bluuebunny/crossref_metadata_2025_split huggingface dataset:
De novo missense variants in the PP2A regulatory subunit PPP2R2B in a neurodevelopmental syndrome: potential links to mitochondrial dynamics and spinocerebellar ataxias
Authors: Sandal Priyanka , Jong Chian Ju , Merrill Ronald A , Kollman Grace J , Paden Austin H , Bend Eric G , Sullivan Jennifer , Spillmann Rebecca C , Shashi Vandana , Vulto-van Silfhout Anneke T , Pfundt Rolph , de Vries Bert B A , Li Pan P , Bicknell Louise S , Strack Stefan 
Published: November 2024

Abstract
The heterotrimeric protein phosphatase 2A (PP2A) complex catalyzes about half of Ser/Thr dephosphorylations in eukaryotic cells. A CAG repeat expansion in the neuron-specific protein PP2A regulatory subunit PPP2R2B gene causes spinocerebellar ataxia type 12 (SCA12). We established five monoallelic missense variants in PPP2R2B (four confirmed as de novo) as a cause of intellectual disability with developmental delay (R149P, T246K, N310K, E37K, I427T). In addition to moderate to severe intellectual disability and developmental delay, affected individuals presented with seizures, microcephaly, aggression, hypotonia, as well as broad-based or stiff gait. We used biochemical and cellular assays, including a novel luciferase complementation assay to interrogate PP2A holoenzyme assembly and activity, as well as deregulated mitochondrial dynamics as possible pathogenic mechanisms. Cell-based assays documented impaired ability of PPP2R2B missense variants to incorporate into the PP2A holoenzyme, localize to mitochondria, induce fission of neuronal mitochondria, and dephosphorylate the mitochondrial fission enzyme dynamin-related protein 1. AlphaMissense-based pathogenicity prediction suggested that an additional seven unreported missense variants may be pathogenic. In conclusion, our studies identify loss-of-function at the PPP2R2B locus as the basis for syndromic intellectual disability with developmental delay. They also extend PPP2R2B-related pathologies from neurodegenerative (SCA12) to neurodevelopmental disorders and suggests that altered mitochondrial dynamics may contribute to mechanisms.
Brain multi-omic Mendelian randomisation to identify novel drug targets for gliomagenesis
Authors: Thornton Zak A , Andrews Lily J , Zhao Huiling , Zheng Jie , Paternoster Lavinia , Robinson Jamie W , Kurian Kathreena M 
Published: November 2024

Abstract

Background
Genetic variants associated with molecular traits that are also associated with liability to glioma can provide causal evidence for the identification and prioritisation of drug targets.

Methods
We performed comprehensive two-sample Mendelian randomisation (Wald ratio and/or IVW) and colocalisation analyses of molecular traits on glioma. Instrumentable traits (QTLs P &lt; 5 × 10−8) were identified amongst 11 985 gene expression measures, 13 285 splicing isoforms and 10 198 protein abundance measures, derived from 15 brain regions. Glioma summary-level data was extracted from a genome-wide association meta-analysis of 12 496 cases and 18 190 controls.

Results
We found evidence for causal effect of 22 molecular traits (across 18 genes/proteins) on glioma risk. Thirteen molecular traits have been previously linked with glioma risk and five were novel; HBEGF (5q31.3) expression and all glioma [OR 1.36 (95%CI 1.19–1.55); P = 4.41 × 10−6]; a CEP192 (18p11.21) splice isoform and glioblastoma [OR 4.40 (95%CI 2.28–8.48); P = 9.78 × 10−4]; a FAIM (3q22.3) splice isoform and all glioma [OR 2.72–3.43; P = 1.03 × 10−5 to 1.09 × 10−5]; a SLC8A1 (2p22.1) splice isoform and all glioma [OR 0.37 (95%CI 0.24–0.56; P = 5.72 × 10−6]; D2HGDH (2q37.3) protein and all glioma [OR 0.86 (95%CI 0.80–0.92); P = 5.94 × 10−6)].

Conclusions
We provide robust causal evidence for prioritising genes and their protein products in glioma research. Our results highlight the importance of alternative splicing as a mechanism in gliomagenesis and as an avenue for exploration of drug targets.
Integrative multi-environmental genomic prediction in apple
Authors: Jung Michaela , Quesada-Traver Carles , Roth Morgane , Aranzana Maria José , Muranty Hélène , Rymenants Marijn , Guerra Walter , Holzknecht Elias , Pradas Nicole , Lozano Lidia , Didelot Frédérique , Laurens François , Yates Steven , Studer Bruno , Broggini Giovanni A L , Patocchi Andrea 
Published: November 2024

Abstract
Genomic prediction for multiple environments can aid the selection of genotypes suited to specific soil and climate conditions. Methodological advances allow effective integration of phenotypic, genomic (additive, nonadditive), and large-scale environmental (enviromic) data into multi-environmental genomic prediction models. These models can also account for genotype-by-environment interaction, utilize alternative relationship matrices (kernels), or substitute statistical approaches with deep learning. However, the application of multi-environmental genomic prediction in apple remained limited, likely due to the challenge of building multi-environmental datasets and structurally complex models. Here, we applied efficient statistical and deep learning models for multi-environmental genomic prediction of eleven apple traits with contrasting genetic architectures by integrating genomic- and enviromic-based model components. Incorporating genotype-by-environment interaction effects into statistical models improved predictive ability by up to 0.08 for nine traits compared to the benchmark model. This outcome, based on Gaussian and Deep kernels, shows these alternatives can effectively substitute the standard genomic best linear unbiased predictor (G-BLUP). Including nonadditive and enviromic-based effects resulted in a predictive ability very similar to the benchmark model. The deep learning approach achieved the highest predictive ability for three traits with oligogenic genetic architectures, outperforming the benchmark by up to 0.10. Our results demonstrate that the tested statistical models capture genotype-by-environment interactions particularly well, and the deep learning models efficiently integrate data from diverse sources. This study will foster the adoption of multi-environmental genomic prediction to select apple cultivars adapted to diverse environmental conditions, providing an opportunity to address climate change impacts.
Defining the causes for Fontan circulatory failure in total cavopulmonary connection patients
Authors: Van Puyvelde Joeri , Rega Filip , Budts Werner , Van De Bruaene Alexander , Cools Bjorn , Gewillig Marc , Eyskens Benedicte , Heying Ruth , Salaets Thomas , Meyns Bart 
Published: November 2024

Abstract

OBJECTIVES
This study aims to identify the causes of failure in Fontan patients with a total cavopulmonary connection.

METHODS
We conducted a comprehensive review of all patients who underwent a total cavopulmonary connection procedure at our centre between 1988 and 2023, aiming to identify and analyse the factors contributing to Fontan failure (defined as mortality, heart transplantation, Fontan takedown, protein-losing enteropathy, plastic bronchitis or New York Heart Association Functional Classification class III or IV).

RESULTS
The study included 217 patients (median age at time of Fontan completion 3.7 years) with a median follow-up of 12.7 years (interquartile range 7.2–17.7). Systolic ventricular function decreased significantly over time in patients with right ventricular dominant morphology (P = 0.002), while systolic ventricular function remained stable in patients with left ventricular dominant morphology. Fontan failure occurred in 24 patients, with estimated freedom from Fontan failure rates of 97.7% [95% confidence interval (CI), 95–99] at 1 year, 93.9% (95% CI, 89–97) at 15 years and 77.2% (95% CI, 65–86) at 20 years of follow-up. Systolic ventricular dysfunction was the most common cause of failure (29%), followed by atrioventricular valve regurgitation (16.7%), a high pulmonary vascular resistance (16.7%), restrictive pathophysiology (16.7%) and obstruction (12.5%). Patients with right ventricular dominance developed most often systolic ventricular dysfunction, while patients with left ventricular dominant morphology developed most often restrictive pathophysiology or a high pulmonary vascular resistance.

CONCLUSIONS
Approximately 10% of patients experienced Fontan failure within 15 years postoperatively. Patients with right ventricular dominance experienced progressive decline due to systolic dysfunction, while those with left ventricular dominance exhibited failure due to restrictive pathophysiology or high pulmonary vascular resistance.
Risk of psychiatric hospitalization in low-income youth: longitudinal findings from the 100 Million Brazilian Cohort
Authors: Toledo Lidiane , Rodrigues Rodrigo , Alves Flávia , Guedes Fillipe , de Araújo Jacyra Azevedo Paiva , Naslund John A , Barreto Maurício L , Patel Vikram , Machado Daiane Borges 
Published: November 2024

Abstract

Background
Youth psychiatric hospitalizations have been associated with negative outcomes, including premature death and post-discharge self-harm. Identifying risk factors for youth psychiatric hospitalization is crucial for informing prevention strategies. We aimed to evaluate the risk factors for psychiatric hospitalizations among low-income youth in Brazil.

Methods
This cohort study used interpersonal violence and psychiatric hospitalization data linked to the 100 Million Brazilian Cohort baseline. We considered 9 985 917 youths aged 5–24 years who enrolled at the baseline, between 2011 and 2018. We estimated the incidence rate (IR) with 95% confidence interval (CI) for psychiatric hospitalization by calculating the number of hospitalizations per person-year in 100 000 individuals at risk. The multilevel, multivariate Cox proportional hazards regression estimated the hazard risks (HR) with 95% CI for psychiatric hospitalization.

Results
The IR of psychiatric hospitalization was 12.28 per 100 000 person-years (95% CI, 11.96–12.6). Interpersonal violence victimization was the main risk factor for youth psychiatric hospitalization (HR, 5.24; 95% CI, 4.61–5.96). Other risk factors for psychiatric hospitalization included living with the oldest family member who had low education (HR, 2.51; 95% CI, 2.16–2.91) or was unemployed (HR, 1.49; 95% CI, 1.36–1.62), living with seven or more family members (HR, 1.84; 95% CI, 1.49–2.26) and being male (HR, 1.28; 95% CI, 1.21–1.36).

Conclusions
Urgent action is needed to prevent youth from suffering violence. Addressing this may alleviate the mental health burden in developmental ages, benefiting youth, families and the government through reduced costs in preventable psychiatric hospitalizations.
Advancements in parabolic trough water heaters with dimpled tube–CuO deionized nanofluid: experimental and numerical investigation
Authors: Arun M , Barik Debabrata , Naik Channa Keshava , Bora Bhaskor Jyoti , Dasarathy A K , Singh Sanjay , Alqarni Sondos Abdullah , Islam Saiful , Kumar Sandeep , Pathani Ashish , Wodajo Anteneh Wogasso 
Published: November 2024

Abstract
The goal of this study was to improve the performance of a parabolic trough solar water heater (PTSWH) by using a dimpled texture design on the water tube and copper oxide/deionized water (CuO/DI-H2O) as a cell-side nanofluid (NF). Experimental tests will be conducted to measure and validate the thermal performance improvements using the dimpled tube–CuO NF combination. The nanoparticle (NP) concentration in the NF and the water mass flow rate (MFR) through the dimpled tube were varied for experimental and numerical analysis. The PTSWH achieved the highest efficiency of 38.25% with a CuO volume concentration (VC) of 0.3% and a water MFR of 2.5 kg/min, 12% higher than the unembellished tube with base fluid. Furthermore, the PTSWH’s overall output performance index under the same conditions was 3.56. Furthermore, at an MFR of 3.0 kg/min and a VC of 0.5%, the pressure drop was 7.24% greater. For dimple tube (computational fluid dynamics analysis), at an MFR of 3.0 kg/min, the increase in temperature [$\Delta T=({T}_O-{T}_I$)] at CuO NP VC of 0.1%, 0.2%, 0.3%, 0.4%, and 0.5% was found to be 54°C, 56°C, 58°C, 60°C, and 62°C, respectively. These findings show that using NF and dimpled tubes to improve the performance of PTSWH systems has a high potential for a more sustainable and efficient use of solar energy.
Malaria Surveillance: A Cross-sectional Study in the Peruvian Amazon Basin, 2012–2023
Authors: Sanchez Juan F , Valdivia Hugo O , Pannebaker Danielle L 
Published: November 2024

Abstract
Loreto, a region located in the Amazon basin, has reported more than 80% of malaria cases in Peru. Application of diagnostic methods in remote areas is challenging; hence, the identification of factors associated with Plasmodium infection is necessary to improve malaria control. A cross-sectional study was conducted in health facilities in Loreto from 2012 to 2023. Data and blood samples for malaria diagnosis were collected. We performed an analysis to identify associated factors to malaria positivity. Among 2989 participants with malaria symptoms, the prevalence was 87.6% and Plasmodium vivax was the most prevalent species (74.0%). We identified several factors associated with malaria positivity such as age, occupation, sleeping with open windows, previous malaria episodes, number of malaria episodes in the last 12 months, and others. The high prevalence of malaria and the predominance of P. vivax highlight the relevance of P. vivax-targeted control programs to reach elimination in low-endemic areas.
The North–South Distinction: From Consensus to Contestation
Authors: Thérien Jean-Philippe 
Published: November 2024

Abstract
Rooted in the field of intellectual history, this article examines how the meaning of the North–South distinction has changed since its appearance in the 1960s. It explains how the largely consensual vision espoused during the early years has gradually given way to growing polarization and contestation. This evolution is unpacked by studying the genealogy of North–South narratives formulated through the ideologies of liberal internationalism and systemic reformism. The article shows that the 1960–1990 period brought about an international compromise regarding the existence of a North–South divide. Moving to the post-1990 period, the analysis then dissects the growing disagreements over the utility of the North–South terminology for interpreting the global order. While today moderate and radical reformists continue to argue that the North–South cleavage remains a structural feature of global politics, most liberals maintain that it simply fails to describe the real world. Overall, the article helps to clarify what makes the North–South distinction highly contested and nonetheless “sticky” in contemporary global affairs.
The Politics of Public Health Emergencies of International Concern
Authors: Pagotto Barbara Frossard , Eccleston-Turner Mark 
Published: November 2024

Abstract
The declaration of a Public Health Emergency of International Concern (PHEIC) was created by the International Health Regulations (2005) and is WHO's highest level of alert for a health emergency. PHEICs are declared by the WHO Director-General on the basis of a recommendation provided by the International Health Regulations (IHR) Emergency Committee. This paper challenges the orthodox thinking around PHEIC declarations, using a methodological approach that has not been used in this space, through a series of interviews with those involved in the PHEIC declaration process. This paper provides vital insights into the PHEIC process, allowing us to fully understand what happens “in the room” during these deliberations, something which until now, has not been possible. We argue that the PHEIC declaration, and the Emergency Committee's role in this process, is not a politically neutral technocratic one, as is commonly claimed by WHO, but a highly politicized process that is driven by a range of factors beyond the criteria set down in IHR. We show that the PHEIC is informed by health surveillance practices that operate within the colonial construction of “global health security,” which is clearly embedded within every level of the PHEIC declaration process.
Breaking up Big Tech: scissor-line suggestions for smart cuts
Authors: Schinkel Maarten Pieter , van Oosten Ruben J 
Published: November 2024

Abstract
Calls for the breakup of Big Tech, especially where behavioural remedies are cumbersome to enforce effectively, are becoming louder on both sides of the Atlantic. If there are going to be structural remedies against network companies, we propose they better be ‘smart cuts’: targeted interventions to insulate core platform functions with minimal damage to positive network effects. One major concern with dominant platforms is information bias: intentional distortion of information presented to a user to steer them away from the best matches to their query and towards content that benefits the platform instead. It can be addressed by separating a hybrid platform’s recommender system from its peripheral services with commercial tentacles in the real economy. This realigns incentives to provide users with unbiased information and invites competition on and between intermediaries. We offer scissor-line suggestions for the gatekeepers Alphabet, Amazon, and Apple. Smart cuts have a conceptual basis: they go beyond unwinding recent acquisitions and open up ecosystem structures to competition, allow for targeted flanking access regulation, and alleviate competition law enforcement.
Sustainable practice in gastroenterology: travel-related CO2 emissions for gastroenterology clinic appointments in Canada
Authors: Galts Ciarán , Anvari Sama , Kim Amy , Leontiadis Gregorios , Armstrong David 
Published: November 2024

Abstract

Background
Telemedicine is increasingly common in gastroenterology and may represent an opportunity for improving sustainability in medical care. The purpose of this study was to determine the carbon emissions related to travel for in-person gastroenterology clinic appointments.

Methods
We conducted a cross-sectional analysis evaluating carbon emissions associated with travel to gastroenterology appointments over a 2-week period. We determined the average number of appointments per day and used patient’s postal codes to estimate travel distances. We estimated carbon emissions based on these travel distances and completed sensitivity analyses to model methods for emissions reductions.

Results
We assessed 975 clinic appointments, of which 71 were excluded (eg, insufficient data, non-physician appointments), leaving 904 included appointments of which 75% were follow-up (678) and the remainder were new consultations (226). Sixteen different gastroenterologists had an average of 22.7 patients per clinic. The mean return distance travelled per appointment was 57.3 km which translates to 14.9 kg CO2 per patient visit. An average day at our clinic was equal to burning 146.6 L of gasoline or the annual carbon capture of 15.5 trees. By changing follow-up appointments or those with a travel distance over 100 km to telehealth, emissions were reduced by 77%.

Conclusions
We demonstrate that a relatively modest change in the number of in-person visits can save thousands of litres of gasoline emissions annually from each practicing clinician. While we cannot avoid emissions related to travel for procedure-based appointments, the use of telemedicine is one potential strategy to reduce healthcare-related emissions.
The Ordinary Soldier in Military Organization
Authors: Song Tianying 
Published: November 2024

Abstract
Drawing on social psychology, this article raises seemingly counterintuitive questions about international criminal law’s assumptions of human agency in a highly specific social environment. Is military institution hostile to the ‘normative individualism’ underlying international criminal law? If so, is it fair to demand individual criminal responsibility of members of a military organization in the same way as in peacetime situations? This article takes the perspective of an ordinary soldier and asks whether international criminal law is biased in describing causes of atrocities and dispensing solutions. After explicating some assumptions of individual criminal responsibility, it introduces the military organization as a total institution that subsumes individuals. It continues to examine the impact of the military mission and structure on the normative and behavioural competences of the ordinary soldier as a potential perpetrator of war crimes. It then contemplates how such a social environment undermines international criminal law’s fiction of human agency and, ultimately, its normative effect. This article not only invites further legal doctrinal reflections but also contributes to the criminological study of international crimes.
First cycle toxicity and survival in patients with rare cancers treated with checkpoint inhibitors
Authors: Othus Megan , Patel Sandip P , Chae Young Kwang , Dietrich Eliana , Streicher Howard , Sharon Elad , Kurzrock Razelle 
Published: November 2024

Abstract

Background
Associations between immune-related adverse events from checkpoint inhibitor therapy and outcomes have been previously evaluated, with most prior research finding a positive association between toxicity and survival. This prior research has generally reported on more common tumor types. We use a unique data resource of a federally funded basket trial (NCT02834013) for patients with rare cancers (n = 684) to evaluate associations between immune-related adverse events and overall survival and progression-free survival (PFS).

Methods
Patients were treated with nivolumab and ipilimumab; the trial was opened at more than 1000 sites. Landmark Cox regression models were used to assess first cycle immune-related adverse event associations with PFS and overall survival.

Results
We found that grade 1-2 treatment-related immune-related adverse events in the first cycle of therapy were associated with longer overall survival (multivariable hazard ratio [HR] = 0.61, 95% confidence interval [CI] = 0.49 to 0.75; P &lt; .001) compared with no treatment-related immune-related adverse event, while grade 3-4 immune-related adverse events were associated with shorter overall survival (HR = 1.41, 95% CI = 1.04 to 1.90; P = .025). Similar but weaker associations were observed with PFS and grade 1-2 treatment-related immune-related adverse events (HR = 0.83, 95% CI = 0.67 to 1.01; P = .067) and grade 3-4 (HR = 1.35, 95% CI = 1.02 to 1.78; P = .037) compared with no treatment-related immune-related adverse events. Grade 1-2 dermatologic toxicity was associated with improved overall survival compared with other grade 1-2 toxicities (HR = 0.67, 95% CI = 0.52 to 0.85; P = .002). There was no statistically significant overall survival difference between patients with grade 1-2 fatigue, gastrointestinal, metabolic, hepatic, endocrine, and thyroid toxicities vs other grade 1-2 toxicities.

Conclusion
In this large cohort of patients with rare tumors receiving checkpoint inhibitor therapy, grade of immune-related adverse event in the first cycle was predictive for survival.