Limited HIV-associated neuropathologies and lack of immune activation in sub-saharan African individuals with late-stage subtype C HIV-1 infection.

Although previous studies have suggested that subtype B HIV-1 proviruses in the brain are associated with physiological changes and immune activation accompanied with microgliosis and astrogliosis, and indicated that both HIV-1 subtype variation and geographical location might influence the neuropathogenicity of HIV-1 in the brain. The natural course of neuropathogenesis of the most widespread subtype C HIV-1 has not been adequately investigated, especially for people living with HIV (PLWH) in sub-Saharan Africa. To characterize the natural neuropathology of subtype C HIV-1, postmortem frontal lobe and basal ganglia tissues were collected from nine ART-naïve individuals who died of late-stage AIDS with subtype C HIV-1 infection, and eight uninfected deceased individuals as controls. Histological staining was performed on all brain tissues to assess brain pathologies. Immunohistochemistry (IHC) against CD4, p24, Iba-1, GFAP, and CD8 in all brain tissues was conducted to evaluate potential viral production and immune activation. Histological results showed mild perivascular cuffs of lymphocytes only in a minority of the infected individuals. Viral capsid p24 protein was only detected in circulating immune cells of one infected individual, suggesting a lack of productive HIV-1 infection of the brain even at the late-stage of AIDS. Notably, similar levels of Iba-1 or GFAP between HIV + and HIV- brain tissues indicated a lack of microgliosis and astrogliosis, respectively. Similar levels of CD8 + cytotoxic T lymphocyte (CTL) infiltration between HIV + and HIV- brain tissues indicated CTL were not likely to be involved within subtype C HIV-1 infected participants of this cohort. Results from this subtype C HIV-1 study suggest that there is a lack of productive infection and limited neuropathogenesis by subtype C HIV-1 even at late-stage disease, which is in contrast to what was reported for subtype B HIV-1 by other investigators.

Malnutrition enteropathy in Zambian and Zimbabwean children with severe acute malnutrition: A multi-arm randomized phase II trial.

Malnutrition underlies almost half of all child deaths globally. Severe Acute Malnutrition (SAM) carries unacceptable mortality, particularly if accompanied by infection or medical complications, including enteropathy. We evaluated four interventions for malnutrition enteropathy in a multi-centre phase II multi-arm trial in Zambia and Zimbabwe and completed in 2021. The purpose of this trial was to identify therapies which could be taken forward into phase III trials. Children of either sex were eligible for inclusion if aged 6-59 months and hospitalised with SAM (using WHO definitions: WLZ <-3, and/or MUAC <11.5 cm, and/or bilateral pedal oedema), with written, informed consent from the primary caregiver. We randomised 125 children hospitalised with complicated SAM to 14 days treatment with (i) bovine colostrum (n = 25), (ii) N-acetyl glucosamine (n = 24), (iii) subcutaneous teduglutide (n = 26), (iv) budesonide (n = 25) or (v) standard care only (n = 25). The primary endpoint was a composite of faecal biomarkers (myeloperoxidase, neopterin, α1-antitrypsin). Laboratory assessments, but not treatments, were blinded. Per-protocol analysis used ANCOVA, adjusted for baseline biomarker value, sex, oedema, HIV status, diarrhoea, weight-for-length Z-score, and study site, with pre-specified significance of P < 0.10. Of 143 children screened, 125 were randomised. Teduglutide reduced the primary endpoint of biomarkers of mucosal damage (effect size -0.89 (90% CI: -1.69,-0.10) P = 0.07), while colostrum (-0.58 (-1.4, 0.23) P = 0.24), N-acetyl glucosamine (-0.20 (-1.01, 0.60) P = 0.67), and budesonide (-0.50 (-1.33, 0.33) P = 0.32) had no significant effect. All interventions proved safe. This work suggests that treatment of enteropathy may be beneficial in children with complicated malnutrition. The trial was registered at ClinicalTrials.gov with the identifier NCT03716115.

Single-cell profiling of environmental enteropathy reveals signatures of epithelial remodeling and immune activation.

Environmental enteropathy (EE) is a subclinical condition of the small intestine that is highly prevalent in low- and middle-income countries. It is thought to be a key contributing factor to childhood malnutrition, growth stunting, and diminished oral vaccine responses. Although EE has been shown to be the by-product of a recurrent enteric infection, its full pathophysiology remains unclear. Here, we mapped the cellular and molecular correlates of EE by performing high-throughput, single-cell RNA-sequencing on 33 small intestinal biopsies from 11 adults with EE in Lusaka, Zambia (eight HIV-negative and three HIV-positive), six adults without EE in Boston, United States, and two adults in Durban, South Africa, which we complemented with published data from three additional individuals from the same clinical site. We analyzed previously defined bulk-transcriptomic signatures of reduced villus height and decreased microbial translocation in EE and showed that these signatures may be driven by an increased abundance of surface mucosal cells-a gastric-like subset previously implicated in epithelial repair in the gastrointestinal tract. In addition, we determined cell subsets whose fractional abundances associate with EE severity, small intestinal region, and HIV infection. Furthermore, by comparing duodenal EE samples with those from three control cohorts, we identified dysregulated WNT and MAPK signaling in the EE epithelium and increased proinflammatory cytokine gene expression in a T cell subset highly expressing a transcriptional signature of tissue-resident memory cells in the EE cohort. Together, our work elucidates epithelial and immune correlates of EE and nominates cellular and molecular targets for intervention.

Epithelial Abnormalities in the Small Intestine of Zambian Children With Stunting.

Background: Environmental enteropathy (EE) contributes to impaired linear growth (stunting), in millions of children worldwide. We have previously reported that confocal laser endomicroscopy (CLE) shows fluorescein leaking from blood to gut lumen in vivo in adults and children with EE. We set out to identify epithelial lesions which might explain this phenomenon in Zambian children with stunting non-responsive to nutritional support. Methods: We performed confocal laser endomicroscopy (CLE) in 75 children and collected intestinal biopsies for histology in 91 children. CLE videos were evaluated, employing the Watson score to determine severity of leakiness. Morphometry was carried out on well-orientated mucosa and 3 biopsies were examined by electron microscopy. Results: Confocal laser endomicroscopy demonstrated substantial leakage from circulation to gut lumen in 73 (97%) children. Histology consistently showed characteristic changes of EE: villus blunting, lamina propria and epithelial inflammation, and depletion of secretory cells (Paneth cells and goblet cells). Epithelial abnormalities included marked variability in epithelial height, disorganised and shortened microvilli, dilated intercellular spaces, pseudostratification, formation of synechiae between epithelium on adjacent villi, crypt destruction, and abundant destructive lesions which may correspond to the microerosions identified on CLE. Conclusion: Epithelial abnormalities were almost universal in Zambian children with non-responsive stunting, including epithelial microerosions, cell-cell adhesion anomalies, and defects in secretory cells which may all contribute to impairment of mucosal barrier function and microbial translocation.

Histopathological Evaluation of Deceased Persons in Lusaka, Zambia With or Without Coronavirus Disease 2019 (COVID-19) Infection: Results Obtained From Minimally Invasive Tissue Sampling.

BACKGROUND: Although much has been learned about the pathophysiology of coronavirus disease 2019 (COVID-19) infections, pathology data from patients who have died of COVID-19 in low- and middle-income country settings remain sparse. We integrated minimally invasive tissue sampling (MITS) into an ongoing postmortem surveillance study of COVID-19 in deceased individuals of all ages in Lusaka, Zambia. METHODS: We enrolled deceased subjects from the University Teaching Hospital Morgue in Lusaka, Zambia within 48 hours of death. We collected clinical and demographic information, a nasopharyngeal swab, and core tissue biopsies from the lung, liver, and kidneys for pathologic analysis. Individuals were considered eligible for MITS if they had a respiratory syndrome prior to death or a COVID-19+ polymerase chain reaction (PCR) nasopharyngeal swab specimen. Samples were retested using quantitative reverse transcriptase PCR. RESULTS: From June to September 2020 we performed MITS on 29 deceased individuals. PCR results were available for 28/29 (96.5%) cases. Three had a COVID-19+ diagnosis antemortem, and 5 more were identified postmortem using the recommended cycle threshold cut-point <40. When expanding the PCR threshold to 40 ≤ cycle threshold (Ct) ≤ 45, we identified 1 additional case. Most cases were male and occurred in the community The median age at death was 47 years (range 40-64). Human immunodeficiency virus (HIV)/AIDS, tuberculosis, and diabetes were more common among the COVID-19+ cases. Diffuse alveolar damage and interstitial pneumonitis were common among COVID-19+ cases; nonspecific findings of hepatic steatosis and acute kidney injury were also prevalent in the COVID-19+ group. Vascular thrombi were rarely detected. CONCLUSIONS: Lung abnormalities typical of viral pneumonias were common among deceased COVID-19+ individuals, as were nonspecific findings in the liver and kidneys. Pulmonary vascular thrombi were rarely detected, which could be a limitation of the MITS technique. Nonetheless, MITS offers a valuable alternative to open autopsy for understanding pathological changes due to COVID-19.

Spectrum of common Hodgkin lymphoma and non-Hodgkin lymphomas subtypes in Zambia: a 3-year records review.

BACKGROUND: Lymphomas usually present with different occurrence patterns across different geographical locations, but their epidemiology in Zambia is yet to be extensively explored. OBJECTIVES: To study the spectrum of lymphoma subtypes prevalent within the Zambian population. METHODS: Histopathological records with suspected lymphoma at the University Teaching Hospital (UTH) in Lusaka from the year 2014 to 2016, diagnosed based on the 2008 World Health Organization (WHO) criteria were reviewed. The analysis was done in terms of type, sex, age, and site of biopsy; and Fisher's exact test was used for significance testing. RESULTS: During the study period (2014-2016), there were more B cell neoplasms {222 (92.5%)} than T cell neoplasms {18 (7.5%)}. Non-Hodgkin's lymphoma (NHL) was seen in 191 (79.6%) whereas classic Hodgkin's lymphoma (CHL) was seen in 39 (16.3%). Burkitt's lymphoma (BL) and diffuse large B cell lymphoma (DLBCL) showed equal proportions {17.5% of all lymphoma cases (42/240) each}, as the most prevalent subtypes of NHL whereas marginal zone B cell lymphoma was the rarest subtype with 1.4% (4/240). For CHL, mixed cellularity and lymphocyte rich subtypes (4.6% of all lymphoma cases) were the most common subtypes. There was a statistically significant difference in the occurrences of lymphoma subtypes across different age categories (p = 0.002). CONCLUSION: Zambia has a diverse lymphoma subtypes population, affecting a relatively young population. The data from this study will serve as a baseline for improved health care provision and more robust future studies.

Addressing the shortage of pathologists in Africa: Creation of a MMed Programme in Pathology in Zambia.

BACKGROUND: With approximately one pathologist for one million people compared to ratios of approximately 1 to 25 000 in the United States and United Kingdom, there is a severe shortage of pathologists in much of Africa. The situation is particularly severe in Zambia, where, in 2009, the ratio was 1 to 1.4 million. OBJECTIVE: To address this, a postgraduate Master of Medicine (MMed) training programme was launched in Lusaka in 2011. METHODS: The process and most significant challenges and lessons learned were documented, as they may be of value to other countries facing similar challenges. RESULTS: Since 2011, four Zambian pathologists have graduated, doubling the number of indigenous pathologists in the country. Currently 10 students are in training. The most significant problem was issues arising from the split responsibilities of the Ministries of Health and of Education and the most important lesson learned was the crucial need for broad local ownership and commitment. CONCLUSION: Successfully addressing the shortage of local pathologists by creating country-specific, postgraduate MMed training programmes, even in situations of restricted resources, is feasible. However, having access to and support from the shared resources, expertise and knowledge of a regional College of Pathologists would be a major advantage.

Establishing the College of Pathologists of East, Central and Southern Africa - The Regional East Central and Southern Africa College of Pathology.

ISSUES: The scarcity of pathologists in sub-Saharan Africa is a well established fact that is attributable to few training programmes in the region; this is further compounded by the lack of harmonised curricula, training and exams within and without member countries. DESCRIPTION OF THE INTERVENTION: Through the Association of Pathologists of East, Central and Southern Africa, the College of Pathologists of East, Central and Southern Africa (COPECSA) was formed with the clear-cut goal of establishing a regional and internationally recognised college to support and inform good quality medical and laboratory practice by promoting leadership, mentorship and excellence in the safe practice of pathology through training, exams, accreditation, advocacy and professional development for health. LESSONS LEARNT: Since its inception in 2010, COPECSA has conferred fellowships to 120 practising pathologists in the East, Central and Southern Africa in partnership with international organisations; the college has been awarded five competitive grants and conducted several quality improvement workshops. RECOMMENDATIONS: This paper describes the journey that COPECSA has made towards standardising the practice and training of pathology in the East Central and Southern Africa region.

Dermatitis herpetiformis in an African woman.

Dermatitis herpetiformis (DH) is an autoimmune blistering disease of the skin. It is a result of hypersensitivity to dietary gluten. Diagnosis of DH can be challenging in a low prevalence, resource-limited population. We present the case of an African woman who presented with clinical features of DH.

Evaluation of in-house loop-mediated isothermal amplification for tuberculosis diagnosis compared with Xpert MTB/RIF.

INTRODUCTION: To evaluate the diagnostic performances of an in-house loop-mediated isothermal amplification (LAMP) kit and the Xpert MTB/RIF test for the diagnosis of pulmonary tuberculosis in a resource-limited setting, this study was performed at the University Teaching Hospital, Ministry of Health, the Republic of Zambia. METHODOLOGY: Two hundred sputum specimens obtained from new tuberculosis (TB) suspects were used for the evaluation of the diagnostic performance of an in-house LAMP kit in comparison with the Xpert MTB/RIF kit. RESULTS: The sensitivity of in-house LAMP and Xpert MTB/RIF was 96.9% and 95.4% in smear-positive samples, 96.8% and 100% in smear-positive/culture-positive samples, and 39.1% and 73.9% in smear-negative/culture-positive samples, respectively. The specificity of in-house LAMP and MTB/RIF kits with culture was 96.5% and 94.5%, respectively. This indicated the superiority of the Xpert MTB/RIF kit; however, mechanical errors during sample processing and the insufficient quantity of samples by Xpert MTB/RIF kit occurred at 2.0% and 19.7%, respectively, comparing to the 100% accessibility of in-house LAMP. CONCLUSIONS: Considering the results obtained in this study together with the easy setup with much simpler equipment, such as an aluminum heat block or water bath, in in-house LAMP compared with real-time polymerase chain reaction equipment in Xpert MTB/RIF kit, the applicability of in-house LAMP for the screening of tuberculosis directly from sputum in resource-limited setting seemed to be high.

Stage of disease in hepatitis B virus infection in Zambian adults is associated with large cell change but not well defined using classic biomarkers.

Background: Hepatocellular malignancy in young adults is a prominent feature of hepatitis B virus (HBV) infection in southern Africa. Here we report a cross-sectional study of liver pathology correlated with biomarkers in adults with HBV infection in Zambia. Methods: We analysed liver biopsies from Zambian patients with persistent HBV infection. Results: We analysed 104 patients with HBV infection and evidence of liver disease. We obtained liver biopsies from 53 adults; of these, 12 (23%) were hepatitis B e antigen seropositive. The genotype was evenly distributed between A and E. One biopsy showed malignancy. Stage was 3 or more in 11 of 52 (21%) biopsies free of malignancy and lobular inflammation was found in 50 (94%). Neither alanine aminotransferase (ALT) nor the γ-glutamyl transferase:platelet ratio (GPR) were correlated with the stage of disease but were correlated with total Ishak score (ρ=0.47, p=0.0004 and ρ=0.33, p=0.02, respectively). Large cell change was observed in 10 of 11 biopsies with fibrosis stage 3 or more and 16 of 41 with early disease (p=0.005). Serum α-fetoprotein was elevated, although still within the normal range, in patients with large cell change (median 3.6 [interquartile range {IQR} 1.6-5.1]) compared with those without (1.7 [IQR 1.0-2.8]; p=0.03). Neither ALT nor GPR predicted large cell change. Conclusions: Large cell change was common in young HBV-infected adults in Zambia. Only serum α-fetoprotein was identified as a biomarker of this phenotype.

Kaposi's Sarcoma-Associated Herpesvirus Infection of Neurons in HIV-Positive Patients.

Background: Kaposi's sarcoma-associated herpesvirus (KSHV) is the causative agent of Kaposi sarcoma (KS), one of the leading cancers in human immunodeficiency virus (HIV)-infected patients in Zambia. KSHV was detected in the human central nervous system (CNS) by polymerase chain reaction (PCR) analysis, but tissue location and cell tropism for KSHV infection has not been established. Given the neurotropism exhibited by other herpesviruses and the frequent coinfection of HIV-positive individuals by KSHV, we sought to determine whether the central nervous system (CNS) can be infected by KSHV in HIV-positive Zambian individuals. Methods: Postmortem brain tissue specimens were collected from individuals coinfected with KSHV and HIV. PCR and Southern blots were performed on DNA extracted from the brain tissue specimens to verify KSHV infection. Immunohistochemical analysis and immunofluorescent microscopy were used to localize and identify KSHV-infected cells. Tropism was further established by in vitro infection of primary human neurons with rKSHV.219. Results: KSHV DNA was detected in the CNS from 4 of 11 HIV-positive individuals. Immunohistochemical analysis and immunofluorescent microscopy demonstrated that KSHV infected neurons and oligodendrocytes in parenchymal brain tissues. KSHV infection of neurons was confirmed by in vitro infection of primary human neurons with rKSHV.219. Conclusion: Our study showed that KSHV infects human CNS-resident cells, primarily neurons, in HIV-positive Zambian individuals.

Burden of respiratory tract infections at post mortem in Zambian children.

BACKGROUND: Autopsy studies are the gold standard for determining cause-of-death and can inform on improved diagnostic strategies and algorithms to improve patient care. We conducted a cross-sectional observational autopsy study to describe the burden of respiratory tract infections in inpatient children who died at the University Teaching Hospital in Lusaka, Zambia. METHODS: Gross pathology was recorded and lung tissue was analysed by histopathology and molecular diagnostics. Recruitment bias was estimated by comparing recruited and non-recruited cases. RESULTS: Of 121 children autopsied, 64 % were male, median age was 19 months (IQR, 12-45 months). HIV status was available for 97 children, of whom 34 % were HIV infected. Lung pathology was observed in 92 % of cases. Bacterial bronchopneumonia was the most common pathology (50 %) undiagnosed ante-mortem in 69 % of cases. Other pathologies included interstitial pneumonitis (17 %), tuberculosis (TB; 8 %), cytomegalovirus pneumonia (7 %) and pneumocystis Jirovecii pneumonia (5 %). Comorbidity between lung pathology and other communicable and non-communicable diseases was observed in 80 % of cases. Lung tissue from 70 % of TB cases was positive for Mycobacterium tuberculosis by molecular diagnostic tests. A total of 80 % of TB cases were comorbid with malnutrition and only 10 % of TB cases were on anti-TB therapy when they died. CONCLUSIONS: More proactive testing for bacterial pneumonia and TB in paediatric inpatient settings is needed.

Proceedings from the NIMH symposium on "NeuroAIDS in Africa: neurological and neuropsychiatric complications of HIV".

Despite major advances in HIV-1 treatment, the prevalence of HIV-associated neurocognitive disorders (HAND) remains a problem, particularly as individuals on suppressive treatment continue to live longer. To facilitate discussion on emerging and future directions in HAND research, a meeting was held in Durban, South Africa in March 2015 as part of the Society of Neuroscientists of Africa (SONA) conference. The objective of the meeting was to assess the impact of HIV subtype diversity on HAND and immunological dysfunction. The meeting brought together international leaders in the area of neurological complications of HIV-1 infection with special focus on the African population. Research presentations indicated that HAND was highly prevalent and that inflammatory cytokines and immune-activation played important roles in progression of neurocognitive impairment. Furthermore, children on antiretroviral therapy were also at risk for developing neurocognitive impairment. With respect to the effect of HIV-1 subtype diversity, analyses of HIV-1 clade C infection among South Africans revealed that clade C infection induced cognitive impairment that was independent of the substitution in HIV-1 Trans-Activator of Transcription (Tat; C31S). At the cellular level, a Zambian study showed that clade C infection resulted in reduced brain cell death compared with clade B infection suggesting clade specific variations in mediating brain cell injury. Furthermore, ex vivo Tat protein from clade CRF02_AG, prevalent in West/ Central Africa, exhibited reduced disruption of brain endothelium compared with clade B Tat protein. Discussions shed light on future research directions aimed at understanding biomarkers and disease mechanisms critical for HAND.

Esophageal squamous cell cancer in a highly endemic region.

AIM: To identify risk factors associated with esophageal cancer in Zambia and association between dietary intake and urinary 8-iso prostaglandin F2α (8-isoPGF2α). METHODS: We conducted a prospective, case control study at the University Teaching Hospital. Subjects included both individuals admitted to the hospital and those presenting for an outpatient upper endoscopy. Esophageal cancer cases were compared to age and sex-matched controls. Cases were defined as patients with biopsy proven esophageal cancer; controls were defined as subjects without endoscopic evidence of esophageal cancer. Clinical and dietary data were collected using a standard questionnaire, developed a priori. Blood was collected for human immunodeficiency virus (HIV) serology. Urine was collected, and 8-isoPGF2α was measured primarily by enzyme-linked immunosorbent assay and expressed as a ratio to creatinine. RESULTS: Forty five controls (mean age 54.2 ± 15.3, 31 male) and 27 cases (mean age 54.6 ± 16.4, 17 males) were studied. Body mass index was lower in cases (median 16.8) than controls (median 23.2), P = 0.01. Histopathologically, 25/27 (93%) were squamous cell carcinoma and 2/27 (7%) adenocarcinoma. More cases smoked cigarettes (OR = 11.24, 95%CI: 1.37-92.4, P = 0.02) but alcohol consumption and HIV seropositivity did not differ significantly (P = 0.14 for both). Fruit, vegetables and fish consumption did not differ significantly between groups (P = 0.11, 0.12, and 0.10, respectively). Mean isoprostane level was significantly higher in cases (0.03 ng/mg creatinine) than controls (0.01 ng/mg creatinine) (OR = 2.35, 95%CI: 1.19-4.65, P = 0.014). CONCLUSION: Smoking and isoprostane levels were significantly associated with esophageal cancer in Zambians, but diet, HIV status, and alcohol consumption were not.

A 27-Year-Old Severely Immunosuppressed Female with Misleading Clinical Features of Disseminated Cutaneous Sporotrichosis.

Sporotrichosis is a subacute or chronic granulomatous mycosis caused by fungus of the Sporothrix schenckii complex. It is considered to be a rare condition in most parts of the world. It mostly causes cutaneous infection but can also cause multisystemic disease. Unlike most deep cutaneous mycoses which have a primary pulmonary focus, it is usually caused by direct inoculation of the fungus into the skin causing a classical linear, lymphocutaneous nodular eruption. However, atypical presentations of the condition can occur especially in immunosuppressed individuals. We report the case of a severely immunosuppressed female who presented with disseminated cutaneous sporotrichosis which was initially diagnosed and treated as disseminated cutaneous Kaposi's sarcoma.

Implementation and Operational Research: Age Distribution and Determinants of Invasive Cervical Cancer in a "Screen-and-Treat" Program Integrated With HIV/AIDS Care in Zambia.

BACKGROUND: Cervical cancer screening efforts linked to HIV/AIDS care programs are being expanded across sub-Saharan Africa. Evidence on the age distribution and determinants of invasive cervical cancer (ICC) cases detected in such programs is limited. METHODS: We analyzed program operations data from the Cervical Cancer Prevention Program in Zambia, the largest public sector programs of its kind in sub-Saharan Africa. We examined age distribution patterns by HIV serostatus of histologically confirmed ICC cases and used multivariable logistic regression to evaluate independent risk factors for ICC among younger (≤35 years) and older (>35 years) women. RESULTS: Between January 2006 and April 2010, of 48,626 women undergoing screening, 571 (1.2%) were diagnosed with ICC, including 262 (46%) HIV seropositive (median age: 35 years), 131 (23%) HIV seronegative (median age: 40 years), and 178 (31%) of unknown HIV serostatus (median age: 38 years). Among younger (≤35 years) women, being HIV seropositive was associated with a 4-fold higher risk of ICC [adjusted odds ratio = 4.1 (95% confidence interval: 2.8, 5.9)] than being HIV seronegative. The risk of ICC increased with increasing age among HIV-seronegative women and women with unknown HIV serostatus, but among HIV-seropositive women, the risk peaked around age 35 and nonsignificantly declined with increasing ages. Other factors related to ICC included being married (vs. being unmarried/widowed) in both younger and older women, and with having 2+ (vs. ≤1) lifetime sexual partners among younger women. CONCLUSIONS: HIV infection seems to have increased the risk of cervical cancer among younger women in Zambia, pointing to the urgent need for expanding targeted screening interventions.

Laryngeal involvement causing dysphonia in a 29 year old nursing mother with lepromatous leprosy.

Leprosy is a granulomatous disease that mainly affects the skin and peripheral nerves. It is caused by infection with mycobacterium leprae or mycobacterium lepromatosus. In most instances, diagnosis of leprosy can easily be made based on the clinical signs and symptoms. However, when patients present with atypical features, clinical diagnosis can be a challenge. We report a case of a nursing mother with lepromatous leprosy who presented with dysphonia and skin lesions initially thought to be a deep cutaneous mycosis.

Population-level scale-up of cervical cancer prevention services in a low-resource setting: development, implementation, and evaluation of the cervical cancer prevention program in Zambia.

BACKGROUND: Very few efforts have been undertaken to scale-up low-cost approaches to cervical cancer prevention in low-resource countries. METHODS: In a public sector cervical cancer prevention program in Zambia, nurses provided visual-inspection with acetic acid (VIA) and cryotherapy in clinics co-housed with HIV/AIDS programs, and referred women with complex lesions for histopathologic evaluation. Low-cost technological adaptations were deployed for improving VIA detection, facilitating expert physician opinion, and ensuring quality assurance. Key process and outcome indicators were derived by analyzing electronic medical records to evaluate program expansion efforts. FINDINGS: Between 2006-2013, screening services were expanded from 2 to 12 clinics in Lusaka, the most-populous province in Zambia, through which 102,942 women were screened. The majority (71.7%) were in the target age-range of 25-49 years; 28% were HIV-positive. Out of 101,867 with evaluable data, 20,419 (20%) were VIA positive, of whom 11,508 (56.4%) were treated with cryotherapy, and 8,911 (43.6%) were referred for histopathologic evaluation. Most women (87%, 86,301 of 98,961 evaluable) received same-day services (including 5% undergoing same-visit cryotherapy and 82% screening VIA-negative). The proportion of women with cervical intraepithelial neoplasia grade 2 and worse (CIN2+) among those referred for histopathologic evaluation was 44.1% (1,735/3,938 with histopathology results). Detection rates for CIN2+ and invasive cervical cancer were 17 and 7 per 1,000 women screened, respectively. Women with HIV were more likely to screen positive, to be referred for histopathologic evaluation, and to have cervical precancer and cancer than HIV-negative women. INTERPRETATION: We creatively disrupted the 'no screening' status quo prevailing in Zambia and addressed the heavy burden of cervical disease among previously unscreened women by establishing and scaling-up public-sector screening and treatment services at a population level. Key determinants for successful expansion included leveraging HIV/AIDS program investments, and context-specific information technology applications for quality assurance and filling human resource gaps.

Burden of tuberculosis at post mortem in inpatients at a tertiary referral centre in sub-Saharan Africa: a prospective descriptive autopsy study.

BACKGROUND: Patients with subclinical tuberculosis, smear-negative tuberculosis, extrapulmonary tuberculosis, multidrug-resistant tuberculosis, and asymptomatic tuberculosis are difficult to diagnose and may be missed at all points of health care. We did an autopsy study to ascertain the burden of tuberculosis at post mortem in medical inpatients at a tertiary care hospital in Lusaka, Zambia. METHODS: Between April 5, 2012, and May 22, 2013, we did whole-body autopsies on inpatients aged at least 16 years who died in the adult inpatient wards at University Teaching Hospital, Lusaka, Zambia. We did gross pathological and histopathological analysis and processed lung tissues from patients with tuberculosis through the GeneXpert MTB/RIF assay to identify patients with multidrug-resistant tuberculosis. The primary outcome measure was specific disease or diseases stratified by HIV status. Secondary outcomes were missed tuberculosis, multidrug-resistant tuberculosis, and comorbidities with tuberculosis. Data were analysed using Pearson χ(2), the Mann-Whitney U test, and binary logistic regression. FINDINGS: The median age of the 125 included patients was 35 years (IQR 29-43), 80 (64%) were men, and 101 (81%) were HIV positive. 78 (62%) patients had tuberculosis, of whom 66 (85%) were infected with HIV. 35 (45%) of these 78 patients had extrapulmonary tuberculosis. The risk of extrapulmonary tuberculosis was higher among HIV-infected patients than among uninfected patients (adjusted odds ratio 5·14, 95% CI 1·04-24·5; p=0·045). 20 (26%) of 78 patients with tuberculosis were not diagnosed during their life and 13 (17%) had undiagnosed multidrug-resistant tuberculosis. Common comorbidities with tuberculosis were pyogenic pneumonia in 26 patients (33%) and anaemia in 15 (19%). INTERPRETATION: Increased clinical awareness and more proactive screening for tuberculosis and multidrug-resistant tuberculosis in inpatient settings is needed. Further autopsy studies are needed to ascertain the generalisability of the findings. FUNDING: UBS Optimus Foundation, EuropeAID, and European Developing Countries Clinical Trials Partnership (EDCTP).