Using a Fitbit-based Walking Game to Improve Physical Activity Among U.S. Veterans.

INTRODUCTION: Physical inactivity, hereafter inactivity, is a serious health problem among U.S. veterans, hereafter veterans. Inactive adults are at risk for adverse cardiac events and premature mortality. Specifically, among veterans, inactivity has been associated with a 23% increase in mortality. In order to increase physical activity among veterans, we developed Veterans Affairs (VA) MapTrek, a mobile-phone-based web app that allows users to take a virtual walk in interesting locations around the world while tracking their progress against that of others like themselves on an interactive map. Steps are counted by a commercially available Fitbit triaxial accelerometer, and users see their progress along a predefined scenic path overlaid on Google Maps. The objective of this study was to determine the effectiveness of VA MapTrek to increase physical activity in a population of veterans at risk for obesity-related morbidity. MATERIALS AND METHODS: We recruited overweight and obese veterans obtaining care at the Iowa City Veterans Affairs Health Center. Half of the veterans were assigned to participate in VA MapTrek. Each week, participants were assigned virtual walking races (Monday through Saturday), which followed a predetermined route that is displayed on Google Maps. The participant's position on the map is automatically updated each time their Fitbit syncs to their phone. In addition, challenges were issued periodically. Veterans in the control group were only given a Fitbit. We regressed daily step counts on the days of the week, the days since the start of the intervention period, whether the user was in the VA MapTrek or Control group, and an interaction between the study group and the days since the start of the intervention period. We included subject-specific random intercepts and subject-specific random slopes. This model was estimated using Bayesian Hamiltonian Monte Carlo using Stan's No-U-Turns sampler. We set vague, uniform priors on all the parameters. RESULTS: We enrolled 276 participants, but only 251 (102 in the control group and 149 in the VA MapTrek group) contributed data during the intervention period. Our analysis suggests an 86.8% likelihood that the VA MapTrek intervention led to a minimum increase of 1,000 daily steps over the 8-week period, compared to the control group. Throughout the 8-week intervention, we project that VA MapTrek participants would have taken an extra 96,627 steps, equivalent to 77.8 additional kilometers (km) (48.3 additional miles), assuming an average of 1,242 steps per km (2,000 steps per mile). CONCLUSIONS: Our study underscores the potential of VA MapTrek as an intervention for promoting walking among veterans who face elevated risks of obesity and cardiac issues. Rural veterans are a high-risk population, and new interventions like VA MapTrek are needed to improve veterans' health.

Neurodegenerative disorders: Mechanisms of degeneration and therapeutic approaches with their clinical relevance.

Neurodegenerative disorders (NDs) are expected to pose a significant challenge for both medicine and public health in the upcoming years due to global demographic changes. NDs are mainly represented by degeneration/loss of neurons, which is primarily accountable for severe mental illness. This neuronal degeneration leads to many neuropsychiatric problems and permanent disability in an individual. Moreover, the tight junction of the brain, blood-brain barrier (BBB)has a protective feature, functioning as a biological barrier that can prevent medicines, toxins, and foreign substances from entering the brain. However, delivering any medicinal agent to the brain in NDs (i.e., Multiple sclerosis, Alzheimer's, Parkinson's, etc.) is enormously challenging. There are many approved therapies to address NDs, but most of them only help treat the associated manifestations. The available therapies have failed to control the progression of NDs due to certain factors, i.e., BBB and drug-associated undesirable effects. NDs have extremely complex pathology, with many pathogenic mechanisms involved in the initiation and progression; thereby, a limited survival rate has been observed in ND patients. Hence, understanding the exact mechanism behind NDs is crucial to developing alternative approaches for improving ND patients' survival rates. Thus, the present review sheds light on different cellular mechanisms involved in NDs and novel therapeutic approaches with their clinical relevance, which will assist researchers in developing alternate strategies to address the limitations of conventional ND therapies. The current work offers the scope into the near future to improve the therapeutic approach of NDs.

Patient reported and functional outcome measures after surgical salvage procedures for posttraumatic radiocarpal osteoarthritis - a systematic review.

BACKGROUND: Posttraumatic wrist osteoarthritis is an irreversible and often progressive condition. Many surgical treatments, used in (daily) practice, aim to relieve symptoms like pain and restore function. The aim of this systematic review is to assess the patient reported and functional outcomes of the most common surgical interventions in patients with posttraumatic wrist osteoarthritis. This overview can help clinicians select the best treatment and manage patient's expectations. METHODS: A literature search was performed in Pubmed, Embase and Cochrane for articles published between 1990 and November 2022 according to the PRISMA guidelines. The study protocol has been registered in the PROSPERO database (CRD42017080427). Studies that describe patient reported outcomes (pain and Disability of Arm, Shoulder and Hand (DASH) -score) and functional outcomes (range of motion (ROM) and grip strength) after surgical intervention with a minimal follow-up of 1 year were included. The identified surgical procedures included denervation, proximal row carpectomy, interpositional- and total arthroplasty, and midcarpal-, radiocarpal- and total arthrodesis. The pre-and postoperative outcomes were pooled and presented per salvage procedure. RESULTS: Data from 50 studies was included. Pain score improved after all surgeries except denervation. Flexion/extension decreased after radiocarpal arthrodesis, did not show significant changes after proximal row carpectomy, and improved for all other surgeries. DASH score improved after arthroplasty, proximal row carpectomy and midcarpal arthrodesis. Grip strength improved after interposition arthroplasty and partial arthrodesis. CONCLUSION: Evidence from this review did not support the indication for denervation in this particular patient population. In patients with SLAC/SNAC II, proximal row carpectomy might be favourable to a midcarpal arthrodesis solely based on better FE ROM of the radiocarpal joint after proximal row carpectomy. In terms of radiocarpal mobility, total wrist arthroplasty might be preferred to radiocarpal arthrodesis in patients with osteoarthritis after a distal radius fracture. More uniform measurements of outcomes would improve the understanding of the effect of surgical treatments of the posttraumatic osteoarthritic wrist.

A workflow for targeted proteomics assay development using a versatile linear ion trap.

Advances in proteomics and mass spectrometry have enabled the study of limited cell populations, such as single-cell proteomics, where high-mass accuracy instruments are typically required. While triple quadrupoles offer fast and sensitive nominal resolution measurements, these instruments are effectively limited to targeted proteomics. Linear ion traps (LITs) offer a versatile, cost-effective alternative capable of both targeted and global proteomics. We demonstrate a workflow using a newly released, hybrid quadrupole-LIT instrument for developing targeted proteomics assays from global data-independent acquisition (DIA) measurements without needing high-mass accuracy. Gas-phase fraction-based DIA enables rapid target library generation in the same background chemical matrix as each quantitative injection. Using a new software tool embedded within EncyclopeDIA for scheduling parallel reaction monitoring assays, we show consistent quantification across three orders of magnitude of input material. Using this approach, we demonstrate measuring peptide quantitative linearity down to 25x dilution in a background of only a 1 ng proteome without requiring stable isotope labeled standards. At 1 ng total protein on column, we found clear consistency between immune cell populations measured using flow cytometry and immune markers measured using LIT-based proteomics. We believe hybrid quadrupole-LIT instruments represent an economic solution to democratizing mass spectrometry in a wide variety of laboratory settings.

Hybrid Quadrupole Mass Filter - Radial Ejection Linear Ion Trap and Intelligent Data Acquisition Enable Highly Multiplex Targeted Proteomics.

Targeted mass spectrometry (MS) methods are powerful tools for selective and sensitive analysis of peptides identified by global discovery experiments. Selected reaction monitoring (SRM) is currently the most widely accepted MS method in the clinic, due to its reliability and analytical performance. However, due to limited throughput and the difficulty in setting up and analyzing large scale assays, SRM and parallel reaction monitoring (PRM) are typically used only for very refined assays of on the order of 100 targets or less. Here we introduce a new MS platform with a quadrupole mass filter, collision cell, linear ion trap architecture that has increased acquisition rates compared to the analogous hardware found in the Orbitrap™ Tribrid™ series instruments. The platform can target more analytes than existing SRM and PRM instruments - in the range of 5000 to 8000 peptides per hour. This capability for high multiplexing is enabled by acquisition rates of 70-100 Hz for peptide applications, and the incorporation of real-time chromatogram alignment that adjusts for retention time drift and enables narrow time scheduled acquisition windows. Finally, we describe a Skyline external software tool that implements the building of targeted methods based on data independent acquisition chromatogram libraries or unscheduled analysis of heavy labeled standards. We show that the platform delivers ~10x lower LOQs than traditional SRM analysis for a highly multiplex assay and also demonstrate how analytical figures of merit change while varying method duration with a constant number of analytes, or by keeping a constant time duration while varying the number of analytes.

Dual Antiplatelet Therapy After Embolic Stroke of Undetermined Source: A Subgroup Analysis of the CHANCE-2 Trial.

BACKGROUND: The atherosclerotic sources of embolism are a significant contributor to embolic stroke of undetermined source (ESUS). However, there is limited evidence for the efficacy of intensive dual antiplatelet therapy for ESUS. We conducted an investigation to determine whether gene-directed dual antiplatelet therapy could reduce the risk of recurrent stroke in patients with ESUS. METHODS: CHANCE-2 (Clopidogrel in High-Risk Patients with Acute Nondisabling Cerebrovascular Events-II) was an investigator-initiated, multicenter, randomized, double-blind, placebo-controlled trial that objectively compared ticagrelor plus aspirin and clopidogrel plus aspirin in patients with minor stroke or transient ischemic attack who carried CYP2C19 loss-of-function alleles in China. All study participants were classified into ESUS and non-ESUS groups for the prespecified exploratory analysis. Cox proportional hazards models were used to assess the interaction of the state of ESUS with the effects of dual antiplatelet therapy with ticagrelor-aspirin versus clopidogrel-aspirin, adjusting for sociodemographic and clinical factors. RESULTS: The subgroup analysis comprised 5796 participants (90.4% of the total 6412 participants) in the CHANCE-2 trial, with a median age of 64.9 years (range, 57.0-71.4 years), of whom 1964 (33.9%) were female. These participants underwent diffusion-weighted imaging as part of the study protocol. After systematic evaluation, 15.2% of patients (881/5796) were deemed to have ESUS. The incidence of stroke recurrence in patients with ESUS was found to be 5.6% in the ticagrelor-aspirin group and 9.2% in the clopidogrel-aspirin group (hazard ratio, 0.57 [95% CI, 0.33-0.99]; P=0.04). In patients without ESUS, the respective incidence rates were 5.6% and 7.5% (hazard ratio, 0.72 [95% CI, 0.58-0.90]; P<0.01). The P value was 0.56 for the treatment × ESUS status interaction effect. CONCLUSIONS: In this prespecified exploratory analysis, ticagrelor with aspirin was superior to clopidogrel with aspirin for preventing stroke at 90 days in patients with acute ischemic stroke or transient ischemic attack who carried CYP2C19 loss-of-function alleles and were classified as ESUS. REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT04078737.

Characterisation of the Muscle Protein Synthetic Response to Resistance Exercise in Healthy Adults: A Systematic Review and Exploratory Meta-Analysis.

Methods: Five electronic databases (PubMed (Medline), Web of Science, Embase, Sport Discus, and Cochrane Library) were searched for controlled trials that assessed the MPS response to RE in healthy, adult humans, postabsorptive state. Individual study and random-effects meta-analysis arewere used to inform the effects of RE and covariates on MPS. Results from 79 controlled trials with 237 participants were analysed. Results: Analysis of the pooled effects revealed robust increases in MPS following RE (weighted mean difference (WMD): 0.032% h-1, 95% CI: [0.024, 0.041] % h-1, I2 = 92%, k = 37, P < 0.001). However, the magnitude of the increase in MPS was lower in older adults (>50 y: WMD: 0.015% h-1, 95% CI: [0.007, 0.022] % h-1, I2 = 76%, k = 12, P = 0.002) compared to younger adults (<35 y: WMD: 0.041% h-1, 95% CI: [0.030, 0.052] % h-1, I2 = 88%, k = 25, P < 0.001). Individual studies have reported that the temporal proximity of the RE, muscle group, muscle protein fraction, RE training experience, and the loading parameters of the RE (i.e., intensity, workload, and effort) appeared to affect the MPS response to RE, whereas sex or type of muscle contraction does not. Conclusion: A single bout of RE can sustain measurable increases in postabsorptive MPS soon after RE cessation and up to 48 h post-RE. However, there is substantial heterogeneity in the magnitude and time course of the MPS response between trials, which appears to be influenced by participants' age and/or the loading parameters of the RE itself.

Reproducibility in Radiomics: A Comparison of Feature Extraction Methods and Two Independent Datasets.

Radiomics involves the extraction of information from medical images that are not visible to the human eye. There is evidence that these features can be used for treatment stratification and outcome prediction. However, there is much discussion about the reproducibility of results between different studies. This paper studies the reproducibility of CT texture features used in radiomics, comparing two feature extraction implementations, namely the MATLAB toolkit and Pyradiomics, when applied to independent datasets of CT scans of patients: (i) the open access RIDER dataset containing a set of repeat CT scans taken 15 min apart for 31 patients (RIDER Scan 1 and Scan 2, respectively) treated for lung cancer; and (ii) the open access HN1 dataset containing 137 patients treated for head and neck cancer. Gross tumor volume (GTV), manually outlined by an experienced observer available on both datasets, was used. The 43 common radiomics features available in MATLAB and Pyradiomics were calculated using two intensity-level quantization methods with and without an intensity threshold. Cases were ranked for each feature for all combinations of quantization parameters, and the Spearman's rank coefficient, rs, calculated. Reproducibility was defined when a highly correlated feature in the RIDER dataset also correlated highly in the HN1 dataset, and vice versa. A total of 29 out of the 43 reported stable features were found to be highly reproducible between MATLAB and Pyradiomics implementations, having a consistently high correlation in rank ordering for RIDER Scan 1 and RIDER Scan 2 (rs > 0.8). 18/43 reported features were common in the RIDER and HN1 datasets, suggesting they may be agnostic to disease site. Useful radiomics features should be selected based on reproducibility. This study identified a set of features that meet this requirement and validated the methodology for evaluating reproducibility between datasets.

Cortico-limbic interactions and carotid atherosclerotic burden during chronic stress exposure.

BACKGROUND AND AIMS: Chronic stress associates with cardiovascular disease, but mechanisms remain incompletely defined. Advanced imaging was used to identify stress-related neural imaging phenotypes associated with atherosclerosis. METHODS: Twenty-seven individuals with post-traumatic stress disorder (PTSD), 45 trauma-exposed controls without PTSD, and 22 healthy controls underwent 18F-fluorodeoxyglucose positron emission tomography/magnetic resonance imaging (18F-FDG PET/MRI). Atherosclerotic inflammation and burden were assessed using 18F-FDG PET (as maximal target-to-background ratio, TBR max) and MRI, respectively. Inflammation was assessed using high-sensitivity C-reactive protein (hsCRP) and leucopoietic imaging (18F-FDG PET uptake in spleen and bone marrow). Stress-associated neural network activity (SNA) was assessed on 18F-FDG PET as amygdala relative to ventromedial prefrontal cortex (vmPFC) activity. MRI diffusion tensor imaging assessed the axonal integrity (AI) of the uncinate fasciculus (major white matter tract connecting vmPFC and amygdala). RESULTS: Median age was 37 years old and 54% of participants were female. There were no significant differences in atherosclerotic inflammation between participants with PTSD and controls; adjusted mean difference in TBR max (95% confidence interval) of the aorta 0.020 (-0.098, 0.138), and of the carotids 0.014 (-0.091, 0.119). Participants with PTSD had higher hsCRP, spleen activity, and aorta atherosclerotic burden (normalized wall index). Participants with PTSD also had higher SNA and lower AI. Across the cohort, carotid atherosclerotic burden (standard deviation of wall thickness) associated positively with SNA and negatively with AI independent of Framingham risk score. CONCLUSIONS: In this study of limited size, participants with PTSD did not have higher atherosclerotic inflammation than controls. Notably, impaired cortico-limbic interactions (higher amygdala relative to vmPFC activity or disruption of their intercommunication) associated with carotid atherosclerotic burden. Larger studies are needed to refine these findings.

BSP Implementation of Prevention and Treatment of Peri-implant Diseases - The EFP S3 Level Clinical Practice Guideline.

OBJECTIVES: to adapt the supranational European Federation of Periodontology (EFP) Prevention and Treatment of Peri-implant Diseases - The EFP S3 Level Clinical Practice Guideline for UK healthcare environment, taking into account a broad range of views from stakeholders and patients. SOURCES: This UK version, based on the supranational EFP guideline [1] published in the Journal of Clinical Periodontology, was developed using S3-level methodology, combining assessment of formal evidence from 13 systematic reviews with a moderated consensus process of a representative group of stakeholders, and accounts for health equality, environmental factors and clinical effectiveness. It encompasses 55 clinical recommendations for the Prevention and Treatment of Peri-implant Diseases, based on the classification for periodontal and peri-implant diseases and conditions [2]. METHODOLOGY: The UK version was developed from the source guideline using a formal process called the GRADE ADOLOPMENT framework. This framework allows for adoption (unmodified acceptance), adaptation (acceptance with modifications) and the de novo development of clinical recommendations. Using this framework, following the S3-process, the underlying evidence was updated and a representative guideline group of 111 delegates from 26 stakeholder organisations was assembled into four working groups. Following the formal S3-process, all clinical recommendations were formally assessed for their applicability to the UK and adoloped accordingly. RESULTS AND CONCLUSION: Using the ADOLOPMENT protocol, a UK version of the EFP S3-level clinical practice guideline for the Prevention and Treatment of Peri-implant Diseases was developed. This guideline delivers evidence- and consensus-based clinical recommendations of direct relevance to the UK healthcare community including the public. CLINICAL SIGNIFICANCE: The S3-level-guidelines combine evaluation of formal evidence, grading of recommendations and synthesis with clinical expertise of a broad range of stakeholders. The international S3-level-guideline was implemented for direct clinical applicability in the UK healthcare system, facilitating a consistent, interdisciplinary, evidence-based approach with public involvement for the prevention and treatment of peri-implant diseases.

Effects of Eimeria acervulina infection on the luminal and mucosal microbiota of the cecum and ileum in broiler chickens.

Coccidiosis, an intestinal disease caused by Eimeria parasites, is responsible for major losses in the poultry industry by impacting chicken health. The gut microbiota is associated with health factors, such as nutrient exchange and immune system modulation, requiring understanding on the effects of Eimeria infection on the gut microbiota. This study aimed to determine the effects of Eimeria acervulina infection on the luminal and mucosal microbiota of the cecum (CeL and CeM) and ileum (IlL and IlM) at multiple time points (days 3, 5, 7, 10, and 14) post-infection. E. acervulina infection decreased evenness in CeL microbiota at day 10, increased richness in CeM microbiota at day 3 before decreasing richness at day 14, and decreased richness in IlL microbiota from day 3 to 10. CeL, CeM, and IlL microbiota differed between infected and control birds based on beta diversity at varying time points. Infection reduced relative abundance of bacterial taxa and some predicted metabolic pathways known for short-chain fatty acid production in CeL, CeM, and IlL microbiota, but further understanding of metabolic function is required. Despite E. acervulina primarily targeting the duodenum, our findings demonstrate the infection can impact bacterial diversity and abundance in the cecal and ileal microbiota.

Tenecteplase versus standard of care for minor ischaemic stroke with proven occlusion (TEMPO-2): a randomised, open label, phase 3 superiority trial.

BACKGROUND: Individuals with minor ischaemic stroke and intracranial occlusion are at increased risk of poor outcomes. Intravenous thrombolysis with tenecteplase might improve outcomes in this population. We aimed to test the superiority of intravenous tenecteplase over non-thrombolytic standard of care in patients with minor ischaemic stroke and intracranial occlusion or focal perfusion abnormality. METHODS: In this multicentre, prospective, parallel group, open label with blinded outcome assessment, randomised controlled trial, adult patients (aged ≥18 years) were included at 48 hospitals in Australia, Austria, Brazil, Canada, Finland, Ireland, New Zealand, Singapore, Spain, and the UK. Eligible patients with minor acute ischaemic stroke (National Institutes of Health Stroke Scale score 0-5) and intracranial occlusion or focal perfusion abnormality were enrolled within 12 h from stroke onset. Participants were randomly assigned (1:1), using a minimal sufficient balance algorithm to intravenous tenecteplase (0·25 mg/kg) or non-thrombolytic standard of care (control). Primary outcome was a return to baseline functioning on pre-morbid modified Rankin Scale score in the intention-to-treat (ITT) population (all patients randomly assigned to a treatment group and who did not withdraw consent to participate) assessed at 90 days. Safety outcomes were reported in the ITT population and included symptomatic intracranial haemorrhage and death. This trial is registered with ClinicalTrials.gov, NCT02398656, and is closed to accrual. FINDINGS: The trial was stopped early for futility. Between April 27, 2015, and Jan 19, 2024, 886 patients were enrolled; 369 (42%) were female and 517 (58%) were male. 454 (51%) were assigned to control and 432 (49%) to intravenous tenecteplase. The primary outcome occurred in 338 (75%) of 452 patients in the control group and 309 (72%) of 432 in the tenecteplase group (risk ratio [RR] 0·96, 95% CI 0·88-1·04, p=0·29). More patients died in the tenecteplase group (20 deaths [5%]) than in the control group (five deaths [1%]; adjusted hazard ratio 3·8; 95% CI 1·4-10·2, p=0·0085). There were eight (2%) symptomatic intracranial haemorrhages in the tenecteplase group versus two (<1%) in the control group (RR 4·2; 95% CI 0·9-19·7, p=0·059). INTERPRETATION: There was no benefit and possible harm from treatment with intravenous tenecteplase. Patients with minor stroke and intracranial occlusion should not be routinely treated with intravenous thrombolysis. FUNDING: Heart and Stroke Foundation of Canada, Canadian Institutes of Health Research, and the British Heart Foundation.

Statistical Analysis Plan for the INTEnsive ambulance-delivered blood pressure Reduction in hyper-ACute stroke Trial (INTERACT4).

INTRODUCTION: Recruitment is complete in the fourth INTEnsive ambulance-delivered blood pressure Reduction in hyper-ACute stroke Trial (INTERACT4) is a multicenter, prospective, randomized, open-label, blinded endpoint assessed trial of pre-hospital blood pressure (BP) lowering initiated in the ambulance for patients with a suspected acute stroke and elevated BP in China. According to the registered and published trial protocol and developed by the blinded trial Steering Committee and Operations team, this manuscript outlines a detailed statistical analysis plan for the trial prior to database lock. METHODS: Patients were randomized (1:1) to intensive (target systolic BP [SBP] 130-140 mmHg within 30 minutes) or guideline-recommended BP management (BP lowering only considered if SBP >220 mmHg) group. Primary outcome is an ordinal analysis of the full range of scores on the modified Rankin scale at 90 days. A modified sample size of 2320 was estimated to provide 90% power to detect a 22% reduction in the odds (common odds ratio of 0.78) of a worse functional outcome using ordinal logistic regression, on the assumption of 5% patients with missing outcome and 6% patients with a stroke mimic. CONCLUSION: The statistical analysis plan for the trial has been developed to ensure transparent, verifiable, and prespecified analysis, and to avoid potential bias in the evaluation of the trial intervention.

Poxviridae Pneumonia.

Poxviridae family includes several viruses that infecting humans usually causes skin lesions only, but in some cases their clinical course is complicated by viral pneumonia (with or without bacterial superinfections). Historically variola virus has been the poxviridae most frequently associated with the development of pneumonia with many large outbreaks worldwide before its eradication in 1980. It is still considered a biological threat for its potential in biological warfare and bioterrorism. Smallpox pneumonia can be severe with the onset of acute respiratory distress syndrome (ARDS) and death. Vaccinia virus, used for vaccination against smallpox exceptionally, in immunocompromised patients, can induce generalized (with also lung involvement) severe disease after vaccination. MPXV virus occasionally can cause pneumonia particularly in immunocompromised patients. The pathophysiology of poxviridae pneumonia is still an area of active research; however, in animal models these viruses can cause both direct damage to the lower airways epithelium and a hyperinflammatory syndrome, like a cytokine storm. Multiple mechanisms of immune evasion have also been described. The treatment of poxviridae pneumonia is mainly based on careful supportive care. Despite the absence of randomized clinical trials in patients with poxviridae pneumonia there are antiviral drugs, such as tecovirimat, cidofovir and brincidofovir, FDA-approved for use in smallpox and also available under an expanded access protocol for treatment of MPXV. There are 2 (replication-deficient modified vaccinia Ankara and replication-competent vaccinia virus) smallpox vaccines FDA-approved with the first one also approved for prevention of MPXV in adults that are at high risk of infection.

Immediate- or Delayed-Intensive Statin in Acute Cerebral Ischemia: The INSPIRES Randomized Clinical Trial.

Importance: Comparisons are limited for immediate-intensive and delayed-intensive statin for secondary stroke prevention and neuroprotection in patients with acute mild ischemic stroke or transient ischemic attack (TIA) from atherosclerosis. Objective: To estimate whether immediate-intensive statin therapy is safe and can lower the risk of recurrent stroke compared with delayed-intensive statin in patients with acute mild ischemic stroke or high-risk TIA from atherosclerosis. Design, Setting, and Participants: The Intensive Statin and Antiplatelet Therapy for High-Risk Intracranial or Extracranial Atherosclerosis (INSPIRES) trial, a double-blind, placebo-controlled, 2 × 2 factorial, randomized clinical trial enrolled patients from September 2018 to October 2022. The trial was conducted at 222 hospitals in China. Patients aged 35 to 80 years with mild ischemic stroke or high-risk TIA of presumed atherosclerosis within 72 hours of symptom onset were assessed. Interventions: Patients were randomly assigned to receive immediate-intensive atorvastatin (80 mg daily on days 1-21; 40 mg daily on days 22-90) or 3-day delayed treatment (placebo for days 1-3, followed by placebo and atorvastatin, 40 mg daily on days 4-21, and then atorvastatin, 40 mg daily on days 22-90). Main Outcomes and Measures: The primary efficacy outcome was new stroke within 90 days, and a secondary efficacy outcome was poor functional outcome. Moderate to severe bleeding was the primary safety outcome. Results: A total of 11 431 patients were assessed for eligibility, and 6100 patients (median [IQR] age, 65 [57-71] years; 3915 men [64.2%]) were enrolled, with 3050 assigned to each treatment group. Within 90 days, new stroke occurred in 245 patients (8.1%) in the immediate-intensive statin group and 256 patients (8.4%) in the delayed group (hazard ratio, 0.95; 95% CI, 0.80-1.13). Poor functional outcome occurred in 299 patients (9.8%) and 348 patients (11.4%) in the immediate-intensive and delayed-intensive statin groups, respectively (odds ratio, 0.83; 95% CI, 0.71-0.98). Moderate to severe bleeding occurred in 23 of 3050 patients (0.8%) and 17 of 3050 patients (0.6%), in the immediate-intensive and delayed-intensive statin groups, respectively. Conclusions and Relevance: Immediate-intensive statin initiated within 72 hours did not reduce the risk of stroke within 90 days and may be associated with improved functional outcomes without significant difference in moderate to severe bleeding, compared with 3-day delayed-intensive statin in Chinese patients with acute mild ischemic stroke or TIA from atherosclerosis. Trial Registration: ClinicalTrials.gov Identifier: NCT03635749.

Psychosis as a disorder of muscarinic signalling: psychopathology and pharmacology.

Dopaminergic receptor antagonism is a crucial component of all licensed treatments for psychosis, and dopamine dysfunction has been central to pathophysiological models of psychotic symptoms. Some clinical trials, however, indicate that drugs that act through muscarinic receptor agonism can also be effective in treating psychosis, potentially implicating muscarinic abnormalities in the pathophysiology of psychosis. Here, we discuss understanding of the central muscarinic system, and we examine preclinical, behavioural, post-mortem, and neuroimaging evidence for its involvement in psychosis. We then consider how altered muscarinic signalling could contribute to the genesis and maintenance of psychotic symptoms, and we review the clinical evidence for muscarinic agents as treatments. Finally, we discuss future research that could clarify the relationship between the muscarinic system and psychotic symptoms.

Identifying Post-Acute Sequelae of SARS-CoV-2 Among Children in New York State Medicaid Managed Care.

Persons who contract COVID-19 are at risk of developing post-acute sequelae of SARS-CoV-2 (PASC). The objective of this study was to describe the incidence of PASC in a pediatric Medicaid population. Using a retrospective cohort of children enrolled in New York State Medicaid Managed Care we compared incident diagnoses between children with a positive laboratory test for SARS-CoV-2 in 2021 to children without a positive test in 2021 and children with a viral respiratory diagnosis in 2019. Logistic regression models estimated adjusted odds ratios using the Cohen's d statistic to assess the strength of associations. Most unadjusted incidence of clinical outcomes were less than 1% for all cohorts. Relative to the 2021 comparison cohort, significant increases among SARS-CoV-2 cases were observed in sequela of infectious disease conditions, general signs and symptoms, and pericarditis and pericardial disease and for the 2019 comparison, sequela of infectious disease conditions and suicidal ideation. However, associations were mostly determined to be weak or marginal. In this low socioeconomic status pediatric population, incidence of new clinical sequelae was low with mostly weak or marginal increases associated with SARS-CoV-2 infection. Though the incidence was low, some outcomes may be severe. Observed associations may have been impacted by pandemic behavior modification including social distancing policies.

Tapinarof Cream 1% Once Daily: Significant Efficacy in the Treatment of Moderate to Severe Atopic Dermatitis in Adults and Children Down to 2 Years of Age in the Pivotal Phase 3 ADORING Trials.

BACKGROUND: Tapinarof cream 1% once daily (QD), a topical aryl hydrocarbon receptor agonist, downregulates pro-inflammatory Th2 cytokines, upregulates skin-barrier components, and reduces oxidative stress. OBJECTIVE: To assess tapinarof efficacy and safety in adults and children down to 2 years of age with atopic dermatitis (AD). METHODS: 813 patients were randomized to tapinarof or vehicle QD in two 8-week phase 3 trials. RESULTS: The primary efficacy endpoint, Validated Investigator Global Assessment for Atopic DermatitisTM score of 0 or 1 and ≥2-grade improvement from baseline at Week 8, was met with statistical significance in both trials: 45.4% vs 13.9% and 46.4% vs 18.0% (tapinarof versus vehicle; both P<0.0001). Significantly superior EASI75 responses were also observed with tapinarof versus vehicle at Week 8: 55.8% vs 22.9% and 59.1% vs 21.2% (both P<0.0001). Rapid improvements in patient-reported pruritus were also significant with tapinarof versus vehicle. Common adverse events (≥5%) of folliculitis, headache, and nasopharyngitis were mostly mild or moderate, with lower discontinuations due to adverse events in the tapinarof groups than with vehicle. LIMITATIONS: Long-term efficacy was not assessed. CONCLUSION: Tapinarof demonstrated highly significant efficacy and favorable safety and tolerability in a diverse population of patients with AD down to 2 years of age.

Exploring the role of the ocular surface in the lung-eye axis: Insights into respiratory disease pathogenesis.

Chronic respiratory diseases (CRDs) represent a significant proportion of global health burden, with a wide spectrum of varying, heterogenic conditions largely affecting the pulmonary system. Recent advances in immunology and respiratory biology have highlighted the systemic impact of these diseases, notably through the elucidation of the lung-eye axis. The current review focusses on understanding the pivotal role of the lung-eye axis in the pathogenesis and progression of chronic respiratory infections and diseases. Existing literature published on the immunological crosstalk between the eye and the lung has been reviewed. The various roles of the ocular microbiome in lung health are also explored, examining the eye as a gateway for respiratory virus transmission, and assessing the impact of environmental irritants on both ocular and respiratory systems. This novel concept emphasizes a bidirectional relationship between respiratory and ocular health, suggesting that respiratory diseases may influence ocular conditions and vice versa, whereby this conception provides a comprehensive framework for understanding the intricate axis connecting both respiratory and ocular health. These aspects underscore the need for an integrative approach in the management of chronic respiratory diseases. Future research should further elucidate the in-depth molecular mechanisms affecting this axis which would pave the path for novel diagnostics and effective therapeutic strategies.