bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacogenomics-assisted treatment versus standard of care in schizophrenia: a systematic review and meta-analysis
Authors: Das Saibal , Kalita Manoj , Makhal Manabendra , Devaraja M , Bagepally Bhavani Shankara , Cherian Jerin Jose , Aadityan Rajesh , Bhattacharjee Mounamukhar , Mondal Sarnendu , Sen Sreyashi , Mondal Manaswini , Basu Aniruddha , Dutta Atanu Kumar , Saha Indranil , Saha Asim , Chakrabarti Amit 
Published: October 2024

Abstract
Background
Pharmacogenomic (PGx) factors significantly influence how patients respond to antipsychotic medications This systematic review was performed to synthesize the clinical utility of PGx-assisted treatment versus standard of care in schizophrenia.

Methods
PubMed, Embase, and Cochrane CENTRAL databases were searched for randomized controlled trials (RCTs) from inception till June 2024 that had compared the clinical utility of PGx-assisted intervention as compared to the standard of care in schizophrenia. The primary outcome was safety, and the secondary outcomes were efficacy and medication adherence. Pooled standardized mean differences (SMD) along with a 95% confidence interval (CI) were calculated (random-effects model) wherever feasible.

Results
A total of 18,821 studies were screened, and five were included for review. All the RCTs had a high risk of bias. Four studies included the commonly used antipsychotics. Three studies reported negative outcomes (safety, efficacy, and medication adherence) and two reported positive outcomes (safety) using different scales. In the meta-analysis, there were significant differences in the total Udvalg for Kliniske Undersogelser Side-Effect Rating scale score [SMD 0.95 (95% CI: 0.76–1.13), p < 0.001); I2 = 0%] and the total Positive and Negative Syndrome Scale score [SMD 10.65 (95% CI: 2.37–18.93), p = 0.01); I2 = 100%] between the PGx-assisted treatment and standard of care arms. However, the results were inconsistent, and the certainty of evidence (GRADE criteria) was very low.

Conclusion
Current evidence on the clinical utility of PGx-assisted treatment in schizophrenia is limited and inconsistent and further evidence is required in this regard.
The dissemination and implementation of trauma-focused cognitive behavioural therapy for children and adolescents in seven European countries
Authors: Pfeiffer Elisa , Unterhitzenberger Johanna , Enderby Pia , Juusola Aino , Kostova Zlatina , Lindauer Ramon J. L. , Nuotio Sanna-Kaija , Samuelberg Poa , Jensen Tine K. 
Published: October 2024

Abstract
Background
There is broad scientific evidence for the effectiveness of individual trauma-focused evidence-based treatments (EBTs) such as “trauma-focused cognitive behavioural therapy” (TF-CBT) for children and adolescents with posttraumatic stress symptoms. However, there is a significant research-to-practice gap resulting in traumatized children in high-income countries in Europe having only very limited access to these treatments. The aim of this study was, therefore, to identify common barriers and successful dissemination and implementation (D&I) strategies of evidence-based trauma-focused treatments (in particular TF-CBT) in seven European countries.

Methods
For this study, we chose a mixed-method approach: an online survey among certified European TF-CBT trainers (N = 22) and the collection of country-based narratives from TF-CBT experts in different European countries (Finland, Germany, Italy, Netherlands, Norway, Sweden).

Results
Common modifiable barriers to the implementation of TF-CBT were identified on different levels (e.g. government or treatment level), and successful D&I strategies were highlighted across all countries, such as translations of materials. Additionally, the experts from the country narratives put together a broad overview of TF-CBT research in Europe.

Conclusions
The results of this study revealed that especially learning collaborations and the development of joint European efforts in funding and researching D&I strategies are crucial for future implementation of trauma-focused EBTs in Europe.
Prediction of homologous recombination deficiency from routine histology with attention-based multiple instance learning in nine different tumor types
Authors: Loeffler Chiara Maria Lavinia , El Nahhas Omar S. M. , Muti Hannah Sophie , Carrero Zunamys I. , Seibel Tobias , van Treeck Marko , Cifci Didem , Gustav Marco , Bretz Kevin , Gaisa Nadine T. , Lehmann Kjong-Van , Leary Alexandra , Selenica Pier , Reis-Filho Jorge S. , Ortiz-Bruechle Nadina , Kather Jakob Nikolas 
Published: October 2024

Abstract
Background
Homologous recombination deficiency (HRD) is recognized as a pan-cancer predictive biomarker that potentially indicates who could benefit from treatment with PARP inhibitors (PARPi). Despite its clinical significance, HRD testing is highly complex. Here, we investigated in a proof-of-concept study whether Deep Learning (DL) can predict HRD status solely based on routine hematoxylin & eosin (H&E) histology images across nine different cancer types.

Methods
We developed a deep learning pipeline with attention-weighted multiple instance learning (attMIL) to predict HRD status from histology images. As part of our approach, we calculated a genomic scar HRD score by combining loss of heterozygosity (LOH), telomeric allelic imbalance (TAI), and large-scale state transitions (LST) from whole genome sequencing (WGS) data of n = 5209 patients across two independent cohorts. The model’s effectiveness was evaluated using the area under the receiver operating characteristic curve (AUROC), focusing on its accuracy in predicting genomic HRD against a clinically recognized cutoff value.

Results
Our study demonstrated the predictability of genomic HRD status in endometrial, pancreatic, and lung cancers reaching cross-validated AUROCs of 0.79, 0.58, and 0.66, respectively. These predictions generalized well to an external cohort, with AUROCs of 0.93, 0.81, and 0.73. Moreover, a breast cancer-trained image-based HRD classifier yielded an AUROC of 0.78 in the internal validation cohort and was able to predict HRD in endometrial, prostate, and pancreatic cancer with AUROCs of 0.87, 0.84, and 0.67, indicating that a shared HRD-like phenotype occurs across these tumor entities.

Conclusions
This study establishes that HRD can be directly predicted from H&E slides using attMIL, demonstrating its applicability across nine different tumor types.
The efficacy of different biomarkers and endpoints to refine referrals for suspected prostate cancer: the TARGET study (Tiered integrAted tests for eaRly diaGnosis of clinically significant ProstatE Tumours)
Authors: Lophatananon Artitaya , Muir Kenneth R. , Gnanapragasam Vincent J. 
Published: October 2024

Abstract
Background
The majority of men referred with a raised PSA for suspected prostate cancer will receive unnecessary tertiary investigations including MRI and biopsy. Here, we compared different types of biomarkers to refine tertiary referrals and when different definitions of clinically significant cancer were used.

Methods
Data and samples from 798 men referred for a raised PSA (≥ 3 ng/mL) and investigated through an MRI-guided biopsy pathway were accessed for this study. Bloods were acquired pre-biopsy for liquid biomarkers and germline DNA. Variables explored included PSA + Age (base model), free/total PSA (FTPSA), Prostate Health Index (phi), PSA density (PSAd), polygenic risk score (PRS) and MRI (≥ LIKERT 3). Different diagnostic endpoints for significant cancer (≥ grade group 2 [GG2], ≥ GG3, ≥ Cambridge Prognostic Group 2 [CPG2], ≥ CPG3) were tested. The added value of each biomarker to the base model was evaluated using logistic regression models, AUC and decision curve analysis (DCA) plots.

Results
The median age and PSA was 65 years and 7.13 ng/mL respectively. Depending on definition of clinical significance, ≥ grade group 2 (GG2) was detected in 57.0% (455/798), ≥ GG3 in 27.5% (220/798), ≥ CPG2 in 61.6% (492/798) and ≥ CPG3 in 42.6% (340/798). In the pre-MRI context, the PSA + Age (base model) AUC for prediction of ≥ GG2, ≥ GG3, ≥ CPG2 and ≥ CPG3 was 0.66, 0.68, 0.70 and 0.75 respectively. Adding phi and PSAd to base model improved performance across all diagnostic endpoints but was notably better when the composite CPG prognostic score was used: AUC 0.82, 0.82, 0.83, 0.82 and AUC 0.74, 0.73, 0.79, 0.79 respectively. In contrast, neither FTPSA or PRS scores improved performance especially in detection of ≥ GG3 and ≥ CPG3 disease. Combining biomarkers did not alter results. Models using phi and PSAd post-MRI also improved performances but again benefit varied with diagnostic endpoint. In DCA analysis, models which incorporated PSAd and phi in particular were effective at reducing use of MRI and/or biopsies especially for ≥ CPG3 disease.

Conclusion
Incorporating phi or PSAd can refine and tier who is referred for tertiary imaging and/or biopsy after a raised PSA test. Incremental value however varied depending on the definition of clinical significance and was particularly useful when composite prognostic endpoints are used.
Monitoring the efficiency of reversal on anti-Xa direct oral anticoagulants using point-of-care viscoelastic testing
Authors: Heubner Lars , Grottke Oliver , Vicent Oliver , Spieth Peter Markus , Beyer-Westendorf Jan 
Published: October 2024

AbstractBleeding events in patients receiving direct oral anticoagulation (DOAC) can be life-threatening even at therapeutic DOAC plasma concentrations, as anticoagulation impairs hemostasis and should therefore be identified immediately after hospital admission. The anticoagulatory effects of DOAC are typically not measurable in standard coagulation tests, such as PT or aPTT. Specific calibrated anti-FXa-tests allow specific drug monitoring, but they are too time-consuming for critical bleeding events and are commonly not available for 24 h/7 days in routine care. However, recent advances in point-of-care (POC) viscoelastic testing (VET) have shown a promising approach for rapid and quantitative detection of DOAC plasma concentrations using the Russell viper venom factor V activator (RVV for FXa-inhibitors) test or the ecarin clotting time (thrombin inhibitors). In acute bleeding situations, direct FXa inhibitors can be reversed by specific antidote andexanet alfa or hemostasis can be improved by prothrombin complex factor concentrates (PCCs). After reversal, confirmation of reversal efficacy is often requested, but no routine assays are currently available. Thus, the emergency management of bleeding DOAC patients is usually “blinded” with regard to reversal efficacy. POC VET laboratory assays might therefore also be helpful for measuring DOAC effects after reversal. We present a case series demonstrating the usefulness of RVV-clotting time post-DOAC reversal with andexanet alfa.
A pilot study of the cardiopulmonary effects in healthy volunteers after exposure to high levels of PM2.5 in a New York City subway station
Authors: Luglio David G. , Farrell Kayla Rae , Gordon Terry 
Published: October 2024

Abstract
Background
Subway systems are becoming increasingly common worldwide transporting large populations in major cities. PM2.5 concentrations have been demonstrated to be exceptionally high when underground, however. Studies on the impact of subway PM exposure on cardiopulmonary health in the United States are limited.

Methods
Healthy volunteers in New York City were exposed to a 2-h visit on the 9th Street Station platform on the Port Authority Trans-Hudson train system. Blood pressure, heart rate variability (HRV), spirometry, and forced impulse oscillometry were measured, and urine, blood spot, and nasal swab biosamples were collected for cytokine analysis at the end of the 2-h exposure period. These endpoints were compared against individual control measurements collected after 2-h in a “clean” control space. In addition to paired comparisons, mixed effects models with subject as a random effect were employed to investigate the effect of the PM2.5 concentrations and visit type (i.e., subway vs. control).

Results
Mean PM2.5 concentrations on the platform and during the control visit were 293.6 ± 65.7 (SD) and 4.6 ± 1.9 µg/m3, respectively. There was no change in any of the health metrics, but there was a non-significant trend for SDNN to be lower after subway exposure compared to control exposure. Total symptomatic scores did increase post-subway exposure compared to reported values prior to exposure or after the control visit. No significant changes in cytokine concentrations in any specimen type were observed. Mixed-effects models mostly corroborated these paired comparisons.

Conclusions
Acute exposures to PM on a subway platform do not cause measurable cardiopulmonary effects apart from reductions in HRV and increases in symptoms in healthy volunteers. These findings match other studies that found little to no changes in lung function and blood pressure after exposure in underground subway stations. Future work should still target potentially more vulnerable populations, such as individuals with asthma or those who spend increased time underground on the subway such as transit workers.
Nanopore sequencing with unique molecular identifiers enables accurate mutation analysis and haplotyping in the complex lipoprotein(a) KIV-2 VNTR
Authors: Amstler Stephan , Streiter Gertraud , Pfurtscheller Cathrin , Forer Lukas , Di Maio Silvia , Weissensteiner Hansi , Paulweber Bernhard , Schönherr Sebastian , Kronenberg Florian , Coassin Stefan 
Published: October 2024

Abstract
Background
Repetitive genome regions, such as variable number of tandem repeats (VNTR) or short tandem repeats (STR), are major constituents of the uncharted dark genome and evade conventional sequencing approaches. The protein-coding LPA kringle IV type-2 (KIV-2) VNTR (5.6 kb per unit, 1–40 units per allele) is a medically highly relevant example with a particularly intricate structure, multiple haplotypes, intragenic homologies, and an intra-VNTR STR. It is the primary regulator of plasma lipoprotein(a) [Lp(a)] concentrations, an important cardiovascular risk factor. Lp(a) concentrations vary widely between individuals and ancestries. Multiple variants and functional haplotypes in the LPA gene and especially in the KIV-2 VNTR strongly contribute to this variance.

Methods
We evaluated the performance of amplicon-based nanopore sequencing with unique molecular identifiers (UMI-ONT-Seq) for SNP detection, haplotype mapping, VNTR unit consensus sequence generation, and copy number estimation via coverage-corrected haplotypes quantification in the KIV-2 VNTR. We used 15 human samples and low-level mixtures (0.5 to 5%) of KIV-2 plasmids as a validation set. We then applied UMI-ONT-Seq to extract KIV-2 VNTR haplotypes in 48 multi-ancestry 1000 Genome samples and analyzed at scale a poorly characterized STR within the KIV-2 VNTR.

Results
UMI-ONT-Seq detected KIV-2 SNPs down to 1% variant level with high sensitivity, specificity, and precision (0.977 ± 0.018; 1.000 ± 0.0005; 0.993 ± 0.02) and accurately retrieved the full-length haplotype of each VNTR unit. Human variant levels were highly correlated with next-generation sequencing (R2 = 0.983) without bias across the whole variant level range. Six reads per UMI produced sequences of each KIV-2 unit with Q40 quality. The KIV-2 repeat number determined by coverage-corrected unique haplotype counting was in close agreement with droplet digital PCR (ddPCR), with 70% of the samples falling even within the narrow confidence interval of ddPCR. We then analyzed 62,679 intra-KIV-2 STR sequences and explored KIV-2 SNP haplotype patterns across five ancestries.

Conclusions
UMI-ONT-Seq accurately retrieves the SNP haplotype and precisely quantifies the VNTR copy number of each repeat unit of the complex KIV-2 VNTR region across multiple ancestries. This study utilizes the KIV-2 VNTR, presenting a novel and potent tool for comprehensive characterization of medically relevant complex genome regions at scale.
Increase in PVC-BSI during the second COVID-19 pandemic year: analysis of catheter and patient characteristics
Authors: Pianca Eva , Zanella Marie-Céline , Obama Basilice Minka , Nguyen Aude , Fortchantre Loïc , Chraiti Marie-Noëlle , Harbarth Stephan , Catho Gaud , MacPhail Aleece , Buetti Niccolò 
Published: October 2024

Abstract
Background
Increasing nosocomial infections during the COVID-19 pandemic have been reported. However, data describing peripheral venous catheter associated bloodstream infections (PVC-BSI) are limited.

Aims
To describe the epidemiology and risk factors for PVC-BSI during the COVID-19 pandemic.

Methods
We conducted retrospective cohort study of prospectively collected PVC-BSI data in a 2100 bed hospital network in Switzerland. Adult patients with a PVC inserted between January 1, 2020 and December 31, 2021 were included. Risk factors for PVC-BSI were identified through descriptive analysis of patient and catheter characteristics, and univariable marginal Cox models.

Results
206,804 PVCs and 37 PVC-BSI were analysed. Most PVC-BSI were attributed to catheters inserted in the Emergency department (76%) or surgical wards (22%). PVC-BSI increased in 2021 compared to 2020 (hazard ratio 2021 vs. 2020 = 2.73; 95% confidence interval 1.19–6.29), with a numerically higher rate of Staphylococcus aureus (1/10, 10%, vs. 5/27, 19%) and polymicrobial infection (0/10, 0% vs. 4/27, 15%). PVC insertions, patient characteristics, and catheter characteristics remained similar across the study period. PVC-BSI risk was associated with admission to the intensive care unit (ICU), and use of wide gauge catheter ( < = 16G).

Conclusion
Increased PVC-BSI during the COVID-19 pandemic was not explained by catheter or patient factors alone, and may result from system-wide changes. PVC-BSI events are primarily attributed to acute care settings, including the emergency department, surgical wards, and the ICU.
Global burden of viral infectious diseases of poverty based on Global Burden of Diseases Study 2021
Authors: Li Xin-Chen , Zhang Yan-Yan , Zhang Qi-Yu , Liu Jing-Shu , Ran Jin-Jun , Han Le-Fei , Zhang Xiao-Xi 
Published: October 2024

Abstract
Background
Viral infectious diseases of poverty (vIDPs) remain a significant global health challenge. Despite their profound impact, the burden of these diseases is not comprehensively quantified. This study aims to analyze the global burden of six major vIDPs, including coronavirus disease 2019 (COVID-19), HIV/AIDS, acute hepatitis, dengue, rabies, and Ebola virus disease (EVD), using data from the Global Burden of Diseases, Injuries, and Risk Factors Study 2021 (GBD 2021).

Methods
Following the GBD 2021 framework, we analyzed the incidence, mortality, and disability-adjusted life years (DALYs) of the six vIDPs across 204 countries and territories from 1990 to 2021. We examined the association between the Socio-Demographic Index (SDI) and the burden of vIDPs. All estimates were reported as numbers and rates per 100,000 population, calculated using the Bayesian statistical model employed by GBD 2021, with 95% uncertainty intervals (UI).

Results
In 2021, vIDPs caused approximately 8.7 million deaths and 259.2 million DALYs, accounting for 12.8% and 9.0% of the global all-cause totals, respectively. Globally, the burden of vIDPs varied significantly: COVID-19 caused around 7.9 million (95% UI: 7.5, 8.4) deaths and 212.0 million (95% UI 197.9, 234.7) DALYs in 2021. Acute hepatitis had the second-highest age-standardized incidence rate, with 3411.5 (95% UI: 3201.8, 3631.3) per 100,000 population, while HIV/AIDS had a high age-standardized prevalence rate, with 483.1 (95% UI: 459.0, 511.4) per 100,000 population. Dengue incidence cases rose from 26.5 million (95% UI: 3.9, 51.9) in 1990 to 59.0 million (95% UI: 15.5, 106.9) in 2021. Rabies, although reduced in prevalence, continued to pose a significant mortality risk. EVD had the lowest overall burden but significant outbreak impacts. Age-standardized DALY rates for vIDPs were significantly negatively correlated with SDI: acute hepatitis (r = −0.8, P < 0.0001), rabies (r = −0.7, P < 0.0001), HIV/AIDS (r = −0.6, P < 0.0001), COVID-19 (r = −0.5, P < 0.0001), dengue (r = −0.4, P < 0.0001), and EVD (r = −0.2, P < 0.005).

Conclusions
VIDPs pose major public health challenges worldwide, with significant regional, age, and gender disparities. The results underscore the need for targeted interventions and international cooperation to mitigate the burden of these diseases. Policymakers can use these findings to implement cost-effective interventions and improve health outcomes, particularly in regions with high or increasing burdens.
Evaluation of the therapeutic potential of novel nanoparticle formulations of glutathione and virgin coconut oil in an experimental model of carbon tetrachloride-induced liver failure
Authors: Allam Essmat A. H. , Darwish Madeha H. A. , Abou Khalil Nasser S. , El-Baset Shimaa H. A. Abd , El-Aal Mohamed Abd , Elrawy Ahmed , Ahmed Ahmed A. N. , Sabra Mahmoud S. 
Published: October 2024

Abstract
Background
Acute liver failure (ALF) is a critical condition characterized by rapid liver dysfunction, leading to high mortality rates. Current treatments are limited, primarily supportive, and often require liver transplantation. This study investigates the potential of a novel nanoparticle formulation of glutathione (GSH) and virgin coconut oil (VCO) alone and in combination to enhance therapeutic outcomes in a rat model of ALF induced by orogastric carbon tetrachloride (CCl4).

Methods
The study employed adult male Albino rats divided into ten groups, with ALF induced via a single oral dose of CCl4. Various treatment regimens were administered over seven days, including conventional and nanoparticle forms of GSH and VCO and their combinations. The efficacy of treatments was evaluated through biochemical analysis of liver function markers, oxidative stress indicators, inflammatory biomarkers, and histopathological examinations. Nanoparticles were synthesized using established methods, and characterization techniques were employed to ensure their quality and properties.

Results
The nanoparticle formulations significantly improved liver function, as indicated by reduced serum levels of alanine aminotransferase and aspartate aminotransferase, alongside decreased oxidative stress markers such as malondialdehyde. Furthermore, they reduced tumor necrosis factor alpha and interleukin-1 beta inflammatory markers. Histological analysis revealed reduced hepatocellular necrosis and inflammation in treated groups compared to controls. Also, decreased nuclear factor-kappa B was detected by immunohistochemical analysis.

Conclusion
The findings show that the nanoparticle mixture of GSH and VCO effectively reduces liver damage in ALF. This suggests a promising drug-based approach for improving liver regeneration and protection. This innovative strategy may pave the way for new therapeutic interventions in the management of ALF.