bluuebunny/crossref_metadata_2025_split huggingface dataset:
Autonomic modulation with mindfulness‐based stress reduction in chronic kidney disease: a randomized controlled trial
Authors: Jeong Jinhee , Hu Yingtian , Zanuzzi Matias , DaCosta Dana , Sabino‐Carvalho Jeann L. , Li Sabrina , Park Jeanie 
Published: December 2024

AbstractChronic kidney disease (CKD) is characterized by overactivation of the sympathetic nervous system (SNS) that leads to increased risk of cardiovascular disease. This study was conducted to evaluate the effects of a Mindfulness‐Based Stress Reduction (MBSR) programme on SNS activity in CKD patients. Participants with CKD stages III–IV were randomized to the 8 week MBSR programme or Health Enhancement Program (HEP; a structurally parallel, active control group). Intraneural measures of SNS activity directed to muscle [muscle sympathetic nerve activity (MSNA)] via microneurography was recorded at rest and during stress manoeuvres (mental arithmetic, handgrip exercise and cold pressor test). Data analyses were performed based on the intent‐to‐treat principle. In total, 29 participants (64 ± 9 years; 86% males) completed the intervention with 17 in the MBSR and 12 in the HEP groups. There was a significant Group (MBSR vs. HEP) by Time (baseline vs. post‐intervention) interaction in MSNA reactivity to mental stress (P = 0.029), with a significant reduction in the mean ∆MSNA over 3 min of mental arithmetic at post‐intervention (10.3 ± 4.2–5.9 ± 5.6 bursts/min, P < 0.001; Hedges’ g = −0.858, 95% confidence interval [−1.578, −0.167]), while no change was observed within the HEP group (P = 0.818). Reduced ∆MSNA during handgrip exercise was also observed, while ∆MSNA during the cold pressor test and resting MSNA remained unchanged in both groups from baseline to post‐intervention. In this randomized controlled trial, patients with CKD had a reduction of sympathetic reactivity during mental stress and static handgrip exercise following 8 weeks of MBSR but not after HEP. Our findings demonstrate that mindfulness training is feasible and may have clinically beneficial effects on autonomic function in CKD.
imageKey points
Question: Does the Mindfulness‐Based Stress Reduction (MBSR) programme reduce sympathetic activity in patients with chronic kidney disease (CKD)?
Finding: In this randomized controlled trial including 29 patients with CKD, 8 weeks of MBSR decreased sympathetic reactivity to mental stress compared to the control Health Enhancement Program (HEP).
Meaning: These finding suggest that mindfulness training may have clinically beneficial effects on autonomic function in CKD.
Structural basis for nuclear import of adeno-associated virus serotype 6 capsid protein
Authors: Hoad Mikayla , Nematollahzadeh Sepehr , Petersen Gayle F. , Roby Justin A. , Alvisi Gualtiero , Forwood Jade K. 
Published: December 2024

ABSTRACT

Adeno-associated viruses (AAVs) are the most extensively researched viral vectors for gene therapy globally. The AAV viral protein 1 (VP1) N-terminus controls the capsid’s ability to translocate into the cell nucleus; however, the exact mechanism of this process is largely unknown. In this study, we sought to elucidate the precise interactions between AAV serotype 6 (AAV6), a promising vector for immune disorders, and host transport receptors responsible for vector nuclear localization. Focusing on the positively charged basic areas within the N-terminus of AAV6 VP1, we identified a 53-amino acid region that interacts with nuclear import receptors. We measured the binding affinities between this region and various nuclear import receptors, discovering a notably strong interaction with IMPα5 and IMPα7 in the low nanomolar range. We also elucidated the X-ray crystal structure of this region in complex with an importin alpha (IMPα) isoform, uncovering its binding as a bipartite nuclear localization signal (NLS). Furthermore, we show that using this bipartite NLS, AAV6 VP1 capsid protein can localize to the nucleus of mammalian cells in a manner dependent on the IMPα/IMPβ nuclear import pathway. This study provides detailed insights into the interaction between the AAV6 VP1 capsid protein and nuclear import receptors, deepening our knowledge of AAV nuclear import mechanisms and establishing a basis for the improvement of AAV6-based gene therapy vectors.

IMPORTANCE
AAVs, recognized as the most extensively researched viral vectors for gene therapy globally, offer significant advantages over alternatives due to their small size, non-pathogenic nature, and innate ability for tissue-specific targeting. AAVs are required to localize to the nucleus to perform their role as a gene therapy vector; however, the precise mechanisms that facilitate this process remain unknown. Despite sharing overt genomic similarities with AAV1 and AAV2, AAV6 is a unique serotype. It is currently recognized for its ability to effectively transduce hematopoietic cell lineages and, consequently, is considered promising for the treatment of immune disorders. Identifying the exact mechanisms that permit AAV6 to access the nucleus can open up new avenues for gene therapy vector engineering, which can ultimately lead to increased therapeutic benefits.
A gut-derived
Streptococcus salivarius
produces the novel nisin variant designated nisin G and inhibits
Fusobacterium nucleatum
in a model of the human distal colon microbiome
Authors: Lawrence Garreth W. , Garcia-Gutierrez Enriqueta , O’Mahony A. Kate , Walsh Calum J. , O'Connor Paula M. , Begley Máire , Guinane Caitriona M. , Cotter Paul D. 
Published: December 2024

ABSTRACT

Fusobacterium nucleatum
is a human pathogen associated with intestinal conditions including colorectal cancer. Screening for gut-derived strains that exhibit anti-
F
.
nucleatum
activity
in vitro
revealed
Streptococcus salivarius
DPC6487 as a strain of interest. Whole-genome sequencing of
S. salivarius
DPC6487 identified a nisin operon with a novel structural variant designated nisin G. The structural nisin G peptide differs from the prototypical nisin A with respect to seven amino acids (Ile4Tyr, Ala15Val, Gly18Ala, Asn20His, Met21Leu, His27Asn, and His31Ile), including differences that have not previously been associated with a natural nisin variant. The nisin G gene cluster consists of
nsgGEFABTCPRK
with transposases encoded between the nisin G structural gene (
nsgA
) and
nsgF
, notably lacking an equivalent to the
nisI
immunity determinant.
S. salivarius
DPC6487 exhibited a narrower spectrum of activity
in vitro
compared to the nisin A-producing
Lactococcus lactis
NZ9700. Nisin G-producing
S. salivarius
DPC6487 demonstrated the ability to control
F. nucleatum
DSM15643 in an
ex vivo
model colonic environment while exerting minimal impact on the surrounding microbiota. The production of this bacteriocin by a gut-derived
S. salivarius
, its narrow-spectrum activity, and its anti-
F. nucleatum
activity in a model colonic environment indicates that this strain merits further attention with a view to harnessing its probiotic potential.

IMPORTANCE

Fusobacterium nucleatum
is a human pathogen associated with intestinal conditions, including colorectal cancer, making it a potentially important therapeutic target. Bacteriocin-producing probiotic bacteria demonstrate the potential to target disease-associated taxa
in situ
in the gut. A gut-derived strain
Streptococcus salivarius
DPC6487 was found to demonstrate anti-
F
.
nucleatum
activity, which was attributable to a gene encoding a novel nisin variant designated nisin G. Nisin G-producing
S. salivarius
DPC6487 demonstrated the ability to control an infection of
F. nucleatum
in a simulated model of the human distal colon while exerting minimal impact on the surrounding microbiota. Here, we describe this nisin variant produced by
S. salivarius
, a species that is frequently a focus for probiotic development. The production of nisin G by a gut-derived
S. salivarius
, its narrow-spectrum activity against
F. nucleatum
, and its anti-
F
.
nucleatum
activity in a model colonic environment warrants further research to determine its probiotic-related applications.
Impact of postpartum exercise on pelvic floor disorders and diastasis recti abdominis: a systematic review and meta-analysis
Authors: Beamish Nicole F , Davenport Margie H , Ali Muhammad Usman , Gervais Matthew J , Sjwed Talia Noel , Bains Gyanjot , Sivak Allison , Deering Rita E , Ruchat Stephanie-May 
Published: December 2024

ObjectiveTo examine the effect of exercise during the first year postpartum on pelvic floor disorders and diastasis recti abdominis.DesignSystematic review with random effects meta-analysis.Data sources: MEDLINE, EMBASE, CINAHL, SPORTDiscuss, Evidence-Based Medicine Reviews (Ovid), Scopus, Web of Science and ClinicalTrials.gov were searched until 12 January 2024.Eligibility criteria for selecting studiesStudies of all designs (except case studies) and languages were included if they contained information on the Population (individuals in the first year postpartum), Intervention (subjective or objective measures of frequency, intensity, duration, volume or type of exercise alone (‘exercise-only’) or in combination with other intervention (eg, biofeedback; ‘exercise+co-intervention’)), Comparator (no exercise or different exercise measures) and Outcome (symptom severity and risk of urinary incontinence, anal incontinence, pelvic organ prolapse, diastasis recti abdominis and sexual function).Results65 studies (n=21 334 participants) from 24 countries were included. ‘Moderate’ certainty of evidence revealed that pelvic floor muscle training reduced the odds of urinary incontinence by 37% (seven randomised controlled trials (RCTs), n=1930; OR 0.63, 95% CI 0.41 to 0.97, I272%) and pelvic organ prolapse by 56% (one RCT, n=123; OR 0.44, 95% CI 0.21 to 0.91) compared with control groups. ‘Low’ certainty of evidence showed a greater reduction in inter-rectus distance measured at rest and during a head lift following abdominal muscle training compared with no exercise. Evidence on the effect of exercise on the risk of anal incontinence and diastasis recti abdominis, as well as the severity of anal incontinence, urinary incontinence, pelvic organ prolapse and sexual function, is limited.ConclusionEvidence supports the effectiveness of postpartum pelvic floor muscle training in reducing the odds of urinary incontinence and pelvic organ prolapse and postpartum abdominal exercise training in reducing inter-rectus distance.PROSPERO registration numberCRD42022359282.
Cost-effectiveness of integrating paediatric tuberculosis services into child healthcare services in Africa: a modelling analysis of a cluster-randomised trial
Authors: Mafirakureva Nyashadzaishe , Denoeud-Ndam Lise , Tchounga Boris Kevin , Otieno-Masaba Rose , Herrera Nicole , Mukherjee Sushant , Casenghi Martina , Tiam Appolinaire , Dodd Peter J 
Published: December 2024

BackgroundIn 2021, over one million children developed tuberculosis, resulting in 214 000 deaths, largely due to inadequate diagnosis and treatment. The diagnosis and treatment of tuberculosis is limited in most high-burden countries because services are highly centralised at secondary/tertiary levels and are managed in a vertical, non-integrated way. To improve case detection and treatment among children, the World Health Organisation (WHO) recommends decentralised and integrated tuberculosis care models. The Integrating Paediatric TB Services Into Child Healthcare Services in Africa (INPUT) stepped-wedge cluster-randomised trial evaluated the impact of integrating tuberculosis services into healthcare for children under five in Cameroon and Kenya, compared with usual care, finding a 10-fold increase in tuberculosis case detection in Cameroon but no effect in Kenya.MethodsWe estimated intervention impact on healthcare outcomes, resource use, health system costs and cost-effectiveness relative to the standard of care (SoC) using a decision tree analytical approach and data from the INPUT trial. INPUT trial data on cascades, resource use and intervention diagnostic rate ratios were used to parametrise the decision tree model. Health outcomes following tuberculosis treatment were modelled in terms of mortality and disability-adjusted life-years (DALYs).FindingsFor every 100 children starting antituberculosis treatment under SoC, an additional 876 (95% uncertainty interval (UI) −76 to 5518) in Cameroon and −6 (95% UI −61 to 96) in Kenya would start treatment under the intervention. Treatment success would increase by 5% in Cameroon and 9% in Kenya under the intervention compared with SoC. An estimated 350 (95% UI −31 to 2204) and 3 (95% UI −22 to 48) deaths would be prevented in Cameroon and Kenya, respectively. The incremental cost-effectiveness ratio for the intervention compared with SoC was US$506 and US$1299 per DALY averted in Cameroon and Kenya, respectively.InterpretationAlthough likely to be effective, the cost-effectiveness of integrating tuberculosis services into child healthcare services depends on baseline service coverage, tuberculosis detection and treatment outcomes.
Cerebral gas embolism and multifocal ischemic stroke during oxygen-ozone therapy: a case report
Authors: Khosravi Sepehr , Mirzaasgari Zahra 
Published: December 2024

IntroductionIschaemic stroke, primarily caused by thromboembolic events, typically arises as a consequence of underlying vascular or cardiac pathology. Non-thrombotic embolic strokes, although rare, are increasingly seen in interventional and intravascular procedures. Oxygen-ozone therapy (OOT) is one of the popular treatments for lumbar disc herniation, providing pain relief. However, it has been linked to gas embolisms, posing severe risks. This article details a case of cerebral gas embolism and multifocal acute ischaemic stroke that occurred during OOT for lumbar disc herniation pain relief.Case presentationWe present a case of a 58-year-old woman with acute onset limb weakness and speech disturbance that happened during a lumbar intradiscal oxygen-ozone injection session. Brain CT and MRI scans showed multiple cerebral gas embolisms and diffusion-restricted areas in both cerebral hemispheres. Echocardiography revealed a patent foramen ovale, hinting at a conduit for paradoxical embolism. Follow-up of the patient after 1 year showed significant improvement.ConclusionOOT, as a popular treatment for chronic pain, has been associated with severe adverse events. When facing cases of acute postoperative or postinterventional encephalopathy or stroke, arterial cerebral gas embolism should be considered a possibility. The presence of intracardiac defects or intrapulmonary shunts paves the way for paradoxical emboli to happen, resulting in a higher chance of neurological complications.
Long term exposure to ambient air pollution and hospital admission burden in Scotland: 16 year prospective population cohort study
Authors: Abed Al Ahad Mary , Demšar Urška , Sullivan Frank , Kulu Hill 
Published: December 2024

ObjectivesAir pollution is considered a major threat for global health and is associated with various health outcomes. Previous research on long term exposure to ambient air pollution and health placed more emphasis on mortality rather than hospital admission outcomes and was characterised by heterogeneities in the size of effect estimates between studies, with less focus on mental/behavioural or infectious diseases outcomes. In this study, we investigated the association between long term exposure to ambient air pollution and all cause and cause specific hospital admissions.DesignThis was a prospective cohort study.SettingIndividual level data from the Scottish Longitudinal Study (SLS) were linked to yearly concentrations of four pollutants (nitrogen dioxide (NO2), sulphur dioxide (SO2), particulate matter diameter ≤10 µm (PM10) and particulate matter diameter ≤2.5 µm (PM2.5)) at 1 km2spatial resolution using the individual’s residential postcode for each year between 2002 and 2017.ParticipantsThe study included 202 237 adult individuals aged ≥17 years.Outcome measuresThe associations between air pollution and all cause, cardiovascular, respiratory, infectious, mental/behavioural disorders and other cause hospital admissions were examined using multi-level, mixed effects, negative binomial regression.ResultsHigher exposure to NO2, PM10and PM2.5was associated with a higher incidence of all cause, cardiovascular, respiratory and infectious hospital admissions before adjusting for the area of residence, and in fully adjusted models when considering cumulative exposure across time. In fully adjusted models, the incidence rate for respiratory hospital admissions increased by 4.2% (95% CI 2.1% to 6.3%) and 1.2% (95% CI 0.8% to 1.7%) per 1 µg/m3increase in PM2.5and NO2pollutants, respectively. SO2was mainly associated with respiratory hospital admissions (incidence rate ratio (IRR)=1.016; 95% CI 1.004 to 1.027) and NO2was related to a higher incidence of hospital admissions for mental/behavioural disorders (IRR=1.021; 95% CI 1.011 to 1.031). Average cumulative exposure to air pollution showed stronger positive associations with higher rates of hospital admissions.ConclusionsThe results of this study support an association between long term (16 years) exposure to ambient air pollution and increased all cause and cause specific hospital admissions for both physical and mental/behavioural illnesses. The results suggest that interventions on air pollution through stricter environmental regulations could help ease the hospital care burden in Scotland in the long term.
Pathological findings at invasive assessment in MINOCA: a systematic review and meta-analysis
Authors: Fedele Damiano , Cavallo Daniele , Bodega Francesca , Suma Nicole , Canton Lisa , Ciarlantini Mariachiara , Ryabenko Khrystyna , Amicone Sara , Marinelli Virginia , Asta Claudio , Pastore Giuseppe , Casuso Alvarez Marcello , Belà Rebecca , Sansonetti Angelo , Angeli Francesco , Armillotta Matteo , Foà Alberto , Bergamaschi Luca , Paolisso Pasquale , Belmonte Marta , Rucci Paola , Barbato Emanuele , Pizzi Carmine 
Published: December 2024

BackgroundPathological mechanisms of myocardial infarction with non-obstructive coronary arteries (MINOCA) are heterogeneous, with an unknown impact on prognosis, and often remain unrecognised in clinical practice. This study aimed to evaluate the prevalence and prognostic impact of pathological findings by invasive coronary angiography (ICA), optical coherence tomography (OCT), and coronary function testing in MINOCA.MethodsStudies published until August 2023 were searched on PubMed and SCOPUS and included if reporting the prevalence of patients with non-obstructive coronary arteries (NObs-CA; 1–49% coronary stenosis) versus normal coronary arteries (NCA; 0% coronary stenosis) by ICA, pathological findings by OCT, and/or coronary vasomotor tests in MINOCA. Newcastle-Ottawa Scale was used for quality assessment. The pooled prevalence of pathological findings was estimated with random-effects models. Pooled risk ratios (RRs) with 95% CIs of all-cause death, MI and the composite of both in patients with NObs-CA versus NCA were calculated at short-term (<1 month), 1-year and long-term follow-up (> 1 year).ResultsForty-five studies including 17 539 patients were analysed. The pooled prevalence of NObs-CA at ICA was 53% (95% CI 0.47 to 0.60). OCT showed acute pathological findings in 62% (95% CI 0.44 to 0.78) of patients and coronary vasomotor tests were positive in 49% (95% CI 0.31 to 0.67). NObs-CA compared with NCA was associated with an increased 1-year risk of all-cause death or MI (RR=1.49 (95% CI 1.17 to 1.90)) and MI alone (RR=1.80 (95% CI 1.26 to 2.59)), whereas the risk of all-cause death was comparable. Similar results were seen at long-term, but not at short-term follow-up.ConclusionsStratification of MINOCA into NObs-CA versus NCA has prognostic value. OCT and vasospasm testing, often informative about the pathological mechanism of MINOCA, should be part of an invasive diagnostic algorithm.PROSPERO registration numberCRD42023468183
LKB1 dictates sensitivity to immunotherapy through Skp2-mediated ubiquitination of PD-L1 protein in non-small cell lung cancer
Authors: Lv Liting , Miao Qing , Zhan Sutong , Chen Peilin , Liu Wei , Lv Jiawen , Yan Wenjie , Wang Dong , Liu Hongbing , Yin Jie , Feng Jian , Song Yong , Ye Mingxiang , Lv Tangfeng 
Published: December 2024

BackgroundLoss-of-function mutations ofliver kinase B(LKB1, also termed asSTK11(serine/threonine kinase 11)) are frequently detected in patients with non-small cell lung cancer (NSCLC). TheLKB1mutant NSCLC was refractory to almost all the antitumor treatments, including programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) blockade therapy. Unfortunately, mechanisms underlying resistance to immunotherapy are not fully understood. In this study, we deciphered how LKB1 regulated sensitivity to anti-PD-1/PD-L1 immunotherapy.MethodsWe investigated the mutational landscape ofLKB1mutant NSCLC in next generation sequencing (NGS) data sets. Expression of LKB1, PD-L1 and S-phase kinase-associated protein 2 (Skp2) in NSCLC samples were assessed by immunohistochemistry (IHC). The tumor microenvironment (TME) profiling ofLKB1wild type (WT) and mutant NSCLC was performed using fluorescent multiplex IHC. Mass spectrometry and enrichment analysis were used to identify LKB1 interacting proteins. Mechanistic pathways were explored by immunoblotting, ubiquitination assay, cycloheximide chase assay and immunoprecipitation assay.ResultsBy using NGS data sets and histological approaches, we demonstrated that LKB1 status was positively associated with PD-L1 protein expression and conferred a T cell-enriched “hot” TME in NSCLC. Patients with good responses to anti-PD-1/PD-L1 immunotherapy possessed a high level of LKB1 and PD-L1. Skp2 emerged as the molecular hub connecting LKB1 and PD-L1, by which Skp2 catalyzed K63-linked polyubiquitination on K136 and K280 residues to stabilize PD-L1 protein. Inhibition of Skp2 expression by short hairpin RNA or its E3 ligase activity by compound #25 abrogated intact expression of PD-L1 in vitro and generated a T cell-excluded “cold” TME in vivo. Thus, the LKB1-Skp2-PD-L1 regulatory loop was crucial for retaining PD-L1 protein expression and manipulation of this pathway would be a feasible approach for TME remodeling.ConclusionLKB1 and Skp2 are required for intact PD-L1 protein expression and TME remodeling in NSCLC. Inhibition of Skp2 resulted in a conversion from “hot” TME to “cold” TME and abrogated therapeutic outcomes of immunotherapy. Screening LKB1 and Skp2 status would be helpful to select recipients who may benefit from anti-PD-1/PD-L1 immunotherapy.