Significant advances have been made in the development of Adverse Outcome Pathways (AOPs) over the last decade, mainly focused on the toxicity mechanisms of chemicals. These AOPs, although relevant to manufactured nanomaterials (MNs), do not currently capture the reported roles of size-associated properties of MNs on toxicity. Moreover, some AOs of relevance to airborne exposures to MNs such as lung inflammation and fibrosis shown in animal studies may not be targeted in routine regulatory decision making. The primary objective of the present study was to establish an approach to advance the development of AOPs of relevance to MNs using existing, publicly available, nanotoxicology literature. A systematic methodology was created for curating, organizing and applying the available literature for identifying key events (KEs). Using a case study approach, the study applied the available literature to build the biological plausibility for 'tissue injury', a KE of regulatory relevance to MNs. The results of the analysis reveal the various endpoints, assays and specific biological markers used for assessing and reporting tissue injury. The study elaborates on the limitations and opportunities of the current nanotoxicology literature and provides recommendations for the future reporting of nanotoxicology results that will expedite not only the development of AOPs for MNs but also aid in application of existing data for decision making.

BACKGROUND: In 2012, Rwanda introduced a Treat All approach for HIV-infected children younger than 5 years. We compared antiretroviral therapy (ART) initiation, outcomes, and retention, before and after this change. METHODS: We conducted a retrospective study of children enrolled into care between June 2009 and December 2011 [Before Treat All (BTA) cohort] and between July 2012 and April 2015 [Treat All (TA) cohort]. SETTING: Medical records of a nationally representative sample were abstracted for all eligible aged 18-60 months from 100 Rwandan public health facilities. RESULTS: We abstracted 374 medical records: 227 in the BTA and 147 in the TA cohorts. Mean (SD) age at enrollment was [3 years (1.1)]. Among BTA, 59% initiated ART within 1 year, vs. 89% in the TA cohort. Median time to ART initiation was 68 days (interquartile range 14-494) for BTA and 9 days (interquartile range 0-28) for TA (P < 0.0001), with 9 (5%) undergoing same-day initiation in BTA compared with 50 (37%) in TA (P < 0.0001). Before ART initiation, 59% in the BTA reported at least one health condition compared with 35% in the TA cohort (P < 0.0001). Although overall loss to follow-up was similar between cohorts (BTA: 13%, TA: 8%, P = 0.18), loss to follow-up before ART was significantly higher in the BTA (8%) compared with the TA cohort (2%) (P = 0.02). CONCLUSIONS: Nearly 90% of Rwandan children started on ART within 1 year of enrollment, most within 1 month, with greater than 90% retention after implementation of TA. TA was also associated with fewer morbidities.

BACKGROUND: The World Health Organization (WHO) 2010 guidelines for intensified tuberculosis (TB) case finding (ICF) among people living with HIV (PLHIV) includes a recommendation that PLHIV receive routine TB screening. Since 2005, the Rwandan Ministry of Health has been using a five-question screening tool. Our study objective was to assess the operating characteristics of the tool designed to identify PLHIV with presumptive TB as measured against a composite reference standard, including bacteriologically confirmed TB. METHODS: In a cross-sectional study, the TB screening tool was routinely administered at enrolment in outpatient HIV care and treatment services at seven public health facilities. From March to September 2011, study enrollees were examined for TB disease irrespective of TB screening outcome. The examination consisted of a chest radiograph (CXR), three sputum smears (SS), sputum culture (SC) and polymerase chain reaction line-probe assay (Hain test). PLHIV were classified as having "laboratory-confirmed TB" with positive results on SS for acid-fast bacilli, SC on Lowenstein-Jensen medium, or a Hain test. RESULTS: Overall, 1,767 patients were enrolled and screened of which; 1,017 (57.6%) were female, median age was 33 (IQR, 27-41), and median CD4+ cell count was 385 (IQR, 229-563) cells/mm3. Of the patients screened, 138 (7.8%) were diagnosed with TB of which; 125 (90.5%) were laboratory-confirmed pulmonary TB. Of 404 (22.9%) patients who screened positive and 1,363 (77.1%) who screened negative, 79 (19.5%) and 59 (4.3%), respectively, were diagnosed with TB. For laboratory-confirmed TB, the tool had a sensitivity of 54.4% (95% CI 45.3-63.3), specificity of 79.5% (95% CI 77.5-81.5), PPV of 16.8% and NPV of 95.8%. CONCLUSION: TB prevalence among PLHIV newly enrolling into HIV care and treatment was 65 times greater than the overall population prevalence. However, the performance of the tool was poorer than the predicted performance of the WHO recommended TB screening questions.

BACKGROUND: In 2005, Rwanda drafted a national TB/HIV policy and began scaling-up collaborative TB/HIV activities. Prior to the scale-up, we evaluated existing TB/HIV practices, possible barriers to policy and programmatic implementation, and patient treatment outcomes. We then used our evaluation data as a baseline for assessing the national scale-up of collaborative TB/HIV activities from 2005 through 2009. METHODS: Our baseline evaluation included a cross-sectional evaluation of 23/161 TB clinics. We conducted structured interviews with patients and clinic staff and then reviewed TB registers and patient records to assess HIV testing practices, provision of HIV care and treatment for people with TB that tested positive for HIV, and patients' TB treatment outcomes. Following our baseline evaluation, we used nationally representative TB/HIV surveillance data to monitor the scale-up of collaborative TB/HIV activities. RESULTS: Of 207 patients interviewed, 76% were offered HIV testing, 99% accepted, and 49% reported positive test results. Of 40 staff interviewed, 68% reported offering HIV testing to >50% of patients. From 2005-2009, scale-up of TB/HIV activities resulted in increased HIV testing of patients with TB (69% to 97%) and for patients with TB disease and HIV infection (TB/HIV) increases in provision of cotrimoxazole (15% to 92%) and antiretroviral therapy (13% to 49%). The risk of death among patients with TB/HIV relative to patients with TB not infected with HIV declined from 2005 (RR=6.1, 95%CI 2.6, 14.0) to 2007 (RR=1.8, 95%CI 1.68, 1.94). CONCLUSIONS: Our baseline evaluation highlighted that staff and patients were receptive to HIV testing. However, expanded access to testing, care, and treatment was needed based on the proportion of patients with TB having unknown HIV status and the high rate of HIV infection and poorer TB treatment outcomes for patients with TB/HIV. Following our evaluation, scale-up of TB/HIV services resulted in almost all patients with TB knowing their HIV status. Routine HIV testing allowed for dramatic increases in the uptake of lifesaving HIV care and treatment coinciding with a decline in the risk of death among patients with TB/HIV.