interplay between these two chiral inputs leads to the breaking of symmetry of the associated dispersion diagram, resulting in a unidirectional waveform with the direction of propagation being tunable through the gyricity.
Missing genetic diversity impacts variant prioritisation for rare disorders
Authors: Tallman Sam , Moutsianas Loukas , Nguyen Thuy , Cho Yoonsu , Mackintosh Maxine , Kasperaviciute Dalia , Brown Matthew A , Ellingford Jamie , Kuchenbaecker Karoline , Silver Matt J
Published: August 2024

Whole genome sequencing identifies millions of genetic variants per individual. When applied to rare disease diagnosis, potentially pathogenic variants are prioritised for clinical interpretation, a process that may be influenced by an individual’s genetic ancestry. We analysed millions of rare protein-altering variants prioritised in 29,425 participants with rare disease from the UK 100,000 Genomes Project. We observed disparities in the number of variants prioritised across genetic ancestry groups, with an up to 3-fold increase in participants with African compared to European ancestries. Variants prioritised in participants with non-European ancestries were less likely to be assessed as pathogenic. Leveraging a cohort of 34,701 diverse genomes from the UK, we identified thousands of candidate variants that were ultra-rare or unobserved across populations in gnomAD but common among ancestry-matched individuals. Our findings highlight the importance of using reference databases that reflect patient genetic diversity when prioritising variants for rare disease diagnosis.
Impending Heart Failure : An Artificial Intellectual Reality
Authors: Ray Abhijit
Published: August 2024

Background

Having a prevalence of almost 64 million patients globally, Heart Failure (HF) remains a leading cause of cardiac death with high morbidity and mortality rates despite constant updates in diagnostic and therapeutic measures. One of the main reasons behind this might be a delay in initiating treatment.

Purpose

To obtain a method of screening patients for Heart Failure even before they develop symptoms.

Methods

An Artificial Intelligence-based algorithm, named Heart Failure Predictor (HFP), born from mathematical calculations of a patented formula, came up with a cutting-edge solution that can predict the chances of HF in patients not suffering from any symptoms of Heart Failure. HFP was applied to data from the Framingham Heart Study as a retrospective analysis. LVEF and NT pro-BNP levels were used as a method of correlation. Asymptomatic patients who had been followed up extensively for at-least 24 months were included, while patients already diagnosed with HF were excluded.

Results

Data from 20896 patients were analysed.

17 out of 1230 were false positive while 31 out of 19660 were false negative.

Thus, HFP has a Positive Predictive Value of 98.6% and a Specificity of 99.9%.

Discussion

Early screening and detection may lead to vast improvements in HF treatment efficacy. HFP fills this need with a new classification of HF, “Impending Heart Failure”, and synonymously “Ray’s Disease”.

Apart from screening HF patients, HFP can also be used for continuous monitoring of LVEF in cardiac beds, bringing about a revolution in the cardiac space.
The Aryl Hydrocarbon Receptor Controls IFNγ-Induced Immune Checkpoints PD-L1 and IDO via the JAK/STAT Pathway in Lung Adenocarcinoma
Authors: Snyder Megan , Wang Zhongyan , Lara Brian , Fimbres Jocelyn , Pichardo Tachira , Mazzilli Sarah , Khan Mohammed Muzamil , Duggineni Vinay K. , Monti Stefano , Sherr David H.
Published: August 2024

While immunotherapy has shown efficacy in lung adenocarcinoma (LUAD) patients, many respond only partially or not at all. One limitation in improving outcomes is the lack of a complete understanding of immune checkpoint regulation. Here, we investigated a possible link between an environmental chemical receptor implicated in lung cancer and immune regulation,(the aryl hydrocarbon receptor/AhR), a known but counterintuitive mediator of immunosuppression (IFNγ), and regulation of two immune checkpoints (PD-L1 and IDO). AhR gene-edited LUAD cell lines, a syngeneic LUAD mouse model, bulk- and scRNA sequencing of LUADs and tumor-infiltrating leukocytes were used to map out a signaling pathway leading from IFNγ through the AhR to JAK/STAT, PD-L1, IDO, and tumor-mediated immunosuppression. The data demonstrate that:1)IFNγ activation of the JAK/STAT pathway leading to PD-L1 and IDO1 upregulation is mediated by the AhR in murine and human LUAD cells,2)AhR-driven IDO1 induction results in the production of Kynurenine (Kyn), an AhR ligand, which likely mediates an AhR➔IDO1➔Kyn➔AhR amplification loop,3)transplantation of AhR-knockout LUAD cells results in long-term tumor immunity in most recipients.4)The 23% of AhR-knockout tumors that do grow do so at a much slower pace than controls and exhibit higher densities of CD8+T cells expressing markers of immunocompetence, increased activity, and increased cell-cell communication. The data definitively link the AhR to IFNγ-induced JAK/STAT pathway and immune checkpoint-mediated immunosuppression and support the targeting of the AhR in the context of LUAD.
Thalamus normalisation improves detectability of hypoperfusion via arterial spin labelling in an Alzheimer’s disease cohort
Authors: Zhang Logan X. , Kirk Thomas F. , Craig Martin S. , Chappell Michael A.
Published: August 2024

Data normalisation is an important approach to reduce inter-subject variability in group studies, but care must be taken when choosing a normalisation strategy to not introduce further confounds or artefacts into the data. Normalisation of arterial spin labelling perfusion measurements remains challenging, especially in the context of Alzheimer’s disease, where there may be global hypoperfusion present. We propose that using the thalamus as a reference region for normalisation could improve the detectability of hypoperfusion in Alzheimer’s disease and alleviate the pseudo-hyperperfusion artefacts caused by the commonly-used strategy of normalisation using global mean perfusion. Evaluation on an Alzheimer’s disease dataset found this strategy was able to reduce coefficient of variation in perfusion measurements by around 60% and yield increases in statistical power of comparisons against healthy controls.
A variant of the autophagic receptor NDP52 counteracts phospho-TAU accumulation and emerges as a protective factor for Alzheimer Disease
Authors: Mattioni Anna , Carsetti Claudia , Bruqi Krenare , Caputo Valerio , Cianfanelli Valentina , Bacalini Maria Giulia , Casa Mariella , Gabelli Carlo , Giardina Emiliano , Cestra Gianluca , Strappazzon Flavie
Published: August 2024

Selective elimination of early pathological TAU species may be a promising therapeutic strategy to reduce TAU accumulation that contributes to neurodegeneration and hallmarks Alzheimer disease (AD). By performing a genetic analysis of a cohort of 435 patients with AD, we defined the NDP52GEvariant (rs550510) of the autophagic receptor NDP52 (also known as CALCOCO2) as a protective factor for AD. We provide evidence that inin vitrosystems and in aDrosophila melanogastermodel of TAU-induced AD, NDP52 reduces the accumulation of pathological forms of TAU through the autophagic process and rescues typical neurodegenerative phenotypes induced by hTAU-toxicity. More importantly, we showed that the NDP52GEvariant is much more effective in this respect than NDP52WT. Mechanistically, we showed that NDP52 directly binds pathological phospho-TAU, and that NDP52WTand NDP52GEbind them with comparable efficiency. On the contrary, we showed that NDP52GEbinds the autophagic machinery (LC3C and LC3B) more efficiently than NDP52WT. We also showed for the first time that NDP52 is a direct target of protein phosphatase 2A (PP2A)in vitro, opening the way to the possibility that this phosphatase may fine-tune the autophagic function of NDP52 in AD. Finally, we found a positive correlation between the worldwide distribution of the allele encoding NDP52GEand the incidence or prevalence of AD. Overall, our work highlights the variant NDP52GEas a resilience factor in AD that shows a robust effectiveness to drive pathological TAU degradation.
Towards validation of clinical measures to discriminate between nociceptive, neuropathic and nociplastic pain: cluster analysis of a cohort with chronic musculoskeletal pain
Authors: Hodges Paul W , Sanchez Raimundo , Pritchard Shane , Turnbull Adam , Hahne Andrew , Ford Jon
Published: August 2024

The International Association for the Study of Pain defines three pain types presumed to involve different mechanisms - nociceptive, neuropathic and nociplastic. Based on the hypothesis that these pain types should guide matching of patients with treatments, work has been undertaken to identify features to discriminate between them for clinical use. This study aimed to evaluate the validity of these features to discriminate between pain types. Subjective and physical features were evaluated in a cohort of 350 individuals with chronic musculoskeletal pain attending a chronic pain management program. Analysis tested the hypothesis that, if the features nominated for each pain type represent 3 different groups, then (i) cluster analysis should identify 3 main clusters of patients, (ii) these clusters should align with the pain type allocated by an experienced clinician, (iii) patients within a cluster should have high expression of the candidate features proposed to assist identification of that pain type. Supervised machine learning interrogated features with the greatest and least importance for discrimination; and probabilistic analysis probed the potential for coexistence of multiple pain types. Results confirmed that data could be best explained by 3 clusters, clusters were characterized by a priori specified features, and agreed with the designation of the experienced clinical with 82% accuracy. Supervised analysis highlighted features that contributed most and least to the classification of pain type and probabilistic analysis reinforced the presence of mixed pain types. These findings support the foundation for further refinement of a clinical tool to discriminate between pain types.
Dual Metrics of Obesity: Evaluating BMI and Central Obesity as Indicators of Cardiometabolic Risk in Rural India
Authors: Prasad Raghav , Sagiraju Manogna , Chatterjee Priya , Sahadevan Pravin , Pradhan Hitesh , Sundarakumar Jonas S ,   SANSCOG Team
Published: August 2024

Purpose

Indians face a higher risk of cardiometabolic diseases (CMDs) at the same BMI compared to Caucasians. This study explored the use of the Dual Metric Obesity Criteria (DMOC), combining central obesity (CO) indices with BMI, to assess sex-specific associations with CMDs in rural Indians.

Methods

Baseline cross-sectional data from 3,397 participants aged ≥45 from the Centre for Brain Research-Srinivaspura Aging, Neuro Senescence and COGnition (CBR-SANSCOG) study were analysed. Five obesity indices were examined: BMI, Waist Circumference, Waist-Hip Ratio (WHR), Waist-Height Ratio (WHtR), and Visceral Fat Percentage. Cohen’s Kappa assessed the agreement between BMI and CO indices. Participants were classified based on BMI and CO status: NWNC (Normal Weight No CO), AWNC (Abnormal Weight No CO), NWCO (Normal Weight CO), and AWCO (Abnormal Weight CO). Multinomial logistic regression models evaluated associations between DMOC groups and CMDs. Interaction analyses explored CO and CMD relationships across sex, BMI categories, and age groups. The mediation effect of CO indices on the relationship between BMI and cardiometabolic risk factors was investigated.

Results

BMI showed a slight to fair agreement with WHR and moderate agreement with WHtR. Individuals with AWCO had the highest odds for all CMDs (p<0.001). Males with NWCO had a 3.51 (2.14,6.04) times increased odds times for diabetes and 2.04 (1.22,3.37) times odds for dyslipidemia. Individuals < 58 years and males had stronger associations with CMDs.

Conclusion

Combining CO indices with BMI effectively identifies high-risk CMD groups in rural Indians, including those with NWCO a previously overlooked group.
“I wanted to be a responsible public health professional”: applying serious games for deep learning in global health courses
Authors: Smith Julia , Gooderham Ellie , Piper Julianne
Published: August 2024

Serious games, including simulations, are increasingly used in university teaching, including medical and humanitarian studies as well as political science and international relations. There is less evidence of application in global health pedagogy. This article reports and reflects on the application of a simulation of negotiations around a global pandemic treaty in a Master of Public Health class on Global Health and International Affairs. Through participant observation and thematic analysis of students’ reflective essays we find that the simulation enabled deep learning in line with the assignment objectives (to apply learning from past health crisis, engage with key concepts, and experience global health cooperation and challenges), as well as prompted critical reflections on moral dilemmas related to global health cooperation and decolonizing global health. The simulation provided an opportunity for students to engage with the wicked problems embedded within global health by drawing on multiple perspectives and approaches. While the students failed in negotiating a successful pandemic treaty, it was these failures that provided opportunities for deep learning and critical reflection as they questioned constraints on their underlying motivations and actions. This experience suggests simulations can serve as a particularly apt approach for teaching interdisciplinary approaches to global health as they enable to students to apply different sets of knowledge to a particular problem, explore unfamiliar concepts and critically asses their assumptions.
CarD-T: Interpreting Carcinomic Lexicon via Transformers
Authors: O’Neill Jamey , Reddy Gudur Ashrith , Dhillon Nermeeta , Tripathi Osika , Alexandrov Ludmil , Katira Parag
Published: August 2024

The identification and classification of carcinogens is critical in cancer epidemiology, necessitating updated methodologies to manage the burgeoning biomedical literature. Current systems, like those run by the International Agency for Research on Cancer (IARC) and the National Toxicology Program (NTP), face challenges due to manual vetting and disparities in carcinogen classification spurred by the volume of emerging data. To address these issues, we introduced the Carcinogen Detection via Transformers (CarD-T) framework, a text analytics approach that combines transformer-based machine learning with probabilistic statistical analysis to efficiently nominate carcinogens from scientific texts. CarD-T uses Named Entity Recognition (NER) trained on PubMed abstracts featuring known carcinogens from IARC groups and includes a context classifier to enhance accuracy and manage computational demands. Using this method, journal publication data indexed with carcinogenicity & carcinogenesis Medical Subject Headings (MeSH) terms from the last 25 years was analyzed, identifying potential carcinogens. Training CarD-T on 60% of established carcinogens (Group 1 and 2A carcinogens, IARC designation), CarD-T correctly to identifies all of the remaining Group 1 and 2A designated carcinogens from the analyzed text. In addition, CarD-T nominates roughly 1500 more entities as potential carcinogens that have at least two publications citing evidence of carcinogenicity. Comparative assessment of CarD-T against GPT-4 model reveals a high recall (0.857 vs 0.705) and F1 score (0.875 vs 0.792), and comparable precision (0.894 vs 0.903). Additionally, CarD-T highlights 554 entities that show disputing evidence for carcinogenicity. These are further analyzed using Bayesian temporal Probabilistic Carcinogenic Denomination (PCarD) to provide probabilistic evaluations of their carcinogenic status based on evolving evidence. Our findings underscore that the CarD-T framework is not only robust and effective in identifying and nominating potential carcinogens within vast biomedical literature but also efficient on consumer GPUs. This integration of advanced NLP capabilities with vital epidemiological analysis significantly enhances the agility of public health responses to carcinogen identification, thereby setting a new benchmark for automated, scalable toxicological investigations.
Porcine Nasal Organoids as a model to study the interactions between the swine nasal microbiota and the host
Authors: Bonillo-Lopez Laura , Carmona-Vicente Noelia , Tarrés-Freixas Ferran , Kochanowski Karl , Martínez Jorge , Perez Mònica , Sibila Marina , Correa-Fiz Florencia , Aragon Virginia
Published: August 2024

Interactions between the nasal epithelium, commensal nasal microbiota, and respiratory pathogens play a key role in respiratory infections. Currently there is a lack of experimental models to study such interactions under definedin vitroconditions. Here, we developed a Porcine Nasal Organoid (PNO) system from nasal tissue of pigs as well as from cytological brushes. PNOs exhibited similar structure and cell types than the nasal mucosa, as evaluated by immunostaining. PNOs were inoculated with porcine commensal strains ofMoraxella pluranimalium, Rothia nasimuriumand the pathobiontGlaesserella parasuisfor examining host-commensal-pathogen interactions. All strains adhered to the PNOs, although at different levels.M. pluranimaliumandG. parasuisstrains stimulated the production of proinflammatory cytokines, whereasR. nasimuriuminduced the production of IFNγ and diminished the proinflammatory effect of the other strains. Overall, PNOs mimic thein vivonasal mucosa and can be useful to perform host-microbe interaction studies.

In brief

Interactions between nasal epithelium, commensal nasal microbiota, and respiratory pathogens play a key role in respiratory infections. We developed porcine nasal organoids to mimic the nasal mucosa and use as a model to study those interactions. Additionally, this development supports the reduction of the number of animals for animal experimentation.

Highlights

First generation of Porcine Nasal Organoids (PNOs) from nasal turbinates and swabs

PNOs recapitulate features ofin vivotissue and maintain self-renewal capacity

Host-microbe interactions can be studied using the PNO system

Rothia nasimuriuminhibits the inflammation induced by other bacteria