bluuebunny/crossref_metadata_2025 huggingface dataset:
Single-dose effectiveness of mpox vaccine in Quebec, Canada: test-negative design with and without adjustment for self-reported exposure risk
Authors: Brousseau Nicholas , Carazo Sara , Febriani Yossi , Padet Lauriane , Hegg-Deloye Sandrine , Cadieux Geneviève , Bergeron Geneviève , Fafard Judith , Charest Hugues , Lambert Gilles , Talbot Denis , Longtin Jean , Dumont-Blais Alexandre , Bastien Steve , Dalpé Virginie , Minot Pierre-Henri , De Serres Gaston , Skowronski Danuta M.
Published: July 2023

Introduction

During the 2022 mpox outbreak, the province of Quebec, Canada prioritized first doses for pre-exposure vaccination of people at high mpox risk, delaying second doses due to limited supply. We estimated single-dose mpox vaccine effectiveness (VE) adjusting for virus exposure risk based only on surrogate indicators available within administrative databases (e.g. clinical record of sexually transmitted infections), or supplemented by self-reported risk factor information (e.g. sexual contacts).

Methods

We conducted a test-negative case-control study between June 19 and September 24, 2022. Information from administrative databases was supplemented by a questionnaire collecting self-reported risk factors specific to the three-week period before testing. Two study populations were assessed: all within the administrative databases (All-Admin) and the subset completing the questionnaire (Sub-Quest). Logistic regression models were adjusted for age, calendar-time and exposure-risk, the latter based on administrative indicators only (All-Admin and Sub-Quest populations) or supplemented by questionnaire information (Sub-Quest population).

Results

There were 532 All-Admin participants, of which 199 (37%) belonged to Sub-Quest. With exposure-risk adjustment based only on administrative indicators, single-dose mpox VE among All-Admin and Sub-Quest populations was similar at 35% (95%CI:-2-59) and 30% (95%CI:-38-64), respectively. With adjustment supplemented by questionnaire information, Sub-Quest VE increased to 65% (95%CI:1-87). Protection against severe outcomes was higher (VE=82%; 95%CI:-50-98) but with overlapping confidence intervals.

Conclusions

One vaccine dose reduced mpox risk by about two-thirds when adjustment incorporated self-reported risk factors, but by only one-third when adjustment relied solely upon administrative indicators. Inadequate adjustment for exposure risk may substantially under-estimate mpox VE.
Modeling the Therapeutic Process of Patients with Cocaine Use Disorders: The Texas Christian University Process Model as a Guidance to Predict Readmission
Authors: Dacosta-Sánchez Daniel , Fernández-Calderón Fermín , Díaz-Batanero Carmen , Mancheño-Velasco Cinta , Lozano Óscar M.
Published: July 2023

Background

Patients readmitted for Cocaine Use Disorders are, along with Opiates Use Disorder, one of the group of patients with highest demand of treatment in specialized centers of addiction and with greater therapeutic failure.

Objective

Our aim is to apply the Texas Christian University Process Model to modeling the relationships between patient’s attributes at intake of treatment, treatment progress indicators and outcomes, including treatment success and readmissions.

Method

A retrospective observational design was used with 10,298 Cocaine Use Disorder patients. Electronic health records were used for statistical analysis of the data. Randomized subsample 1 (n= 5,150) was used for exploratory analysis and subsample 2 (n = 5,148) to modeling variables relations.

Results

Patients attributes at intake have limited relevance in explaining the treatment progress indicators and outcomes. Time on treatment and patient’s adherence are relevant to explain treatment success. Readmissions are mainly explained by time in treatment and therapeutic success. Been referred to addiction centers by health of services also appear to be relevant.

Discussion and conclusion

Our study reflects that the therapeutic process is important in order to have and adequate therapeutic adherence and to stay longer in treatment. Patients with a successful treatment and longer stay in treatment are less likely to have future readmissions. Through this study we highlight, therefore, the value of an adequate therapeutic adherence to obtain successful short- and medium-term results. This would make the treatment of these patients more efficient, and alleviate suffering for the patients and their families.
Tetracycline transactivator overexpression in keratinocytes triggers a TRPV1 primary sensory neuron-dependent neuropathic itch
Authors: Crowther Andrew J. , Kashem Sakeen W. , Jewell Madison E. , Chang Henry Le , Casillas Mariela Rosa , Midavaine Élora , Rodriguez Sian , Braz Joao M. , Kania Artur , Basbaum Allan I.
Published: July 2023

Mouse models that combine tetracycline-controlled gene expression systems and conditional genetic activation can tightly regulate transgene expression in discrete cell types and tissues. However, the commonly used Tet-Off variant, tetracycline transactivator (tTA), when overexpressed and fully active, can lead to developmental lethality, disease, or more subtle behavioral phenotypes. Here we describe a profound itch phenotype in mice expressing a genetically encoded tTA that is conditionally activated within the Phox2a lineage. Phox2a; tTA mice develop intense, localized scratching and regional skin lesions that can be controlled by the tTA inhibitor, doxycycline. As gabapentin, but not morphine, relieved the scratching, we consider this phenotype to result from chronic neuropathic itch, not pain. In contrast to the Phox2a lineage, mice with tTA activated within the Phox2b lineage, which has many similar areas of recombination within the nervous system, did not recapitulate the scratching phenotype. In Phox2a-Cre mice, but not Phox2b-Cre, intense Cre-dependent reporter expression was found in skin keratinocytes which formed the area at which skin lesions developed. Most interestingly, repeated topical application of the DREADD agonist, CNO, which chronically induced Gisignaling in Phox2a-keratinocytes, completely reversed the localized scratching and skin lesions. Furthermore, ablation of TRPV1-expressing, primary afferent neurons reduced the scratching with a time course comparable to that produced by Gi-DREADD inhibition. These temporal properties suggest that the neuropathic itch condition arises not only from localized keratinocyte activation of peripheral nerves but also from a persistent, gabapentin-sensitive state of central sensitization.
CT validation of intraoperative imageless navigation (Naviswiss) for component positioning accuracy in primary total hip arthroplasty in supine patient position: A prospective observational cohort study in a single-surgeon practice
Authors: Scholes Corey , Schwagli Tobias , Ireland John
Published: July 2023

The aim of this study was to report on the validity of the Naviswiss handheld image-free navigation device for accurate measurement of THA component positioning intraoperatively, in comparison with the three-dimensional (3D) reconstruction of computed tomography (CT) images as gold standard.

Methods

A series of patients presenting to a single-surgeon clinic with end-stage hip osteoarthritis received primary hip arthroplasty with anterolateral muscle-sparing surgical approach in the supine position. Imageless navigation was applied during the procedure with bone-mounted trackers applied to the greater trochanter and ASIS. Patients underwent routine CT scans before and after surgery and these were analysed using three-dimensional reconstruction to generate cup orientation, offset and leg length changes which were compared to the intraoperative measurements provided by the navigation system. Estimates of agreement between the intraoperative and image-derived measurements were assessed with and without correction for bias and declared cases with potential measurement issues.

Results

The mean difference between intraoperative and postoperative CT measurements was within 2° for angular measurements and 2mm for leg length. Absolute differences for the two indices were within 5° and 4mm. Mean bias was 1.9 - 3.6° underestimation for cup orientation and up to 2mm overestimation for leg length change, but absolute thresholds of 10° and 10mm were not exceeded by 95% limits of agreement (LOA), especially after correction for bias. Four cases (12%) were declared intraoperatively for issues with fixation on the greater trochanter. Inclusion of these cases generated acceptable accuracy overall and their omission failed to improve between-case variability in accuracy or LOA for both offset and leg length.

Conclusions

The accuracy of the Naviswiss system applied during primary THA in supine patient position and anterolateral surgical approach falls within clinically acceptable recommendations for acetabular cup placement, femoral offset and length length. With refinements to surgical technique to adapt to the navigation hardware, the system could be further improved with regression-based bias correction.
The effect of combining antibiotics on resistance: A systematic review and meta-analysis
Authors: Siedentop Berit , Kachalov Viacheslav N. , Witzany Christopher , Egger Matthias , Kouyos Roger D. , Bonhoeffer Sebastian
Published: July 2023

When and under which conditions antibiotic combination therapy decelerates rather than accelerates resistance evolution is not well understood. We examined the effect of combining antibiotics on within-patient resistance development across various bacterial pathogens and antibiotics.

We searched CENTRAL, EMBASE and PubMed for (quasi)-randomised controlled trials (RCTs) published from database inception to November 24th, 2022. Trials comparing antibiotic treatments with different numbers of antibiotics were included. A patient was considered to have acquired resistance if, at the follow-up culture, a resistant bacterium (as defined by the study authors) was detected that had not been present in the baseline culture. We combined results using a random effects model and performed meta-regression and stratified analyses. The trials’ risk of bias was assessed with the Cochrane tool.

42 trials were eligible and 29, including 5054 patients, were qualified for statistical analysis. In most trials, resistance development was not the primary outcome and studies lacked power. The combined odds ratio (OR) for the acquisition of resistance comparing the group with the higher number of antibiotics with the comparison group was 1.23 (95% CI 0.68-2.25), with substantial between-study heterogeneity (I2=77%). We identified tentative evidence for potential beneficial or detrimental effects of antibiotic combination therapy for specific pathogens or medical conditions.

The evidence for combining a higher number of antibiotics compared to fewer from RCTs is scarce and overall, is compatible with both benefit or harm. Trials powered to detect differences in resistance development or well-designed observational studies are required to clarify the impact of combination therapy on resistance.
Automatic Detection and Assessment of Freezing of Gait Manifestations
Authors: Yang Po-Kai , Filtjens Benjamin , Ginis Pieter , Goris Maaike , Nieuwboer Alice , Gilat Moran , Slaets Peter , Vanrumste Bart
Published: July 2023

Freezing of gait (FOG) is an episodic and highly disabling symptom of Parkinson’s disease (PD). Although described as a single phenomenon, FOG is not univocal and can express as different manifestations, such as trembling in place or complete akinesia. We aimed to analyze the utility of deep learning trained on inertial measurement unit data to classify FOG into both manifestations. We developed a temporal convolutional neural network, which we compared to three state-of-the-art FOG detection algorithms that were adapted to the FOG manifestation detection task. Next, we investigated its performance in distinguishing between the two manifestations and other forms of movement cessation (e.g., volitional stopping and sitting) based on gold-standard video annotations. Experiments were conducted on a dataset of twelve PD patients with FOG that completed a FOG-provoking protocol, including the timed-up-and-go and 360-degree turning-in-place tasks during ON and OFF anti-Parkinsonian medication. The results showed that our model enables accurate detection of FOG manifestations with an 11.43% higher F1 score than the second-best model. Assessment of FOG manifestation severity was moderately strong for trembling in place (Intra-class Correlation Coefficient (ICC)=0.64, [0.16,0.88]) and strong for complete akinesia (ICC=0.87, [0.63,0.96]). Remarkably, our results show that complete akinesia can be distinguished from volitional stopping. In conclusion, we established that FOG manifestations could be accurately detected and assessed with deep learning. Future work should establish whether these results hold firm for a more extensive and varied verification cohort.
CSF proteome profiling reveals highly specific biomarkers for dementia with Lewy bodies
Authors: del Campo Marta , Vermunt Lisa , Peeters Carel FW , Hok-A-Hin Yanaika S. , Lleó Alberto , Alcolea Daniel , van Nee Mirrelijn , Engelborghs Sebastiaan , Sieben Anne , Chen-Plotkin Alice , Irwin David J , van der Flier Wiesje M , Lemstra Afina W , Teunissen Charlotte E
Published: July 2023

Diagnosis of dementia with Lewy bodies (DLB) is challenging and biofluid biomarkers specific for DLB are highly needed. Here we use proximity extension-based multiplex assays to establish the specific cerebrospinal fluid (CSF) proteomic changes that underlie DLB in an unprecedented well-characterized cohort of 109 DLB patients, 235 patients with Alzheimeŕs disease (AD) and 190 controls. We identified more than 50 CSF proteins dysregulated in DLB, which were especially related to myelination processes. An enzyme involved in dopamine biosynthesis (L-amino acid decarboxylase, DDC) was the strongest dysregulated protein in DLB (>1.5 fold-change vs.CON or AD; q<1E-16) and could discriminate DLB from controls and AD patients with high accuracy (AUC: 0.91 and 0.81 respectively). We modelled a CSF protein panel containing only seven of these markers, which discriminate DLB from AD with higher performance (AUC: 0.93, 95%CI: 0.86-0.98). We developed custom multiplex assays for six of these markers (DDC, CRH, MMP-3, ABL1, MMP-10 and THOP1); and validated their performance in independent cohorts (n=329; AUCs: 0.68-0.90), including an autopsy cohort (n=76; AUCs: 0.90-0.95). This extensive and unique DLB CSF proteome study depicts specific protein changes underlying DLB pathophysiology. It translates these findings into a custom CSF biomarker panel able to identify DLB patients with high accuracy in different independent cohorts, providing new testing opportunities for diagnostic settings and clinical trials.
Same-day versus rapid ART initiation in HIV-positive individuals presenting with symptoms of tuberculosis: protocol for an open-label randomized non-inferiority trial in Lesotho and Malawi
Authors: Gerber Felix , Semphere Robina , Lukau Blaise , Mahlatsi Palesa , Mtenga Timeo , Lee Tristan , Kohler Maurus , Glass Tracy R. , Amstutz Alain , Molatelle Mamello , MacPherson Peter , Marake Nthuseng Bridgett , Nliwasa Marriot , Ayakaka Irene , Burke Rachael , Labhardt Niklaus
Published: July 2023

Background

In absence of contraindications, same-day initiation (SDI) of antiretroviral therapy (ART) is recommended for people testing HIV-positive who are ready to start treatment. Until 2021, World Health Organization (WHO) guidelines considered the presence of TB symptoms (presumptive TB) a contraindication to SDI due to the risk of TB-immune reconstitution inflammatory syndrome (TB-IRIS). To reduce TB-IRIS risk, ART initiation was recommended to be postponed until results of TB investigations were available, and TB treatment initiated if active TB was confirmed. In 2021, the WHO guidelines changed to recommending SDI even in the presence of TB symptoms without awaiting results of TB investigations based on the assumption that TB investigations often unnecessarily delay ART initiation, increasing the risk for pre-ART attrition from care, and noting that the clinical relevance of TB- IRIS outside the central nervous system remains unclear. However, this guideline change was not based on conclusive evidence, and it remains unclear whether SDI of ART or TB test results should be prioritized in people with HIV (PWH) and presumptive TB.

Design and methods

SaDAPT is an open-label, pragmatic, parallel, 1:1 individually randomized, non-inferiority trial comparing two strategies for the timing of ART initiation in PWH with presumptive TB (“ART first” versus “TB results first”). PWH in Lesotho and Malawi, aged 12 years and older (re)initiating ART who have at least one TB symptom (cough, fever, night sweats or weight loss) and no signs of intracranial infection are eligible. After a baseline assessment, participants in the “ART first” arm will be offered SDI of ART, while those in the “TB results first” arm will be offered ART only after active TB has been confirmed or refuted. We hypothesize that the “ART first” approach is safe and non-inferior to the “TB results first” approach with regard to HIV viral suppression (<400 copies/ml) six months after enrolment. Secondary outcomes include retention in care and adverse events consistent with TB-IRIS.

Expected outcomes

SaDAPT will provide evidence on the safety and effects of SDI of ART in PWH with presumptive TB in a pragmatic clinical trial setting.

Trial registration

The trial has been registered onclinicaltrials.gov(NCT05452616; July 11 2022).
Implications ofDobbs v.Jackson for patients and providers: a scoping review
Authors: Zhu David T. , Zhao Lucy , Alzoubi Tala , Shenin Novera , Baskaran Teerkasha , Tikhonov Julia , Wang Catherine
Published: July 2023

Introduction

On June 24, 2022, the U.S. Supreme Court’s decision inDobbs v. Jacksonoverturned the right to abortion set forth byRoe v. Wade, granting states the authority to regulate access to abortion services. This has led to widespread bans, threatening patients’ access to, and healthcare providers’ abilities to provide, the full spectrum of reproductive health services. The ruling disproportionately affects marginalized groups, exacerbating existing social disparities in health and is an emerging public health crisis.

Methods

We conducted a scoping review to evaluate the impact ofDobbson patients’ health outcomes and access to health services, as well as on medical trainees’ and healthcare providers’ ability to access abortion training and provide reproductive health services. The search was based on the PRISMA Extension for Scoping Reviews (PRSIMA-ScR) guidelines. We searched eight bibliographic databases (PubMed, Scopus, Embase, PsycINFO, Google Scholar, Science Direct, JSTOR, and Web of Science) and three preprint servers (medRxiv, bioRxiv, and Europe PMC) using various combinations of keywords related to ‘abortion’ and ‘Dobbs v. Jackson’ on March 22, 2023. Four reviewers independently screened the studies based on pre-specified eligibility criteria and one reviewer performed data extraction for pre-identified themes.

Results

A total of 18 studies met the inclusion criteria. We found thatDobbsled to a surge in demand for contraception, compounded existing travel- and cost-related barriers to access, increased polarizing views on social media (e.g., Twitter), and evoked significant fears and concerns among medical trainees regarding their scope of practice and fears of legal repercussions for offering standard-of-care and related services to patients seeking abortions.

Conclusion

Our study offers valuable insights into the clinical implications ofDobbson patients’ health outcomes and access to health services, as well as providers’ reproductive health practices.
A Preliminary Investigation Of Repetitive Transcranial Magnetic Stimulation Applied To The Left Dorsolateral Prefrontal Cortex In Treatment Seeking Participants With Cannabis Use Disorder
Authors: Sahlem Gregory L. , Kim Bohye , Baker Nathaniel L. , Wong Brendan L. , Caruso Margaret A. , Campbell Lauren A. , Kaloani Irakli , Sherman Brian J. , Ford Tiffany J. , Musleh Ahmad H. , Kim Jane P. , Williams Nolan R. , Manett Andrew J. , Kratter Ian H. , Short Edward B. , Killeen Terese K. , George Mark S. , McRae-Clark Aimee L.
Published: July 2023

Background

Cannabis use disorder (CUD) is a common and consequential disorder. When applied to the dorsolateral prefrontal cortex (DLPFC), repetitive transcranial magnetic stimulation (rTMS) reduces craving across substance use disorders and may have a therapeutic clinical effect when applied in serial sessions. The present study sought to preliminarily determine whether serial sessions of rTMS applied to the DLPFC had a therapeutic effect in CUD.

Methods

This study was a two-site, phase-2, double-blind, randomized-controlled-trial. Seventy-two treatment-seeking participants (37.5% Women, mean age 30.2±9.9SD) with ≥moderate-CUD were randomized to active or sham rTMS (Beam-F3, 10Hz, 20-total-sessions, with cannabis cues) while undergoing a three-session motivational enhancement therapy intervention. The primary outcome was the change in craving between pre- and post- treatment (Marijuana Craving Questionnaire Short-Form—MCQ-SF). Secondary outcomes included the number of weeks of abstinence and the number of days-per-week of cannabis use during 4-weeks of follow-up.

Results

There were no significant differences in craving between conditions. Participants who received active rTMS reported numerically, but not significantly, more weeks of abstinence in the follow-up period than those who received sham rTMS (15.5%-Active; 9.3%-Sham; rate ratio = 1.66 [95% CI: 0.84, 3.28];p=0.14). Participants who received active rTMS reported fewer days-per-week of cannabis use over the final two-weeks of the follow-up period (Active vs. Sham: -0.72; Z=-2.33,p=0.02).

Conclusions

This trial suggests rTMS is safe and feasible in individuals with CUD and may have a therapeutic effect on frequency of cannabis use, though further study is needed with additional rTMS-sessions and a longer follow-up period.

Highlights

This phase-2 RCT tested the efficacy of prefrontal rTMS for cannabis use disorder

The study paradigm was safe and feasible, and participants tolerated rTMS well

The active-group had numerically more weeks of abstinence during follow-up

The active-group had fewer days-per-week of cannabis use during follow-up

More rTMS and a longer follow-up may result in a larger effect in future studies
Dimensions, social and healthcare setting determinants of client satisfaction for HIV/AIDS services: a systematic review
Authors: Endalamaw Aklilu , Gilks Charles F , Ambaw Fentie , Chatfield Mark D. , Assefa Yibeltal
Published: July 2023

Introduction

Quality HIV/AIDS care affects clients’ health-seeking behaviour and adherence to services, which can be evaluated through the patient’s satisfaction with the services. There was an information gap on the status and contributors to HIV/AIDS clients satisfaction, which supports comprehending universal health coverage. This review presented dimensions and comprehensive determinants of HIV/AIDS clients satisfaction.

Methods

We conducted a systematic review based on articles from Web of Science, EMBASE, PubMed, Google Scholar, and grey literature sources. Studies that have reported satisfaction of people living with HIV or at least one determinant and are written in English with full-text available were included. Findings from each study were described in a narrative description.

Results

There was a heterogeneous level of HIV/AIDS clients’ satisfaction in different settings and countries. Accessibility of services, confidentiality, waiting time to receive care, technical competency, knowledge, and attitude of health care workers were frequently reported determinants. Educational and employment status were common modifiable social factors.

Conclusions

Public health programmes should follow a multi-pronged approach to fulfil people living with HIV clients’ healthcare needs. It is vital to improve HIV care integration with primary healthcare, improve financing of HIV care, digitalise healthcare settings, invest in pre-service education and in-service training, provide culturally sensitive services, strengthen social works and behavioural change communication services.
How do perceptions of Covid-19 risk impact pregnancy-related health decisions? A convergent parallel mixed-methods study protocol
Authors: Vanstone Meredith , Correia Rebecca H. , Howard Michelle , Darling Elizabeth , Bayrampour Hamideh , Carruthers Andrea , Davis Amie , Hadid Dima , Hetherington Erin , Jones Aaron , Kandasamy Sujane , Kuyvenhoven Cassandra , Liauw Jessica , McDonald Sarah D. , Mniszak Caroline , Molinaro Monica L. , Pahwa Manisha , Patel Tejal , Sadik Marina , Sanya Njideka , Shen Katrina , Greyson Devon
Published: July 2023

Introduction

Pregnant people have a higher risk of severe COVID-19 disease. They have been disproportionately impacted by COVID-19 infection control policies, which exacerbated conditions resulting in intimate partner violence, healthcare access, and mental health distress. This project examines the impact of accumulated individual health decisions and describes how perinatal care and health outcomes changed during the COVID-19 pandemic.

Objectives

Quantitative strand:Describe differences between 2019, 2021, and 2022 birth groups related to maternal vaccination, perinatal care, and mental health care. Examine the differential impacts on racialized and low-income pregnant people.

Qualitative strand:Understand how pregnant people’s perceptions of COVID-19 risk influenced their decision-making about vaccination, perinatal care, social support, and mental health.

Methods and analysis

This is a Canadian convergent parallel mixed-methods study. Thequantitative stranduses a retrospective cohort design to assess birth group differences in rates of Tdap and COVID-19 vaccination, gestational diabetes screening, length of post-partum hospital stay, and onset of depression, anxiety, and adjustment disorder, using administrative data from ICES, formerly the Institute for Clinical Evaluative Sciences (Ontario) and PopulationData BC (PopData) (British Columbia). Differences by socioeconomic and ethnocultural status will also be examined. Thequalitative strandemploys qualitative description to interview people who gave birth between May 2020-December 2021 about their COVID-19 risk perception and health decision-making process. Data integration will occur during design and interpretation.

Ethics and dissemination

This study received ethical approval from McMaster University and the University of British Columbia. Findings will be disseminated via manuscripts, presentations, and patient-facing infographics.

Strengths and limitations of this study

Population-based administrative data cohorts are very large, ensuring that analyses are high-powered.

Mixed-methods design will allow us to offer explanation for changes in healthcare use observed through administrative data.

Cross-provincial design permits examination of the potential impacts of COVID-19 infection prevention and control policies on pregnant people’s health.

Use of Canadian Index of Multiple Deprivation will allow us to examine differences in healthcare use according to economic, racial, and immigration factors.

Team includes 5 co-investigators with lived experience of pandemic pregnancies.
Associations of Very Low Lipoprotein(a) Levels With Risks Of New-Onset Diabetes And Non-Alcoholic Liver Disease
Authors: Yeung Ming Wai , Said M. Abdullah , van de Vegte Yordi J. , Verweij Niek , Dullaart Robin P.F. , van der Harst Pim
Published: July 2023

Background and aims

We aimed to study the association of very low serum Lipoprotein(a) [Lp(a)] concentrations with new-onset type 2 diabetes (T2D) and non-alcoholic liver disease (NAFLD) in the context of statin usage in the UK Biobank, a large prospective population cohort.

Methods

Using an extended biomarker dataset, we identified 47,362 participants with very low Lp(a) concentrations (<3.8 nmol/L) from a total of 451,479 participants. With a median follow-up of 12.3 years, we assessed the risk of new-onset cardiometabolic diseases in participants stratified by statin usage with Cox proportional hazards models. We performed two-sample Mendelian randomization MR analyses to test causal relationship between genetically predicted Lp(a) and T2D and NAFLD.

Results

Taking the participants with Lp(a) within reportable range as the reference group, the hazard ratios (HR) for T2D were 1.06 (95% confidence interval, CI 1.01-1.12) and for NAFLD 1.35 (95% CI 1.26-1.45) respectively for participants with very low Lp(a) (<3.8 nmol/L). The risk for new-onset T2D was higher in participants using statin (adjusted HR 1.14; 95% CI 1.05-1.24). This was contrasted by higher risk of NAFLD in participants not on statin (HR 1.40; 95%CI 1.28-1.53). There was no evidence for causal links between genetically predicted Lp(a) and T2D nor NAFLD in two-sample MR analyses.

Conclusions

Very low Lp(a) was associated with higher risks of T2D and NAFLD in a prospective analysis of the UK Biobank. These associations were influenced by lipid lowering medication usage. MR analyses did not support causality for these inverse associations.
Comparing frequency of booster vaccination to prevent severe COVID-19 by risk group in the United States
Authors: Park Hailey J. , Gonsalves Gregg S. , Tan Sophia T. , Kelly J. Daniel , Rutherford George W. , Wachter Robert M. , Schechter Robert , Paltiel A. David , Lo Nathan C.
Published: July 2023

There is a public health need to understand how different frequencies of COVID-19 booster vaccines may mitigate the risk of severe COVID-19, while accounting for waning of protection and differential risk by age and immune status. By analyzing United States COVID-19 surveillance and seroprevalence data in a microsimulation model, here we show that more frequent COVID-19 booster vaccination (every 6-12 months) in older age groups and the immunocompromised population would effectively reduce the burden of severe COVID-19, while frequent boosters in the younger population may only provide modest benefit against severe disease. In persons 75+ years, the model estimated that annual boosters would reduce absolute annual risk of severe COVID-19 by 199 (uncertainty interval: 188-229) cases per 100,000 persons, compared to a one-time booster dose. In contrast, for persons 18-49 years, the model estimated that annual boosters would reduce this risk by 14 (11-19) cases per 100,000 persons. Those with prior infection had lower benefit of more frequent boosting, and immunocompromised persons had larger benefit. Scenarios with emerging variants with immune evasion increased the benefit of more frequent variant-targeted boosters. This study underscores the benefit of considering key risk factors to inform frequency of COVID-19 booster vaccines in public health guidance and ensuring at least annual boosters in high-risk populations.
Pre-stroke loop diuretics and anemia in elderly patients were associated with severe renal dysfunction at the onset of acute stroke
Authors: Mori Takahisa , Yano Tetsundo , Yoshioka Kazuhiro , Miyazaki Yuichi
Published: July 2023

Introduction

Severe renal dysfunction (SRD) is a common complication of chronic kidney disease (CKD) that is a risk factor for heart disease and acute stroke (AS).

Furthermore, SRD can limit the treatment options for AS patients and influence their prognosis. Thus, preventing CKD progression to SRD and identifying the factors contributing to SRD at AS onset is crucial. However, the frequency of SRD in AS patients and the associated factors are poorly understood in different genders. In this study, we aimed to investigate the frequency of SRD in AS patients and analyze the associated factors by sex.

Methods

Our cross-sectional study included patients who met the following criteria: 1) admission within 24 hours of AS onset between 2013 and 2019 and 2) availability of pre-stroke medication information. We used the Cockcroft-Gault equation for calculating creatinine clearance (Ccr) and defined SRD as Ccr <30 ml/min. Then, we performed a multivariable logistic regression analysis to identify independent factors associated with SRD on admission separately for males and females.

Results

Out of 4294 patients with AS, 3472 were included for analysis. Of these, 1905 (54.9%) were male, with a median age of 75 and 81 years for males and females, respectively. The prevalence of SRD was 9.7% in males and 18.7% in females. For males, factors associated with SRD were loop diuretics, aspirin, L-type calcium channel blockers, alpha-beta blockers, and anemia. For females, factors associated with SRD were loop diuretics, mineralocorticoid receptor antagonists, and anemia.

Conclusions

Loop diuretic use and anemia before AS onset were associated with SRD in both males and females. To prevent SRD, individualized drug and anemia management are essential. Further prospective studies are warranted to confirm our findings and to elucidate the causal mechanism of SRD in patients with AS.
Self-propagating wave drives noncanonical antidurotaxis of skull bones in vivo
Authors: Dang Yiteng , Lattner Johanna , Lahola-Chomiak Adrian A. , Alves Afonso Diana , Taubenberger Anna , Ulbricht Elke , Rulands Steffen , Tabler Jacqueline M.
Published: July 2023

Cell motility is a key feature of tissue morphogenesis, and it is thought to be driven primarily by the active migration of individual cells or collectives. However, this model is unlikely to apply to cells lacking overt cytoskeletal, stable cell-cell or cell-cell adhesions, and molecular polarity, such as mesenchymal cells. Here, by combining a novel imaging pipeline with biophysical modeling, we discover that during skull morphogenesis, a self-generated collagen gradient expands a population of osteoblasts towards a softer matrix. Biomechanical measurements revealed a gradient of stiffness and collagen along which cells move and divide. The moving cells generate an osteogenic front that travels faster than individual tracked cells, indicating that expansion is also driven by cell differentiation. Through biophysical modeling and perturbation experiments, we found that mechanical feedback between stiffness and cell fate drives bone expansion and controls bone size. Our work provides a mechanism for coordinated motion that does not rely upon the cytoskeletal dynamics of cell migration. We term this self-propagating motion down a stiffness gradient, noncanonical antidurotaxis. Identification of alternative mechanisms of cellular motion will help in understanding how directed cellular motility arises in complex environments with inhomogeneous material properties.
Granular retrosplenial cortex layer 2/3 generates high-frequency oscillations coupled with hippocampal theta and gamma in online states or sharp-wave ripples in offline states
Authors: Arndt Kaiser C. , Gilbert Earl T. , Klaver Lianne M. F. , Kim Jongwoon , Buhler Chelsea M. , Basso Julia C. , McKenzie Sam , English Daniel Fine
Published: July 2023

Neuronal oscillations support information transfer by temporally aligning the activity of anatomically distributed ‘writer’ and ‘reader’ cell assemblies. High-frequency oscillations (HFOs) such as hippocampal CA1 sharp-wave ripples (SWRs; 100-250 Hz) are sufficiently fast to initiate synaptic plasticity between assemblies and are required for memory consolidation. HFOs are observed in parietal and midline cortices including granular retrosplenial cortex (gRSC). In ‘offline’ brain states (e.g. quiet wakefulness) gRSC HFOs co-occur with CA1 SWRs, while in ‘online’ states (e.g. ambulation) HFOs persist with the emergence of theta oscillations. The mechanisms of gRSC HFO oscillations, specifically whether the gRSC can intrinsically generate HFOs, and which layers support HFOs across states, remain unclear. We addressed these issues in behaving mice using optogenetic excitation in individual layers of the gRSC and high density silicon-probe recordings across gRSC layers and hippocampus CA1. Optogenetically induced HFOs (iHFOs) could be elicited by depolarizing excitatory neurons with 100 ms half-sine wave pulses in layer 2/3 (L2/3) or layer 5 (L5) though L5 iHFOs were of lower power than in L2/3. Critically, spontaneous HFOs were only observed in L2/3 and never in L5. Intra-laminar monosynaptic connectivity between excitatory and inhibitory neurons was similar across layers, suggesting other factors restrict HFOs to L2/3. To compare HFOs in online versus offline states we analyzed, separately, HFOs that did or did not co-occur with CA1 SWRs. Using current-source density analysis we found uniform synaptic inputs to L2/3 during all gRSC HFOs, suggesting layer-specific inputs may dictate the localization of HFOs to L2/3. HFOs occurring without SWRs were aligned with the descending phase of both gRSC and CA1 theta oscillations and were coherent with CA1 high frequency gamma oscillations (50-80 Hz). These results demonstrate that gRSC can internally generate HFOs without rhythmic inputs and that HFOs occur exclusively in L2/3, coupled to distinct hippocampal oscillations in online versus offline states.
High throughput functional profiling of genes at intraocular pressure loci reveals distinct networks for glaucoma
Authors: Greatbatch Connor J , Lu Qinyi , Hung Sandy , Wing Kristof , Liang Helena , Han Xikun , Zhou Tiger , Siggs Owen M , Mackey David A , Cook Anthony L , Senabouth Anne , Liu Guei-Sheung , Craig Jamie E , MacGregor Stuart , Powell Joseph E , Hewitt Alex W
Published: July 2023

INTRODUCTION

Primary open angle glaucoma (POAG) is a leading cause of blindness globally. Characterised by progressive retinal ganglion cell degeneration, the precise pathogenesis remains unknown. Genome-wide association studies (GWAS) have uncovered many genetic variants associated with elevated intraocular pressure (IOP), one of the key risk factors for POAG. This study sought to investigate the morphological and transcriptional consequences of perturbation of key genes at IOP loci in trabecular meshwork cell (TMC); the cellular regulators of IOP. We aimed to identify genetic and morphological variation that can be attributed to TMC dysfunction and raised IOP in POAG.

METHODS

62 genes across 55 loci were knocked-out in a primary human TMC line. Each knockout group, including five non-targeting control groups, underwent single-cell RNA-sequencing (scRNA-seq) for differentially-expressed gene (DEG) analysis. Multiplexed fluorescent staining of key organelles, was coupled with high-throughput microscopy for single-cell morphological analysis using CellProfiler image analysis.

RESULTS

Across many of the individual gene knockouts scRNA-seq highlighted genes relating to matrix metalloproteinases and interferon-induced proteins. Our work has prioritised genes at four loci of interest to identify gene knockouts that may contribute to the pathogenesis of POAG, includingANGPTL2, LMX1B, CAV1,andKREMEN1. Three genetic networks of gene knockouts with similar transcriptomic profiles were identified (ABO/CAV1/MYOC,ANGPT2/PKHD1/TNS1/TXNRD2, andCAPZA1/KALRN/LMO7/PLEKHA7/GNB1L/TEX41), suggesting a synergistic function in trabecular meshwork cell physiology.TEKknockout caused significant upregulation of nuclear granularity on morphological analysis, whilst knockout ofTRIOBP, TMCO1andPLEKHA7increased granularity and intensity of actin and the cell-membrane.

CONCLUSION

High throughput analysis of cellular structure and function through multiplex fluorescent single-cell analysis and scRNA-seq assays enabled the direct study of genetic perturbations at the single-cell resolution. This work provides a framework for investigating the role of genes in the pathogenesis of glaucoma and heterogenous diseases with a strong genetic basis.
kGWASflow: a modular, flexible, and reproducible Snakemake workflow for k-mers-based GWAS
Authors: Corut Adnan Kivanc , Wallace Jason G.
Published: July 2023

Genome-wide association studies (GWAS) have been widely used to identify genetic variation associated with complex traits. Despite its success and popularity, the traditional GWAS approach comes with a variety of limitations. For this reason, newer methods for GWAS have been developed, including the use of pan-genomes instead of a reference genome and the utilization of markers beyond single-nucleotide polymorphisms, such as structural variations and k-mers. The k-mers based GWAS approach has especially gained attention from researchers in recent years. However, these new methodologies can be complicated and challenging to implement. Here we present kGWASflow, a modular, user-friendly, and scalable workflow to perform GWAS using k-mers. We adopted an existing kmersGWAS method into an easier and more accessible workflow using management tools like Snakemake and Conda and eliminated the challenges caused by missing dependencies and version conflicts. kGWASflow increases the reproducibility of the kmersGWAS method by automating each step with Snakemake and using containerization tools like Docker. The workflow encompasses supplemental components such as quality control, read-trimming procedures, and generating summary statistics. kGWASflow also offers post-GWAS analysis options to identify the genomic location and context of trait-associated k-mers. kGWASflow can be applied to any organism and requires minimal programming skills. kGWASflow is freely available on GitHub (https://github.com/akcorut/kGWASflow) and Bioconda (https://anaconda.org/bioconda/kgwasflow).
miR-324 mediates bone homeostasis through the regulation of osteoblast and osteoclast differentiation and activity
Authors: Hayman Dan J. , Lin Hua , Prior Amanda , Charlesworth Gemma , Johnson de Sousa Brito Francesca M. , Hao Yao , Patel Krutik , Soul Jamie , Clark Ian M. , Piróg Katarzyna A. , Barter Matt J. , Van ’T Hof Rob , Young David A.
Published: July 2023

microRNAs (miRNAs) are non-coding RNAs which modulate the expression of other RNA molecules. One miRNA can target many transcripts, allowing each miRNA to play key roles in many biological pathways. miR-324 is a miRNA previously implicated in bone and cartilage maintenance, defects of which result in common age-related diseases, such as osteoporosis or osteoarthritis (OA).

In global miR-324-null mice cartilage damage was increased in both surgically and ageing-induced OA, despite minimal changes to the cartilage transcriptome, with few predicted miR-324 targets dysregulated. However, micro-computed tomography and histology demonstrated that global miR- 324-null the mice had an increase in bone mineral density, trabecular thickness and cortical thickness, with many parameters increasing with age. The bone marrow of miR-324-null mice also had reduced lipid content while andin vivoTRAP staining revealed a decrease in osteoclasts, with histomorphometry demonstrating an increased rate of bone formation in miR-324-null mice.

Ex vivoassays revealed that the high bone mass phenotype of the miR-324-null mice resulted from increased osteoblast activity and decreased osteoclastogenesis. RNA-seq and qRT-PCR followed by miR-324 target prediction and validation in osteoblasts, osteoclasts and bone marrow macrophages identified the osteoclast fusion regulatorPin1as a miR-324 target in the osteoclast lineage and the master osteogenic regulatorRunx2as a target of miR-324-5p in osteoblasts, thein vitrooverexpression of which recapitulated the increased osteogenesis and decreased adipogenesis phenotype observedin vivo.

These data point to important roles of miR-324 in skeletal biology with altered bone homeostasis in miR-324-null mice potentially causal for the increased cartilage damage observed during OA and ageing. Elucidation of pathways regulated by miR-324 offer promise for the treatment of bone diseases such as osteoporosis.
The protein interactome of the citrus Huanglongbing pathogenCandidatusLiberibacter asiaticus
Authors: Carter Erica W. , Peraza Orlene Guerra , Wang Nian
Published: July 2023

CandidatusLiberibacter asiaticus (CLas) is the causal agent of the devastating citrus Huanglongbing (HLB) disease. Our understanding of the pathogenicity mechanism and biology of CLas remain limited because CLas has not been cultured in artificial media. CLas encodes 1136 proteins of which 415 have unknown functions. Since genetic studies of CLas genes with unknown functions are impossible, we utilized genome-wide protein-protein interactions (PPIs) yeast-two-hybrid (Y2H) assays to help solve the mystery. PPIs are fundamental to all cellular processes and machinery and instrumental in investigating uncharacterized proteins and inferring biological pathways. In total, 916 bait and 936 prey proteins were included in the three-phase screening, which identified 4245 interactions. The false positive rate of the Y2H assay was estimated to be 3.1%. Pull-down assays confirmed the robustness of our Y2H. The average interactions per node for CLas Y2H interactome were approximately 15.6, significantly higher than free-living bacteria, indicating genome reduction has led to a multi-function of proteins. PPIs provide clues for functions of 371 uncharacterized proteins of CLas. Forty HUB node proteins were identified which might play critical roles in CLas, including a quinone oxidoreductase and LysR that are known to protect bacteria against oxidative stress. This explains why CLas survives well in the phloem even though it triggers immune-mediated disease, systemic and chronic production of reactive oxygen species, and phloem cell death. This PPI database facilitates the investigation of CLas cellular biochemistry and physiology, functions of uncharacterized proteins, and pathogenicity mechanisms of the pathogen.
C-terminal truncation of CXCL10 attenuates inflammatory activity but retains angiostatic properties
Authors: Dillemans Luna , Yu Karen , De Zutter Alexandra , Noppen Sam , Gouwy Mieke , Berghmans Nele , De Bondt Mirre , Vanbrabant Lotte , Brusselmans Stef , Martens Erik , Schols Dominique , Marques Pedro Elias , Struyf Sofie , Proost Paul
Published: July 2023

Interferon-γ-inducible protein of 10 kDa (IP-10/CXCL10) is a dual-function CXC chemokine that coordinates chemotaxis of activated T cells and natural killer (NK) cells via interaction with its G protein-coupled receptor (GPCR), CXC chemokine receptor 3 (CXCR3). As a consequence of natural posttranslational modifications, human CXCL10 exhibits a high degree of structural and functional heterogeneity. However, the biological effect of natural posttranslational processing of CXCL10 at the carboxy (C)-terminus has remained partially elusive. The truncated CXCL10 proteoform CXCL10(1-73), lacking the four endmost C-terminal amino acids, was previously identified in human cell culture supernatant. To further explore the functioning of CXCL10(1-73), we optimized its production in this study through Fmoc-based solid phase peptide synthesis (SPPS) and propose an SPPS strategy to efficiently generate human CXCL10 proteoforms. Compared to intact CXCL10(1-77), CXCL10(1-73)had diminished affinity for glycosaminoglycans including heparin, heparan sulfate and chondroitin sulfate A. Moreover, CXCL10(1-73)exhibited an attenuated capacity to induce CXCR3A-mediated signaling, as evidenced in calcium mobilization assays and through quantification of phosphorylated extracellular signal-regulated kinase-1/2 (ERK1/2) and protein kinase B/Akt. Furthermore, CXCL10(1-73)incited reduced primary human T lymphocyte chemotaxisin vitroand evoked less peritoneal ingress of CXCR3+T lymphocytes in mice receiving intraperitoneal chemokine injections. In contrast, loss of the four endmost C-terminal residues did not affect the inhibitory properties of CXCL10 on spontaneous and/or FGF-2-induced migration, proliferation, wound healing, phosphorylation of ERK1/2, and sprouting of human microvascular endothelial cells. Thus, C-terminally truncated CXCL10 has attenuated inflammatory properties, but preserved anti-angiogenic capacity.

GRAPHICAL ABSTRACT