Dolutegravir induces FOLR1 expression during brain organoid development.

During the first month of pregnancy, the brain and spinal cord are formed through a process called neurulation. However, this process can be altered by low serum levels of folic acid, environmental factors, or genetic predispositions. In 2018, a surveillance study in Botswana, a country with a high incidence of human immunodeficiency virus (HIV) and lacking mandatory food folate fortification programs, found that newborns whose mothers were taking dolutegravir (DTG) during the first trimester of pregnancy had an increased risk of neural tube defects (NTDs). As a result, the World Health Organization and the U.S. Food and Drug Administration have issued guidelines emphasizing the potential risks associated with the use of DTG-based antiretroviral therapies during pregnancy. To elucidate the potential mechanisms underlying the DTG-induced NTDs, we sought to assess the potential neurotoxicity of DTG in stem cell-derived brain organoids. The gene expression of brain organoids developed in the presence of DTG was analyzed by RNA sequencing, Optical Coherence Tomography (OCT), Optical Coherence Elastography (OCE), and Brillouin microscopy. The sequencing data shows that DTG induces the expression of the folate receptor (FOLR1) and modifies the expression of genes required for neurogenesis. The Brillouin frequency shift observed at the surface of DTG-exposed brain organoids indicates an increase in superficial tissue stiffness. In contrast, reverberant OCE measurements indicate decreased organoid volumes and internal stiffness.

Effect of the enhancing nutrition and antenatal infection treatment (ENAT) intervention on birth weight in Ethiopia: a cluster randomized controlled trial.

BACKGROUND: The Enhancing Nutrition and Antenatal Infection Treatment (ENAT) intervention was implemented in Ethiopia to improve newborn birth weight (BW) by strengthening the contents and quality of antenatal care (ANC), especially point-of-care testing for maternal infections. This study examined the effect of the ENAT intervention on birth weight. METHODS: We conducted a cluster randomized controlled trial of 22 clusters (health centers), randomized equally between 11 intervention and 11 control clusters. This study enrolled and followed pregnant women from ANC booking to the end of pregnancy or loss to follow-up. The primary outcome was mean BW, and the incidence of low birth weight (LBW) was the secondary outcome. We presented univariate comparisons of outcomes between the intervention and control arms for mean BW and LBW. Multilevel analyses using random effects models were performed to adjust for clustering and individual-level covariates. RESULTS: We enrolled and followed up 4,868 and 4,821 pregnant women in the intervention and control arms, respectively, from March 2021-July 2022. During follow-up, 3445 pregnant women in the intervention and 3192 in the control delivered in the health centers, and BW measurements of their babies were recorded within 48 h. The mean BW was 3,152 g (standard deviation (SD) = 339.8 g) in the intervention and 3,044 g (SD = 353.8 g) in the control arms (mean difference, 108 g; 95% confidence interval (CI): 91.3-124.6; P = 0.000). Adjusting for clustering and several covariates, the mean BW remained significantly higher in the intervention arm than in the control arm (adjusted ß coef., 114.3; p = 0.011). The incidence of LBW was 4.7% and 7.3% in the intervention and control arms, respectively. The adjusted risk of LBW was significantly lower by 36% in the intervention arm than in the control arm (adjusted relative risk, 0.645; p = 0.027). CONCLUSION: This study provided sufficient evidence of the effectiveness of the ENAT intervention in improving birth weight in the study population. The intervention demonstrated that an increase in birth weight can be attained by availing point-of-care testing, strengthening infection prevention, and maternal nutrition within the ANC platform of public health facilities in a low-income setting. TRIAL REGISTRATION: Registered at Pan African Clinical Trial Registry (PACTR) database dated 09/05/2023, https://pactr.samrc.ac.za/TrialDisplay.aspx?TrialID=25493 . The unique identification number for the registry is PACTR202305694761480.

High Level of HIV Drug Resistance and Virologic Nonsuppression Among Female Sex Workers in Ethiopia: A Nationwide Cross-Sectional Study.

OBJECTIVE: To determine viral load (VL) nonsuppression (VLN) rates, HIV drug resistance (HIVDR) prevalence, and associated factors among female sex workers (FSWs) in Ethiopia. METHODS: A cross-sectional biobehavioral survey was conducted among FSWs in 11 cities in Ethiopia in 2014. Whole blood was collected, and HIVDR genotyping was performed. Logistic regression analysis was performed to identify factors associated with VLN and HIVDR. RESULTS: Among 4900 participants, 1172 (23.9%) were HIV-positive and 1154 (98.5%) had a VL result. Participants were categorized into antiretroviral therapy (ART) (n = 239) and ART-naive (n = 915) groups based on self-report. From the 521 specimens (ART, 59; ART-naive, 462) with VL ≥1000 copies/mL, genotyping was successful for 420 (80.6%) and 92 (21.9%) had drug resistance mutations (DRMs). Pretreatment drug resistance (PDR) was detected in 16.5% (63/381) of the ART-naive participants. Nucleoside reverse transcriptase inhibitor (NRTI), non-NRTIs (NNRTIs), and dual-class DRMs were detected in 40 (10.5%), 55 (14.4%), and 35 (9.2%) of the participants, respectively. Among 239 participants on ART, 59 (24.7%) had VLN. Genotyping was successfully performed for 39 (66.1%). DRMs were detected in 29 (74.4%). All 29 had NNRTI, 23 (79.3%) had NRTI or dual-class DRMs. VLN was associated with age 35 years or older, CD4+ T-cell count <350 cells/mm3, and being forced into selling sex. PDR and acquired drug resistance were associated with CD4+ T-cell count <350 cells/mm3 (P < 0.001). CONCLUSIONS: The high VLN and HIVDR rates among FSWs underscore the need for targeted interventions to improve ART access and virologic monitoring to maximize the benefit of ART and limit the spread of HIV and HIVDR.

Tuberculosis screening among ambulatory people living with HIV: a systematic review and individual participant data meta-analysis.

BACKGROUND: The WHO-recommended tuberculosis screening and diagnostic algorithm in ambulatory people living with HIV is a four-symptom screen (known as the WHO-recommended four symptom screen [W4SS]) followed by a WHO-recommended molecular rapid diagnostic test (eg Xpert MTB/RIF [hereafter referred to as Xpert]) if W4SS is positive. To inform updated WHO guidelines, we aimed to assess the diagnostic accuracy of alternative screening tests and strategies for tuberculosis in this population. METHODS: In this systematic review and individual participant data meta-analysis, we updated a search of PubMed (MEDLINE), Embase, the Cochrane Library, and conference abstracts for publications from Jan 1, 2011, to March 12, 2018, done in a previous systematic review to include the period up to Aug 2, 2019. We screened the reference lists of identified pieces and contacted experts in the field. We included prospective cross-sectional, observational studies and randomised trials among adult and adolescent (age ≥10 years) ambulatory people living with HIV, irrespective of signs and symptoms of tuberculosis. We extracted study-level data using a standardised data extraction form, and we requested individual participant data from study authors. We aimed to compare the W4SS with alternative screening tests and strategies and the WHO-recommended algorithm (ie, W4SS followed by Xpert) with Xpert for all in terms of diagnostic accuracy (sensitivity and specificity), overall and in key subgroups (eg, by antiretroviral therapy [ART] status). The reference standard was culture. This study is registered with PROSPERO, CRD42020155895. FINDINGS: We identified 25 studies, and obtained data from 22 studies (including 15 666 participants; 4347 [27·7%] of 15 663 participants with data were on ART). W4SS sensitivity was 82% (95% CI 72-89) and specificity was 42% (29-57). C-reactive protein (≥10 mg/L) had similar sensitivity to (77% [61-88]), but higher specificity (74% [61-83]; n=3571) than, W4SS. Cough (lasting ≥2 weeks), haemoglobin (<10 g/dL), body-mass index (<18·5 kg/m2), and lymphadenopathy had high specificities (80-90%) but low sensitivities (29-43%). The WHO-recommended algorithm had a sensitivity of 58% (50-66) and a specificity of 99% (98-100); Xpert for all had a sensitivity of 68% (57-76) and a specificity of 99% (98-99). In the one study that assessed both, the sensitivity of sputum Xpert Ultra was higher than sputum Xpert (73% [62-81] vs 57% [47-67]) and specificities were similar (98% [96-98] vs 99% [98-100]). Among outpatients on ART (4309 [99·1%] of 4347 people on ART), W4SS sensitivity was 53% (35-71) and specificity was 71% (51-85). In this population, a parallel strategy (two tests done at the same time) of W4SS with any chest x-ray abnormality had higher sensitivity (89% [70-97]) and lower specificity (33% [17-54]; n=2670) than W4SS alone; at a tuberculosis prevalence of 5%, this strategy would require 379 more rapid diagnostic tests per 1000 people living with HIV than W4SS but detect 18 more tuberculosis cases. Among outpatients not on ART (11 160 [71·8%] of 15 541 outpatients), W4SS sensitivity was 85% (76-91) and specificity was 37% (25-51). C-reactive protein (≥10 mg/L) alone had a similar sensitivity to (83% [79-86]), but higher specificity (67% [60-73]; n=3187) than, W4SS and a sequential strategy (both test positive) of W4SS then C-reactive protein (≥5 mg/L) had a similar sensitivity to (84% [75-90]), but higher specificity than (64% [57-71]; n=3187), W4SS alone; at 10% tuberculosis prevalence, these strategies would require 272 and 244 fewer rapid diagnostic tests per 1000 people living with HIV than W4SS but miss two and one more tuberculosis cases, respectively. INTERPRETATION: C-reactive protein reduces the need for further rapid diagnostic tests without compromising sensitivity and has been included in the updated WHO tuberculosis screening guidelines. However, C-reactive protein data were scarce for outpatients on ART, necessitating future research regarding the utility of C-reactive protein in this group. Chest x-ray can be useful in outpatients on ART when combined with W4SS. The WHO-recommended algorithm has suboptimal sensitivity; Xpert for all offers slight sensitivity gains and would have major resource implications. FUNDING: World Health Organization.

Drug Resistance in HIV-Positive Adults During the Initial Year of Antiretroviral Treatment at Ethiopian Health Centers.

BACKGROUND: The increasing prevalence of antiretroviral drug resistance in Sub-Saharan Africa threatens the success of HIV programs. We have characterized patterns of drug resistance mutations (DRMs) during the initial year of antiretroviral treatment (ART) in HIV-positive adults receiving care at Ethiopian health centers and investigated the impact of tuberculosis on DRM acquisition. METHODS: Participants were identified from a cohort of ART-naïve individuals aged ≥18 years, all of whom had been investigated for active tuberculosis at inclusion. Individuals with viral load (VL) data at 6 and/or 12 months after ART initiation were selected for this study. Genotypic testing was performed on samples with VLs ≥500 copies/mL obtained on these occasions and on pre-ART samples from those with detectable DRMs during ART. Logistic regression analysis was used to investigate the association between DRM acquisition and tuberculosis. RESULTS: Among 621 included individuals (110 [17.5%] with concomitant tuberculosis), 101/621 (16.3%) had a VL ≥500 copies/mL at 6 and/or 12 months. DRMs were detected in 64/98 cases with successful genotyping (65.3%). DRMs were detected in 7/56 (12.5%) pre-ART samples from these individuals. High pre-ART VL and low mid-upper arm circumference were associated with increased risk of DRM acquisition, whereas no such association was found for concomitant tuberculosis. CONCLUSIONS: Among adults receiving health center-based ART in Ethiopia, most patients without virological suppression during the first year of ART had detectable DRM. Acquisition of DRM during this period was the dominant cause of antiretroviral drug resistance in this setting. Tuberculosis did not increase the risk of DRM acquisition.

Detection of Mycobacterium tuberculosis complex DNA in CD34-positive peripheral blood mononuclear cells of asymptomatic tuberculosis contacts: an observational study.

BACKGROUND: Haematopoietic stem cells expressing the CD34 surface marker have been posited as a niche for Mycobacterium tuberculosis complex bacilli during latent tuberculosis infection. Our aim was to determine whether M tuberculosis complex DNA is detectable in CD34-positive peripheral blood mononuclear cells (PBMCs) isolated from asymptomatic adults living in a setting with a high tuberculosis burden. METHODS: We did a cross-sectional study in Ethiopia between Nov 22, 2017, and Jan 10, 2019. Digital PCR (dPCR) was used to determine whether M tuberculosis complex DNA was detectable in PBMCs isolated from 100 mL blood taken from asymptomatic adults with HIV infection or a history of recent household or occupational exposure to an index case of human or bovine tuberculosis. Participants were recruited from HIV clinics, tuberculosis clinics, and cattle farms in and around Addis Ababa. A nested prospective study was done in a subset of HIV-infected individuals to evaluate whether administration of isoniazid preventive therapy was effective in clearing M tuberculosis complex DNA from PBMCs. Follow-up was done between July 20, 2018, and Feb 13, 2019. QuantiFERON-TB Gold assays were also done on all baseline and follow-up samples. FINDINGS: Valid dPCR data (ie, droplet counts >10 000 per well) were available for paired CD34-positive and CD34-negative PBMC fractions from 197 (70%) of 284 participants who contributed data to cross-sectional analyses. M tuberculosis complex DNA was detected in PBMCs of 156 of 197 participants with valid dPCR data (79%, 95% CI 74-85). It was more commonly present in CD34-positive than in CD34-negative fractions (154 [73%] of 197 vs 46 [23%] of 197; p<0·0001). Prevalence of dPCR-detected M tuberculosis complex DNA did not differ between QuantiFERON-negative and QuantiFERON-positive participants (77 [78%] of 99 vs 79 [81%] of 98; p=0·73), but it was higher in HIV-infected than in HIV-uninfected participants (67 [89%] of 75 vs 89 [73%] of 122, p=0·0065). By contrast, the proportion of QuantiFERON-positive participants was lower in HIV-infected than in HIV-uninfected participants (25 [33%] of 75 vs 73 [60%] of 122; p<0·0001). Administration of isoniazid preventive therapy reduced the prevalence of dPCR-detected M tuberculosis complex DNA from 41 (95%) of 43 HIV-infected individuals at baseline to 23 (53%) of 43 after treatment (p<0·0001), but it did not affect the prevalence of QuantiFERON positivity (17 [40%] of 43 at baseline vs 13 [30%] of 43 after treatment; p=0·13). INTERPRETATION: We report a novel molecular microbiological biomarker of latent tuberculosis infection with properties that are distinct from those of a commercial interferon-γ release assay. Our findings implicate the bone marrow as a niche for M tuberculosis in latently infected individuals. Detection of M tuberculosis complex DNA in PBMCs has potential applications in the diagnosis of latent tuberculosis infection, in monitoring response to preventive therapy, and as an outcome measure in clinical trials of interventions to prevent or treat latent tuberculosis infection. FUNDING: UK Medical Research Council.

Distribution of HLA-DQ risk genotypes for celiac disease in Ethiopian children.

Most patients with celiac disease are positive for either HLA-DQA1*05:01-DQB1*02 (DQ2.5) or DQA1*03:01-DQB1*03:02 (DQ8). Remaining few patients are usually DQA1*02:01-DQB1*02 (DQ2.2) carriers. Screenings of populations with high frequencies of these HLA-DQA1-DQB1 haplotypes report a 1% to 3% celiac disease prevalence. The aim was to determine the prevalence of HLA-DQ risk haplotypes for celiac disease in Ethiopian children. Dried blood spots collected from 1193 children from the Oromia regional state of Ethiopia were genotyped for HLA-DQA1 and DQB1 genotyping using an asymmetric polymerase chain reaction (PCR) and a subsequent hybridization of allele-specific probes. As references, 2000 previously HLA-genotyped children randomly selected from the general population in Sweden were included. DQ2.2 was the most common haplotype and found in 15.3% of Ethiopian children, which was higher compared with 6.7% of Swedish references (P < .0001). Opposed to this finding, DQ2.5 and DQ8 occurred in 9.7% and 6.8% of Ethiopian children, which were less frequent compared with 12.8% and 13.1% of Swedish references, respectively (P < .0001). The DQ2.5-trans genotype encoded by DQA1*05-DQB1*03:01 in combination with DQ2.2 occurred in 3.6% of Ethiopian children, which was higher compared with 1.3% of Swedish references (P < .0001). However, when children with moderate high to very high-risk HLA genotypes were grouped together, there was no difference between Ethiopian children and Swedish references (27.4% vs 29.0%) (P = .3504). The frequency of HLA risk haplotypes for celiac disease is very similar in Ethiopian and Swedish children. This finding of importance will be useful in future screening of children for celiac disease in Ethiopia.

Serological evidence for a decline in malaria transmission following major scale-up of control efforts in a setting selected for Plasmodium vivax and Plasmodium falciparum malaria elimination in Babile district, Oromia, Ethiopia.

BACKGROUND: Following successful malaria control during the last decade, Ethiopia instituted a stepwise malaria elimination strategy in selected low-transmission areas. METHODS: Cross-sectional surveys were conducted in Babile district, Oromia, Ethiopia from July to November 2017 to evaluate malaria infection status using microscopy and nested polymerase chain reaction (nPCR) and serological markers of exposure targeting Plasmodium falciparum and Plasmodium vivax apical membrane antigen-1 (AMA-1). RESULTS: Parasite prevalence was 1.2% (14/1135) and 5.1% (58/1143) for P. falciparum and 0.4% (5/1135) and 3.6% (41/1143) for P. vivax by microscopy and nPCR, respectively. Antibody prevalence was associated with current infection by nPCR for both P. falciparum (p<0.001) and P. vivax (p=0.014) and showed an age-dependent increase (p<0.001, for both species). Seroconversion curves indicated a decline in malaria exposure 15 y prior to sampling for P. falciparum and 11.5 y prior to sampling for P. vivax, broadly following malaria incidence data from district health offices, with higher antibody titres in adults than children for both species. CONCLUSIONS: Malaria transmission declined substantially in the region with continuing heterogeneous but measurable local transmission, arguing in favour of continued and tailored control efforts to accelerate the progress towards elimination efforts.

Establishing Health Biotech and Enhancing Local Manufacturing of Pharmaceuticals in Sub-Saharan Africa.

Although many nations in Sub-Saharan Africa (SSA) have recently recorded impressive economic growth, and several countries could attain middle-income status in the next decade, there is no or little concurrent advance in health biotech with little capabilities for manufacturing of medicines, medical supplies, and health commodities in the region. They import majority of medicines, medical supplies, and health commodities used in national programs including immunization, family planning, tuberculosis, HIV, and malaria that drive health outcomes and population-level impact with supports mainly obtained from high-income countries, multilateral agencies, or philanthropies. Nevertheless, there is a growing global debate that countries should graduate from receiving development assistance which goes to the most important health programs like immunization when nations transition from low-income to middle-income economic status. Since sudden withdrawal of all or partial development assistance could send a shock to the health care and dent the trajectory toward achieving the health Sustainable Development Goal, it is imperative to urgently establish or strengthen health biotech and enhance manufacturing of pharmaceuticals in SSA.

Screening for cryptococcal antigenemia using the lateral flow assay in antiretroviral therapy-naïve HIV-positive adults at an Ethiopian hospital clinic.

BACKGROUND: Since treatment for latent cryptococcal infection (CI) before starting antiretroviral therapy (ART) reduces mortality in HIV-infected subjects, screening for cryptococcal antigen (CrAg) in blood is recommended for individuals with CD4 cell counts < 100 cells/µL in regions with high CI prevalence. We assessed CrAg screening using the lateral flow assay in HIV-infected adults eligible for ART in central Ethiopia. RESULTS: HIV-positive patients (age ≥ 18 years, CD4 cell count < 350 cells/µL and/or WHO stage IV, no current or previous ART) were recruited at Adama Regional Hospital, Ethiopia (February 2013 until March 2014). CrAg was determined in plasma by lateral flow assay. Among 129 included participants (median age 35 years, 64 % female) the median CD4 cell count was 210 cells/µL (interquartile range 110-309); 29 (23 %) had CD4 cell count < 100 cells/µL. Two (1.6 %) participants were CrAg-positive (CD4 cell counts 171 vs. 250 cells/µL), one of whom had clinically manifest cryptococcal meningitis at the time of testing. CONCLUSIONS: In contrast to two recent reports from Ethiopia, we found few cases of CI among ART-naïve adults. Our study, which is the first using lateral flow assay for CrAg screening in this country, illustrates the need of larger surveys of CI prevalence among ART-naïve patients before defining recommendations on CI screening.

Genetic differentiation analysis for the identification of complementary parental pools for sorghum hybrid breeding in Ethiopia.

KEY MESSAGE: The potential for exploiting heterosis for sorghum hybrid production in Ethiopia with improved local adaptation and farmers preferences has been investigated and populations suitable for initial hybrid development have been identified. Hybrids in sorghum have demonstrated increased productivity and stability of performance in the developed world. In Ethiopia, the uptake of hybrid sorghum has been limited to date, primarily due to poor adaptation and absence of farmer's preferred traits in existing hybrids. This study aimed to identify complementary parental pools to develop locally adapted hybrids, through an analysis of whole genome variability of 184 locally adapted genotypes and introduced hybrid parents (R and B). Genetic variability was assessed using genetic distance, model-based STRUCTURE analysis and pair-wise comparison of groups. We observed a high degree of genetic similarity between the Ethiopian improved inbred genotypes and a subset of landraces adapted to lowland agro-ecology with the introduced R lines. This coupled with the genetic differentiation from existing B lines, indicated that these locally adapted genotype groups are expected to have similar patterns of heterotic expression as observed between introduced R and B line pools. Additionally, the hybrids derived from these locally adapted genotypes will have the benefit of containing farmers preferred traits. The groups most divergent from introduced B lines were the Ethiopian landraces adapted to highland and intermediate agro-ecologies and a subset of lowland-adapted genotypes, indicating the potential for increased heterotic response of their hybrids. However, these groups were also differentiated from the R lines, and hence are different from the existing complementary heterotic pools. This suggests that although these groups could provide highly divergent parental pools, further research is required to investigate the extent of heterosis and their hybrid performance.

Outcome of tuberculosis treatment in HIV-positive adults diagnosed through active versus passive case-finding.

BACKGROUND: The World Health Organization strongly recommends regular screening for tuberculosis (TB) in HIV-positive individuals. OBJECTIVE: To compare the outcome of anti-tuberculosis treatment (ATT) in HIV-positive adults diagnosed with TB through active case-finding (ACF) or passive case-finding (PCF). DESIGN: Antiretroviral therapy (ART)-naïve adults diagnosed with TB were included from two prospective cohort studies conducted in Ethiopia between September 2010 and March 2013. The PCF cohort was based at out-patient TB clinics, whereas participants in the ACF cohort were actively screened for TB by bacteriological sputum testing (smear microscopy, Xpert MTB/RIF assay, and liquid culture) without pre-selection on the basis of symptoms and signs. Outcomes of ATT were compared between participants in the two cohorts; characteristics at diagnosis and predictors of adverse outcomes were analysed. RESULTS: Among 439 TB/HIV co-infected participants, 307 and 132 belonged to PCF and ACF cohorts, respectively. Compared with the ACF participants, hemoptysis, conjunctival pallor, bedridden status, and low mid upper-arm circumference (MUAC) were significantly more common in participants identified through PCF. Sputum smear-positivity rates among pulmonary TB cases were 44.2% and 21.1% in the PCF and ACF cohorts, respectively (p<0.001). Treatment success was ascertained in 247 (80.5%) of the participants in the PCF cohort and 102 (77.2%) of the participants in the ACF cohorts (p=0.223). Low MUAC (p=0.001) independently predicted mortality in the participants in both cohorts. CONCLUSION: Although patients identified through ACF had less advanced TB disease, ATT outcome was similar to the patients identified through PCF. To achieve a better outcome, case management in ACF strategy should be strengthened through enhanced patient-centred counselling and adherence support.

Detection of lipoarabinomannan in urine for identification of active tuberculosis among HIV-positive adults in Ethiopian health centres.

OBJECTIVE: To assess the diagnostic performance of urine lipoarabinomannan (LAM) detection for TB screening in HIV-positive adults in Ethiopia. METHODS: Testing for LAM was performed using the Determine TB-LAM lateral flow assay on urine samples from participants in a prospective cohort with baseline bacteriological categorisation for active TB in sputum. Characteristics of TB patients with regard to LAM status were determined. Participants were followed for 6 months to evaluate survival, retention in care and incident TB. RESULTS: Positive LAM results were found in 78/757 participants. Among 128 subjects with definite (confirmed by culture and/or Xpert MTB/RIF) TB, 33 were LAM-positive (25.8%); the respective figure for clinically diagnosed cases was 2/20 (10%). Five of the remaining 43 LAM-positive individuals had died during the 6-month follow-up period, whereas 38 remained in care without clinical signs of TB. The overall sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were 25.8%, 92.9%, 42.3% and 86.0%, respectively. Among TB patients, LAM positivity was associated with higher WHO clinical stage, lower body mass index (BMI), CD4 cell and haemoglobin levels, and with increased mortality. A combination algorithm of urine LAM testing and sputum smear microscopy detected 49 (38.2%) of definite TB cases; among those with CD4 count ≤100 cells/mm3 , this proportion was 66.7%. CONCLUSIONS: The performance of urine LAM testing for TB detection was poor in this population. However, this was improved among subjects with CD4 count ≤100 cells/mm3 . In combination with sputum microscopy urine, LAM could be considered for targeted TB screening in this subgroup.

Development of a clinical scoring system for assessment of immunosuppression in patients with tuberculosis and HIV infection without access to CD4 cell testing--results from a cross-sectional study in Ethiopia.

BACKGROUND: Currently, antiretroviral therapy (ART) is recommended for all HIV-positive patients with tuberculosis (TB). The timing of ART during the course of anti-TB treatment is based on CD4 cell counts. Access to CD4 cell testing is not universally available; this constitutes an obstacle for the provision of ART in low-income countries. OBJECTIVE: To determine clinical variables associated with HIV co-infection in TB patients and to identify correlations between clinical variables and CD4 cell strata in HIV/TB co-infected subjects, with the aim of developing a clinical scoring system for the assessment of immunosuppression. DESIGN: Cross-sectional study of adults with TB (with and without HIV co-infection) recruited in Ethiopian outpatient clinics. Clinical variables potentially associated with immunosuppression were recorded using a structured questionnaire, and they were correlated to CD4 cell strata used to determine timing of ART initiation. Variables found to be significant in multivariate analysis were used to construct a scoring system. Results : Among 1,116 participants, the following findings were significantly more frequent in 307 HIV-positive patients compared to 809 HIV-negative subjects: diarrhea, odynophagia, conjunctival pallor, herpes zoster, oral candidiasis, skin rash, and mid-upper arm circumference (MUAC) <20 cm. Among HIV-positive patients, conjunctival pallor, MUAC <20 cm, dyspnea, oral hairy leukoplakia (OHL), oral candidiasis, and gingivitis were significantly associated with <350 CD4 cells/mm(3). A scoring system based on these variables had a negative predictive value of 87% for excluding subjects with CD4 cell counts <100 cells/mm(3); however, the positive predictive value for identifying such individuals was low (47%). CONCLUSIONS: Clinical variables correlate with CD4 cell strata in HIV-positive patients with TB. The clinical scoring system had adequate negative predictive value for excluding severe immunosuppression. Clinical scoring systems could be of use to categorize TB/HIV co-infected patients with regard to the timing of ART initiation in settings with limited access to laboratory facilities.

Intensified tuberculosis case-finding in HIV-positive adults managed at Ethiopian health centers: diagnostic yield of Xpert MTB/RIF compared with smear microscopy and liquid culture.

BACKGROUND: Detection of active tuberculosis (TB) before antiretroviral therapy (ART) initiation is important, but optimal diagnostic methods for use in resource-limited settings are lacking. We assessed the prevalence of TB, evaluated the diagnostic yield of Xpert MTB/RIF in comparison with smear microscopy and culture, and the impact of Xpert results on clinical management in HIV-positive adults eligible for ART at health centers in a region of Ethiopia. METHODS: Participants were prospectively recruited and followed up at 5 health centers. Trained nurses collected data on socio-demographic characteristics, medical history and symptoms, and performed physical examination. Two paired morning sputum samples were obtained, and lymph node aspirates in case of lymphadenopathy. Diagnostic yield of Xpert MTB/RIF in sputum was compared with smear microscopy and liquid culture. RESULTS: TB was diagnosed in 145/812 participants (17.9%), with bacteriological confirmation in 137 (16.9%). Among bacteriologically confirmed cases, 31 were smear-positive (22.6%), 96 were Xpert-positive (70.1%), and 123 were culture-positive (89.8%). Xpert MTB/RIF increased the TB detection rate by 64 cases (47.4%) compared with smear microscopy. The overall sensitivity of Xpert MTB/RIF was 66.4%, and was not significantly lower when testing one compared with two samples. While Xpert MTB/RIF was 46.7% sensitive among patients with CD4 cell counts >200 cells/mm(3), this increased to 82.9% in those with CD4 cell counts ≤100 cells/mm(3). Compared with Xpert-positive TB patients, Xpert-negative cases had less advanced HIV and TB disease characteristics. CONCLUSIONS: Previously undiagnosed TB is common among HIV-positive individuals managed in Ethiopian health centers. Xpert MTB/RIF increased TB case detection, especially in patients with advanced immunosuppression. An algorithm based on the use of a single morning sputum sample for individuals with negative sputum smear microscopy could be considered for intensified case finding in patients eligible for ART. However, technical and cost-effectiveness issues relevant for low-income countries warrant further study.

The impact of indoor residual spraying on malaria incidence in East Shoa Zone, Ethiopia.

BACKGROUND: In Ethiopia, nearly 70% of the population resides in areas prone to malaria infection. The objective of this study is to evaluate the impact of indoor residual spraying (IRS) on the incidence of malaria in East Shoa Zone of Ethiopia. METHODS: Data from the registers of malaria cases at Debrezeit Malaria Control Center in East Shoa Zone of Ethiopia were collected and analyzed. Records of 22 villages with no previous rounds of spraying that were entirely covered with IRS using DDT during the peak malaria transmission season of 2001 and 2002 and other 22 adjacent villages with similar malaria incidence but remained unsprayed were used for the analyses. RESULTS: The incidence of malaria in 2011 and 2002 among the sprayed villages was lower than the respective preceding years for both Plasmodium species (incidence rate ratio 0.60; CI 0.35 to 0.95; p < 0.0001). After the focal spray, there was significant reduction in malaria incidence in the villages sprayed. Spraying was associated with a 62% reduction in malaria incidence. CONCLUSIONS: This study demonstrated that IRS with DDT was effective in reducing malaria incidence in highland epidemic-prone areas in the East Shoa Zone of Ethiopia. A larger scale study should evaluate the effectiveness of DDT in reducing malaria incidence against its environmental impact and alternative strategies for malaria prevention.

Strategic Challenges of PMTCT Program Implementation in Ethiopia.

OBJECTIVES: The objective of this study is to evaluate the achievement of the prevent mother-to-child transmission (PMTCT) program and to describe the strategic challenges of its implementation in the the Oromia region, Ethiopia. METHODS: PMTCT program reports were collected over a period of 12 months from 25 zones of Oromia region. The health facilities in these zones include 28 hospitals and 84 health centers. The reports were analyzed with regard to international and national policies, guidelines, and priorities. Meanwhile, in-depth interviews were conducted with key informants from the government and an nongovernmental organization (NGO). RESULTS: The reports showed that 72 277 (47%) pregnant women who attended antenatal care were tested for HIV. Although 1461 (65%) HIV-positive women walked away without intervention, 1579 (71%) babies born to HIV-positive mothers did not access prophylactic medicine. Interviews with key informants revealed that stakeholders' inertia to coordinated action, disconnect between the regional office and service providers at the grassroots, and an unclear national policy on HIV were major challenges to the program. CONCLUSION: Addressing policy issues and setting clear purposes for all partners need a committed local leadership and program ownership at regional and federal levels.

Barriers to antiretroviral treatment in ethiopia: a qualitative study.

OBJECTIVE: Ethiopia has made meaningful headway in improving access to HIV care and treatment but client attrition remains a daunting challenge. The objective of this study was to describe the major reasons of patient attrition from treatment at hospital and health center levels in Oromia region of Ethiopia. METHODS: This qualitatively designed study was based on semistructured interview with antiretroviral therapy (ART) service providers and focus group discussions with ART clients. The participants were recruited purposively to obtain robust and programmatically important information on in retention HIV care and treatment. FINDINGS: The analysis identified four major themes: antiretroviral (ARV) medications as ''long-term life support,'' free ART as ''expensive,'' regular follow up as ''devotion to a life-long crisis management,'' and expansion of free ART as ''sharing the new hope,'' CONCLUSION: The finding clearly illustrated that while financial constraints and some sociocultural factors impede adherence, disclosure, community support, and decentralization of ART to primary health care units enhance retention in care and treatment.

Outcomes of antiretroviral treatment: a comparison between hospitals and health centers in Ethiopia.

OBJECTIVE: the objective of this study was to compare the outcomes of antiretroviral therapy (ART) between hospital and health center levels in Ethiopia. METHODS: medical records of 1709 ART patients followed for 24 months at 2 hospitals and 3 health centers in the Oromia region of Ethiopia were reviewed. Noted outcomes of ART were currently alive and on treatment; lost to follow-up (LTFU); transferred out (TO); and died (D). RESULTS: of 1709 HIV-positive patients started on ART between September 2006 and February 2007, 1044 (61%) remained alive and were on treatment after 24-month follow-up. In all, 835 (57%) of ART patients at hospitals and 209 (83%) at health centers were retained in the program. Of those who were alive and receiving ART, 79% of patients at health centers and 72% at hospitals were clinically or immunologically improving. In addition, 331 (23%) patients at hospitals were LFTU as compared to 24 (10%) of patients at health centers (relative risk [RR] at 95% confidence interval [CI]: .358 [.231-.555]). While 11% was the mortality rate at hospitals, 5% of patients at health centers also died (RR at 95% CI: .360 [.192-.673]). CONCLUSION: antiretroviral therapy at health centers was associated with more favorable outcomes than at hospitals.

Obsessive-compulsive disorder in UK clozapine-treated schizophrenia and schizoaffective disorder: a cause for clinical concern.

The association between schizophrenia and obsessive-compulsive disorder (OCD) is complex. This study systematically examined a UK cohort of clozapine-treated individuals with schizophrenia/schizoaffective disorder. Fourteen of 59 cases (24%) scored positively on item H of the Mini-International Neuropsychiatric Interview (MINI) for OCD. The mean Yale- Brown Obsessive-Compulsive Scale (Y-BOCS) score in MINI-positive cases was 17.6 (SD+/-6.3). Sixty-four percent scored 16 or more on the Y-BOCS, representing clinically meaningful illness severity. Seven (50%) patients with OCD had previously received the diagnosis by their treating clinicians and were already receiving with selective serotonin re-uptake inhibitors (SSRIs) treatment. OCD cases scored significantly worse than their non-OCD counterparts on the Abnormal Involuntary Movement Scale (P=0.01) and the Simpson Angus Scale (SAS; P=0.01). There was also a non-significant trend toward higher ratings for OCD cases on the Clinical Global Impression-Schizophrenia scale (P=0.06). Comparing the OCD cases taking SSRI (n=7) with those not on SSRI (n=7), significant differences emerged on the SAS (P=0.03). Our results suggest that OCD is common among patients receiving clozapine for schizophrenic disorders and that the comorbidity is associated with greater motoric impairment. The role of medication in this condition remains unclear.