Bayesian spatio-temporal analysis of malaria prevalence in children between 2 and 10 years of age in Gabon.

BACKGROUND: Gabon still bears significant malaria burden despite numerous efforts. To reduce this burden, policy-makers need strategies to design effective interventions. Besides, malaria distribution is well known to be related to the meteorological conditions. In Gabon, there is limited knowledge of the spatio-temporal effect or the environmental factors on this distribution. This study aimed to investigate on the spatio-temporal effects and environmental factors on the distribution of malaria prevalence among children 2-10 years of age in Gabon. METHODS: The study used cross-sectional data from the Demographic Health Survey (DHS) carried out in 2000, 2005, 2010, and 2015. The malaria prevalence was obtained by considering the weighting scheme and using the space-time smoothing model. Spatial autocorrelation was inferred using the Moran's I index, and hotspots were identified with the local statistic Getis-Ord General Gi. For the effect of covariates on the prevalence, several spatial methods implemented in the Integrated Nested Laplace Approximation (INLA) approach using Stochastic Partial Differential Equations (SPDE) were compared. RESULTS: The study considered 336 clusters, with 153 (46%) in rural and 183 (54%) in urban areas. The prevalence was highest in the Estuaire province in 2000, reaching 46%. It decreased until 2010, exhibiting strong spatial correlation (P < 0.001), decreasing slowly with distance. Hotspots were identified in north-western and western Gabon. Using the Spatial Durbin Error Model (SDEM), the relationship between the prevalence and insecticide-treated bed nets (ITNs) coverage was decreasing after 20% of coverage. The prevalence in a cluster decreased significantly with the increase per percentage of ITNs coverage in the nearby clusters, and per degree Celsius of day land surface temperature in the same cluster. It slightly increased with the number of wet days and mean temperature per month in neighbouring clusters. CONCLUSIONS: In summary, this study showed evidence of strong spatial effect influencing malaria prevalence in household clusters. Increasing ITN coverage by 20% and prioritizing hotspots are essential policy recommendations. The effects of environmental factors should be considered, and collaboration with the national meteorological department (DGM) for early warning systems is needed.

Fidelity of implementation of national guidelines on malaria diagnosis for children under-five years in Rivers State, Nigeria.

BACKGROUND: Malaria is still a disease of global public health importance and children under-five years of age are the most vulnerable to the disease. Nigeria adopted the "test and treat" strategy in the national malaria guidelines as one of the ways to control malaria transmission. The level of adherence to the guidelines is an important indicator for the success or failure of the country's roadmap to malaria elimination by 2030. This study aimed to assess the fidelity of implementation of the national guidelines on malaria diagnosis for children under-five years and examine its associated moderating factors in health care facilities in Rivers State, Nigeria. METHODS: This was a descriptive, cross-sectional study conducted in Port Harcourt metropolis. Data were collected from 147 public, formal private and informal private health care facilities. The study used a questionnaire developed based on Carroll's Conceptual Framework for Implementation Fidelity. Frequency, mean and median scores for implementation fidelity and its associated factors were calculated. Associations between fidelity and the measured predictors were examined using Mann Whitney U test, Kruskal Wallis test, and multiple linear regression modelling using robust estimation of errors. Regression results are presented in adjusted coefficient (ß) and 95% confidence intervals. RESULTS: The median (IQR) score fidelity score for all participants was 65% (43.3, 85). Informal private facilities (proprietary patent medicine vendors) had the lowest fidelity scores (47%) compared to formal private (69%) and public health facilities (79%). Intervention complexity had a statistically significant inverse relationship to implementation fidelity (ß = - 1.89 [- 3.42, - 0.34]). Increase in participant responsiveness (ß = 8.57 [4.83, 12.32]) and the type of malaria test offered at the facility (e.g., RDT vs. no test, ß = 16.90 [6.78, 27.03]; microscopy vs. no test, ß = 21.88 [13.60, 30.16]) were positively associated with fidelity score. CONCLUSIONS: This study showed that core elements of the "test and treat" strategy, such as testing all suspected cases with approved diagnostic methods before treatment, are still not fully implemented by health facilities. There is a need for strategies to increase fidelity, especially in the informal private health sector, for malaria elimination programme outcomes to be achieved.

Multimorbidity and overall survival among women with breast cancer: results from the South African Breast Cancer and HIV Outcomes Study.

BACKGROUND: Breast cancer survival in South Africa is low, but when diagnosed with breast cancer, many women in South Africa also have other chronic conditions. We investigated the impact of multimorbidity (≥ 2 other chronic conditions) on overall survival among women with breast cancer in South Africa. METHODS: Between 1 July 2015 and 31 December 2019, we enrolled women newly diagnosed with breast cancer at six public hospitals participating in the South African Breast Cancer and HIV Outcomes (SABCHO) Study. We examined seven chronic conditions (obesity, hypertension, diabetes, HIV, cerebrovascular diseases (CVD), asthma/chronic obstructive pulmonary disease, and tuberculosis), and we compared socio-demographic, clinical, and treatment factors between patients with and without each condition, and with and without multimorbidity. We investigated the association of multimorbidity with overall survival using multivariable Cox proportional hazard models. RESULTS: Of 3,261 women included in the analysis, 45% had multimorbidity; obesity (53%), hypertension (41%), HIV (22%), and diabetes (13%) were the most common individual conditions. Women with multimorbidity had poorer overall survival at 3 years than women without multimorbidity in both the full cohort (60.8% vs. 64.3%, p = 0.036) and stage groups: stages I-II, 80.7% vs. 86.3% (p = 0.005), and stage III, 53.0% vs. 59.4% (p = 0.024). In an adjusted model, women with diabetes (hazard ratio (HR) = 1.20, 95% confidence interval (CI) = 1.03-1.41), CVD (HR = 1.43, 95% CI = 1.17-1.76), HIV (HR = 1.21, 95% CI = 1.06-1.38), obesity + HIV (HR = 1.24 95% CI = 1.04-1.48), and multimorbidity (HR = 1.26, 95% CI = 1.13-1.40) had poorer overall survival than women without these conditions. CONCLUSIONS: Irrespective of the stage, multimorbidity at breast cancer diagnosis was an important prognostic factor for survival in our SABCHO cohort. The high prevalence of multimorbidity in our cohort calls for more comprehensive care to improve outcomes for South African women with breast cancer.

The impact of HIV on non-adherence for tamoxifen among women with breast cancer in South Africa.

PURPOSE: Women living with HIV (WLWH) and breast cancer (BC) have worse overall survival than HIV-negative women with BC, and poor adherence to prescribed tamoxifen is known to contribute to poor survival. We therefore investigated the association of HIV infection with adherence to adjuvant tamoxifen among women with localized hormone receptor (HR)-positive breast cancer in South Africa. METHODS: Among 4,097 women diagnosed with breast cancer at six hospitals in the prospective South African Breast Cancer and HIV Outcomes (SABCHO) cohort study between July 2015 and December 2020, we focused on black women with stages I-III HR-positive breast cancer who were prescribed 20 mg of adjuvant tamoxifen daily. We collected venous blood once from each participant during a routine clinic visit, and analyzed concentrations of tamoxifen and its metabolites using a triple quadruple mass spectrometer. We defined non-adherence as a tamoxifen level < 60 ng/mL after 3 months of daily tamoxifen use. We compared tamoxifen-related side effects, and concurrent medication use among women with and without HIV and developed multivariable logistic regression models of tamoxifen non-adherence. RESULTS: Among 369 subjects, 78 (21.1%) were WLWH and 291 (78.9%) were HIV-negative. After a median (interquartile range) time of 13.0 (6.2-25.2) months since tamoxifen initiation, the tamoxifen serum concentration ranged between 1.54 and 943.0 ng/mL and 208 (56.4%) women were non-adherent to tamoxifen. Women < 40 years of age were more likely to be non-adherent than women > 60 years (73.4% vs 52.6%, odds ratio (OR) = 2.49, 95% confidence interval (CI) = 1.26-4.94); likewise, WLWH (70.5% vs 52.6%, OR = 2.16, 95% CI = 1.26-3.70) than HIV-negative women. In an adjusted model WLWH had twice the odds of non-adherence to tamoxifen, compared to HIV-negative women (OR = 2.40, 95% CI = 1.11-5.20). CONCLUSION: High rates of non-adherence to adjuvant tamoxifen may limit the overall survival of black South African women with HR-positive breast cancer, especially among WLWH.

Impact of HIV infection on survival among women with stage I-III breast cancer: Results from the South African breast cancer and HIV outcomes study.

In some countries of sub-Saharan Africa, the prevalence of HIV exceeds 20%; in South Africa, 20.4% of people are living with HIV. We examined the impact of HIV infection on the overall survival (OS) of women with nonmetastatic breast cancer (BC) enrolled in the South African Breast Cancer and HIV Outcomes (SABCHO) study. We recruited women with newly diagnosed BC at six public hospitals from 1 July 2015 to 30 June 2019. Among women with stages I-III BC, we compared those with and without HIV infection on sociodemographic, clinical, and treatment factors. We analyzed the impact of HIV on OS using multivariable Cox proportional hazard models. Of 2367 women with stages I-III BC, 499 (21.1%) had HIV and 1868 (78.9%) did not. With a median follow-up of 29 months, 2-year OS was poorer among women living with HIV (WLWH) than among HIV-uninfected women (72.4% vs 80.1%, P < .001; adjusted hazard ratio (aHR) 1.49, 95% confidence interval (CI) = 1.22-1.83). This finding was consistent across age groups ≥45 years and <45 years, stage I-II BC and stage III BC, and ER/PR status (all P < .03). Both WLWH with <50 viral load copies/mL and WLWH with ≥50 viral load copies/mL had poorer survival than HIV-uninfected BC patients [aHR: 1.35 (1.09-1.66) and 1.54 (1.20-2.00), respectively], as did WLWH who had ≥200 CD4+ cells/mL at diagnosis [aHR: 1.39 (1.15-1.67)]. Because receipt of antiretroviral therapy has become widespread, WLWH is surviving long enough to develop BC; more research is needed on the causes of their poor survival.

Determinants of utilization of malaria preventive measures during pregnancy among women aged 15 to 49 years in Kenya: an analysis of the Malaria Indicator Survey 2020.

BACKGROUND: Malaria is a significant cause of morbidity and mortality. Malaria infection in pregnancy can have severe consequences for the fetus and the mother. To fight against malaria infection in pregnancy, Kenya integrated the issuance of an insecticide-treated net (ITN) and intermittent preventive treatment with sulfadoxine-pyrimethamine (IPTpSP) with antenatal care (ANC) for pregnant women. However, the uptake of the ITN and IPTpSP is still low. Individual, social, or structural factors may influence the low uptake. It is, therefore, important to identify the determinants associated with the uptake of ITN and IPTpSP during pregnancy in Kenya. METHODS: Data were from the 2020 Kenya Malaria Indicator Survey (MIS). A total of 1779 women between the ages of 15 to 49 years who had a history of either being pregnant or having given birth within 5 years before the MIS survey were included. Survey-adjusted multinomial logistic regression was used in the analysis. RESULTS: During pregnancy, ITN use was more than half (54.9%). The use of at least one dose of IPTpSP was 43.5%, three or more doses of IPTpSP was 27.2%, and only 28.2% of the participants used both ITN and IPTpSP during pregnancy. The significant determinants of combined use of ITN and IPTpSP during pregnancy were maternal age (RR 3.57, CI 1.80-7.08; p=<0.001), maternal education (RRR 2.84, CI 1.33-6.06; p=0.007), wealth index (RR 2.14, CI 1.19-3.84; p=0.011) and living in the different malaria epidemiological zones: lake endemic (RRR 10.57 CI 5.65-19.76; p=<0.001), coastal endemic area (RRR 4.86 CI 1.86-12.67; p=0.001), seasonal (RRR 0.21 CI 0.10-0.39; p=<0.001) and low risk (RRR 0.07, CI 0.03-0.17; p=<0.001). CONCLUSION: The uptake of malaria preventive measures is still below 80% for both ITN and IPTpSP during pregnancy in Kenya. The significant results on determinants of the use of ITN and IPTpSP could be considered in implementing malaria prevention programmes during pregnancy. For example, sensitizing the community on the importance of antenatal care visits will provide a platform to teach the importance of malaria prevention in pregnancy. Moreover, the pregnant mothers receive an ITN and IPTpSP during the ANC visit.

Training and capacity building in medical statistics in Sub-Saharan Africa: Impact of the London School of Hygiene & Tropical Medicine MSc in Medical Statistics, 1969 to 2021.

Since its inception in 1969, the MSc in medical statistics program has placed a high priority on training students from Africa. In this article, we review how the program has shaped, and in turn been shaped by, two substantial capacity building initiatives: (a) a fellowship program, funded by the UK Medical Research Council, and run through the International Statistical Epidemiology Group at the LSHTM, and (b) the Sub-Saharan capacity building in Biostatistics (SSACAB) initiative, administered through the Developing Excellence in Leadership, Training and Science in Africa (DELTAS) program of the African Academy of Sciences. We reflect on the impact of both initiatives, and the implications for future work in this area.

Comparison of statistical methods for the analysis of recurrent adverse events in the presence of non-proportional hazards and unobserved heterogeneity: a simulation study.

BACKGROUND: In preventive drug trials such as intermittent preventive treatment for malaria prevention during pregnancy (IPTp), where there is repeated treatment administration, recurrence of adverse events (AEs) is expected. Challenges in modelling the risk of the AEs include accounting for time-to-AE and within-patient-correlation, beyond the conventional methods. The correlation comes from two sources; (a) individual patient unobserved heterogeneity (i.e. frailty) and (b) the dependence between AEs characterised by time-dependent treatment effects. Potential AE-dependence can be modelled via time-dependent treatment effects, event-specific baseline and event-specific random effect, while heterogeneity can be modelled via subject-specific random effect. Methods that can improve the estimation of both the unobserved heterogeneity and treatment effects can be useful in understanding the evolution of risk of AEs, especially in preventive trials where time-dependent treatment effect is expected. METHODS: Using both a simulation study and the Chloroquine for Malaria in Pregnancy (NCT01443130) trial data to demonstrate the application of the models, we investigated whether the lognormal shared frailty models with restricted cubic splines and non-proportional hazards (LSF-NPH) assumption can improve estimates for both frailty variance and treatment effect compared to the conventional inverse Gaussian shared frailty model with proportional hazard (ISF-PH), in the presence of time-dependent treatment effects and unobserved patient heterogeneity. We assessed the bias, precision gain and coverage probability of 95% confidence interval of the frailty variance estimates for the models under varying known unobserved heterogeneity, sample sizes and time-dependent effects. RESULTS: The ISF-PH model provided a better coverage probability of 95% confidence interval, less bias and less precise frailty variance estimates compared to the LSF-NPH models. The LSF-NPH models yielded unbiased hazard ratio estimates at the expense of imprecision and high mean square error compared to the ISF-PH model. CONCLUSION: The choice of the shared frailty model for the recurrent AEs analysis should be driven by the study objective. Using the LSF-NPH models is appropriate if unbiased hazard ratio estimation is of primary interest in the presence of time-dependent treatment effects. However, ISF-PH model is appropriate if unbiased frailty variance estimation is of primary interest. TRIAL REGISTRATION: ClinicalTrials.gov; NCT01443130.

Factors influencing the implementation of TB screening among PLHIV in selected HIV clinics in Ghana: a qualitative study.

BACKGROUND: Decreasing the burden of Tuberculosis (TB) among PLHIV through TB screening is an effective intervention recommended by the World Health Organization (WHO). However, after over a decade of implementation in Ghana, the intervention does not realize the expected outcomes. It is also not well understood whether this lack of success is due to implementation barriers. Our study, therefore, sought to examine the factors influencing the implementation of the intervention among people living with HIV (PLHIV) attending HIV clinics at district hospitals in Ghana. METHODS: This was a qualitative study conducted from 6th to 31 May 2019 in three regions of Ghana. We conducted 17 in-depth interviews (IDIs - comprising two regional, six districts and nine facility TB/HIV coordinators) and eight focus group discussions (FGD - consisting of a total of 65 participants) with HIV care providers. The Consolidated Framework for Implementation Research (CFIR) guided the design of interview guides, data collection and analysis. All responses were digitally audio-recorded and transcribed verbatim for coding and analysis using the Framework Approach. Participants consented to the interview and recording. RESULTS: The main barriers to TB screening relate to the low commitment of the implementers to screen for TB and limited facility infrastructure for the screening activities. Facilitators of TB screening include (1) ease in TB screening, (2) good communication and referral channels, (3) effective goals and feedback mechanisms, (4) health workers recognizing the need for the intervention and (5) the role of chemical sellers. CONCLUSIONS: Key barriers and facilitators to the intervention are revealed. The study has shown that there is a need to increase HIV care providers and institutional commitment towards TB screening interventions. In addition, cost issues need to be assessed as they are drivers of sustainability. Our study also advances the field of implementation science through CFIR to better understand the factors influencing the implementation.

Markov modelling of viral load adjusting for CD4 orthogonal variable and multivariate conditional autoregressive mapping of the HIV immunological outcomes among ART patients in Zimbabwe.

BACKGROUND: This study aimed to jointly model HIV disease progression patterns based on viral load (VL) among adult ART patients adjusting for the time-varying "incremental transients states" variable, and the CD4 cell counts orthogonal variable in a single 5-stage time-homogenous multistate Markov model. We further jointly mapped the relative risks of HIV disease progression outcomes (detectable VL (VL ≥ 50copies/uL) and immune deterioration (CD4 < 350cells/uL) at the last observed visit) conditional not to have died or become loss to follow-up (LTFU). METHODS: Secondary data analysis of individual-level patients on ART was performed. Adjusted transition intensities, hazard ratios (HR) and regression coefficients were estimated from the joint multistate model of VL and CD4 cell counts. The mortality and LTFU transition rates defined the extent of patients' retention in care. Joint mapping of HIV disease progression outcomes after ART initiation was done using the Bayesian intrinsic Multivariate Conditional Autoregressive prior model. RESULTS: The viral rebound from the undetectable state was 1.78times more likely compared to viral suppression among patients with VL ranging from 50-1000copies/uL. Patients with CD4 cell counts lower than expected had a higher risk of viral increase above 1000copies/uL and death if their VL was above 1000copies/uL (state 2 to 3 (λ23): HR = 1.83 and (λ34): HR = 1.42 respectively). Regarding the time-varying effects of CD4 cell counts on the VL transition rates, as the VL increased, (λ12 and λ23) the transition rates increased with a decrease in the CD4 cell counts over time. Regardless of the individual's VL, the transition rates to become LTFU decreased with a decrease in CD4 cell counts. We observed a strong shared geographical pattern of 66% spatial correlation between the relative risks of detectable VL and immune deterioration after ART initiation, mainly in Matabeleland North. CONCLUSION: With high rates of viral rebound, interventions which encourage ART adherence and continual educational support on the barriers to ART uptake are crucial to achieve and sustain viral suppression to undetectable levels. Area-specific interventions which focus on early ART screening through self-testing, behavioural change campaigns and social support strategies should be strengthened in heavily burdened regions to sustain the undetectable VL. Sustaining undetectable VL lowers HIV transmission in the general population and this is a step towards achieving zero HIV incidences by 2030.

Joint modelling of multivariate longitudinal clinical laboratory safety outcomes, concomitant medication and clinical adverse events: application to artemisinin-based treatment during pregnancy clinical trial.

BACKGROUND: In drug trials, clinical adverse events (AEs), concomitant medication and laboratory safety outcomes are repeatedly collected to support drug safety evidence. Despite the potential correlation of these outcomes, they are typically analysed separately, potentially leading to misinformation and inefficient estimates due to partial assessment of safety data. Using joint modelling, we investigated whether clinical AEs vary by treatment and how laboratory outcomes (alanine amino-transferase, total bilirubin) and concomitant medication are associated with clinical AEs over time following artemisinin-based antimalarial therapy. METHODS: We used data from a trial of artemisinin-based treatments for malaria during pregnancy that randomized 870 women to receive artemether-lumefantrine (AL), amodiaquine-artesunate (ASAQ) and dihydroartemisinin-piperaquine (DHAPQ). We fitted a joint model containing four sub-models from four outcomes: longitudinal sub-model for alanine aminotransferase, longitudinal sub-model for total bilirubin, Poisson sub-model for concomitant medication and Poisson sub-model for clinical AEs. Since the clinical AEs was our primary outcome, the longitudinal sub-models and concomitant medication sub-model were linked to the clinical AEs sub-model via current value and random effects association structures respectively. We fitted a conventional Poisson model for clinical AEs to assess if the effect of treatment on clinical AEs (i.e. incidence rate ratio (IRR)) estimates differed between the conventional Poisson and the joint models, where AL was reference treatment. RESULTS: Out of the 870 women, 564 (65%) experienced at least one AE. Using joint model, AEs were associated with the concomitant medication (log IRR 1.7487; 95% CI: 1.5471, 1.9503; p < 0.001) but not the total bilirubin (log IRR: -0.0288; 95% CI: - 0.5045, 0.4469; p = 0.906) and alanine aminotransferase (log IRR: 0.1153; 95% CI: - 0.0889, 0.3194; p = 0.269). The Poisson model underestimated the effects of treatment on AE incidence such that log IRR for ASAQ was 0.2118 (95% CI: 0.0082, 0.4154; p = 0.041) for joint model compared to 0.1838 (95% CI: 0.0574, 0.3102; p = 0.004) for Poisson model. CONCLUSION: We demonstrated that although the AEs did not vary across the treatments, the joint model yielded efficient AE incidence estimates compared to the Poisson model. The joint model showed a positive relationship between the AEs and concomitant medication but not with laboratory outcomes. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00852423.

Adherence of HIV clinics to guidelines for the delivery of TB screening among people living with HIV/AIDS in Ghana.

BACKGROUND: Tuberculosis screening of people living with HIV (PLHIV) - an intervention to reduce the burden of TB among PLHIV - is being implemented at HIV clinics in Ghana since 2007, but TB screening coverage remains low. Facility adherence to intervention guidelines may be a factor but is missing in implementation science literature. This study assesses the level of HIV clinic adherence to the guidelines and related facility characteristics in selected district hospitals in Ghana. METHODS: This cross-sectional study was conducted in all 27 district hospitals with HIV clinics, X-ray and geneXpert machines in Ghana. These hospitals are in 27 districts representing about 27% of the 100 district hospitals with HIV clinics in Ghana. A data collection tool with 18-items (maximum score of 29) was developed from the TB/HIV collaborative guidelines to assess facility adherence to four interrelated components of the TB screening programme as stated in the guidelines: intensive TB case-finding among PLHIV (ITCF), Isoniazid preventive therapy initiation (IPT), TB infection control (TIC), and programme review meetings (PRM). Data were collected through record review and interviews with 27 key informants from each hospital. Adherence scores per component were summed to determine an overall adherence score per facility and summarized using medians and converted to proportions. Facility characteristics were assessed and compared across facilities with high (above median) versus low (below median) overall adherence scores, using nonparametric test statistics. RESULTS: From the 27 key interviews and facility records reviewed, the median adherence scores for ITCF, IPT, TIC, and PRM components were 85.7% (IQR: 85.5-100.0), 0% (IQR: 0-66.7), 33.3% (IQR: 33.3-50.0), and 90.0% (IQR: 70.0-90.0), respectively. The overall median adherence score was 62.1% (IQR: 58.6-65.1), and 17 clinics (63%) with overall adherence score above the median were categorized as high adherence. Compared to low adherence facilities, high adherence facilities had statistically significant lower PLHIV clinic attendees per month (256 (IQR: 60-904) vs. 900 (IQR: 609-2622); p = 0.042), and lower HIV provider workloads (28.6 (IQR: 8.6-113) vs. 90 (IQR: 66.7-263.5); p = 0.046), and most had screening guidelines (76%, p < 0.01) and questionnaire (80%, p < 0.01) available on-site. CONCLUSION: PRM had highest score while the IPT component had the lowest score. Almost a third of the facilities implemented the TB screening programme activities with a high level of adherence to the guidelines. We suggest to ensure adherence to all four components, reducing staff workloads and making TB screening questionnaires and guidelines available on-site would increase facility adherence to the intervention and ultimately achieve intervention targets.

A comparison of complete pathologic response rates following neoadjuvant chemotherapy among South African breast cancer patients with and without concurrent HIV infection.

PURPOSE: Among patients diagnosed with breast cancer (BC), women also living with HIV (WLWH) have worse survival than women without HIV. Chronic HIV infection may interfere with the effectiveness of BC treatment, contributing to this disparity. We attempted to determine the impact of HIV infection on response to neoadjuvant chemotherapy (NACT) among South African women with BC. METHODS: We evaluated women from the South African Breast Cancer and HIV Outcomes cohort study who had stage I-III disease, initiated NACT, underwent definitive breast surgery, and had available surgical pathology reports. We compared pathologic complete response (pCR) rates among women with and without HIV infection, using multivariable logistic regression to control for differences in tumor characteristics. We also evaluated the impact of HIV infection on pCR within subgroups based on patient and tumor factors. RESULTS: Of 715 women, the 173 (24.2%) WLWH were less likely to achieve pCR than women without HIV (8.7% vs 16.4%, [odds ratio (OR) 0.48, 95% confidence interval (95% CI) 0.27-0.86]). WLWH continued to have lower likelihood of achieving pCR on multivariable analysis (OR 0.52, 95% CI 0.28-0.98). A similar pattern was seen within subgroups, although HIV infection appeared to affect pCR more in ER/PR-positive BC (OR 0.24, 95% CI 0.08-0.71) than in ER/PR-negative BC (OR 0.94, 95% CI 0.39-2.29). CONCLUSION: WLWH were less like to achieve pCR following NACT for BC than women without HIV. This reduced response to systemic therapy may contribute to the poorer BC outcomes seen in WLWH.

Systematic review of statistical methods for safety data in malaria chemoprevention in pregnancy trials.

BACKGROUND: Drug safety assessments in clinical trials present unique analytical challenges. Some of these include adjusting for individual follow-up time, repeated measurements of multiple outcomes and missing data among others. Furthermore, pre-specifying appropriate analysis becomes difficult as some safety endpoints are unexpected. Although existing guidelines such as CONSORT encourage thorough reporting of adverse events (AEs) in clinical trials, they provide limited details for safety data analysis. The limited guidelines may influence suboptimal analysis by failing to account for some analysis challenges above. A typical example where such challenges exist are trials of anti-malarial drugs for malaria prevention during pregnancy. Lack of proper standardized evaluation of the safety of antimalarial drugs has limited the ability to draw conclusions about safety. Therefore, a systematic review was conducted to establish the current practice in statistical analysis for preventive antimalarial drug safety in pregnancy. METHODS: The search included five databases (PubMed, Embase, Scopus, Malaria in Pregnancy Library and Cochrane Central Register of Controlled Trials) to identify original English articles reporting Phase III randomized controlled trials (RCTs) on anti-malarial drugs for malaria prevention in pregnancy published from January 2010 to July 2019. RESULTS: Eighteen trials were included in this review that collected multiple longitudinal safety outcomes including AEs. Statistical analysis and reporting of the safety outcomes in all the trials used descriptive statistics; proportions/counts (n = 18, 100%) and mean/median (n = 2, 11.1%). Results presentation included tabular (n = 16, 88.9%) and text description (n = 2, 11.1%). Univariate inferential methods were reported in most trials (n = 16, 88.9%); including Chi square/Fisher's exact test (n = 12, 66.7%), t test (n = 2, 11.1%) and Mann-Whitney/Wilcoxon test (n = 1, 5.6%). Multivariable methods, including Poisson and negative binomial were reported in few trials (n = 3, 16.7%). Assessment of a potential link between missing efficacy data and safety outcomes was not reported in any of the trials that reported efficacy missing data (n = 7, 38.9%). CONCLUSION: The review demonstrated that statistical analysis of safety data in anti-malarial drugs for malarial chemoprevention in pregnancy RCTs is inadequate. The analyses insufficiently account for multiple safety outcomes potential dependence, follow-up time and informative missing data which can compromise anti-malarial drug safety evidence development, based on the available data.

Systematic review of analytical methods applied to longitudinal studies of malaria.

BACKGROUND: Modelling risk of malaria in longitudinal studies is common, because individuals are at risk for repeated infections over time. Malaria infections result in acquired immunity to clinical malaria disease. Prospective cohorts are an ideal design to relate the historical exposure to infection and development of clinical malaria over time, and analysis methods should consider the longitudinal nature of the data. Models must take into account the acquisition of immunity to disease that increases with each infection and the heterogeneous exposure to bites from infected Anopheles mosquitoes. Methods that fail to capture these important factors in malaria risk will not accurately model risk of malaria infection or disease. METHODS: Statistical methods applied to prospective cohort studies of clinical malaria or Plasmodium falciparum infection and disease were reviewed to assess trends in usage of the appropriate statistical methods. The study was designed to test the hypothesis that studies often fail to use appropriate statistical methods but that this would improve with the recent increase in accessibility to and expertise in longitudinal data analysis. RESULTS: Of 197 articles reviewed, the most commonly reported methods included contingency tables which comprised Pearson Chi-square, Fisher exact and McNemar's tests (n = 102, 51.8%), Student's t-tests (n = 82, 41.6%), followed by Cox models (n = 62, 31.5%) and Kaplan-Meier estimators (n = 59, 30.0%). The longitudinal analysis methods generalized estimating equations and mixed-effects models were reported in 41 (20.8%) and 24 (12.2%) articles, respectively, and increased in use over time. A positive trend in choice of more appropriate analytical methods was identified over time. CONCLUSIONS: Despite similar study designs across the reports, the statistical methods varied substantially and often represented overly simplistic models of risk. The results underscore the need for more effort to be channelled towards adopting standardized longitudinal methods to analyse prospective cohort studies of malaria infection and disease.

Determinants of health workers intention to use malaria rapid diagnostic test in Kintampo North Municipality, Ghana - a cross-sectional study.

BACKGROUND: Resistance to antimalarial drugs resulting from overuse of the medication remains a threat to malaria control and elimination in endemic settings including Ghana. Reliance on clinical signs alone results in patients being diagnosed with malaria falsely. The World Health Organization and local guidelines recommend test-based diagnosis with malaria rapid diagnostic test (mRDT) or microscopy before prescription of antimalarial drugs. Despite the scale-up of mRDT through the procurement of mRDT kits and training of health workers on mRDT-led diagnosis of malaria, its use remains low with about 85% health workers reporting satisfaction with the presumptive diagnosis. METHODS: A quantitative cross-sectional study was conducted to investigate the determinants of intention to use mRDT among health workers in Kintampo North Municipality, Ghana. A total of 110 health workers were surveyed from February to April 2017. Intention to use mRDT was measured as the primary outcome with a 5-item scale questionnaire based on the Technology Acceptance Model (TAM). We then tested its association with hypothesized determinants: coherence, cognitive participation, collective action, and reflexive action informed by the Normalization Process Theory (NPT) as well as health workers' background characteristics using linear regression modeling. RESULTS: The mean intention to use mRDT score was 82% (SD: 12.6). The regression model showed health workers intention to use mRDT was positively associated with coherence (ß = 0.40, 95% CI 0.16-0.65) and cognitive participation (ß = 0.36, 95% CI 0.15-0.58). Intention to use mRDT score was 6.85 units higher among health workers with three or more years of experience compared to those with less than 3 years of experience (ß = 6.85 95% CI 0.59-13.12). However, intention to use mRDT score was inversely related to reflexive monitoring and collective action but not significant. CONCLUSION: The study identified that intention to use mRDT was positively influenced by health workers having a proper understanding of the aims and expected benefits (coherence) of the intervention and the availability of experienced staff and intervention champions (cognitive participation) to promote mRDT use among health workers.

A biostatistical support system in health sciences: is this sustainable in a resource-restricted environment?

BACKGROUND: Training in biostatistics is important for strengthening capacity in health research. This is particularly true for Africa, where research output in the health sciences has been low. Training initiatives for the continent are therefore essential. The aim of the present study was to analyse the quality and financial sustainability of the expanded biostatistical support system at a South African health sciences institution between 2013 and 2017. METHODS: A cross-sectional investigation of the initiatives created between the years 2013 and 2017 in the University of the Witwatersrand, Faculty of Health Sciences Research Office was undertaken. An assessment of the one-on-one consultations carried out by postgraduate students and staff, financial costs of the support system and the number of postgraduate student graduations were analysed. RESULTS: The number of statistical consultations increased over the period examined. The consultations were highly recommended by the postgraduate students and staff (consulters). A clear rise in the number of Masters and PhD student graduates and an increase in research units were observed from 2013 to 2017, although these cannot be solely associated with the biostatistical support system. The finances for maintaining the support system are cost effective as the number of graduates increases. The total cost to the Research Office is US$ 225 per graduate per annum. CONCLUSIONS: The expansion of the biostatistical support system has indirectly contributed to an increased number of graduates and research publication units in the institution. While the current finances support the system, any increases in enrolments or growth in diversification of biostatistical requirements may place a strain on the financial sustainability. This service is of value to developed and developing countries.

Neurodevelopmental outcome of late preterm infants in Johannesburg, South Africa.

BACKGROUND: Late preterm infants, previously considered low risk, have been identified to be at risk of developmental problems in infancy and early childhood. There is limited information on the outcome of these infants in low and middle income countries. METHODS: Bayley scales of infant and toddler development, version III, were done on a group of late preterm infants in Johannesburg, South Africa. The mean composite cognitive, language and motor sub-scales were compared to those obtained from a group of typically developed control infants. Infants were considered to be "at risk" if the composite subscale score was below 85 and "disabled" if the composite subscale score was below 70. Infants identified with cerebral palsy were also reported. RESULTS: 56 of 73 (76.7%) late preterm infants enrolled in the study had at least one Bayley assessment at a mean age of 16.5 months (95% CI 15.2-17.6). The mean birth weight was 1.9 kg (95%CI 1.8-2.0) and mean gestational age 33.0 weeks (95% CI 32.56-33.51). There was no difference in the mean cognitive subscales between late preterm infants and controls (95.4 9, 95% CI 91.2-99.5 vs 91.9.95% CI 87.7-96.0). There was similarly no difference in mean language subscales (94.5, 95% CI 91.3-97.7 vs 95.9, 95% CI 92.9-99.0) or motor subscales (96.2, 95% CI 91.8-100.7 vs 97.6, 95% CI 94.7-100.5). There were four late preterm infants who were classified as disabled, two of whom had cerebral palsy. None of the control group was disabled. CONCLUSIONS: This study demonstrates that overall developmental outcome, as assessed by the Bayley scales of infant and toddler development, was not different between late preterm infants and a group of normal controls. However, 7.1% of the late preterm infants, had evidence of developmental disability. Thus late preterm infants in low and middle income countries require long term follow up to monitor developmental outcome. In a resource limited setting, this may best be achieved by including a parental screening questionnaire, such as the Ages and Stages Questionnaire, in the routine well baby clinic visits.

Treatment outcomes of children with Hodgkin lymphoma between 2000 and 2010: First report by the South African Children's Cancer Study Group.

BACKGROUND: Children with Hodgkin lymphoma (HL) have excellent survival rates in high-income countries, but there are minimal outcome data in South African patients. Differing approaches to treatment are used in centres across South Africa, and the South African Children's Cancer Study Group (SACCSG) embarked on a programme to audit outcomes to improve survival rates. PATIENTS AND METHODS: A multicentre study was conducted to analyse outcomes and prognostic factors of children with HL in South Africa. Ten dedicated South African paediatric oncology units participated in a retrospective data review. All patients with HL treated consecutively between January 2000 and December 2010 were included. Kaplan-Meier curves and Cox regression model were employed to determine survival rates and prognostic factors. RESULTS: Two hundred and ninety-four patients were eligible for inclusion. The median age at presentation was 9.6 years (range 2.9-18.8); 55.4% of the patients presented with Stage III and IV disease and 9.9% were human immunodeficiency virus (HIV) positive. First-line therapy consisted of adriamycin, bleomycin, vinblastine and dacarbazine (ABVD) in 158 patients, vincristine, procarbazine/etoposide, prednisone and doxorubicin in 97 and adriamycin, bleomycin, vincristine and dacarbazine-chlorambucil, vinblastine, prednisone and procarbazine in 23 patients. The 5-year overall survival (OS) was 79% (95% confidence interval 73-84%). Multivariate analysis demonstrated that HIV infection (P = 0.018) and Ann Arbor Stage III and IV disease (P = 0.006) conferred a poor prognosis, while treatment with ABVD was associated with higher survival rates (P = 0.028). CONCLUSION: OS rates are encouraging for a middle-income country, although economic disparities continue to impact negatively on outcomes. Study results will form the basis for the development of national protocol and continued advocacy to rectify disparities.