'I am on treatment since 5 months but I have not received any money': coverage, delays and implementation challenges of 'Direct Benefit Transfer' for tuberculosis patients - a mixed-methods study from South India.

Background: In March 2018, the Government of India launched a direct benefit transfer (DBT) scheme to provide nutritional support for all tuberculosis (TB) patients in line with END TB strategy. Here, the money (@INR 500 [~8 USD] per month) is deposited electronically into the bank accounts of beneficiaries. To avail the benefit, patients are to be notified in NIKSHAY (web-based notification portal of India's national TB programme) and provide bank account details. Once these details are entered into NIKSHAY, checked and approved by the TB programme officials, it is sent to the public financial management system (PFMS) portal for further processing and payment. Objectives: To assess the coverage and implementation barriers of DBT among TB patients notified during April-June 2018 and residing in Dakshina Kannada, a district in South India. Methods: This was a convergent mixed-methods study involving cohort analysis of patient data from NIKSHAY and thematic analysis of in-depth interviews of providers and patients. Results: Of 417 patients, 208 (49.9%) received approvals for payment by PFMS and 119 (28.7%) got paid by 1 December 2018 (censor date). Reasons for not receiving DBT included (i) not having a bank account especially among migrant labourers in urban areas, (ii) refusal to avail DBT by rich patients and those with confidentiality concerns, (iii) lack of knowledge and (iv) perception that money was too little to meet the needs. The median (IQR) delay from diagnosis to payment was 101 (67-173) days. Delays were related to the complexity of processes requiring multiple layers of approval and paper-based documentation which overburdened the staff, bulk processing once-a-month and technological challenges (poor connectivity and issues related to NIKSHAY and PFMS portals). Conclusion: DBT coverage was low and there were substantial delays. Implementation barriers need to be addressed urgently to improve uptake and efficiency. The TB programme has begun to take action

Detection of Transgenerational Spermatogenic Inheritance of Adult Male Acquired CNS Gene Expression Characteristics Using a Drosophila Systems Model

Available instances of inheritance of epigenetic transgenerational phenotype are limited to environmental exposures during embryonic and adult gonadal development. Adult exposures can also affect gametogenesis and thereby potentially result in reprogramming of the germline. Although examples of epigenetic effects on gametogenesis exist, it is notable that transgenerational inheritance of environment-induced adult phenotype has not yet been reported. Epigenetic codes are considered to be critical in neural plasticity. A Drosophila systems model of pentylenetetrazole (PTZ) induced long-term brain plasticity has recently been described. In this model, chronic PTZ treatment of adult males causes alterations in CNS transcriptome. Here, we describe our search for transgenerational spermatogenic inheritance of PTZ induced gene expression phenotype acquired by adult Drosophila males. We generated CNS transcriptomic profiles of F1 adults after treating F0 adult males with PTZ and of F2 adults resulting from a cross between F1 males and normal females. Surprisingly, microarray clustering showed F1 male profile as closest to F1 female and F0 male profile closest to F2 male. Differentially expressed genes in F1 males, F1 females and F2 males showed significant overlap with those caused by PTZ. Interestingly, microarray evidence also led to the identification of upregulated rRNA in F2 males. Next, we generated microarray expression profiles of adult testis from F0 and F1 males. Further surprising, clustering of CNS and testis profiles and matching of differentially expressed genes in them provided evidence of a spermatogenic mechanism in the transgenerational effect observed. To our knowledge, we report for the first time detection of transgenerational spermatogenic inheritance of adult acquired somatic gene expression characteristic. The Drosophila systems model offers an excellent opportunity to understand the epigenetic mechanisms underlying the phenomenon. The finding that adult acquired transcriptomic alteration in soma is spermatogenically inherited across generations has potential implications in human health and evolution

Outcomes and implementation challenges of using daily treatment regimens with an innovative adherence support tool among HIV-infected tuberculosis patients in Karnataka, India: a mixed-methods study

Background: In India, a new care package consisting of (i) daily regimen with fixed-dose combination drugs, collected once-a-month and self-administered by the patient, (ii) ‘one stop service’ at antiretroviral treatment (ART) centre for both HIV and tuberculosis (TB) treatment and (iii) technology-enabled adherence support (99DOTS, which required patients to give a missed phone call after consuming drugs) was piloted for treatment of TB among HIV-infected TB patients. Conventional care included intermittent regimen (drugs consumed thrice-weekly) delivered under direct observation of treatment supporter and the patients needing to visit TB and HIV care facilities, separately for treatment. Objective: To assess the effect of new care package on TB treatment outcomes among HIV-TB patients registered during January–December 2016, as compared to conventional care and explore the implementation challenges. Methods: A mixed-methods study was conducted in four districts of Karnataka, India where new care package was piloted in few ART centres while the rest provided conventional care. Quantitative component involved a secondary cohort analysis of routine programme data. Adjusted relative risk(aRR) was calculated using Poisson regression to measure association between new care package and unsuccessful treatment outcome. We conducted in-depth interviews with healthcare providers and patients to understand the challenges. Results: Unsuccessful TB treatment outcomes (death, loss to follow-up and failure) were higher in new care package (n = 871) compared to conventional care (n = 961) (30.5% vs 23.4%; P value<0.001) and aRR was 1.3(95% CI: 1.1–1.7). Key challenges included patients’ inability to give missed call, increased work load for ART staff, reduced patient–provider interaction, deficiencies in training and lack of role clarity among providers and reduced involvement of TB program staff. Conclusion: With new care package, TB treatment outcomes did not improve as expected and conversely declined compared to conventional care. TB and HIV programs need to address the operational challenges to improve the outcomes

Disease-specific tau filaments assemble via polymorphic intermediates.

Acknowledgements: We thank C. Charlier and F. Ferrage for providing the Mathematica script for IMPACT analysis; H. Wang and T. P. J. Knowles for helpful discussions; J. Grimmett, T. Darling and I. Clayson for help with high-performance computing; and M. Wilkinson and R. A. Crowther for critical reading of the manuscript. This work was supported by the facilities for biophysics, electron microscopy, NMR and scientific computing of the MRC Laboratory of Molecular Biology, and by the Francis Crick Institute through provision of access to the MRC Biomedical NMR Centre. The Francis Crick Institute receives its core funding from Cancer Research UK (CC1078), the UK MRC (CC1078) and the Wellcome Trust (CC1078). This work was supported by the MRC, as part of United Kingdom Research and Innovation (MC_U105184291 to M.G. and MC_UP_A025-1013 to S.H.W.S.), and a Marshall scholarship to D.L.Intermediate species in the assembly of amyloid filaments are believed to play a central role in neurodegenerative diseases and may constitute important targets for therapeutic intervention1,2. However, structural information about intermediate species has been scarce and the molecular mechanisms by which amyloids assemble remain largely unknown. Here we use time-resolved cryogenic electron microscopy to study the in vitro assembly of recombinant truncated tau (amino acid residues 297-391) into paired helical filaments of Alzheimer's disease or into filaments of chronic traumatic encephalopathy3. We report the formation of a shared first intermediate amyloid filament, with an ordered core comprising residues 302-316. Nuclear magnetic resonance indicates that the same residues adopt rigid, β-strand-like conformations in monomeric tau. At later time points, the first intermediate amyloid disappears and we observe many different intermediate amyloid filaments, with structures that depend on the reaction conditions. At the end of both assembly reactions, most intermediate amyloids disappear and filaments with the same ordered cores as those from human brains remain. Our results provide structural insights into the processes of primary and secondary nucleation of amyloid assembly, with implications for the design of new therapies