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1.  Point-of-Care Diagnosis and Prognostication of Cryptococcal Meningitis With the Cryptococcal Antigen Lateral Flow Assay on Cerebrospinal Fluid 
The cryptococcal antigen (CRAG) lateral flow assay (LFA) had 100% sensitivity and specificity on cerebrospinal fluid samples. Pretreatment LFA titers correlated with quantitative cultures (R2 = 0.7) and predicted 2- and 10-week mortality. The CRAG LFA is an accurate diagnostic assay for CSF and should be considered for point-of-care diagnosis of cryptococcal meningitis.
doi:10.1093/cid/cit641
PMCID: PMC3864499  PMID: 24065327
HIV; cryptococcal meningitis; diagnosis; point-of-care; sub-Saharan Africa
2.  Low Resistance to First and Second Line Anti-Tuberculosis Drugs among Treatment Naive Pulmonary Tuberculosis Patients in Southwestern Uganda 
PLoS ONE  2015;10(2):e0118191.
Background
There are limited data on region-specific drug susceptibility of tuberculosis (TB) in Uganda. We performed resistance testing on specimens collected from treatment-naive patients with pulmonary TB in Southwestern Uganda for first and second line anti-TB drugs. We sought to provide data to guide regional recommendations for empiric TB therapy.
Methods
Archived isolates, obtained from patients at Mbarara Regional Referral Hospital from February 2009 to February 2013, were tested for resistance to isoniazid and rifampicin using the MTBDRplus and Xpert MTB/RIF assays. A subset of randomly selected isolates was tested for second line agents, including fluoroquinolones (FQs), aminoglycosides, cyclic peptides, and ethambutol using the MTBDRsl assay. We performed confirmatory testing for FQ resistance using repeated MTBDRsl, the Mycobacteria growth indicator tube (MGIT) assay, and sequencing of the gyrA and gyrB genes.
Results
We tested isolates from 190 patients. The cohort had a median age of 33 years (IQR 26-43), 69% (131/190) were male, and the HIV prevalence was 42% (80/190). No isolates (0/190) were rifampicin-resistant and only 1/190 (0.5%) was isoniazid-resistant. Among 92 isolates tested for second-line drug resistance, 71 (77%) had interpretable results, of which none were resistant to aminoglycosides, cyclic peptides or ethambutol. Although 7 (10%) initially tested as resistant to FQs by the MTBDRsl assay, they were confirmed as susceptible by repeat MTBDRsl testing as well as by MGIT and gyrase gene sequencing
Conclusion
We found no MDR-TB and no resistance to ethambutol, FQs, or injectable anti-TB drugs in treatment naïve patients with pulmonary TB in Southwestern Uganda. Standard treatment guidelines for susceptible TB should be adequate for most patients with TB in this population. Where possible, molecular susceptibility testing methods should be routinely validated by culture methods.
doi:10.1371/journal.pone.0118191
PMCID: PMC4320102  PMID: 25658921
3.  Treatment as long-term prevention: Sustained reduction in HIV sexual transmission risk with use of antiretroviral therapy in rural Uganda 
AIDS (London, England)  2014;28(2):267-271.
Objectives
Suppressive anti-retroviral therapy (ART) substantially decreases HIV transmission in clinical research settings. We sought to measure the frequency and correlates of periods of transmission risk among individuals taking ART during multiple years of observation in rural, southwestern Uganda.
Design
Observational cohort study
Methods
We collected sexual behavior and viral load data in a Ugandan cohort of people living with HIV/AIDS from the time of ART initiation. We defined each 90-day visit as a potential transmission period if HIV-1 RNA was > 400 copies/mL and the participant reported sexual transmission risk behavior, defined as unprotected sexual contact with ≥1 HIV-uninfected partners or partners of unknown serostatus in the prior 90 days.
Results
We evaluated data from 463 individuals on ART over a median 3.5 years of observation and 5,293 total study visits. During that time, over half (259, 56%) had detectable viremia or reported sexual transmission risk behavior at least once. However only 23 (5%) had both simultaneously, at 28 (<1%) of all visits. Transmission sexual behavior was reported at 6% of visits with detectable viremia. In multivariable regression modeling, correlates of transmission risk periods included younger age, lower CD4 count, low household asset ownership and increased internalized stigma.
Conclusions
Although detectable viremia and/or sexual transmission risk behavior occurred in over half of individuals, ART reduced periods of HIV transmission risk by over 90% during up to six years of observation time. These findings provide further support for provision of ART, along with interventions to promote long-term adherence, to reduce HIV transmission in HIV-endemic settings.
doi:10.1097/QAD.0000000000000136
PMCID: PMC4038415  PMID: 24361683
HIV/AIDS; Anti-retroviral therapy; sub-Saharan Africa; treatment as prevention; Uganda
4.  Shang Ring versus forceps-guided adult male circumcision: a randomized controlled effectiveness study in southwestern Uganda 
Adult male circumcision (AMC) reduces HIV transmission but uptake is limited in part by current surgical methods. We randomized HIV-uninfected men (n=138) to receive Shang ring (SR) or forceps-guided (FG) AMC from a locally-trained surgeon. In as-treated analyses, more SR procedures were completed within 10 minutes (79% vs 0%, p<0.01) and more subjects reported high satisfaction (77% vs 58%, p=0.03). Healing time and pain scores were similar, though minor complication rates were higher in SR subjects (56% vs 24%, p<0.01). SR circumcision is a rapid and acceptable method of AMC and should be further evaluated to increase uptake of AMC.
doi:10.1097/QAI.0b013e3182965d67
PMCID: PMC3778093  PMID: 23599013
HIV/AIDS; Uganda; sub-Saharan Africa; Adult Male Circumcision; HIV prevention; acceptability; feasibility
5.  Sublingual Misoprostol versus Intramuscular Oxytocin for Prevention of Postpartum Hemorrhage in Uganda: A Double-Blind Randomized Non-Inferiority Trial 
PLoS Medicine  2014;11(11):e1001752.
In a double-blind randomized controlled trial, Esther Atukunda and colleagues evaluated whether sublingual misoprostol administered to women in labor was non-inferior to intramuscular oxytocin in preventing postpartum hemorrhage and reducing blood loss.
Please see later in the article for the Editors' Summary
Background
Postpartum hemorrhage (PPH) is a leading cause of maternal death in sub-Saharan Africa. Although the World Health Organization recommends use of oxytocin for prevention of PPH, misoprostol use is increasingly common owing to advantages in shelf life and potential for sublingual administration. There is a lack of data about the comparative efficacy of oxytocin and sublingual misoprostol, particularly at the recommended dose of 600 µg, for prevention of PPH during active management of labor.
Methods and Findings
We performed a double-blind, double-dummy randomized controlled non-inferiority trial between 23 September 2012 and 9 September 2013 at Mbarara Regional Referral Hospital in Uganda. We randomized 1,140 women to receive 600 µg of misoprostol sublingually or 10 IU of oxytocin intramuscularly, along with matching placebos for the treatment they did not receive. Our primary outcome of interest was PPH, defined as measured blood loss ≥500 ml within 24 h of delivery. Secondary outcomes included measured blood loss ≥1,000 ml; mean measured blood loss at 1, 2, and 24 h after delivery; death; requirement for blood transfusion; hemoglobin changes; and use of additional uterotonics.
At 24 h postpartum, primary PPH occurred in 163 (28.6%) participants in the misoprostol group and 99 (17.4%) participants in the oxytocin group (relative risk [RR] 1.64, 95% CI 1.32 to 2.05, p<0.001; absolute risk difference 11.2%, 95% CI 6.44 to 16.1). Severe PPH occurred in 20 (3.6%) and 15 (2.7%) participants in the misoprostol and oxytocin groups, respectively (RR 1.33, 95% CI 0.69 to 2.58, p = 0.391; absolute risk difference 0.9%, 95% CI −1.12 to 2.88). Mean measured blood loss was 341.5 ml (standard deviation [SD] 206.2) and 304.2 ml (SD 190.8, p = 0.002) at 2 h and 484.7 ml (SD 213.3) and 432.8 ml (SD 203.5, p<0.001) at 24 h in the misoprostol and oxytocin groups, respectively. There were no significant differences between the two groups in any other secondary outcomes. Women in the misoprostol group more commonly experienced shivering (RR 1.91, 95% CI 1.65 to 2.21, p<0.001) and fevers (RR 5.20, 95% CI 3.15 to 7.21, p = 0.005).
This study was conducted at a regional referral hospital with capacity for emergency surgery and blood transfusion. High-risk women were excluded from participation.
Conclusions
Misoprostol 600 µg is inferior to oxytocin 10 IU for prevention of primary PPH in active management of labor. These data support use of oxytocin in settings where it is available. While not powered to do so, the study found no significant differences in rate of severe PPH, need for blood transfusion, postpartum hemoglobin, change in hemoglobin, or use of additional uterotonics between study groups. Further research should focus on clarifying whether and in which sub-populations use of oxytocin would be preferred over sublingual misoprostol.
Trial registration
ClinicalTrials.gov NCT01866241
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Every year, worldwide nearly 290,000 women die during pregnancy or labor or during the first six weeks after giving birth (the postpartum period). Almost all of these “maternal” deaths occur in low- or middle-income countries, and most are caused by a handful of preventable or treatable conditions—postpartum hemorrhage (severe bleeding from the uterus [womb] within 24 hours of childbirth), post-delivery infections, unsafe abortion, obstructive (difficult) labor, and blood pressure disorders during pregnancy. The leading cause of maternal deaths worldwide is postpartum hemorrhage, which is responsible for 25%–30% of all maternal deaths. Postpartum hemorrhage can be prevented by giving the mother an intramuscular injection of oxytocin, a hormone that stimulates uterine contractions and limits uterine bleeding, immediately after her child is born.
Why Was This Study Done?
Unfortunately, oxytocin needs to be kept cool, which limits its use in low- and middle-income countries, and, until recently, it was thought that only trained personnel could give intramuscular injections. Consequently, administration of misoprostol, a synthetic prostaglandin that has effects similar to those of oxytocin, has been proposed as an alternative way to prevent postpartum hemorrhage in resource-limited settings. Misoprostol is stable at room temperature, and because it can be given sublingually (beneath the tongue), it acts very quickly. However, the comparative efficacy of sublingual misoprostol and intramuscular oxytocin for the prevention of postpartum hemorrhage has not been established. Here, the researchers undertake a double-blinded, double-dummy randomized controlled non-inferiority trial to compare sublingual misoprostol and intramuscular oxytocin for the prevention of postpartum hemorrhage in Uganda, a country where there are more than 5,500 maternal deaths every year. A randomized controlled trial compares the outcomes of individuals assigned to different interventions through the play of chance. In a double-blinded trial, neither the researchers nor the participants know who is receiving which intervention. In this particular trial, double-blinding is achieved by giving a dummy (placebo) sublingual pill to the women assigned to the oxytocin group and a dummy injection to the women assigned to the misoprostol group, as well as their assigned treatments. A non-inferiority trial investigates whether one treatment is not worse than another treatment.
What Did the Researchers Do and Find?
The researchers measured blood loss over the first 24 hours after delivery in 1,140 women admitted to a regional referral hospital in Uganda. The women were given either sublingual misoprostol or intramuscular oxytocin at the currently recommended doses, along with matching placebos, immediately after the birth of their child. Postpartum hemorrhage (defined as the loss of more than 500 ml of blood within 24 hours of delivery; the trial's primary outcome) occurred in 28.6% and 17.4% of the women in the misoprostol and oxytocin groups, respectively (an absolute risk difference of 11.2%). Severe postpartum hemorrhage (loss of more than 1,000 ml of blood within 24 hours of delivery) occurred in 3.6% and 2.7% of participants in the misoprostol and oxytocin groups, respectively, but this difference was not statistically significant (it could have happened by chance). On average, women given misoprostol had lost slightly more blood by two and 24 hours after delivery than those given oxytocin. There were no significant differences between the groups in terms of death, the need for blood transfusion, or the use of additional drugs to prevent blood loss, but women given misoprostol experienced shivering and fever more often than those given oxytocin.
What Do These Findings Mean?
In their study protocol, the researchers specified that sublingual misoprostol would be deemed non-inferior to intramuscular oxytocin if the absolute risk difference for postpartum hemorrhage between the misoprostol and oxytocin treatment groups was less than 6% (the “non-inferiority” margin). These findings therefore indicate that sublingual misoprostol given at the recommended dose is inferior to intramuscular oxytocin for the prevention of postpartum hemorrhage in women undergoing an uncomplicated birth at a regional referral hospital in Uganda. Although several aspects of this study may affect the accuracy and generalizability of its findings (for example, women at high risk of birth complications were excluded from the study), the researchers conclude that oxytocin should remain the preferred agent for the prevention of postpartum hemorrhage where it is available. However, they note, sublingual misoprostol remains important for the prevention of postpartum hemorrhage where oxytocin is unavailable or its administration is not feasible.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001752.
The United Nations Children's Fund (UNICEF) provides information on maternal mortality; “Trends in Maternal Mortality: 1990 to 2013” is a recent WHO/UNICEF/UNFPA/World Bank publication that provides up-to-date information on maternal mortality worldwide
The World Health Organization provides information on maternal health (in several languages)
The Postpartum Hemorrhage Prevention and Treatment Website provides a forum for information sharing and learning between organizations and individuals working on the prevention and treatment of postpartum hemorrhage in developing countries; the website includes basic information about postpartum hemorrhage and links to additional resources
“Veil of Tears” contains personal stories (including stories about postpartum hemorrhage) from Afghanistan about loss in childbirth
“Maternal Death: The Avoidable Crisis” is a briefing paper published by Médecins Sans Frontières in 2012
More information about this trial is available
doi:10.1371/journal.pmed.1001752
PMCID: PMC4219663  PMID: 25369200
7.  Empiric Deworming and CD4 Count Recovery in HIV-Infected Ugandans Initiating Antiretroviral Therapy 
Background
There is conflicting evidence on the immunologic benefit of treating helminth co-infections (“deworming”) in HIV-infected individuals. Several studies have documented reduced viral load and increased CD4 count in antiretroviral therapy (ART) naïve individuals after deworming. However, there are a lack of data on the effect of deworming therapy on CD4 count recovery among HIV-infected persons taking ART.
Methodology/Principal Findings
To estimate the association between empiric deworming therapy and CD4 count after ART initiation, we performed a retrospective observational study among HIV-infected adults on ART at a publicly operated HIV clinic in southwestern Uganda. Subjects were assigned as having received deworming if prescribed an anti-helminthic agent between 7 and 90 days before a CD4 test. To estimate the association between deworming and CD4 count, we fit multivariable regression models and analyzed predictors of CD4 count, using a time-by-interaction term with receipt or non-receipt of deworming. From 1998 to 2009, 5,379 subjects on ART attended 21,933 clinic visits at which a CD4 count was measured. Subjects received deworming prior to 668 (3%) visits. Overall, deworming was not associated with a significant difference in CD4 count in either the first year on ART (β = 42.8; 95% CI, −2.1 to 87.7) or after the first year of ART (β = −9.9; 95% CI, −24.1 to 4.4). However, in a sub-analysis by gender, during the first year of ART deworming was associated with a significantly greater rise in CD4 count (β = 63.0; 95% CI, 6.0 to 120.1) in females.
Conclusions/Significance
Empiric deworming of HIV-infected individuals on ART conferred no significant generalized benefit on subsequent CD4 count recovery. A significant association was observed exclusively in females and during the initial year on ART. Our findings are consistent with recent studies that failed to demonstrate an immunologic advantage to empirically deworming ART-naïve individuals, but suggest that certain sub-populations may benefit.
Author Summary
It is estimated that up to half of all people infected with HIV in sub-Saharan Africa are co-infected with one or more gastrointestinal parasites. These parasitic infections may negatively impact the ability of the immune system to combat the HIV virus, leading to worse clinical outcomes in people with HIV. Therefore, routine, universal, empiric treatment of gastrointestinal parasite infections (“deworming”) has been suggested as one strategy for optimizing HIV outcomes in this region. Previous studies have provided conflicting results on whether empiric deworming positively impacts markers of HIV disease progression such as CD4 count and viral load, but all of these studies were performed in HIV-infected individuals not yet on antiretroviral therapy. In this study, we measured the association between receipt of empiric deworming and CD4 count over time in HIV-infected adults taking antiretroviral therapy in southwestern Uganda, an area with a high parasite burden. We found that, overall, there was no significant association between deworming and change in CD4 count; however, when we performed a sub-analysis looking exclusively at females during the first year of ART, deworming was associated with significantly increased CD4 count. These results suggest that empiric deworming may not be an effective generalized strategy for improving HIV treatment outcomes in sub-Saharan Africa; however, the possibility of targeted benefit in specific sub-populations deserves further investigation.
doi:10.1371/journal.pntd.0003036
PMCID: PMC4125278  PMID: 25101890
8.  Higher baseline CD4 cell count predicts treatment interruptions and persistent viremia in patients initiating ARVs in rural Uganda 
We examined the association between CD4 cell count and adherence in a cohort of Ugandans initiating ARVs. Outcomes were: a) adherence<90%; b) any treatment interruptions>72 hours; c) number of treatment interruptions; and d) HIV RNA>400 copies/ml. We fit regression models to estimate associations with our exposure of interest, baseline CD4 cell count ≥250 cells/μL (n=60) versus <250 cells/μL (n=413). CD4 cell count≥250 cells/μL was independently associated with increased odds and number of treatment interruptions, and increased odds of persistent viremia. Interventions to support adherence in patients with higher CD4 cell counts should be considered as drug availability to this population increases.
doi:10.1097/QAI.0b013e3182800daf
PMCID: PMC3696032  PMID: 23242160
Adherence; Test and Treat; Uganda; HIV/AIDS; Adherence Monitoring; MEMS
9.  Effects of Ascent to High Altitude on Human Antimycobacterial Immunity 
PLoS ONE  2013;8(9):e74220.
Background
Tuberculosis infection, disease and mortality are all less common at high than low altitude and ascent to high altitude was historically recommended for treatment. The immunological and mycobacterial mechanisms underlying the association between altitude and tuberculosis are unclear. We studied the effects of altitude on mycobacteria and antimycobacterial immunity.
Methods
Antimycobacterial immunity was assayed in 15 healthy adults residing at low altitude before and after they ascended to 3400 meters; and in 47 long-term high-altitude residents. Antimycobacterial immunity was assessed as the extent to which participants’ whole blood supported or restricted growth of genetically modified luminescent Bacille Calmette-Guérin (BCG) mycobacteria during 96 hours incubation. We developed a simplified whole blood assay that could be used by a technician in a low-technology setting. We used this to compare mycobacterial growth in participants’ whole blood versus positive-control culture broth and versus negative-control plasma.
Results
Measurements of mycobacterial luminescence predicted the number of mycobacterial colonies cultured six weeks later. At low altitude, mycobacteria grew in blood at similar rates to positive-control culture broth whereas ascent to high altitude was associated with restriction (p≤0.002) of mycobacterial growth to be 4-times less than in culture broth. At low altitude, mycobacteria grew in blood 25-times more than negative-control plasma whereas ascent to high altitude was associated with restriction (p≤0.01) of mycobacterial growth to be only 6-times more than in plasma. There was no evidence of differences in antimycobacterial immunity at high altitude between people who had recently ascended to high altitude versus long-term high-altitude residents.
Conclusions
An assay of luminescent mycobacterial growth in whole blood was adapted and found to be feasible in low-resource settings. This demonstrated that ascent to or residence at high altitude was associated with decreased mycobacterial growth in whole blood relative to controls, consistent with altitude-related augmentation of antimycobacterial cellular immunity.
doi:10.1371/journal.pone.0074220
PMCID: PMC3772817  PMID: 24058530
10.  GPS-measured distance to clinic, but not self-reported transportation factors, are associated with missed HIV clinic visits in rural Uganda 
AIDS (London, England)  2013;27(9):1503-1508.
Objective
Studies of the association between transportation barriers and HIV-related health outcomes have shown both positive and negative effects, possibly because a reliable, validated measure of transportation barriers has not been identified.
Design
Prospective cohort study of HIV-infected patients in rural Uganda.
Methods
Participants were enrolled from the HIV clinic at the regional referral hospital in Mbarara, Uganda as part of the Uganda AIDS Rural Treatment Outcomes (UARTO) Study. We collected the following measures of transportation barriers to HIV clinic: global positioning systems (GPS)-tracked distance measured by driving participants to their homes along their typical route; straight-line GPS distance from clinic to home, calculated with the Great Circle Formula; self-reported travel time; and self-reported travel cost. We assessed inter-measure agreement using linear regression, correlation coefficients and κ statistics (by measure quartile) and validated measures by fitting linear regression models to estimate associations with days late for clinic visits.
Results
One hundred and eighty-eight participants were tracked with GPS. Seventy-six percent were women, with a median age of 40 years and median CD4 cell count of 193 cells/μl. We found a high correlation between GPS-based distance measures (β = 0.74, P < 0.001, R2 = 0.92, k = 0.73), but little correlation between GPS-based and self-reported measures (all R2 ≤ 0.4). GPS-based measures were associated with days late to clinic (P < 0.001); but neither self-reported measure was associated (P > 0.85).
Conclusion
GPS-measured distance to clinic is associated with HIV clinic absenteeism and should be prioritized over self-reported measures to optimally risk-stratify patients accessing care in rural, resource-limited settings.
doi:10.1097/QAD.0b013e32835fd873
PMCID: PMC3745818  PMID: 23435294
distance to clinic; global positioning systems; HIV/AIDS; linkage to care; sub-Saharan Africa; transportation; Uganda
11.  Sexual Relationship Power and Malnutrition Among HIV-Positive Women in Rural Uganda 
AIDS and behavior  2012;16(6):1542-1548.
Inequality within partner relationships is associated with HIV acquisition and gender violence, but little is known about more pervasive effects on women’s health. We performed a cross-sectional analysis of associations between sexual relationship power and nutritional status among women in Uganda. Participants completed questionnaires and anthropometric measurements. We assessed sexual relationship power using the Sexual Relationship Power Scale (SRPS). We performed logistic regression to test for associations between sexual relationship power and poor nutritional status including body mass index, body fat percentage, and mid-upper arm circumference. Women with higher sexual relationship power scores had decreased odds of low body mass index (OR 0.29, p = 0.01), low body fat percentage (OR 0.54, p = 0.04), and low midupper arm circumference (OR 0.22, p = 0.01). These relationships persisted in multivariable models adjusted for potential confounders. Targeted interventions to improve intimate partner relationship equality should be explored to improve health status among women living with HIV in rural Africa.
doi:10.1007/s10461-012-0162-9
PMCID: PMC3439197  PMID: 22382629
Gender Equality; Malnutrition HIV/AIDS; Sub-Saharan Africa
12.  Disinhibition in Risky Sexual Behavior in Men, but Not Women, during Four Years of Antiretroviral Therapy in Rural, Southwestern Uganda 
PLoS ONE  2013;8(7):e69634.
Background
In resource-rich areas, risky sexual behavior (RSB) largely diminishes after initiation of anti-retroviral therapy, with notable exceptions among some populations who perceive a protected benefit from anti-retroviral therapy (ART). Yet, there is limited data about long-term trends in risky sexual behavior among HIV-infected people in sub-Saharan Africa after initiation of anti-retroviral therapy.
Methods
We administered questionnaires every three months to collect sexual behavior data among patients taking ART in southwestern Uganda over four years of follow-up time. We defined RSB as having unprotected sex with an HIV-negative or unknown status partner, or unprotected sex with a casual partner. We fit logistic regression models to estimate changes in RSB by time on ART, with and without adjustment for calendar year and CD4 count.
Results
506 participants were enrolled between 2005 and 2011 and contributed a median of 13 visits and 3.5 years of observation time. The majority were female (70%) and median age was 34 years (interquartile range 29–39). There was a decrease in the proportion of men reporting RSB from the pre-ART visit to the first post-ART visit (16.2 to 4.3%, p<0.01) but not women (14.1 to 13.3%, p = 0.80). With each year of ART, women reported decreasing RSB (OR 0.85 per year, 95%CI 0.74–0.98, p = 0.03). In contrast, men had increasing odds of reporting RSB with each year of ART to near pre-treatment rates (OR 1.41, 95%CI 1.14–1.74, p = 0.001), which was partially confounded by changes in calendar time and CD4 count (AOR = 1.24, 95%CI 0.92–1.67, p = 0.16).
Conclusions
Men in southwestern Uganda reported increasing RSB over four years on ART, to levels approaching pre-treatment rates. Strategies to promote long-term safe sex practices targeted to HIV-infected men on ART might have a significant impact on preventing HIV transmission in this setting.
doi:10.1371/journal.pone.0069634
PMCID: PMC3716596  PMID: 23894514
13.  Malaria is an uncommon cause of adult sepsis in south-western Uganda 
Malaria Journal  2013;12:146.
Background
Malaria is often considered a cause of adult sepsis in malaria endemic areas. However, diagnostic limitations can make distinction between malaria and other infections challenging. Therefore, the objective of this study was to determine the relative contribution of malaria to adult sepsis in south-western Uganda.
Methods
Adult patients with sepsis were enrolled at the Mbarara Regional Referral Hospital between February and May 2012. Sepsis was defined as infection plus ≥2 of the following: axillary temperature >37.5°C or <35.5°C, heart rate >90 or respiratory rate >20. Severe sepsis was defined as sepsis plus organ dysfunction (blood lactate >4 mmol/L, confusion, or a systolic blood pressure <90 mmHg). Sociodemographic, clinical and laboratory data, including malaria PCR and rapid diagnostic tests, as well as acid fast bacteria sputum smears and blood cultures were collected. Patients were followed until in-patient death or discharge. The primary outcome of interest was the cause of sepsis. Multivariable logistic regression was performed to assess predictors of mortality.
Results
Enrollment included 216 participants who were 51% female with a median age of 32 years (IQR 27–43 years). Of these, 122 (56%) subjects were HIV-seropositive of whom 75 (66%) had a CD4+ T cell count <100 cells/μL. The prevalence of malaria was 4% (six with Plasmodium falciparum, two with Plasmodium vivax). Bacteraemia was identified in 41 (19%) patients. In-hospital mortality was 19% (n = 42). In multivariable regression analysis, Glasgow Coma Score <9 (IRR 4.81, 95% CI 1.80-12.8) and severe sepsis (IRR, 2.07, 95% CI 1.03-4.14), but no specific diagnoses were statistically associated with in-hospital mortality.
Conclusion
Malaria was an uncommon cause of adult sepsis in a regional referral hospital in south-western Uganda. In this setting, a thorough evaluation for alternate causes of disease in patients presenting with sepsis is recommended.
doi:10.1186/1475-2875-12-146
PMCID: PMC3654878  PMID: 23634654
Sepsis; Uganda; Africa; Malaria; Adult
14.  Optimizing Network Connectivity for Mobile Health Technologies in sub-Saharan Africa 
PLoS ONE  2012;7(9):e45643.
Background
Mobile health (mHealth) technologies hold incredible promise to improve healthcare delivery in resource-limited settings. Network reliability across large catchment areas can be a major challenge. We performed an analysis of network failure frequency as part of a study of real-time adherence monitoring in rural Uganda. We hypothesized that the addition of short messaging service (SMS+GPRS) to the standard cellular network modality (GPRS) would reduce network disruptions and improve transmission of data.
Methods
Participants were enrolled in a study of real-time adherence monitoring in southwest Uganda. In June 2011, we began using Wisepill devices that transmit data each time the pill bottle is opened. We defined network failures as medication interruptions of >48 hours duration that were transmitted when network connectivity was re-established. During the course of the study, we upgraded devices from GPRS to GPRS+SMS compatibility. We compared network failure rates between GPRS and GPRS+SMS periods and created geospatial maps to graphically demonstrate patterns of connectivity.
Results
One hundred fifty-seven participants met inclusion criteria of seven days of SMS and seven days of SMS+GPRS observation time. Seventy-three percent were female, median age was 40 years (IQR 33–46), 39% reported >1-hour travel time to clinic and 17% had home electricity. One hundred one had GPS coordinates recorded and were included in the geospatial maps. The median number of network failures per person-month for the GPRS and GPRS+SMS modalities were 1.5 (IQR 1.0–2.2) and 0.3 (IQR 0–0.9) respectively, (mean difference 1.2, 95%CI 1.0–1.3, p-value<0.0001). Improvements in network connectivity were notable throughout the region. Study costs increased by approximately $1USD per person-month.
Conclusions
Addition of SMS to standard GPRS cellular network connectivity can significantly reduce network connection failures for mobile health applications in remote areas. Projects depending on mobile health data in resource-limited settings should consider this upgrade to optimize mHealth applications.
doi:10.1371/journal.pone.0045643
PMCID: PMC3460947  PMID: 23029155
15.  Rethinking the “Pre” in Pre-Therapy Counseling: No Benefit of Additional Visits Prior to Therapy on Adherence or Viremia in Ugandans Initiating ARVs 
PLoS ONE  2012;7(6):e39894.
Background
Many guidelines recommend adherence counseling prior to initiating antiretrovirals (ARVs), however the additional benefit of pre-therapy counseling visits on early adherence is not known. We sought to assess for a benefit of adherence counseling visits prior to ARV initiation versus adherence counseling during the early treatment period.
Methods
We performed a secondary analysis of data from a prospective cohort of HIV-infected patients in Mbarara, Uganda. Adults were enrolled upon initiation of ARVs. Our primary exposure of interest was ARV adherence counseling prior to initiating therapy (versus concurrent with initiation of therapy). Our outcomes of interest were: 1) average adherence >90% in first three months; 2) absence of treatment interruptions >72 hours in first three months; and 3) Viral load >400 copies/ml at the three month visit. We fit univariable and multivariable regression models, adjusted for predictors of ARV adherence, to estimate the association between additional pre-therapy counseling visits and our outcomes.
Results
300 participants had records of counseling, of whom 231 (77%) completed visits prior to initiation of ARVs and 69 (23%) on or shortly after initiation. Median age was 33, 71% were female, and median CD4 was 133 cell/ml. Median 90-day adherence was 95%. Participants who completed pre-therapy counseling visits had longer delays from ARV eligibility to initiation (median 49 vs 14 days, p<0.01). In multivariable analyses, completing adherence counseling prior to ARV initiation was not associated with average adherence >90% (AOR 0.8, 95%CI 0.4–1.5), absence of treatment gaps (AOR 0.7, 95%CI 0.2–1.9), or HIV viremia (AOR 1.1, 95%CI 0.4–3.1).
Conclusions
Completion of adherence counseling visits prior to ARV therapy was not associated with higher adherence in this cohort of HIV-infected patients in Uganda. Because mortality and loss-to-follow-up remain high in the pre-ARV period, policy makers should reconsider whether counseling can be delivered with ARV initiation, especially in patients with advanced disease.
doi:10.1371/journal.pone.0039894
PMCID: PMC3383698  PMID: 22761924
16.  High acceptability for cell phone text messages to improve communication of laboratory results with HIV-infected patients in rural Uganda: a cross-sectional survey study 
Background
Patient-provider communication is a major challenge in resource-limited settings with large catchment areas. Though mobile phone usership increased 20-fold in Africa over the past decade, little is known about acceptability of, perceptions about disclosure and confidentiality, and preferences for cell phone communication of health information in the region.
Methods
We performed structured interviews of fifty patients at the Immune Suppression Syndrome clinic in Mbarara, Uganda to assess four domains of health-related communication: a) cell phone use practices and literacy, b) preferences for laboratory results communication, c) privacy and confidentiality, and d) acceptability of and preferences for text messaging to notify patients of abnormal test results.
Results
Participants had a median of 38 years, were 56% female, and were residents of a large catchment area throughout southwestern Uganda. All participants expressed interest in a service to receive information about laboratory results by cell phone text message, stating benefits of increased awareness of their health and decreased transportation costs. Ninety percent reported that they would not be concerned for unintended disclosure. A minority additionally expressed concerns about difficulty interpreting messages, discouragement upon learning bad news, and technical issues. Though all respondents expressed interest in password protection of messages, there was also a strong desire for direct messages to limit misinterpretation of information.
Conclusions
Cell phone text messaging for communication of abnormal laboratory results is highly acceptable in this cohort of HIV-infected patients in rural Uganda. The feasibility of text messaging, including an optimal balance between privacy and comprehension, should be further studied.
doi:10.1186/1472-6947-12-56
PMCID: PMC3470938  PMID: 22720901
SMS; Cellular phones; HIV; Sub-Saharan Africa; Confidentiality; Privacy
17.  Association between human immunodeficiency virus (HIV) infection and stiffness of the common carotid artery 
Background and purpose
Human immunodeficiency virus (HIV)-infected persons taking highly active antiretroviral therapy (HAART) may have an increased risk for cardiovascular-related events, although the underlying mechanism remains unclear. We tested the hypothesis that carotid arterial stiffness was higher among persons taking HAART compared to HAART-naïve and HIV-uninfected persons.
Methods
Between 2004 and 2006, we performed high resolution B-mode ultrasound on 2,789 HIV-infected and HIV-uninfected participants of the Women’s Interagency HIV Study (WIHS; 1865 women) and the Multicenter AIDS Cohort Study (MACS; 924 men) and determined carotid arterial distensibility, a direct measure of carotid arterial stiffness. We used generalized estimating equations to evaluate the association between distensibility and HIV infection, CD4+ cell count, and exposure to HAART adjusted for demographic, behavioral, and clinical characteristics.
Results
In multivariable analysis, distensibility was 4.3% lower (95% confidence interval (CI): -7.4% to -1.1%) among HIV-infected versus uninfected participants. Among HIV-infected participants with fewer than 200 CD4+ cells, distensibility was 10.5% lower (95% CI: -14.5% to -6.2%) than that among HIV-uninfected participants, and this effect did not differ significantly by cohort or race. Concurrent HAART use was independently associated with lower distensibility among MACS participants but not among WIHS participants.
Conclusions
Our finding that advanced HIV-related immunosuppression was associated with increased carotid arterial stiffness independent from the effects of traditional atherosclerosis risk factors suggests that the etiologic mechanism underlying reports of an increased cardiovascular disease risk among HIV-infected individuals might involve HIV-related immunosuppression leading to vascular dysfunction and arterial stiffening.
doi:10.1161/STROKEAHA.110.583856
PMCID: PMC2972735  PMID: 20798374
atherosclerosis; cardiovascular disease; carotid arteries; HIV; epidemiology
18.  Improved Diagnosis of Pleural Tuberculosis Using the Microscopic-Observation Drug-Susceptibility Technique 
Tests for pleural tuberculosis are insensitive and expensive. We compared nonproprietary microscopic-observation drug-susceptibility (MODS) culture with Löwenstein-Jensen culture for evaluation of pleural specimens. MODS culture was associated with greatly increased diagnostic sensitivity and shorter time to diagnosis, compared with Löwenstein-Jensen culture (sensitivity of culture of biopsy specimens, 81% vs. 51%; time to diagnosis, 11 days vs. 24 days; P < .001). The MODS technique is inexpensive, allows drug-susceptibility testing, and is a considerably improved diagnostic method for pleural tuberculosis.
doi:10.1086/527447
PMCID: PMC2912496  PMID: 18300380
19.  Real-Time PCR Assay for Detection of Quinolone-Resistant Neisseria gonorrhoeae in Urine Samples▿  
Journal of Clinical Microbiology  2007;45(4):1250-1254.
A need exists for the development of applicable surveillance tools to detect fluoroquinolone-resistant Neisseria gonorrhoeae (QRNG) in urine samples. We describe here a real-time PCR assay for detecting mutations in the Ser91 codon of the gyrA gene of N. gonorrhoeae in urine specimens. We tested 96 urine samples collected along with Gonorrhea Isolate Surveillance Project (GISP) urethral swab samples and compared the results with matched MICs of ciprofloxacin, as reported by the regional GISP laboratory. We then tested 100 urine specimens, known to be gonorrhea positive by nucleic acid amplification testing, provided by females to challenge the real-time PCR assay with urine specimens containing potentially less target DNA content than specimens from symptomatic males. With an MIC threshold of 0.125 μg of ciprofloxacin/ml, our assay correctly identified resistance in 41 of 44 (93.2%; 95% confidence interval [CI] = 81.3 to 98.6%) corresponding resistant culture specimens and correctly identified 51 of 51 (100%; 95% CI = 93.0 to 100%) susceptible specimens. One specimen did not amplify. The assay successfully amplified the gyrA amplicon and determined a susceptibility genotype in 72 of 100 (72%) urine specimens collected from female patients. We developed an assay for detecting QRNG in urine specimens that correlated well with MIC results of cultured specimens and had moderate sensitivity with urine specimens. This methodology might fulfill the need for a QRNG detection system for urine specimens, a useful characteristic in the age of nucleic acid amplification testing for gonococcal infection.
doi:10.1128/JCM.01909-06
PMCID: PMC1865802  PMID: 17267635

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