In 2018, WHO issued guidelines for the diagnosis, prevention, and management of HIV-related cryptococcal disease. Two strategies are recommended to reduce the high mortality associated with HIV-related cryptococcal meningitis in low-income and middle-income countries (LMICs): optimised combination therapies for confirmed meningitis cases and cryptococcal antigen screening programmes for ambulatory people living with HIV who access care. WHO's preferred therapy for the treatment of HIV-related cryptococcal meningitis in LMICs is 1 week of amphotericin B plus flucytosine, and the alternative therapy is 2 weeks of fluconazole plus flucytosine. In the ACTA trial, 1-week (short course) amphotericin B plus flucytosine resulted in a 10-week mortality of 24% (95% CI -16 to 32) and 2 weeks of fluconazole and flucytosine resulted in a 10-week mortality of 35% (95% CI -29 to 41). However, with widely used fluconazole monotherapy, mortality because of HIV-related cryptococcal meningitis is approximately 70% in many African LMIC settings. Therefore, the potential to transform the management of HIV-related cryptococcal meningitis in resource-limited settings is substantial. Sustainable access to essential medicines, including flucytosine and amphotericin B, in LMICs is paramount and the focus of this Personal View.

Although HIV/AIDS has been anything but neglected over the last decade, opportunistic infections (OIs) are increasingly overlooked as large-scale donors shift their focus from acute care to prevention and earlier antiretroviral treatment (ART) initiation. Of these OIs, cryptococcal meningitis, a deadly invasive fungal infection, continues to affect hundreds of thousands of HIV patients with advanced disease each year and is responsible for an estimated 15%–20% of all AIDS-related deaths [1, 2]. Yet cryptococcal meningitis ranks amongst the most poorly funded “neglected” diseases in the world, receiving 0.2% of available relevant research and development (R&D) funding, according to Policy Cures’ 2016 Global Funding of Innovation for Neglected Diseases (G-Finder) Report [3, 4]. | Although cryptococcal meningitis is not formally recognised by the World Health Organisation (WHO) or PLOS Neglected Tropical Diseases (PLOS NTDs) as a neglected tropical disease (NTD), it is listed in the G-Finder report, as it disproportionately affects people in low- and middle-income countries (LMICs), with market failure evident for existing essential antifungal medicines and an urgent need for new, effective, and less toxic medicines. PLOS NTDs defines NTDs as a “group of poverty-promoting chronic infectious diseases, which primarily occur in rural areas and poor urban areas of LMICs” [5] and according to the WHO, NTDs are “a proxy for poverty and disadvantage”, have “an important impact on morbidity and mortality”, and are relatively “neglected by research” [6]. Although the greatest burden of cryptococcal disease is undoubtedly related to HIV, we demonstrate herein that cryptococcal meningitis meets both the WHO and PLOS NTDs definitions of an NTD, as the disease (1) disproportionately affects populations in poverty and causes substantial morbidity and mortality, (2) primarily affects populations living in tropical and subtropical areas, (3) is immediately amenable to broad control, elimination, or eradication, and (4) is neglected by research [7].

BACKGROUND: In Iraq, where Islamic State of Iraq and Syria (ISIS) and other groups have contributed to escalating violence in recent years, understanding the epidemiology of intentional firearm-related fatalities is essential for public health action. METHODS: The Iraqi Ministry of Health (MoH; Baghdad, Iraq) compiles surveillance of fatal injuries in eight of Iraq's 18 governorates (Baghdad, Al-Anbar, Basrah, Erbil, Kerbala, Maysan, Ninevah, and Al-Sulaimaniya). Information is collected from coroner's reports and interviews with family members. Analysis was performed on intentional firearm-related injuries, excluding injuries from intentional self-harm or negligent discharges, that occurred during 2010-2013, a subset of all fatal injuries, and compared to previously published explosive-related fatalities. RESULTS: Overall, the dataset included 7,985 firearm-related fatalities. Yearly fatalities were: 2010=1,706; 2011=1,642; 2012=1,662; and 2013=2,975. Among fatalities, 86.0% were men and 13.7% women; 83.4% were adults and 6.2% children <18 years of age. Where age and sex were both known, men aged 20-39 years accounted for 56.3% of fatalities. Three "high-burden" governorates had the highest fatality rate per 100,000 population-Baghdad (12.9), Ninevah (17.0), and Al-Anbar (14.6)-accounting for 85.9% of fatalities recorded in the eight governorates. Most fatalities occurred in the street (56.3%), followed by workplace (12.2%), home (11.3%), and farm/countryside (8.4%). Comparing the ratio of firearm-related fatalities to explosives-related fatalities revealed an overall ratio of 2.8:1. The ratio in Baghdad more than doubled from 2.9 in 2010 to 6.1 in 2013; the highest ratios were seen outside the high-burden governorates. CONCLUSIONS: Firearm-related fatalities remained relatively stable throughout 2010-2012, and almost doubled in 2013, correlating with increased ISIS activity. Three governorates contributed the majority of fatalities and experienced the highest fatality rates; these saw high levels of conflict. Firearm-related fatalities disproportionately affected younger men, who historically are over-represented as victims and perpetrators of violence. More than one-half of fatalities occurred in the street, indicating this as a common environment for conflict involving firearms. Firearms appear to account for more fatalities in Iraq than explosives and largely accounted for escalating violence in Baghdad during the study period. The high ratio observed outside the high-burden governorates is reflective of very low numbers of explosives-related fatalities; thus, violence in these governorates is likely non-conflict-related. These observations provide valuable public health information for targeted intervention to prevent violence. Nerlander MP , Leidman E , Hassan A , Sultan ASS , Hussain SJ , Browne LB , Bilukha OO . Fatalities from firearm-related injuries in selected governorates of Iraq, 2010-2013. Prehosp Disaster Med. 2017;32(5):1-8.

INTRODUCTION: The aim of this study was to describe the most recent trends and epidemiologic patterns of fatal injuries resulting from explosions in Iraq, one of the countries most affected by violence from explosive devices. METHODS: Iraqi Ministry of Health (MoH) routine prospective injury surveillance collects information on all fatal injuries recorded by coroners from physical examinations, police reports, and family members in eight governorates of Iraq: Baghdad, Al-Anbar, Basrah, Erbil, Kerbala, Maysan, Ninevah, and Al-Sulaimaniya. This study analyzed explosive-related fatal injuries that occurred from January 1, 2010 through December 31, 2013. RESULTS: Analysis included 2,803 fatal injuries. The number of fatal injuries declined from 2010 through 2012, followed by an increase in 2013. One-thousand one-hundred and one explosion-related fatalities were documented in 2013, more than twice as many as in 2012 or in 2011. Most fatalities were among men aged 20-39 years. Of all causalities, 194 (6.9%) were among females and 302 (10.8%) were among children aged less than 18 years. The majority of fatalities were caused by improvised explosive devices (IEDs): car bombs (15.3%), suicide bombs (4.0%), and other IEDs (29.6%). The highest number of fatalities occurred in streets and roads. Of all deaths, 95.6% occurred in three governorates: Baghdad, Ninevah, and Al-Anbar. CONCLUSIONS: Explosives continue to result in a high number of fatal injuries in Iraq. Following a period of declining violence from explosives, in 2013, fatalities increased. Most explosion-related injuries resulted from IEDs; males aged 20-39 years were at greatest risk.

BACKGROUND: The QuantiFERON(R)-TB Gold In-Tube test (QFT-GIT) detects Mycobacterium tuberculosis (Mtb) infection by measuring release of interferon gamma (IFN-gamma) when T-cells (in heparinized whole blood) are stimulated with specific Mtb antigens. The amount of IFN-gamma is determined by enzyme-linked immunosorbent assay (ELISA). Automation of the ELISA method may reduce variability. To assess the impact of ELISA automation, we compared QFT-GIT results and variability when ELISAs were performed manually and with automation. METHODS: Blood was collected into two sets of QFT-GIT tubes and processed at the same time. For each set, IFN-gamma was measured in automated and manual ELISAs. Variability in interpretations and IFN-gamma measurements was assessed between automated (A1 vs. A2) and manual (M1 vs. M2) ELISAs. Variability in IFN-gamma measurements was also assessed on separate groups stratified by the mean of the four ELISAs. RESULTS: Subjects (N = 146) had two automated and two manual ELISAs completed. Overall, interpretations were discordant for 16 (11%) subjects. Excluding one subject with indeterminate results, 7 (4.8%) subjects had discordant automated interpretations and 10 (6.9%) subjects had discordant manual interpretations (p = 0.17). Quantitative variability was not uniform; within-subject variability was greater with higher IFN-gamma measurements and with manual ELISAs. For subjects with mean TB Responses +/-0.25 IU/mL of the 0.35 IU/mL cutoff, the within-subject standard deviation for two manual tests was 0.27 (CI95 = 0.22-0.37) IU/mL vs. 0.09 (CI95 = 0.07-0.12) IU/mL for two automated tests. CONCLUSION: QFT-GIT ELISA automation may reduce variability near the test cutoff. Methodological differences should be considered when interpreting and using IFN-gamma release assays (IGRAs).

BACKGROUND: The QuantiFERON(R)-TB Gold In-Tube test (QFT-GIT) is a viable alternative to the tuberculin skin test (TST) for detecting Mycobacterium tuberculosis infection. However, within-subject variability may limit test utility. To assess variability, we compared results from the same subjects when QFT-GIT enzyme-linked immunosorbent assays (ELISAs) were performed in different laboratories. METHODS: Subjects were recruited at two sites and blood was tested in three labs. Two labs used the same type of automated ELISA workstation, 8-point calibration curves, and electronic data transfer. The third lab used a different automated ELISA workstation, 4-point calibration curves, and manual data entry. Variability was assessed by interpretation agreement and comparison of interferon-gamma (IFN-gamma) measurements. Data for subjects with discordant interpretations or discrepancies in TB Response >0.05 IU/mL were verified or corrected, and variability was reassessed using a reconciled dataset. RESULTS: Ninety-seven subjects had results from three labs. Eleven (11.3%) had discordant interpretations and 72 (74.2%) had discrepancies >0.05 IU/mL using unreconciled results. After correction of manual data entry errors for 9 subjects, and exclusion of 6 subjects due to methodological errors, 7 (7.7%) subjects were discordant. Of these, 6 (85.7%) had all TB Responses within 0.25 IU/mL of the manufacturer's recommended cutoff. Non-uniform error of measurement was observed, with greater variation in higher IFN-gamma measurements. Within-subject standard deviation for TB Response was as high as 0.16 IU/mL, and limits of agreement ranged from -0.46 to 0.43 IU/mL for subjects with mean TB Response within 0.25 IU/mL of the cutoff. CONCLUSION: Greater interlaboratory variability was associated with manual data entry and higher IFN-gamma measurements. Manual data entry should be avoided. Because variability in measuring TB Response may affect interpretation, especially near the cutoff, consideration should be given to developing a range of values near the cutoff to be interpreted as "borderline," rather than negative or positive.

OBJECTIVE: Due to high rates of undiagnosed and untreated HIV infection in Africa, we compared HIV counseling and testing (VCT) uptake among household members of patients receiving antiretroviral therapy. METHODS: HIV-infected persons attending an AIDS clinic were randomized to a home-based or clinic-based antiretroviral therapy program including VCT for household members. Clinic arm participants were given free VCT vouchers and encouraged to invite their household members to the clinic for VCT. Home arm participants were visited, and their household members offered VCT using a 3-test rapid finger-stick testing algorithm. VCT uptake and HIV prevalence were compared. FINDINGS: Of 7184 household members, 3974 (55.3%) were female and 4798 (66.8%) were in the home arm. Home arm household members were more likely to receive VCT than those from the clinic arm (55.8% vs. 10.9%, odds ratio: 10.41, 95% confidence interval: 7.89 to 13.73; P < 0.001), although the proportion of HIV-infected household members was higher in the clinic arm (17.3% vs. 7.1%, odds ratio: 2.76, 95% confidence interval: 1.97 to 3.86, P < 0.001). HIV prevalence among all household members tested in the home arm was 56% compared with 27% in the clinic arm. Of 148 spouses of HIV-infected patients, 69 (46.6%) were uninfected. Persons aged 15-24 were less likely to test than other age groups, and in the home arm, women were more likely to test than men. CONCLUSIONS: Home-based VCT for household members of HIV-infected persons was feasible, associated with lower prevalence, higher uptake, and increased identification of HIV-infected persons than clinic-based provision.

BACKGROUND: Identification of new ways to increase access to antiretroviral therapy in Africa is an urgent priority. We assessed whether home-based HIV care was as effective as was facility-based care. METHODS: We undertook a cluster-randomised equivalence trial in Jinja, Uganda. 44 geographical areas in nine strata, defined according to ratio of urban and rural participants and distance from the clinic, were randomised to home-based or facility-based care by drawing sealed cards from a box. The trial was integrated into normal service delivery. All patients with WHO stage IV or late stage III disease or CD4-cell counts fewer than 200 cells per muL who started antiretroviral therapy between Feb 15, 2005, and Dec 19, 2006, were eligible, apart from those living on islands. Follow-up continued until Jan 31, 2009. The primary endpoint was virological failure, defined as RNA more than 500 copies per mL after 6 months of treatment. The margin of equivalence was 9% (equivalence limits 0.69-1.45). Analyses were by intention to treat and adjusted for baseline CD4-cell count and study stratum. This trial is registered at http://isrctn.org, number ISRCTN 17184129. FINDINGS: 859 patients (22 clusters) were randomly assigned to home and 594 (22 clusters) to facility care. During the first year, 93 (11%) receiving home care and 66 (11%) receiving facility care died, 29 (3%) receiving home and 36 (6%) receiving facility care withdrew, and 8 (1%) receiving home and 9 (2%) receiving facility care were lost to follow-up. 117 of 729 (16%) in home care had virological failure versus 80 of 483 (17%) in facility care: rates per 100 person-years were 8.19 (95% CI 6.84-9.82) for home and 8.67 (6.96-10.79) for facility care (rate ratio [RR] 1.04, 0.78-1.40; equivalence shown). Two patients from each group were immediately lost to follow-up. Mortality rates were similar between groups (0.95 [0.71-1.28]). 97 of 857 (11%) patients in home and 75 of 592 (13%) in facility care were admitted at least once (0.91, 0.64-1.28). INTERPRETATION: This home-based HIV-care strategy is as effective as is a clinic-based strategy, and therefore could enable improved and equitable access to HIV treatment, especially in areas with poor infrastructure and access to clinic care. FUNDING: US Centers for Disease Control and Prevention and UK Medical Research Council.