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Data continue to emerge that suggest treating HIV infection as early as possible is beneficial. In this trial assessing the timing of antiretroviral therapy initiation in patients with acute cryptococcal meningitis and newly diagnosed HIV infection, early initiation was associated with increased mortality. Cryptococcus neoformans is the most common cause of meningitis in adults in sub-Saharan Africa, 1 – 5 and meningitis caused by C. neoformans accounts for approximately 20 to 25% of deaths from the acquired immunodeficiency syndrome (AIDS) in Africa. 6 – 9 Determining when antiretroviral therapy (ART) should be initiated after a diagnosis of cryptococcal meningitis involves balancing the survival benefit conferred by ART against the risk of the immune reconstitution inflammatory syndrome (IRIS), a paradoxical reaction that occurs during immunologic recovery with ART despite effective therapy for the opportunistic infection. Since 2009, the international standard of care has shifted toward earlier ART . . .

Sexually Transmitted Infections (STIs) rank in the top 5 disease categories for which adults in developing countries seek healthcare services. Community pharmacies offer clients convenience, proximity, extended opening hours, privacy, and efficiency, which could make them desirable locations for HIV and STI screening and treatment. We examined the feasibility of using point-of-care (POC) STI tests for screening HIV and other STIs at community pharmacies. We conducted a prospective cohort study of persons seeking medication and other services at 18 purposively selected community pharmacies in Kampala, Uganda. Study participants comprised two broad categories: i) Symptomatic persons aged 18 years who presented with at least one STI sign or symptom and were purchasing treatment for themselves; ii) persons presenting with no STI symptom who had come to purchase any other medication, including family planning services such as emergency contraception. POC tests were used to test HIV, Chlamydia trachomatis (Ct), Neisseria gonorrhoeae (Ng), Trichomonas vaginalis (Tv), and Syphilis. Test results were returned on-site or via telephone within 48 to 72 hours. Descriptive statistics were used to estimate the prevalence of STIs. Of the 450 participants enrolled, 235 (52.2%) were symptomatic, 215 (47.8%) were asymptomatic, and 280 (62.2%) were females. STI testing was feasible, with an acceptability rate of 99.8%. 135 (30%) of participants had at least one STI; HIV prevalence was 39 (8.7%), Syphilis prevalence was 14 (3.1%), 50 (11.1%) tested positive for Ng, 39 (8.7%) were positive for Ct while. The prevalence of Tv was 25 (8.9%) (tested among women). A total of 107 (23.8%) participants had used an antibiotic in the preceding month. Our research underscores the potentially pivotal role of community pharmacies in deploying POC diagnostics for STIs and antimicrobial stewardship by decreasing unnecessary antibiotic dispensation across Africa.

Tuberculosis (TB) mortality estimates derived only from cohorts of patients initiated on TB treatment do not consider outcomes of patients with pretreatment loss to follow-up (LFU). We aimed to assess the effect of pretreatment LFU on TB-associated mortality in the six months following TB diagnosis at public health facilities in Uganda. At ten public health facilities, we retrospectively reviewed treatment data for all patients with a positive Xpert®MTB/RIF test result from January to June 2018. Pretreatment LFU was defined as not initiating TB treatment within two weeks of a positive test. We traced patients with pretreatment LFU to ascertain their vital status. We performed Kaplan Meier survival analysis to compare the cumulative incidence of mortality, six months after diagnosis among patients who did and did not experience pretreatment LFU. We also determined the health facility level estimates of TB associated mortality before and after incorporating deaths prior to treatment initiation among patients who experienced pretreatment LFU. Of 510 patients with positive test, 100 (19.6%) experienced pretreatment LFU. Of these, we ascertained the vital status of 49 patients. In the six months following TB diagnosis, mortality was higher among patients who experienced pretreatment LFU 48.1/1000py vs 22.9/1000py. Hazard ratio [HR] 3.18, 95% confidence interval [CI] (1.61-6.30). After incorporating deaths prior to treatment initation among patients who experienced pretreatment LFU, health facility level estimates of TB associated mortality increased from 8.4% (95% CI 6.1%-11.6%) to 10.2% (95% CI 7.7%-13.4%). Patients with confirmed TB who experience pretreatment LFU have high mortality within the first six months. Efforts should be made to prioritise linkage to treatment for this group of patients. Deaths that occur prior to treatment initation should be included when reporting TB mortality in order to more accurately reflect the health impact of TB.

Tuberculosis preventive therapy (TPT) effectively decreases rates of developing active tuberculosis disease in people living with HIV (PLHIV) who are at increased risk. The Uganda Ministry of Health launched a 100-day campaign to scale-up TPT in PLHIV in July 2019. We sought to examine the effect of the campaign on trends of TPT uptake and characteristics associated with TPT uptake and completion among persons in HIV care. We retrospectively reviewed routinely collected data from 2016 to 2019 at six urban public health facilities in Uganda. HIV care database and paper-based TPT registers at six public health facilities in Kampala, Uganda were retrospectively reviewed. Estimated trends of TPT (given as Isoniazid monotherapy) uptake and completion across the 4 years, among PLHIV aged 15 years and above, and factors associated, were examined using Poisson regression model with robust standard errors using generalized estimating equation (GEE) models. On average, a total of 39,774 PLHIV aged 15 years and above were eligible for TPT each calendar year at the six health facilities. Across all 4 years, more than 70% were females (range: 73.5% -74.6%) and the median age ranged from 33 to 34 years. From 2016 quarter one to 2019 quarter two, TPT uptake was consistently below 25%, but, as expected, the uptake significantly increased by about 3-folds from 22.1% to 61.2%, in 2019 quarter two (i.e. before the roll-out of the 100-day accelerated TPT intervention) and quarter three (i.e. after the roll-out of the 100-day accelerated TPT intervention) respectively. This increase remained highly significant even after adjusting for patients’ baseline characteristics (adjusted prevalence ratio [aPR] = 2.58 [95%CI 2.45, 2.72], P-value<0.001). TPT completion was consistently high at above 70% at most of the time, but, it increased significantly among those initiated during 2018 quarter four and in the subsequent two quarters after the roll-out of the 100-day accelerated TPT intervention (i.e. TPT completion was: 83.2%, 95.3%, and 97.1% among individuals initiated during 2018 quarter4, and 2019 quarters 1 and 2, respectively). The increase in TPT completion during this period remained significant even after adjusting for patients’ baseline characteristics (aPR [95%CI] = 1.09 [1.04, 1.14], P value<0.001, and 1.10 [1.05,1.15], P value<0.001, for individuals initiated during 2019 quarter 1, and 2, respectively compared to those initiated during 2018 quarter 4). Not on ART or newly started on ART compared to ART experienced, and pregnant at TPT initiation compared to not pregnant were associated with poor TPT completion, whereas older age (≥25 years versus 15–24 years) was associated with higher TPT completion. The targeted 100-day campaign dramatically increased TPT uptake and completion among PLHIV suggesting a viable catch up strategy to meet WHO guidelines. Future analysis with additional years of data post 100-days TPT intervention is required to evaluate the sustainability of the observed gains.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has emphasized the importance and challenges of correctly interpreting antibody test results. Identification of positive and negative samples requires a classification strategy with low error rates, which is hard to achieve when the corresponding measurement values overlap. Additional uncertainty arises when classification schemes fail to account for complicated structure in data. We address these problems through a mathematical framework that combines high dimensional data modeling and optimal decision theory. Specifically, we show that appropriately increasing the dimension of data better separates positive and negative populations and reveals nuanced structure that can be described in terms of mathematical models. We combine these models with optimal decision theory to yield a classification scheme that better separates positive and negative samples relative to traditional methods such as confidence intervals (CIs) and receiver operating characteristics. We validate the usefulness of this approach in the context of a multiplex salivary SARS-CoV-2 immunoglobulin G assay dataset. This example illustrates how our analysis: (i) improves the assay accuracy, (e.g. lowers classification errors by up to 42% compared to CI methods); (ii) reduces the number of indeterminate samples when an inconclusive class is permissible, (e.g. by 40% compared to the original analysis of the example multiplex dataset) and (iii) decreases the number of antigens needed to classify samples. Our work showcases the power of mathematical modeling in diagnostic classification and highlights a method that can be adopted broadly in public health and clinical settings.

IntroductionThe incidence of long COVID is substantial, even in people with mild to moderate acute COVID-19. The role of early viral kinetics in the subsequent development of long COVID is largely unknown, especially in individuals who were not hospitalized for acute COVID-19.MethodsSeventy-three non-hospitalized adult participants were enrolled within approximately 48 hours of their first positive SARS-CoV-2 RT-PCR test, and mid-turbinate nasal and saliva samples were collected up to 9 times within the first 45 days after enrollment. Samples were assayed for SARS-CoV-2 using RT-PCR and additional SARS-CoV-2 test results were abstracted from the clinical record. Each participant indicated the presence and severity of 49 long COVID symptoms at 1-, 3-, 6-, 12-, and 18-months post-COVID-19 diagnosis. Time from acute COVID-19 illness onset to SARS-CoV-2 RNA clearance greater or less than 28 days was tested for association with the presence or absence of each of 49 long COVID symptoms at 90+ days from acute COVID-19 symptom onset.ResultsSelf-reported brain fog and muscle pain at 90+ days after acute COVID-19 onset were negatively associated with viral RNA clearance within 28 days of acute COVID-19 onset with adjustment for age, sex, BMI ≥ 25, and COVID vaccination status prior to COVID-19 (brain fog: aRR 0.46, 95% CI 0.22-0.95; muscle pain: aRR 0.28, 95% CI 0.08-0.94). Participants reporting higher severity brain fog or muscle pain at 90+ days after acute COVID-19 onset were less likely to have cleared SARS-CoV-2 RNA within 28 days. The acute viral RNA decay trajectories of participants who did and did not later go on to experience brain fog 90+ days after acute COVID-19 onset were distinct.DiscussionThis work indicates that at least two long COVID symptoms - brain fog and muscle pain – at 90+ days from acute COVID-19 onset are specifically associated with prolonged time to clearance of SARS-CoV-2 RNA from the upper respiratory tract during acute COVID-19. This finding provides evidence that delayed immune clearance of SARS-CoV-2 antigen or greater amount or duration of viral antigen burden in the upper respiratory tract during acute COVID-19 are directly linked to long COVID. This work suggests that host-pathogen interactions during the first few weeks after acute COVID-19 onset have an impact on long COVID risk months later.

Untreated syphilis in pregnancy is associated with adverse clinical outcomes for the infant. Most syphilis infections occur in sub-Saharan Africa (SSA), where coverage of antenatal screening for syphilis is inadequate. Recently introduced point-of-care syphilis tests have high accuracy and demonstrate potential to increase coverage of antenatal screening. However, country-specific cost-effectiveness data for these tests are limited. The objective of this analysis was to evaluate the cost-effectiveness and budget impact of antenatal syphilis screening for 43 countries in SSA and estimate the impact of universal screening on stillbirths, neonatal deaths, congenital syphilis, and disability-adjusted life years (DALYs) averted. The decision analytic model reflected the perspective of the national health care system and was based on the sensitivity (86%) and specificity (99%) reported for the immunochromatographic strip (ICS) test. Clinical outcomes of infants born to syphilis-infected mothers on the end points of stillbirth, neonatal death, and congenital syphilis were obtained from published sources. Treatment was assumed to consist of three injections of benzathine penicillin. Country-specific inputs included the antenatal prevalence of syphilis, annual number of live births, proportion of women with at least one antenatal care visit, per capita gross national income, and estimated hourly nurse wages. In all 43 sub-Saharan African countries analyzed, syphilis screening is highly cost-effective, with an average cost/DALY averted of US$11 (range: US$2-US$48). Screening remains highly cost-effective even if the average prevalence falls from the current rate of 3.1% (range: 0.6%-14.0%) to 0.038% (range: 0.002%-0.113%). Universal antenatal screening of pregnant women in clinics may reduce the annual number of stillbirths by up to 64,000, neonatal deaths by up to 25,000, and annual incidence of congenital syphilis by up to 32,000, and avert up to 2.6 million DALYs at an estimated annual direct medical cost of US$20.8 million. Use of ICS tests for antenatal syphilis screening is highly cost-effective in SSA. Substantial reduction in DALYs can be achieved at a relatively modest budget impact. In SSA, antenatal programs should expand access to syphilis screening using the ICS test. Please see later in the article for the Editors' Summary.

The complexity of rickettsial serodiagnostics during acute illness has limited clinical characterization in Africa. We used archived samples from sepsis (n = 259) and acute febrile illness (n = 70) cohorts in Uganda to identify spotted fever and typhus group rickettsiae by using immunofluorescence assay and clinically validated rRNA reverse transcription PCR (RT-PCR). Among 329 participants, 10.0% had rickettsial infections (n = 33; n = 20 identified with immunofluorescence assay and n = 13 by RT-PCR). Serum rRNA RT-PCR was 75.0% (95% CI 42.8-94.5%) sensitive and 91.2% (95% CI 85.8-95.1%) specific. Thrombocytopenia was more common among patients with rickettsial infections than with other nonmalarial infections (adjusted odds ratio 3.7; p = 0.003). No participants were on a tetracycline antimicrobial drug at admission. rRNA RT-PCR is a promising diagnostic strategy for identifying acute rickettsial infections. Doxycycline should be included in empiric antimicrobial drug regimens for nonmalarial febrile illness in this region.

Background. Cryptococcal meningitis (CM) remains a common AIDS-defining illness in Africa and Asia. Subclinical cryptococcal antigenemia is frequently unmasked with antiretroviral therapy (ART). We sought to define the cost-effectiveness of serum cryptococcal antigen (CRAG) screening to identify persons with subclinical cryptococcosis and the efficacy of preemptive fluconazole therapy. Methods. There were 609 ART-naive adults with AIDS who started ART in Kampala, Uganda, and who had a serum CRAG prospectively measured during 2004–2006. The number needed to test and treat with a positive CRAG was assessed for ≥30-month outcomes. Results. In the overall cohort, 50 persons (8.2%) were serum CRAG positive when starting ART. Of 295 people with a CD4+ cell count ≤100 cells/μL and without prior CM, 26 (8.8%; 95% confidence interval [CI], 5.8%–12.6%) were CRAG positive, of whom 21 were promptly treated with fluconazole (200–400 mg) for 2–4 weeks. Clinical CM developed in 3 fluconazole-treated persons, and 30-month survival was 71% (95% CI, 48%–89%). In the 5 CRAG-positive persons with a CD4+ cell count ≤100 cells/μL treated with ART but not fluconazole, all died within 2 months of ART initiation. The number needed to test and treat with CRAG screening and fluconazole to prevent 1 CM case is 11.3 (95% CI, 7.9–17.1) at costs of $190 (95% CI, $132–$287). The number needed to test and treat to save 1 life is 15.9 (95% CI, 11.1–24.0) at costs of $266 (95% CI, $185–$402). The cost per disability-adjusted life year saved is $21 (95% CI, $15–$32). Conclusions. Integrating CRAG screening into HIV care, specifically targeting people with severe immunosuppression (CD4+ cell count ≤100 cells/μL) should be implemented in treatment programs in resource-limited settings. ART alone is insufficient treatment for CRAG-positive persons.

One in five patients diagnosed with TB in Uganda are not initiated on TB treatment within two weeks of diagnosis. We evaluated a multifaceted intervention for improving TB treatment initiation among patients diagnosed with TB using Xpert® MTB/RIF testing in Uganda. This was a pre-post interventional study at one tertiary referral hospital. The intervention was informed by the COM-B model and included; i) medical education sessions to improve healthcare worker knowledge about the magnitude and consequences of pretreatment loss to follow-up; ii) modified laboratory request forms to improve recording of patient contact information; and iii) re-designed workflow processes to improve timeliness of sputum testing and results dissemination. TB diagnostic process and outcome data were collected and compared from the period before (June to August 2019) and after (October to December 2019) intervention initiation. In September 2019, four CME sessions were held at the hospital and were attended by 58 healthcare workers. During the study period, 1242 patients were evaluated by Xpert® MTB/RIF testing at the hospital (679 pre and 557 post intervention). Median turnaround time for sputum test results improved from 12 hours (IQR 4-46) in the pre-intervention period to 4 hours (IQR 3-6) in the post-intervention period. The proportion of patients started on treatment within two weeks of diagnosis improved from 59% (40/68) to 89% (49/55) (difference 30%, 95% CI 14%-43%, p<0.01) while the proportion of patients receiving a same-day diagnosis increased from 7.4% (5/68) to 25% (14/55) (difference 17.6%, 95% CI 3.9%-32.7%, p<0.01). The multifaceted intervention was feasible and resulted in a higher proportion of patients initiating TB treatment within two weeks of diagnosis.