Effects of microgravity on neuromuscular control of the spine: a protocol for a systematic review and meta-analysis

Introduction
As spaceflight missions become more frequent and prolonged, the effects of microgravity on the musculoskeletal system represent a critical concern for astronauts’ health given their increased risk of spinal pain and injury. A better understanding of the adaptations induced by microgravity on neuromuscular control of the spine is essential to guide the development of effective countermeasures. Thus, this systematic review will aim to investigate the effects of microgravity on the neuromuscular control of the spine.

Methods and analysis
This protocol has been developed following the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols. MEDLINE, EMBASE, CINAHL, Web of Science, PubMed, grey literature and specialised space research resources will be searched from inception up to December 31, 2024. Screening processes, data extraction and risk of bias assessment will be conducted by two independent reviewers. Studies investigating the acute and long-term effects of microgravity on neuromuscular control of the spine will be included. Studies investigating spaceflight conditions or other protocols simulating microgravity, such as parabolic flights, dry immersion and long-term bed rest, will be considered eligible. Non-randomised studies of intervention with before-and-after design will represent the main studies of interest, and their risk of bias will be evaluated with the Risk Of Bias In Non-randomised Studies-of Interventions tool. Random-effect meta-analyses will be conducted for quantitative synthesis when clinical and methodological consistency is ensured. The certainty of evidence will be evaluated using the Grading of Recommendations, Assessment, Development and Evaluation guidelines.

Ethics and dissemination
As this systematic review is based on previously published studies, no ethical approval is required. The findings will be disseminated through publication in an international peer-reviewed journal and presented at conferences. All data relevant to the study will be included in the article or uploaded as supplementary information.

PROSPERO registration number
CRD42024608544.

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Promoting smoking cessation and preventing relapse to tobacco use following a smoke-free mental health inpatient stay (SCEPTRE feasibility study): a multicentre randomised controlled feasibility study protocol

Introduction
Thousands of patients with mental illness are admitted to acute adult mental health wards every year in England, where local guidance recommends that all mental health settings be entirely smokefree. Mental health Trusts presently invest substantial effort and resources to implement smoke-free policies and to deliver tobacco dependence treatment to patients. Providing adequate support can help those who smoke remain abstinent or quit smoking during their smoke-free inpatient stay and beyond. At present, little is known about how best to support patients to prevent their return to pre-admission smoking behaviours after discharge from a smoke-free mental health inpatient stay. We have developed an intervention which includes targeted resources to support smoking-related behaviour change in patients following discharge from a smoke-free mental health setting. The aim of this trial is to determine the feasibility of a large-scale clinical trial to test the effectiveness and cost-effectiveness of the SCEPTRE intervention, compared with usual care.

Methods and analysis
This feasibility study will be an individually randomised, controlled trial in eight National Health Service mental health Trusts recruiting adults (≥18 years) admitted to an acute adult mental health inpatient setting who smoke tobacco on admission, or at any point during their inpatient stay. Consenting participants will be randomised to receive a 12-week intervention consisting of components aimed at promoting or maintaining positive smoking-related behaviour change following discharge from a smoke-free mental health inpatient setting or usual care. Data will be collected at baseline, 3 months and a second timepoint between 4 and 6 months post-randomisation. With 64 participants (32 in each group), the trial will allow a participation rate of 15% and completion rate of 80% to be estimated within a 95% CI of ±3% and ±10%, respectively. The analysis will be descriptive and follow a prespecified plan.

Ethics and dissemination
Ethics approval was obtained from the North West—Greater Manchester West Research Ethics Committee. We will share results widely through local, national and international academic, clinical and patient and public involvement networks. The results will be disseminated through conference presentations, peer-reviewed journals and will be published on the trial website: https://sceptreresearch.com/.

Trial registration number
ISRCTN77855199.

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Correction: Differences in acute ischaemic stroke inhospital mortality across referral stroke hospitals in Spain: a retrospective, longitudinal observational study

Estupiñán-Romero F, Pinilla Dominguez J, BernalDelgado E, et al. Differences in acute ischaemic stroke inhospital mortality across referral stroke hospitals in Spain: a retrospective, longitudinal observational study. BMJ Open 2023;13:e068183. doi:10.1136/ bmjopen-2022-068183. This article has been corrected since it was published online. The funding statement has been updated from ‘This study was partially funded by grants from CONCEPT-STROKE: Effectiveness and efficiency of acute ischaemic stroke care pathways in five Spanish Regions (PI19/00154); REDISSEC: Red de Investigación en Servicios de Salud en Enfermedades Crónicas (RD16/0001/0007); and RICCAPS: Red de Investigación en cronicidad, atención primaria y promoción de la salud (RD21/0016/0023).’ to ‘This study was partially funded through the projects CONCEPT-STROKE: Effectiveness and efficiency of acute ischaemic stroke care pathways in five Spanish Regions (PI19/00154) REDISSEC: Red de Investigación en Servicios de Salud en Enfermedades Crónicas (RD16/0001/0007) and RICCAPS: Red de Investigación en cronicidad, atención primaria y promoción de la salud…

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Restrictive Versus A Liberal Transfusion Strategy in Patients With Spontaneous Intracerebral Hemorrhage: A Secondary Analysis of TRAIN Randomized Clinical Trial

Stroke, Ahead of Print. BACKGROUND:Red blood cell transfusions are commonly administered to anemic patients with spontaneous intracerebral hemorrhage (ICH); however, the optimal hemoglobin threshold to initiate transfusion is uncertain in this population. Therefore, we aimed to assess the impact of 2 different hemoglobin thresholds to guide transfusion on the neurological outcome of anemic critically ill patients with ICH.METHODS:This is a secondary analysis of a prospective, multicenter, phase 3 randomized study conducted in 72 intensive care units across 22 countries from 2017 to 2022. Eligible patients for the original trial had an acute brain injury, hemoglobin values ≤9 g/dL within the first 10 days after admission, and an expected intensive care unit stay of at least 72 hours; in this study, only patients with spontaneous ICH were assessed. Patients were randomly assigned to undergo a restrictive (transfusion triggered by hemoglobin ≤7 g/dL) or a liberal (transfusion triggered by hemoglobin ≤9 g/dL) strategy over a 28-day period. The primary outcome was the occurrence of an unfavorable neurological outcome, defined as a Glasgow Outcome Scale Extended score of 1 to 5, at 180 days following randomization.RESULTS:A total of 144 patients with spontaneous ICH were analyzed: 45.8% of them were male, with a mean age of 58.4 (SD, 13.4). Mean Glasgow Coma Scale on admission was 7.3 (SD, 3.3), and 75.7% of patients had a volume of hematoma >30 mL. Among all patients, 73 were randomized to the restrictive transfusion strategy, while 71 to the liberal one. Baseline characteristics were comparable between the 2 groups. At 180 days after randomization, patients assigned to the liberal transfusion strategy had a nonsignificant decrease in the probability of unfavorable neurological outcome (71.8 versus 84.7%; risk ratio, 0.85 [95% CI, 0.71–1.01];P=0.06). Also, the occurrence of the composite outcome (mortality and organ failure at day 28) was significantly lower in the liberal group (71.8% versus 87.7%, risk ratio, 0.82 [95% CI, 0.69–0.97];P=0.02).CONCLUSIONS:A liberal transfusion strategy was associated with a lower risk of mortality and organ failure, but not of unfavorable outcome in patients presenting with spontaneous ICH, compared with a restrictive strategy. However, the study cohort might have been underpowered to detect clinically relevant differences between the 2 interventions.

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Incidence and predictors of mortality among children with severe acute malnutrition admitted to therapeutic feeding units in Ethiopia: a systematic review and meta-analysis

Objective
To estimate the mortality rate and identify predictors of mortality among under-five children with severe acute malnutrition (SAM) admitted to therapeutic feeding units (TFUs) in Ethiopia.

Methods
We searched PubMed, HINARI, Science Direct, Google Scholar and African Journals Online from 1 March to 30 May 2024. The Joanna Briggs Institute checklist was used to appraise the included studies. Heterogeneity was identified using I2 statistics. Funnel plots and Egger’s tests were used to determine publication bias.

Results
Out of 1085 studies, 15 were included in this analysis. The pooled mortality rate among under-five children with SAM admitted to TFUs in Ethiopia was 8.32 per 1000 person-days of observation (95% CI: 6.25 to 11.06). The mortality rate has not changed over time. HIV infection (HR: 2.84; 95% CI: 1.25 to 6.42), tuberculosis (HR: 1.86; 95% CI: 1.35 to 2.56), intravenous fluid use (HR: 3.37; 95% CI: 2.39 to 4.75), altered body temperature (HR: 4.47; 95% CI: 1.90 to 10.51), impaired consciousness (HR: 2.91; 95% CI: 1.94 to 4.37), not receiving F-100 supplementation (HR: 4.51; 95% CI: 3.25 to 6.26), shock (HR: 4.20; 95% CI: 2.92 to 6.04), and nasogastric tube feeding (HR: 2.02; 95% CI: 1.67 to 2.44) were predictors of mortality.

Conclusion
The pooled mortality rate in Ethiopia was 8.32 per 1000 person-days, and it has not decreased over time. Most of the identified factors are related to comorbidities and complications of SAM, as well as nutritional therapy. Thus, it is essential to strengthen nutrition policies, programme implementation and healthcare services, which focus on the timely management of SAM complications, integrated care for comorbidities and improved F-100 supplementation.

PROSPERO registration number
CRD42024555014.

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Inactivation of RhoA for Hypertension Treatment Through the TRPV4–RhoA–RhoGDI1 Axis

Circulation, Ahead of Print. BACKGROUND:The RhoA (Ras homolog family member A) signaling pathway is pivotal in regulating vascular smooth muscle cells (VSMCs) function and blood pressure homeostasis. Current inhibitors of the RhoA signaling pathway are limited in hypertension treatment, suffering from poor efficacy, insufficient specificity, and developmental challenges.METHODS:Cryo-electron microscopy (EM), proximity ligation assay (PLA), and site-directed mutagenesis were used to explore the mechanism of RhoA activity regulation. VSMC, hypertensive animal models,Trpv4-/-andArhgdiaf/fMyh11-CREERT2(smooth muscle–specific RhoGDI1 knockout) mice were used to investigate the role of the TRPV4 (transient receptor potential cation channel subfamily V member 4)–RhoA–RhoGDI1 (Rho GDP dissociation inhibitor 1) axis in hypertension.RESULTS:AH001 ((R)-1-(3-ethylphenyl) ethane-1,2-diol) was identified as a novel inhibitor of the RhoA signaling pathway. It targets the TRPV4–RhoA–RhoGDI1 axis to effectively sequester inactive RhoA–GDP in the plasma membrane and cytoplasm, which is distinct from typical RhoA inhibition modes. The cryo-EM structure of the TRPV4AH001–RhoA complex showed that AH001-bound TRPV4 adopts a closed state with RhoA in an inactive GDP-bound state. Functional studies further revealed that AH001 reduced the pool of active RhoA by enhancing TRPV4–RhoA binding and facilitating RhoGDI1–RhoA interaction in VSMC. This inhibition notably decreased both acute and long-term blood pressure and prevented vascular remodeling in Ang II–induced hypertensive mice and spontaneously hypertensive rats. However, these antihypertensive effects were weakened inTrpv4-/-andArhgdiaf/fMyh11-CREERT2mice. Additionally, AH001 effectively inhibited VSMC contraction via the RhoA/ROCK (Rho-associated protein kinase)/MYPT1 (myosin phosphatase target subunit 1)/MLC (myosin light chain 2) signaling pathway and suppressed VSMC phenotype switching to myofibroblasts through the RhoA/ROCK/LIMK1 (LIM domain kinase)/cofilin/MRTF-A (myocardin-related transcription factor A)/SRF (serum response factor) signaling cascade. TRPV4 and RhoGDI1 knockdown attenuated AH001’s inhibition of VSMC contraction and phenotypic switching to myofibroblasts.CONCLUSIONS:This study revealed a novel mode of RhoA signaling inhibition targeting the TRPV4–RhoA–RhoGDI1 axis, offering new insights for future antihypertensive drug development and proposing innovative strategies for targeting challenging Rho GTPases.

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Effect of Remote Ischemic Preconditioning on Myocardial Injury in Noncardiac Surgery: the PRINCE Randomized Clinical Trial

Circulation, Ahead of Print. Background: Major noncardiac surgery carries high rates of postoperative myocardial injury and other complications. Remote ischemic preconditioning (RIPC) was reported to decrease these complications. However, such supportive evidence lacks robustness.Methods: In a multinational, double-blind trial, we randomly assigned adult high-risk patients undergoing noncardiac surgical procedures to receive RIPC or sham-RIPC after the induction of general anesthesia and before surgery. RIPC involved three 5-minute ischemic cycles, each followed by 5 minutes of reperfusion, using a blood-pressure cuff inflated to 200 mmHg. The primary endpoint was the rate of myocardial injury defined by an increase in postoperative troponin levels above the highest 99th percentile of reference values. Secondary outcomes included myocardial infarction, stroke, acute kidney injury, need for intensive care unit, length of hospital stay and 30-day all-cause mortality.Results: We recruited 1213 patients in 25 hospitals and 8 countries. We randomly assigned 599 to RIPC and 614 to sham-RIPC. The most frequent surgical procedures were abdominal and intrathoracic surgeries (406 patients, 33.6%). RIPC was applied to the upper limb in 1,014 patients (84.8%) and to the lower limb in 182 patients (15.2%). Postoperative myocardial injury occurred in 215/566 patients (38.0%) in the RIPC group and in 223/596 patients (37.4%) in the sham-RIPC group (relative risk, 1.02; 95% confidence interval, 0.88 to 1.18;P=0.84). There were no significant differences in the rate of any secondary outcomes. We observed eleven episodes of limb petechiae (10 [1.7%] in the RIPC group vs 1 [0.2%] in the sham-RIPC group) and 34 (6.0%) hospital readmissions in the RIPC group vs 20 (3.5%) in the sham-RIPC group.Conclusions: Among adult patients undergoing noncardiac surgery, RIPC did not reduce myocardial injury or other postoperative complications.

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Protocol for a prospective cohort study to determine the multimodal biomarkers of delirium and new dementia after acute illness in older adults: ORCHARD-PS

Introduction
Delirium is common in the older hospital population and is often precipitated by acute illness. Delirium is associated with poor outcomes including subsequent cognitive decline and dementia and may therefore be a modifiable risk factor for dementia. However, the mechanisms underpinning the delirium–dementia relationship and the role of coexisting acute illness factors remain uncertain. Current biomarker studies of delirium have limitations including lack of detailed delirium characterisation with few studies on neurodegenerative or neuroimaging biomarkers especially in the acute setting. The Oxford and Reading Cognitive Health After Recovery from acute illness and Delirium—Prospective Study (ORCHARD-PS) aims to elucidate the pathophysiology of delirium and subsequent cognitive decline after acute illness in older adults, through acquisition of multimodal biomarkers for deep phenotyping of delirium and acute illness, and follow-up for incident dementia.

Methods and analysis
ORCHARD-PS is a bi-centre, prospective cohort study. Consecutive eligible patients requiring acute hospital admission or assessment are identified by the relevant acute clinical care team. All patients age >65 years without advanced dementia, nursing home residence, end-stage frailty or terminal illness are eligible. Details of potential participants are communicated to the research team and written informed consent or consultee agreement is obtained. Participants are interviewed as soon as possible after admission/assessment using a structured proforma.
Data are collected on demographics, diagnosis and comorbidities, social and functional background. Delirium is assessed using the 4A’s test, Confusion Assessment Method (long-form), Observational Scale of Level of Arousal, Richmond Agitation-Sedation Scale and Memorial Delirium Assessment Scale and diagnosed using the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition criteria. Delirium is categorised by time of onset (prevalent vs incident), dementia status, motoric subtype, severity and duration. Cognitive tests include the 10-point Abbreviated Mental Test and Montreal Cognitive Assessment. Participants are reassessed every 48–72 hours if remaining in hospital. Informant questionnaire data and interview are supplemented by hand searching of medical records and linkage to electronic patient records for nursing risk assessments, vital observations, laboratory results and International Classification of Diseases, Tenth Revision diagnostic and procedure codes.
In-person follow-up with more detailed cognitive testing and informant interview is undertaken at 3 months, and 1 and 3 years supplemented with indirect follow-up using medical records. Blood banking is performed at baseline and all follow-ups for future biomarker analyses. CT-brain and MRI-brain imaging acquired as part of standard care is obtained for quantification of brain atrophy and white matter disease/stroke supplemented by research CT-brain imaging. Outcomes include length of hospitalisation, change in care needs, institutionalisation, mortality, readmission, longitudinal changes in cognitive and functional status and incident dementia. Biomarker associations with delirium, and with incident dementia on follow-up, will be determined using logistic or Cox regression as appropriate, unadjusted and adjusted for covariates including demographics, baseline cognition, frailty, comorbidity and apolipoprotein E genotype.

Ethics and dissemination
ORCHARD-PS is approved by the South Central—Berkshire Research Ethics Committee (REC Reference: 23/SC/0199). Results will be disseminated through peer-reviewed publications and conference presentations.

Trial registration number
ISRCTN24171810.

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Comparison of elective hemicolectomy patients before and after establishment of a preoperative anaesthesia assessment clinic: a retrospective, observational study in a hospital in Norway

Objectives
To compare outcome data of hemicolectomy patients before and after the establishment of a preoperative anaesthesia assessment clinic (PAC).

Design
This observational study was conducted retrospectively through an electronic health record review covering periods before (2014–2017) and after (2017–2022) the PAC was established.

Setting
An acute care hospital in Norway.

Participants
A total of 612 patients undergoing elective open or laparoscopic hemicolectomy were included, of whom 338 (55.2%) had attended the PAC.

Primary and secondary outcome measures
The primary outcome was the rate of cancellation of planned surgeries, and the secondary outcomes were length of hospital stay (LOS), unanticipated intraoperative anaesthesia-related events and the presence of documentation relevant to the planning of anaesthesia in the patient’s medical records preoperatively.

Results
Compared with the after-PAC cohort, the before-PAC cohort was numerically more likely to have their planned surgery cancelled (OR=1.97, 95% CI (0.84 to 4.61); p=0.12). The before-PAC cohort also had a numerically lower rate of unanticipated intraoperative anaesthesia-related events (18.6%) than the after-PAC cohort (22.5%; p=0.240). However, neither of these differences was statistically significant. Median LOS was significantly shorter in the after-PAC cohort (4.79 days, IQR (3.80–6.12)) than in the before-PAC cohort (5.16 days (4.09–7.18); p=0.001). Moreover, the presence of documentation relevant to the planned anaesthesia in the medical records was significantly more common for after-PAC patients.

Conclusions
The establishment of the PAC reduced the rate of planned surgery cancellations but increased the rate of recorded intraoperative anaesthesia events. Patients who attended the PAC had a significantly shorter LOS and more anaesthesia-related information in their medical records.

Trial registration number
NCT05520229.

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