Long Delays and Missed Opportunities in Diagnosing Smear-Positive Pulmonary Tuberculosis in Kampala, Uganda: A Cross-Sectional Study

BACKGROUND: Early detection and treatment of tuberculosis cases are the hallmark of successful tuberculosis control. We conducted a cross-sectional study at public primary health facilities in Kampala city, Uganda to quantify diagnostic delay among pulmonary tuberculosis (PTB) patients, assess associated factors, and describe trajectories of patients' health care seeking. METHODOLOGY/PRINCIPAL FINDINGS: Semi-structured interviews with new smear-positive PTB patients (≥ 15 years) registered for treatment. Between April 2007 and April 2008, 253 patients were studied. The median total delay was 8 weeks (IQR 4-12), median patient delay was 4 weeks (inter-quartile range [IQR] 1-8) and median health service delay was 4 weeks (IQR 2-8). Long total delay (>14 weeks) was observed for 61/253 (24.1%) of patients, long health service delay (>6 weeks) for 71/242 (29.3%) and long patient delay (>8 weeks) for 47/242 (19.4%). Patients who knew that TB was curable were less likely to have long total delay (adjusted Odds Ratio [aOR] 0.28; 95%CI 0.11-0.73) and long patient delay (aOR 0.36; 95%CI 0.13-0.97). Being female (aOR 1.98; 95%CI 1.06-3.71), staying for more than 5 years at current residence (aOR 2.24 95%CI 1.18-4.27) and having been tested for HIV before (aOR 3.72; 95%CI 1.42-9.75) was associated with long health service delay. Health service delay contributed 50% of the total delay. Ninety-one percent (231) of patients had visited one or more health care providers before they were diagnosed, for an average (median) of 4 visits (range 1-30). All but four patients had systemic symptoms by the time the diagnosis of TB was made. CONCLUSIONS/SIGNIFICANCE: Diagnostic delay among tuberculosis patients in Kampala is common and long. This reflects patients waiting too long before seeking care and health services waiting until systemic symptoms are present before examining sputum smears; this results in missed opportunities for diagnosis

Cognitive function and drivers of cognitive impairment in a European and a Korean cohort of people living with HIV

Although cognitive impairments are still prevalent in the current antiretroviral therapy era, limited investigations have compared the prevalence of cognitive disorder in people living with HIV (PLWH) and its determinants in different regions and ethnicities. We compared cognitive performance across six domains using comparable batteries in 134 PLWH aged ≥45 years from the COBRA study (Netherlands, UK), and 194 PLWH aged ≥18 years from the NeuroAIDS Project (South Korea). Cognitive scores were standardized and averaged to obtain domain and global T-scores. Associations with global T-scores were evaluated using multivariable regression and the ability of individual tests to detect cognitive impairment (global T-score ≤45) was assessed using the area-under-the-receiver-operating-characteristic curve (AUROC). The median (interquartile range) age of participants was 56 (51, 62) years in COBRA (88% white ethnicity, 93% male) and 45 (37, 52) years in NeuroAIDS (100% Korean ethnicity, 94% male). The rate of cognitive impairment was 18.8% and 18.0%, respectively (p = 0.86). In COBRA, Black-African ethnicity was the factor most strongly associated with cognitive function (11.1 [7.7, 14.5] lower scores vs. white ethnicity, p < 0.01), whereas in NeuroAIDS, age (0.6 [0.1, 1.3] per 10-year, p<0.01) and education (0.7 [0.5, 0.9] per year, p<0.01) were significantly associated with cognitive function with anemia showing only a weak association (−1.2 [−2.6, 0.3], p=0.12). Cognitive domains most associated with cognitive impairment were attention (AUROC = 0.86) and executive function (AUROC = 0.87) in COBRA and processing speed (AUROC = 0.80), motor function (AUROC = 0.78) and language (AUROC = 0.78) in NeuroAIDS. Two cohorts of PLWH from different geographical regions report similar rates of cognitive impairment but different risk factors and cognitive profiles of impairment

Placental Malaria is associated with reduced early life weight development of affected children independent of low birth weight

<p>Abstract</p> <p>Background</p> <p>Infection with <it>Plasmodium falciparum </it>during pregnancy contributes substantially to the disease burden in both mothers and offspring. Placental malaria may lead to intrauterine growth restriction or preterm delivery resulting in low birth weight (LBW), which, in general, is associated with increased infant morbidity and mortality. However, little is known about the possible direct impact of the specific disease processes occurring in PM on longer term outcomes such as subsequent retarded growth development independent of LBW.</p> <p>Methods</p> <p>In an existing West-African cohort, 783 healthy infants with a birth weight of at least 2,000 g were followed up during their first year of life. The aim of the study was to investigate if <it>Plasmodium falciparum </it>infection of the placenta, assessed by placental histology, has an impact on several anthropometric parameters, measured at birth and after three, six and 12 months using generalized estimating equations models adjusting for moderate low birth weight.</p> <p>Results</p> <p>Independent of LBW, first to third born infants who were exposed to either past, chronic or acute placental malaria during pregnancy had significantly lower weight-for-age (-0.43, 95% CI: -0.80;-0.07), weight-for-length (-0.47, 95% CI: -0.84; -0.10) and BMI-for-age z-scores (-0.57, 95% CI: -0.84; -0.10) compared to infants born to mothers who were not diagnosed with placental malaria (p = 0.019, 0.013, and 0.012, respectively). Interestingly, the longitudinal data on histology-based diagnosis of PM also document a sharp decline of PM prevalence in the Sukuta cohort from 16.5% in 2002 to 5.4% in 2004.</p> <p>Conclusions</p> <p>It was demonstrated that PM has a negative impact on the infant's subsequent weight development that is independent of LBW, suggesting that the longer term effects of PM have been underestimated, even in areas where malaria transmission is declining.</p

CD4 cell count response to first-line combination ART in HIV-2+patients compared with HIV-1+patients: a multinational, multicohort European study

BACKGROUND: CD4 cell recovery following first-line combination ART (cART) is poorer in HIV-2+ than in HIV-1+ patients. Only large comparisons may allow adjustments for demographic and pretreatment plasma viral load (pVL). METHODS: ART-naive HIV+ adults from two European multicohort collaborations, COHERE (HIV-1 alone) and ACHIeV2e (HIV-2 alone), were included, if they started first-line cART (without NNRTIs or fusion inhibitors) between 1997 and 2011. Patients without at least one CD4 cell count before start of cART, without a pretreatment pVL and with missing a priori-defined covariables were excluded. Evolution of CD4 cell count was studied using adjusted linear mixed models. RESULTS: We included 185 HIV-2+ and 30321 HIV-1+ patients with median age of 46 years (IQR 36–52) and 37 years (IQR 31–44), respectively. Median observed pretreatment CD4 cell counts/mm3 were 203 (95% CI 100–290) in HIV-2+ patients and 223 (95% CI 100–353) in HIV-1+ patients. Mean observed CD4 cell count changes from start of cART to 12 months were +105 (95% CI 77–134) in HIV-2+ patients and +202 (95% CI 199–205) in HIV-1+ patients, an observed difference of 97 cells/mm3 in 1 year. In adjusted analysis, the mean CD4 cell increase was overall 25 CD4 cells/mm3/year lower (95% CI 5–44; P = 0.0127) in HIV-2+ patients compared with HIV-1+ patients. CONCLUSIONS: A poorer CD4 cell increase during first-line cART was observed in HIV-2+ patients, even after adjusting for pretreatment pVL and other potential confounders. Our results underline the need to identify more potent therapeutic regimens or strategies against HIV-2

Single-dose administration and the influence of the timing of the booster dose on immunogenicity and efficacy of ChAdOx1 nCoV-19 (AZD1222) vaccine: a pooled analysis of four randomised trials.

BACKGROUND: The ChAdOx1 nCoV-19 (AZD1222) vaccine has been approved for emergency use by the UK regulatory authority, Medicines and Healthcare products Regulatory Agency, with a regimen of two standard doses given with an interval of 4-12 weeks. The planned roll-out in the UK will involve vaccinating people in high-risk categories with their first dose immediately, and delivering the second dose 12 weeks later. Here, we provide both a further prespecified pooled analysis of trials of ChAdOx1 nCoV-19 and exploratory analyses of the impact on immunogenicity and efficacy of extending the interval between priming and booster doses. In addition, we show the immunogenicity and protection afforded by the first dose, before a booster dose has been offered. METHODS: We present data from three single-blind randomised controlled trials-one phase 1/2 study in the UK (COV001), one phase 2/3 study in the UK (COV002), and a phase 3 study in Brazil (COV003)-and one double-blind phase 1/2 study in South Africa (COV005). As previously described, individuals 18 years and older were randomly assigned 1:1 to receive two standard doses of ChAdOx1 nCoV-19 (5 × 1010 viral particles) or a control vaccine or saline placebo. In the UK trial, a subset of participants received a lower dose (2·2 × 1010 viral particles) of the ChAdOx1 nCoV-19 for the first dose. The primary outcome was virologically confirmed symptomatic COVID-19 disease, defined as a nucleic acid amplification test (NAAT)-positive swab combined with at least one qualifying symptom (fever ≥37·8°C, cough, shortness of breath, or anosmia or ageusia) more than 14 days after the second dose. Secondary efficacy analyses included cases occuring at least 22 days after the first dose. Antibody responses measured by immunoassay and by pseudovirus neutralisation were exploratory outcomes. All cases of COVID-19 with a NAAT-positive swab were adjudicated for inclusion in the analysis by a masked independent endpoint review committee. The primary analysis included all participants who were SARS-CoV-2 N protein seronegative at baseline, had had at least 14 days of follow-up after the second dose, and had no evidence of previous SARS-CoV-2 infection from NAAT swabs. Safety was assessed in all participants who received at least one dose. The four trials are registered at ISRCTN89951424 (COV003) and ClinicalTrials.gov, NCT04324606 (COV001), NCT04400838 (COV002), and NCT04444674 (COV005). FINDINGS: Between April 23 and Dec 6, 2020, 24 422 participants were recruited and vaccinated across the four studies, of whom 17 178 were included in the primary analysis (8597 receiving ChAdOx1 nCoV-19 and 8581 receiving control vaccine). The data cutoff for these analyses was Dec 7, 2020. 332 NAAT-positive infections met the primary endpoint of symptomatic infection more than 14 days after the second dose. Overall vaccine efficacy more than 14 days after the second dose was 66·7% (95% CI 57·4-74·0), with 84 (1·0%) cases in the 8597 participants in the ChAdOx1 nCoV-19 group and 248 (2·9%) in the 8581 participants in the control group. There were no hospital admissions for COVID-19 in the ChAdOx1 nCoV-19 group after the initial 21-day exclusion period, and 15 in the control group. 108 (0·9%) of 12 282 participants in the ChAdOx1 nCoV-19 group and 127 (1·1%) of 11 962 participants in the control group had serious adverse events. There were seven deaths considered unrelated to vaccination (two in the ChAdOx1 nCov-19 group and five in the control group), including one COVID-19-related death in one participant in the control group. Exploratory analyses showed that vaccine efficacy after a single standard dose of vaccine from day 22 to day 90 after vaccination was 76·0% (59·3-85·9). Our modelling analysis indicated that protection did not wane during this initial 3-month period. Similarly, antibody levels were maintained during this period with minimal waning by day 90 (geometric mean ratio [GMR] 0·66 [95% CI 0·59-0·74]). In the participants who received two standard doses, after the second dose, efficacy was higher in those with a longer prime-boost interval (vaccine efficacy 81·3% [95% CI 60·3-91·2] at ≥12 weeks) than in those with a short interval (vaccine efficacy 55·1% [33·0-69·9] at <6 weeks). These observations are supported by immunogenicity data that showed binding antibody responses more than two-fold higher after an interval of 12 or more weeks compared with an interval of less than 6 weeks in those who were aged 18-55 years (GMR 2·32 [2·01-2·68]). INTERPRETATION: The results of this primary analysis of two doses of ChAdOx1 nCoV-19 were consistent with those seen in the interim analysis of the trials and confirm that the vaccine is efficacious, with results varying by dose interval in exploratory analyses. A 3-month dose interval might have advantages over a programme with a short dose interval for roll-out of a pandemic vaccine to protect the largest number of individuals in the population as early as possible when supplies are scarce, while also improving protection after receiving a second dose. FUNDING: UK Research and Innovation, National Institutes of Health Research (NIHR), The Coalition for Epidemic Preparedness Innovations, the Bill & Melinda Gates Foundation, the Lemann Foundation, Rede D'Or, the Brava and Telles Foundation, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland's NIHR Clinical Research Network, and AstraZeneca

Determining the most likely source of infection: an application to Neisseria gonorrhoeae among men who have sex with men

Background The source of an infection is often unknown. To inform directed prevention measures, it is useful to know the location and partner type with the highest transmission risk. We developed a method to estimate infection risk of Neisseria gonorrhoeae (NG) per meeting location among men who have sex with men (MSM). Methods In 2008-2009, we collected information from 2438 MSM attending the Sexually Transmitted Infections clinic of Amsterdam. For up to 4 partners per participant (8028 in total), details on meeting location, partner, and partnership characteristics were asked. We used logistic regression to relate these to the participant’s infection risk, accounting for unobserved transmission information in the likelihood. Based on the model estimates, we predicted the probability of a partner having NG. The probability that a partner was the source was proportional to his predicted infection risk. Each source was linked to the meeting location. We used a Bayesian method. Results Rectal NG was diagnosed in 157 MSM who reported data on 422 possible source partners, urethral NG in 126 reporting 285 possible sources, and pharyngeal NG in 162 reporting 451 possible sources. We estimated that most infections were acquired from long-lasting steady partners (20.61%; 95% CI 17.11-24.34). Partners met in an Amsterdam street with gay venues posed the highest transmission risk (13.16%; 95% CI 7.89-17.76). Conclusions The presented method estimates the source of infection when there are multiple possible sources and enables the summation over various kinds of epidemiological characteristics (here meeting locations) that are relevant for prevention.</p