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Background The decreasing residual efficacy of insecticides is an important factor when making decisions on insecticide choice for national malaria control programmes. The major challenge to using chemicals for vector control is the selection for the development of insecticide resistance. Since insecticide resistance has been recorded for most of the existing insecticides used for indoor residual spraying, namely, DDT, pyrethroids, organophosphates and carbamates, and new chemicals are necessary for the continued success of indoor residual spraying. The aim of this study was to assess the residual efficacy of Actellic 300CS, SumiShield™ 50WG and Fludora®Fusion by spraying on different wall surfaces. Methods One hundred and sixty-eight houses with different wall surface types (mud, cement, painted cement, and tin) which represented the rural house wall surface types in KwaZulu-Natal, South Africa were used to evaluate the residual efficacy of Actellic 300CS, SumiShield 50WG and Fludora®Fusion with DDT as the positive control. All houses were sprayed by experienced spray operators from the Malaria Control Programme. Efficacy of these insecticides were evaluated by contact bioassays against Anopheles arabiensis , a vector species. The residual efficacy of the insecticide formulations was evaluated against a susceptible insectary-reared population of An. arabiensis using WHO cone bioassays. Results Effectiveness of the three insecticides was observed up to 12 months post-spray. When assessing the achievement of 100% mortality over time, SumiShield performed significantly better than DDT on mud (OR 2.28, 95% CI 1.72–3.04) and painted cement wall types (OR 3.52, 95% CI 2.36–5.26). On cement wall types, Actellic was found to be less effective than DDT (OR 0.55, 95% CI 0.37–0.82) while Fludora®Fusion was less effective on tin wall types (OR 0.67, 95% CI 0.47–0.95). When compared to the combined efficacy of DDT on mud surfaces, SumiShield applied to each of the mud, cement and painted cement wall types and DDT applied to the cement wall types was found to be significantly more effective. These insecticides usually resulted in 100% mortality for up to 12 months with a delayed mortality period of 96–144 h, depending on the insecticide evaluated and the surface type sprayed. Conclusion Field evaluation of these insecticides have shown that Actellic, SumiShield and Fludora®Fusion are suitable replacements for DDT. Each of these insecticides can be used for malaria vector control, requiring just one spray round. These insecticides can be used in rotation or as mosaic spraying.

Background Although malaria remains a noteworthy disease in South Africa, the provinces are at differing stages of the malaria elimination continuum. KwaZulu-Natal has consistently reported the lowest number of cases over the past 5 years and it is expected that the goal of elimination will be achieved in this province over the next few years. The study reports on few key indicators that realistically represents the provinces progress over the past decade. Local and imported morbidity and mortality is seen as the key indicator as is malaria in children under the age of five and pregnant women. The only vector control intervention in the province is indoor residual spraying (IRS) and this gives an estimate of the population protected by this intervention. Methods Trend analysis was used to examine the changing epidemiology in KwaZulu-Natal over the past decade from 2008 to 2018. The data used in this decadal analysis was obtained from the provincial Department of Health. Since malaria is a medically notifiable disease, all malaria cases diagnosed in the province are reported from health facilities and are captured in the malaria information system in the province. Results The results have shown that imported cases are on the increase whilst local cases are decreasing, in keeping with an elimination objective. Preventing secondary cases is the key to reaching elimination. Only 10% of the cases reported occur in children under 5 years whereas the cases in pregnant women account for about 1% of the reported cases. Over 85% of the houses receive IRS and this is also the same proportion of the population protected by the intervention. Conclusion Several challenges to elimination have been identified but these are not insurmountable. Although there are major impediments to achieving elimination, the changing epidemiology suggests that major strides have been made in the past 10 years and KwaZulu-Natal is on track to achieving this milestone in the next few years.

Observational data suggest lower HIV risk with norethisterone enanthate (NET-EN) than with depo-medroxyprogesterone acetate intramuscular (DMPA-IM) injectable contraceptives. If confirmed, a switch between these similar injectable methods would be programmatically feasible and could impact the trajectory of the HIV epidemic. We aimed in this paper to investigate the effects of DMPA-IM and NET-EN on estradiol levels, measures of depression and sexual activity and menstrual effects, relevant to HIV risk; and to ascertain whether these measures are associated with estradiol levels. This open-label trial conducted at two sites in South Africa from 5 November 2018 to 30 November 2019, randomized HIV-negative women aged 18-40 to DMPA-IM 150 mg intramuscular 12-weekly (n = 262) or NET-EN 200 mg intramuscular 8-weekly (n = 259). Data were collected on hormonal, behavioral and menstrual effects at baseline and at 25 weeks (25W). At 25W, median 17β estradiol levels were substantially lower than at baseline (p<0.001) for both methods: 76.5 pmol/L (interquartile range (IQR) 54.1 to 104.2) in the DMPA-IM group (n = 222), and 69.8 pmol/L (IQR: 55.1 to 89.3) in the NET-EN group (n = 225), with no statistical difference between the two methods (p = 0.450). Compared with DMPA-IM, NET-EN users reported significantly less amenorrhoea, fewer sexual acts, fewer users reporting at least one act of unprotected sex, more condom use with steady partner, more days with urge for sexual intercourse, more days feeling partner does not love her, and more days feeling sad for no reason. We did not find a clear association between estradiol levels and sexual behavior, depression and menstrual effects. Behavioral outcomes suggest less sexual exposure with NET-EN than DMPA-IM. The strength of this evidence is high due to the randomized study design and the consistency of results across the outcomes measured. Estradiol levels were reduced to postmenopausal levels by both methods. Secondary outcomes suggesting less sexual exposure with NET-EN are consistent with reported observational evidence of less HIV risk with NET-EN. A randomized trial powered for HIV acquisition is feasible and needed to answer this important question. PACTR 202009758229976.

Background Imported malaria from southern Mozambique drives low levels of disease transmission in KwaZulu-Natal, South Africa. Therefore, the South African Department of Health funded implementation of indoor residual spraying (IRS) in Mozambiquan districts identified as sources of malaria infection for border communities in KwaZulu-Natal. IRS was initiated in districts of Guija, Inharrime, Panda and Zavala. To determine impact of spraying on malaria transmission in these districts, data relating to incidence and prevalence was collected before spraying (2018) and before the second round of spraying was completed (2023). Implementation of IRS was also monitored to ensure optimal spray coverage was achieved. Methods The study was a cross-sectional survey conducted in 6 sentinel sites in each of the four afore-mentioned districts, focusing on children 6 months to < 15 years from selected households. There was a baseline and an endline cross-sectional survey. Baseline prevalence took place during March–April 2022 whereas the endline surveys occurred during February–March 2023. One hundred and twenty children from each sentinel site were tested for malaria using rapid diagnostic tests. Monthly malaria cases were obtained from health facilities in each study district. Spray data was obtained from LSDI2 initiative who implemented IRS in the targeted districts. Results The study showed a definite impact of IRS on malaria prevalence in the targeted districts. Prevalence for sentinel sites in Guija district indicated that the prevalence of malaria increased slightly from baseline to endline in all sentinel sites in Guija. Overall, there was no significant change in prevalence in Zavala, from baseline to endline (p-value = 0.611). Panda’s overall malaria prevalence decreased from 19.20% to 10.82% (p-value < 0.001) whereas overall prevalence in Inharrime, decreased from 27.68% to 19.50% (p-value < 0.001). Malaria prevalence in children younger than 5 years decreased significantly in all four districts. In Panda there was a decrease in numbers of males and females being infected between surveys (p < 0.001), whereas for Inharrime the decrease was significant in females (p < 0.001). High coverage with IRS (> 95%) resulted in greater population protection. Conclusion The study revealed that IRS implementation decreased malaria prevalence in Inharrime and Panda but not in Guija and Zavala. To ensure that cross-border movement of people does not result in increased malaria transmission, targeting areas identified as source of infection in travelers is paramount to reaching elimination.

HIV acquisition risk with norethisterone (NET) enanthate (NET-EN) is reportedly less than for depo-medroxyprogesterone acetate intramuscular (DMPA-IM). We investigated the effects of these progestin-only injectable contraceptives on serum testosterone and sex hormone binding globulin (SHBG) levels, since these may play a role in sexual behavior and HIV acquisition. The open-label WHICH clinical trial, conducted at two sites in South Africa from 2018–2019, randomized HIV-negative women aged 18–40 years to 150 mg DMPA-IM 12-weekly (n = 262) or 200 mg NET-EN 8-weekly (n = 259). We measured testosterone by UHPLC-MS/MS and SHBG by immunoassay in matched pairs of serum samples collected at baseline (D0) and at peak serum progestin levels at 25 weeks post initiation (25W) (n = 214–218 pairs). Both contraceptives substantially decreased, from D0 to 25W, the total testosterone [DMPA-IM D0 0.560, 25W 0.423 nmol/L, -24.3% (p < 0.0001); NET-EN D0 0.551, 25W 0.253 nmol/L, -54.1%, (p < 0.0001)], SHBG [DMPA-IM D0 45.0, 25W 32.7 nmol/L, -29.8% (p < 0.0001); NET-EN D0 50.2, 25W 17.6 nmol/L, -65.1% (p < 0.0001)], and calculated free testosterone levels [DMPA-IM D0 6.87, 25W 5.38 pmol/L, -17.2% (p = 0.0371); NET-EN D0 6.00, 25W 3.70, -40.0% (p < 0.0001)]. After adjusting for change from D0, the total testosterone, SHBG and calculated free testosterone levels were significantly higher for DMPA-IM than NET-EN (64.9%, p < 0.0001; 101.2%, p < 0.0001; and 38.0%, p = 0.0120, respectively). The substantial and differential decrease in testosterone and SHBG levels does not explain our previous finding of no detected decrease in risky sexual behavior or sexual function for DMPA-IM or NET-EN users from D0 to 25W. Medroxyprogesterone (MPA) and NET are androgenic and are both present in molar excess over testosterone and SHBG concentrations at 25W. Any within or between contraceptive group androgenic effects on behavior in the brain are likely dominated by the androgenic activities of MPA and NET and not by the decreased endogenous testosterone levels. The clinical trial was registered with the Pan African Clinical Trials Registry (PACTR 202009758229976).

Background For a country such as South Africa which is targeting malaria elimination, mobile and migrant populations pose a substantial risk to importation of malaria parasites. It has been hypothesized that halting cross-border movement of mobile and migrant populations will decrease the importation of malaria, however this option is not a politically, operationally, and financially viable prospect. It has social impacts as well, since families live on either side of the border and preventing travel will challenge family ties. Due to the COVID-19 pandemic and closure of ports of entry (land and air) for non-essential travel into South Africa, a unique opportunity arose to test the hypothesis. Methodology An interrupted time series analysis was done to assess whether the post-lockdown trends (April–December 2020) in monthly reported imported and local cases differed from the pre-lockdown trends (January 2015–March 2020). The analysis was conducted separately for KwaZulu-Natal, Mpumalanga, and Limpopo provinces. Results On average, imported cases were lower in the post-intervention period in all three provinces, and local cases were lower in Mpumalanga and Limpopo, though no results were statistically significant. Conclusion Since population movement continued after the travel restrictions were lifted, border screening with testing and treating should be considered for reducing parasite movement. Another option is reducing malaria cases at the source in neighbouring countries by implementing proven, effective vector and parasite control strategies and through a downstream effect reduce malaria entering South Africa.

Progestin-only injectable contraceptives, mainly depo-medroxyprogesterone acetate intramuscular (DMPA-IM), are the most widely used contraceptive methods in sub-Saharan Africa. Insufficient robust data on their relative side-effects and serum concentrations limit understanding of reported outcomes in contraception trials. The WHICH clinical trial randomized HIV-negative women to DMPA-IM (n = 262) or norethisterone enanthate (NET-EN) (n = 259) at two South African sites between 2018–2019. We measured serum concentrations of study and non-study progestins at initiation (D0) and peak serum levels, one week after the 24-week injection [25 weeks (25W)], (n = 435) and investigated associations between study progestin levels, and BMI and weight of participants. Peak median serum concentrations were 6.59 (IQR 4.80; 8.70) nM for medroxyprogesterone (MPA) (n = 161) and 13.6 (IQR 9.01; 19.0) nM for norethisterone (NET) (n = 155). MPA was the most commonly quantifiable non-study progestin at D0 in both arms (54%) and at 25W in the NET-EN arm (27%), followed by NET at D0 in both arms (29%) and at 25W in the DMPA-IM arm (19%). Levonorgestrel was quantifiable in both arms [D0 (6.9%); 25W (3.4%)], while other progestins were quantifiable in ≤ 14 participants. Significant negative time-varying associations were detected between MPA and NET concentrations and weight and BMI in both contraceptive arms and a significant increase was detected for peak serum progestin concentrations for normal weight versus obese women. Contraceptive-related reported outcomes are likely confounded by MPA, more so than NET, with reported DMPA-IM effects likely underestimated, at sites where DMPA-IM is widely used, due to misreporting of contraceptive use before and during trials, and ‘tail’ effects of DMPA-IM use more than six months before trial enrolment. Peak serum levels of MPA and NET are negatively associated with BMI and weight, suggesting another source of variability between trial outcomes and a potential increase in side-effects for normal weight versus overweight and obese women. Trail registration: The clinical trial was registered with the Pan African Clinical Trials Registry (PACTR 202009758229976 ).

Background Real-world evaluation of the safety profile of vaccines after licensure is crucial to accurately characterise safety beyond clinical trials, support continued use, and thereby improve public confidence. The Sisonke study aimed to assess the safety and effectiveness of the Janssen Ad26.COV2.S vaccine among healthcare workers (HCWs) in South Africa. Here, we present the safety data. Methods and findings In this open-label phase 3b implementation study among all eligible HCWs in South Africa registered in the national Electronic Vaccination Data System (EVDS), we monitored adverse events (AEs) at vaccination sites through self-reporting triggered by text messages after vaccination, healthcare provider reports, and active case finding. The frequency and incidence rate of non-serious and serious AEs were evaluated from the day of first vaccination (17 February 2021) until 28 days after the final vaccination in the study (15 June 2021). COVID-19 breakthrough infections, hospitalisations, and deaths were ascertained via linkage of the electronic vaccination register with existing national databases. Among 477,234 participants, 10,279 AEs were reported, of which 138 (1.3%) were serious AEs (SAEs) or AEs of special interest. Women reported more AEs than men (2.3% versus 1.6%). AE reports decreased with increasing age (3.2% for age 18–30 years, 2.1% for age 31–45 years, 1.8% for age 46–55 years, and 1.5% for age > 55 years). Participants with previous COVID-19 infection reported slightly more AEs (2.6% versus 2.1%). The most common reactogenicity events were headache (n = 4,923) and body aches (n = 4,483), followed by injection site pain (n = 2,767) and fever (n = 2,731), and most occurred within 48 hours of vaccination. Two cases of thrombosis with thrombocytopenia syndrome and 4 cases of Guillain-Barré Syndrome were reported post-vaccination. Most SAEs and AEs of special interest (n = 138) occurred at lower than the expected population rates. Vascular (n = 37; 39.1/100,000 person-years) and nervous system disorders (n = 31; 31.7/100,000 person-years), immune system disorders (n = 24; 24.3/100,000 person-years), and infections and infestations (n = 19; 20.1/100,000 person-years) were the most common reported SAE categories. A limitation of the study was the single-arm design, with limited routinely collected morbidity comparator data in the study setting. Conclusions We observed similar patterns of AEs as in phase 3 trials. AEs were mostly expected reactogenicity signs and symptoms. Furthermore, most SAEs occurred below expected rates. The single-dose Ad26.COV2.S vaccine demonstrated an acceptable safety profile, supporting the continued use of this vaccine in this setting. Trial registration ClinicalTrials.gov NCT04838795; Pan African Clinical Trials Registry PACTR202102855526180.

In clinical trials, a vital protocol requirement for par ticipants is adherence to scheduled visits. A substantial number of missed visits and the resultant missing data could affect generalisability of the findings and undermine the scientific conclusions. We aimed to investigate the extent of and reasons for missed visits in the Evidence for Contraceptive Options and HIV Outcomes (ECHO) trial in order to optimise recruitment and retention practices. Despite being a multi-country study, we investigated missed visits only at Setshaba Research Centre in Soshanguve, Tshwane, South Africa. Of 810 par ticipants enrolled at Setshaba Research Centre, 94 (11.6%) par ticipants missed visits and 231 missed visits were recorded. Of the 94 par ticipants who missed visits, 53 (56.4%) missed at least two visits; 37 (39.4%) missed three or more visits, and of these, 32 (86.5%) missed at least two visits for the same reason. Overall, the main reasons for missed visits were: par ticipant had to work (60; 26.0%), unable to contact par ticipant (60; 26.0%), par ticipant relocated (32; 13.9%), and par ticipant travelled out of area (23; 10%). The large propor tion of par ticipants who missed two or more visits indicates that par ticipants who miss a single visit are likely to miss even more, often for the same reason. Site staff need to be vigilant to detect any trends in missed visits early and innovative in developing personalised strategies to minimise missed visits and retain par ticipants until completion of their scheduled visits.

INTRODUCTION : Household air pollution from domestic solid fuel use remains a global public health concern, particularly in low‑income communities. This study assessed associations between household fuel use, indoor air pollution, and respiratory health outcomes in two Mpumalanga communities in South Africa. METHODS : A cross‑sectional study was conducted in KwaZamokuhle and eMzinoni between July 2019 and February 2020. Indoor PM2‧5 concentrations were measured using Airmetrics MiniVol samplers and TSI DustTrak II monitors. We carried out household surveys, lung function tests and allergen sensitivity testing and performed multivariable logistic regression to assess associations between indoor pollutant exposure and respiratory health outcomes. RESULTS : Indoor and ambient PM2‧5 concentrations in KwaZamokuhle were more than twice as high as those in eMzinoni, exceeding both national standards and WHO Air Quality Guidelines. Coal use for heating was more prevalent in KwaZamokuhle and appeared directly related to elevated PM2‧5 levels. Approximately 9% of participants exhibited signs of obstructive airway disease, and 25% had positive results for allergen sensitisation. Although the associations between PM2‧5 levels, solid fuel use and measured respiratory outcomes did not reach statistical significance, consistent trends in the expected direction were observed, suggesting a potential relationship that warrants longitudinal studies with larger sample sizes. CONCLUSION : These findings suggest complex, possibly nonlinear relationships between indoor air pollution and respiratory health effects. The study underscores the urgent need for a greater use of clean energy alternatives and increased public awareness about the risks of household air pollution in low‑income South African communities.