The bidirectional longitudinal association between depressive symptoms and HbA 1c : a systematic review and meta‐analysis

Aim To investigate whether there is a bidirectional longitudinal association of depression with HbA1c. Methods We conducted a systematic literature search in PubMed, PsycINFO, CINAHL and EMBASE for observational, longitudinal studies published from January 2000 to September 2020, assessing the association between depression and HbA1c in adults. We assessed study quality with the Newcastle-Ottawa-Scale. Pooled effect estimates were reported as partial correlation coefficients (rp) or odds ratios (OR). Results We retrieved 1,642 studies; 26 studies were included in the systematic review and eleven in the meta-analysis. Most studies (16/26) focused on type 2 diabetes. Study quality was rated as good (n=19), fair (n=2) and poor (n=5). Of the meta-analysed studies, six investigated the longitudinal association between self-reported depressive symptoms and HbA1c and five the reverse longitudinal association, with a combined sample size of n=48,793 and a mean follow-up of 2 years. Higher levels of baseline depressive symptoms were associated with subsequent higher levels of HbA1c (partial r=0.07;[95%CI0.03,0.12]; I238%). Higher baseline HbA1c values were also associated with 18% increased risk of (probable) depression (OR=1.18;[95%CI1.12,1.25]; I20.0%). Conclusions Our findings support a bidirectional longitudinal association between depressive symptoms and HbA1c. However, the observed effect sizes were small and future research in large-scale longitudinal studies is needed to confirm this association. Future studies should investigate the role of type of diabetes and depression, diabetes distress and diabetes self-management behaviours. Our results may have clinical implications, as depressive symptoms and HbA1c levels could be targeted concurrently in the prevention and treatment of diabetes and depression

Implementation of Antiretroviral Therapy for Life in Pregnant/Breastfeeding HIV+ Women (Option B+) Alongside Rollout and Changing Guidelines for ART Initiation in Rural Zimbabwe: The Lablite Project Experience.

BACKGROUND: Lifelong antiretroviral therapy (ART) for pregnant and breastfeeding women (Option B+) was rolled out in Zimbabwe from 2014, with simultaneous raising of the CD4 treatment threshold to 500 cells per cubic millimeter in nonpregnant/breastfeeding adults and children 5 years and over. METHODS: Lablite is an implementation project in Zimbabwe, Malawi, and Uganda evaluating ART rollout. Routine patient-level data were collected for 6 months before and 12 months after Option B+ rollout at a district hospital and 3 primary care facilities in Zimbabwe (2 with outreach ART and 1 with no ART provision before Option B+). RESULTS: Between September 2013 and February 2015, there were 1686 ART initiations in the 4 facilities: 91% adults and 9% children younger than 15 years. In the 3 facilities with established ART, initiations rose from 300 during 6 months before Option B+ to 869 (2.9-fold) and 463 (1.5-fold), respectively, 0-6 months and 6-12 months after Option B+. Post-Option B+, an estimated 43% of pregnant/breastfeeding women needed ART for their own health, based on World Health Organization stage 3/4 or CD4 ≤350 per cubic millimeter (64% for CD4 ≤500). Seventy-four men (22%) and 123 nonpregnant/breastfeeding women (34%) initiated ART with CD4 >350 after the CD4 threshold increase. Estimated 12-month retention on ART was 79% (69%-87%) in Option B+ women (significantly lower in younger women, P = 0.01) versus 93% (91%-95%) in other adults (difference P < 0.001). CONCLUSIONS: There were increased ART initiations in all patient groups after implementation of World Health Organization 2013 guidelines. Retention of Option B+ women was poorer than retention of other adults; younger women require attention because they are more likely to disengage from care

The bidirectional longitudinal association between depressive symptoms and HbA_1c: A systematic review and met-analysis

Aim: To investigate whether there is a bidirectional longitudinal association of depression with HbA1c. Methods: We conducted a systematic literature search in PubMed, PsycINFO, CINAHL and EMBASE for observational, longitudinal studies published from January 2000 to September 2020, assessing the association between depression and HbA in adults. We assessed study quality with the Newcastle-Ottawa-Scale. Pooled effect estimates were reported as partial correlation coefficients (rp) or odds ratios (OR). Results: We retrieved 1,642 studies; 26 studies were included in the systematic review and eleven in the meta-analysis. Most studies (16/26) focused on type 2 diabetes. Study quality was rated as good (n = 19), fair (n = 2) and poor (n = 5). Of the meta-analysed studies, six investigated the longitudinal association between self-reported depressive symptoms and HbA1c and five the reverse longitudinal association, with a combined sample size of n = 48,793 and a mean follow-up of 2 years. Higher levels of baseline depressive symptoms were associated with subsequent higher levels of HbA1c (partial r = 0.07; [95% CI 0.03, 0.12]; I238%). Higher baseline HbA1c values were also associated with 18% increased risk of (probable) depression (OR = 1.18; [95% CI 1.12,1.25]; I20.0%). Conclusions: Our findings support a bidirectional longitudinal association between depressive symptoms and HbA1c. However, the observed effect sizes were small and future research in large-scale longitudinal studies is needed to confirm this association. Future studies should investigate the role of type of diabetes and depression, diabetes distress and diabetes self-management behaviours. Our results may have clinical implications, as depressive symptoms and HbA1c levels could be targeted concurrently in the prevention and treatment of diabetes and depression. Registration: PROSPERO ID CRD42019147551

The Lablite project: A cross-sectional mapping survey of decentralized HIV service provision in Malawi, Uganda and Zimbabwe

Background In sub-Saharan Africa antiretroviral therapy (ART) is being decentralized from tertiary/secondary care facilities to primary care. The Lablite project supports effective decentralization in 3 countries. It began with a cross-sectional survey to describe HIV and ART services. Methods 81 purposively sampled health facilities in Malawi, Uganda and Zimbabwe were surveyed. Results The lowest level primary health centres comprised 16/20, 21/39 and 16/22 facilities included in Malawi, Uganda and Zimbabwe respectively. In Malawi and Uganda most primary health facilities had at least 1 medical assistant/clinical officer, with average 2.5 and 4 nurses/midwives for median catchment populations of 29,275 and 9,000 respectively. Primary health facilities in Zimbabwe were run by nurses/midwives, with average 6 for a median catchment population of 8,616. All primary health facilities provided HIV testing and counselling, 50/53 (94%) cotrimoxazole preventive therapy (CPT), 52/53 (98%) prevention of mother-to-child transmission of HIV (PMTCT) and 30/53 (57%) ART management (1/30 post ART-initiation follow-up only). All secondary and tertiary-level facilities provided HIV and ART services. In total, 58/81 had ART provision. Stock-outs during the 3 months prior to survey occurred across facility levels for HIV test-kits in 55%, 26% and 9% facilities in Malawi, Uganda and Zimbabwe respectively; for CPT in 58%, 32% and 9% and for PMTCT drugs in 26%, 10% and 0% of facilities (excluding facilities where patients were referred out for either drug). Across all countries, in facilities with ART stored on-site, adult ART stock-outs were reported in 3/44 (7%) facilities compared with 10/43 (23%) facility stock-outs of paediatric ART. Laboratory services at primary health facilities were limited: CD4 was used for ART initiation in 4/9, 5/6 and 13/14 in Malawi, Uganda and Zimbabwe respectively, but frequently only in selected patients. Routine viral load monitoring was not used; 6/58 (10%) facilities with ART provision accessed centralised viral loads for selected patients. Conclusions Although coverage of HIV testing, PMTCT and cotrimoxazole prophylaxis was high in all countries, decentralization of ART services was variable and incomplete. Challenges of staffing and stock management were evident. Laboratory testing for toxicity and treatment effectiveness monitoring was not available in most primary level facilities

Are infections associated with cognitive decline and neuroimaging outcomes? A historical cohort study using data from the UK Biobank study linked to electronic health records.

Funder: Royal SocietyWhile there is growing evidence of associations between infections and dementia risk, associations with cognitive impairment and potential structural correlates of cognitive decline remain underexplored. Here we aimed to investigate the presence and nature of any associations between common infections, cognitive decline and neuroimaging parameters. The UK Biobank is a large volunteer cohort (over 500,000 participants recruited aged 40-69) with linkage to primary and secondary care records. Using linear mixed effects models, we compared participants with and without a history of infections for changes in cognitive function during follow-up. Linear regression models were used to investigate the association of infections with hippocampal and white matter hyperintensity (WMH) volume. 16,728 participants (median age 56.0 years [IQR 50.0-61.0]; 51.3% women) had baseline and follow-up cognitive measures. We found no evidence of an association between the presence of infection diagnoses and cognitive decline for mean correct response time (slope difference [infections versus no infections] = 0.40 ms, 95% CI: -0.17-0.96 per year), visual memory (slope difference 0.0004 log errors per year, 95% CI: -0.003-0.004, fluid intelligence (slope difference 0.007, 95% CI: -0.010-0.023) and prospective memory (OR 0.88, 95% CI: 0.68-1.14). No evidence of an association was found between infection site, setting or frequency and cognitive decline except for small associations on the visual memory test. We found no association between infections and hippocampal or WMH volume. Limitations of our study include selection bias, potential practice effects and the relatively young age of our cohort. Our findings do not support a major role for common midlife infections in contributing to cognitive decline for this cohort. Further research is warranted in individuals with more severe infections, for infections occurring later in life

Incident dementia risk among patients with type 2 diabetes receiving metformin versus alternative oral glucose-lowering therapy: an observational cohort study using UK primary healthcare records

Introduction 4.2 million individuals in the UK have type 2 diabetes, a known risk factor for dementia and mild cognitive impairment (MCI). Diabetes treatment may modify this association, but existing evidence is conflicting. We therefore aimed to assess the association between metformin therapy and risk of incident all-cause dementia or MCI compared with other oral glucose-lowering therapies (GLTs).Research design and methods We conducted an observational cohort study using the Clinical Practice Research Datalink among UK adults diagnosed with diabetes at ≥40 years between 1990 and 2019. We used an active comparator new user design to compare risks of dementia and MCI among individuals initially prescribed metformin versus an alternative oral GLT using Cox proportional hazards regression controlling for sociodemographic, lifestyle and clinical confounders. We assessed for interaction by age and sex. Sensitivity analyses included an as-treated analysis to mitigate potential exposure misclassification.Results We included 211 396 individuals (median age 63 years; 42.8% female), of whom 179 333 (84.8%) initiated on metformin therapy. Over median follow-up of 5.4 years, metformin use was associated with a lower risk of dementia (adjusted HR (aHR) 0.86 (95% CI 0.79 to 0.94)) and MCI (aHR 0.92 (95% CI 0.86 to 0.99)). Metformin users aged under 80 years had a lower dementia risk (aHR 0.77 (95% CI 0.68 to 0.85)), which was not observed for those aged ≥80 years (aHR 0.95 (95% CI 0.87 to 1.05)). There was no interaction with sex. The as-treated analysis showed a reduced effect size compared with the main analysis (aHR 0.90 (95% CI 0.83 to 0.98)).Conclusions Metformin use was associated with lower risks of incident dementia and MCI compared with alternative GLT among UK adults with diabetes. While our findings are consistent with a neuroprotective effect of metformin against dementia, further research is needed to reduce risks of confounding by indication and assess causality

Incident dementia risk among patients with type 2 diabetes receiving metformin versus alternative oral glucose-lowering therapy: an observational cohort study using UK primary healthcare records.

Peer reviewed: TrueAcknowledgements: The data are provided by patients and collected by the NHS as part of their care and support.INTRODUCTION: 4.2 million individuals in the UK have type 2 diabetes, a known risk factor for dementia and mild cognitive impairment (MCI). Diabetes treatment may modify this association, but existing evidence is conflicting. We therefore aimed to assess the association between metformin therapy and risk of incident all-cause dementia or MCI compared with other oral glucose-lowering therapies (GLTs). RESEARCH DESIGN AND METHODS: We conducted an observational cohort study using the Clinical Practice Research Datalink among UK adults diagnosed with diabetes at ≥40 years between 1990 and 2019. We used an active comparator new user design to compare risks of dementia and MCI among individuals initially prescribed metformin versus an alternative oral GLT using Cox proportional hazards regression controlling for sociodemographic, lifestyle and clinical confounders. We assessed for interaction by age and sex. Sensitivity analyses included an as-treated analysis to mitigate potential exposure misclassification. RESULTS: We included 211 396 individuals (median age 63 years; 42.8% female), of whom 179 333 (84.8%) initiated on metformin therapy. Over median follow-up of 5.4 years, metformin use was associated with a lower risk of dementia (adjusted HR (aHR) 0.86 (95% CI 0.79 to 0.94)) and MCI (aHR 0.92 (95% CI 0.86 to 0.99)). Metformin users aged under 80 years had a lower dementia risk (aHR 0.77 (95% CI 0.68 to 0.85)), which was not observed for those aged ≥80 years (aHR 0.95 (95% CI 0.87 to 1.05)). There was no interaction with sex. The as-treated analysis showed a reduced effect size compared with the main analysis (aHR 0.90 (95% CI 0.83 to 0.98)). CONCLUSIONS: Metformin use was associated with lower risks of incident dementia and MCI compared with alternative GLT among UK adults with diabetes. While our findings are consistent with a neuroprotective effect of metformin against dementia, further research is needed to reduce risks of confounding by indication and assess causality

The Lablite project: A cross-sectional mapping survey of decentralized HIV service provision in Malawi, Uganda and Zimbabwe

Abstract Background In sub-Saharan Africa antiretroviral therapy (ART) is being decentralized from tertiary/secondary care facilities to primary care. The Lablite project supports effective decentralization in 3 countries. It began with a cross-sectional survey to describe HIV and ART services. Methods 81 purposively sampled health facilities in Malawi, Uganda and Zimbabwe were surveyed. Results The lowest level primary health centres comprised 16/20, 21/39 and 16/22 facilities included in Malawi, Uganda and Zimbabwe respectively. In Malawi and Uganda most primary health facilities had at least 1 medical assistant/clinical officer, with average 2.5 and 4 nurses/midwives for median catchment populations of 29,275 and 9,000 respectively. Primary health facilities in Zimbabwe were run by nurses/midwives, with average 6 for a median catchment population of 8,616. All primary health facilities provided HIV testing and counselling, 50/53 (94%) cotrimoxazole preventive therapy (CPT), 52/53 (98%) prevention of mother-to-child transmission of HIV (PMTCT) and 30/53 (57%) ART management (1/30 post ART-initiation follow-up only). All secondary and tertiary-level facilities provided HIV and ART services. In total, 58/81 had ART provision. Stock-outs during the 3 months prior to survey occurred across facility levels for HIV test-kits in 55%, 26% and 9% facilities in Malawi, Uganda and Zimbabwe respectively; for CPT in 58%, 32% and 9% and for PMTCT drugs in 26%, 10% and 0% of facilities (excluding facilities where patients were referred out for either drug). Across all countries, in facilities with ART stored on-site, adult ART stock-outs were reported in 3/44 (7%) facilities compared with 10/43 (23%) facility stock-outs of paediatric ART. Laboratory services at primary health facilities were limited: CD4 was used for ART initiation in 4/9, 5/6 and 13/14 in Malawi, Uganda and Zimbabwe respectively, but frequently only in selected patients. Routine viral load monitoring was not used; 6/58 (10%) facilities with ART provision accessed centralised viral loads for selected patients. Conclusions Although coverage of HIV testing, PMTCT and cotrimoxazole prophylaxis was high in all countries, decentralization of ART services was variable and incomplete. Challenges of staffing and stock management were evident. Laboratory testing for toxicity and treatment effectiveness monitoring was not available in most primary level facilities

Shifting human resources for health in the context of ART provision: qualitative and quantitative findings from the Lablite baseline study

Background: Lablite is an implementation project supporting and studying decentralized antiretroviral therapy (ART) rollout to rural communities in Malawi, Uganda and Zimbabwe. Task shifting is one of the strategies to deal with shortage of health care workers (HCWs) in ART provision. Evaluating Human Resources for Health (HRH) optimization is essential for ensuring access to ART. The Lablite project started with a baseline survey whose aim was to describe and compare national and intercountry delivery of ART services including training, use of laboratories and clinical care. Methods: A cross-sectional survey was conducted between October 2011 and August 2012 in a sample of 81 health facilities representing different regions, facility levels and experience of ART provision in Malawi, Uganda and Zimbabwe. Using a questionnaire, data were collected on facility characteristics, human resources and service provision. Thirty three (33) focus group discussions were conducted with HCWs in a subset of facilities in Malawi and Zimbabwe. Results: The survey results showed that in Malawi and Uganda, primary care facilities were run by non-physician clinical officers/medical assistants while in Zimbabwe, they were run by nurses/midwives. Across the three countries, turnover of staff was high especially among nurses. Between 10 and 20% of the facilities had at least one clinical officer/medical assistant leave in the 3 months prior to the study. Qualitative results show that HCWs in ART and non-ART facilities perceived a shortage of staff for all services, even prior to the introduction of ART provision. HCWs perceived the introduction of ART as having increased workload. In Malawi, the number of people on ART and hence the workload for HCWs has further increased following the introduction of Option B+ (ART initiation and life-long treatment for HIV positive pregnant and lactating women), resulting in extended working times and concerns that the quality of services have been affected. For some HCWs, perceived low salaries, extended working schedules, lack of training opportunities and inadequate infrastructure for service provision were linked to low job satisfaction and motivation. Conclusions: ART has been decentralized to lower level facilities in the context of an ongoing HRH crisis and staff shortage, which may compromise the provision of high-quality ART services. Task shifting interventions need adequate resources, relevant training opportunities, and innovative strategies to optimize the operationalization of new WHO treatment guidelines which continue to expand the number of people eligible for ART

Routine versus clinically driven laboratory monitoring of HIV antiretroviral therapy in Africa (DART): a randomised non-inferiority trial.

BACKGROUND: HIV antiretroviral therapy (ART) is often managed without routine laboratory monitoring in Africa; however, the effect of this approach is unknown. This trial investigated whether routine toxicity and efficacy monitoring of HIV-infected patients receiving ART had an important long-term effect on clinical outcomes in Africa. METHODS: In this open, non-inferiority trial in three centres in Uganda and one in Zimbabwe, 3321 symptomatic, ART-naive, HIV-infected adults with CD4 counts less than 200 cells per microL starting ART were randomly assigned to laboratory and clinical monitoring (LCM; n=1659) or clinically driven monitoring (CDM; n=1662) by a computer-generated list. Haematology, biochemistry, and CD4-cell counts were done every 12 weeks. In the LCM group, results were available to clinicians; in the CDM group, results (apart from CD4-cell count) could be requested if clinically indicated and grade 4 toxicities were available. Participants switched to second-line ART after new or recurrent WHO stage 4 events in both groups, or CD4 count less than 100 cells per microL (LCM only). Co-primary endpoints were new WHO stage 4 HIV events or death, and serious adverse events. Non-inferiority was defined as the upper 95% confidence limit for the hazard ratio (HR) for new WHO stage 4 events or death being no greater than 1.18. Analyses were by intention to treat. This study is registered, number ISRCTN13968779. FINDINGS: Two participants assigned to CDM and three to LCM were excluded from analyses. 5-year survival was 87% (95% CI 85-88) in the CDM group and 90% (88-91) in the LCM group, and 122 (7%) and 112 (7%) participants, respectively, were lost to follow-up over median 4.9 years' follow-up. 459 (28%) participants receiving CDM versus 356 (21%) LCM had a new WHO stage 4 event or died (6.94 [95% CI 6.33-7.60] vs 5.24 [4.72-5.81] per 100 person-years; absolute difference 1.70 per 100 person-years [0.87-2.54]; HR 1.31 [1.14-1.51]; p=0.0001). Differences in disease progression occurred from the third year on ART, whereas higher rates of switch to second-line treatment occurred in LCM from the second year. 283 (17%) participants receiving CDM versus 260 (16%) LCM had a new serious adverse event (HR 1.12 [0.94-1.32]; p=0.19), with anaemia the most common (76 vs 61 cases). INTERPRETATION: ART can be delivered safely without routine laboratory monitoring for toxic effects, but differences in disease progression suggest a role for monitoring of CD4-cell count from the second year of ART to guide the switch to second-line treatment. FUNDING: UK Medical Research Council, the UK Department for International Development, the Rockefeller Foundation, GlaxoSmithKline, Gilead Sciences, Boehringer-Ingelheim, and Abbott Laboratories