Retrospective analysis of necropsy findings in patients of H1N1 and their correlation to clinical features

India reported its first case of H1N1 in July 2009 in Pune and since then, the number of reported cases and deaths exploded in India. Since very little data is available about histopathological findings in patients of H1N1 fatal cases in India, a retrospective chart analysis of necropsy findings of 15 cases of 2009 H1N1 fatal cases was performed. Common clinical features were fever, cough , and breathlessness followed by sore throat and rhinorrhea. Common lung findings were mononuclear cell infiltration, thick alveolar septae, intraalveolar hemorrhage . The other findings were congested pulmonary blood vessels, pulmonary edema, cytomegaly, fibrin accumulation and formation of eosinophilic membrane. These findings are suggestive of diffuse alveolar damage ( DAD) and DAD with hemorrhage. All patients who underwent necropsy had radiographic findings suggestive of unilobar or multilobar pneumonia. This clinical finding can be correlated pathologically in these patients as all of them had either polymorphonuclear or mononuclear infiltrate. Furthermore, necrotizing pneumonitis pattern seen on these patients is the likely cause of mortality in these patients. Although clinical ARDS pattern was noted in all these patients, it was well correlated in lung pathology in all these cases

The Healthy Activity Program (HAP), a lay counsellor-delivered brief psychological treatment for severe depression, in primary care in India: a randomised controlled trial

Background Although structured psychological treatments are recommended as fi rst-line interventions for depression, only a small fraction of people globally receive these treatments because of poor access in routine primary care. We assessed the effectiveness and cost-effectiveness of a brief psychological treatment (Healthy Activity Program [HAP]) for delivery by lay counsellors to patients with moderately severe to severe depression in primary health-care settings. Methods In this randomised controlled trial, we recruited participants aged 18–65 years scoring more than 14 on the Patient Health Questionnaire 9 (PHQ-9) indicating moderately severe to severe depression from ten primary health centres in Goa, India. Pregnant women or patients who needed urgent medical attention or were unable to communicate clearly were not eligible. Participants were randomly allocated (1:1) to enhanced usual care (EUC) alone or EUC combined with HAP in randomly sized blocks (block size four to six [two to four for men]), stratified by primary health centre and sex, and allocation was concealed with use of sequential numbered opaque envelopes. Physicians providing EUC were masked. Primary outcomes were depression symptom severity on the Beck Depression Inventory version II and remission from depression (PHQ-9 score of <10) at 3 months in the intention to-treat population, assessed by masked fi eld researchers. Secondary outcomes were disability, days unable to work, behavioural activation, suicidal thoughts or attempts, intimate partner violence, and resource use and costs of illness. We assessed serious adverse events in the per-protocol population. This trial is registered with the ISRCTN registry, number ISRCTN95149997. Findings Between Oct 28, 2013, and July 29, 2015, we enrolled and randomly allocated 495 participants (247 [50%] to the EUC plus HAP group [two of whom were subsequently excluded because of protocol violations] and 248 [50%] to the EUC alone group), of whom 466 (95%) completed the 3 month primary outcome assessment (230 [49%] in the EUC plus HAP group and 236 [51%] in the EUC alone group). Participants in the EUC plus HAP group had significantly lower symptom severity (Beck Depression Inventory version II in EUC plus HAP group 19·99 [SD 15·70] vs 27·52 [13·26] in EUC alone group; adjusted mean difference –7·57 [95% CI –10·27 to –4·86]; p<0·0001) and higher remission (147 [64%] of 230 had a PHQ-9 score of <10 in the HAP plus EUC group vs 91 [39%] of 236 in the EUC alone group; adjusted prevalence ratio 1·61 [1·34–1·93]) than did those in the EUC alone group. EUC plus HAP showed better results than did EUC alone for the secondary outcomes of disability (adjusted mean difference –2·73 [–4·39 to –1·06]; p=0·001), days out of work (–2·29 [–3·84 to –0·73]; p=0·004), intimate partner physical violence in women (0·53 [0·29–0·96]; p=0·04), behavioural activation (2·17 [1·34–3·00]; p<0·0001), and suicidal thoughts or attempts (0·61 [0·45–0·83]; p=0·001). The incremental cost per quality-adjusted life-year gained was $9333 (95% CI 3862–28 169; 2015 international dollars), with an 87% chance of being cost-effective in the study setting. Serious adverse events were infrequent and similar between groups (nine [4%] in the EUC plus HAP group vs ten [4%] in the EUC alone group; p=1·00). Interpretation HAP delivered by lay counsellors plus EUC was better than EUC alone was for patients with moderately severe to severe depression in routine primary care in Goa, India. HAP was readily accepted by this previously untreated population and was cost-effective in this setting. HAP could be a key strategy to reduce the treatment gap for depressive disorders, the leading mental health disorder worldwide

Sustained effectiveness and cost-effectiveness of the Healthy Activity Programme, a brief psychological treatment for depression delivered by lay counsellors in primary care: 12-month follow-up of a randomised controlled trial

BACKGROUND:The Healthy Activity Programme (HAP), a brief behavioural intervention delivered by lay counsellors, enhanced remission over 3 months among primary care attendees with depression in peri-urban and rural settings in India. We evaluated the sustainability of the effects after treatment termination, the cost-effectiveness of HAP over 12 months, and the effects of the hypothesized mediator of activation on clinical outcomes. METHODS AND FINDINGS:Primary care attendees aged 18-65 years screened with moderately severe to severe depression on the Patient Health Questionnaire 9 (PHQ-9) were randomised to either HAP plus enhanced usual care (EUC) (n = 247) or EUC alone (n = 248), of whom 95% completed assessments at 3 months, and 91% at 12 months. Primary outcomes were severity on the Beck Depression Inventory-II (BDI-II) and remission on the PHQ-9. HAP participants maintained the gains they showed at the end of treatment through the 12-month follow-up (difference in mean BDI-II score between 3 and 12 months = -0.34; 95% CI -2.37, 1.69; p = 0.74), with lower symptom severity scores than participants who received EUC alone (adjusted mean difference in BDI-II score = -4.45; 95% CI -7.26, -1.63; p = 0.002) and higher rates of remission (adjusted prevalence ratio [aPR] = 1.36; 95% CI 1.15, 1.61; p < 0.009). They also fared better on most secondary outcomes, including recovery (aPR = 1.98; 95% CI 1.29, 3.03; p = 0.002), any response over time (aPR = 1.45; 95% CI 1.27, 1.66; p < 0.001), higher likelihood of reporting a minimal clinically important difference (aPR = 1.42; 95% CI 1.17, 1.71; p < 0.001), and lower likelihood of reporting suicidal behaviour (aPR = 0.71; 95% CI 0.51, 1.01; p = 0.06). HAP plus EUC also had a marginal effect on WHO Disability Assessment Schedule score at 12 months (aPR = -1.58; 95% CI -3.33, 0.17; p = 0.08); other outcomes (days unable to work, intimate partner violence toward females) did not statistically significantly differ between the two arms. Economic analyses indicated that HAP plus EUC was dominant over EUC alone, with lower costs and better outcomes; uncertainty analysis showed that from this health system perspective there was a 95% chance of HAP being cost-effective, given a willingness to pay threshold of Intl$16,060-equivalent to GDP per capita in Goa-per quality-adjusted life year gained. Patient-reported behavioural activation level at 3 months mediated the effect of the HAP intervention on the 12-month depression score (β = -2.62; 95% CI -3.28, -1.97; p < 0.001). Serious adverse events were infrequent, and prevalence was similar by arm. We were unable to assess possible episodes of remission and relapse that may have occurred between our outcome assessment time points of 3 and 12 months after randomisation. We did not account for or evaluate the effect of mediators other than behavioural activation. CONCLUSIONS:HAP's superiority over EUC at the end of treatment was largely stable over time and was mediated by patient activation. HAP provides better outcomes at lower costs from a perspective covering publicly funded healthcare services and productivity impacts on patients and their families. TRIAL REGISTRATION:ISRCTN registry ISRCTN95149997

Growth status of children and adolescents with type 1 diabetes mellitus

Background and Objectives: Growth parameters are important indicators of a child′s overall health, and they are influenced by factors like blood glucose control in diabetic children. Data on growth parameters of Indian diabetic children is scarce. This retrospective, cross-sectional, case control study was conducted at diabetes clinic for children at a tertiary care center at Pune, to study growth parameters of diabetic children in comparison with age-gender matched healthy controls and evaluate effect of different insulin regimes and age at diagnosis of diabetes on growth. Materials and Methods: One twenty five diabetic children (boys: 50) and age gender matched healthy controls were enrolled. All subjects underwent anthropometric measurements (standing height and weight). Mean height (HAZ), weight (WAZ) and body mass index (BAZ) for age Z scores were calculated. Diabetes control was evaluated by measuring glycosylated hemoglobin (HbA1C). Statistical analysis was done by SPSS version 12. Results: Mean age of diabetic children and age gender matched controls was 9.7 ± 4.4 years. Diabetic children were shorter (128.3 ± 24.3 cm vs. 133.6 ± 24.7 cm) and lighter (29.2 kg ± 15.3 vs. 31.3 ± 15.4 kg). HAZ (−1.1 ± 1.2 vs. −0.2 ± 0.8) and WAZ (−1.2 ± 1.3 vs. −0.7 ± 1.3) were significantly lower in diabetic children (P 14 years) were comparable to healthy controls. Conclusions: Growth was compromised in diabetic children in comparison to controls. Children diagnosed at younger age need more attention to optimize growth

Systematic identification of structure-specific protein–protein interactions

The physical interactome of a protein can be altered upon perturbation, modulating cell physiology and contributing to disease. Identifying interactome differences of normal and disease states of proteins could help understand disease mechanisms, but current methods do not pinpoint structure-specific PPIs and interaction interfaces proteome-wide. We used limited proteolysis–mass spectrometry (LiP–MS) to screen for structure-specific PPIs by probing for protease susceptibility changes of proteins in cellular extracts upon treatment with specific structural states of a protein. We first demonstrated that LiP–MS detects well-characterized PPIs, including antibody–target protein interactions and interactions with membrane proteins, and that it pinpoints interfaces, including epitopes. We then applied the approach to study conformation-specific interactors of the Parkinson’s disease hallmark protein alpha-synuclein (aSyn). We identified known interactors of aSyn monomer and amyloid fibrils and provide a resource of novel putative conformation-specific aSyn interactors for validation in further studies. We also used our approach on GDP- and GTP-bound forms of two Rab GTPases, showing detection of differential candidate interactors of conformationally similar proteins. This approach is applicable to screen for structure-specific interactomes of any protein, including posttranslationally modified and unmodified, or metabolite-bound and unbound protein states

Systematic identification of structure-specific protein–protein interactions

Protein–protein interactions (PPIs) mediate numerous essential functions and regulatory events in living organisms. The physical interactome of a protein can be abnormally altered in response to external and internal cues, thus modulating cell physiology and contributing to human disease. In particular, neurodegenerative diseases due to the accumulation of aberrantly folded and aggregated proteins may lead to alterations in protein interactomes. Identifying changes in the interactomes of normal and disease states of proteins could help to understand molecular disease mechanisms, but current interactomics methods are limited in the ability to pinpoint structure-specific PPIs and their interaction interfaces on a proteome-wide scale. Here, we adapted limited proteolysis–mass spectrometry (LiP–MS) to systematically identify putative structure-specific PPIs by probing protein structural alterations within cellular extracts upon treatment with specific structural states of a given protein. We demonstrate the feasibility of our method to detect well-characterized PPIs, including antibody–target protein interactions and interactions with membrane proteins, and show that it pinpoints PPI interfaces. We then applied the LiP–MS approach to study the structure-specific interactors of the Parkinson’s disease hallmark protein alpha-synuclein (aSyn). We identified several previously known interactors of both aSyn monomer and amyloid fibrils and provide a resource of novel putative structure-specific interactors for further studies. This approach is applicable to identify structure-specific interactomes of any protein, including posttranslationally modified and unmodified, or metabolite-bound and unbound structural states of proteins

Structural basis of the Meinwald rearrangement catalysed by styrene oxide isomerase

Membrane-bound styrene oxide isomerase (SOI) catalyses the Meinwald rearrangement—a Lewis-acid-catalysed isomerization of an epoxide to a carbonyl compound—and has been used in single and cascade reactions. However, the structural information that explains its reaction mechanism has remained elusive. Here we determine cryo-electron microscopy (cryo-EM) structures of SOI bound to a single-domain antibody with and without the competitive inhibitor benzylamine, and elucidate the catalytic mechanism using electron paramagnetic resonance spectroscopy, functional assays, biophysical methods and docking experiments. We find ferric haem b bound at the subunit interface of the trimeric enzyme through H58, where Fe(III) acts as the Lewis acid by binding to the epoxide oxygen. Y103 and N64 and a hydrophobic pocket binding the oxygen of the epoxide and the aryl group, respectively, position substrates in a manner that explains the high regio-selectivity and stereo-specificity of SOI. Our findings can support extending the range of epoxide substrates and be used to potentially repurpose SOI for the catalysis of new-to-nature Fe-based chemical reactions. (Figure presented.).BT/Biocatalysi

The mediating effect of behavioural activation at 3 months on the effectiveness of the HAP on depression severity at 12 months.

<p>Variables as follows: β, Beta coefficient; a, a-path (HAP–mediator); b, b-path (mediator–outcome); c, direct effect (HAP–outcome); a × b, indirect effect. BDI-II, Beck Depression Inventory–II; PHQ-9, Patient Health Questionnaire 9.</p

Effect of HAP plus EUC compared with EUC alone on disability and intimate partner violence at 12 months.

<p>Effect of HAP plus EUC compared with EUC alone on disability and intimate partner violence at 12 months.</p