Investigating potential confounding by indication when considering the association between proton pump inhibitor use, infection, hepatic encephalopathy and mortality in hospitalised decompensated cirrhosis: a post-hoc analysis of the ATTIRE trial.

Background: Proton pump inhibitors (PPIs) are commonly prescribed to prevent and treat upper gastrointestinal ulceration and bleeding. Studies have identified increased incidence of spontaneous bacterial peritonitis and hepatic encephalopathy (HE) in cirrhosis patients taking PPIs. However, results are conflicting, and as PPIs are prescribed for variceal bleeding, a major risk factor for infection and HE, it is challenging to discern whether these associations are causal. Methods: In this post-hoc analysis of the ATTIRE trial, we pooled all patient data to investigate the effects of PPI use on clinical outcomes. ATTIRE was a multicentre, open-label, randomised trial of targeted 20% human albumin solution (HAS) daily infusions versus standard care involving 777 adults with decompensated cirrhosis hospitalised with acute complications and albumin <30 g/L. Study recruitment was between Jan 25, 2016, and June 28, 2019, at 35 hospitals across England, Scotland, and Wales. Key exclusion criteria were advanced hepatocellular carcinoma with life expectancy <8 weeks and patients receiving palliative care. In ATTIRE, patients were grouped by PPI use at trial entry. We studied infection and HE at baseline and incidence of hospital acquired infection, new onset HE, renal dysfunction and mortality. We attempted with propensity score matching to account for differences in disease severity. Findings: Overall PPI use at baseline was not associated with increased incidence of infection, renal dysfunction or mortality, but was associated with significantly increased incidence of grade III/IV HE during hospital stay (P = 0.011). This was only significant for those taking intravenous PPIs and these patients had >10 times the incidence of variceal bleeding and near double the 28-day mortality compared to non-PPI patients. However, propensity score matching was not possible as there was such a strong selection of patients for PPI use, that we could not find sufficient non-PPI patients to match to. We found no impact of PPI use on plasma markers of bacterial translocation, infection or systemic inflammation. Interpretations: Our real-world data from a completed randomised trial show that PPIs are widely prescribed in the UK and judicious use appears safe in patients hospitalised with decompensated cirrhosis. However, patients prescribed PPIs had fundamentally different phenotypes to those not prescribed PPIs, a form of confounding by indication, which should be strongly considered when interpreting studies and making recommendations about their use. Funding: Wellcome Trust and Department of Health and Social Care.

ASEPTIC: primary antibiotic prophylaxis using co-trimoxazole to prevent SpontanEous bacterial PeritoniTIs in Cirrhosis-study protocol for an interventional randomised controlled trial.

BACKGROUND: Bacterial infection is a major cause of mortality in patients with cirrhosis. Spontaneous bacterial peritonitis (SBP) is a serious and common infection in patients with cirrhosis and ascites. Secondary prophylactic antibiotic therapy has been shown to improve outcomes after an episode of SBP but primary prophylaxis to prevent the first episode of SBP remains contentious. The aim of this trial is to assess whether primary antibiotic prophylaxis with co-trimoxazole improves overall survival compared to placebo in adults with cirrhosis and ascites. METHODS: The ASEPTIC trial is a multicentre, placebo-controlled, double-blinded, randomised controlled trial (RCT) in England, Scotland, and Wales. Patients aged 18 years and older with cirrhosis and ascites requiring diuretic treatment or paracentesis, and no current or previous episodes of SBP, are eligible, subject to exclusion criteria. The trial aims to recruit 432 patients from at least 30 sites. Patients will be randomised in a 1:1 ratio to receive either oral co-trimoxazole 960 mg or an identical placebo once daily for 18 months, with 6 monthly follow-up visits thereafter (with a maximum possible follow-up period of 48 months, and a minimum of 18 months). The primary outcome is overall survival. Secondary outcomes include the time to the first incidence of SBP, hospital admission rates, incidence of other infections (including Clostridium difficile) and antimicrobial resistance, patients' health-related quality of life, health and social care resource use, incidence of cirrhosis-related decompensation events, liver transplantation, and treatment-related serious adverse events. DISCUSSION: This trial will investigate the efficacy, safety, and cost-effectiveness of co-trimoxazole for patients with liver cirrhosis and ascites to determine whether this strategy improves clinical outcomes. Given there are no treatments that improve survival in decompensated cirrhosis outside of liver transplant, if the trial has a positive outcome, we anticipate widespread adoption of primary antibiotic prophylaxis. TRIAL REGISTRATION: ClinicalTrials.gov NCT043955365 . Registered on 18 April 2020. Research ethical approval was granted by the Research Ethics Committee (South Central - Oxford B; REC 19/SC/0311) and the Medicines and Healthcare products Regulatory Agency (MHRA).

A web-based survey assessing perceived changes in diet, physical activity and sleeping behaviours in adults with type 1 and type 2 diabetes during the COVID-19 pandemic in the UK.

Background: The COVID-19 pandemic may have contributed to poorer self-management (ie, diet, physical activity and sleep) of diabetes mellitus (DM), which might predispose individuals to more severe COVID-19 outcomes. Objective: The first objective was to capture perceived changes in diet, physical activity and sleeping during the COVID-19 pandemic in adults with type 1 (T1DM) and type 2 diabetes mellitus (T2DM) in the UK. A second objective was to explore differences between individuals with DM compared with 'no' or 'other' health conditions. Methods: Participants aged >18 years were selected by convenience. Individuals subscribed to the Diabetes.co.uk community were sent a web-based survey including questions about demographics and health, followed by 5-point Likert-type scale questions relating to lifestyle-related behaviours during the COVID-19 pandemic. Individuals were grouped by diagnosis of DM, 'other' or 'no' health condition and responses were compared. Results: 4764 individuals responded, with 2434 (51.3%) being female and 1550 (32.6%) aged 55-64 years. T2DM (2974; 62.7%), hypertension (2147; 45.2%) and T1DM (1299; 27.4%) were most frequently reported. Compared with T1DM, 'no' or 'other' health conditions, respondents with T2DM reported making a less conscious effort to get outside and exercise daily (p<0.001) and spending no time outdoors (p=0.001). Weight loss was more frequently reported in respondents with T2DM (p=0.005). More individuals with T2DM reported consuming convenience foods (p=0.012) and sugary foods (p=0.021), yet eating more fresh foods (p=0.001) and drinking less alcohol than normal (p<0.001). More individuals with T1DM and T2DM reported worse sleep quality (p=0.004). Conclusions: Our study highlighted important differences in lifestyle by individuals with T1DM, T2DM, other and no health conditions in relation to the COVID-19 pandemic. Establishing surveillance systems and conducting repeated assessments are required to analyse how the situation shifted over time and whether adverse collateral effects of the pandemic were sustained in those with chronic health conditions.

Renal function in patients following a low carbohydrate diet for type 2 diabetes: a review of the literature and analysis of routine clinical data from a primary care service over 7 years.

PURPOSE OF REVIEW: People with T2 Diabetes (T2D) who follow a low carbohydrate diet (LCD) may increase their dietary protein intake. Dietary protein can modulate renal function so there is debate about its role in renal disease. There is concern that higher protein intakes may promote renal damage, and that LCDs themselves may impact on cardiovascular risk. We review the evidence around LCDs, renal and cardiovascular risk factors and compare to results obtained in a real-world, primary care setting. RECENT FINDINGS: Chronic kidney disease (CKD) is a well-recognised microvascular complication of T2D caused in part by; chronically increased glomerular pressure, hyperfiltration, increased blood pressure and advanced glycation end products. Hyperglycemia can be seen as central to all of these factors. A LCD is an effective first step in its correction as we demonstrate in our real-world cohort. SUMMARY: We found evidence that LCDs for people with T2D may improve many renal and cardiovascular risk factors. In our own LCD cohort of 143 patients with normal renal function or only mild CKD, over an average of 30 months the serum creatinine improved by a significant mean of 4.7 (14.9) µmol/L. What remains to be shown is the effect of the approach on people with T2D and moderate/severe CKD.

Nutritional parameters and outcomes in patients admitted to intensive care with COVID-19: a retrospective single-centre service evaluation.

COVID-19 is an inflammatory syndrome caused by novel coronavirus SARS-CoV-2. Symptoms range from mild infection to severe acute respiratory distress syndrome (ARDS) requiring ventilation and intensive care. At the time of data collection, UK cases were around 300 000 with a fatality rate of 13% necessitating over 10 000 critical care admissions; now there have been over 4 million cases. Nutrition is important to immune function and influences metabolic risk factors such as obesity and glycaemic control, as well as recovery from acute illnesses. Poor nutritional status is associated with worse outcomes in ARDS and viral infections, yet limited research has assessed pre-morbid nutritional status and outcomes in patients critically unwell with COVID-19. OBJECTIVES: Investigate the effect of body mass index (BMI), glycaemic control and vitamin D status on outcomes in adult patients with COVID-19 admitted to an intensive care unit (ICU). METHODS: Retrospective review of all patients admitted to a central London ICU between March and May 2020 with confirmed COVID-19. Electronic patient records data were analysed for patient demographics; comorbidities; admission BMI; and serum vitamin D, zinc, selenium and haemoglobin A1c (HbA1c) concentrations. Serum vitamin D and HbA1c were measured on admission, or within 1 month of admission to ICU. Primary outcome of interest was mortality. Secondary outcomes included time intubated, ICU stay duration and ICU-related morbidity. RESULTS: Seventy-two patients; 54 (75%) men, mean age 57.1 (±9.8) years, were included. Overall, mortality was 24 (33%). No significant association with mortality was observed across BMI categories. In the survival arm admission, HbA1c (mmol/mol) was lower, 50.2 vs 60.8, but this was not statistically significant. Vitamin D status did not significantly associate with mortality (p=0.131). However, 32% of patients with low vitamin D (<25 IU/L) died, compared with 13% of patients with vitamin D levels >26 IU/L. Serum zinc and selenium, and vitamin B12 and folate levels were measured in 46% and 26% of patients, respectively. DISCUSSION/CONCLUSION: Increased adiposity and deranged glucose homeostasis may potentially increase risk of COVID-19 infection and severity, possibly relating to impaired lung and metabolic function, increased proinflammatory and prothrombotic mechanisms. Vitamin D deficiency may also associate with poorer outcomes and mortality, supporting a possible role of vitamin D in immune function specific to pulmonary inflammation and COVID-19 pathophysiology. There are plausible associations between raised BMI, glycaemic control, vitamin D status and poor prognosis, as seen in wider studies; however, in this service evaluation audit during the first wave of the pandemic in the UK, with a limited data set available for this analysis, the associations did not reach statistical significance. Further research is needed into specific nutritional markers influencing critical care admissions with COVID-19.

'Bhavishya Shakti: Empowering the Future': establishing and evaluating a pilot community mobile teaching kitchen as an innovative model, training marginalised women to become nutrition champions and culinary health educators in Kolkata, India.

BACKGROUND: Malnutrition is a global emergency, creating an overlapping burden on individual, public and economic health. The double burden of malnutrition affects approximately 2.3 billion adults worldwide. Following 3 years of capacity building work in Kolkata, with assistance of local volunteers and organisations, we established an empowering nutrition education model in the form of a 'mobile teaching kitchen (MTK)' with the aim of creating culinary health educators from lay slum-dwelling women. AIMS: To evaluate the piloting of a novel MTK nutrition education platform and its effects on the participants, alongside data collection feasibility. METHODS: Over 6 months, marginalised (RG Kar and Chetla slums) women underwent nutrition training using the MTK supported by dietitians, doctors and volunteers. Preintervention and postintervention assessments of knowledge, attitudes and practices (KAP), as well as anthropometric and clinical nutritional status of both the women and their children were recorded. The education was delivered by a 'See One, Do One, Teach One' approach with a final assessment of teaching delivery performed in the final session. RESULTS: Twelve women were trained in total, six from each slum. Statistically significant improvements were noted in sections of KAP, with improvements in nutrition knowledge (+4.8) and practices (+0.8). In addition, statistically significant positive changes were seen in 'understanding of healthy nutrition for their children' (p=0.02), 'sources of protein rich food' (p=0.02) and 'not skipping meals if a child is ill' (p≤0.001). CONCLUSION: The MTK as a public health intervention managed to educate, empower and upskill two groups of lay marginalised women into MTK Champions from the urban slums of Kolkata, India. Improvements in their nutrition KAP demonstrate just some of the effects of this programme. By the provision of healthy meals and nutritional messages, the MTK Champions are key drivers nudging improvements in nutrition and health related awareness with a ripple effect across the communities that they serve. There is potential to upscale and adapt this programme to other settings, or developing into a microenterprise model, that can help future MTK Champions earn a stable income.

Time for nutrition in medical education.

AIM: To synthesise a selection of UK medical students' and doctors' views surrounding nutrition in medical education and practice. METHODS: Information was gathered from surveys of medical students and doctors identified between 2015 and 2018 and an evaluation of nutrition teaching in a single UK medical school. Comparative analysis of the findings was undertaken to answer three questions: the perceived importance of nutrition in medical education and practice, adequacy of nutrition training, and confidence in current nutrition knowledge and skills. RESULTS: We pooled five heterogeneous sources of information, representing 853 participants. Most agreed on the importance of nutrition in health (>90%) and in a doctor's role in nutritional care (>95%). However, there was less desire for more nutrition education in doctors (85%) and in medical students (68%). Most felt their nutrition training was inadequate, with >70% reporting less than 2 hours. There was a preference for face-to-face rather than online training. At one medical school, nutrition was included in only one module, but this increased to eight modules following an increased nutrition focus. When medical students were asked about confidence in their nutrition knowledge and on advising patients, there was an even split between agree and disagree (p=0.869 and p=0.167, respectively), yet few were confident in the UK dietary guidelines. Only 26% of doctors were confident in their nutrition knowledge and 74% gave nutritional advice less than once a month, citing lack of knowledge (75%), time (64%) and confidence (62%) as the main barriers. There was some recognition of the importance of a collaborative approach, yet 28% of doctors preferred to get specialist advice rather than address nutrition themselves. CONCLUSION: There is a desire and a need for more nutrition within medical education, as well as a need for greater clarity of a doctor's role in nutritional care and when to refer for specialist advice. Despite potential selection bias and limitations in the sampling frame, this synthesis provides a multifaceted snapshot via a large number of insights from different levels of training through medical students to doctors from which further research can be developed.

Insights from a general practice service evaluation supporting a lower carbohydrate diet in patients with type 2 diabetes mellitus and prediabetes: a secondary analysis of routine clinic data including HbA1c, weight and prescribing over 6 years.

BACKGROUND: In a single general practice (GP) surgery in England, there was an eightfold increase in the prevalence of type 2 diabetes (T2D) in three decades with 57 cases and 472 cases recorded in 1987 and 2018, respectively. This mirrors the growing burden of T2D on the health of populations round the world along with healthcare funding and provision more broadly. Emerging evidence suggests beneficial effects of carbohydrate-restricted diets on glycaemic control in T2D, but its impact in a 'real-world' primary care setting has not been fully evaluated. METHODS: Advice on a lower carbohydrate diet was offered routinely to patients with newly diagnosed and pre-existing T2D or prediabetes between 2013 and 2019, in the Norwood GP practice with 9800 patients. Conventional 'one-to-one' GP consultations were used, supplemented by group consultations, to help patients better understand the glycaemic consequences of their dietary choices with a particular focus on sugar, carbohydrates and foods with a higher Glycaemic Index. Those interested were computer coded for ongoing audit to compare 'baseline' with 'latest follow-up' for relevant parameters. RESULTS: By 2019, 128 (27%) of the practice population with T2D and 71 people with prediabetes had opted to follow a lower carbohydrate diet for a mean duration of 23 months. For patients with T2D, the median (IQR) weight dropped from of 99.7 (86.2, 109.3) kg to 91.4 (79, 101.1) kg, p<0.001, while the median (IQR) HbA1c dropped from 65.5 (55, 82) mmol/mol to 48 (43, 55) mmol/mol, p<0.001. For patients with prediabetes, the median (IQR) HbA1c dropped from 44 (43, 45) mmol/mol to 39 (38, 41) mmol/mol, p<0.001. Drug-free T2D remission occurred in 46% of participants. In patients with prediabetes, 93% attained a normal HbA1c. Since 2015, there has been a relative reduction in practice prescribing of drugs for diabetes leading to a T2D prescribing budget £50 885 per year less than average for the area. CONCLUSIONS: This approach to lower carbohydrate dietary advice for patients with T2D and prediabetes was incorporated successfully into routine primary care over 6 years. There were statistically significant improvements in both groups for weight, HbA1c, lipid profiles and blood pressure as well as significant drug budget savings. These results suggest a need for more empirical research on the effects of lower carbohydrate diet and long-term glycaemic control while recording collateral impacts to other metabolic health outcomes.

The impact of delayed paper communication to primary care from secondary care and out of hours services.

The safe and effective treatment of patients accessing multiple NHS services relies upon efficient communication between primary care, secondary care, and out of hours providers. There is a theoretical risk to patient safety from delays in these processes, to which paper communications are particularly vulnerable. When letters are received they must be reviewed and prioritised in order of clinical importance, a process that requires both time and clinical resources. This is relevant to the challenge of resource allocation to maximise patient benefit. This retrospective study investigated the impact on patient safety of 249 clinical letters reporting routine clinical encounters in secondary care and out of hours services that were delayed by an average of 18-24 months to a suburban London general practice. No clinical harm could be attributed to the delay. This small study did not suggest delays in routine communications pose a significant risk to patient safety. Conversely, it questions the efficiency and benefit to patients of prioritising clinical time to reviewing routine letters. The adoption of fully integrated, shared electronic patient records with the function to highlight clinically urgent or important communications might ease clinician workload, to the ultimate benefit of patient care.

Twelve tips on setting up and running a peer-led medical education society.

Peer-led teaching is an established paradigm with benefits for student teachers, learners and the wider medical community. Students are increasingly taking ownership of such teaching, which has fuelled the creation of new peer-led medical education societies at universities around the UK. Students wishing to undertake such an endeavor must contend with concerns over the quality of peer-led teaching, logistical challenges, lack of senior support and difficulties accessing relevant resources to design and appraise their initiatives. Peer-led medical education societies represent a relatively novel concept, and students may struggle to find practical information on how to approach these challenges. We propose that these obstacles can be overcome by thorough event planning, understanding the role and features of high quality peer-led education in supplementing medical school curricula, maintaining a strong working relationship with local medical faculty, and learning from the wider medical education community.