bluuebunny/crossref_metadata_2025 huggingface dataset:
Illuminating the Challenges and Diagnostic Utility of Plasma Microbial Cell-Free DNA Sequencing in Suspected Infective Endocarditis: A Retrospective Observational Cohort Study
Authors: Kim Myeongji , Damronglerd Pansachee , Molina Garcia Sofia , Yetmar Zachary A , Razi Samrah , Ranganath Nischal , Mahmood Maryam , Abu Saleh Omar M
Published: February 2025

Background

Infective endocarditis (IE) is a life-threatening infection often challenging to diagnose, particularly in culture-negative cases. Plasma microbial cell-free DNA (mcfDNA) sequencing has shown potential for detecting pathogens in IE. However, the clinical utility, diagnostic impact, and limitations of mcfDNA sequencing remain debated. This study evaluates its use in diagnosing and managing IE in a tertiary care setting.

Methods

This single-center retrospective cohort study included adult patients (≥18 years) who underwent mcfDNA sequencing via the Karius test for suspected IE at Mayo Clinic Rochester between December 2019 and February 2024. Diagnostic classification followed the 2023 Duke - International Society of Cardiovascular Infectious Diseases (ISCVID) criteria. Data on demographics, clinical features, routine microbiological work-up, and mcfDNA sequencing results were collected. Statistical analysis was conducted to evaluate the diagnostic utility and treatment impact.

Results

Among 141 patients, 66 had a diagnosis of IE, with mcfDNA sequencing identifying pathogens in 60.6% of cases compared to 39.4% with routine work-up. mcfDNA sequencing was the sole positive microbiologic test in 33.3% of cases, leading to antimicrobial adjustments in 50.0% of these patients. Clinically insignificant mcfDNA sequence detection occurred in 28.6% of cases without a diagnosis of IE.

Conclusions

mcfDNA sequencing is a valuable adjunctive tool for diagnosing culture-negative IE and guiding antimicrobial therapy when clinical suspicion is high. However, its utility depends on appropriate clinical context, highlighting the need for careful test interpretation and further prospective studies to assess patient-centered outcomes and cost-effectiveness.
Enhancing the Thermostability and solubility of a single-domain catalytic antibody
Authors: Cui Yunhang , Zhou Xuchen , Li Sainan , Chen Jingfei , Qin Mingming , An Liaoyuan , Wang Yefei , Yao Lishan
Published: February 2025

Catalytic antibodies have the ability to bind to and degrade antigens, offering a significant potential for therapeutic use. The light chain of an antibody, UA15-L, can cleave the peptide bond of Helicobacter pylori urease, thus inhibiting the spread of the bacteria. However, the variable domain of UA15-L has a poor thermostability and solubility. In this study, we employed a combined computational and experimental approach to enhance the protein’s stability and solubility properties. The protein unfolding hotspots were initially identified using molecular dynamics simulations. Following this, a disulfide bond was designed in an unfolding hotspot to stabilize the protein. Subsequently, protein solubility was enhanced with the assistance of computational methods by introducing polar or charged residues on the protein surface. The combination of multiple mutations resulted in UA15-L variable domain variants with improved thermostability, solubility, expression, and enhanced activity at elevated temperatures. These variants represent promising candidates for further engineering of catalytic activity and specificity.
Early acupuncture intervention for pain relief in emergency department patients with suspected acute renal colic caused by urinary calculi: A randomized clinical trial
Authors: Cao Ying , Qu Zhicheng , Zhang Shuwen , Liu Yunhua , Jia Liancheng , Pei Xiaolu , Wang Xiao , Zhang Dantong , Li Binyan , Lu Haitian , Ding Maoyu , Bai Yinglu , Wang Shuang , Yang Yufei , Hu Jing , Peng Wei , Guo Wei , Xu Xiaolong , Liu Qingquan
Published: February 2025

Background

Renal colic is one of the worst types of pain in acute renal colic caused by urinary calculi (ARCUC). We previously proved that acupuncture can alleviate the pain in ARCUC patients, but its effect on suspected ARCUC remains unclear.

Objective

The objective was to evaluate the effectiveness and safety of acupuncture in patients with suspected ARCUC.

Design

This prospective, double-blind, sham acupuncture-controlled, randomized clinical trial was conducted from July 2021 to June 2024 in an emergency department in China.

Methods

The patients immediately received acupuncture treatment or sham acupuncture treatment after randomization.The primary outcome was the response rate at 10 minutes (pain relief rate) after needle manipulation.The secondary outcomes included the response rates at 0, 5, 15, 20, and 30 minutes, trends in the NRS score over time, patient satisfaction, the analgesic injection rate at 30 minutes, the surgical intervention rate, the revisit rate, and the occurrence of adverse events.

Results

This trial enrolled 84 participants with suspected ARCUC patients, who immediately received acupuncture treatment or sham treatment after randomization. The pain response rates at 10 minutes were 64.3% and 16.7% in the acupuncture group and sham group, respectively, and the difference between the groups was 47.6% (95% CI, 29.3% to 66%; P < 0.01). The response rates of acupuncture were also significantly higher than those of sham acupuncture at 0, 5, 15, 20, and 30 minutes.

Conclusions

These results suggest that acupuncture could alleviate the pain in patients with suspected ARCUC safely.

Trial Registration

Chinese Clinical Trial Registry: ChiCTR2100049069.
Harnessing the diversity and potential of endogenous skeletal stem cells for musculoskeletal tissue regeneration
Authors: Weldon Kelly C , Longaker Michael T , Ambrosi Thomas H
Published: February 2025

In our aging society, the degeneration of the musculoskeletal system and adjacent tissues is a growing orthopedic concern. As bones age, they become more fragile, increasing the risk of fractures and injuries. Furthermore, tissues like cartilage accumulate damage, leading to widespread joint issues. Compounding this, the regenerative capacity of these tissues declines with age, exacerbating the consequences of fractures and cartilage deterioration. With rising demand for fracture and cartilage repair, bone-derived stem cells have attracted significant research interest. However, the therapeutic use of stem cells has produced inconsistent results, largely due to ongoing debates and uncertainties regarding the precise identity of the stem cells responsible for musculoskeletal growth, maintenance and repair. This review focuses on the potential to leverage endogenous skeletal stem cells (SSCs)—a well-defined population of stem cells with specific markers, reliable isolation techniques, and functional properties—in bone repair and cartilage regeneration. Understanding SSC behavior in response to injury, including their activation to a functional state, could provide insights into improving treatment outcomes. Techniques like microfracture surgery, which aim to stimulate SSC activity for cartilage repair, are of particular interest. Here, we explore the latest advances in how such interventions may modulate SSC function to enhance bone healing and cartilage regeneration.
Towards optimization in the use of hemostatic agents and blood products in the early treatment of patients with traumatic brain injury (TBI)
Authors: Maegele Marc
Published: February 2025

Purpose of the review

The treatment of patients with traumatic brain injury (TBI) with subsequently evolving hemostatic failure and hemorrhagic lesion progression remains challenging. New studies highlight windows of opportunity for treatment optimization.

Recent findings

Results from recent randomized studies suggest an earlier treatment with antifibrinolytic tranexamic acid at a higher initial bolus dose. There seems to be a new window of opportunity for the early prehospital use of thawed plasma. Viscoelastic-based goal-directed treatment strategies are still not delivered timely in most patients although a recent meta-analysis has confirmed a survival benefit with this approach.

Mortality in TBI with subsequent evolving hemostatic failure can be reduced through treatment optimization delivering early prehospital high-dose tranexamic acid and in-hospital goal-directed treatment algorithms to timely correct coagulopathy and restore hemostasis.
Pregnancy-Related Mortality in California Due to Obstetric Hemorrhage
Authors: Krakowiak Paula , Morton Christine H. , McCain Christy , Sun Dan , Mathur Deepika , Butwick Alexander J. , Gupta Neeru , Nijagal Malini A. , Williams Amanda , Seacrist Marla , Shields Laurence E. , Reyes Carolina , Klassen Miranda , Yznaga Elizabeth , Main Elliott K.
Published: February 2025

OBJECTIVE:

To identify underlying causes, contributing factors, and quality-improvement opportunities of pregnancy-related hemorrhage deaths.

METHODS:

The California Pregnancy-Associated Mortality Review examined pregnancy-related hemorrhage deaths in California that occurred in 2014–2018. Data were abstracted from multiple sources (vital records, hospital encounter data, medical records, and coroner or autopsy reports). A multidisciplinary expert panel reviewed all case summaries. Data from reviews were aggregated to determine underlying causes of death, preventability, contributing factors, and quality-improvement opportunities at the patient, clinician, facility, and system levels.

RESULTS:

During the study period, there were 2,409,732 live births and 49 pregnancy-related hemorrhage deaths. Placenta accreta spectrum accounted for 16 (32.7%) of deaths; intra-abdominal bleeding and uterine atony each accounted for 10 deaths (20.4%). Compared with the California birth population, a significantly higher proportion of women who died were born in China (14.3% vs 3.9%); were 35 years of age or older (49.0% vs 21.9%); had two or more prior births (57.4% vs 29.1%); had cesarean deliveries (74.4% vs 31.8%); or delivered at hospitals with fewer than 1,200 births per year (33.3% vs 12.2%) (all P<.05). The committee determined that 63.3% of all hemorrhage deaths were highly preventable with substantial variation by cause. Clinician-, facility-, and system-level contributing factors were noted in 88.9% of cases and included delayed response or escalation (77.8%), delayed recognition (72.2%), and insufficient quantities of blood products used (52.8%). Corresponding quality-improvement opportunities included timely hemorrhage risk assessment; increased vigilance for identifying signs and symptoms of hemorrhage; escalation of care and aggressive management; preparation for hemorrhage complications and ongoing training for all hospitals, particularly low-resource facilities; and adherence to severe hemorrhage protocols.

CONCLUSION:

Obstetric hemorrhage remains a leading cause of pregnancy-related mortality and has multiple causes with various levels of preventability. Optimizing system-based approaches for hemorrhage preparedness, detection, and clinical management is critical to reduce preventable deaths from hemorrhage, especially among patients who do not respond to first-line treatment.
Nocturnal hypertension represents an uncontrolled burden in patients with metabolic dysfunction-associated steatotic liver disease
Authors: Martin Anna , Lang Sonja , Schifferdecker Felix , Allo Gabriel , Chon Seung-Hun , Neumann-Haefelin Christoph , Demir Münevver , Steffen Hans-Michael , Kasper Philipp
Published: February 2025

Background&Aims:

Metabolic dysfunction-associated steatotic liver disease (MASLD) is an independent risk factor for cardiovascular morbidity and mortality. Another critical risk factor in these patients is arterial hypertension (AH). Although it is estimated that 50% of MASLD patients are suffering from AH, 24-h ambulatory blood pressure monitoring (24-h-ABPM), the gold standard for diagnosing hypertension, is often neglected. However, only 24-h-ABPM can identify hypertension subtypes, particularly nocturnal hypertension (NH), which is a stronger predictor of cardiovascular mortality than daytime or 24-h blood pressure. The aim of this study was to investigate the prevalence of NH in MASLD patients and to identify associated risk factors.

Methods:

To this end, 226 MASLD patients with or without known AH were prospectively recruited in an outpatient liver department and underwent 24-h-ABPM together with repeated office-blood-pressure measurements.

Results:

24-h-ABPM datasets from 218 patients were included in the final analysis. NH was observed in 112 patients (51.3%), of whom 54 (48.2%) were receiving antihypertensive treatment (uncontrolled hypertension). Univariable regression analysis showed that age, increased waist-to-hip ratio, a waist-to-height ratio ≥0.5, type 2 diabetes mellitus (T2DM), dyslipidemia, a lower estimated glomerular filtration rate and increased liver stiffness were significantly associated with a higher risk of NH. In multivariable regression analysis, T2DM [odds ratio (OR) 2.56; 95% confidence interval (CI) 1.09–6.23; P = 0.033], dyslipidemia (OR 3.30; 95% CI, 1.67–6.73; P = 0.001) and liver stiffness (OR 1.09; 95% CI, 1.02–1.18; P = 0.021) were identified as independent risk factors.

Conclusions:

In conclusion, particularly MASLD patients with accompanying T2DM, dyslipidemia, and increased liver stiffness should undergo 24-h-ABPM to detect and treat NH, as they are at the highest risk of adverse cardiovascular events.

Clinical trial:

NCT-04543721
Tension band tendon-approximating cerclage for surgical fixation of patellar fractures: a novel surgical technique
Authors: Revelt Nicolas , Beason Austin , Sleiman Anthony , Gardner Matthew
Published: February 2025

Patellar fractures are potentially debilitating injuries due to loss of extensor mechanism function, resulting in an inability to extend the leg. Traditionally, these fractures have been surgically managed with open reduction and internal fixation using a tension band construct. This can be performed with K-wires or cannulated screws with suture or cable as the tension band. Plate osteosynthesis is another option that is increasing in popularity. Incorporating the tension band construct converts tensile force into a healing-compatible compressive force. However, these techniques often fail when used for comminuted patellar fractures. There is also a high reoperation rate due to metal implant discomfort. Reoperation rates have been reported as high as 41% for K-wires and 23% for cannulated screws. A more optimal technique would provide adequate reduction and strong fixation without the risk of implant irritation that can apply to all/most fracture types. We report a new technique that implements a multistrand, long-chain, ultra–high-molecular weight, polyethylene core suture material with a braided jacket of polyester (FiberWire) without the need for any associated plates, K-wires, or cannulated screws. The suture is woven to create a tension band tendon-approximating cerclage construct that incorporates the proximal and distal bone fragments as well as the patellar and quadriceps tendons. This technique can be used for both simple and comminuted fractures and provides optimal fixation strength while minimizing the complications associated with metal implants. The efficacy of this technique may lend to future studies including biomechanical and retrospective analyses.
Prevalence and insecticide resistance in Anopheles coluzzii in Ado-Ota, Nigeria

Authors: Nwinyi Obinna C. , Balogun Daniel Oluwatobiloba , Isibor Patrick O.
Published: February 2025

The increasing resistance to pyrethroids poses a significant challenge to effective vector control in Africa. This study assessed mosquito species composition and resistance level to pyrethroids in selected towns in Ado Odo Ota Local Govt, Ogun; a 6-month longitudinal entomological survey was carried out using light trap and larval sampling. Mosquitoes were collected, and Anopheles species were identified through morphological examination using Coetzee’s taxonomic keys and molecular analyses. Sporozoite detection using ELISA was conducted. The susceptibility status of Anopheles gambiae sensu lato to permethrin (0.75%) and deltamethrin (0.05%) was assessed using the World Health Organization insecticide susceptibility test. The identified species were also screened for knockdown (kdr) target site resistance alleles. Five hundred seventy-nine (579) adult mosquitoes were collected and morphologically identified. Two-thirds (376/579) of the mosquitoes were identified as Culex spp., constituting the most abundant species in the selected towns. Molecular identification using intentional mismatch primers confirmed Anopheles coluzzii's presence as the communities' main species. Thirty per cent 30% (22.5 – 37.5) of the Anopheles gambiae mosquitoes were susceptible to permethrin after 24 hours, while 98% (95.7 -100) of the vectors were susceptible to deltamethrin. Sporozoite detection showed none (0/40) of the tested blood-fed female Anopheles gambiae were positive for sporozoites, and the West African and East African knockdown resistance genes were detected in very high frequencies among the sampled population (L1014F – 64% [0.36 – 0.83], L1014S – 60% [0.30 – 0.77]). This study revealed that Anopheles coluzzii (99%) is the predominant species in the study area, and Deltamethrin is still effective in the tested communities; however, the high knockdown resistance of both the east and west alleles calls for urgent implementation of integrated vector control.
Computational Mechanisms of Approach-Avoidance Conflict Predictively Differentiate Between Affective and Substance Use Disorders
Authors: Mehta Marishka M. , Hakimi Navid , Pena Orestes , Torres Taylor , Goldman Carter M. , Lavalley Claire A. , Stewart Jennifer L. , Berg Hannah , Ironside Maria , Paulus Martin P. , Aupperle Robin , Smith Ryan
Published: February 2025

Psychiatric disorders are highly heterogeneous and often co-morbid, posing specific challenges for effective treatment. Recently, computational modeling has emerged as a promising approach for characterizing sources of this heterogeneity, which could potentially aid in clinical differentiation. In this study, we tested whether computational mechanisms of decision-making under approach-avoidance conflict (AAC) – where behavior is expected to have both positive and negative outcomes – may have utility in this regard. We first carried out a set of pre-registered modeling analyses in a sample of 480 individuals who completed an established AAC task. These analyses aimed to replicate cross-sectional and longitudinal results from a prior dataset (N=478) – suggesting that mechanisms of decision uncertainty (DU) and emotion conflict (EC) differentiate individuals with depression, anxiety, substance use disorders, and healthy comparisons. We then combined the prior and current datasets and employed a stacked machine learning approach to assess whether these computational measures could successfully perform out-of-sample classification between diagnostic groups. This revealed above-chance differentiation between affective and substance use disorders (balanced accuracy > 0.688), both in the presence and absence of co-morbidities. These results demonstrate the predictive utility of computational measures in characterizing distinct mechanisms of psychopathology and may point to novel treatment targets.
IMPROVING THE MANAGEMENT OF LEPROSY ULCERS THROUGH A COMMUNITY SELF-CARE INTERVENTION USING A STEPPED WEDGE CLUSTER RANDOMISED TRIAL IN SOUTH-EAST NIGERIA
Authors: Meka Anthony , Ugwu Linda , Wang Yixin , Watson Samuel I. , Ilozumba Onaedo , Akunna Uchechukwu , Choudhury Sopna , Chukwu Joseph N , Gill Paramjit , Lindenmeyer Antje , Murphy-Okpala Ngozi , Ndubuizu Nchekwube , Sartori Jo , Griffiths Frances , Lilford Richard J.
Published: February 2025

Background: People with sensory neuropathy caused by leprosy suffer from recurrent ulcers. Self-care is used to promote ulcer healing and reduce recurrence. The challenge is to maximise use of self-care and to optimise the way it is practised. RedAid Nigeria in South-East Nigeria adapted and implemented a recently developed international guideline for self-care of ulcers in an area with a high prevalence of leprosy. We report a prospective evaluation of the effectiveness of this intervention in reducing the prevalence and severity of ulcers and in improving wellbeing. Methods: A mixed methods partial stepped wedge cluster randomized trial across 15 clinics serving patients affected by neuropathy and recurrent ulcers. Outcomes were number and area of ulcers, self-rated health and wellbeing. We used a Bayesian analysis to estimate treatment effects and a process analysis based on descriptive statistics and thematic analysis of qualitative data.  Results: The ulcers at baseline were long-standing – mean (sd) of ulcer duration at baseline was 58.55 (94.49) months and total disability rate was high (65.99%). There was no evidence of an intervention effect on the persistence of ulcers (OR: 1.00 (95% credible interval (CrI) 0.29 – 3.56) or relative area of ulcers (cm2) 1.12 (0.53 – 2.27). There was evidence of an increase in self-reported health and wellbeing associated with the intervention (EQ-5D VAS mean difference 10.93 (8.60, 13.23) out of 100; life satisfaction 1.18 (0.65, 1.72) out of 10). Process data indicate the intervention was delivered as planned. Qualitative data triangulated with quantitative data findings suggest enthusiasm among participants for and adherence to the intervention. Improved wellbeing was described in terms of improved confidence in administering self-care and better integration in local communities. Discussion: The intervention improved perceptions of health and wellbeing, despite having small and uncertain effects on ulcer-related outcomes. Effecting an improvement in ulcer size and number through a community intervention may be difficult to achieve in poor, rural contexts, even if patients respond positively to the intervention.
Build heatmaps of cell frequencies and marker intensities for correct interpretations
Authors: Lohmann Eugénie , Gorvel Laurent , Granjeaud Samuel
Published: February 2025

High-content cytometry is an important technique in clinical research, producing data that is rich and complex to analyze. The resulting clusters of cells must be profiled to determine their role and function, and analyzed to identify changes in cell frequency or marker intensity. The heat map is the most suitable tool for presenting this information in a synthetic way. However, its construction must be adapted to the information and the objective. Here we describe the step-by-step construction of heat maps of marker intensity and cell frequency using Excel, Phantasus or R, including the conversion of numbers to colors and the organization of rows and columns. Researchers who master these steps will be able to correctly interpret heat maps and derive the most benefit from high-content cytometry.
Dissecting DNA-mismatch-repair-driven mutational processes in human cells
Authors: Owusu Michel , Menche Jörg , Loizou Joanna , Weghorn Donate
Published: February 2025

Mismatch repair (MMR) is a crucial DNA repair pathway that maintains genomic integrity by correcting replication errors and various forms of DNA damage. MMR deficiency (MMRd) leads to increased mutation rates, microsatellite instability, and contributes to tumorigenesis in multiple cancer types. Using a CRISPR-Cas9-mediated knockout assay in human isogenic cell lines, we characterised mutational profiles in MMR-deficient cells. Our findings revealed expected increases in mutation burden and the emergence of known MMR-associated mutational signatures. Notably, we identified a previously unconnected process, SBS57, and linked it to germline single-nucleotide polymorphisms and MMR-driven indels in MMRd cells, establishing its association with tensor signature TS27. Comparative analyses ofin vitroMMRd profiles andin vivotumour data uncovered key differences in mutational signatures, highlighting the biological context dependence of MMR-associated mutations. Furthermore, we provide direct experimental evidence that MMR plays a role in repairing 5-methylcytosine deamination, a repair process previously inferred from tumour sequencing data. These findings offer novel insights into MMR deficiency, shedding light on previously uncharacterised mutational mechanisms and their implications in cancer.
Understanding Acute Respiratory Illness in Nepalese Children Under Five: Insights from the 2016 NDHS
Authors: Dhodari Anish , Dhakal Anisha , Pokhrel Joshna , Bhattarai Pragya
Published: February 2025

Acute Respiratory Illness (ARI) remains a critical public health challenge for children under five in Nepal, with persistent socioeconomic inequities in disease burden. This cross-sectional study analyzed Nepal’s 2016 Demographic and Health Survey (n=4,887) to identify determinants of ARI using caregiver reported symptoms of rapid breathing and chest-related issues within two weeks of the survey. Weighted logistic regression analyses examined associations between ARI and variables such as wealth quintile, residence type, maternal education, and child age.

Nationally, ARI prevalence stood at 2.41%, with pronounced disparities: children from the poorest wealth quintile had 5.6× higher prevalence than the richest (3.32% vs 0.59%), while Province 6 reported the highest regional burden (3.37%). Multivariate analysis confirmed household wealth as the significant predictor (AOR=1.60, 95% CI:0.063–40.836), though wide confidence intervals indicated model overdispersion. Notably, 84.92% of caregivers sought healthcare—primarily through private facilities (32.30%) and pharmacies (27.92%)—highlighting gaps in public sector utilization

These findings reveal wealth-based health disparities despite Nepal’s progress toward SDG child mortality targets. The results advocate for province-specific interventions in high-burden regions like Province 6, including mobile pneumonia clinics and biomass fuel transition programs. Socioeconomic disparities play a key role in ARI prevalence among children under five in Nepal. Interventions aimed at reducing care-seeking fragmentation while targeting poverty-alleviation strategies to reduce ARI’s disproportionate impact on marginalized populations could be beneficial. Future research should focus on identifying additional risk factors that were not looked into by the NDHS survey and evaluating targeted prevention strategies.
Pathways to suicidal ideation for young people engaged in mental health care
Authors: Varidel Mathew , Hickie Ian B. , An Victor , Cripps Sally , Marchant Roman , Robinson Jo , La Sala Louise , Capon William , Turner Ashlee , Tashevski-Beckwith Alexander , Scott Elizabeth , Iorfino Frank
Published: February 2025

Background

Suicidal thoughts and behaviours (STBs) have a profound impact on individuals, communities, and healthcare systems. A wide range of factors have been shown to be associated with STBs. Within prior research it is also common to distinguish between proximal and distal factors, usually by distinction of short compared to long-term prediction. We frame the distinction between proximal and distal factors on suicidal ideation as direct or indirect dependencies using the inferred structure of probabilistic graphical models (PGMs).

Methods

We used cross-sectional data from a sample of 1020 help-seeking individuals aged 12-25 years from Australia that while engaged in a mental health care, contributed data to a digital platform. We inferred the posterior distribution of the dependency structure assuming both undirected PGMs and Bayesian networks (BNs). We then used the BN analysis to infer the causal effect that changing one variable has on another using a counterfactual query.

Results

We show that factors encompassing depressed mood, functional impairment, poor social connection, and psychosis-like experiences are proximal. Whereas experiencing a traumatic event, anxiety, insomnia, and unrefreshed sleep are distal factors. Proximal factors tended to have the greatest effect on suicidal ideation, while anxiety symptoms and experiencing a traumatic event were the most influential distal factors.

Conclusions

These relative timings of events and their effects on suicidal ideation could be used to understand the future likelihood of suicidal ideation, and aid planning of targeted interventions.
Neural Networks Accurately Predict Precise Metrics of Hospital Resource Utilization for Total Hip Arthroplasty: A Retrospective Database Study
Authors: Abbas Aazad , Lex Johnathan R. , Toor Jay , Khalil Elias B. , Ravi Bheeshma , Whyne Cari
Published: February 2025

Abstract

Background

Total hip and knee arthroplasties (THAs and TKAs) are some of the most common and successful surgeries. Predicting their duration of surgery (DOS) and length of stay (LOS) has massive implications for costs and resource management. The purpose of this study was to predict the DOS and LOS of THAs using machine learning models (MLMs) based on preoperative factors.

Methods

The American College of Surgeons (ACS) National Surgical and Quality Improvement (NSQIP) database was queried for elective unilateral THA procedures. Multiple MLMs were constructed to predict DOS and LOS. Models were evaluated according to mean squared error (MSE), buffer accuracy, and classification accuracy. To ensure useful predictions, the results of the models were compared to a mean regressor and previous MLM predictions for primary TKAs.

Results

196,942 patients were included. The neural network had the best MSE, buffer and training accuracies for both DOS and LOS. For DOS testing, the neural network MSE was 0.916, with the 30-minute buffer and ≤120 min, >120 min accuracies being 75.4% and 88.5%. For LOS testing, the neural network MSE was 0.567, with the 1-day buffer and ≤2 days, >2 accuracies being 70.3% and 80.9%. Slightly reduced performance was found for THA compared to TKA for DOS and LOS (3 to 5%), with similar important features identified.

Conclusion

MLMs based on preoperative factors successfully predicted the DOS and LOS of elective unilateral THAs, with similar performance to TKA. Future work should include operational factors to apply these models to real world resource optimization.
Sex-specific Trends in the Use of Temporary Mechanical Circulatory Support in patients listed for Orthotopic Heart Transplant Before and After the UNOS Allocation System Change
Authors: Cyrille-Superville Nicole , Patel Priyesh A , White Brian N , Patel Snehal R , Garcia Rachel , Rose Heather , Bernado Susan , Harmon Lauren , Nandkeolyar Shuktika , Mishkin Joseph D , Gulati Sanjeev K , Doshi Amar , Frank Theodore A , Devore Adam D
Published: February 2025

Background

Since the United Network for Organ Sharing (UNOS) allocation system change patients listed for orthotopic heart transplant (OHT) are more likely to be on temporary mechanical circulatory support (tMCS). Limited sex specific data exits for use and outcomes of tMCS since the allocation change.

Methods

We queried the UNOS registry for patients listed for OHT on tMCS from October 1, 2015 to June 28, 2023, comparing baseline characteristics and outcomes between sexes pre- and post-allocation change.

Results

Women comprised 23% of patients listed for OHT on tMCS before and after the allocation change, despite similar cardiac index (CI) compared with men (pre: 2.03 vs 2.09 L/min m2p=0.21; post: 1.92 vs 1.92 L/min m2p=0.89). Women were significantly younger (54 vs 57 years; p<0.001), had lower BMI (26.9 vs 27.2; p 0.006), were more likely to be on intra-aortic balloon pump (IABP) (67% vs 61% p <0.001) and had shorter waitlist times (13 vs 16 days; p <0.001). Waitlist mortality decreased similarly for both sexes (3.6% vs 3.8%; p= 0.7). There was no significant difference in 1-year post-transplant survival between the sexes in either era (HR: 0.9, 95% CI: 0.76, 1.06 p=0.2), however, 1-year post-transplant survival improved overall for patients bridged with tMCS post allocation change independent of sex (HR 0.70 (95% CI: 0.54 to 0.90; p=0.005).

Conclusion

Despite an increase in the use of tMCS as a bridge to OHT since the UNOS allocation change, women comprise less than a quarter of patients listed on tMCS despite similar CI, suggesting possible underuse in women. Notably, for those bridged to OHT in the post allocation era, waitlist mortality has improved for both sexes and 1-year post-transplant survival has also improved independent of sex.
Decay and Solid-Liquid Partitioning of Mpox and Vaccinia Viruses in Primary Influent and Settled Solids to Guide Wastewater-Based Epidemiology Practices
Authors: Phaneuf Jacob R. , Cha Gyuhyon , Hatt Janet K. , Konstantinidis Konstantinos T. , Graham Katherine E.
Published: February 2025

Wastewater-based epidemiology (WBE) has proven to be a powerful tool for tracking the spread of viral pathogens, such as SARS-CoV-2, but as WBE has expanded to include new pathogens, such as mpox virus, more data is needed to guide practitioners on how to design WBE campaigns. Here, we investigated the decay rates of heat-inactivated mpox (HI-MPXV) and attenuated vaccinia virus (VV) in primary influent and settled solids collected from a local POTW at 4°C, 22°C, or 35°C using digital PCR. Subsequently, we studied the solid-liquid partitioning of the viruses in primary influent. Over the 30-day study period, we observed no significant difference in log-linear decay rates between viruses (p=0.5258), with significantly higher decay rates in primary influent (0.109-0.144/day) compared to settled solids (0.019-0.040/day) at both 22°C (p=0.0030) and 35°C (p=0.0166). Furthermore, as part of the partitioning experiment, we found that HI-MPXV and VV adsorb to the solids fraction of primary influent at higher intensities than previously studied enveloped viruses (KF= 1,000-31,800 mL/g, n = 1.01-1.41). Likewise, it was determined in the partitioning experiment that a concentration of greater than 103gc/mL in raw influent was needed for the viable quantification of mpox and vaccinia viruses in the clarified liquid fraction of raw primarily influent. Our study provides essential insights into informative sample collection and storage conditions for the analysis of wastewater and for transport modeling studies. Due to the slow decay observed in settled solids at all tested temperatures in the persistence experiment, this matrix may be most suitable for retrospective analyses of community infection of the mpox virus.
Leveraging long-read assemblies and machine learning to enhance short-read transposable element detection and genotyping
Authors: Daigle Austin , Whitehouse Logan S. , Zhao Roy , Emerson JJ , Schrider Daniel R.
Published: February 2025

Transposable elements (TEs) are parasitic genomic elements that are ubiquitous across the tree of life and play a crucial role in genome evolution. Advances in long-read sequencing have allowed highly accurate TE detection, though at a higher cost than short-read sequencing. Recent studies using long reads have shown that existing short-read TE detection methods perform inadequately when applied to real data. In this study, we use a machine learning approach (called TEforest) to discover and genotype TE insertions and deletions with short-read data by using TEs detected from long-read genome assemblies as training data. Our method first uses a highly sensitive algorithm to discover potential TE insertion or deletion sites in the genome, extracting relevant features from short-read alignments. To discriminate between true and false TE insertions, we train a random forest model with a labeled ground-truth dataset for which we have calculated the same set of short-read features. We conduct a comprehensive benchmark of TEforest and traditional TE detection methods using real data, finding that TEforest identifies more true positives and fewer false positives across datasets with different read lengths and coverages, while also accurately inferring genotypes and the precise breakpoints of insertions.

By learning short-read signatures of TEs previously only discoverable using long reads, our approach bridges the gap between large-scale population genetic studies and the accuracy of long-read assemblies. This work provides a user-friendly tool to study the prevalence and phenotypic effects of TE insertions across the genome.
Latent activity in TnpB revealed by mutational scanning
Authors: Thornton Brittney W. , Weissman Rachel F. , Tran Ryan V. , Duong Brenda T. , Rodriguez Jorge E. , Terrace Cynthia I. , Groover Evan D. , Park Jung-Un , Tartaglia Julia , Doudna Jennifer A. , Savage David F.
Published: February 2025

TnpB is an evolutionarily diverse family of RNA-guided endonucleases associated with prokaryotic transposons. Due to their small size and putative evolutionary relationship to Cas12s, TnpB holds significant potential for genome editing and mechanistic exploration. However, most TnpBs lack robust gene-editing activity, and unbiased profiling of mutational effects on editing activity has not been experimentally explored. Here, we mapped comprehensive sequence-function landscapes of a TnpB ribonucleoprotein and discovered many activating mutations in both the protein and RNA. Single-position changes in the RNA outperform existing variants, highlighting the utility of systematic RNA scaffold mutagenesis. Leveraging the mutational landscape of the TnpB protein, we identified enhanced protein variants from a combinatorial library of activating mutations. These variants increased editing in human cells andN. benthamianaby over two-fold and fifty-fold relative to wild-type TnpB, respectively. In total, this study highlights unknown elements critical for regulation of endonuclease activity in both the TnpB protein and the RNA, and reveals a surprising amount of latent activity accessible through mutation.
Type VI secretion phenotypic heterogeneity ensures trade-off between antibacterial activity and resistance in EnteroaggregativeE. coli
Authors: Taillefer Boris , Schattenberg Florian , Doan Thierry , Müller Susann , Cascales Eric
Published: February 2025

The type VI secretion system (T6SS) is a nanoweapon deployed by bacteria to deliver effectors into target cells, allowing niche colonization or host invasion. In entero-aggregativeEscherichia coli(EAEC), the expression of the T6SS gene cluster is responsive to iron starvation by the Fur regulator, and to Dam-dependent methylation. However, fluorescence microscopy recordings showed that the T6SS displays heterogeneous expression in a clonal population. The population is composed of three types of cells in a stable equilibrium: non producers (OFF), producers, and assemblers (ON). Single-cell analyses further showed that the activation state is transmitted to the progeny, but the overall distribution respects the equilibrium suggesting a genetic control of heterogeneity. Mutagenesis of Fur-binding boxes and GATC sites revealed that specific promoter elements control this heterogeneity. Phenotypic characterization of the ON and OFF subpopulations demonstrated that ON cells eliminate susceptible target cells, whereas OFF cells survive attacks from T6SS-defensive bacteria. The heterogeneity of EAEC T6SS is therefore an attenuation strategy conferring a trade-off between antibacterial efficiency and survival in polymicrobial environments.
tadar: an R/Bioconductor package to reduce eQTL noise in differential expression analysis
Authors: Baer Lachlan , Lardelli Michael , Pederson Stevie M.
Published: February 2025

Despite the relative maturity of bulk RNA-sequencing, compared to more recent developments such as single-cell and spatial RNA-sequencing, biases which impact data analysis continue to surface. One such bias, termed “Differential Allelic Representation” (DAR), is particularly evident when experimental samples are taken from non-isogenic genetic backgrounds. DAR is an uneven distribution of polymorphic loci between groups of experimental samples undergoing differential gene expression (DGE) analysis. When unequally represented polymorphic loci are also expression quantitative trait loci (eQTLs), DAR can lead to differences in gene expression which are not directly relevant to the primary research objectives. To mitigate DAR in both new and existing datsets, we introducetadar, a Bioconductor package designed to facilitate transcriptome analysis by accounting for differential allelic representation.tadarimplements a methodology that calculates a DAR metric at each polymorphic locus across the genome, which then serves as a predictive measure of a locus’ potential to cause eQTL-driven expression differences. This metric is then used to reduce eQTL noise in bulk RNA-Sequencing data.
Breath Volatile Flux Reveals Age-Dependent Metabolic Markers for Breast Cancer Detection
Authors: Issitt Theo , Turvill James , Piper Jenny , Redeker Kelly
Published: February 2025

Breast cancer remains a dominant health risk for women globally with early detection a primary indicator for successful treatment and survival. Current approaches for diagnosis are invasive, costly, and accuracy can be improved. Breath testing using volatile organic compounds (VOCs) as biomarkers presents an exciting avenue for non-invasive cancer diagnosis. However, breath sampling for cancer diagnosis has not yet delivered reliable biomarkers or technology. This is, in-part due to methodology, which introduces confounding factors when attempting to scale to diverse patient populations. We utilize a novel approach to human clinical breath sampling, in which we quantify breath volatile flux. Breath volatile flux considers inhaled air alongside exhaled air to generate a dynamic breath profile which enhances our ability to identify compounds metabolized in humans. We present a novel breath collection platform into which breast cancer clinic patients, in a pilot study of 60 women, provided 5 mins duration breath samples for analysis by gas chromatography mass spectrometry (GC-MS). GC methods targeted a suit of 11 previously identified compounds alongside non-targeted scans. When examining the data across the entire cohort, butanone was the only significantly altered (increased) breath volatile and was able to separate benign tumour and cancer patients from normal patients. However, patient age was observed as a primary confounding factor and reduced the accuracy of butanone’s diagnostic potential. When age was controlled for, chloroform, styrene and isopropyl alcohol acted as indicators of breast cancer health status. Furthermore, once age was accounted for and cancer patients were identified, grade of cancer was indicated by chloroform and DMS fluxes. Using the top 5 discriminate compounds and receiver operator curves we were able to identify cancer from normal patients with area under the curve of 93.4%, grade 2/3 cancers from normal patients with 97.6% AUC, and benign from normal patients with 90.5% AUC. This study suggests that volatile flux measurements from breath allows successful identification, and separation of, cancer, benign tumour and healthy patients.
Use of Computational Phenotypes for Predicting Genetic Subgroups of Cerebral Palsy
Authors: Alkuraya Imen , Almansa Alexandra Santana , Eleonu Azubuike , Avillach Paul , Poduri Annapurna , Srivastava Siddharth
Published: February 2025

Introduction

Emerging evidence suggests that 20–30% of cases of cerebral palsy (CP) may have a genetic cause. Our group previously identified subsets of patients with CP or CP-masquerading conditions who warrant genetic testing, including those with regression or progressive neurological symptoms (CP masqueraders) and those without any known risk factors for CP (cryptogenic CP). Recognition of these subgroups in clinical settings remains challenging.

Methods

To address this challenge, we developed and evaluated a computational phenotyping approach using ICD- 9/ICD-10 billing codes to automatically identify patients with unexplained CP or CP-masquerading conditions who may benefit from genetic testing. We applied this computational phenotyping approach to a cohort of 250 participants from the Boston Children’s Hospital CP Sequencing Study, aimed at identifying genetic causes in CP and CP-masquerading conditions.

Results

Manual review served as the gold standard, identifying 8% as CP masqueraders, 42% as cryptogenic CP, and 50% as non-cryptogenic CP. Computational phenotyping based on ICD-9/10 codes achieved a sensitivity of 95%, specificity of 72%, positive predictive value of 77%, and negative predictive value of 94% in identifying cases warranting genetic testing.

Conclusions

Our findings demonstrate the feasibility of using computational phenotyping to identify patients with CP or CP- masquerading conditions who warrant genetic testing. Further studies are needed to evaluate the effectiveness and real-world application of this tool in larger healthcare systems. Nonetheless, the computational phenotyping approach holds promise as a possible clinical decision support that could be integrated into electronic health record systems, enhancing clinical workflows and facilitating actionable genetic diagnoses.
Causal association of long COVID with brain structure changes: Findings from a 2-sample Mendelian randomization study
Authors: Li Hui , Yang Yihe , Ding Pingjian , Xu Rong
Published: February 2025

Nearly 7.5% U.S. adults have long COVID. Recent epidemiological studies indicated that long COVID, is significantly associated with subsequent brain structure changes. However, it remains unknown if long COVID is causally associated with brain structure change. Here we applied two Mendelian Randomization (MR) methods – Inverse Variance Weighting MR method (IVW) for correlated instrument variables and Component analysis-based Generalized Method of Moments (PC-GMM) – to examine the potential causal relationships from long COVID to brain structure changes. The MR study was based on an instrumental variable analysis of data from a recent long COVID genome-wide association study (GWAS) (3,018 cases and 994,582 controls), the Enhancing NeuroImaging Genetics through Meta Analysis (ENIGMA) (Global and regional cortical measures, N = 33,709; combined hemispheric subcortical volumes, N = 38,851), and UK Biobank (left/right subcortical volumes, N = 19,629). We found no significant causal relationship between long COVID and brain structure changes. As we gain more insights into long COVID and its long-term health outcomes, future works are necessary to validate our findings and understand the mechanisms underlying the observed associations, though not causal, of long COVID with subsequent brain structure changes.
Exposure to bullying engages social distress circuits in the adolescent and adult brain
Authors: Paranko Birgitta , Garandeau Claire , Seppälä Kerttu , Putkinen Vesa , Santavirta Severi , Hirvonen Jussi , Salmivalli Christina , Nummenmaa Lauri
Published: February 2025

Despite advances in understanding the psychological and social consequences of peer victimization, the immediate effects of bullying on the central nervous system remain elusive. Here we mapped the neural responses to simulated bullying in adolescents and adults and tested whether these responses are associated with real-life victimization experiences. Fifty-one adolescents aged 11–14 years, and 47 adults underwent a functional MRI (fMRI) while watching first-person videos of bullying (victimization) in the school environment, as well as neutral and positive social interactions in a similar setting. Exposure to bullying versus positive social interaction engaged the socio-emotional and threat response systems, as well as regions related to social cognition, sensory and interoceptive processing, and motor control. These responses were consistent across adolescents and adults and dependent on the current and past victimization experiences of the participants. This large-scale activation of neural systems subserving socioemotional, somatosensory, and interoceptive processing highlights how peer victimization evokes a severe stress and alarm state in the central nervous system.