Integrated management of HIV, diabetes, and hypertension in sub-Saharan Africa (INTE-AFRICA): a pragmatic cluster-randomised, controlled trial.

BACKGROUND: In sub-Saharan Africa, health-care provision for chronic conditions is fragmented. The aim of this study was to determine whether integrated management of HIV, diabetes, and hypertension led to improved rates of retention in care for people with diabetes or hypertension without adversely affecting rates of HIV viral suppression among people with HIV when compared to standard vertical care in medium and large health facilities in Uganda and Tanzania. METHODS: In INTE-AFRICA, a pragmatic cluster-randomised, controlled trial, we randomly allocated primary health-care facilities in Uganda and Tanzania to provide either integrated care or standard care for HIV, diabetes, and hypertension. Random allocation (1:1) was stratified by location, infrastructure level, and by country, with a permuted block randomisation method. In the integrated care group, participants with HIV, diabetes, or hypertension were managed by the same health-care workers, used the same pharmacy, had similarly designed medical records, shared the same registration and waiting areas, and had an integrated laboratory service. In the standard care group, these services were delivered vertically for each condition. Patients were eligible to join the trial if they were living with confirmed HIV, diabetes, or hypertension, were aged 18 years or older, were living within the catchment population area of the health facility, and were likely to remain in the catchment population for 6 months. The coprimary outcomes, retention in care (attending a clinic within the last 6 months of study follow-up) for participants with either diabetes or hypertension (tested for superiority) and plasma viral load suppression for those with HIV (>1000 copies per mL; tested for non-inferiority, 10% margin), were analysed using generalised estimating equations in the intention-to-treat population. This trial is registered with ISCRTN 43896688. FINDINGS: Between June 30, 2020, and April 1, 2021 we randomly allocated 32 health facilities (17 in Uganda and 15 in Tanzania) with 7028 eligible participants to the integrated care or the standard care groups. Among participants with diabetes, hypertension, or both, 2298 (75·8%) of 3032 were female and 734 (24·2%) of 3032 were male. Of participants with HIV alone, 2365 (70·3%) of 3365 were female and 1000 (29·7%) of 3365 were male. Follow-up lasted for 12 months. Among participants with diabetes, hypertension, or both, the proportion alive and retained in care at study end was 1254 (89·0%) of 1409 in integrated care and 1457 (89·8%) of 1623 in standard care. The risk differences were -0·65% (95% CI -5·76 to 4·46; p=0·80) unadjusted and -0·60% (-5·46 to 4·26; p=0·81) adjusted. Among participants with HIV, the proportion who had a plasma viral load of less than 1000 copies per mL was 1412 (97·0%) of 1456 in integrated care and 1451 (97·3%) of 1491 in standard care. The differences were -0·37% (one-sided 95% CI -1·99 to 1·26; pnon-inferiority<0·0001 unadjusted) and -0·36% (-1·99 to 1·28; pnon-inferiority<0·0001 adjusted). INTERPRETATION: In sub-Saharan Africa, integrated chronic care services could achieve a high standard of care for people with diabetes or hypertension without adversely affecting outcomes for people with HIV. FUNDING: European Union Horizon 2020 and Global Alliance for Chronic Diseases.

Bovine viral diarrhoea viruses from New Zealand belong predominantly to the BVDV-1a genotype.

AIM: To determine which genotypes of bovine viral diarrhoea virus (BVDV) circulate among cattle in New Zealand. METHODS: Samples comprised BVDV-1-positive sera sourced from submissions to veterinary diagnostic laboratories in 2019 (n = 25), 2020 (n = 59) and 2022 (n = 74) from both beef and dairy herds, as well as archival BVDV-1 isolates (n = 5). Fragments of the 5' untranslated region (5' UTR) and glycoprotein E2 coding sequence of the BVDV genome were amplified and sequenced. The sequences were aligned to each other and to international BVDV-1 sequences to determine their similarities and phylogenetic relationships. The 5' UTR sequences were also used to create genetic haplotype networks to determine if they were correlated with selected traits (location, type of farm, and year of collection). RESULTS: The 5' UTR sequences from New Zealand BVDV were closely related to each other, with pairwise identities between 89% and 100%. All clustered together and were designated as BVDV-1a (n = 144) or BVDV-1c (n = 5). There was no evidence of a correlation between the 5' UTR sequence and the geographical origin within the country, year of collection or the type of farm. Partial E2 sequences from New Zealand BVDV (n = 76) showed 74-100% identity to each other and clustered in two main groups. The subtype assignment based on the E2 sequence was the same as based on the 5' UTR analysis. This is the first comprehensive analysis of genomic variability of contemporary New Zealand BVDV based on the analysis of the non-coding (5' UTR) and coding (E2) sequences. CONCLUSIONS AND CLINICAL RELEVANCE: Knowledge of the diversity of the viruses circulating in the country is a prerequisite for the development of effective control strategies, including a selection of suitable vaccines. The data presented suggest that New Zealand BVDV are relatively homogeneous, which should facilitate eradication efforts including selection or development of the most suitable vaccines.

Metformin for the prevention of diabetes among people with HIV and either impaired fasting glucose or impaired glucose tolerance (prediabetes) in Tanzania: a Phase II randomised placebo-controlled trial.

AIMS/HYPOTHESIS: In sub-Saharan Africa (SSA), 5% of adults are living with type 2 diabetes and this is rising sharply, with a greater increase among people with HIV. Evidence on the efficacy of prevention strategies in this cohort is scarce. We conducted a Phase II double-blind placebo-controlled trial that aimed to determine the impact of metformin on blood glucose levels among people with prediabetes (defined as impaired fasting glucose [IFG] and/or impaired glucose tolerance [IGT]) and HIV in SSA. METHODS: Adults (≥18 years old) who were stable in HIV care and found to have prediabetes (IFG and/or IGT) and who were attending hospitals in Dar es Salaam, Tanzania, were randomised to receive sustained-release metformin, 2000 mg daily, or matching placebo between 4 November 2019 and 21 July 2020. Randomisation used permuted blocks. Allocation was concealed in the trial database and made visible only to the Chief Pharmacist after consent was taken. All participants, research and clinical staff remained blinded to the allocation. Participants were provided with information on diet and lifestyle and had access to various health information following the start of the coronavirus disease 2019 (COVID-19) pandemic. Participants were followed up for 12 months. The primary outcome measure was capillary blood glucose measured 2 h following a 75 g glucose load. Analyses were by intention-to-treat. RESULTS: In total, 364 participants (182 in each arm) were randomised to the metformin or placebo group. At enrolment, in the metformin and placebo arms, mean fasting glucose was 6.37 mmol/l (95% CI 6.23, 6.50) and 6.26 mmol/l (95% CI 6.15, 6.36), respectively, and mean 2 h glucose levels following a 75 g oral glucose load were 8.39 mmol/l (95% CI 8.22, 8.56) and 8.24 mmol/l (95% CI 8.07, 8.41), respectively. At the final assessment at 12 months, 145/182 (79.7%) individuals randomised to metformin compared with 158/182 (86.8%) randomised to placebo indicated that they had taken >95% of their medicines in the previous 28 days (p=0.068). At this visit, in the metformin and placebo arms, mean fasting glucose levels were 6.17 mmol/l (95% CI 6.03, 6.30) and 6.30 mmol/l (95% CI 6.18, 6.42), respectively, and mean 2 h glucose levels following a 75 g oral glucose load were 7.88 mmol/l (95% CI 7.65, 8.12) and 7.71 mmol/l (95% CI 7.49, 7.94), respectively. Using a linear mixed model controlling for respective baseline values, the mean difference between the metformin and placebo group (metformin-placebo) was -0.08 mmol/l (95% CI -0.37, 0.20) for fasting glucose and 0.20 mmol/l (95% CI -0.17, 0.58) for glucose levels 2 h post a 75 g glucose load. Weight was significantly lower in the metformin arm than in the placebo arm: using the linear mixed model adjusting for baseline values, the mean difference in weight was -1.47 kg (95% CI -2.58, -0.35). In total, 16/182 (8.8%) individuals had a serious adverse event (Grade 3 or Grade 4 in the Division of Acquired Immunodeficiency Syndrome [DAIDS] adverse event grading table) or died in the metformin arm compared with 18/182 (9.9%) in the placebo arm; these events were either unrelated to or unlikely to be related to the study drugs. CONCLUSIONS/INTERPRETATION: Blood glucose decreased over time in both the metformin and placebo arms during the trial but did not differ significantly between the arms at 12 months of follow up. Metformin therapy was found to be safe for use in individuals with HIV and prediabetes. A larger trial with longer follow up is needed to establish if metformin can be safely used for the prevention of diabetes in people who have HIV. TRIAL REGISTRATION: The trial is registered on the International Standard Randomised Controlled Trial Number (ISRCTN) registry ( www.isrctn.com/ ), registration number: ISCRTN76157257. FUNDING: This research was funded by the National Institute for Health Research using UK aid from the UK Government to support global health research.

Understanding the pathogenesis of lean non-autoimmune diabetes in an African population with newly diagnosed diabetes.

AIMS/HYPOTHESIS: Apparent type 2 diabetes is increasingly reported in lean adult individuals in sub-Saharan Africa. However, studies undertaking robust clinical and metabolic characterisation of lean individuals with new-onset type 2 diabetes are limited in this population. This cross-sectional study aimed to perform a detailed clinical and metabolic characterisation of newly diagnosed adult patients with diabetes in Uganda, in order to compare features between lean and non-lean individuals. METHODS: Socio-demographic, clinical, biophysical and metabolic (including oral glucose tolerance test) data were collected on 568 adult patients with newly diagnosed diabetes. Participants were screened for islet autoantibodies to exclude those with autoimmune diabetes. The remaining participants (with type 2 diabetes) were then classified as lean (BMI <25 kg/m2) or non-lean (BMI ≥25 kg/m2), and their socio-demographic, clinical, biophysical and metabolic characteristics were compared. RESULTS: Thirty-four participants (6.4%) were excluded from analyses because they were positive for pancreatic autoantibodies, and a further 34 participants because they had incomplete data. For the remaining 500 participants, the median (IQR) age, BMI and HbA1c were 48 years (39-58), 27.5 kg/m2 (23.6-31.4) and 90 mmol/mol (61-113) (10.3% [7.7-12.5]), respectively, with a female predominance (approximately 57%). Of the 500 participants, 160 (32%) and 340 (68%) were lean and non-lean, respectively. Compared with non-lean participants, lean participants were mainly male (60.6% vs 35.3%, p<0.001) and had lower visceral adiposity level (5 [4-7] vs 11 [9-13], p<0.001) and features of the metabolic syndrome (uric acid, 246.5 [205.0-290.6] vs 289 [234-347] µmol/l, p<0.001; leptin, 660.9 [174.5-1993.1] vs 3988.0 [1336.0-6595.0] pg/ml, p<0.001). In addition, they displayed markedly reduced markers of beta cell function (oral insulinogenic index 0.8 [0.3-2.5] vs 1.6 [0.6-4.6] pmol/mmol; 120 min serum C-peptide 0.70 [0.33-1.36] vs 1.02 [0.60-1.66] nmol/l, p<0.001). CONCLUSIONS/INTERPRETATION: Approximately one-third of participants with incident adult-onset non-autoimmune diabetes had BMI <25 kg/m2. Diabetes in these lean individuals was more common in men, and predominantly associated with reduced pancreatic secretory function rather than insulin resistance. The underlying pathological mechanisms are unclear, but this is likely to have important management implications.

Patient and health provider costs of integrated HIV, diabetes and hypertension ambulatory health services in low-income settings - an empirical socio-economic cohort study in Tanzania and Uganda.

BACKGROUND: Integration of health services might be an efficient strategy for managing multiple chronic conditions in sub-Saharan Africa, considering the scope of treatments and synergies in service delivery. Proven to promote compliance, integration may lead to increased economies-of-scale. However, evidence on the socio-economic consequences of integration for providers and patients is lacking. We assessed the clinical resource use, staff time, relative service efficiency and overall societal costs associated with integrating HIV, diabetes and hypertension services in single one-stop clinics where persons with one or more of these conditions were managed. METHODS: 2273 participants living with HIV infection, diabetes, or hypertension or combinations of these conditions were enrolled in 10 primary health facilities in Tanzania and Uganda and followed-up for up to 12 months. We collected data on resources used from all participants and on out-of-pocket costs in a sub-sample of 1531 participants, while a facility-level costing study was conducted at each facility. Health worker time per participant was assessed in a time-motion morbidity-stratified study among 228 participants. The mean health service cost per month and out-of-pocket costs per participant visit were calculated in 2020 US$ prices. Nested bootstrapping from these samples accounted for uncertainties. A data envelopment approach was used to benchmark the efficiency of the integrated services. Last, we estimated the budgetary consequences of integration, based on prevalence-based projections until 2025, for both country populations. RESULTS: Their average retention after 1 year service follow-up was 1911/2273 (84.1%). Five hundred and eighty-two of 2273 (25.6%) participants had two or all three chronic conditions and 1691/2273 (74.4%) had a single condition. During the study, 84/2239 (3.8%) participants acquired a second or third condition. The mean service costs per month of managing two conditions in a single participant were $39.11 (95% CI 33.99, 44.33), $32.18 (95% CI 30.35, 34.07) and $22.65 (95% CI 21.86, 23.43) for the combinations of HIV and diabetes and of HIV and hypertension, diabetes and hypertension, respectively. These costs were 34.4% (95% CI 17.9%, 41.9%) lower as compared to managing any two conditions separately in two different participants. The cost of managing an individual with all three conditions was 48.8% (95% CI 42.1%, 55.3%) lower as compared to managing these conditions separately. Out-of-pocket healthcare expenditure per participant per visit was $7.33 (95% CI 3.70, 15.86). This constituted 23.4% (95% CI 9.9, 54.3) of the total monthly service expenditure per patient and 11.7% (95% CI 7.3, 22.1) of their individual total household income. The integrated clinics' mean efficiency benchmark score was 0.86 (range 0.30-1.00) suggesting undercapacity that could serve more participants without compromising quality of care. The estimated budgetary consequences of managing multi-morbidity in these types of integrated clinics is likely to increase by 21.5% (range 19.2-23.4%) in the next 5 years, including substantial savings of 21.6% on the provision of integrated care for vulnerable patients with multi-morbidities. CONCLUSION: Integration of HIV services with diabetes and hypertension control reduces both health service and household costs, substantially. It is likely an efficient and equitable way to address the increasing burden of financially vulnerable households among Africa's ageing populations. Additional economic evidence is needed from longer-term larger-scale implementation studies to compare extended integrated care packages directly simultaneously with evidence on sustained clinical outcomes.

Handgrip strength as a simple measure for screening prediabetes and type 2 diabetes mellitus risk among adults in Malawi: A cross-sectional study.

OBJECTIVE: Handgrip strength, a simple measure of muscle strength, has been reported as a predictor of both prediabetes and type 2 diabetes mellitus (T2DM) and has been suggested for screening prediabetes and T2DM risk. This study examined the relationship of handgrip strength with prediabetes and T2DM among rural- and urban-dwelling adults in Malawi. METHODS: This was a cross-sectional study nested in a follow-up study of prediabetic and prehypertensive individuals identified during an extensive noncommunicable disease survey in Malawi. A total of 261 participants (women: 64%) were recruited. Univariate and multivariate binary logistic regression analyses were performed to examine the association of prediabetes and T2DM with relative handgrip strength. RESULTS: The mean (SD) age of the participants was 49.7 (13.6) years, and 54.0% were between the ages of 40 and 59 years. The mean (SD) absolute handgrip strength and relative handgrip strength were 28.8 (7.3) kg and 1.16 (0.40) kg/BMI, respectively, and the mean relative handgrip strength differed significantly (p < 0.001) by T2DM status. In unadjusted model, the odds ratio (OR) of prediabetes and T2DM per unit increase in relative handgrip strength was 0.12 [95% CI; 0.04-0.33]. The result remained significant after adjusting for age (continuous), sex, place of study, hypertension, dyslipidaemia and level of education (aOR [95% CI]; 0.19 [0.03-0.95]). CONCLUSIONS: The findings suggest that handgrip strength could be a relatively inexpensive, noninvasive measure for contributing to risk scores to identify high-risk individuals for screening diabetes in SSA.

Antenatal management and maternal/fetal outcomes associated with hyperglycaemia in pregnancy (HIP) in Uganda; a prospective cohort study.

BACKGROUND: Hyperglycaemia in pregnancy (HIP) is associated with complications for both mother and baby. The prevalence of the condition is likely to increase across Africa as the continent undergoes a rapid demographic transition. However, little is known about the management and pregnancy outcomes associated with HIP in the region, particularly less severe forms of hyperglycaemia. It is therefore important to generate local data so that resources may be distributed effectively. The aim of this study was to describe the antenatal management and maternal/fetal outcomes associated with HIP in Ugandan women. METHODS: A prospective cohort study of 2917 pregnant women in five major hospitals in urban/semi-urban central Uganda. Women were screened with oral glucose tolerance test (OGTT) at 24-28 weeks of gestation. Cases of gestational diabetes (GDM) and diabetes in pregnancy (DIP) were identified (WHO 2013 diagnostic criteria) and received standard care. Data was collected on maternal demographics, anthropometrics, antenatal management, umbilical cord c-peptide levels, and pregnancy outcomes. RESULTS: Two hundred and seventy-six women were diagnosed with HIP (237 classified as GDM and 39 DIP). Women had between one and four fasting capillary blood glucose checks during third trimester. All received lifestyle advice, one quarter (69/276) received metformin therapy, and one woman received insulin. HIP was associated with large birthweight (unadjusted relative risk 1.30, 95% CI 1.00-1.68), Caesarean delivery (RR 1.34, 95% CI 1.14-1.57) and neonatal hypoglycaemia (RR 4.37, 95% CI 1.36-14.1), but not perinatal mortality or preterm birth. Pregnancy outcomes were generally worse for women with DIP compared with GDM. CONCLUSION: HIP is associated with significant adverse pregnancy outcomes in this population, particularly overt diabetes in pregnancy. However pregnancy outcomes in women with milder forms of hyperglycaemia are similar to those with normoglycaemic pregnancies. Intervention strategies are required to improve current monitoring and management practice, and more research needed to understand if this is a cost-effective way of preventing poor perinatal outcomes.

A comparison of the associations between adiposity and lipids in Malawi and the United Kingdom.

BACKGROUND: The prevalence of excess adiposity, as measured by elevated body mass index (BMI) and waist-hip ratio (WHR), is increasing in sub-Saharan African (SSA) populations. This could add a considerable burden of cardiovascular and metabolic diseases for which these populations are currently ill-prepared. Evidence from white, European origin populations shows that higher adiposity leads to an adverse lipid profile; whether these associations are similar in all SSA populations requires further exploration. This study compared the association of BMI and WHR with lipid profile in urban Malawi with a contemporary cohort with contrasting socioeconomic, demographic, and ethnic characteristics in the United Kingdom (UK). METHODS: We used data from 1248 adolescents (mean 18.7 years) and 2277 Malawian adults (mean 49.8 years), all urban-dwelling, and from 3201 adolescents (mean 17.8 years) and 6323 adults (mean 49.7 years) resident in the UK. Adiposity measures and fasting lipids were assessed in both settings, and the associations of BMI and WHR with total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and triglycerides (TG) were assessed by sex and age groups in both studies. RESULTS: Malawian female adults were more adipose and had more adverse lipid profiles than their UK counterparts. In contrast, Malawian adolescent and adult males were leaner and had more favourable lipid profiles than in the UK. Higher BMI and WHR were associated with increased TC, LDL-C and TG and reduced HDL-C in both settings. The magnitude of the associations of BMI and WHR with lipids was mostly similar or slightly weaker in the Malawian compared with the UK cohort in both adolescents and adults. One exception was the stronger association between increasing adiposity and elevated TC and LDL-C in Malawian compared to UK men. CONCLUSIONS: Malawian adult women have greater adiposity and more adverse lipid profiles compared with their UK counterparts. Similar associations of adiposity with adverse lipid profiles were observed for Malawian and UK adults in most age and sex groups studied. Sustained efforts are urgently needed to address the excess adiposity and adverse lipid profiles in Malawi to mitigate a future epidemic of cardio-metabolic disease among the poorest populations.

Prevalence and risk factors for chronic kidney disease of unknown cause in Malawi: a cross-sectional analysis in a rural and urban population.

BACKGROUND: An epidemic of chronic kidney disease of unknown cause (CKDu) is occurring in rural communities in tropical regions of low-and middle-income countries in South America and India. Little information is available from Southern African countries which have similar climatic and occupational characteristics to CKDu-endemic countries. We investigated whether CKDu is prevalent in Malawi and identified its potential risk factors in this setting. METHODS: We conducted a cross-sectional study from January-August 2018 collecting bio samples and anthropometric data in two Malawian populations. The sample comprised adults > 18 years (n = 821) without diabetes, hypertension, and proteinuria. Estimates of glomerular filtration rate (eGFR) were calculated using the CKD-EPI equation. Linear and logistic regression models were applied with potential risk factors, to estimate risk of reduced eGFR. RESULTS: The mean eGFR was 117.1 ± 16.0 ml/min per 1.73m2 and the mean participant age was 33.5 ± 12.7 years. The prevalence of eGFR< 60 was 0.2% (95% confidence interval (95% CI) 0.1, 0.9); the prevalence of eGFR< 90 was 5% (95% CI =3.2, 6.3). We observed a higher prevalence in the rural population (5% (3.6, 7.8)), versus urban (3% (1.4, 6.7)). Age and BMI were associated with reduced eGFR< 90 [Odds ratio (OR) (95%CI) =3.59 (2.58, 5.21) per ten-year increment]; [OR (95%CI) =2.01 (1.27, 3.43) per 5 kg/m2 increment] respectively. No increased risk of eGFR < 90 was observed for rural participants [OR (95%CI) =1.75 (0.50, 6.30)]. CONCLUSIONS: Reduced kidney function consistent with the definition of CKDu is not common in the areas of Malawi sampled, compared to that observed in other tropical or sub-tropical countries in Central America and South Asia. Reduced eGFR< 90 was related to age, BMI, and was more common in rural areas. These findings are important as they contradict some current hypothesis that CKDu is endemic across tropical and sub-tropical countries. This study has enabled standardized comparisons of impaired kidney function between and within tropical/subtropical regions of the world and will help form the basis for further etiological research, surveillance strategies, and the implementation and evaluation of interventions.

Brain MRI and cognitive function seven years after surviving an episode of severe acute malnutrition in a cohort of Malawian children.

OBJECTIVE: To assess differences in cognition functions and gross brain structure in children seven years after an episode of severe acute malnutrition (SAM), compared with other Malawian children. DESIGN: Prospective longitudinal cohort assessing school grade achieved and results of five computer-based (CANTAB) tests, covering three cognitive domains. A subset underwent brain MRI scans which were reviewed using a standardized checklist of gross abnormalities and compared with a reference population of Malawian children. SETTING: Blantyre, Malawi.ParticipantsChildren discharged from SAM treatment in 2006 and 2007 (n 320; median age 9·3 years) were compared with controls: siblings closest in age to the SAM survivors and age/sex-matched community children. RESULTS: SAM survivors were significantly more likely to be in a lower grade at school than controls (adjusted OR = 0·4; 95 % CI 0·3, 0·6; P < 0·0001) and had consistently poorer scores in all CANTAB cognitive tests. Adjusting for HIV and socio-economic status diminished statistically significant differences. There were no significant differences in odds of brain abnormalities and sinusitis between SAM survivors (n 49) and reference children (OR = 1·11; 95 % CI 0·61, 2·03; P = 0·73). CONCLUSIONS: Despite apparent preservation in gross brain structure, persistent impaired school achievement is likely to be detrimental to individual attainment and economic well-being. Understanding the multifactorial causes of lower school achievement is therefore needed to design interventions for SAM survivors to thrive in adulthood. The cognitive and potential economic implications of SAM need further emphasis to better advocate for SAM prevention and early treatment.

Intratumoral heterogeneity: pathways to treatment resistance and relapse in human glioblastoma.

Intratumoral heterogeneity (ITH) has increasingly being described for multiple cancers as the root cause of therapy resistance. Recent studies have started to explore the scope of ITH in glioblastoma (GBM), a highly aggressive and fatal form of brain tumor, to explain its inevitable therapy resistance and disease relapse. In this review, we detail the emerging data that explores the extensive genetic, cellular and functional ITH present in GBM. We discuss current experimental models of human GBM recurrence and suggest harnessing new technologies (CRISPR-Cas9 screening, CyTOF, cellular barcoding, single cell analysis) to delineate GBM ITH and identify treatment-refractory cell populations, thus opening new therapeutic windows. We will also explore why current therapeutics have failed in clinical trials and how ITH can inform us on developing empiric therapies for the treatment of recurrent GBM.

Long-term effects of severe acute malnutrition on lung function in Malawian children: a cohort study.

Early nutritional insults may increase risk of adult lung disease. We aimed to quantify the impact of severe acute malnutrition (SAM) on spirometric outcomes 7 years post-treatment and explore predictors of impaired lung function.Spirometry and pulse oximetry were assessed in 237 Malawian children (median age: 9.3 years) who had been treated for SAM and compared with sibling and age/sex-matched community controls. Spirometry results were expressed as z-scores based on Global Lung Function Initiative reference data for the African-American population.Forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) were low in all groups (mean FEV1 z-score: -0.47 for cases, -0.48 for siblings, -0.34 for community controls; mean FVC z-score: -0.32, -0.38, and -0.15 respectively). There were no differences in spirometric or oximetry outcomes between SAM survivors and controls. Leg length was shorter in SAM survivors but inter-group sitting heights were similar. HIV positive status or female sex was associated with poorer FEV1, by 0.55 and 0.31 z-scores, respectively.SAM in early childhood was not associated with subsequent reduced lung function compared to local controls. Preservation of sitting height and compromised leg length suggest "thrifty" or "lung-sparing" growth. Female sex and HIV positive status were identified as potentially high-risk groups.

Noncommunicable Lung Disease in Sub-Saharan Africa. A Community-based Cross-Sectional Study of Adults in Urban Malawi.

RATIONALE: Noncommunicable diseases are major causes of morbidity and mortality in sub-Saharan Africa (sSA). Valid burden of disease estimates are lacking for noncommunicable lung disease in sSA. OBJECTIVES: We performed a community-based survey to determine the prevalence of chronic lung disease among adults 18 years or older in Malawi, using American Thoracic Society standard spirometry, internationally validated respiratory symptom and exposure questionnaires, and an assessment of HIV status. METHODS: An age- and sex-stratified random sample of 2,000 adults was taken from the population of the Chilomoni district of Blantyre, Malawi. Fieldworkers collected questionnaire data, conducted HIV testing, and performed pre- and post-bronchodilator spirometry on eligible participants. Survey-weighted population prevalence estimates of respiratory symptoms and spirometric abnormalities were computed, and bivariate and multivariable regression were used to identify associated variables. MEASUREMENTS AND MAIN RESULTS: Questionnaire data, HIV status, and standard spirometry were obtained from 1,059, 933, and 749 participants, respectively. Current respiratory symptoms, exposure to biomass, and ever-smoking were reported by 11.8, 85.2, and 10.4% of participants, respectively. HIV prevalence was 24.2%. Moderate to severe airway obstruction was seen in 3.6%. The prevalence of spirometric restriction was 38.6% using National Health and Nutrition Examination Survey III reference ranges and 9.0% using local reference ranges. Age was positively associated with obstruction, whereas low body mass index was associated with restriction. CONCLUSIONS: More than 40% of the Malawian adults in our urban population sample had abnormal lung function (mostly restrictive) in the context of widespread exposure to biomass smoke and a high prevalence of HIV. These findings potentially have major public health implications for Malawi and the broader sSA region.

Comparing surface properties of melanoma cells using time of flight secondary ions mass spectrometry.

Various techniques have been already reported to differentiate between normal (non-malignant) and cancerous cells based on their physico-chemical properties. This is relatively simple when studied cancerous cells originate from distant stages of cancer progression. Here, studies on chemical properties of two closely related human melanoma cell lines are presented: WM115 melanoma cells were taken from the vertical growth phase while WM266-4 from the skin metastatic site of the same patient. Their chemical properties were studied by two techniques, namely time-of-flight secondary ion mass spectra (ToF SIMS) and photothermal microspectroscopy (PTMS), used to record mass and photothermal spectra of cells, respectively. In our approach, independently of the spectra type, its full range, i.e. masses and wavenumbers within the range 0-500 kDa and 500-4000 cm-1, underwent a similar methodology for principal component analysis (PCA). PCA outcome shows results groupped depending on the sample type (either WM115 or WM266-4 cells). The results are independent of the method applied to study chemical properties of melanoma cells, indicating that cancer-related changes are large enough to be identified with these techniques and to differentiate between cells originating from vertical growth phase and skin metastatis.

The burden of hypertension, diabetes mellitus, and cardiovascular risk factors among adult Malawians in HIV care: consequences for integrated services.

BACKGROUND: Hypertension and diabetes prevalence is high in Africans. Data from HIV infected populations are limited, especially from Malawi. Integrating care for chronic non-communicable co-morbidities in well-established HIV services may provide benefit for patients by preventing multiple hospital visits but will increase the burden of care for busy HIV clinics. METHODS: Cross-sectional study of adults (≥18 years) at an urban and a rural HIV clinic in Zomba district, Malawi, during 2014. Hypertension and diabetes were diagnosed according to stringent criteria. Proteinuria, non-fasting lipids and cardio/cerebro-vascular disease (CVD) risk scores (Framingham and World Health Organization/International Society for Hypertension) were determined. The association of patient characteristics with diagnoses of hypertension and diabetes was studied using multivariable analyses. We explored the additional burden of care for integrated drug treatment of hypertension and diabetes in HIV clinics. We defined that burden as patients with diabetes and/or stage II and III hypertension, but not with stage I hypertension unless they had proteinuria, previous stroke or high Framingham CVD risk. RESULTS: Nine hundred fifty-two patients were enrolled, 71.7% female, median age 43.0 years, 95.9% on antiretroviral therapy (ART), median duration 47.7 months. Rural and urban patients' characteristics differed substantially. Hypertension prevalence was 23.7% (95%-confidence interval 21.1-26.6; rural 21.0% vs. urban 26.5%; p = 0.047), of whom 59.9% had stage I (mild) hypertension. Diabetes prevalence was 4.1% (95%-confidence interval 3.0-5.6) without significant difference between rural and urban settings. Prevalence of proteinuria, elevated total/high-density lipoprotein-cholesterol ratio and high CVD risk score was low. Hypertension diagnosis was associated with increasing age, higher body mass index, presence of proteinuria, being on regimen zidovudine/lamivudine/nevirapine and inversely with World Health Organization clinical stage at ART initiation. Diabetes diagnosis was associated with higher age and being on non-standard first-line or second-line ART regimens. CONCLUSION: Among patients in HIV care 26.6% had hypertension and/or diabetes. Close to two-thirds of hypertension diagnoses was stage I and of those few had an indication for antihypertensive pharmacotherapy. According to our criteria, 13.0% of HIV patients in care required drug treatment for hypertension and/or diabetes.

The impact of national cancer awareness campaigns for bowel and lung cancer symptoms on sociodemographic inequalities in immediate key symptom awareness and GP attendances.

BACKGROUND: National campaigns focusing on key symptoms of bowel and lung cancer ran in England in 2012, targeting men and women over the age of 50 years, from lower socioeconomic groups. METHODS: Data from awareness surveys undertaken with samples of the target audience (n=1245/1140 pre-/post-bowel campaign and n=1412/1246 pre-/post-lung campaign) and Read-code data extracted from a selection general practitioner (GP) practices (n=355 for bowel and n=486 for lung) were analysed by population subgroups. RESULTS: Unprompted symptom awareness: There were no significant differences in the magnitude of shift in ABC1 vs C2DE groups for either campaign. For the bowel campaign, there was a significantly greater increase in awareness of blood in stools in the age group 75+ years compared with the 55-74 age group, and of looser stools in men compared with women. Prompted symptom awareness: Endorsement of 'blood in poo' remained stable, overall and across different population subgroups. Men showed a significantly greater increase in endorsement of 'looser poo' as a definite warning sign of bowel cancer than women. There were no significant differences across subgroups in endorsement of a 3-week cough as a definite warning sign of lung cancer. GP attendances: Overall, there were significant increases in attendances for symptoms directly linked to the campaigns, with the largest percentage increase seen in the 50-59 age group. For the bowel campaign, the increase was significantly greater for men and for practices in the most-deprived quintile, whereas for lung the increase was significantly greater for practices in the least-deprived quintile. CONCLUSIONS: The national bowel and lung campaigns reached their target audience and have also influenced younger and more affluent groups. Differences in impact within the target audience were also seen. There would seem to be no unduly concerning widening in inequalities, but further analyses of the equality of impact across population subgroups is warranted.

Phenotypic characterization of nonautoimmune diabetes in adult Ugandans with low body mass index.

Background: Type 2 diabetes is common in relatively lean individuals in sub-Saharan Africa. It is unclear whether phenotypic differences exist between underweight and normal-weight African patients with type 2 diabetes. This study compared specific characteristics between underweight (body mass index <18.5 kg/m2) and normal-weight (body mass index of 18.5-24.9 kg/m2) adult Ugandans with new-onset nonautoimmune diabetes. Methods: We collected the demographic, clinical, anthropometric, and metabolic characteristics of 160 participants with nonobese new-onset type 2 diabetes (defined as diabetes diagnosed <3 months, body mass index <25 kg/m2, and absence of islet-cell autoimmunity). These participants were categorized as underweight and normal weight, and their phenotypic characteristics were compared. Results: Of the 160 participants with nonobese new-onset type 2 diabetes, 18 participants (11.3%) were underweight. Compared with those with normal weight, underweight participants presented with less co-existing hypertension (5.6% versus 28.2%, p = 0.04) and lower median visceral fat levels [2 (1-3) versus 6 (4-7), p < 0.001], as assessed by bioimpedance analysis. Pathophysiologically, they presented with a lower median 120-min post-glucose load C-peptide level [0.29 (0.13-0.58) versus 0.82 (0.39-1.50) nmol/l, p = 0.04] and a higher prevalence of insulin deficiency (66.7% versus 31.4%, p = 0.003). Conclusion: This study demonstrates that nonautoimmune diabetes occurs in underweight individuals in sub-Saharan Africa and is characterized by the absence of visceral adiposity, reduced late-phase insulin secretion, and greater insulin deficiency. These findings necessitate further studies to inform how the prevention, identification, and management of diabetes in such individuals can be individualized.

Type 2 diabetes in underweight Ugandans In this study that investigated how type 2 diabetes presents in adult Ugandans with normal body mass index, about one in ten were underweight. Type 2 diabetes in these individuals was characterized by a low prevalence of hypertension, lower body fat levels, and features of reduced insulin production by the pancreas.

Primary health care preparedness to integrate diabetes care in Blantyre, Malawi: A mixed methods study.

BACKGROUND: There is limited access to diabetes care services at primary care facilities in Malawi. Assessing the capacity of facilities to provide diabetes care is an initial step to integrating services at primary care. AIM: To assess the preparedness for delivering diabetes services at primary care level within the Blantyre District Health Office (DHO) to support the response to NCD epidemic in Malawi. SETTING: Blantyre DHO primary care facilities. MATERIALS AND METHODS: A mixed methods approach nested in a national needs assessment for NCD response in Malawi was used. Fourteen primary healthcare facilities from Blantyre DHO were assessed. A tool adapted from the WHO rapid assessment questionnaire was used to identify human resource, equipment, supplies, and medication needed for comprehensive diabetes care. Descriptive statistics were done to analyze the quantitative data. Fisher's exact test was used to assess if there was a statistically significant difference between urban and rural facilities. Seventeen health care workers from the selected facilities participated in key informant interviews. Framework analysis method guided the qualitative data analysis. The quantitative and qualitative data were merged and displayed jointly. RESULTS: The quantitative assessment showed that none of the facilities assessed had capacity to provide all the interventions recommended by WHO for diabetes care at primary level. Eight (57%) of the facilities had the capacity to diagnose diabetes, monitor glucose, prevent limb amputations and manage hypoglycemia and hyperglycemia. Four themes emerged from the qualitative data: differences in level of preparedness and implementation of diabetes care; disparities in resources between urban and rural facilities; low utilization of diabetes services; and strategy and policy recommendations for improvement of diabetes care. CONCLUSION: Inadequate health financing resulted in significant disparities in the available resources between the rural and urban facilities to offer diabetes care services. There is need to develop national policies and guidelines for diabetes care to strengthen the capacity of primary care facilities to facilitate achievement of universal health coverage.

Type 2 diabetes progression in an adult Ugandan population with new-onset diabetes: an observational prospective study.

BACKGROUND: The rate of progression of type 2 diabetes following diagnosis varies across individuals and populations. Studies investigating the progression of type 2 diabetes in adult African populations with newly diagnosed diabetes are limited. We aimed to investigate the prevalence and predictors of short-term (one year) diabetes progression in an adult Ugandan population with new-onset type 2 diabetes (type 2 diabetes diagnosed in < 3 months) initiated on oral hypoglycaemic agents (OHA). METHODS: Two hundred and seven adult participants with type 2 diabetes diagnosed within the previous three months were followed up for 12 months. We investigated the association of specific demographic, clinical, and metabolic characteristics, and short-term diabetes progression (defined as glycated haemoglobin or HbA1c ≥ 8% on ≥ 2 OHA and/or treatment intensification). RESULTS: One hundred sixteen participants (56%) completed the follow-up period. Sixty-four participants (55.2%, 95% CI 45.7-64.4) showed evidence of diabetes progression during the 12-month period of follow-up. An HbA1c ≥ 8% on ≥ 2 OHA and treatment intensification were noted in 44.8% and 29.3% of the participants, respectively. On multivariate analysis, only the female gender (AOR 3.2, 95% CI 1.1-9.2, p = 0.03) was noted to be independently associated with short-term diabetes progression. CONCLUSION: Short-term diabetes progression was relatively common in this study population and was independently associated with the female gender. Early intensified diabetes therapy in adult Ugandan female patients with new-onset type 2 diabetes should be emphasised to avert rapid short-term diabetes progression.

Current insights and emerging trends in early-onset type 2 diabetes.

Type 2 diabetes diagnosed in childhood or early adulthood is termed early-onset type 2 diabetes. Cases of early-onset type 2 diabetes are increasing rapidly globally, alongside rising obesity. Compared with a diagnosis later in life, an earlier-onset diagnosis carries an unexplained excess risk of microvascular complications, adverse cardiovascular outcomes, and earlier death. Women with early-onset type 2 diabetes also have a higher risk of adverse pregnancy outcomes. The high burden of complications renders individuals with early-onset type 2 diabetes at future risk of multimorbidity and interventions to reverse these concerning trends should be a priority. Within the early-onset cohort, disease pathophysiology and interventions have been better studied in paediatric-onset (<19 years) type 2 diabetes compared to adults; however, young adults aged 19-39 years (a larger number proportionally) are not well characterised and are also invisible in the current evidence base supporting management, which is derived from trials in later-onset type 2 diabetes. Young adults with type 2 diabetes face challenges in self-management that older individuals are less likely to experience (being in education or of working age, higher diabetes distress, and possible obesity-related stigma and diabetes-related stigma). There is a major research gap as to the optimal strategies to deploy in managing type 2 diabetes in adolescents and young adults, given that current models of care appear to not work as well in this age group. In the face of manifold risk factors (obesity, female sex, social deprivation, non-White European ethnicity, and genetic risk factors) prevention strategies with tailored lifestyle interventions, where needed, are likely to have greater success, but more evidence is needed. In this Review, we draw on evidence from both adolescents and young adults to provide a contemporary update on the current insights and emerging trends in early-onset type 2 diabetes.