bluuebunny/crossref_metadata_2025 huggingface dataset:
Feasibility characteristics of wrist-worn fitness trackers in health status monitoring for post-COVID patients in remote and rural areas
Authors: Wiebe Madeleine , Mackay Marnie , Krishnan Ragur , Tian Julie , Larsson Jake , Modanloo Setayesh , Mcintosh Christiane Job , Sztym Melissa , Elton-Smith Gail , Rose Alyssa , Ho Chester , Greenshaw Andrew , Cao Bo , Chan Andrew , Hayward Jake
Published: December 2023

Introduction

Common, consumer-grade biosensors mounted on fitness trackers and smartwatches can measure an array of biometrics that have potential utility in post-discharge medical monitoring, especially in remote/rural communities. The feasibility characteristics for wrist-worn biosensors are poorly described for post-COVID conditions and rural populations.

Methods

We prospectively recruited patients in rural communities who were enrolled in an at-home rehabilitation program for post-COVID conditions. They were asked to wear a FitBit Charge 2 device and biosensor parameters were analyzed (e.g. heart rate, sleep, and activity). Electronic patient reported outcome measures (E-PROMS) for mental (bi-weekly) and physical (daily) symptoms were collected using SMS text or email (per patient preference). Exit surveys and interviews evaluated the patient experience.

Results

Ten patients were observed for an average of 58 days and half (N=5) were monitored for 8 weeks or more. Five patients (50%) had been hospitalized with COVID (mean stay = 41 days) and 4 (36%) had required mechanical ventilation. As baseline, patients had moderate to severe levels of anxiety, depression, and stress; fatigue and shortness of breath were the most prevalent physical symptoms. Four patients (40%) already owned a smartwatch. In total, 575 patient days of patient monitoring occurred across 10 patients. Biosensor data was usable for 91.3% of study hours and surveys were completed 82.1% and 78.7% of the time for physical and mental symptoms, respectively. Positive correlations were observed between stress and resting heart rate (r=0.360, p<0.01), stress and daily steps (r=0.335, p<0.01), and anxiety and daily steps (r=0.289, p<0.01). There was a trend toward negative correlation between sleep time and physical symptom burden (r=-0.211, p=0.05). Patients reported an overall positive experience and identified the potential for wearable devices to improve medical safety and access to care. Concerns around data privacy/security were infrequent.

Conclusions

We report excellent feasibility characteristics for wrist-worn biosensors and e-PROMS as a possible substrate for multi-modal disease tracking in post-COVID conditions. Adapting consumer-grade wearables for medical use and scalable remote patient monitoring holds great potential.
The role ofAnopheles arabiensisandAnopheles funestusin malaria transmission within houses with different characteristics in South-eastern Tanzania
Authors: Limwagu Alex J. , Msugupakulya Betwel J. , Ngowo Halfan S. , Mwelugelo Yohana A. , Kilalangongono Masoud S. , Okumu Fredros O. , Ngasala Bill E. , Lyimo Issa N.
Published: December 2023

Background

Malaria vectors persist predominantly in houses lacking screened windows, doors, and eave space, leading to ongoing transmission. Some other vectors adapt their feeding behavior to sustain reproduction. This study evaluates the role of primary malaria vectors on malaria transmission in relation to house characteristics in Kilombero Valley.

Methods

Mosquito data collection was done using three methods: a CDC light trap, a miniaturized double net trap (DN-Mini trap), and a Prokopack aspirator through 222 households that were randomly selected in the three villages, namely Ebuyu, Chirombora, and Mzelezi. The houses are characterized during mosquito collections, and the Geographical Position System (GPS) was used to geolocate the sampled houses. Morphological identification was done on the collected sample (i.e., fed, part-fed, gravid, and unfed), and a sub-sample was sent to the laboratory to assess the sibling species, blood meal, and sporozoite.

Results

A total of 1542 Anopheline mosquitoes were collected, of which 79.1% (n= 1219) wereAn. funestusand 20.3% (n= 313) wereAn. arabiensisas primary malaria vectors, while the secondary malaria vector was 0.6% (n = 10). Out of 487 anopheline mosquitoes assayed forplasmodium falciparumsporozoite, 92.8% (n = 13) ofAn. funestuswas reported to be dominant whileAn. arabiensiswas dominant by 7.2% (n = 1). WhileAn. funestuswas the only species that had a blood meal and was found to feed on humans (88.16%, n = 134), dogs (11.18% n = 17), and a mixture of both human and chicken blood meal. In addition to that, the house with screened eave space had fewerAn. funestuscompared to the house with open eave space (RR = 0.978, p =0.864), while the house with a brick wall had a higherAn. funestuscompared with the house with a mud wall (RR = 0.690, p =0.107).

Conclusion

Anopheles funestusremained the dominant malaria vector responsible for all transmissions in the villages. The human population is at risk due to their preference forAn. funestus, which contributes about 92.8% of infections in the village. Additionally, the house design appears to play a significant role in facilitating malaria vectors to continue transmitting malaria.
The economic effects of kidney failure treatment on the household welfare of patients on Dialysis in Buea and Bamenda–Cameroon
Authors: Dingana Therence Nwana , Ngasa Stewart Ndutard , Ngasa Neh Chang , Fozeu Leo Fosso , Kum Fuein V. , Aloysius Njong M.
Published: December 2023

Background

Noncommunicable diseases, such as kidney failure, diabetes, and cancer, are among the leading causes of death worldwide. There is a sharp increase in the incidence and prevalence of patients with kidney failure requiring replacement therapy. This has led to a very high cost, especially in resource-limited settings like Cameroon. The aim of this study is to determine the effects of direct and indirect costs of kidney failure treatment on their household income.

Methods

A descriptive cross-sectional study design was used. Primary data was collected using a self-administered pre-tested questionnaire for the economic impact of chronic disease. For bivariate analysis, we used the Cochran-Mantel-Haenszel test to obtain crude Odd Ratios (OR) of factors associated with household welfare. Multivariate logistic regression, the OLS model was used to identify independent associations between kidney failure treatment and household welfare. This was presented as adjusted odd ratios along with their p-values. A p-value of <0.05 was used as a cut-off for statistical significance.

Results

The mean age of participants was 44.6±15.5 years; most patients (83(62.4%)) were married. Seventy-nine (59.4%) were unemployed, and eighty-one (60.9%) had no financial support. Their annual household expenditure ranged from 300,000FCFA to 3,360,000FCFA, with a mean and standard deviation of 1,547,729FCFA and 781,882FCFA, respectively. The yearly total cost of kidney failure treatment ranged from 520,000FCFA to 10,000,000FCFA with a mean and standard deviation of 2,137,556FCFA and 1,541,163FCFA, respectively. The cost of consultation and laboratory tests had negative regression coefficients (P=0.001 and <0.001 respectively).

Conclusion

kidney failure has a significant negative effect on the household welfare of patients on dialysis. Kidney disease screening and prevention programs are necessary to reduce the number of persons in need of hemodialysis. Health insurance schemes and universal health coverage should target patients on hemodialysis.
HIV prevention and missed opportunities among people with recently acquired HIV infection: Α protocol for a systematic review
Authors: Karakosta Argyro , Ruiz-Burga Elisa , Tariq Shema , Touloumi Giota , Nicholls Emily Jay , Pantazis Nikos , Jarrin Inma , Van der Valk Marc , Sabin Caroline , Mussini Christina , Meyer Laurence , Anne Alain Volny , Carlander Christina , Grabar Sophie , Wittkop Linda , Spire Bruno , Gill Jonh , Porter Kholoud , Burns Fiona ,   CASCADE Collaboration
Published: December 2023

Background

Individuals who have recently acquired HIV represent a unique population because the time frame since HIV acquisition is relatively short and identification of missed HIV prevention opportunities is, therefore, closer to real time and less subject to recall bias. Identifying prevention measures used and missed opportunities for using them, can help stop further HIV transmission.

Objectives

This systematic review aims to synthesise current global evidence on uptake of HIV prevention methods among people with recently acquired HIV from 2007, the year that the concept of ART as a prevention method was first introduced.

Methods and analysis

MEDLINE/PubMed, EMBASE, PsycINFO, Cochrane and Web of Science databases, will be searched for articles published January 2007 - July 2023. Eligible studies will be those that reported on HIV prevention methods among people with recently acquired HIV. Quality assessment of the studies selected will be undertaken, and reporting of the systematic review will be informed by Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.

Results

The results of the systematic review will be available by the end of January 2024.

Conclusions

The findings will be of key relevance to researchers, healthcare providers including third sector organisations/ community groups and policymakers, as they will offer insight into better understanding of missed or failed HIV prevention efforts and will help ensure future efforts meet the needs of those in need of them.
Exposure to valsartan products containing nitrosamine impurities in the US, Canada, and Denmark
Authors: Eworuke Efe , Shinde Mayura U. , Hou Laura , Paterson J. Michael , Jensen Peter Bjødstrup , Maro Judith C. , Rai Ashish , Pottegård Anton , Scarnecchia Daniel , Liang Yuanling , Johnson Deborah , Platt Robert W. , Lee Hana , Bradley Marie C.
Published: December 2023

Background

Following the mass recall of valsartan products with nitrosamine impurities in July 2018, the number of patients exposed to these valsartan products, the duration of exposure, and the potential for cancer remains unknown. Therefore, we assessed the extent and duration of use of valsartan products with a nitrosamine impurity in the US, Canada, and Denmark.

Methods

We conducted a retrospective cohort study using administrative healthcare data from the US FDA Sentinel System, four Canadian provinces that contribute to the Canadian Network for Observational Drug Effect Studies (CNODES), and the Danish National Prescription Registry. Patients, 18 years and older between May 2012 and December 2020 with a valsartan dispensing were identified in each database. Patients were followed from the date of valsartan dispensing until discontinuation. We defined four valsartan exposure categories based on nitrosamine impurity status; recalled generic products with confirmed NDMA/NDEA levels (recalled-tested); recalled generic products that were not tested (recalled); non-recalled generic and non-recalled branded products. In Denmark, recalled-tested category was not included due to absence of testing data. The proportion and duration of use of valsartan episodes stratified by nitrosamine-impurity status.

Results

We identified 3.3 and 2.8 million (US) and 51.3 and 229 thousand (Canada) recalled-tested and recalled valsartan exposures. In Denmark, where valsartan exposure was generally low, there were 10,747 recalled exposures. Immediately after the recall notices were issued, there was increased rates of switching to a non-valsartan ARB. The mean duration of use of the recalled-tested products was 167(±223.1) and 146(±255.8) days in the US and Canada respectively. For the recalled products, mean cumulative duration of use was 178(±249.6), 269(±397.3) and 166(±251.0) days in the US, Canada, and Denmark, respectively.

Conclusion

In this cohort study, despite widespread use of recalled generic valsartan between 2012 and 2018, the duration of use was relatively short and likely did not pose an elevated risk of nitrosamine-induced cancer. However, since products with nitrosamine impurity could have been on the market over a six-year period, patients potentially exposed to these products for longer duration could have a different risk of cancer.
The validation and clinical applicability of angiography-derived assessment of coronary microcirculatory resistance: a [15O]H2O PET study
Authors: Jukema Ruurt A. , Raijmakers Pieter G , Hoshino Masahiro , Driessen Roel S. , van Diemen Pepijn A. , Knuuti Juhani , Maaniitty Teemu , Twisk Jos , Kooistra Rolf A. , Timmer Janny , Reiber Johan H.C. , van der Harst Pim , Cramer Maarten J. , van der Hoef Tim , Knaapen Paul , Danad Ibrahim
Published: December 2023

Background

The introduction of wire-free microcirculatory resistance index from functional angiography (angio-IMR) promises swift detection of coronary microvascular dysfunction, however it has not been properly validated. We sought to validate angio-IMR against invasive IMR and PET derived microvascular resistance (MVR). Moreover, we studied if angio-IMR could aid in the detection of ischemia with non-obstructive coronary arteries (INOCA).

Methods

In this investigator-initiated study symptomatic patients underwent [15O]H2O positron emission tomography (PET) and invasive angiography with 3-vessel fractional flow reserve (FFR). Invasive IMR was measured in 40 patients. Angio-IMR and QFR were computed retrospectively. MVR was defined as the ratio of mean distal coronary pressure to PET derived coronary flow. PET and QFR/angio-IMR analyses were performed by blinded core labs. The right coronary artery was excluded.

Results

A total of 211 patients (mean age 61±9, 148 (70%) male) with 312 vessels with successful angio-IMR analyses were included. Angio-IMR correlated moderately with invasive IMR (r=0.48, p<0.01), whereas no correlation was found between angio-IMR and MVR (r=-0.07, p=0.25). Angio-IMR did not differ for vessels without obstructive coronary artery disease (CAD) (FFR-) but with reduced stress perfusion (PET+) compared to vessels without obstructive CAD (FFR-) with normal stress perfusion (PET-) (median 28.19 IQR 20.42 – 38.99 vs 31.67 IQR 23.47 – 40.63, p=0.40).

Conclusion

Angio-IMR correlated moderately with invasively measured IMR, whereas angio-IMR did not correlate with PET derived MVR. Moreover, angio-IMR was similar in patients without obstructive CAD, irrespective of ischaemia status, hampering the identification of INOCA.
Nomograms for Predicting the Risk of Acute Heart Failure in ICU Patients with Atrial Fibrillation: A Retrospective Cohort Study
Authors: Wu Ziyang , Qiao Yong , Yan Gaoliang , Qin Yuhan , Tang Huihong , Liu Shiqi , Wang Dong , Tang Chengchun
Published: December 2023

Aim

This study developed two nomograms to predict the incidence of acute heart failure (AHF) in patients of atrial fibrillation (AF) and evaluated the predictive value of the nomograms.

Method

18179 patients of AF from the Medical Information Mart for Intensive Care IV (MIMIC-IV) database were analysed. The patients were randomly divided into two groups in a seven-to-three ratio to form a training cohort (n = 12725) and a validation cohort (n = 5454). Least absolute shrinkage and selection operator (LASSO) regression analyses were used to identify associated risk variables. Two nomograms were established to predict the rate of AHF in patients of AF for use by patients and clinicians, respectively. The new models were assessed in terms of the concordance index (C-index), the area under the curve (AUC) of receiver operating characteristic (ROC) analysis, calibration curve, and decision curve analysis (DCA).

Results

Least absolute shrinkage and selection operator (LASSO) regression analysis identified seven potential predictors of acute heart failure in nomogram 1 and three potential predictors in nomogram 2. Multivariate logistic regression analysis was used to evaluate the effects of these predictors and create final models. The concordance index values were 0.768 and 0.696, respectively. The areas under the curves for the training and validation sets in nomogram 1 were 0.768 and 0.763, respectively. The areas under the curves for the training and validation sets in nomogram 2 were 0.696 and 0.692, respectively.

Conclusion

The age, respiratory rate, fluid management, mean corpuscular hemoglobin concentration (MCHC), bicarbonate, blood urea nitrogen (BUN) and chloride were identified as predictors of the development of acute heart failure in patients with atrial fibrillation in nomogram 1. The charlson score, lods score and sapsII score were identified as predictors of the development of acute heart failure in nomogram 2. Our nomograms are reliable convenient approaches for predicting acute heart failure in patients with atrial fibrillation.
Cost-Utility Analysis of PCSK9 Inhibitors and Quality of Life: A Two-Year Multicenter Non-Randomized Study
Authors: Seijas-Amigo José , Mauriz-Montero M. José , Suarez-Artime Pedro , Gayoso-Rey Mónica , Reyes-Santías Francisco , Estany-Gestal Ana , Casas-Martínez Antonia , González-Freire Lara , Rodriguez-Vazquez Ana , Pérez-Rodriguez Natalia , Villaverde-Piñeiro Laura , Castro-Rubinos Concepción , Espino-Faisán Esther , Cordova-Arevalo Octavio , Rodríguez-Mañero Moisés , Cordero Alberto , González-Juanatey José R. ,   e Investigadores MEMOGAL
Published: December 2023

Background

The use of PCSK9 inhibitors in the management of cardiovascular disease has gained increasing attention. However, there is limited evidence on their cost-utility and impact on quality of life in real-world settings. This study aimed to conduct a real-world cost-utility analysis of PCSK9 inhibitors and evaluating their effects on quality of life.

Methods

A multicenter prospective study was conducted across 12 Spanish hospitals from May 2020 to April 2022, involving 158 patients. QoL was assessed using the EQ-5D questionnaire. Cost-utility analysis assessed the economic impact of PCSK9 inhibitors when used with standard care compared to standard care alone, calculating the incremental cost-effectiveness ratio (ICER).

Results

The study encompassed 158 patients with an average age of 61, predominantly male (66.5%). For patients initiating PCSK9 inhibitors, the cost of PCSK9 inhibitor treatment was €13,633.39, while standard therapy cost €3,638.25 over two years. Qualys for PCSK9 inhibitors stood at 1.648851948 over two years, compared to 1.454807792 for standard therapy. The results revealed favorable cost-utility outcomes, with an ICER of €51,427.72. Significant improvements were observed in the domains of mobility, self-care, daily activities, pain/discomfort, and anxiety/depression (p<0.001).

Conclusions

This study represents the first real-world cost-utility analyses of PCSK9 inhibitors. The findings support the economic justification and potential benefits of incorporating PCSK9 inhibitors into clinical practice. Healthcare decision-makers can consider these results when making informed decisions and reimbursement regarding the use of PCSK9 inhibitors in clinical practice.

Trial Registrationclinicaltrials.govIdentifier:NCT04319081
Effect of Renin-Angiotensin System (RAS) Inhibitors in Acute Ischemic Stroke to Improve Outcomes in In-Patient Settings: A Cross Sectional and Longitudinal Analysis
Authors: Samuel Sophie , Craver Kyndol , Miller Charles , Pelsue Brittany , Gonzalez Catherine , Allison Teresa A , Gulbis Brian , Choi H Alex , Kim Seokhun
Published: December 2023

Background

Acute ischemic stroke (AIS) is a major health challenge, often resulting in long-term disability and death. This study assesses the impact of renin-angiotensin system (RAS) inhibitors (angiotensin-converting enzyme inhibitors and angiotensin receptor blockers) on AIS patient mortality compared to non-RAS antihypertensive medications.

Methods

This retrospective cohort study, conducted at Memorial Hermann–Texas Medical Center in Houston, Texas, from August 31, 2017, to August 31, 2022, examined AIS patient mortality. We used a cohort design, evaluating the effects of RAS inhibitors, either alone or in combination with beta-blockers (BBs), while exploring interactions, including those related to end-stage renal disease (ESRD) and serum creatinine levels. Eligible subjects included AIS patients aged 18 or older with specific AIS subtypes who received in-patient antihypertensive treatment. Missing data were addressed using imputation, followed by Inverse Probability of Treatment Weighting (IPTW) to achieve covariate balance. Our primary outcome was mortality rates. Statistical analyses involved cross-sectional and longitudinal approaches, including generalized linear models, G-computation, and discrete time survival analysis over a 20-day follow-up period.

Results

In our study of 3058 AIS patients, those using RAS inhibitors had significantly lower in-hospital mortality (2.2%) compared to non-users (12.1%), resulting in a relative risk (RR) of 0.18 (95% CI 0.12-0.26). Further analysis using G-computation revealed a marked reduction in mortality risk associated with RAS inhibitors (Risk 0.0281 vs. 0.0913, Risk Difference (RD) of 6.31% or 0.0631, 95% CI 0.046-0.079). Subgroup analysis demonstrated notable benefits, with individuals having creatinine levels below and above 1.3 mg/dL exhibiting statistically significant RD (RD −0.0510 vs. −0.0895), and a significant difference in paired comparison (−0.0385 or 3.85%, CI 0.023-0.054). Additionally, longitudinal analysis confirmed a consistent daily reduction of 0.93% in mortality risk associated with the intake of RAS inhibitors.

Conclusion

RAS inhibitors are associated with a significant reduction in in-hospital mortality in AIS patients, suggesting potential clinical benefits in improving patient outcomes.
The Role of Early Cerebral Edema and Hematoma assessment in Aneurysmal Subarachnoid Hemorrhage (a-SAH) in predicting Structural Brain Abnormalities in Cognitive Impairments
Authors: Wang Ming-Dong , Fu Qian-Hui , Ni Andrew , Yuan Yun-Peng , Li Chun-Hui , Wang Zhan-Xiang , Wang Hong
Published: December 2023

Background

Early assessment and management of cerebral edema and hematoma following aneurysmal subarachnoid hemorrhage (a-SAH) can significantly impact clinical cognitive outcomes. However, current clinical practices lack predictive models to identify early structural brain abnormalities affecting cognition. To address this gap, we propose the development of a predictive model termed the a-SAH Early Brain Edema/Hematoma Compression Neural (Structural Brain) Networks Score System (SEBE-HCNNSS).

Methods

In this study, 202 consecutive patients with spontaneous a-SAH underwent initial computed tomography (CT) or magnetic resonance imaging (MRI) scans within 24 hours of ictus with follow-up 2 months after discharge. Using logistic regression analysis (univariate and multivariate), we evaluated clinically relevant factors and various traditional scale ratings for cognitive impairment (CI). Risk factors with the highest area under the curve (AUC) values were included in the multivariate analysis and least absolute shrinkage and selection operator (LASSO) analysis or Cox regression analysis.

Results

A total of 177 patients were enrolled in the study, and 43 patients were classified with a high SEBE-HCNNSS grade (3 to 5). After a mean follow-up of 2 months, 121 individuals (68.36%) with a-SAH and 3 control subjects developed incident CI. The CT inter-observer reliability of the SEBE-HCNNSS scale was high, with a Kappa value of 1. Furthermore, ROC analysis identified the SEBE-HCNNSS scale (OR 3.322, 95% CI 2.312-7.237, p = 0.00025) as an independent predictor of edema, CI, and unfavorable prognosis. These results were also replicated in a validation cohort.

Conclusion

Overall, the SEBE-HCNNSS scale represents a simple assessment tool with promising predictive value for CI and clinical outcomes post-a-SAH. Our findings indicate its practical utility as a prognostic instrument for risk evaluation after a-SAH, potentially facilitating early intervention and treatment.
Characterization of CSF inflammatory markers after hemorrhagic stroke and their relationship to disease severity
Authors: Magid-Bernstein Jessica , Yan Jennifer , Herman Alison L. , He Zili , Johnson Conor W. , Beatty Hannah , Choi Rachel , Velazquez Sofia , Neeman Eitan , Falcone Guido , Kim Jennifer , Petersen Nils , Gilmore Emily J. , Matouk Charles , Sheth Kevin , Sansing Lauren
Published: December 2023

Background

The inflammatory response within the central nervous system is a key driver of secondary brain injury after hemorrhagic stroke, both in patients with intracerebral hemorrhage (ICH) and aneurysmal subarachnoid hemorrhage (aSAH). In this study, we aimed to characterize inflammatory molecules in the blood and cerebrospinal fluid (CSF) of patients within 72 hours of hemorrhage to understand how such molecules vary across disease types and disease severity.

Methods

Biological samples were collected from patients admitted to a single-center Neurosciences Intensive Care Unit with a diagnosis of ICH or aSAH between 2014 and 2022. Control CSF samples were collected from patients undergoing CSF diversion for normal pressure hydrocephalus. A panel of immune molecules in the plasma and CSF samples was analyzed using Cytometric Bead Array assays. Clinical variables, including demographics, disease severity, and intensive care unit length of stay were collected.

Results

Plasma and/or CSF samples were collected from 260 patients (188 ICH patients, 54 aSAH patients, 18 controls). C-C motif chemokine ligand-2 (CCL2), interleukin-6 (IL-6), granulocyte-colony stimulating factor (G-CSF), interleukin-8 (IL-8), and vascular endothelial growth factor (VEGF), were detectable in the CSF within the first 3 days after hemorrhage, and all were elevated compared to plasma. Compared with controls, CCL2, IL-6, IL-8, G-CSF, and VEGF were elevated in the CSF of both ICH and aSAH patients (p<0.01 for all comparisons). VEGF was increased in ICH patients compared to aSAH patients (p<0.01). CCL2, G-CSF, and VEGF in the CSF were associated with more severe disease in aSAH patients only.

Conclusions

Within 3 days of hemorrhagic stroke, proinflammatory molecules can be detected in the CSF at higher concentrations than in the plasma. Early concentrations of some pro-inflammatory molecules may be associated with markers of disease severity.
Genetic assessment of efficacy and safety profiles of coagulation cascade proteins identifies Factors II and XI as actionable anticoagulant targets
Authors: Gagnon Eloi , Girard Arnaud , Bourgault Jérôme , Abner Erik ,   Estonian Biobank Research Team, Gill Dipender , Thériault Sébastien , Vohl Marie-Claude , Tchernof André , Esko Tõnu , Mathieu Patrick , Arsenault Benoit J.
Published: December 2023

Background

Anticoagulants are routinely used by millions of patients worldwide to prevent blood clots. Yet, problems with anticoagulant therapy remain, including a persistent and cumulative bleeding risk in patients undergoing prolonged anticoagulation. New safer anticoagulant targets are needed.

Methods

We performed two-sample Mendelian randomization (MR) and genetic colocalization to prioritize anticoagulant targets with the strongest efficacy (venous thromboembolism [VTE] prevention) and safety (low bleeding risk) profiles. We leveraged three large-scale plasma protein datasets (deCODE, n=35,559; Fenland n = 10,708; ARIC n= 7,213) and one liver gene expression dataset (n =246) to evaluate evidence for a causal effect of 26 coagulation cascade plasma proteins on VTE from a new genome-wide association meta-analysis of 44,232 VTE cases and 847,152 controls (from the UK Biobank, FinnGen and Estonian Biobank), stroke subtypes (from UK Biobank and International Stroke Genetics consortium 73,652 cases and 1,234,808 controls), bleeding outcomes (FinnGen, n=309,154) and over one million parental lifespans (UK Biobank and LifeGen consortium).

Results

Genetically predicted reductions in F2 blood levels were associated with lower VTE risk (OR [odds ratio] per 1 standard deviation [SD] lower F2=0.44, 95% CI=0.38-0.51, p=2.6E-28) and cardioembolic stroke risk (OR = 0.55, 95% CI=0.39-0.76, p=4.2e-04) but not with bleeding (OR = 1.13, 95% CI=0.93-1.36, p=2.2e-01). Genetically predicted F11 reduction were associated with lower risk of VTE (OR = 0.61, 95% CI=0.58-0.64, p=4.1e-85) and cardioembolic stroke (OR = 0.77, 95% CI=0.69-0.86, p=4.1e-06), but not with bleeding (OR = 1.01, 95% CI=0.95-1.08, p=7.5e-01) (Figure 3). These MR associations were concordant across the three blood protein datasets and the hepatic gene expression dataset as well as three different MR and colocalization analyses.

Conclusion

These results provide strong genetic evidence that F2 and F11 may represent safe and efficacious therapeutic targets to prevent VTE and cardioembolic strokes without substantially increasing bleeding risk.
A Multi-State Markov Model for the Longitudinal Analysis of Clinical Composite Outcomes in Heart Failure
Authors: Lora Pablos David , Leiva-García Andrea , Bernal José Luis , Vélez Jorge , Palacios Beatriz , Villarreal Miriam , Capel Margarita , Rosillo Nicolás , Hernández Miguel , Bueno Héctor
Published: December 2023

Background

The statistical analysis of composite outcomes is challenging. The Clinical Outcomes, HEalthcare REsource utilizatioN, and relaTed costs (COHERENT) model was developed to describe and compare all components (incidence, timing and duration) of composite outcomes, but its statistical analysis remained unsolved. The aim of the study is to assess a multi-State Markov model as one statistical solution for the COHERENT model.

Methods

A cohort of 3280 patients admitted to the emergency department or hospital for heart failure during year 2018 were followed during one year. The state of the patient was registered at the end of each day during 365 days as: home, emergency department (ED), hospital, re-hospital, re-ED, and death. Outcomes of patients with or without severe renal disease (sRD) were compared as an example. A Multi-State Markov model was developed to explain transitions to and from these states during follow-up.

Results

A Multi-State Markov model showed, adjusted for age and sex, a significantly lower likelihood of patients with sRD to return home regardless of the state in which they were (ED → HOME (HR, 0.72; 95%CI, 0.54-0.95), RE-ED → HOME (HR, 0.83; 95%CI, 0.75-0.93), HOSPITAL → HOME (HR, 0.77; 95%CI, 0.69-0.86), RE-HOSPITAL → HOME (HR, 0.82; 95%CI, 0.74-0.92) and a higher mortality risk, in particular at the hospital and at home (HOME → Death [HR, 1.54; 95%CI, 1.01-2.37] and HOSPITAL → Death [HR, 1.71; 95%CI, 1.30-2.24].

Conclusion

Multi-state Markov models offer a statistical solution for the comprehensive analysis of composite outcomes assessed as transitions from different clinical states.

Clinical Perspective

What is new?

An integrated analysis of all components of composite endpoints including its incidence and duration is possible using the COHERENT model with analysis of transition risks.

A statistical approach based on Markov chain models is a new potential statistical solution for the multivariate estimation of the risk of transitions in mutually exclusive composite endpoints.

What are the clinical implications?

The use of the COHERENT model and Markov models is an opportunity to analyze composite endpoints and understand better the relationships between its components and, potentially, to improve the performance of statistical analysis in randomized controlled trials.

The utilization of the COHERENT model and Markov models in randomized controlled trials should be validated in future observational studies and in randomized controlled trials.
Machine learning-based meta-analysis reveals gut microbiome alterations associated with Parkinson’s disease
Authors: Romano Stefano , Wirbel Jakob , Ansorge Rebecca , Schudoma Christian , Ducarmon Quinten Raymond , Narbad Arjan , Zeller Georg
Published: December 2023

There is strong interest in exploring the potential of the gut microbiome for Parkinson’s disease (PD) diagnosis and treatment. However, a consensus on the microbiome features associated with PD and a multi-study assessment of their diagnostic value is lacking. Here, we present a machine learning meta-analysis of PD microbiome studies of unprecedented scale (including 4,490 samples). Within most studies, microbiome-based machine learning models could accurately classify PD patients. However, models were study-specific and did not generalise well across other studies. By training models on multiple datasets, we could improve their general applicability and disease specificity as assessed against microbiomes from other neurodegenerative diseases. Meta-analysis of shotgun metagenomes moreover delineated PD-associated microbial pathways potentially contributing to the deterioration of gut health and favouring the translocation of pathogenic molecules along the gut-brain axis. Strikingly, diverse microbial pathways for the biotransformation of solvents and pesticides were enriched in PD. These results align with the epidemiological evidence that exposure to these molecules increases PD risk and raise the question of whether gut microbial metabolism modulates their toxicity. Taken together, we offer the most comprehensive overview to date about the PD gut microbiome and provide future reference for its diagnostic and functional potential.
wQFM-DISCO: DISCO-enabled wQFM improves phylogenomic analyses despite the presence of paralogs
Authors: Hakim Sheikh Azizul , Ratul MD Rownok Zahan , Bayzid Md. Shamsuzzoha
Published: December 2023

Gene trees often differ from the species trees that contain them due to various factors, including incomplete lineage sorting (ILS), gene duplication and loss (GDL), and horizontal gene transfer (HGT). Several highly accurate species tree estimation methods have been introduced to explicitly address ILS, including AS-TRAL, a widely used statistically consistent method, and wQFM, a quartet amalgamation approach that is experimentally shown to be more accurate than ASTRAL. Two recent advancements, ASTRAL-Pro and DISCO, have emerged in the field of phylogenomics to consider gene duplication and loss (GDL) events. ASTRAL-Pro introduces a refined measure of quartet similarity, accounting for both orthology and paralogy. DISCO, on the other hand, offers a general strategy to decompose multicopy gene family trees into a collection of single-copy trees, allowing the utilization of methods previously designed for species tree inference in the context of single-copy gene trees. In this study, we first introduce some variants of DISCO to examine its underlying hypotheses and present analytical results on the statistical guarantees of DISCO. In particular, we introduce DISCO-R, a variant of DISCO with a refined and improved pruning strategy that provides more accurate and robust results. We then propose wQFM-DISCO (wQFM paired with DISCO) as an adaptation of wQFM to handle multicopy gene trees resulting from GDL events. Extensive evaluation studies on a collection of simulated and real data sets demonstrate that wQFM-DISCO is significantly more accurate than ASTRAL-Pro and other competing methods.
Evolution of a biological thermocouple by adaptation of cytochrome c oxidase in a subterrestrial metazoan
Authors: Guerin Megan N. , Ellis TreVaughn , Ware Mark J. , Manning Alexandra , Coley Ariana , Amini Ali , Chung George , Gunsalus Kristin C. , Bracht John R.
Published: December 2023

In this study we report a naturally evolved temperature-sensing electrical regulator in the cytochrome c oxidase of the Devil Worm,Halicephalobus mephisto.This extremophile metazoan was isolated 1.3 km underground in a South African goldmine, where it adapted to heat and potentially to hypoxia, making its mitochondrial sequence a likely target of adaptational change. We obtained the full mitochondrial genome sequence of this organism, and show through dN/dS analysis statistically robust evidence of positive selection inH. mephistocytochrome c oxidase subunits. Seventeen of these positively-selected amino acid substitutions were localized in proximity to the H- and K-pathway proton channels of the complex. Surprisingly, theH. mephistocytochrome c oxidase proton pump completely shuts down at low temperatures (20°C) leading to approximately a 4.8-fold reduction in the transmembrane proton gradient voltage (ΔΨm) compared to optimal temperature (37°C). Direct measurement of oxygen consumption found a corresponding 4.7-fold drop at 20°C compared to 37°C. Correspondingly, the lifecycle ofH. mephistotakes four-fold longer at the low temperature compared to higher. This elegant evolutionary adaptation creates a finely-tuned mitochondrial temperature sensor, allowing this ectothermic organism to maximize its reproductive success in varying environmental temperatures. Our study shows that evolutionary innovation may remodel core metabolism to make it more accurately map onto environmental variation.
Accurate multi-population imputation of MICA, MICB, HLA-E, HLA-F and HLA-G alleles from genome SNP data
Authors: Tammi Silja , Koskela Satu , Biobank Blood Service , Hyvärinen Kati , Partanen Jukka , Ritari Jarmo
Published: December 2023

In addition to the classical HLA genes, the major histocompatibility complex (MHC) harbors a high number of other polymorphic genes with less established roles in disease associations and transplantation matching. To facilitate studies of the non-classical and non-HLA genes in large patient and biobank cohorts, we trained imputation models for MICA, MICB, HLA-E, HLA-F and HLA-G alleles on genome SNP array data. We show, using both population-specific and multi-population 1000 Genomes references, that the alleles of these genes can be accurately imputed for screening and research purposes. The best imputation model for MICA, MICB, HLA-E, -F and -G achieved a mean accuracy of 99.3% (min, max: 98.6, 99.9). Furthermore, validation of the 1000 Genomes exome short-read sequencing-based allele calling against a clinical-grade reference data showed an average accuracy of 99.8%, testifying for the quality of the 1000 Genomes data as an imputation reference. The imputation models, trained using the HIBAG algorithm, are available at GitHub (https://github.com/FRCBS/HLA_EFG_MICAB_imputation) and can be run locally, thus avoiding the need of sending sensitive genome data to remote portals.
Metagenome-based microbial community analysis of urine-derived fertilizer
Authors: Woldeyohannis Nebiyat N. , Desta Adey F.
Published: December 2023

The present study aimed to understand the bacterial portion of the microbial community composition and dynamics of plasmid-mediated antimicrobial resistant genes during the optimized process of struvite production from composite human urine. Samples for DNA extraction was collected from fresh urine, stored urine and struvite during the process of struvite production. Shotgun metagenomic analysis was employed to understand the bacterial community. The most dominant phyla in the fresh and stored urine samples were Pseudomonadata, which comprised of 60% and 43% respectively, followed by Bacillota, comprised of 25% and 39% respectively. The struvite sample was dominated by the phylum Bacilliota (61%), Pseudomonadota (18%) and bacteroidota (12%). The members of the above phyla persisted in dominating each sample accordingly. Member of the family Morganellaceae was dominant in the fresh sample while the stored urine and struvite samples were dominated by the family Clostridiaceae. A decrease of members of the class Gammaproteobacteria was observed from the fresh to the struvite sample though not statistically significant. The genusPseudomonasremained to be the most dominant member of Gammaproteobacteria in the fresh and stored urine sample with OTU count of 12,116 and 6,155 with a marked decrease by half in the stored sample. On the other hand, members of the generaClostridium, Enterococcus, Bacteroidesin the stored samples andClostridium, AlkaliphilusandPseudomonasin the struvite samples were dominant. Ninety-six percent of the identified genera were shared in all the samples and the antimicrobial resistance genes (ARGs) identified in the fresh urine were shared by the struvite but not by the stored urine (eg.sul, cat, aphandaacmembers). the presence of high abundance of ARGs in struvite needs attention in the persistence and transmissibility of the ARGs before application for agriculture.
Unraveling the role of γδ T cells in the pathogenesis of an oncogenic avian herpesvirus
Authors: Sabsabi Mohammad A. , Kheimar Ahmed , You Yu , von La Roche Dominik , Härtle Sonja , Göbel Thomas W. , von Heyl Theresa , Schusser Benjamin , Kaufer Benedikt B.
Published: December 2023

Marek’s disease virus (MDV) is an oncogenic alphaherpesvirus that causes deadly T cell lymphomas in chickens. MDV is highly cell associated which allows the virus to evade antibody-mediated virus neutralization. Therefore, T cell-mediated immune responses are thought to be crucial for combating this deadly pathogen. In chickens, gamma delta (γδ) T cells represent a major population with up to 50% of all peripheral T cells. However, their role in MDV pathogenesis and tumor formation remains poorly understood. To investigate the role of γδ T cells in MDV pathogenesis, we infected genetically modified chickens that lack γδ T cells (TCR Cγ-/-) with very virulent MDV. Strikingly, disease and tumor incidence were highly increased in the absence of γδ T cells, indicating that γδ T cells play an important role in the immune response against MDV. In the absence of γδ T cells, virus replication was increased by up to 89-fold in the thymus and spleen, both potential sites of T cell transformation. Taken together, our data provide the first evidence that γδ T cells play an important role in restricting MDV replication, pathogenesis and tumors caused by this deadly pathogen.

Author Summary

γδ T cells are the most abundant T cells in chickens, but their role in fighting pathogens remains poorly understood. Marek’s disease virus (MDV) is an important veterinary pathogen, causes one of the most frequent cancers in animals and is used as a model for virus-induced tumor formation. Our study revealed that γδ T cells play a crucial role in combating MDV, as disease and tumor incidence was drastically increased in the absence of these cells. γδ T cells restricted virus replication in the key lymphoid organs, thereby decreasing the likelihood of causing tumors and disease. This study provides novel insights into the role of γδ T cells in the pathogenesis of this highly oncogenic virus.
Beta and theta oscillations track effort and previous reward in human basal ganglia and prefrontal cortex during decision making
Authors: Hoy Colin W. , de Hemptinne Coralie , Wang Sarah S. , Harmer Catherine J. , Apps Mathew A. J. , Husain Masud , Starr Philip A. , Little Simon
Published: December 2023

Choosing whether to exert effort to obtain rewards is fundamental to human motivated behavior. However, the neural dynamics underlying the evaluation of reward and effort in humans is poorly understood. Here, we investigate this with chronic intracranial recordings from prefrontal cortex (PFC) and basal ganglia (BG; subthalamic nuclei and globus pallidus) in people with Parkinson’s disease performing a decision-making task with offers that varied in levels of reward and physical effort required. This revealed dissociable neural signatures of reward and effort, with BG beta (12-20 Hz) oscillations tracking subjective effort on a single trial basis and PFC theta (4-7 Hz) signaling previous trial reward. Stimulation of PFC increased overall acceptance of offers in addition to increasing the impact of reward on choices. This work uncovers oscillatory mechanisms that guide fundamental decisions to exert effort for reward across BG and PFC, as well as supporting a causal role of PFC for such choices.
Pseudomonas aeruginosa kills Staphylococcus aureus in a polyphosphate-dependent manner
Authors: Shah Ritika , Jankiewicz Olivia , Johnson Colton , Livingston Barry , Dahl Jan-Ulrik
Published: December 2023

Due to their frequent coexistence in many polymicrobial infections, including in patients with burn or chronic wounds or cystic fibrosis, recent studies have started to investigate the mechanistic details of the interaction between the opportunistic pathogensPseudomonas aeruginosaandStaphylococcus aureus.P. aeruginosarapidly outcompetesS. aureusunderin vitroco-cultivation conditions, which is mediated by several ofP. aeruginosa’s virulence factors. Here, we report that polyphosphate (polyP), an efficient stress defense system and virulence factor inP. aeruginosa, plays a role for the pathogen’s ability to inhibit and killS. aureusin a contact-independent manner. We show thatP. aeruginosacells characterized by low polyP level are less detrimental toS. aureusgrowth and survival while the gram-positive pathogen is significantly more compromised by the presence ofP. aeruginosacells that produce high level of polyP. We show that the polyP-dependent phenotype could be a direct effect by the biopolymer, as polyP is present in the spent media and causes significant damage to theS. aureuscell envelope. However, more likely is that polyP’s effects are indirect through the regulation of one ofP. aeruginosa’svirulence factors, pyocyanin. We show that pyocyanin production inP. aeruginosaoccurs polyP-dependent and harmsS. aureusthrough membrane damage and the generation of reactive oxygen species, resulting in increased expression of antioxidant enzymes. In summary, our study adds a new component to the list of biomolecules that the gram-negative pathogenP. aeruginosagenerates to compete withS. aureusfor resources.

IMPORTANCE

How do interactions between microorganisms shape the course of polymicrobial infections? Previous studies have provided evidence that the two opportunistic pathogensP. aeruginosaandS. aureusgenerate molecules that modulate their interaction with potentially significant impact on disease outcomes. Our study identified the biopolymer polyP as a new effector molecule that impactsP. aeruginosa’s interaction withS. aureus. We show thatP. aeruginosakillsS. aureusin a polyP-dependent manner, which occurs primarily through the polyP-dependent production of theP. aeruginosavirulence factor pyocyanin. Our findings add a new role for polyP to an already extensive list of functions. A more in-depth understanding of how polyP influences interspecies interactions is critical, as targeting polyP synthesis in bacteria such asP. aeruginosamay have a significant impact on other microorganisms and potentially result in dynamic changes in the microbial composition.
Astrocyte-dependent local neurite pruning and Hox gene-mediated cell death in Beat-Va neurons
Authors: Lehmann Katherine S , Hupp Madison T , Jefferson Amanda , Cheng Ya-Chen , Sheehan Amy E , Kang Yunsik , Freeman Marc R
Published: December 2023

Neuronal remodeling is extensive and mechanistically diverse across the nervous systems of complex metazoans. To explore circuit refinement mechanisms, we screened for new neuronal subtypes in theDrosophilanervous system that undergo remodeling early in metamorphosis. We find Beat-VaMneurons elaborate a highly branched neurite network during larval stages that undergoes local neurite pruning during early metamorphosis. Surprisingly, Beat-VaMneurons remodel their branches despite blockade of steroid hormone signaling and instead depend on signaling from astrocytes to activate pruning. We show Beat-VaLneurons undergo steroid hormone-dependent cell death in posterior but not anterior abdominal segments. Correct activation of apoptotic cell death relies on segment-specific expression of the hox geneAbd-B, which is capable of activating cell death in any Beat-VaLneuron. Our work provides new model cells in which to study neuronal remodeling, highlights an important role for astrocytes in activating local pruning inDrosophilaindependent of steroid signaling, and defines a Hox gene-mediated mechanism for segment-specific cell elimination.

Lehmann et al. characterize two new populations of neurons that undergo remodeling duringDrosophilametamorphosis. Beat-VaMneurons undergo drastic neurite pruning that is largely independent of ecdysone signaling and instead is driven by astrocytes. Beat-VaLneurons undergoAbd-Bmediated, caspase driven cell death in a segmentally restricted manner.