Is diabetic retinopathy screening worthwhile among people first diagnosed with diabetes at older ages? A cohort study of Norfolk diabetic retinopathy screening programme.

AIMS: England's Diabetic Eye Disease Screening Programme offers screening to every resident over age 12 with diabetes, starting as soon as possible after diagnosis and repeated annually. People first diagnosed with diabetes at older ages have shorter life expectancy and therefore may be less likely to benefit from screening and treatment. To inform decisions about whether diabetic eye screening policy should be stratified by age, we investigated the probability of receiving treatment according to age at first screening episode. METHODS: This was a cohort study of participants in the Norfolk Diabetic Retinopathy Screening Programme from 2006 to 2017, with individuals' programme data linked to hospital treatment and death data recorded up to 2021. We estimated and compared the probability, annual incidence and screening costs of receiving retinal laser photocoagulation or intravitreal injection and of death, in age groups defined by age at first screening episode. RESULTS: The probability of death increased with increasing age at diagnosis, while the probability of receiving either treatment decreased with increasing age. The estimated cost of screening per person who received either or both treatments was £18,608 among all participants, increasing with age up to £21,721 in those aged 70-79 and £26,214 in those aged 80-89. CONCLUSIONS: Diabetic retinopathy screening is less effective and less cost-effective with increasing age at diagnosis of diabetes, because of the increasing probability of death before participants develop sight-threatening diabetic retinopathy and can benefit from treatment. Upper age limits on entry into screening programmes or risk stratification in older age groups may, therefore, be justifiable.

Geographical access to GPs and modes of cancer diagnosis in England: a cross-sectional study.

BACKGROUND: Poor geographical access to health services and routes to a cancer diagnosis such as emergency presentations have previously been associated with worse cancer outcomes. However, the extent to which access to GPs determines the route that patients take to obtain a cancer diagnosis is unknown. METHODS: We used a linked dataset of cancer registry and hospital records of patients with a cancer diagnosis between 2006 and 2010 across eight different cancer sites. Primary outcomes were defined as 'desirable routes to diagnosis' [screen-detected and 2-week wait (TWW) referrals] and 'less desirable routes' [emergency presentations and death certificate only (DCO)]. All other routes (GP referral, inpatient elective and other outpatient) were specified as the reference category. Geographical access was measured as travel time in minutes from patients to their GP, and multinomial logistic regression was used to estimate relative risk ratios (RRR). RESULTS: Longer travel was associated with increased risk of diagnosis via emergency and DCO, but decreased risk of diagnosis via screening and TWW. Patients travelling over 30 minutes had the highest risk of a DCO diagnosis, which was statistically significant for breast, colorectal, lung, prostate, stomach and ovarian cancers (compared with patients with travel times ≤10 minutes: RRR 5.89, 7.02, 2.30, 4.75, 10.41; P < 0.01 and 3.51, P < 0.05). DISCUSSION: Poor access to GPs may discourage early engagement with health services, decreasing the likelihood of screening uptake and increasing the likelihood of emergency presentations. Extra effort is needed to promote early diagnosis in more distant patients.

Self-help materials for smoking relapse prevention: a process evaluation of the SHARPISH randomized controlled trial.

Background: UK Stop Smoking Services are effective at assisting smokers to quit. However, smoking relapse rates are high, representing a significant public health problem. No effective interventions are currently available. This embedded qualitative process evaluation, within a randomized controlled trial of a self-help smoking relapse prevention intervention, aimed to understand patient perspectives in explaining the null trial finding, and to make recommendations for intervention development. Methods: The intervention was a British version of the 'Forever Free' self-help booklets (SHARPISH-ISRCTN 36980856). The qualitative evaluation purposefully sampled 43 interview participants, triangulated with the views of 10 participants and 12 health professionals in focus groups. Data were thematically analysed. Results: Analysis revealed important variation in individual engagement with the self-help booklets. Variation was interpreted by the meta-themes of 'motivation for cessation', and 'positioning on information provision', interacting with the theme of 'mechanisms for information provision'. Conclusions: Targeting self-help information towards those most motivated to engage may be beneficial, considering the social and cultural realities of individual's lives. Individual preferences for the mechanisms of information delivery should be appraised when designing future interventions. Long-term personalized follow-up may be a simple step in improving smoking relapse rates.

Educational Outreach with an Integrated Clinical Tool for Nurse-Led Non-communicable Chronic Disease Management in Primary Care in South Africa: A Pragmatic Cluster Randomised Controlled Trial.

BACKGROUND: In many low-income countries, care for patients with non-communicable diseases (NCDs) and mental health conditions is provided by nurses. The benefits of nurse substitution and supplementation in NCD care in high-income settings are well recognised, but evidence from low- and middle-income countries is limited. Primary Care 101 (PC101) is a programme designed to support and expand nurses' role in NCD care, comprising educational outreach to nurses and a clinical management tool with enhanced prescribing provisions. We evaluated the effect of the programme on primary care nurses' capacity to manage NCDs. METHODS AND FINDINGS: In a cluster randomised controlled trial design, 38 public sector primary care clinics in the Western Cape Province, South Africa, were randomised. Nurses in the intervention clinics were trained to use the PC101 management tool during educational outreach sessions delivered by health department trainers and were authorised to prescribe an expanded range of drugs for several NCDs. Control clinics continued use of the Practical Approach to Lung Health and HIV/AIDS in South Africa (PALSA PLUS) management tool and usual training. Patients attending these clinics with one or more of hypertension (3,227), diabetes (1,842), chronic respiratory disease (1,157) or who screened positive for depression (2,466), totalling 4,393 patients, were enrolled between 28 March 2011 and 10 November 2011. Primary outcomes were treatment intensification in the hypertension, diabetes, and chronic respiratory disease cohorts, defined as the proportion of patients in whom treatment was escalated during follow-up over 14 mo, and case detection in the depression cohort. Primary outcome data were analysed for 2,110 (97%) intervention and 2,170 (97%) control group patients. Treatment intensification rates in intervention clinics were not superior to those in the control clinics (hypertension: 44% in the intervention group versus 40% in the control group, risk ratio [RR] 1.08 [95% CI 0.94 to 1.24; p = 0.252]; diabetes: 57% versus 50%, RR 1.10 [0.97 to 1.24; p = 0.126]; chronic respiratory disease: 14% versus 12%, RR 1.08 [0.75 to 1.55; p = 0.674]), nor was case detection of depression (18% versus 24%, RR 0.76 [0.53 to 1.10; p = 0.142]). No adverse effects of the nurses' expanded scope of practice were observed. Limitations of the study include dependence on self-reported diagnoses for inclusion in the patient cohorts, limited data on uptake of PC101 by users, reliance on process outcomes, and insufficient resources to measure important health outcomes, such as HbA1c, at follow-up. CONCLUSIONS: Educational outreach to primary care nurses to train them in the use of a management tool involving an expanded role in managing NCDs was feasible and safe but was not associated with treatment intensification or improved case detection for index diseases. This notwithstanding, the intervention, with adjustments to improve its effectiveness, has been adopted for implementation in primary care clinics throughout South Africa. TRIAL REGISTRATION: The trial is registered with Current Controlled Trials (ISRCTN20283604).

Cumulative subgroup analysis to reduce waste in clinical research for individualised medicine.

BACKGROUND: Although subgroup analyses in clinical trials may provide evidence for individualised medicine, their conduct and interpretation remain controversial. METHODS: Subgroup effect can be defined as the difference in treatment effect across patient subgroups. Cumulative subgroup analysis refers to a series of repeated pooling of subgroup effects after adding data from each of related trials chronologically, to investigate the accumulating evidence for subgroup effects. We illustrated the clinical relevance of cumulative subgroup analysis in two case studies using data from published individual patient data (IPD) meta-analyses. Computer simulations were also conducted to examine the statistical properties of cumulative subgroup analysis. RESULTS: In case study 1, an IPD meta-analysis of 10 randomised trials (RCTs) on beta blockers for heart failure reported significant interaction of treatment effects with baseline rhythm. Cumulative subgroup analysis could have detected the subgroup effect 15 years earlier, with five fewer trials and 71% less patients, than the IPD meta-analysis which first reported it. Case study 2 involved an IPD meta-analysis of 11 RCTs on treatments for pulmonary arterial hypertension that reported significant subgroup effect by aetiology. Cumulative subgroup analysis could have detected the subgroup effect 6 years earlier, with three fewer trials and 40% less patients than the IPD meta-analysis. Computer simulations have indicated that cumulative subgroup analysis increases the statistical power and is not associated with inflated false positives. CONCLUSIONS: To reduce waste of research data, subgroup analyses in clinical trials should be more widely conducted and adequately reported so that cumulative subgroup analyses could be timely performed to inform clinical practice and further research.

Differences in Longer-Term Smoking Abstinence After Treatment by Specialist or Nonspecialist Advisors: Secondary Analysis of Data From a Relapse Prevention Trial.

INTRODUCTION: Smokers receiving support in specialist centers tend to have a higher short-term quit rate, compared with those receiving support in other settings from professionals for whom smoking cessation is only a part of their work. We investigated the difference in longer-term abstinence after short-term smoking cessation treatment from specialist and nonspecialist smoking cessation services. METHODS: We conducted a secondary analysis of data from a randomized controlled trial of self-help booklets for the prevention of smoking relapse. The trial included 1088 short-term quitters from specialist stop smoking clinics and 316 from nonspecialist cessation services (such as general practice, pharmacies, and health trainer services). The difference in prolonged smoking abstinence from months 4 to 12 between specialist and nonspecialist services was compared. Multivariable logistic regression analyses were conducted to investigate the association between continuous smoking abstinence and the type of smoking cessation services, adjusted for possible confounding factors (including demographic, socioeconomic, and smoking history variables). RESULTS: The proportion of continuous abstinence from 4 to 12 months was higher in short-term quitters from specialist services compared with those from nonspecialist services (39% vs. 32%; P = .023). After adjusting for a range of participant characteristics and smoking variables, the specialist service was significantly associated with a higher rate of longer-term smoking abstinence (odds ratio: 1.48, 95% CI = 1.09% to 2.00%; P = .011). CONCLUSIONS: People who receive support to stop smoking from a specialist appear to be at lower risk of relapse than those receiving support from a nonspecialist advisor.

Time to Computerized Tomography Scan, Age, and Mortality in Acute Stroke.

BACKGROUND: Time to computerized tomography (CT) is important to institute appropriate and timely hyperacute management in stroke. We aimed to evaluate mortality outcomes in relation to age and time to CT scan. METHODS: We used routinely collected data in 8 National Health Service trusts in East of England between September 2008 and April 2011. Stroke cases were prospectively identified and confirmed. Odds ratios (ORs) for unadjusted and adjusted models for age categories (<65, 65-74, 75-84, and ≥85 years) as well as time to CT categories (<90 minutes, ≥90 to <180 minutes, ≥180 minutes to 24 hours, and >24 hours) and in-hospital and early (<7 days) mortality outcomes were calculated. RESULTS: Of the 7693 patients (mean age 76.1 years, 50% male) included, 1151 (16%) died as inpatients and 336 (4%) died within 7 days. Older patients and those admitted from care home had a significantly longer time from admission until CT (P < .001). Patients who had earlier CT scans were admitted to stroke units more frequently (P < .001) but had higher in-patient (P < .001) and 7-day mortality (P < .001). Whereas older age was associated with increased odds of mortality outcomes, longer time to CT was associated with significantly reduced mortality within 7 days (corresponding ORs for the above time periods were 1.00, .61 [95% confidence interval {CI}: .39-.95], .39 [.24-.64], and .16 [.08-.33]) and in-hospital mortality (ORs 1.00, .86 [.64-1.15], .57 [.42-.78] and .71 [.52-.98]). CONCLUSIONS: Older age was associated with a significantly longer time to CT. However, using CT scan time as a benchmarking tool in stroke may have inherent limitations and does not appear to be a suitable quality marker.

Socioeconomic predictors and consequences of depression among primary care attenders with non-communicable diseases in the Western Cape, South Africa: cohort study within a randomised trial.

BACKGROUND: Socioeconomic predictors and consequences of depression and its treatment were investigated in 4393 adults with specified non-communicable diseases attending 38 public sector primary care clinics in the Eden and Overberg districts of the Western Cape, South Africa. METHODS: Participants were interviewed at baseline in 2011 and 14 months later, as part of a randomised controlled trial of a guideline-based intervention to improve diagnosis and management of chronic diseases. The 10-item Center for Epidemiologic Studies Depression Scale (CESD-10) was used to assess depression symptoms, with higher scores representing more depressed mood. RESULTS: Higher CESD-10 scores at baseline were independently associated with being less educated (p = 0.004) and having lower income (p = 0.003). CESD-10 scores at follow-up were higher in participants with less education (p = 0.010) or receiving welfare grants (p = 0.007) independent of their baseline scores. Participants with CESD-10 scores of ten or more at baseline (56 % of all participants) had 25 % higher odds of being unemployed at follow-up (p = 0.016), independently of baseline CESD-10 score and treatment status. Among participants with baseline CESD-10 scores of ten or more, antidepressant medication at baseline was independently more likely in participants who had more education (p = 0.002), higher income (p < 0.001), or were unemployed (p = 0.001). Antidepressant medication at follow up was independently more likely in participants with higher income (p = 0.023), and in clinics with better access to pharmacists (p = 0.053) and off-site drug delivery (p = 0.013). CONCLUSIONS: Socioeconomic disadvantage appears to be both a cause and consequence of depression, and may also be a barrier to treatment. There are opportunities for improving the prevention, diagnosis and treatment of depression in primary care in inequitable middle income countries like South Africa. TRIAL REGISTRATION: The trial is registered with Current Controlled Trials ( ISRCTN20283604 ).

Comparison of the effectiveness of a milk-free soy-maize-sorghum-based ready-to-use therapeutic food to standard ready-to-use therapeutic food with 25% milk in nutrition management of severely acutely malnourished Zambian children: an equivalence non-blinded cluster randomised controlled trial.

Community-based Management of Acute Malnutrition using ready-to-use therapeutic food (RUTF) has revolutionised the treatment of severe acute malnutrition (SAM). However, 25% milk content in standard peanut-based RUTF (P-RUTF) makes it too expensive. The effectiveness of milk-free RUTF has not been reported hitherto. This non-blinded, parallel group, cluster randomised, controlled, equivalence trial that compares the effectiveness of a milk-free soy-maize-sorghum-based RUTF (SMS-RUTF) with P-RUTF in treatment of children with SAM, closes the gap. A statistician randomly assigned health centres (HC) either to the SMS-RUTF (n = 12; 824 enrolled) or P-RUTF (n = 12; 1103 enrolled) arms. All SAM children admitted at the participating HCs were enrolled. All the outcomes were measured at individual level. Recovery rate was the primary outcome. The recovery rates for SMS-RUTF and P-RUTF were 53.3% and 60.8% for the intention-to-treat (ITT) analysis and 77.9% and 81.8% for per protocol (PP) analyses, respectively. The corresponding adjusted risk difference (ARD) and 95% confidence interval, were -7.6% (-14.9, 0.6%) and -3.5% (-9,6., 2.7%) for ITT (P = 0.034) and PP analyses (P = 0.257), respectively. An unanticipated interaction (interaction P < 0.001 for ITT analyses and 0.0683 for PP analyses) between the study arm and age group was observed. The ARDs were -10.0 (-17.7 to -2.3)% for ITT (P = 0.013) and -4.7 (-10.0 to 0.7) for PP (P = 0.083) analyses for the <24 months age group and 2.1 (-10.3,14.6)% for ITT (P = 0.726) and -0.6 (-16.1, 14.5) for PP (P = 0.939) for the ≥24 months age group. In conclusion, the study did not confirm our hypothesis of equivalence between SMS-RUTF and P-RUTF in SAM management.

Self-reported quality of care for older adults from 2004 to 2011: a cohort study.

BACKGROUND: little is known about changes in the quality of medical care for older adults over time. OBJECTIVE: to assess changes in technical quality of care over 6 years, and associations with participants' characteristics. DESIGN: a national cohort survey covering RAND Corporation-derived quality indicators (QIs) in face-to-face structured interviews in participants' households. PARTICIPANTS: a total of 5,114 people aged 50 or more in four waves of the English Longitudinal Study of Ageing. METHODS: the percentage achievement of 24 QIs in 10 general medical and geriatric clinical conditions was calculated for each time point, and associations with participants' characteristics were estimated using logistic regression. RESULTS: participants were eligible for 21,220 QIs. QI achievement for geriatric conditions (cataract, falls, osteoarthritis and osteoporosis) was 41% [95% confidence interval (CI): 38-44] in 2004-05 and 38% (36-39) in 2010-11. Achievement for general medical conditions (depression, diabetes mellitus, hypertension, ischaemic heart disease, pain and cerebrovascular disease) improved from 75% (73-77) in 2004-05 to 80% (79-82) in 2010-11. Achievement ranged from 89% for cerebrovascular disease to 34% for osteoarthritis. Overall achievement was lower for participants who were men, wealthier, infrequent alcohol drinkers, not obese and living alone. CONCLUSION: substantial system-level shortfalls in quality of care for geriatric conditions persisted over 6 years, with relatively small and inconsistent variations in quality by participants' characteristics. The relative lack of variation by participants' characteristics suggests that quality improvement interventions may be more effective when directed at healthcare delivery systems rather than individuals.

A model-based approach to estimating the prevalence of disease combinations in South Africa.

BACKGROUND: The development of strategies to better detect and manage patients with multiple long-term conditions requires estimates of the most prevalent condition combinations. However, standard meta-analysis tools are not well suited to synthesising heterogeneous multimorbidity data. METHODS: We developed a statistical model to synthesise data on associations between diseases and nationally representative prevalence estimates and applied the model to South Africa. Published and unpublished data were reviewed, and meta-regression analysis was conducted to assess pairwise associations between 10 conditions: arthritis, asthma, chronic obstructive pulmonary disease (COPD), depression, diabetes, HIV, hypertension, ischaemic heart disease (IHD), stroke and tuberculosis. The national prevalence of each condition in individuals aged 15 and older was then independently estimated, and these estimates were integrated with the ORs from the meta-regressions in a statistical model, to estimate the national prevalence of each condition combination. RESULTS: The strongest disease associations in South Africa are between COPD and asthma (OR 14.6, 95% CI 10.3 to 19.9), COPD and IHD (OR 9.2, 95% CI 8.3 to 10.2) and IHD and stroke (OR 7.2, 95% CI 5.9 to 8.4). The most prevalent condition combinations in individuals aged 15+ are hypertension and arthritis (7.6%, 95% CI 5.8% to 9.5%), hypertension and diabetes (7.5%, 95% CI 6.4% to 8.6%) and hypertension and HIV (4.8%, 95% CI 3.3% to 6.6%). The average numbers of comorbidities are greatest in the case of COPD (2.3, 95% CI 2.1 to 2.6), stroke (2.1, 95% CI 1.8 to 2.4) and IHD (1.9, 95% CI 1.6 to 2.2). CONCLUSION: South Africa has high levels of HIV, hypertension, diabetes and arthritis, by international standards, and these are reflected in the most prevalent condition combinations. However, less prevalent conditions such as COPD, stroke and IHD contribute disproportionately to the multimorbidity burden, with high rates of comorbidity. This modelling approach can be used in other settings to characterise the most important disease combinations and levels of comorbidity.

Task shifting of antiretroviral treatment from doctors to primary-care nurses in South Africa (STRETCH): a pragmatic, parallel, cluster-randomised trial.

BACKGROUND: Robust evidence of the effectiveness of task shifting of antiretroviral therapy (ART) from doctors to other health workers is scarce. We aimed to assess the effects on mortality, viral suppression, and other health outcomes and quality indicators of the Streamlining Tasks and Roles to Expand Treatment and Care for HIV (STRETCH) programme, which provides educational outreach training of nurses to initiate and represcribe ART, and to decentralise care. METHODS: We undertook a pragmatic, parallel, cluster-randomised trial in South Africa between Jan 28, 2008, and June 30, 2010. We randomly assigned 31 primary-care ART clinics to implement the STRETCH programme (intervention group) or to continue with standard care (control group). The ratio of randomisation depended on how many clinics were in each of nine strata. Two cohorts were enrolled: eligible patients in cohort 1 were adults (aged ≥16 years) with CD4 counts of 350 cells per µL or less who were not receiving ART; those in cohort 2 were adults who had already received ART for at least 6 months and were being treated at enrolment. The primary outcome in cohort 1 was time to death (superiority analysis). The primary outcome in cohort 2 was the proportion with undetectable viral loads (<400 copies per mL) 12 months after enrolment (equivalence analysis, prespecified difference <6%). Patients and clinicians could not be masked to group assignment. The interim analysis was blind, but data analysts were not masked after the database was locked for final analysis. Analyses were done by intention to treat. This trial is registered, number ISRCTN46836853. FINDINGS: 5390 patients in cohort 1 and 3029 in cohort 2 were in the intervention group, and 3862 in cohort 1 and 3202 in cohort 2 were in the control group. Median follow-up was 16·3 months (IQR 12·2-18·0) in cohort 1 and 18·0 months (18·0-18·0) in cohort 2. In cohort 1, 997 (20%) of 4943 patients analysed in the intervention group and 747 (19%) of 3862 in the control group with known vital status at the end of the trial had died. Time to death did not differ (hazard ratio [HR] 0·94, 95% CI 0·76-1·15). In a preplanned subgroup analysis of patients with baseline CD4 counts of 201-350 cells per µL, mortality was slightly lower in the intervention group than in the control group (0·73, 0·54-1.00; p=0·052), but it did not differ between groups in patients with baseline CD4 of 200 cells per µL or less (0·94, 0·76-1·15; p=0·577). In cohort 2, viral load suppression 12 months after enrolment was equivalent in intervention (2156 [71%] of 3029 patients) and control groups (2230 [70%] of 3202; risk difference 1·1%, 95% CI -2·4 to 4·6). INTERPRETATION: Expansion of primary-care nurses' roles to include ART initiation and represcription can be done safely, and improve health outcomes and quality of care, but might not reduce time to ART or mortality. FUNDING: UK Medical Research Council, Development Cooperation Ireland, and Canadian International Development Agency.

Cost-effectiveness of nurse-led versus doctor-led antiretroviral treatment in South Africa: pragmatic cluster randomised trial.

OBJECTIVE: To estimate the cost-effectiveness of nurse-led versus doctor-led antiretroviral treatment (ART) for HIV-infected people. DESIGN: Cost-effectiveness analysis alongside a pragmatic cluster randomised controlled trial in 31 primary care clinics (16 intervention, 15 controls) in Free State Province, South Africa. Participants were HIV-infected patients, aged ≥16 years. Cohort 1 (CD4 count ≤350 cells/µl, not yet receiving ART at enrolment): consisted of 5 390 intervention patients and 3 862 controls; Cohort 2 (already received ART for ≥6 months at enrolment) of 3 029 intervention patients and 3 202 controls. Nurses were authorised and trained to initiate and represcribe ART. Management and ART provision were decentralised to primary care clinics. In control clinics, doctors initiated and re-prescribed ART, nurses monitored ART. Main outcome measure(s) were health service costs, death (cohort 1) and undetectable viral load (<400 copies/ml) (cohort 2) during the 12 months after enrolment. RESULTS: For Cohort 1, the intervention had an estimated incremental cost of US$102.52, an incremental effect of 0.42% fewer deaths and an incremental cost-effectiveness ratio (ICER) of US$24 500 per death averted. For Cohort 2, the intervention had an estimated incremental cost of US$59.48, an incremental effect of 0.47% more undetectable viral loads and an ICER of US$12 584 per undetectable viral load. CONCLUSIONS: Nurse-led ART was associated with higher mean health service costs than doctor-led care, with small effects on primary outcomes, and a high associated level of uncertainty. Given this, and the shortage of doctors, further implementation of nurse-led ART should be considered, although this may increase health service costs.

Multimorbidity pattern and risk of dementia in later life: an 11-year follow-up study using a large community cohort and linked electronic health records.

BACKGROUND: Several long-term chronic illnesses are known to be associated with an increased risk of dementia independently, but little is known how combinations or clusters of potentially interacting chronic conditions may influence the risk of developing dementia. METHODS: 447 888 dementia-free participants of the UK Biobank cohort at baseline (2006-2010) were followed-up until 31 May 2020 with a median follow-up duration of 11.3 years to identify incident cases of dementia. Latent class analysis (LCA) was used to identify multimorbidity patterns at baseline and covariate adjusted Cox regression was used to investigate their predictive effects on the risk of developing dementia. Potential effect moderations by C reactive protein (CRP) and Apolipoprotein E (APOE) genotype were assessed via statistical interaction. RESULTS: LCA identified four multimorbidity clusters representing Mental health, Cardiometabolic, Inflammatory/autoimmune and Cancer-related pathophysiology, respectively. Estimated HRs suggest that multimorbidity clusters dominated by Mental health (HR=2.12, p<0.001, 95% CI 1.88 to 2.39) and Cardiometabolic conditions (2.02, p<0.001, 1.87 to 2.19) have the highest risk of developing dementia. Risk level for the Inflammatory/autoimmune cluster was intermediate (1.56, p<0.001, 1.37 to 1.78) and that for the Cancer cluster was least pronounced (1.36, p<0.001, 1.17 to 1.57). Contrary to expectation, neither CRP nor APOE genotype was found to moderate the effects of multimorbidity clusters on the risk of dementia. CONCLUSIONS: Early identification of older adults at higher risk of accumulating multimorbidity of specific pathophysiology and tailored interventions to prevent or delay the onset of such multimorbidity may help prevention of dementia.

Characteristics and result reporting of registered COVID-19 clinical trials of Chinese and Indian traditional medicine: A comparative analysis.

Objective: To assess the main characteristics and result reporting of registered COVID-19 interventional trials of traditional Chinese medicine and traditional Indian medicine. Materials and methods: We assessed design quality and result reporting of COVID-19 trials of traditional Chinese medicine (TCM) and traditional Indian medicine (TIM) registered before 10 February 2021, respectively, on Chinese Clinical Trial Registry (ChiCTR) and Clinical Trial Registry-India (CTRI). Comparison groups included registered COVID-19 trials of conventional medicine conducted in China (WMC), India (WMI), and in other countries (WMO). Cox regression analysis was used to assess the association between time from trial onset to result reporting and trial characteristics. Results: The proportion of COVID-19 trials investigating traditional medicine was 33.7% (130/386) among trials registered on ChiCTR, and 58.6% (266/454) on CTRI. Planned sample sizes were mostly small in all COVID-19 trials (median 100, IQR: 50-200). The proportion of trials that were randomized was 75.4 and 64.8%, respectively, for the TCM and TIM trials. Blinding measures were used in 6.2% of the TCM trials, and 23.6% of the TIM trials. Cox regression analysis revealed that planned COVID-19 clinical trials of traditional medicine were less likely to have results reported than trials of conventional medicine (hazard ratio 0.713, 95% confidence interval: 0.541-0.939; p = 0.0162). Conclusion: There were considerable between-country and within-country differences in design quality, target sample size, trial participants, and reporting of trial results. Registered COVID-19 clinical trials of traditional medicine were less likely to report results than trials of conventional medicine.

Simulation evaluation of statistical properties of methods for indirect and mixed treatment comparisons.

BACKGROUND: Indirect treatment comparison (ITC) and mixed treatment comparisons (MTC) have been increasingly used in network meta-analyses. This simulation study comprehensively investigated statistical properties and performances of commonly used ITC and MTC methods, including simple ITC (the Bucher method), frequentist and Bayesian MTC methods. METHODS: A simple network of three sets of two-arm trials with a closed loop was simulated. Different simulation scenarios were based on different number of trials, assumed treatment effects, extent of heterogeneity, bias and inconsistency. The performance of the ITC and MTC methods was measured by the type I error, statistical power, observed bias and mean squared error (MSE). RESULTS: When there are no biases in primary studies, all ITC and MTC methods investigated are on average unbiased. Depending on the extent and direction of biases in different sets of studies, ITC and MTC methods may be more or less biased than direct treatment comparisons (DTC). Of the methods investigated, the simple ITC method has the largest mean squared error (MSE). The DTC is superior to the ITC in terms of statistical power and MSE. Under the simulated circumstances in which there are no systematic biases and inconsistencies, the performances of MTC methods are generally better than the performance of the corresponding DTC methods. For inconsistency detection in network meta-analysis, the methods evaluated are on average unbiased. The statistical power of commonly used methods for detecting inconsistency is very low. CONCLUSIONS: The available methods for indirect and mixed treatment comparisons have different advantages and limitations, depending on whether data analysed satisfies underlying assumptions. To choose the most valid statistical methods for research synthesis, an appropriate assessment of primary studies included in evidence network is required.

Evaluation of the effectiveness of manual chest physiotherapy techniques on quality of life at six months post exacerbation of COPD (MATREX): a randomised controlled equivalence trial.

BACKGROUND: Manual chest physiotherapy (MCP) techniques involving chest percussion, vibration, and shaking have long been used in the treatment of respiratory conditions. However, methodological limitations in existing research have led to a state of clinical equipoise with respect to this treatment. Thus, for patients hospitalised with an exacerbation of Chronic Obstructive Pulmonary Disease (COPD), clinical preference tends to dictate whether MCP is given to assist with sputum clearance. We standardised the delivery of MCP and assessed its effectiveness on disease-specific quality of life. METHODS: In this randomised, controlled trial powered for equivalence, 526 patients hospitalised with acute COPD exacerbation were enrolled from four centres in the UK. Patients were allocated to receive MCP plus advice on airway clearance or advice on chest clearance alone. The primary outcome was a COPD specific quality of life measure, the Saint Georges Respiratory Questionnaire (SGRQ) at six months post randomisation. Analyses were by intention to treat (ITT). This study was registered, ISRCTN13825248. RESULTS: All patients were included in the analyses, of which 372 (71%) provided evaluable data for the primary outcome. An effect size of 0·3 standard deviations in SGRQ score was specified as the threshold for superiority. The ITT analyses showed no significant difference in SGRQ for patients who did, or did not receive MCP (95% CI -0·14 to 0·19). CONCLUSIONS: These data do not lend support to the routine use of MCP in the management of acute exacerbation of COPD. However, this does not mean that MCP is of no therapeutic value to COPD patients in specific circumstances.

Corrigendum to: Addressing tobacco smoking and drinking to improve TB treatment outcomes, in South Africa: a feasibility study of the ProLife program.

Alcohol and tobacco use may lead to negative treatment outcomes in tuberculosis (TB) patients, and even more so if they are HIV-infected. We developed and tested the feasibility of a complex behavioral intervention (ProLife) delivered by lay health workers (LHWs) to improve treatment outcomes in TB patients who smoke tobacco and/or drink alcohol, at nine clinics in South Africa. The intervention comprised three brief motivational interviewing (MI) sessions augmented with a short message service (SMS) program, targeting as appropriate: tobacco smoking, harmful or hazardous drinking and medication adherence. Patients received SMSs twice a week. We measured recruitment and retention rates and assessed fidelity to the MI technique (MI Treatment Integrity 4.1 tool). Finally, we explored LHWs' and patients' experiences through interviews and semistructured questionnaires, respectively. We screened 137 TB patients and identified 14 smokers, 13 alcohol drinkers, and 18 patients with both behaviors. Participants' mean age was 39.8 years, and 82.2% were men. The fidelity assessments pointed to the LHWs' successful application of key MI skills, but failure to reach MI competency thresholds. Nevertheless, most patients rated the MI sessions as helpful, ascribed positive attributes to their counselors, and reported behavioral changes. SMSs were perceived as reinforcing but difficult language and technical delivery problems were identified as problems. The LHWs' interview responses suggested that they (a) grasped the basic MI spirit but failed to understand specific MI techniques due to insufficient training practice; (b) perceived ProLife as having benefitted the patients (as well as themselves); (c) viewed the SMSs favorably; but (d) considered limited space and privacy at the clinics as key challenges. The ProLife program targeting multiple risk behaviors in TB patients is acceptable but LHW training protocol, and changes in wording and delivery of SMS are necessary to improve the intervention. Trial registration: ISRCTN14213432.

Evaluation of stroke services in Anglia Stroke Clinical Network to examine the variation in acute services and stroke outcomes.

BACKGROUND: Stroke is the third leading cause of death in developed countries and the leading cause of long-term disability worldwide. A series of national stroke audits in the UK highlighted the differences in stroke care between hospitals. The study aims to describe variation in outcomes following stroke and to identify the characteristics of services that are associated with better outcomes, after accounting for case mix differences and individual prognostic factors. METHODS/DESIGN: We will conduct a cohort study in eight acute NHS trusts within East of England, with at least one year of follow-up after stroke. The study population will be a systematically selected representative sample of patients admitted with stroke during the study period, recruited within each hospital. We will collect individual patient data on prognostic characteristics, health care received, outcomes and costs of care and we will also record relevant characteristics of each provider organisation. The determinants of one year outcome including patient reported outcome will be assessed statistically with proportional hazards regression models. Self (or proxy) completed EuroQol (EQ-5D) questionnaires will measure quality of life at baseline and follow-up for cost utility analyses. DISCUSSION: This study will provide observational data about health service factors associated with variations in patient outcomes and health care costs following hospital admission for acute stroke. This will form the basis for future RCTs by identifying promising health service interventions, assessing the feasibility of recruiting and following up trial patients, and provide evidence about frequency and variances in outcomes, and intra-cluster correlation of outcomes, for sample size calculations. The results will inform clinicians, public, service providers, commissioners and policy makers to drive further improvement in health services which will bring direct benefit to the patients.

Vaccination against COVID-19 and society's return to normality in England: a modelling study of impacts of different types of naturally acquired and vaccine-induced immunity.

OBJECTIVES: To project impacts of mass vaccination against COVID-19, and investigate possible impacts of different types of naturally acquired and vaccine-induced immunity on future dynamics of SARS-CoV-2 transmission from 2021 to 2024 in England. DESIGN: Deterministic, compartmental, discrete-time Susceptible-Exposed-Infectious-Recovered (SEIR) modelling. PARTICIPANTS: Population in England. INTERVENTIONS: Mass vaccination programmes. OUTCOME MEASURES: Daily and cumulative number of deaths from COVID-19. RESULTS: If vaccine efficacy remains high (85%), the vaccine-induced sterilising immunity lasts ≥182 days, and the reinfectivity is greatly reduced (by ≥60%), annual mass vaccination programmes can prevent further COVID-19 outbreaks in England. Under optimistic scenarios, with annual revaccination programmes, the cumulative number of COVID-19 deaths is estimated to be from 130 000 to 150 000 by the end of 2024. However, the total number of COVID-19 deaths may be up to 431 000 by the end of 2024, under scenarios with compromised vaccine efficacy (62.5%), short duration of natural and vaccine immunity (365/182 days) and small reduction in reinfectivity (30%). Under the assumed scenarios, more frequent revaccinations are associated with smaller total numbers and lower peaks of daily deaths from COVID-19. CONCLUSIONS: Under optimistic scenarios, mass immunisation using efficacious vaccines may enable society safely to return to normality. However, under plausible scenarios with low vaccine efficacy and short durability of immunity, COVID-19 could continue to cause recurrent waves of severe morbidity and mortality despite frequent vaccinations. It is crucial to monitor the vaccination effects in the real world, and to better understand characteristics of naturally acquired and vaccine-induced immunity against SARS-CoV-2.