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Summary Background Pathology and laboratory medicine diagnostics and diagnostic imaging are crucial to achieving universal health coverage. We analysed Service Provision Assessments (SPAs) from ten low-income and middle-income countries to benchmark diagnostic availability. Methods Diagnostic availabilities were determined for Bangladesh, Haiti, Malawi, Namibia, Nepal, Kenya, Rwanda, Senegal, Tanzania, and Uganda, with multiple timepoints for Haiti, Kenya, Senegal, and Tanzania. A smaller set of diagnostics were included in the analysis for primary care facilities compared with those expected at hospitals, with 16 evaluated in total. Surveys spanned 2004–18, including 8512 surveyed facilities. Country-specific facility types were mapped to basic primary care, advanced primary care, or hospital tiers. We calculated percentages of facilities offering each diagnostic, accounting for facility weights, stratifying by tier, and for some analyses, region. The tier-level estimate of diagnostic availability was defined as the median of all diagnostic-specific availabilities at each tier, and country-level estimates were the median of all diagnostic-specific availabilities of each of the tiers. Associations of country-level diagnostic availability with country income as well as (within-country) region-level availability with region-specific population densities were determined by multivariable linear regression, controlling for appropriate covariates including tier. Findings Median availability of diagnostics was 19·1% in basic primary care facilities, 49·2% in advanced primary care facilities, and 68·4% in hospitals. Availability varied considerably between diagnostics, ranging from 1·2% (ultrasound) to 76·7% (malaria) in primary care (basic and advanced) and from 6·1% (CT scan) to 91·6% (malaria) in hospitals. Availability also varied between countries, from 14·9% (Bangladesh) to 89·6% (Namibia). Availability correlated positively with log(income) at both primary care tiers but not the hospital tier, and positively with region-specific population density at the basic primary care tier only. Interpretation Major gaps in diagnostic availability exist in many low-income and middle-income countries, particularly in primary care facilities. These results can serve as a benchmark to gauge progress towards implementing guidelines such as the WHO Essential Diagnostics List and Priority Medical Devices initiatives. Funding Bill & Melinda Gates Foundation.

Maintenance of cellular proteostasis is vital for post-mitotic cells like neurons to sustain normal physiological function and homeostasis, defects in which are established hallmarks of several age-related conditions like AD, PD, HD, and ALS. The Spatio-temporal accumulation of aggregated proteins in the form of inclusion bodies/plaques is one of the major characteristics of many neurodegenerative diseases, including Huntington’s disease (HD). Toxic accumulation of HUNTINGTIN (HTT) aggregates in neurons bring about the aberrant phenotypes of HD, including severe motor dysfunction, dementia, and cognitive impairment at the organismal level, in an age-dependent manner. In several cellular and animal models, aggrephagy induction has been shown to clear aggregate-prone proteins like HTT and ameliorate disease pathology by conferring neuroprotection. In this study, we used the mouse model of HD, R6/2, to understand the pathogenicity of mHTT aggregates, primarily focusing on autophagy dysfunction. We report that basal autophagy is not altered in R6/2 mice, whilst being functional at a steady-state level in neurons. Moreover, we tested the efficacy of a known autophagy modulator, Nilotinib (Tasigna™), presently in clinical trials for PD, and HD, in curbing mHTT aggregate growth and their potential clearance, which was ineffective in both inducing autophagy and rescuing the pathological phenotypes in R6/2 mice.

SYNGAP1, a Synaptic Ras-GTPase activating protein, regulates synapse maturation during a critical developmental window. Heterozygous mutation in SYNGAP1 (SYNGAP1+/-) has been shown to cause Intellectual Disability (ID) in children. Recent studies have provided evidence for altered neuronal protein synthesis in a mouse model of Syngap1+/-. However, the molecular mechanism behind the same is unclear. Here, we report the reduced expression of a known translation regulator, FMRP, during a specific developmental period in Syngap1+/- mice. Our results demonstrated that FMRP interacts with and regulates the translation of Syngap1 mRNA. We further show that, during development, reduced translation, and subsequent decrease in FMRP level leads to a compensatory increase of Syngap1 translation in Syngap1+/-. These developmental changes are reflected in the altered response of eEF2 phosphorylation downstream of NMDA Receptor (NMDAR)-mediated signalling. In this study, we propose a cross-talk between FMRP and SYNGAP1-mediated signalling which can also explain the compensatory effect of impaired signalling observed in Syngap1+/- mice.

PURPOSE Increasing noncommunicable disease burden in sub-Saharan Africa requires the urgent scale-up of pathology and laboratory medicine (PALM) services. To identify service gaps at the district level, we studied geographic variation in the correlation between travel time to health facilities and population density. METHODS We linked geospatial data for Tanzania from multiple sources. Facility locations were extracted from a comprehensive facility list in Africa. Data on geographic factors, demographics, and roads were collected from government and nonprofit databases. We classified facilities assuming increasing PALM service readiness by level: dispensaries, health centers, district hospitals, and regional/referral hospitals. We input these data into the AccessMod 5 algorithm to estimate travel time across Tanzania with 1-km resolution for each PALM classification. We then calculated district-level averages of population and travel time for each PALM category. Associations between these variables were estimated using a bivariable local indicator of spatial autocorrelation, specifying immediate contiguity neighborhood definition. Spatial analysis was restricted to 172 contiguous districts (islands not included). Significance tests were two sided, with an α of .05. RESULTS Analysis included 5,342 dispensaries, 667 health centers, 185 district hospitals, and 34 regional/referral hospitals. Maps revealed clusters of estimated travel time in excess of 6 hours in less populated western and southern districts. More districts reported an average travel time of less than 1 hour to the nearest dispensary (69%) than to regional/referral hospitals (16%). Bivariable local indicators of spatial autocorrelation revealed few significant clusters of spatial correlations; however, significant correlations between low population density and longer travel times in neighboring districts were obtained for 13%, 16%, 15%, and 13% of districts for dispensaries, health centers, district hospitals, and regional/referral hospitals, respectively. CONCLUSION Limited variability of district-level spatial correlations suggests somewhat equitable geographic allocation of PALM services in Tanzania, with small areas of low population density and long travel times that demand additional intervention. Limitations include a lack of ascertainment of specific PALM services.

The long half-life and stability of human serum albumin (HSA) make it an attractive candidate for fusion to short-lived therapeutic proteins. Albuferon (Human Genome Sciences [HGS], Inc., Rockville, MD) beta is a novel recombinant protein derived from a gene fusion of interferon-beta (IFN-beta ) and HSA. In vitro, Albuferon beta displays antiviral and antiproliferative activities and triggers the IFN-stimulated response element (ISRE) signal transduction pathway. Array analysis of 5694 independent genes in Daudi-treated cells revealed that Albuferon beta and IFN-beta induce the expression of an identical set of 30 genes, including 9 previously not identified. In rhesus monkeys administered a dose of 50 microg/kg intravenously (i.v.) or subcutaneously (s.c.) or 300 microg/kg s.c., Albuferon beta demonstrated favorable pharmacokinetic properties. Subcutaneous bioavailability was 87%, plasma clearance at 4.7-5.7 ml/h/kg was approximately 140-fold lower than that of IFN-beta, and the terminal half-life was 36-40 h compared with 8 h for IFN-beta. Importantly, Albuferon beta induced sustained increases in serum neopterin levels and 2',5' mRNA expression. At a molar dose equivalent to one-half the dose of IFN-beta, Albuferon beta elicited comparable neopterin responses and significantly higher 2',5'-OAS mRNA levels in rhesus monkeys. The enhanced in vivo pharmacologic properties of IFN-beta when fused to serum albumin suggest a clinical opportunity for improved IFN-beta therapy.

IFN-kappa is a recently identified type I IFN that exhibits both structural and functional homology with the other type I IFN subclasses. In this study, we have investigated the effect of IFN-kappa on cells of the innate immune system by comparing cytokine release following treatment of human cells with either IFN-kappa or two recombinant IFN subtypes, IFN-beta and IFN-alpha2a. Although IFN-alpha2a failed to stimulate monocyte cytokine secretion, IFN-kappa, like IFN-beta, induced the release of several cytokines from both monocytes and dendritic cells, without the requirement of a costimulatory signal. IFN-kappa was particularly effective in inhibiting inducible IL-12 release from monocytes. Unlike IFN-beta, IFN-kappa did not induce release of IFN-gamma by PBL. Expression of the IFN-kappa mRNA was observed in resting dendritic cells and monocytes, and it was up-regulated by IFN-gamma stimulation in monocytes, while IFN-beta mRNA was minimally detectable under the same conditions. Monocyte and dendritic cell expression of IFN-kappa was also confirmed in vivo in chronic lesions of psoriasis vulgaris and atopic dermatitis. Finally, biosensor-based binding kinetic analysis revealed that IFN-kappa, like IFN-beta, binds strongly to heparin (K(d): 2.1 nM), suggesting that the cytokine can be retained close to the local site of production. The pattern of cytokines induced by IFN-kappa in monocytes, coupled with the unique induction of IFN-kappa mRNA by IFN-gamma, indicates a potential role for IFN-kappa in the regulation of immune cell functions.