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Gut Dysbiosis in Ocular Mucous Membrane Pemphigoid.
No full textMucous Membrane Pemphigoid is an orphan multi-system autoimmune scarring disease involving mucosal sites, including the ocular surface (OcMMP) and gut. Loss of tolerance to epithelial basement membrane proteins and generation of autoreactive T cell and/or autoantibodies are central to the disease process. The gut microbiome plays a critical role in the development of the immune system. Alteration in the gut microbiome (gut dysbiosis) affects the generation of autoreactive T cells and B cell autoantibody repertoire in several autoimmune conditions. This study examines the relationship between gut microbiome diversity and ocular inflammation in patients with OcMMP by comparing OcMMP gut microbiome profiles with healthy controls. DNA was extracted from faecal samples (49 OcMMP patients, 40 healthy controls), amplified for the V4 region of the 16S rRNA gene and sequenced using Illumina Miseq platform. Sequencing reads were processed using the bioinformatics pipeline available in the mothur v.1.44.1 software. After adjusting for participant factors in the multivariable model (age, gender, BMI, diet, proton pump inhibitor use), OcMMP cohort was found to be associated with lower number of operational taxonomic units (OTUs) and Shannon Diversity Index when compared to healthy controls. Within the OcMMP cohort, the number of OTUs were found to be significantly correlated with both the bulbar conjunctival inflammation score (p=0.03) and the current use of systemic immunotherapy (p=0.02). The linear discriminant analysis effect size scores indicated that and were enriched in OcMMP patients whilst and butyrate-producing bacteria such as were enriched in healthy controls (Log10 LDA score < 2, FDR-adjusted p <0.05). In conclusion, OcMMP patients have gut dysbiosis correlating with bulbar conjunctival inflammation and the use of systemic immunotherapies. This provides a framework for future longitudinal deep phenotyping studies on the role of the gut microbiome in the pathogenesis of OcMMP
Assessing the Effectiveness of Bisphosphonates for the Prevention of Fragility Fractures: An Updated Systematic Review and Network Meta-Analyses.
No full textBisphosphonates have been found to be effective in preventing fragility fractures. However, their comparative effectiveness in populations at risk has yet to be defined. In light of recent clinical trials, we aimed to compare four bisphosphonates (alendronate, ibandronate, risedronate, and zoledronate) and to identify which are the most effective for the prevention of fragility fractures. This is an update of a systematic review previously published as part of a NICE HTA report. We conducted a systematic review and network meta-analysis, updating the estimates regarding the comparative effectiveness of the aforementioned bisphosphonates. Studies identified from published and unpublished sources between 2014 and 2021 were added to the studies identified in the previous review. Screening, data extraction and risk of bias assessment were independently undertaken by two reviewers. Outcomes were fractures, femoral neck bone mineral density (BMD), mortality, and adverse events. We identified 25 additional trials, resulting in a total population of 47,007 participants. All treatments had beneficial effects on fractures versus placebo with zoledronate being the most effective treatment in preventing vertebral fractures (hazard ratio [HR] 0.38; 95% credibility interval [CrI], 0.28-0.49). Zoledronate (HR 0.71; 95% CrI, 0.61-0.81) and risedronate (HR 0.70; 95% CrI, 0.53-0.84) were found to be the most effective treatments in preventing nonvertebral fractures. All treatments were associated with increases in femoral neck BMD versus placebo with zoledronate being the most effective treatment mean difference (MD 4.02; 95% CrI, 3.2-4.84). There was a paucity of data regarding hip and wrist fractures. Depending on its cost-effectiveness, zoledronate could be considered a first-line option for people at increased risk of fragility fractures. © 2022 The Authors. published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research
Chronic Intestinal Failure in Children: An International Multicenter Cross-Sectional Survey.
No full textBACKGROUND
The European Society for Clinical Nutrition and Metabolism database for chronic intestinal failure (CIF) was analyzed to investigate factors associated with nutritional status and the intravenous supplementation (IVS) dependency in children.
METHODS
Data collected: demographics, CIF mechanism, home parenteral nutrition program, z-scores of weight-for-age (WFA), length or height-for-age (LFA/HFA), and body mass index-for-age (BMI-FA). IVS dependency was calculated as the ratio of daily total IVS energy over estimated resting energy expenditure (%IVSE/REE).
RESULTS
Five hundred and fifty-eight patients were included, 57.2% of whom were male. CIF mechanisms at age 1-4 and 14-18 years, respectively: SBS 63.3%, 37.9%; dysmotility or mucosal disease: 36.7%, 62.1%. One-third had WFA and/or LFA/HFA z-scores < -2. One-third had %IVSE/REE > 125%. Multivariate analysis showed that mechanism of CIF was associated with WFA and/or LFA/HFA z-scores (negatively with mucosal disease) and %IVSE/REE (higher for dysmotility and lower in SBS with colon in continuity), while z-scores were negatively associated with %IVSE/REE.
CONCLUSIONS
The main mechanism of CIF at young age was short bowel syndrome (SBS), whereas most patients facing adulthood had intestinal dysmotility or mucosal disease. One-third were underweight or stunted and had high IVS dependency. Considering that IVS dependency was associated with both CIF mechanisms and nutritional status, IVS dependency is suggested as a potential marker for CIF severity in children
Safety, immunogenicity, and reactogenicity of BNT162b2 and mRNA-1273 COVID-19 vaccines given as fourth-dose boosters following two doses of ChAdOx1 nCoV-19 or BNT162b2 and a third dose of BNT162b2 (COV-BOOST): a multicentre, blinded, phase 2, randomised trial.
No full textBACKGROUND
Some high-income countries have deployed fourth doses of COVID-19 vaccines, but the clinical need, effectiveness, timing, and dose of a fourth dose remain uncertain. We aimed to investigate the safety, reactogenicity, and immunogenicity of fourth-dose boosters against COVID-19.
METHODS
The COV-BOOST trial is a multicentre, blinded, phase 2, randomised controlled trial of seven COVID-19 vaccines given as third-dose boosters at 18 sites in the UK. This sub-study enrolled participants who had received BNT162b2 (Pfizer-BioNTech) as their third dose in COV-BOOST and randomly assigned them (1:1) to receive a fourth dose of either BNT162b2 (30 μg in 0·30 mL; full dose) or mRNA-1273 (Moderna; 50 μg in 0·25 mL; half dose) via intramuscular injection into the upper arm. The computer-generated randomisation list was created by the study statisticians with random block sizes of two or four. Participants and all study staff not delivering the vaccines were masked to treatment allocation. The coprimary outcomes were safety and reactogenicity, and immunogenicity (anti-spike protein IgG titres by ELISA and cellular immune response by ELISpot). We compared immunogenicity at 28 days after the third dose versus 14 days after the fourth dose and at day 0 versus day 14 relative to the fourth dose. Safety and reactogenicity were assessed in the per-protocol population, which comprised all participants who received a fourth-dose booster regardless of their SARS-CoV-2 serostatus. Immunogenicity was primarily analysed in a modified intention-to-treat population comprising seronegative participants who had received a fourth-dose booster and had available endpoint data. This trial is registered with ISRCTN, 73765130, and is ongoing.
FINDINGS
Between Jan 11 and Jan 25, 2022, 166 participants were screened, randomly assigned, and received either full-dose BNT162b2 (n=83) or half-dose mRNA-1273 (n=83) as a fourth dose. The median age of these participants was 70·1 years (IQR 51·6-77·5) and 86 (52%) of 166 participants were female and 80 (48%) were male. The median interval between the third and fourth doses was 208·5 days (IQR 203·3-214·8). Pain was the most common local solicited adverse event and fatigue was the most common systemic solicited adverse event after BNT162b2 or mRNA-1273 booster doses. None of three serious adverse events reported after a fourth dose with BNT162b2 were related to the study vaccine. In the BNT162b2 group, geometric mean anti-spike protein IgG concentration at day 28 after the third dose was 23 325 ELISA laboratory units (ELU)/mL (95% CI 20 030-27 162), which increased to 37 460 ELU/mL (31 996-43 857) at day 14 after the fourth dose, representing a significant fold change (geometric mean 1·59, 95% CI 1·41-1·78). There was a significant increase in geometric mean anti-spike protein IgG concentration from 28 days after the third dose (25 317 ELU/mL, 95% CI 20 996-30 528) to 14 days after a fourth dose of mRNA-1273 (54 936 ELU/mL, 46 826-64 452), with a geometric mean fold change of 2·19 (1·90-2·52). The fold changes in anti-spike protein IgG titres from before (day 0) to after (day 14) the fourth dose were 12·19 (95% CI 10·37-14·32) and 15·90 (12·92-19·58) in the BNT162b2 and mRNA-1273 groups, respectively. T-cell responses were also boosted after the fourth dose (eg, the fold changes for the wild-type variant from before to after the fourth dose were 7·32 [95% CI 3·24-16·54] in the BNT162b2 group and 6·22 [3·90-9·92] in the mRNA-1273 group).
INTERPRETATION
Fourth-dose COVID-19 mRNA booster vaccines are well tolerated and boost cellular and humoral immunity. Peak responses after the fourth dose were similar to, and possibly better than, peak responses after the third dose.
FUNDING
UK Vaccine Task Force and National Institute for Health Research
Multi-disciplinary Evaluation of Sexual Assault Referral Centres (SARCs) for better Health (MESARCH): protocol for a 1-year cohort study examining health, well-being and cost outcomes in adult survivors of sexual assault attending SARCs in England.
No full textINTRODUCTION
Sexual violence is commonplace and has serious adverse consequences for physical and mental health. Sexual Assault Referral Centres (SARCs) are viewed as a best practice response. Little is known about their effectiveness and cost-effectiveness. Long-term data on the health and well-being of those who have experienced rape and sexual assault are also lacking.
METHODS AND ANALYSIS
This is a mixed-methods protocol for a 1-year cohort study aiming to examine the health and well-being in survivors of sexual violence after attending a SARC in England. Quantitative measures are being taken at baseline, 6 and 12 months. Post-traumatic stress (PTS) is the primary outcome (target N=270 at 12-month follow-up). Secondary measures include anxiety, depression, substance use and sexual health and well-being. Using mixed-effects regression, our main analysis will examine whether variation in SARC service delivery and subsequent mental healthcare is associated with improvement in trauma symptoms after 12 months. An economic analysis will compare costs and outcomes associated with different organisational aspects of SARC service delivery and levels of satisfaction with care. A nested qualitative study will employ narrative analysis of transcribed interviews with 30 cohort participants and 20 survivors who have not experienced SARC services.
ETHICS AND DISSEMINATION
The research is supported by an independent study steering committee, data monitoring and ethics committee and patient and public involvement (PPI) group. A central guiding principle of the research is that being involved should feel diametrically opposed to being a victim of sexual violence, and be experienced as empowering and supportive. Our PPI representatives are instrumental in this, and our wider stakeholders encourage us to consider the health and well-being of all involved. We will disseminate widely through peer-reviewed articles and non-academic channels to maximise the impact of findings on commissioning of services and support for survivors.
TRIAL REGISTRATION NUMBER
ISRCTN30846825
Carvedilol versus endoscopic band ligation for secondary prophylaxis of variceal bleeding-long-term follow-up of a randomised control trial.
No full textBACKGROUND AND AIMS
Carvedilol reduces rates of variceal bleeding and rebleeding by lowering portal pressure. However, an associated pleiotropic survival benefit has been proposed. We aimed to assess long-term survival in a cohort of patients previously randomised to receive either carvedilol or endoscopic band ligation (EBL) following oesophageal variceal bleeding (OVB).
METHODS
The index study randomised 64 cirrhotic patients with OVB between 2006 and 2011 to receive either carvedilol or EBL. Follow-up was undertaken to April 2020 by review of electronic patient records. The primary outcome was survival. Other outcomes including variceal rebleeding and liver decompensation events were compared.
RESULTS
26 out of 33 participants received carvedilol in the follow-up period and 28 out of 31 attended regular EBL sessions. The median number of follow-up days for all patients recruited was 1459 (SE = 281.74). On the intention to treat analysis, there was a trend towards improved survival in the carvedilol group (p = 0.09). On per-protocol analysis, carvedilol use was associated with improved long-term survival (p = 0.005, HR 3.083, 95% CI 1.397-6.809), fewer liver-related deaths (0% vs 22.57%, p = 0.013, OR ∞, 95%CI 1.565-∞) and fewer admissions with decompensated liver disease (12% vs 64.29%, p = 0.0002, OR 13.2, 95% CI 3.026-47.23) compared to the EBL group. There was no statistically significant difference in variceal rebleeding rates.
CONCLUSION
Following OVB in cirrhotic patients, carvedilol use is associated with survival benefit, fewer liver-related deaths and fewer hospital admissions with decompensated liver disease. Further studies are needed to validate this finding
Incidence of Cardiometabolic Diseases in People With and Without Human Immunodeficiency Virus in the United Kingdom: A Population-Based Matched Cohort Study.
No full textBACKGROUND
Evidence on the risk of cardiovascular disease (CVD) and CVD risk factors in people with human immunodeficiency virus (PWH) is limited. We aimed to identify the risk of composite CVD, individual CVD events, and common risk factors.
METHODS
This was a nationwide, population-based, cohort study comparing adult (≥18 years old) PWH with people without human immunodeficiency virus (HIV) matched on age, sex, ethnicity, and location. The primary outcome was composite CVD comprising stroke, myocardial infarction, peripheral vascular disease, ischemic heart disease, and heart failure. The secondary outcomes were individual CVD events, hypertension, diabetes, chronic kidney disease (CKD), and all-cause mortality. Cox proportional hazard regression models were used to examine the risk of each outcome.
RESULTS
We identified 9233 PWH and matched them with 35 721 HIV-negative individuals. An increased risk was found for composite CVD (adjusted hazard ratio [aHR], 1.50; 95% confidence interval [CI], 1.28-1.77), stroke (aHR, 1.42; 95% CI, 1.08-1.86), ischemic heart disease (aHR, 1.55; 95% CI, 1.24-1.94), hypertension (aHR, 1.37; 95% CI, 1.23-1.53), type 2 diabetes (aHR, 1.28; 95% CI, 1.09-1.50), CKD (aHR, 2.42; 95% CI, 1.98-2.94), and all-cause mortality (aHR, 2.84; 95% CI, 2.48-3.25).
CONCLUSIONS
PWH have a heightened risk for CVD and common CVD risk factors, reinforcing the importance for regular screening for such conditions
Outpatient parenteral antimicrobial therapy (OPAT) in the UK: findings from the BSAC National Outcomes Registry (2015-19).
No full textBACKGROUND
Reporting of outpatient parenteral antimicrobial therapy (OPAT) outcomes with national benchmarking is key to informing service development and supporting quality improvement.
OBJECTIVES
To analyse and report on data collected by the BSAC OPAT National Outcomes Registry from 2015 to 2019.
METHODS
Quarterly data to 2020 was extracted from the BSAC National Outcomes Registry and analysed.
RESULTS
57 organizations submitted data on 27 841 patient episodes and 442 280 OPAT treatment days. A diverse range of infections and antimicrobials were reported with a mean OPAT treatment duration of 16.7 days (adults) and 7.7 days (paediatrics). In adults, the top five conditions treated were skin and soft tissue (27.6%), bronchiectasis (11.4%), urinary tract infections (7.6%), and diabetic foot infections (5.5%). Ceftriaxone followed by teicoplanin, ertapenem and piperacillin/tazobactam were the most-used antimicrobials. A median of 1.4 vascular-device-related complications were observed per 1000 OPAT treatment days (range 0.11 to 10.4) with device infections in 0.3 per 1000 OPAT days (range 0.1 to 1.7). Other adverse events (rash, blood dyscrasias, antibiotic-associated diarrhoea) were observed in a median of 1.9 per 1000 OPAT days. OPAT infection outcome (cured/improved) was 92.4% and OPAT outcome (success/partial success) was 90.7%.
CONCLUSIONS
This report demonstrates the safety, breadth, and complexity of modern UK OPAT practice. Future analyses of OPAT data should focus on infection- and service-specific quality indicators. OPAT registries remain central to planning and assessing safe, effective, and efficient delivery of patient-centred care and should be an important focus for UK and global OPAT practice
Positive approaches to safety: learning from what we do well.
No full textHistorical and current methodologies in patient safety are based on a deficit-based model, defining safety as the absence of harm. This model is aligned with the human innate negativity bias and the general philosophy of healthcare: to diagnose and cure illness, and to relieve suffering. Whilst this approach has underpinned measurable progress in healthcare outcomes, a common narrative in the healthcare literature indicates that this progress is stalling or slowing. It is important to learn from and improve poor outcomes, but the deficit-based approach has some theoretical limitations. In this article, we discuss some of the theoretical limitations of the prevailing approach to patient safety, and introduce emerging, complementary approaches in this field of practice. Safety-II and resilience engineering represent a new paradigm of safety, characterised by focusing on the entirety of work, with a systems-wide lens, rather than single incidents of failure. More overtly positive approaches are available, specifically focusing on success - both outstanding success and everyday success - including exnovation, appreciative inquiry, learning from excellence and positive deviance. These approaches are not mutually exclusive. The new methods described in this article are not intended as replacements of the current methods, rather they are presented as complementary tools, designed to allow the reader to take a balanced and holistic view of patient safety