Managerial competencies to enhance individual and organisational performance have gained currency in global efforts to strengthen health systems. Competent managers are essential in the implementation of primary health care (PHC) reforms that aim to achieve universal health coverage.
To evaluate the competencies of PHC clinic nursing managers in two South African provinces.
A cross-sectional study was conducted in two South African provinces. Using stratified random sampling, 111 PHC clinic nursing managers were selected. All supervisors (n=104) and subordinate nurses (n=383) were invited to participate in the survey on the day of data collection. Following informed consent, the nursing managers, their supervisors, and subordinate nurses completed a 40-item, 360-degree competency assessment questionnaire, with six domains: communication, leadership and management, staff management, financial management, planning and priority setting, and problem-solving. Standard deviations, medians, and inter-quartile ranges (IQRs) were computed separately for PHC nursing managers, supervisors, and subordinate nurses for competencies in the six domains. The Tinsley and Weiss index was used to assess agreement between each of the three possible pairs of raters.
A 95.4% response rate was obtained, with 105 nursing managers in Gauteng and Free State completing the questionnaires. There was a lack of agreement about nursing managers’ competencies among the three groups of raters. Overall, clinic nursing managers rated themselves high on the five domains of communication (8.6), leadership and management (8.67), staff management (8.75), planning and priority setting (8.6), and problem-solving (8.83). The exception was financial management with a median score of 7.94 (IQR 6.33–9.11). Compared to the PHC clinic managers, the supervisors and subordinate nurses gave PHC nursing managers lower ratings on all six competency domains, with the lowest rating for financial management (supervisor median rating 6.56; subordinate median rating 7.31).
The financial management competencies of PHC clinic nursing managers need to be prioritised in continuing professional development programmes.
competencies; nursing management; primary health care clinics; training; South Africa
COSTOP was a randomised controlled trial designed to assess the risks and benefits to HIV-infected participants stabilised on anti-retroviral treatment of stopping cotrimoxazole (CTX). In order to assess the extent to which patients may have had access to and used CTX other than that supplied as study drug it was decided to conduct an exit interview.
A structured interview was administered by interviewers who were not associated with the COSTOP trial team in order to make it easier for participants to respond truthfully to sensitive questions about adherence to the study protocol.
A total of 1993 participants were interviewed. Only 29 (1.7%) said they had taken their left over CTX; 101 (6.1%) had kept supplies at home. When asked about obtaining open label CTX during the trial 92 (4.7%) participants said they had done so, in contrast to only 12 who admitted doing so when asked at trial visits. The questions participants found most difficult to answer honestly at clinic visits were those concerning adherence to trial drugs (15.6% of participants) and whether they had slept under the insecticide treated mosquito nets (14.9%).
The exit interview demonstrated that there was some evidence of open label drug being taken by the participants. However, the results from the interview do not suggest that the trial results would have been seriously compromised. We would recommend the exit interview as a valuable way of assessing adherence to trial procedures.
Cotrimoxazole prophylaxis; Exit interview; Adherence
Parasitic helminths are potent immunomodulators and chronic infections may protect against allergy‐related disease and atopy. We conducted a cross‐sectional survey to test the hypothesis that in heavily helminth‐exposed fishing villages on Lake Victoria, Uganda, helminth infections would be inversely associated with allergy‐related conditions.
A household survey was conducted as baseline to an anthelminthic intervention trial. Outcomes were reported wheeze in last year, atopy assessed both by skin prick test (SPT) and by the measurement of allergen‐specific IgE to dust mites and cockroach in plasma. Helminth infections were ascertained by stool, urine and haemoparasitology. Associations were examined using multivariable regression.
Two thousand three hundred and sixteen individuals were surveyed. Prevalence of reported wheeze was 2% in under‐fives and 5% in participants ≥5 years; 19% had a positive SPT; median Dermatophagoides‐specific IgE and cockroach‐specific IgE were 1440 and 220 ng/ml, respectively. S. mansoni, N. americanus, S. stercoralis, T. trichiura, M. perstans and A. lumbricoides prevalence was estimated as 51%, 22%, 12%, 10%, 2% and 1%, respectively. S. mansoni was positively associated with Dermatophagoides‐specific IgE [adjusted geometric mean ratio (aGMR) (95% confidence interval) 1.64 (1.23, 2.18)]; T. trichiura with SPT [adjusted odds ratio (aOR) 2.08 (1.38, 3.15)]; M. perstans with cockroach‐specific IgE [aGMR 2.37 (1.39, 4.06)], A. lumbricoides with wheeze in participants ≥5 years [aOR 6.36 (1.10, 36.63)] and with Dermatophagoides‐specific IgE [aGMR 2.34 (1.11, 4.95)]. No inverse associations were observed.
Contrary to our hypothesis, we found little evidence of an inverse relationship between helminths and allergy‐related outcomes, but strong evidence that individuals with certain helminths were more prone to atopy in this setting.
allergy; atopy; helminths; household survey; wheeze
The effect of CD4 count on malaria incidence in HIV infected adults on antiretroviral therapy (ART) was assessed in the context of a randomized controlled trial on the effect of stopping cotrimoxazole (CTX).
This study presents a sub-analysis of the COSTOP trial (ISRCTN44723643) which was carried out among HIV-infected Ugandan adults stable on ART with CD4 counts ≥250 cells/µl. Participants were randomized (1:1) to continue CTX or stop CTX and receive matching placebo, and were followed up for a minimum of 1 year (median 2.5 years). CD4 counts were measured at baseline, 3 months and then every 6 months. Clinical malaria was defined as fever and a positive blood slide. First, the relationship between current CD4 count during follow-up and malaria among participants on placebo was examined; using random effects Poisson regression to account for repeated episodes. Second, the effect of CD4 count at enrolment, CD4 count at ART initiation, and CD4 count during follow-up on malaria, was assessed within each trial arm; to examine whether the effect of CD4 count differed by CTX use.
2180 participants were enrolled into the COSTOP trial. The incidence of clinical malaria was approximately four episodes/100 person years in the CTX arm and 14 episodes/100 person years in the placebo arm. There was no evidence of an association of current CD4 and clinical malaria incidence (P = 0.56), or parasitaemia levels (P = 0.24), in the placebo arm. Malaria incidence did not differ by CD4 count at ART initiation, enrolment or during follow up, irrespective of CTX use. When compared with participants in the lowest CD4 stratum, rate ratios within each trial arm were all close to 1, and P values were all above P = 0.30.
The immune status of HIV infected participants who are stable on ART as measured by CD4 count was not associated with malaria incidence and did not modify the effect of stopping CTX on malaria. The decision of whether to stop or continue CTX prophylaxis for malaria in HIV infected individuals who are stable on ART should not be based on CD4 counts alone.
COSTOP trial registration number ISRCTN44723643
Electronic supplementary material
The online version of this article (doi:10.1186/s12936-016-1426-z) contains supplementary material, which is available to authorized users.
Malaria; CD4; Antiretroviral therapy; Cotrimoxazole; HIV
Anaemia is a common problem in HIV in sub-Saharan Africa. We describe the contribution of ART regimen on the incidence of anaemia and changes in haemoglobin in Ugandan patients.
This study was nested in a prevention of cryptococcal disease trial (CRYPTOPRO; ISCRTN7648152). Patients received three different nucleoside reverse transcriptase inhibitor backbones in a non-randomised manner.
Of 852 patients (161 on zidovudine, 628 on stavudine and 63 on tenofovir (all received lamuvidine), the risk of developing grade 4 anaemia was higher (aHR 2.7) for those taking zidovudine compared with stavudine. Those taking stavudine had a greater average increase in haemoglobin than those taking zidovudine (p=0.024) or tenofovir (p=0.014).
In this observational study zidovudine was associated with higher levels of severe anaemia than stavudine or tenofovir; those receiving zidovudine and tenofovir had smaller haemoglobin rises after ART initiation. We encourage publication of data from African cohorts using tenofovir.
anaemia ART Africa tenofovir zidovudine Uganda haemoglobin
Cryptococcal disease remains an important cause of morbidity and mortality in HIV infected individuals in sub-Saharan Africa, despite the introduction of antiretroviral therapy (ART). Fluconazole has not been previously studied as primary prophylaxis against cryptococcal disease in patients awaiting or starting ART.
This prospective, double blind randomized controlled trial compared 200mg fluconazole three times per week to identical placebo in Uganda. 1519 ART naïve adults with CD4 counts <200 cells/μL were enrolled. Patients were excluded if baseline cryptococcal antigen (CrAg) was positive. Patients were randomly allocated to placebo or control (1:1) in blocks of 40 without stratification. Participants were seen after 4 weeks and referred for ART, then seen every 8 weeks. Participants discontinued trial treatment when CD4 counts reached 200 (median 197 days). Analyses were carried out on an intention to treat basis and included all participants enrolled in the study. Primary end points were invasive cryptococcal disease and all cause mortality. Secondary endpoints were first episode and incidence of oesophageal candidiasis, time to first episode and incidence of oro-pharyngeal or vaginal candidiasis, time to first hospital admission or death. The primary safety end point was stopping trial drug due to elevated transaminases above 5x upper limit of normal or other major adverse events. The trial is registered on controlled-trials.com; ISRCTN 76481529
760 participants received fluconazole and 759 received placebo. 19 developed cryptococcal disease, one on fluconazole and 18 on placebo (P<0.001); adjusted Hazard Ratio (aHR) 18.7 (95%CI 2.5-140.7). One case of cryptococcal disease could be prevented by treating 44.6 patients with baseline CD4 counts <200 cells/μL. Fluconazole was effective both pre-ART (aHR=11.0; 95%CI 1.4-85.3) and after starting ART (no cases on fluconazole vs. 7 cases on placebo after starting ART). Seven participants died from cryptococcal disease, none on fluconazole. All cause mortality (N=189) did not differ between the two arms (P=0.46). The frequency of elevated transaminases (>5x upper limit) was similar in both arms (aHR=0.94, 95% CI 0.65-1.35).
Fluconazole was safe and effective as primary prophylaxis against cryptococcal disease, both before starting and during early ART. Cryptococcal infection was less common than anticipated because of the rapid commencement of ART and exclusion of those with positive CrAg. In patients with negative CrAg on screening, fluconazole prophylaxis can prevent cryptococcal disease while waiting for ART and in the early weeks of ART, particularly in those with CD4 counts <100 cells/μL.
Medical Research Council, UK and Rockefeller Foundation
Cryptococcus; primary prophylaxis; Fluconazole
Recent reports suggest that Schistosoma infection may increase the risk of acquiring human immunodeficiency virus (HIV). We used data from a large cross‐sectional study to investigate whether Schistosoma mansoni infection is associated with increased HIV prevalence.
We conducted a household survey of residents in island fishing communities in Mukono district, Uganda, between October 2012 and July 2013. HIV status was assessed using rapid test kits. Kato‐Katz (KK) stool tests and urine‐circulating cathodic antigen (CCA) were used to test for Schistosoma infection. Multivariable logistic regression, allowing for the survey design, was used to investigate the association between S. mansoni infection and HIV infection.
Data from 1412 participants aged 13 years and older were analysed (mean age 30.3 years, 45% female). The prevalence of HIV was 17.3%. Using the stool Kato‐Katz technique on a single sample, S. mansoni infection was detected in 57.2% (719/1257) of participants; urine CCA was positive in 73.8% (478/650) of those tested. S. mansoni infection was not associated with HIV infection. [KK (aOR = 1.04; 95% CI: 0.74–1.47, P = 0.81), CCA (aOR = 1.53; 95% CI: 0.78–3.00, P = 0.19)]. The median S. mansoni egg count per gram was lower in the HIV‐positive participants (P = 0.005).
These results add to the evidence that S. mansoni has little effect on HIV transmission, but may influence egg excretion.
Schistosoma mansoni; schistosomiasis; Bilharzia; HIV; Schistosoma mansoni; schistosomiase; bilharziose; VIH
Previous unblinded trials have shown increased malaria among HIV-infected adults on antiretroviral therapy (ART) who stop cotrimoxazole (CTX) prophylaxis. We investigated the effect of stopping CTX on malaria in HIV-infected adults on ART in a double-blind, placebo-controlled trial.
HIV-infected Ugandan adults stable on ART and CTX with CD4+ cell count at least 250 cells/μl were randomized (1 : 1) to continue CTX or stop CTX and receive matching placebo (COSTOP trial; ISRCTN44723643). Clinical malaria was defined as fever and a positive blood slide, and considered severe if a participant had at least one clinical or laboratory feature of severity or was admitted to hospital. Malaria incidence and rate ratios were estimated using random effects Poisson regression, accounting for multiple episodes.
A total of 2180 participants were enrolled and followed for a median of 2.5 years; 453 malaria episodes were recorded. Malaria incidence was 9.1/100 person-years (pyrs) [95% confidence interval (CI) = 8.2–10.1] and was higher on placebo (rate ratio 3.47; CI = 2.74–4.39). Malaria in the placebo arm decreased over time; although incidence remained higher than in the CTX arm, the difference between arms reduced slightly (interaction P value = 0.10). Fifteen participants experienced severe malaria (<1%); overall incidence was 0.30/100 pyrs (CI = 0.18–0.49). There was one malaria-related death (CTX arm).
HIV-infected adults – who are stable on ART and stop prophylactic CTX – experience more malaria than those that continue, but this difference is less than has been reported in previous trials. Few participants had severe malaria. Further research might be useful in identifying groups that can safely stop CTX prophylaxis.
antiretroviral therapy; cotrimoxazole; HIV; malaria; trimethoprim/sulfamethoxazole
Fishing communities are potentially suitable for Human immunodeficiency virus (HIV) efficacy trials due to their high risk profile. However, high mobility and attrition could decrease statistical power to detect the impact of a given intervention. We report dropout and associated factors in a fisher-folk observational cohort in Uganda.
Human immunodeficiency virus-uninfected high-risk volunteers aged 13–49 years living in five fishing communities around Lake Victoria were enrolled and followed every 6 months for 18 months at clinics located within each community. Volunteers from two of the five communities had their follow-up periods extended to 30 months and were invited to attend clinics 10–40 km (km) away from their communities. Human immunodeficiency virus counseling and testing was provided, and data on sexual behaviour collected at all study visits. Study completion was defined as completion of 18 or 30 months or visits up to the date of sero-conversion and dropout as missing one or more visits. Discrete time survival models were fitted to find factors independently associated with dropout.
A total of 1000 volunteers (55 % men) were enrolled. Of these, 91.9 % completed 6 months, 85.2 % completed 12 months and 76.0 % completed 18 months of follow-up. In the two communities with additional follow-up, 76.9 % completed 30 months. In total 299 (29.9 %) volunteers missed at least one visit (dropped out). Dropout was independently associated with age (volunteers aged 13–24 being most likely to dropout), gender [men being more likely to dropout than women [adjusted hazard ratio (aHR) 1.4; 95 % confidence interval (CI) 1.1–1.8)], time spent in the fishing community (those who stayed <1 year being most likely to dropout), History of marijuana use (users being more likely to dropout than non-users [1.7; (1.2–2.5)], ethnicity (non-Baganda being more likely to dropout than Baganda [1.5; (1.2–1.9)], dropout varied between the five fishing communities, having a new sexual partner in the previous 3 months [1.3 (1.0–1.7)] and being away from home for ≥2 nights in the month preceding the interview [1.4 (1.1–1.8)].
Despite a substantial proportion dropping out, retention was sufficient to suggest that by incorporating retention strategies it will be possible to conduct HIV prevention efficacy trials in this community.
Electronic supplementary material
The online version of this article (doi:10.1186/s13104-015-1804-6) contains supplementary material, which is available to authorized users.
HIV; Long term; Dropout; Migration; Fishing communities; Lake Victoria Uganda
With the renewed emphasis to implement isoniazid preventive therapy (IPT) in Sub-Saharan Africa, we investigated the effect of IPT on immunological profiles among household contacts with latent tuberculosis.
Household contacts of confirmed tuberculosis patients were tested for latent tuberculosis using the QuantiFERON®-TB Gold In-Tube (QFN) assay and tuberculin skin test (TST). HIV negative contacts aged above 5 years, positive to both QFN and TST, were randomly assigned to IPT and monthly visits or monthly visits only. QFN culture supernatants from enrolment and six months’ follow-up were analysed for M.tb-specific Th1, Th2, Th17, and regulatory cytokines by Luminex assay, and for M.tb-specific IgG antibody concentrations by ELISA. Effects of IPT were assessed as the net cytokine and antibody production at the end of six months.
Sixteen percent of contacts investigated (47/291) were randomised to IPT (n = 24) or no IPT (n = 23). After adjusting for baseline cytokine or antibody responses, and for presence of a BCG scar, IPT (compared to no IPT) resulted in a relative decline in M.tb-specific production of IFN gamma (adjusted mean difference at the end of six months (bootstrap 95 % confidence interval (CI), p-value) -1488.6 pg/ml ((−2682.5, −294.8), p = 0.01), and IL- 2 (−213.1 pg/ml (−419.2, −7.0), p = 0.04). A similar decline was found in anti-CFP-10 antibody levels (adjusted geometric mean ratio (bootstrap 95 % CI), p-value) 0.58 ((0.35, 0.98), p = 0.04). We found no effect on M.tb-specific Th2 or regulatory or Th17 cytokine responses, or on antibody concentrations to PPD and ESAT-6.
IPT led to a decrease in Th1 cytokine production, and also in the anti CFP-10 antibody concentration. This could be secondary to a reduction in mycobacterial burden or as a possible direct effect of isoniazid induced T cell apoptosis, and may have implications for protective immunity following IPT in tuberculosis-endemic countries.
ISRCTN registry, ISRCTN15705625. Registered on 30th September 2015.
Latent tuberculosis infection; Household contacts; Randomised design; Cytokines; Antibodies; Isoniazid preventive therapy
Cotrimoxazole (CTX) prophylaxis is recommended by the World Health Organisation for HIV infected persons. However, once HIV infected patients have commenced ART in resource limited settings, the benefits of continued CTX prophylaxis are not known. The few studies that investigated the safety of discontinuing CTX prophylaxis in these settings had limitations due to their design.
Materials and methods
COSTOP is a randomised double blind placebo controlled non-inferiority trial among HIV infected Ugandan adults stabilised on anti-retroviral treatment (ART). Participants with CD4 count of 250 or more cells/mm3 are randomised to two arms: the intervention arm in which CTX is discontinued and the control arm in which CTX prophylaxis is continued. The study aims to assess whether the intervention regimen is not inferior, with respect to the incidence of pre-defined CTX-preventable events, to the control regimen and superior with respect to the incidence of haematological adverse events.
Studies that have previously evaluated the safety of discontinuing CTX prophylaxis among HIV infected adults in resource limited settings have provided moderate to low quality evidence owing in part to methodological limitations. COSTOP is designed and conducted with sufficient rigour to answer this question. The results of the trial will assist in guiding policy recommendations.
This paper describes the design and methodological considerations important for the conduct of CTX cessation studies.
HIV infection; Cotrimoxazole prophylaxis; Stopping cotrimoxazole; Antiretroviral treatment; Cotrimoxazole cessation study design; Uganda
The burden of non-communicable diseases (NCDs) is increasing in sub-Saharan Africa, but data available for intervention planning are inadequate. We determined the prevalence of selected NCDs and HIV infection, and NCD risk factors in northwestern Tanzania and southern Uganda.
A population-based cross-sectional survey was conducted, enrolling households using multistage sampling with five strata per country (one municipality, two towns, two rural areas). Consenting adults (≥18 years) were interviewed using the WHO STEPS survey instrument, examined, and tested for HIV and diabetes mellitus (DM). Adjusting for survey design, we estimated population prevalences of hypertension, DM, obstructive pulmonary disease, cardiac failure, epilepsy and HIV, and investigated factors associated with hypertension using logistic regression.
Across strata, hypertension prevalence ranged from 16 % (95 % confidence interval (CI): 12 % to 22 %) to 17 % (CI: 14 % to 22 %) in Tanzania, and from 19 % (CI: 14 % to 26 %) to 26 % (CI: 23 % to 30 %) in Uganda. It was high in both urban and rural areas, affecting many young participants. The prevalence of DM (1 % to 4 %) and other NCDs was generally low. HIV prevalence ranged from 6 % to 10 % in Tanzania, and 6 % to 12 % in Uganda. Current smoking was reported by 12 % to 23 % of men in different strata, and 1 % to 3 % of women. Problem drinking (defined by Alcohol Use Disorder Identification Test criteria) affected 6 % to 15 % men and 1 % to 6 % women. Up to 46 % of participants were overweight, affecting women more than men and urban more than rural areas. Most patients with hypertension and other NCDs were unaware of their condition, and hypertension in treated patients was mostly uncontrolled. Hypertension was associated with older age, male sex, being divorced/widowed, lower education, higher BMI and, inversely, with smoking.
The high prevalence of NCD risk factors and unrecognized and untreated hypertension represent major problems. The low prevalence of DM and other preventable NCDs provides an opportunity for prevention. HIV prevalence was in line with national data. In Tanzania, Uganda and probably elsewhere in Africa, major efforts are needed to strengthen health services for the PREVENTION, early detection and treatment of chronic diseases.
Electronic supplementary material
The online version of this article (doi:10.1186/s12916-015-0357-9) contains supplementary material, which is available to authorized users.
Non-communicable diseases; hypertension; diabetes mellitus; heart failure; obstructive pulmonary disease; HIV infection; NCD risk factors; WHO STEPS survey; Africa
Tuberculosis incidence in resource poor countries remains high. We hypothesized that immune modulating co-infections such as helminths, malaria, and HIV increase susceptibility to latent tuberculosis infection (LTBI), thereby contributing to maintaining the tuberculosis epidemic.
Adults with sputum-positive tuberculosis (index cases) and their eligible household contacts (HHCs) were recruited to a cohort study between May 2011 and January 2012. HHCs were investigated for helminths, malaria, and HIV at enrolment. HHCs were tested using the QuantiFERON-TB Gold In-Tube (QFN) assay at enrolment and six months later. Overnight whole blood culture supernatants from baseline QFN assays were analyzed for cytokine responses using an 11-plex Luminex assay. Associations between outcomes (LTBI or cytokine responses) and exposures (co-infections and other risk factors) were examined using multivariable logistic and linear regression models.
We enrolled 101 index cases and 291 HHCs. Among HHCs, baseline prevalence of helminths was 9% (25/291), malaria 16% (47/291), HIV 6% (16/291), and LTBI 65% (179/277). Adjusting for other risk factors and household clustering, there was no association between LTBI and any co-infection at baseline or at six months: adjusted odds ratio (95% confidence interval (CI); p-value) at baseline for any helminth, 1.01 (0.39–2.66; 0.96); hookworm, 2.81 (0.56–14.14; 0.20); malaria, 1.06 (0.48–2.35; 0.87); HIV, 0.74 (0.22–2.47; 0.63). HHCs with LTBI had elevated cytokine responses to tuberculosis antigens but co-infections had little effect on cytokine responses. Exploring other risk factors, Th1 cytokines among LTBI-positive HHCs with BCG scars were greatly reduced compared to those without scars: (adjusted geometric mean ratio) IFNγ 0.20 (0.09–0.42), <0.0001; IL-2 0.34 (0.20–0.59), <0.0001; and TNFα 0.36 (0.16–0.79), 0.01.
We found no evidence that co-infections increase the risk of LTBI, or influence the cytokine response profile among those with LTBI. Prior BCG exposure may reduce Th1 cytokine responses in LTBI.
Observational studies suggest that asthma control improves after adenotonsillectomy, but longitudinal studies that correlate the effect of the procedure on the levels of biomarkers associated with airway inflammation are limited.
We conducted a longitudinal, observational study on pediatric patients, both with and without asthma, undergoing adenotonsillectomy. Asthma Control Test (ACT) scores and chitinase activity in the circulation were measured at time of surgery and at 6-month follow-up.
66 children with asthma and 64 control subjects were enrolled. Mean ACT scores improved by 3 points (p< 0.001) after 6 months. 85% of children with poorly-controlled asthma demonstrated an increase in ACT score of at least 3 points or a decrease in Emergency Department/Urgent Care visits, oral corticosteroid courses, or rescue short acting bronchodilator usage. Chitinase activity decreased significantly in asthmatics who improved (p< 0.01). Higher chitinase activity levels at baseline were associated with improved asthma control following surgery (p< 0.01).
In children with high pre-operative circulating chitinase activity levels, asthma control and healthcare utilization were significantly improved after adenotonsillecotmy. Chitinase activity decreased after surgery in children with improved control. This suggests that adenotonsillectomy modulates chitinase activity, affecting airway inflammation and improving airway disease.
To investigate the effect of seasonal variation on adult clinical laboratory parameters in Rwanda, Zambia, and Uganda and determine its implications for HIV prevention and other clinical trials.
Volunteers in a cross-sectional study to establish laboratory reference intervals were asked to return for a seasonal visit after the local season had changed from dry to rainy or vice versa. Volunteers had to be clinically healthy, not pregnant and negative for HIV, Hepatitis B and C, and syphilis infection at both visits. At each visit, blood was taken for measurement of hemoglobin, haematocrit, mean corpuscular volume, red blood cells, platelets, total white blood cells (WBC), neutrophils, lymphocytes, monocytes, eosinophils, basophils, CD4/CD8 T cells, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, direct bilirubin, total bilirubin, total immunoglobulin gamma, total protein, creatinine, total amylase, creatine phosphokinase and lactate dehydrogenase (LDH). Consensus dry season reference intervals were applied to rainy season values (and vice versa) and the proportion of ‘out-of-range’ values determined. Percentage differences between dry and rainy season parameter mean values were estimated.
In this cohort of 903 volunteers, less than 10.0% of consensus parameter (except LDH) values in one season were “out-of-range” in the other. Twenty-two (22) percent of rainy season LDH values fell outside of the consensus dry season interval with the higher values observed in the rainy season. Variability between consensus seasonal means ranged from 0.0% (total WBC, neutrophils, monocytes, basophils, and direct bilirubin) to 40.0% (eosinophils). Within sites, the largest seasonal variations were observed for monocytes (Masaka, 11.5%), LDH (Lusaka, 21.7%), and basophils (Kigali, 22.2%).
Seasonality had minimal impact on adult clinical laboratory parameter values in Rwanda, Zambia, and Uganda. Seasonal variation may not be an important factor in the evaluation of adult clinical laboratory parameters in HIV prevention and other clinical trials in these countries.
Poor prognosis in patients with later stage colorectal cancer (CRC) necessitates the search for new treatment strategies. Ceramide, because of its role in orchestrating death cascades in cancer cells, is a versatile alternative. Ceramide can be generated by exposure to chemotherapy or ionizing radiation, or it can be administered in the form of short-chain analogs (C6-ceramide). Because intracellular P-glycoprotein (P-gp) plays a role in catalyzing the conversion of ceramide to higher sphingolipids, we hypothesized that administration of P-gp antagonists with C6-ceramide would magnify cell death cascades. Human CRC cell lines were employed, HCT-15, HT-29, and LoVo. The addition of either tamoxifen, VX-710, verapamil, or cyclosporin A, antagonists of P-gp, enhanced C6-ceramide cytotoxicity in all cell lines. In depth studies with C6-ceramide and tamoxifen in LoVo cells showed the regimen induced PARP cleavage, caspase-dependent apoptosis, mitochondrial membrane permeabilization (MMP), and cell cycle arrest at G1 and G2. At the molecular level, the regimen, but not single agents, induced time-dependent upregulation of tumor suppressor protein p53; however, introduction of a p53 inhibitor staved neither MMP nor apoptosis. Nanoliposomal formulations of C6-ceramide and tamoxifen were also effective, yielding synergistic cell kill. We conclude that tamoxifen is a favorable adjuvant for enhancing C6-ceramide cytotoxicity in CRC, and demonstrates uniquely integrated effects. The high frequency of expression of P-gp in CRC presents an adventitious target for complementing ceramide-based therapies, a strategy that could hold promise for treatment of resistant disease.
colorectal cancer; ceramide; C6-ceramide; tamoxifen; P-glycoprotein; p53
In most resource limited settings, new tuberculosis (TB) patients are usually treated as outpatients. We sought to investigate the reasons for hospitalisation and the predictors of poor treatment outcomes and mortality in a cohort of hospitalized new TB patients in Kampala, Uganda
Methods and findings
Ninety-six new TB patients hospitalised between 2003 and 2006 were enrolled and followed for two years. Thirty two were HIV-uninfected and 64 were HIV-infected. Among the HIV-uninfected, the commonest reasons for hospitalization were low Karnofsky score (47%) and need for diagnostic evaluation (25%). HIV-infected patients were commonly hospitalized due to low Karnofsky score (72%), concurrent illness (16%) and diagnostic evaluation (14%). Eleven HIV uninfected patients died (mortality rate 19.7 per 100 person-years) while 41 deaths occurred among the HIV-infected patients (mortality rate 46.9 per 100 person years). In all patients an unsuccessful treatment outcome (treatment failure, death during the treatment period or an unknown outcome) was associated with duration of TB symptoms, with the odds of an unsuccessful outcome decreasing with increasing duration. Among HIV-infected patients, an unsuccessful treatment outcome was also associated with male sex (P = 0.004) and age (P = 0.034). Low Karnofsky score (aHR = 8.93, 95% CI 1.88 – 42.40, P = 0.001) was the only factor significantly associated with mortality among the HIV-uninfected. Mortality among the HIV-infected was associated with the composite variable of CD4 and ART use, with patients with baseline CD4 below 200 cells/µL who were not on ART at a greater risk of death than those who were on ART, and low Karnofsky score (aHR = 2.02, 95% CI 1.02 – 4.01, P = 0.045).
Poor health status is a common cause of hospitalisation for new TB patients. Mortality in this study was very high and associated with advanced HIV Disease and no use of ART.
In sub-Saharan Africa, a large proportion of HIV positive patients on antiretroviral therapy (ART) are lost to follow-up, some of whom are dead. The objective of this study was to validate methods used to correct mortality estimates for loss-to-follow-up using a cohort with complete death ascertainment.
Routinely collected data from HIV patients initiating first line antiretroviral therapy (ART) at the Infectious Diseases Institute (IDI) (Routine Cohort) was used. Three methods to estimate mortality after initiation were: 1) standard Kaplan-Meier estimation (uncorrected method) that uses passively observed data; 2) double-sampling methods by Frangakis and Rubin (F&R) where deaths obtained from patient tracing studies are given a higher weight than those passively ascertained; 3) Nomogram proposed by Egger et al. Corrected mortality estimates in the Routine Cohort, were compared with the estimates from the IDI research observational cohort (Research Cohort), which was used as the “gold-standard”.
We included 5,633 patients from the Routine Cohort and 559 from the Research Cohort. Uncorrected mortality estimates (95% confidence interval ) in the Routine Cohort at 1, 2 and 3 years were 5.5% (4.9%–6.3%), 6.6% (5.9%–7.5%) and 7.4% (6.5%–8.5%), respectively. The F&R corrected estimates at 1, 2 and 3 years were 11.2% (5.8%–21.2%), 15.8% (9.9%–24.8%) and 18.5% (12.3% –27.2%) respectively. The estimates obtained from the Research Cohort were 15.6% (12.8%–18.9%), 17.5% (14.6%–21.0%) and 19.0% (15.3%–21.9%) at 1, 2 and 3 years respectively. Using the nomogram method in the Routine Cohort, the corrected programme-level mortality estimate in year 1 was 11.9% (8.0%–15.7%).
Mortality adjustments provided by the F&R and nomogram methods are adequate and should be employed to correct mortality for loss-to-follow-up in large HIV care centres in Sub-Saharan Africa.
Although the sphingolipid ceramide exhibits potent tumor suppressor effects, efforts to harness this have been hampered by poor solubility, uptake, bioavailability, and metabolic conversion. Therefore, identification of avenues to improve efficacy is necessary for development of ceramide-based therapies. In this study we used mutant p53, triple negative breast cancer (TNBC) cells, a type of breast cancer highly refractory to treatment, and cell-permeable nanoliposomal C6-ceramide in conjunction with the antiestrogen tamoxifen, which has been shown to be an effective modulator of ceramide metabolism. We show for the first time that nanoliposomal tamoxifen enhances nanoliposomal C6-ceramide cytotoxicity in cultured TNBC cells, a response that was accompanied by induction of cell cycle arrest at G1 and G2, caspase-dependent induction of DNA fragmentation, and enhanced mitochondrial and lysosomal membrane permeability, at 18 and 2 hr, respectively. Tamoxifen metabolites were also effective. Only tamoxifen promoted lysosomal membrane permeability. In addition, we demonstrate for the first time that tamoxifen inhibits acid ceramidase, as measured in intact cell assays; this effect was irreversible. Together, our findings show that tamoxifen magnifies the antiproliferative effects of C6-ceramide via combined targeting of cell cycle traverse and lysosomal and mitochondrial integrity. We adduce that C6-ceramide-induced apoptosis is amplified by tamoxifen's impact on lysosomes and perhaps accompanying inhibition of acid ceramidase, which could result in decreased levels of sphingosine 1-phosphate. This drug regimen could serve as a promising therapy for chemoresistant and triple negative types of breast cancer, and thus represents an indication for tamoxifen, irrespective of estrogen receptor status.
ceramide; liposomes; breast cancer; antiestrogen; ceramidase
Thyroid hormones (TH) play an important regulatory role in energy expenditure regulation and are key regulators of mitochondrial activity. We have previously identified a mitochondrial triiodothyronine (T3) receptor (p43) which acts as a mitochondrial transcription factor of the organelle genome, which leads in vitro and in vivo, to a stimulation of mitochondrial biogenesis. Recently, we generated mice carrying a specific p43 invalidation. At 2 months of age, we reported that p43 depletion in mice induced a major defect in insulin secretion both in vivo and in isolated pancreatic islets, and a loss of glucose-stimulated insulin secretion. The present study was designed to determine whether p43 invalidation influences life expectancy and modulates blood glucose and insulin levels as well as glucose tolerance or insulin sensitivity during aging. We report that from 4 months old onwards, mice lacking p43 are leaner than wild-type mice. p43−/− mice also have a moderate reduction of life expectancy compared to wild type. We found no difference in blood glucose levels, excepted at 24 months old where p43−/− mice showed a strong hyperglycemia in fasting conditions compared to controls animals. However, the loss of glucose-stimulated insulin secretion was maintained whatever the age of mice lacking p43. If up to 12 months old, glucose tolerance remained unchanged, beyond this age p43−/− mice became increasingly glucose intolerant. In addition, if up to 12 months old p43 deficient animals were more sensitive to insulin, after this age we observed a loss of this capacity, culminating in 24 months old mice with a decreased sensitivity to the hormone. In conclusion, we demonstrated that during aging the depletion of the mitochondrial T3 receptor p43 in mice progressively induced an increased glycemia in the fasted state, glucose intolerance and an insulin-resistance several features of type-2 diabetes.
Adherence is one of the most important determinants of viral suppression and drug resistance in HIV-infected people receiving antiretroviral therapy (ART).
We examined the association between long-term mortality and poor adherence to ART in DART trial participants in Uganda and Zimbabwe randomly assigned to receive laboratory and clinical monitoring (LCM), or clinically driven monitoring (CDM). Since over 50% of all deaths in the DART trial occurred during the first year on ART, we focussed on participants continuing ART for 12 months to investigate the implications of longer-term adherence to treatment on mortality. Participants’ ART adherence was assessed by pill counts and structured questionnaires at 4-weekly clinic visits. We studied the effect of recent adherence history on the risk of death at the individual level (odds ratios from dynamic logistic regression model), and on mortality at the population level (population attributable fraction based on this model). Analyses were conducted separately for both randomization groups, adjusted for relevant confounding factors. Adherence behaviour was also confounded by a partial factorial randomization comparing structured treatment interruptions (STI) with continuous ART (CT).
In the CDM arm a significant association was found between poor adherence to ART in the previous 3-9 months with increased mortality risk. In the LCM arm the association was not significant. The odds ratios for mortality in participants with poor adherence against those with optimal adherence was 1.30 (95% CI 0.78,2.10) in the LCM arm and 2.18 (1.47,3.22) in the CDM arm. The estimated proportions of deaths that could have been avoided with optimal adherence (population attributable fraction) in the LCM and CDM groups during the 5 years follow-up period were 16.0% (95% CI 0.7%,31.6%) and 33.1% (20.5%,44.8%), correspondingly.
Recurrent poor adherence determined even through simple measures is associated with high mortality both at individual level as well as at the ART programme level. The number of lives saved through effective interventions to improve adherence could be considerable particularly for individuals monitored without using CD4 cell counts. The findings have important implications for clinical practice and for developing interventions to enhance adherence.
Dynamic logistic regression model; Population attributable fraction; ART; Adherence; Mortality; HIV
Child and adolescent anxiety disorders are the most prevalent form of childhood psychopathology. Research on child and adolescent anxiety disorders has predominantly been done in westernized societies. There is a paucity of data on the prevalence, comorbidity, and predictors of anxiety disorders in children and adolescents in non-western societies including those in sub-Saharan Africa. This paper investigates the prevalence, comorbidity, and predictors of anxiety disorders in children and adolescents in north-eastern Uganda.
To determine the prevalence of DSM-IV anxiety disorders, as well as comorbidity patterns and predictors in children and adolescents aged 3 to 19 years in north-eastern Uganda.
Four districts (Lira, Tororo, Kaberamaido and Gulu) in rural north-eastern Uganda participated in this study. Using a multi-stage sampling procedure, a sample of 420 households with children aged 3–19 years from each district was enrolled into the study. The MINI International Neuropsychiatric Interview for children and adolescents (MINI KID) was used to assess for psychiatric disorders in 1587 of 1680 respondents.
The prevalence of anxiety disorders was 26.6%, with rates higher in females (29.7%) than in males (23.1%). The most common disorders in both males and females were specific phobia (15.8%), posttraumatic stress disorder (PTSD) (6.6%) and separation anxiety disorder (5.8%). Children below 5 years of age were significantly more likely to have separation anxiety disorder and specific phobias, while those aged between 14–19 were significantly more likely to have PTSD. Anxiety disorders were more prevalent among respondents with other psychiatric disorders; in respondents with two or more co-morbid psychiatric disorders the prevalence of anxiety disorders was 62.1%. Predictors of anxiety disorders were experience of war trauma (OR = 1.93, p < 0.001) and a higher score on the emotional symptom scale of the SDQ (OR = 2.58, p < 0.001). Significant socio-demograghic associations of anxiety disorders were found for female gender, guardian unemployment, living in permanent housing, living without parents, and having parents without education.
The prevalence of anxiety disorders in children and adolescents in rural north-eastern Uganda is high, but consistent in terms of gender ratio and progression over time with a range of prior work in other contexts. Patterns of comorbidity and predictors of anxiety disorders in this setting are also broadly consistent with previous findings from western community studies. Both psychosocial stressors and exposure to war trauma are significant predictors of anxiety disorders.Prevention and treatment strategies need to be put in place to address the high prevalence rates of anxiety disorders in children and adolescents in Uganda.
Children; Adolescents; Anxiety disorders; Comorbidity; Predictors; Uganda
Millions of African children are having to grow up under harsh and adverse psychosocial conditions but it’s not fully understood how this negative psychosocial environment is affecting their mental health. This paper examines the prevalence and risk factors of depression in childhood and adolescence as seen in a community sample derived from four disadvantaged districts in north-eastern Uganda.
1587 children were assessed using a structured instrument administered by trained psychiatric nurses to collect data on psychiatric disorders (DSM IV criteria), adverse psychosocial factors and socio-demographic factors.
The point prevalence of depressive disorder syndromes (DDS) in this study was 8.6% (95% CI 7.2%–10.1%) with a point prevalence for major depressive episode of 7.6% (95% CI 6.3%–9.0%) and dysthymia of 2.1% (95% CI 1.5%–3.0%). At multiple logistic regression, the factors that were independently significantly associated with DDS were: district (representing ecological factors), nature of living arrangements, domestic violence and psychiatric co-morbidities/psychiatric problems of emotional distress (assessed by the SDQ), suicidality and marginally, anxiety disorder syndromes, eating disorder syndromes, motor disorder syndromes and behavioral and developmental disorder syndromes (the later being protective against depression).
Disadvantaged north-eastern Uganda had a high prevalence of childhood depressive disorders. Ecological factors, markers of the quality of the child-principal caregiver relationship (nature of living arrangements and domestic violence) and the presence of psychiatric co-morbidities/psychiatric problems were the important independent determinants of childhood depression in this study.
A safe and effective vaginal microbicide could substantially reduce HIV acquisition for women. Consistent gel use is, however, of great importance to ensure continued protection against HIV infection, even with a safe and effective microbicide. We assessed the long-term correlates of consistent gel use in the MDP 301 clinical trial among HIV-negative women in sero-discordant couples in south-west Uganda.
HIV-negative women living with an HIV-infected partner were enrolled between 2005 and 2008, in a three-arm phase III microbicide trial and randomized to 2% PRO2000, 0.5% PRO2000 or placebo gel arms. Follow-up visits continued up to September 2009. The 2% arm was stopped early due to futility and the 229 women enrolled in this arm were excluded from this analysis. Data were analyzed on 544 women on the 0.5% and placebo arms who completed at least 52 weeks of follow-up, sero-converted or became pregnant before 52 weeks. Consistent gel use was defined as satisfying all of the following three conditions: (i) reported gel use at the last sex act for at least 92% of the 26 scheduled visits or at least 92% of the visits attended if fewer than 26; (ii) at least one used applicator returned for each visit for which gel use was reported at the last sex act; (iii) attended at least 13 visits (unless the woman sero-converted or became pregnant during follow-up). Logistic regression models were fitted to investigate factors associated with consistent gel use.
Of the 544 women, 473 (86.9%) were followed for at least 52 weeks, 29 (5.3%) sero-converted and 42 (7.7%) became pregnant before their week 52 visit. Consistent gel use was reported by 67.8%. Women aged 25 to 34 years and those aged 35 years or older were both more than twice as likely to have reported consistently using gel compared to women aged 17 to 24 years. Living in a household with three or more rooms used for sleeping compared to one room was associated with a twofold increase in consistent gel use.
In rural Uganda younger women and women in houses with less space are likely to require additional support to achieve consistent microbicide gel use.
Protocol Number ISRCTN64716212
HIV; Vaginal microbicides; Consistent gel use; Adherence; Sero-discordant couples; Phase III trial; Microbicides Development Programme (MDP)