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OBJECTIVES: Potentially harmful non-steroidal anti-inflammatory drugs (NSAIDs) utilisation persists at undesirable rates worldwide. The purpose of this paper is to review the literature on interventions to de-implement potentially harmful NSAIDs in healthcare settings and to suggest directions for future research. DESIGN: Scoping review. DATA SOURCES: PubMed, CINAHL, Embase, Cochrane Central and Google Scholar (1 January 2000 to 31 May 2022). STUDY SELECTION: Studies reporting on the effectiveness of interventions to systematically reduce potentially harmful NSAID utilisation in healthcare settings. DATA EXTRACTION: Using Covidence systematic review software, we extracted study and intervention characteristics, including the effectiveness of interventions in reducing NSAID utilisation. RESULTS: From 7818 articles initially identified, 68 were included in the review. Most studies took place in European countries (45.6%) or the USA (35.3%), with randomised controlled trial as the most common design (55.9%). Interventions were largely clinician-facing (76.2%) and delivered in primary care (60.2%) but were rarely (14.9%) guided by an implementation model, framework or theory. Academic detailing, clinical decision support or electronic medical record interventions, performance reports and pharmacist review were frequent approaches employed. NSAID use was most commonly classified as potentially harmful based on patients' age (55.8%), history of gastrointestinal disorders (47.1%), or history of kidney disease (38.2%). Only 7.4% of interventions focused on over-the-counter (OTC) NSAIDs in addition to prescription. The majority of studies (76.2%) reported a reduction in the utilisation of potentially harmful NSAIDs. Few studies (5.9%) evaluated pain or quality of life following NSAIDs discontinuation. CONCLUSION: Many varied interventions to de-implement potentially harmful NSAIDs have been applied in healthcare settings worldwide. Based on these findings and identified knowledge gaps, further efforts to comprehensively evaluate the effectiveness of interventions and the combination of intervention characteristics associated with effective de-implementation are needed. In addition, future work should be guided by de-implementation theory, focus on OTC NSAIDs and incorporate patient-focused strategies and outcomes, including the evaluation of unintended consequences of the intervention.

OBJECTIVES: We conducted an updated systematic review and meta-analysis to investigate the effect of colchicine treatment on clinical outcomes in patients with COVID-19. DESIGN: Systematic review and meta-analysis. DATA SOURCES: We searched PubMed, Embase, the Cochrane Library, medRxiv and ClinicalTrials.gov from inception to January 2023. ELIGIBILITY CRITERIA: All randomised controlled trials (RCTs) that investigated the efficacy of colchicine treatment in patients with COVID-19 as compared with placebo or standard of care were included. There were no language restrictions. Studies that used colchicine prophylactically were excluded. DATA EXTRACTION AND SYNTHESIS: We extracted all information relating to the study characteristics, such as author names, location, study population, details of intervention and comparator groups, and our outcomes of interest. We conducted our meta-analysis by using RevMan V.5.4 with risk ratio (RR) and mean difference as the effect measures. RESULTS: We included 23 RCTs (28 249 participants) in this systematic review. Colchicine did not decrease the risk of mortality (RR 0.99; 95% CI 0.93 to 1.05; I2=0%; 20 RCTs, 25 824 participants), with the results being consistent among both hospitalised and non-hospitalised patients. There were no significant differences between the colchicine and control groups in other relevant clinical outcomes, including the incidence of mechanical ventilation (RR 0.75; 95% CI 0.48 to 1.18; p=0.22; I2=40%; 8 RCTs, 13 262 participants), intensive care unit admission (RR 0.77; 95% CI 0.49 to 1.22; p=0.27; I2=0%; 6 RCTs, 961 participants) and hospital admission (RR 0.74; 95% CI 0.48 to 1.16; p=0.19; I2=70%; 3 RCTs, 8572 participants). CONCLUSIONS: The results of this meta-analysis do not support the use of colchicine as a treatment for reducing the risk of mortality or improving other relevant clinical outcomes in patients with COVID-19. However, RCTs investigating early treatment with colchicine (within 5 days of symptom onset or in patients with early-stage disease) are needed to fully elucidate the potential benefits of colchicine in this patient population. PROSPERO REGISTRATION NUMBER: CRD42022369850.

OBJECTIVE: To compare vaccination willingness before rollout and 1 year post-rollout uptake among the general population and under-resourced communities in high-income countries. DESIGN: A realist review. DATA SOURCES: Embase, PubMed, Dimensions ai and Google Scholar. SETTING: High-income countries. DEFINITIONS: We defined vaccination willingness as the proportion of participants willing or intending to receive vaccines prior to availability. We defined vaccine uptake as the real proportion of the population with complete vaccination as reported by each country until November 2021. RESULTS: We included data from 62 studies and 18 high-income countries. For studies conducted among general populations, the proportion of vaccination willingness was 67% (95% CI 62% to 72%). In real-world settings, the overall proportion of vaccine uptake among those countries was 73% (95% CI 69% to 76%). 17 studies reported pre-rollout willingness for under-resourced communities. The summary proportion of vaccination willingness from studies reporting results among people from under-resourced communities was 52% (95% CI 0.46% to 0.57%). Real-world evidence about vaccine uptake after rollout among under-resourced communities was limited. CONCLUSION: Our review emphasises the importance of realist reviews for assessing vaccine acceptance. Limited real-world evidence about vaccine uptake among under-resourced communities in high-income countries is a call to context-specific actions and reporting.

Objective To observe the effect of Bifidobacterium on breast milk components and its relationship with the onset of allergic diseases in infants by supplementing probiotic Bifidobacterium to pregnant and lactating mothers. Methods Pregnant women with informed consent were selected and oral administration of Bifidobacterium began at 36 weeks of pregnancy , continue to take it after delivery until the end of breastfeeding, and choose the control group to take oral placebo, and take colostrum and mature milk to test cytokines and immunoglobulins (IgA, sIgA, TGF-β1, TGF-β2, IL-10, sCD14) ; Infants were followed up to 2 years of age to identify eczema and other allergic diseases. Results: The levels of TGF-β1 and TGF-β2 in the colostrum of pregnant women who took Bifidobacterium orally were lower than those in the control group, and the level of IL-10 was higher than that in the control group. sCD14 was higher than that of the control group. The children of pregnant women with low levels of TGF-β in breast milk had a lower rate of allergic diseases within 2 years of age. Oral administration of Bifidobacterium had no effect on the levels of IgA and sIgA in breast milk. Conclusion Oral administration of Bifidobacteria in late pregnancy and lactation Fibrobacterium can reduce the levels of TGF-β1 and TGF-β2 in breast milk. The reduced levels of the latter two in breast milk are related to the low sensitivity of breastfed infants.

BACKGROUND: Approximately two-thirds of patients with relapsed or refractory large B-cell lymphoma (R/R LBCL) do not respond to or relapse after anti-CD19 chimeric antigen receptor T (CAR T)-cell therapy, leading to poor outcomes. Previous studies have suggested that intensified lymphodepletion and hematological stem cell infusion can promote adoptively transferred T-cell expansion, enhancing antitumor effects. Therefore, we conducted a phase I/II clinical trial in which CNCT19 (an anti-CD19 CAR T-cell) was administered after myeloablative high-dose chemotherapy and autologous stem cell transplantation (HDT/ASCT) in patients with R/R LBCL. METHODS: Transplant-eligible patients with LBCL who were refractory to first-line immunochemotherapy or experiencing R/R status after salvage chemotherapy were enrolled. The study aimed to evaluate the safety and efficacy of this combinational therapy. Additionally, frozen peripheral blood mononuclear cell samples from this trial and CNCT19 monotherapy studies for R/R LBCL were used to evaluate the impact of the combination therapy on the in vivo behavior of CNCT19 cells. RESULTS: A total of 25 patients with R/R LBCL were enrolled in this study. The overall response and complete response rates were 92.0% and 72.0%, respectively. The 2-year progression-free survival rate was 62.3%, and the overall survival was 68.5% after a median follow-up of 27.0 months. No unexpected toxicities were observed. All cases of cytokine release syndrome were of low grade. Two cases (8%) experienced grade 3 or higher CAR T-cell-related encephalopathy syndrome. The comparison of CNCT19 in vivo behavior showed that patients in the combinational therapy group exhibited enhanced in vivo expansion of CNCT19 cells and reduced long-term exhaustion formation, as opposed to those receiving CNCT19 monotherapy. CONCLUSIONS: The combinational therapy of HDT/ASCT and CNCT19 demonstrates impressive efficacy, improved CNCT19 behavior, and a favorable safety profile. TRIAL REGISTRATION NUMBERS: ChiCTR1900025419 and NCT04690192.

Cellular therapies for the treatment of human diseases, such as chimeric antigen receptor (CAR) T and NK cells have shown remarkable clinical efficacy in treating hematological malignancies, however current methods mainly utilize viral vectors which are limited by their cargo size capacities, high cost, and long timelines for production of clinical reagent. Delivery of genetic cargo via DNA transposon engineering is a more timely and cost-effective approach, yet has been held back by less efficient integration rates. Here, we report the development of a novel hyperactive TcBuster (TcB-M) transposase engineered through structure guided and in vitro evolution approaches that achieves high-efficiency integration of large, multicistronic CAR-expression cassettes in primary human cells. Our proof of principle TcB-M engineering of CAR-NK and CAR-T cells show low integrated vector copy number, a safe insertion site profile, robust in vitro function, and improves survival in a Burkitt lymphoma xenograft model in vivo. Overall, TcB-M is a versatile, safe, efficient and open-source option for the rapid manufacture and preclinical testing of primary human immune cell therapies through delivery of multicistronic large cargo via transposition.

BACKGROUND: Despite the widespread use of heparin during and following endovascular procedures in the management of aneurysmal subarachnoid hemorrhage (SAH) patients, limited research has explored the incidence and impact of heparin-induced thrombocytopenia (HIT) on SAH. METHODS: Descriptive statistics, multivariate regressions, and propensity score-matching were employed to compare clinical characteristics, comorbidities, interventions, complications, and outcomes of HIT in SAH patients identified within the US National Inpatient Sample database from 2010 to 2019. RESULTS: Among 76 387 SAH patients from 2010 to 2019, 166 (0.22%) developed HIT. HIT was identified as a significant predictor of prolonged length of stay (OR 6.799, 95% CI 3.985 to 11.6, P<0.01) and poor functional outcomes (OR 2.541, 95% CI 1.628 to 3.966, P<0.01) after adjusting for relevant factors. HIT incidence was higher in patients with elevated SAH severity scores (1.42 vs 1.06, P<0.01), younger patients (58.04 vs 61.39 years, P=0.01), overweight individuals (0.4% vs 0.2%, P<0.01), those on long-term anticoagulants (10.84% vs 5.72%, P<0.01), or with a cerebrospinal fluid drainage device (external ventricular drain, ventriculoperitoneal shunt; P<0.01). HIT patients showed increased rates of endovascular coiling, ventricular drain placement, shunt placement, deep vein thrombosis, urinary tract infection, acute kidney injury, pulmonary embolism, venous sinus thrombosis, pneumonia, and cerebral vasospasm (all P<0.01). CONCLUSION: SAH patients with HIT exhibited various comorbidities and increased rates of complications, which may contribute to extended hospital stays. This nationwide study aids clinical suspicion and highlights HIT's impact on SAH patients.

Background: Long term respiratory symptoms are reported following recovery of acute COVID-19 infection and residual lung abnormalities (RLA) on follow-up thoracic computed tomography (CT) after COVID-19 hospitalisation have been observed. It is unknown whether RLA are associated with epithelial lung injury. Methods: Plasma was sampled from the Post HOSPitalisation-COVID cohort at five months post-hospitalisation. Epithelial injury biomarkers Krebs von den Lungen-6 (KL-6), matrix metalloproteinase 7 (MMP-7), surfactant protein-D (SP-D) and surfactant protein-A (SP-A) were assayed. In those without follow-up CT, RLA at-risk was defined by percent predicted DLCO <80% and/or abnormal chest X-ray, otherwise they were considered low-risk. Follow-up CT RLA was defined as combined involvement of ground glass opacity and reticulation ≥10%. Findings: A total of 957 people were included, 846 people with no CT (at-risk n=103; 12.2%), 111 people with follow-up CT (RLA ≥10% n=85; 76.6%). All epithelial injury biomarkers were significantly elevated in people at-risk of RLA compared with low-risk. KL-6 and MMP-7 were significantly higher in people with ≥10% RLA than those with <10%, SP-D and SP-A did not reach significance. SP-D and SP-A were associated with percent involvement of reticulation (3.22%, 95%CI 1.19 to 5.24; 3.03%, 95%CI 0.76 to 5.30, respectively). Interpretation: RLA after acute COVID-19 infection were consistent with elevated epithelial injury biomarkers and pro-fibrotic signalling. Future studies should address the temporal association between fibrotic biomarkers and resolution or progression of radiological involvement. Funding: PHOSP-COVID is jointly funded by a grant from the MRC-UK Research and Innovation and the Department of Health and Social Care through the National Institute for Health Research (NIHR) rapid response panel to tackle COVID-19 (grant references: MR/V027859/1 and COV0319). Declaration of Interest: JJ reports fees from Boehringer Ingelheim, F. Hoffmann-La Roche, GlaxoSmithKline, NHSX, Takeda and patent: UK patent application number 2113765.8 all unrelated to the submitted work. PMG reports honoraria from Boehringer Ingelheim, Roche, AstraZeneca, Cipla, Brainomix. JCP reports grants from LifeArc, NIHR, Breathing Matters, consulting fees from Carrick Therapeutics, AstraZeneca and honoraria from The Limbic. RAE reports speaker fees from Boehringer Ingelheim and membership positions on European Respiratory Society and American Thoracic Society committees. PM reports consulting fees from EUSA pharma and SOBI, and honoraria from SOBI, UCB, Lilly, and Abbvie. MGS reports grants from NIHR, MRC, board positions on Pfizer External Data Monitoring Committee and Integrum Scientific LLC Infectious Disease Scientific Advisory Board, member positions of HMG UK SAGE and MHG UK NERVTAG, stocks in Integrum Scientific LLC and MedEx Solutions Ltd, gifts from Chiesi Farmaceutici S.p.A. AART reports grants and travel support from Janssen-Cilag Ltd. CEB reports consultancy fees paid to institution from GSK, AstraZeneca, Sanofi, Boehringer Ingelheim, Chiesi, Novartis, Roche, Genentech, Mologic, 4DPharma, TEVA. LVW reports recent and current research funding from GSK and Orion, and consultancy from Galapagos. RGJ reports honoraria from Chiesi, Roche, PatientMPower, AstraZeneca, GSK, Boehringer Ingelheim, and consulting fees from Bristol Myers Squibb, Daewoong, Veracyte, Resolution Therapeutics, RedX, Pliant, Chiesi. AM, AS, MP and SY are employees of Sysmex. All remaining authors declare no competing interests. Ethical Approval: The study cohort included participants of the PHOSP–COVID study, a prospective longitudinal cohort study of adults discharged from National Health Service hospitals across the United Kingdom after admission for confirmed or clinically diagnosed COVID-19, previously described in detail (Ethics Approval Ref: 20/YH/0225).

BACKGROUND: The metabolic benefits of bariatric surgery that contribute to the alleviation of metabolic dysfunction-associated steatotic liver disease (MASLD) have been reported. However, the processes and mechanisms underlying the contribution of lipid metabolic reprogramming after bariatric surgery to attenuating MASLD remain elusive. METHODS: A case-control study was designed to evaluate the impact of three of the most common adipokines (Nrg4, leptin, and adiponectin) on hepatic steatosis in the early recovery phase following sleeve gastrectomy (SG). A series of rodent and cell line experiments were subsequently used to determine the role and mechanism of secreted adipokines following SG in the alleviation of MASLD. RESULTS: In morbidly obese patients, an increase in circulating Nrg4 levels is associated with the alleviation of hepatic steatosis in the early recovery phase following SG before remarkable weight loss. The temporal parameters of the mice confirmed that an increase in circulating Nrg4 levels was initially stimulated by SG and contributed to the beneficial effect of SG on hepatic lipid deposition. Moreover, this occurred early following bariatric surgery. Mechanistically, gain- and loss-of-function studies in mice or cell lines revealed that circulating Nrg4 activates ErbB4, which could positively regulate fatty acid oxidation in hepatocytes to reduce intracellular lipid deposition. CONCLUSIONS: This study demonstrated that the rapid effect of SG on hepatic lipid metabolic reprogramming mediated by circulating Nrg4 alleviates MASLD.