Gait Rehabilitation for Early rheumatoid Arthritis Trial (GREAT): lessons learnt from a mixed-methods feasibility study and internal pilot trial

Background: People with rheumatoid arthritis experience foot and lower limb pain due to active synovitis, resulting in impaired lower limb function. Earlier intervention may help with prevention of functional decline. The aims of this research were to develop and evaluate a new gait rehabilitation intervention for people with early rheumatoid arthritis, evaluate its feasibility, and to test whether or not gait rehabilitation plus usual care is more clinically and cost-effective than usual care alone. Design and methods: We undertook a single-arm, repeated measures, pre- and post-intervention, mixed methods feasibility study with embedded qualitative components. We planned to undertake a pragmatic, two-arm, multi-centre, superiority randomised controlled trial, with health economic evaluation, process evaluation, and internal pilot. Setting and participants: Participants with early rheumatoid arthritis (<2 years post-diagnosis) were identified from early arthritis and rheumatology outpatient clinics and referred for intervention in either podiatry or physiotherapy clinics. Intervention(s): Participants were randomised to a gait rehabilitation programme (GREAT Strides) involving a 6-task gait circuit. Sessions were underpinned by motivational interviewing to facilitate behaviour change, supported by trained physiotherapists or podiatrists for a minimum of two sessions. Both groups received their normal usual care from the rheumatology multidisciplinary team. Main outcome measures: Outcome measures for the feasibility study were intervention acceptability, adherence using the Exercise Adherence Rating Scale (EARS) and fidelity using the Motivational Interviewing Treatment Integrity Scale (MITI). The main outcome measure for the internal pilot/RCT was the Foot Function Index disability subscale. Outcomes were measured at baseline, 3-months, 6-months and 12-months. Other outcomes: intervention acceptability questionnaire (IAQ), EARS, exercise treatment beliefs via the Theory of Planned Behaviour Questionnaire, intervention fidelity (MITI), health-related quality of life (EQ5D-5L). Results: Thirty-five participants were recruited for feasibility and 23 (65.7%) completed 12-week follow-up. Intervention acceptability was excellent; 21/23 were confident that it could help and would recommend it; 22/23 indicated it made sense to them. Adherence was good, with a median [IQR] EARS score of 17/24 [12.5–22.5]. Twelve participants’ and 9 therapists’ interviews confirmed intervention acceptability, identified perceptions of benefit, but highlighted some barriers to completion. MITI scores demonstrated good fidelity. The trial did not progress from internal pilot to full main trial as a result of low recruitment and high attrition, after fifty-three participants were recruited from nine sites over 12-months. Process evaluation confirmed good intervention acceptability and adherence, and fair fidelity. Evaluation of clinical and cost-effectiveness was not possible. Limitations: Significant delays were experienced with the impact of COVID-19, regulatory approvals, contracts, and site readiness, resulting in few sites opening in time and low recruitment capacity. Foot and/or ankle pain prevalence was lower than anticipated, resulting in a low potential participant pool and a low conversion rate from screening to enrolment. Conclusions: The GREAT Strides intervention was acceptable to people with early RA and intervention clinicians, safe, with good levels of adherence by participants, and fair intervention fidelity. The RCT stopped early following failure to meet recruitment targets. GREAT Strides is a promising intervention that could be adapted for future evaluations. A definitive trial of the GREAT Strides gait rehabilitation intervention still needs to be done. Study registration: ISRCTN (International Standard Randomised Controlled Trial Number) registry as ISRCTN14277030. Funding details: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme (15/165/04)

Antibiotic Use in Pediatric Care in Ghana: A Call to Action for Stewardship in This Population

Background/Objectives: Antibiotic use is common among hospitalized pediatric patients. However, inappropriate use, including excessive use of Watch antibiotics, can contribute to antimicrobial resistance, adverse events, and increased healthcare costs. Consequently, there is a need to continually assess their usage among this vulnerable population. This was the objective behind this study. Methods: The medical records of all pediatric patients (under 12 years) admitted and treated with antibiotics at a Ghanaian Teaching Hospital between January 2022 and March 2022 were extracted from the hospital’s electronic database. The prevalence and appropriateness of antibiotic use were based on antibiotic choices compared with current guidelines. Influencing factors were also assessed. Results: Of the 410 admitted patients, 319 (77.80%) received at least one antibiotic. The majority (68.65%; n = 219/319) were between 0 and 2 years, and males (54.55%; n = 174/319). Ceftriaxone was the most commonly prescribed antibiotic (20.69%; n = 66/319), and most of the systemic antibiotics used belonged to the WHO Access and Watch groups, including a combination of Access and Watch groups (42.90%; n = 136/319). Neonatal sepsis (24.14%; n = 77/319) and pneumonia (14.42%; n = 46/319) were the most common diagnoses treated with antibiotics. Antibiotic appropriateness was 42.32% (n = 135/319). Multivariate analysis revealed ceftriaxone prescriptions (aOR = 0.12; CI = 0.02–0.95; p-value = 0.044) and surgical prophylaxis (aOR = 0.07; CI = 0.01–0.42; p-value = 0.004) were associated with reduced antibiotic appropriateness, while a pneumonia diagnosis appreciably increased this (aOR = 15.38; CI = 3.30–71.62; p-value < 0.001). Conclusions: There was high and suboptimal usage of antibiotics among hospitalized pediatric patients in this leading hospital. Antibiotic appropriateness was influenced by antibiotic type, diagnosis, and surgical prophylaxis. Targeted interventions, including education, are needed to improve antibiotic utilization in this setting in Ghana and, subsequently, in ambulatory care

Heterologous COVID-19 vaccine schedule with protein-based prime (NVX-CoV2373) and mRNA boost (BNT162b2) induces strong humoral responses: Results from COV-BOOST trial

BACKGROUND: Heterologous schedules of booster vaccines for COVID-19 following initial doses of mRNA or adenoviral vector vaccines have been shown to be safe and immunogenic. There are few data on booster doses following initial doses of protein nanoparticle vaccines. METHODS: Participants of the phase 3 clinical trial of the COVID-19 vaccine NVX-CoV2373 (EudraCT 2020-004123-16) enroled between September 28 and November 28, 2020, who received 2 doses of NVX-CoV2373 administered 21 days apart were invited to receive a third dose booster vaccine of BNT162b2 (wild type mRNA vaccine) as a sub-study of the COV-BOOST clinical trial, and were followed up for assessment of safety, reactogenicity and immunogenicity to day 242 post-booster. RESULTS: The BNT162b2 booster following two doses of NVX-COV2373 was well-tolerated. Most adverse events were mild to moderate, with no serious vaccine-related adverse events reported. Immunogenicity analysis showed a significant increase in spike IgG titres and T-cell responses post-third dose booster. Specifically, IgG levels peaked at day 14 with a geometric mean concentration (GMC) of 216,255 ELISA laboratory units (ELU)/mL (95% CI 191,083-244,743). The geometric mean fold increase from baseline to day 28 post-boost was 168.6 (95% CI 117.5-241.8). Spike IgG titres were sustained above baseline levels at day 242 with a GMC of 58,686 ELU/mL (95% CI 48,954-74,652), with significant decay between days 28 and 84 (geometric mean ratio 0.58, 95% CI 0.53-0.63). T-cell responses also demonstrated enhancement post-booster, with a geometric mean fold increase of 5.1 (95% CI 2.9-9.0) at day 14 in fresh samples and 3.0 (95% CI 1.8-4.9) in frozen samples as measured by ELISpot. In an exploratory analysis, participants who received BNT162b2 after two doses of NVX-COV2373 exhibited higher anti-spike IgG at Day 28 than those who received homologous three doses of BNT162b2, with a GMR of 5.02 (95% CI: 3.17-7.94). This trend remained consistent across all time points, indicating a similar decay rate between the two schedules. CONCLUSIONS: A BNT162b2 third dose booster dose in individuals primed with two doses of NVX-COV2373 is safe and induces strong and durable immunogenic responses, higher than seen in other comparable studies. These findings support the use and investigation of heterologous booster strategies and early investigation of heterologous vaccine technology schedules should be a priority in the development of vaccines against new pathogens

Real-world effectiveness study of guideline-directed COPD STANDARDized management in patients with chronic obstructive pulmonary disease: a cluster randomised trial design

Introduction Chronic obstructive pulmonary disease (COPD) affects the ageing population worldwide. Exacerbations worsen health status and increase health resource use. Existing guidelines recommend disease management, but they are not fully implemented in a clinical setting. Evidence regarding best practice and real-world effectiveness is limited. Methods and analysis A nationwide multicentre clinical effectiveness trial is being performed between 2023 and 2027, involving 99 secondary hospitals in urban and rural areas in China. It is an open-label, adjudicator and assessor-blinded, parallel group, cluster randomised pragmatic trial. Hospitals are randomly allocated to standardised management (SM) or usual care. A total number of 3456 stable patients with COPD who are symptomatic (individuals in the Global Initiative for Chronic Obstructive Lung Disease (GOLD) Group B) or have exacerbation risk (individuals with one moderate exacerbation history in Group A and individuals in Group E) using GOLD 2023 ABE classification will be enrolled. In the SM group, an integrated intervention comprising five components will be delivered using a physician and nurse model. These are: (1) long-term inhaled maintenance therapy, (2) periodic inhaler technique assessment and symptom monitoring, (3) annual pulmonary function testing, (4) COPD education session and (5) health behaviour adoption (smoking cessation, vaccination, pulmonary rehabilitation). In the control group, patients will receive routine care. The primary goal is to assess the real-world effectiveness of guideline-directed disease management on exacerbation prevention, with moderate-to-severe exacerbation as the primary outcome and hospital admission, mortality, health status and COPD self-management as secondary outcomes. It is the first pragmatic trial undertaken of this form in a developing country. It is anticipated that it will provide a feasible and effective COPD management model that can inform guidelines and be rolled out into secondary and primary care, with modification, to ensure standardised COPD care nationwide. Trial registration number NCT04664491

Proliferation makes a substantive contribution to the maintenance of airway resident memory T-cell subsets in young pigs

Tissue-resident memory (TRM) T cells play an important role in protection against respiratory infection but whether this memory is maintained by long-lived or dividing cells remains controversial. To address the rate of division of lung TRM T cells, deuterium-enriched water was administered orally to young pigs to label dividing lymphocytes. T-cell subsets were separated from blood, lymph nodes, and airways [bronchoalveolar lavage (BAL)], the latter comprising almost exclusively TRM. We show that, as in other species, circulating memory T-cell subsets divide more rapidly than naïve T cells. Rates of labelling of memory subsets were similar in blood and lymph nodes, consistent with the rapid and free exchange. Strikingly, the fraction of label in BAL was similar to those in blood/lymph nodes after 5–21 days of labelling, suggesting replacement with recently divided cells, but this was preceded at Day 2 by a phase when labelling was lower in BAL than blood/lymph node in some memory subsets. Our data exclude long-lived TRM as the source of BAL memory cells leaving three possible hypotheses: blood/airway exchange, in situ proliferation, or proliferation in the lung interstitium followed by migration to BAL. When considered in the context of other information, we favour the latter interpretation. These results indicate the dynamic nature of memory in the lung and have implications for harnessing immune responses against respiratory pathogens

Is parvovirus B19 infection upsurge in 2023–2024 associated with adverse pregnancy outcome?

Objective A surge in parvovirus B19 infections has been reported in 2023–2024 across Europe and the USA, raising concerns about the associated perinatal risks. The aim of this study was to compare perinatal outcomes following maternal parvovirus B19 infection during the 2023–2024 period with those from a pre‐2023 cohort. Methods This multicenter, retrospective cohort study compared perinatal outcomes in women with maternal parvovirus B19 infection according to whether infection occurred pre‐2023 (2012–2022) or between 2023 and 2024. Pregnant women with confirmed parvovirus B19 infection were eligible for inclusion. Cases were excluded if they had incomplete records, an ongoing pregnancy, coinfection with cytomegalovirus or Epstein–Barr virus, pre‐existing structural or genetic abnormality, immune fetal hydrops or a maternal serology result not indicative of parvovirus B19 infection. The primary outcome was perinatal mortality, which was defined as intrauterine fetal death ≥ 20 weeks' gestation or neonatal death ≤ 28 days after delivery. The secondary outcomes were persistent fetal anemia requiring more than one intrauterine transfusion (IUT) and a composite adverse perinatal outcome (CAPO), defined as the presence of one or more adverse outcomes, including perinatal mortality, pregnancy loss < 20 weeks, new‐onset structural anomaly and termination of pregnancy owing to parvovirus‐related morbidity. Differences between the two groups were assessed using standard statistical tests, and a generalized linear mixed model was used to identify predictors of perinatal mortality in the 2023–2024 cohort. Results Following exclusions, 140 cases from pre‐2023 and 175 cases from 2023–2024 were analyzed. The rate of fetal hydrops at presentation was similar across the two groups (22.9% in pre‐2023 vs 23.4% in 2023–2024; P = 0.905). The rates of perinatal mortality (6.4% in pre‐2023 vs 8.0% in 2023–2024; P = 0.294) and CAPO (17.9% in pre‐2023 vs 21.7% in 2023–2024; P = 0.395) were not significantly different between groups, but the proportion of fetuses with persistent fetal anemia requiring a second IUT was significantly higher in the 2023–2024 cohort (46.0% vs 19.4%; P = 0.011). For the 2023–2024 cohort, fetal hydrops at presentation was an independent predictor of perinatal mortality (adjusted odds ratio, 10.91 (95% CI, 1.89–63.07); P = 0.007). Conclusion In this multicenter collaboration, we report perinatal outcomes following maternal parvovirus B19 infection during the recent upsurge and compare them with those of a historical cohort. Although perinatal mortality and CAPO rates were similar between cohorts, cases in the recent surge (2023–2024) required more prenatal interventions, including the need for more than one IUT. Early identification and monitoring remain essential to mitigate adverse perinatal outcomes following maternal parvovirus B19 infection. © 2025 The Author(s). Ultrasound in Obstetrics &amp; Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology

Longitudinal gait changes in functional neurological disorder: A 12-month prospective study

Background Functional gait disorder (FGD) is a subtype of functional neurological disorder (FND) characterized by abnormal walking patterns. Long-term symptom progression and factors influencing gait changes in FGD remain poorly understood. Objectives To investigate longitudinal changes in gait and associated symptoms over 12 months in individuals with FGD and examine whether changes in specific symptoms are associated with changes in gait. Methods Individuals with FND and altered gait completed an online survey at baseline and at 3-, 6-, and 12-month follow-up points. The survey collected data on symptom severity, gait changes, and standardised outcome measures. Analyses included descriptive statistics, linear mixed models, Kruskal–Wallis tests, and Spearman's rank correlations. Results Of 156 baseline respondents, 65 completed the 12-month follow-up. Sixteen (28.5 %) reported worsening gait, 17 (30.4 %) no change, 13 (23.2 %) improvement, and 10 (17.8 %) fluctuating gait. Linear mixed-model analyses showed no significant within-subject changes in motor or non-motor symptom severity from baseline to 12 months. Greater baseline functional seizure severity was strongly associated with poorer gait outcomes at 12 months (Rₛ = −0.750, p < 0.001, n = 17). Higher muscle rigidity severity at 12 months was also strongly associated with worse gait (Rₛ = −0.604, p < 0.001, n = 30). Conclusion This study provides insights into the natural course of functional gait disorder over time, based on participant self-report, revealing heterogeneous trajectories. Exploratory analyses found that functional seizure and muscle rigidity severity were associated with gait decline

Comparative Analysis of Glucuronoxylomannogalactan and Glucuronoxylomannan Antibody Responses and Their Associations With Cryptococcal Disease Status in People With HIV

Background Cryptococcosis remains a major cause of mortality in people with HIV (PWH). While glucuronoxylomannan-binding immunoglobulin G (GXM-IgG) levels have been associated with disease status and survival, the clinical significance of glucuronoxylomannogalactan-binding IgG (GXMGal-IgG) has not been investigated. Methods We analyzed serological data from 2 previously reported cohorts of PWH: a prospective asymptomatic South African cohort (67 cryptococcal antigen [CrAg] positive, 130 CrAg negative), and a Vietnamese case-control cohort (30 with symptomatic cryptococcal meningitis [CM], 30 without), both followed for mortality for 6 months. Serum/plasma GXMGal-IgG levels were quantified by enzyme-linked immunosorbent assay and compared to previously reported GXM-IgG levels. Logistic regression adjusted for age, sex, and CD4 count examined associations between antibody levels and CrAg positivity or CM status, while Cox proportional hazards models adjusted for CD4 count estimated associations with time to mortality. Results Higher GXMGal-IgG was associated with CrAg positivity (odds ratio, 1.64; 95% confidence interval [CI], 1.14–2.36), not CM status. Among individuals with asymptomatic cryptococcal antigenemia, higher GXMGal-IgG trended toward higher survival (hazards ratio, 0.67; 95% CI, .41–1.09), but this was not statistically significant and no significant survival benefit was observed for those with CM. Conclusions GXMGal-IgG was associated with CrAg positivity and showed a modest trend toward survival for individuals with asymptomatic cryptococcal antigenemia but had limited predictive value for CM or mortality. These findings in antigenemia largely parallel previous observations for GXM-IgG, although associations observed were generally weaker. Further studies are needed to clarify the immune response to GXMGal and its potential diagnostic or prognostic significance

The Role of Cardiovascular Magnetic Resonance Imaging in Athletic Individuals-A Narrative Review

Cardiovascular magnetic resonance imaging (MRI) is an advanced cardiac imaging modality that is often required when evaluating athletic individuals. Unrestricted imaging planes, excellent spatial resolution, and a lack of ionising radiation are some of the benefits of this modality. Cardiac MRI has been established as the gold standard imaging modality for morphological assessment, volumetric analysis, and tissue characterisation. Cardiac MRI without any doubt is an excellent diagnostic tool when evaluating athletes with symptoms or those individuals exhibiting equivocal findings at screening. It is also useful for athletes who fall within the grey zone and is especially important among athletes with a suspected or confirmed diagnosis. Cardiac MRI plays a strategic role when adopting a shared decision-making model in athletes with heart disease, tailoring and personalising medical care to the condition and the athlete’s wishes. The aim of this review is to provide a comprehensive yet practical overview of the role of cardiac MRI when evaluating athletes in clinic

Pitfalls and practical suggestions for using local field potential recordings in DBS clinical practice and research.

&#xD;Local field potential (LFP) recordings using chronically implanted sensing-enabled stimulators are a powerful tool for indexing symptom presence and severity in neurological and neuropsychiatric disorders, and for enhancing our neurophysiological understanding of brain processes. LFPs have gained interest as input signals for closed-loop deep brain stimulation (DBS) and can be used to inform DBS parameter selection. LFP recordings using chronically implanted sensing-enabled stimulators have various implementational challenges.&#xD;Approach: Here we describe our collective experience using BrainSense (Medtronic®) for clinical and research work. We aim to provide insightful tips and practical advice to empower readers with the knowledge needed to navigate the intricacies of the device and make the most out of its features.&#xD;Main results:&#xD;The central issues that apply to several BrainSense features encompass restricted compatibility of stimulation configuration with sensing, differences in electrophysiological signal properties between 'stimulation OFF' and 'stimulation ON at 0.0 mA', and challenges associated with the internal clock of the neurostimulator. In addition, since recordings are obtained from bipolar and not monopolar channels, spatial certainty regarding the distribution of LFPs around the DBS electrode is limited. Several options exist to synchronize LFP time series with external data streams, but standardization and generalization are lacking. The use of at-home chronic LFP recording is limited by a low temporal and spectral resolution. Regarding at-home LFP snapshots, LFP time series are not stored, parts of the power spectrum are censored when stimulating at high or low frequencies, and the stimulation amplitude is not readily available.&#xD;Significance: We discussed practical applications, implementation, system limitations, and pitfalls with the aim that sensing can be better applied for clinical practice and research.&#xD