Manipulation of the Myc Interactome to Enhance Nerve Regeneration in a Murine Model.

OBJECTIVE: This study was undertaken to explore manipulation of the Myc protein interactome, members of an oncogene group, in enhancing the intrinsic growth of injured peripheral adult postmitotic neurons and the nerves they supply. New approaches to enhance adult neuron growth properties are a key strategy in improving nerve regeneration. METHODS: Expression and impact of Myc interactome members c-Myc, N-Myc, Mad1, and Max were evaluated within naive and "preconditioned" adult sensory neurons and Schwann cells (SCs), using siRNA and transfection of CRISPR/Cas9 or luciferase reporter in vitro. Morphological, behavioral, and electrophysiological indices of nerve regeneration were analyzed in vivo. RESULTS: c-Myc, N-Myc, Max, and Mad were expressed in adult sensory neurons and in partnering SCs. In vitro knockdown (KD) of either Mad1 or Max, competitive inhibitors of Myc, unleashed heightened neurite outgrowth in both naive uninjured or preconditioned adult neurons. In contrast, KD or inhibition of both isoforms of Myc was required to suppress growth. In SCs, Mad1 KD not only enhanced migratory behavior but also conditioned increased outgrowth in separately cultured adult sensory neurons. In vivo, local Mad1 KD improved electrophysiological, behavioral, and structural indices of nerve regeneration out to 60 days of follow-up. INTERPRETATION: Members of the Myc interactome, specifically Mad1, are novel targets for improving nerve regeneration. Unleashing of Myc growth signaling through Mad1 KD enhances the regrowth of both peripheral neurons and SCs to facilitate better regrowth of nerves. ANN NEUROL 2024.

Headache prevalence and demographic associations in the Delhi and National Capital Region of India: estimates from a cross-sectional nationwide population-based study.

BACKGROUND: India is a large and populous country where reliable data on headache disorders are relatively scarce. This study in northern India (Delhi and National Capital Territory Region [NCR], including surrounding districts in the States of Haryana, Uttar Pradesh and Rajasthan) continues the series of population-based studies within the Global Campaign against Headache and follows an earlier study, using the same protocol and questionnaire, in the southern State of Karnataka. METHODS: This cross-sectional study used the Global Campaign's established methodology. Biologically unrelated Indian nationals aged 18-65 years were included through multistage random sampling in both urban and rural areas of NCR. Interviews at unannounced household visits followed the structured Headache-Attributed Restriction, Disability, Social Handicap and Impaired Participation (HARDSHIP) questionnaire in its original English version or in the validated Hindi version. Demographic enquiry was followed by a neutral headache screening question and diagnostic questions based on the International Classification of Headache Disorders edition 3 (ICHD-3), which focused on each respondent's most bothersome headache. Questions about headache yesterday (HY) enabled estimation of 1-day prevalence. A diagnostic algorithm first identified participants reporting headache on ≥ 15 days/month (H15+), diagnosing probable medication-overuse headache (pMOH) in those also reporting acute medication use on ≥ 15 days/month, and "other H15+" in those not. To all others, the algorithm applied ICHD-3 criteria in the order definite migraine, definite tension-type headache (TTH), probable migraine, probable TTH. Definite and probable diagnoses were combined. RESULTS: Adjusted for age, gender and habitation, 1-year prevalences were 26.3% for migraine, 34.1% for TTH, 3.0% for pMOH and 4.5% for other H15+. Female preponderance was seen in all headache types except TTH: migraine 35.7% vs. 15.1% (aOR = 3.3; p < 0.001); pMOH 4.3% vs. 0.7% (aOR = 5.1; p < 0.001); other H15 + 5.9% vs. 2.3% (aOR = 2.5; p = 0.08). One-day prevalence of (any) headache was 12.0%, based on reported HY. One-day prevalence predicted from 1-year prevalence and mean recalled headache frequency over 3 months was slightly lower (10.5%). CONCLUSIONS: The prevalences of migraine and TTH in Delhi and NCR substantially exceed global means. They closely match those in the Karnataka study: migraine 25.2%, TTH 35.1%. We argue that these estimates can reasonably be extrapolated to all India.

The burden of headache disorders in North India: methodology, and validation of a Hindi version of the HARDSHIP questionnaire, for a community-based survey in Delhi and national capital territory region.

BACKGROUND: Knowledge of the prevalence and attributable burden of headache disorders in India is sparse, with only two recent population-based studies from South and East India. These produced conflicting results. A study in North India is needed. We report the methodology of such a study using, and validating, a Hindi translation of the Headache-Attributed Restriction, Disability, Social Handicap, and Impaired Participation (HARDSHIP) questionnaire developed by Lifting The Burden (LTB). Almost half of the Indian population speak Hindi or one of its dialects. METHODS: The study adopted LTB's standardized protocol for population-based studies in a cross-sectional survey using multistage random sampling conducted in urban Delhi and a surrounding rural area. Trained interviewers visited households unannounced, randomly selected one adult member from each and applied the Hindi version of HARDSHIP in face-to-face interviews. The most bothersome headache reported by participants was classified algorithmically into headache on ≥ 15 days/month (H15 +), migraine (including definite and probable) or tension-type headache (including definite and probable). These diagnoses were mutually exclusive. All participants diagnosed with H15 + and a 10% subsample of all others were additionally assessed by headache specialists and classified as above. We estimated the sensitivity and specificity of HARDSHIP diagnoses by comparison with the specialists' diagnoses. RESULTS: From 3,040 eligible households, 2,066 participants were interviewed. The participating proportions were 98.3% in rural areas but 52.9% in urban Delhi. In the validation subsample of 291 participants (149 rural, 142 urban), 61 did not report any headache (seven of those assessed by HARDSHIP, eight by headache specialists and 46 by both) [kappa = 0.83; 95% CI: 0.74-0.91]. In the remaining 230 participants who reported headache in the preceding year, sensitivity, specificity and kappa with (95% CI) were 0.73 (0.65-0.79), 0.80 (0.67-0.90) and 0.43 (0.34-0.58) for migraine; 0.71 (0.56-0.83), 0.80 (0.730.85) and 0.43 (0.37-0.62) for TTH and 0.75 (0.47-0.94), 0.93 (0.89-0.96) and 0.46 (0.34-0.58) for H15 + respectively. CONCLUSION: This study validates the Hindi version of HARDSHIP, finding its performance similar to those of other versions. It can be used to conduct population surveys in other Hindi-speaking regions of India.

Feasibility, safety, and patient acceptability of electronic inspiratory muscle training in patients who require prolonged mechanical ventilation in the intensive care unit: A dual-centre observational study.

BACKGROUND: Inspiratory muscle training (IMT) is an intervention that can be used to rehabilitate the respiratory muscle deconditioning experienced by patients with critical illness, requiring prolonged mechanical ventilation. Clinicians are currently using mechanical threshold IMT devices that have limited resistance ranges. OBJECTIVES: The objective of this study was to evaluate the safety, feasibility, and acceptability of using an electronic device to facilitate IMT with participants requiring prolonged mechanical ventilation. METHOD: A dual-centre observational cohort study, with convenience sampling, was conducted at two tertiary intensive care units. Daily training supervised by intensive care unit physiotherapists was completed with the electronic IMT device. A priori definitions for feasibility, safety, and acceptability were determined. Feasibility was defined as more than 80% of planned sessions completed. Safety was defined as no major adverse events and less than 3% minor adverse event rate, and acceptability was evaluated following the acceptability of intervention framework principles. RESULTS: Forty participants completed 197 electronic IMT treatment sessions. Electronic IMT was feasible, with 81% of planned sessions completed. There were 10% minor adverse events and no major adverse events. All the minor adverse events were transient without clinical consequences. All the participants who recalled completing electronic IMT sessions reported that the training was acceptable. Acceptability was demonstrated; over 85% of participants reported that electronic IMT was either helpful or beneficial and that electronic IMT assisted their recovery. CONCLUSION: Electronic IMT is feasible and acceptable to complete with critically ill participants who require prolonged mechanical ventilation. As all minor adverse events were transient without clinical consequences, electronic IMT can be considered a relatively safe intervention with patients who require prolonged mechanical ventilation.

Global, regional, and national disease burden estimates of acute lower respiratory infections due to respiratory syncytial virus in children younger than 5 years in 2019: a systematic analysis.

BACKGROUND: Respiratory syncytial virus (RSV) is the most common cause of acute lower respiratory infection in young children. We previously estimated that in 2015, 33·1 million episodes of RSV-associated acute lower respiratory infection occurred in children aged 0-60 months, resulting in a total of 118 200 deaths worldwide. Since then, several community surveillance studies have been done to obtain a more precise estimation of RSV associated community deaths. We aimed to update RSV-associated acute lower respiratory infection morbidity and mortality at global, regional, and national levels in children aged 0-60 months for 2019, with focus on overall mortality and narrower infant age groups that are targeted by RSV prophylactics in development. METHODS: In this systematic analysis, we expanded our global RSV disease burden dataset by obtaining new data from an updated search for papers published between Jan 1, 2017, and Dec 31, 2020, from MEDLINE, Embase, Global Health, CINAHL, Web of Science, LILACS, OpenGrey, CNKI, Wanfang, and ChongqingVIP. We also included unpublished data from RSV GEN collaborators. Eligible studies reported data for children aged 0-60 months with RSV as primary infection with acute lower respiratory infection in community settings, or acute lower respiratory infection necessitating hospital admission; reported data for at least 12 consecutive months, except for in-hospital case fatality ratio (CFR) or for where RSV seasonality is well-defined; and reported incidence rate, hospital admission rate, RSV positive proportion in acute lower respiratory infection hospital admission, or in-hospital CFR. Studies were excluded if case definition was not clearly defined or not consistently applied, RSV infection was not laboratory confirmed or based on serology alone, or if the report included fewer than 50 cases of acute lower respiratory infection. We applied a generalised linear mixed-effects model (GLMM) to estimate RSV-associated acute lower respiratory infection incidence, hospital admission, and in-hospital mortality both globally and regionally (by country development status and by World Bank Income Classification) in 2019. We estimated country-level RSV-associated acute lower respiratory infection incidence through a risk-factor based model. We developed new models (through GLMM) that incorporated the latest RSV community mortality data for estimating overall RSV mortality. This review was registered in PROSPERO (CRD42021252400). FINDINGS: In addition to 317 studies included in our previous review, we identified and included 113 new eligible studies and unpublished data from 51 studies, for a total of 481 studies. We estimated that globally in 2019, there were 33·0 million RSV-associated acute lower respiratory infection episodes (uncertainty range [UR] 25·4-44·6 million), 3·6 million RSV-associated acute lower respiratory infection hospital admissions (2·9-4·6 million), 26 300 RSV-associated acute lower respiratory infection in-hospital deaths (15 100-49 100), and 101 400 RSV-attributable overall deaths (84 500-125 200) in children aged 0-60 months. In infants aged 0-6 months, we estimated that there were 6·6 million RSV-associated acute lower respiratory infection episodes (4·6-9·7 million), 1·4 million RSV-associated acute lower respiratory infection hospital admissions (1·0-2·0 million), 13 300 RSV-associated acute lower respiratory infection in-hospital deaths (6800-28 100), and 45 700 RSV-attributable overall deaths (38 400-55 900). 2·0% of deaths in children aged 0-60 months (UR 1·6-2·4) and 3·6% of deaths in children aged 28 days to 6 months (3·0-4·4) were attributable to RSV. More than 95% of RSV-associated acute lower respiratory infection episodes and more than 97% of RSV-attributable deaths across all age bands were in low-income and middle-income countries (LMICs). INTERPRETATION: RSV contributes substantially to morbidity and mortality burden globally in children aged 0-60 months, especially during the first 6 months of life and in LMICs. We highlight the striking overall mortality burden of RSV disease worldwide, with one in every 50 deaths in children aged 0-60 months and one in every 28 deaths in children aged 28 days to 6 months attributable to RSV. For every RSV-associated acute lower respiratory infection in-hospital death, we estimate approximately three more deaths attributable to RSV in the community. RSV passive immunisation programmes targeting protection during the first 6 months of life could have a substantial effect on reducing RSV disease burden, although more data are needed to understand the implications of the potential age-shifts in peak RSV burden to older age when these are implemented. FUNDING: EU Innovative Medicines Initiative Respiratory Syncytial Virus Consortium in Europe (RESCEU).

Bill shape imposes biomechanical tradeoffs in cavity-excavating birds.

Organisms are subject to physical forces that influence morphological evolution. Birds use their bills as implements to perform various functions, each exerting unique physical demands. When excavating cavities, bird bills must resist a range of mechanical stresses to prevent fracture. However, the contribution of bill geometry and material composition to excavation stress resistance remains poorly understood. Here, we study the biomechanical consequences of bill diversification in the cavity-excavating palaeotropical barbets. Using finite-element models and beam theory, we compare excavation performance for two loading regimes experienced by barbet bills during cavity excavation: impact and torsion. We find that deeper and wider maxillae perform better for impact loads than for torsional loads, with the converse for narrower maxillae. This results in tradeoffs between impact and torsion resistance imposed by bill geometry. Analytical beam models validate this prediction, showing that this relationship holds even when maxillae are simplified to solid elliptical beams. Finally, we find that composite bill structures broadly exhibit lower stresses than homogeneous structures of the same geometry, indicating a functional synergy between the keratinous rhamphotheca and bony layers of the bill. Overall, our findings demonstrate the strong link between morphological evolution, behaviour and functional performance in organisms.

Greater occipital nerve blockade for the preventive treatment of chronic migraine: A randomized double-blind placebo-controlled study.

BACKGROUND: Greater occipital nerve blockade for the prevention of chronic migraine has a limited evidence base. A robust randomized double-blind, placebo-controlled trial is needed. METHODS: This double-blind, placebo-controlled, parallel-group trial, following a baseline period of four weeks, randomly assigned patients of chronic migraine 1:1 to receive four-weekly bilateral greater occipital nerve blockade with either 2 ml of 2% (40 mg) lidocaine (active group) or 2 ml of 0.9% saline (placebo) injections for 12 weeks. The primary and key secondary efficacy endpoints were a change from the baseline in the mean number of headache and migraine days and the achievement of ≥50% reduction in headache days from baseline across the weeks 9-12 respectively. Safety evaluations included the documentation and reporting of serious and other adverse events. RESULTS: Twenty-two patients each were randomly allocated to the active and placebo group. Baseline demography and clinical characteristics were similar between the two groups. Mean headache and migraine days at baseline (±SD) were 23.4 ± 4.4 and 15.6 ± 5.7 days in the active group and 22.6 ± 5.0 and 14.6 ± 4.6 days in the placebo group respectively. The active group compared to the placebo had a significantly greater least-squares mean reduction in the number of headache and migraine days (-4.2 days [95% CI: -7.5 to -0.8; p = 0.018] and -4.7 days [95%CI: -7.7 to -1.7; p = 0.003] respectively). 40.9% of patients in the active group achieved ≥50% reduction in headache days as compared with 9.1% of patients receiving a placebo (p = 0.024). Overall, 64 mild and transient adverse events were reported by 16 patients in the active group and 15 in the placebo. No death or serious adverse events were reported. CONCLUSION: Four-weekly greater occipital nerve blockade with 2% lidocaine for 12 weeks was superior to placebo in decreasing the average number of headache and migraine days in patients with chronic migraine with a good tolerability profile.Clinical trial.gov no. CTRI 2020/07/026709.

Biomechanics illuminates form-function relationships in bird bills.

The field of comparative biomechanics examines how form, mechanical properties and environmental interactions shape the function of biological structures. Biomechanics has advanced by leaps and bounds as rapid technological progress opens up new research horizons. In this Review, I describe how our understanding of the avian bill, a morphologically diverse multifunctional appendage, has been transformed by employing a biomechanical perspective. Across functions from feeding to excavating hollows in trees and as a vocal apparatus, the study of the bill spans both solid and fluid biomechanics, rendering it useful to understand general principles across disciplines. The different shapes of the bill across bird species result in functional and mechanical trade-offs, thus representing a microcosm of many broader form-function questions. Using examples from diverse studies, I discuss how research into bird bills has been shaped over recent decades, and its influence on our understanding of avian ecology and evolution. Next, I examine how bill material properties and geometry influence performance in dietary and non-dietary contexts, simultaneously imposing trade-offs on other functions. Following an examination of the interactions of bills with fluids and their role as part of the vocal apparatus, I end with a discussion of the sensory biomechanics of the bill, focusing specifically on the bill-tip mechanosensory organ. With these case studies, I highlight how this burgeoning and consequential field represents a roadmap for our understanding of the function and evolution of biological structures.

Higher-order dialectic variation and syntactic convergence in the complex warble song of budgerigars.

Dialectic signatures in animal acoustic signals are key in the identification of and association with group members. Complex vocal sequences may also convey information about behavioral state, and may thus vary according to social environment. Some bird species, such as psittaciforms, learn and modify their complex acoustic signals throughout their lives. However, the structure and function of vocal sequences in open-ended vocal learners remains understudied. Here, we examined vocal sequence variation in the warble song of budgerigars, and how these change upon contact between social groups. Budgerigars are open-ended vocal learners which exhibit fission-fusion flock dynamics in the wild. We found that two captive colonies of budgerigars exhibited colony-specific differences in the syntactic structure of their vocal sequences. Individuals from the two colonies differed in the propensity to repeat certain note types, forming repetitive motifs which served as higher-order signatures of colony identity. When the two groups were brought into contact, their vocal sequences converged, and these colony-specific repetitive patterns disappeared, with males from both erstwhile colonies now producing similar sequences with similar syntactic structure. We present data suggesting that the higher-order temporal arrangement of notes/vocal units is modified throughout life by social learning as groups of birds continually associate and dissociate. Our study sheds light on the importance of examining signal structure at multiple levels of organization, and the potential for psittaciform birds as model systems to examine the influence of learning and social environment on acoustic signals.

Exosomal miRNAs and breast cancer: a complex theranostics interlink with clinical significance.

Breast cancer (BC) remains the most challenging global health crisis of the current decade, impacting a large population of females annually. In the field of cancer research, the discovery of extracellular vesicles (EVs), specifically exosomes (a subpopulation of EVs), has marked a significant milestone. In general, exosomes are released from all active cells but tumour cell-derived exosomes (TDXs) have a great impact (TDXs miRNAs, proteins, lipid molecules) on cancer development and progression. TDXs regulate multiple events in breast cancer such as tumour microenvironment remodelling, immune cell suppression, angiogenesis, metastasis (EMT-epithelial mesenchymal transition, organ-specific metastasis), and therapeutic resistance. In BC, early detection is the most challenging event, exosome-based BC screening solved the problem. Exosome-based BC treatment is a sign of the transforming era of liquid biopsy, it is also a promising therapeutic tool for breast cancer. Exosome research goes to closer precision oncology via a single exosome profiling approach. Our hope is that this review will serve as motivation for researchers to explore the field of exosomes and develop an efficient, and affordable theranostics approach for breast cancer.

Healthier Food Purchase and Its Determinants in an Urban Resettlement Colony of Delhi.

Dietary risk, one of the major risk factors for the increasing burden of non-communicable diseases, is influenced by household food choices and purchases. A community-based cross-sectional study was conducted in 250 randomly selected households of an urban resettlement colony in Delhi to estimate the proportion of households purchasing different healthier food options during the last purchasing occasion and to identify its key determinants. Purchase of healthier options in staple items like wheat flour with fiber (100%), plant-based oils (97.9%), unpolished pulses (96.2%), and toned milk (94.5%) was high. Affordability and health considerations in food purchases were identified as key determinants.

Association of Common Mental Disorders with Diabetes Mellitus - Evidence from Community-based Matched Case-Control Study in North India.

BACKGROUND: Diabetes mellitus (DM) and depression are major public health problems globally. Evidence of linkage of common mental disorders (CMDs) including depression and anxiety disorders with DM is sparsely reported from community-based settings. OBJECTIVE: The present study aimed to study the association between CMDs and DM among adult population (>30 years) residing in a rural area of North India. MATERIALS AND METHODS: A community-based case-control study was conducted in 28 villages of Ballabgarh block of Faridabad district of Haryana. Cases (diabetes) were recruited from the community with at least 1 year of diabetes. Age- and sex-matched two neighborhood controls were selected from the same community. Diabetic status was confirmed using glycated hemoglobin. CMDs such as depression and anxiety disorders were screened using PRIME-MD Hindi version. Conditional logistic regression was used to study the relationship between diabetes and CMDs. RESULTS: Total 211 cases (diabetic) and 273 controls (nondiabetic) were approached for the study, of which 173 cases and 175 controls were analyzed. Cases and controls were comparable with respect to age, sex, and socioeconomic status. CMDs were found more among cases as compared to controls (67.5% vs. 37.5%) (P < 0.001). On conditional logistic regression analysis, CMDs were significantly higher among diabetes cases (adjusted odds ratio - 3.2, 95% confidence interval: 1.9-5.2). CONCLUSION: Strong evidence of coexistence of CMDs and DM from this population-based study necessitates the need of incorporation of management of CMDs into diabetes control program in India.

Efficacy and tolerability of combination treatment of topiramate and greater occipital nerve block versus topiramate monotherapy for the preventive treatment of chronic migraine: A randomized controlled trial.

OBJECTIVE: To compare the efficacy and tolerability of combination treatment of topiramate and greater occipital nerve block to topiramate monotherapy in adult chronic migraine patients. BACKGROUND: Options for the preventive treatment of chronic migraine are limited and costly. Combination treatments do not have an evidence base yet. METHODS: This was a parallel group, 3 arms with 1:1:1 allocation ratio randomized controlled study in consecutive adult chronic migraine patients attending Headache Clinic in a tertiary care hospital. Patients received either topiramate monotherapy 100 mg/day (group A), or topiramate plus greater occipital nerve block with 40 mg lidocaine (2%) and 80mg (2 ml) methylprednisolone as the first injection followed by monthly injections of lidocaine for the next 2 months (group B) or topiramate plus greater occipital nerve block with 40 mg lidocaine (2%) injections monthly for 3 months (group C). The primary endpoint was the mean change in monthly migraine days at Month 3. Multiple secondary endpoints were assessed that included among others, achievement of ≥50% reduction in mean monthly headache days compared to baseline at Month 3 and assessment for any adverse events. RESULTS: One hundred and twenty-five patients were randomized; 41 to group A, 44 to group B, and 40 to group C. Efficacy assessments were done for 121 patients. Patients receiving combination treatment of topiramate and greater occipital nerve block with steroids and lidocaine and greater occipital nerve block with only lidocaine compared to topiramate monotherapy showed greater reductions in monthly migraine days at Month 3 (-9.6 vs -7.3 days; p = 0.003) and (-10.1 vs -7.3 days; p < 0.001) respectively. Greater proportion of patients in both the combination treatment groups (added greater occipital nerve block with and without steroid) achieved ≥50% reduction in mean monthly headache days [71.4% vs 39%; OR (95% CI) 3.9(1.6-9.8); p = 0.004] and [62.4% vs 39%; OR (95% CI) 2.7(1.1-6.7); p = 0.034] respectively, compared to those receiving topiramate monotherapy. Adverse effects between the groups were comparable although patients receiving combination treatment with added greater occipital nerve block reported transient adverse effects like post-injection dizziness, local site swelling, and pain. No serious adverse event was reported. CONCLUSION: Combination treatments of topiramate with monthly injections of greater occipital nerve block were more effective in reducing monthly migraine days in chronic migraine than topiramate monotherapy at Month 3. Combination treatments were well tolerated.

TOP-PRO study: A randomized double-blind controlled trial of topiramate versus propranolol for prevention of chronic migraine.

OBJECTIVE: The aim of the TOP-PRO-study, a double-blind randomized controlled trial, was to assess the efficacy (non-inferiority) and tolerability of propranolol compared to topiramate for the prevention of chronic migraine. BACKGROUND: Except for topiramate, oral preventive treatment for chronic migraine lacks credible evidence. METHODS: Chronic migraine patients aged above 18 years and less than 65 years of age, not on any preventive treatment were randomly allocated to receive topiramate (100 mg/day) or propranolol (160 mg/day). The primary efficacy outcome was the mean change in migraine days per 28 days at the end of 24 weeks from baseline. A mean difference of 1.5 days per four weeks was chosen as the cut-off delta value. Multiple secondary efficacy outcomes and treatment emergent adverse events were also assessed. RESULTS: As against the planned sample size of 244, only 175 patients could be enrolled before the spread of the corona virus disease-2019 pandemic and enforcement of lockdown in India. Of the 175 randomized patients, 95 (topiramate 46 and propranolol 49) completed the trial. The mean change in migraine days was -5.3 ± 1.2 vs -7.3 ± 1.1 days (p = 0.226) for topiramate and propranolol groups respectively. Propranolol was found to be non-inferior and not superior to topiramate (point estimate of -1.99 with a 95% confidence interval of -5.23 to 1.25 days). Multiple secondary outcomes also did not differ between the two groups. Intention to treat analysis of 175 patients and per-protocol analysis of 95 patients yielded concordant results. There was no significant difference in the incidence of adverse events between the two groups. CONCLUSION: Propranolol (160mg/day) was non-inferior, non-superior to topiramate (100mg/day) for the preventive treatment of chronic migraine and had a comparable tolerability profile.Trial Registration: Clinical Trials Registry-India CTRI/2019/05/018997).

A Comparative Analysis of Catheter Directed Thrombolysis with Anticoagulation Alone or Systemic tPA in Acute Pulmonary Embolism with Cor Pulmonale.

BACKGROUND: Pulmonary embolism (PE) with cor pulmonale causes considerable mortality and morbidity. Randomized trials have failed to show a mortality difference between treatment modalities including anticoagulation (AC), Catheter directed thrombolysis (CDT) and systemic tPA (tissue plasminogen activator). METHODS: This is a cross-sectional retrospective case-control study utilizing the 2017 National Inpatient Sample (NIS). Patients admitted with acute PE with cor pulmonale were divided into groups based on whether they received anticoagulation, CDT or systemic tPA based on appropriate ICD-10 PCS codes. The AC group and CDT group were compared using univariate and multivariate analyses after adjusting for age, gender, race, comorbidities, insurance status and Charlson comorbidity index (CCI). Secondary outcomes included factors influencing length of stay (LOS) and total charges incurred. Similar analyses were done to compare the CDT group with the tPA group. RESULTS: In 2017, 13240 patients were admitted with acute PE and cor pulmonale, of whom 18% underwent CDT, 10% underwent systemic tPA and 72% underwent AC alone. Patients who received CDT over AC alone were significantly younger (61.5 vs. 65.5, p = 0.00). Mortality rate overall was 4.8% with tPA group, CDT group and AC alone group having a 11.2%, 3.0% and 4.4% mortality rate respectively. On multivariate analyses, there was no significant mortality difference between the CDT and AC groups (aOR 0.61, 0.34-1.1 95%CI, p = 0.103). Patients with liver disease had significantly higher mortality while obese patients had a significantly lower mortality after adjusting for treatment strategy and confounders. Length of stay (LOS) was not significantly different between the groups however, compared to AC alone, patients who underwent CDT or tPA incurred significantly higher total hospital charges. CONCLUSIONS: CDT offers an attractive alternative to tPA therapy; however, our study does not show an in-hospital mortality benefit. More studies are required to guide patient selection prior to establishing treatment protocols.

Exploratory analysis of the suitability of data from the civil registration system for estimating excess mortality due to COVID-19 in Faridabad district of India.

Background & objectives: Due to shortcomings in death registration and medical certification, the excess death approach is recommended for COVID-19 mortality burden estimation. In this study the data from the civil registration system (CRS) from one district in India was explored for its suitability in the estimation of excess deaths, both directly and indirectly attributable to COVID-19. Methods: All deaths registered on the CRS portal at the selected registrar's office of Faridabad district in Haryana between January 2016 and September 2021 were included. The deaths registered in 2020 and 2021 were compared to previous years (2016-2019), and excess mortality in both years was estimated by gender and age groups as the difference between the registered deaths and historical average month wise during 2016-2019 using three approaches - mean and 95 per cent confidence interval, FORECAST.ETS function in Microsoft Excel and linear regression. To assess the completeness of registration in the district, 150 deaths were sampled from crematoria and graveyards during 2020 and checked for registration in the CRS portal. Agreement in the cause of death (CoD) in CRS with the International Classification of Diseases-10 codes assigned for a subset of 585 deaths after verbal autopsy was calculated. Results: A total of 7017 deaths were registered in 2020, whereas 6792 deaths were registered till 30 September 2021 which represent a 9 and 44 per cent increase, respectively, from the historical average for that period. The highest increase was seen in the age group >60 yr (19% in 2020 and 56% in 2021). All deaths identified in crematoria and graveyards in 2020 had been registered. Observed peaks of all-cause excess deaths corresponded temporally and in magnitude to infection surges in the district. All three approaches gave overlapping estimates of the ratio of excess mortality to reported COVID-19 deaths of 1.8-4 in 2020 and 10.9-13.9 in 2021. There was poor agreement (κ<0.4) between CoD in CRS and that assigned after physician review for most causes, except tuberculosis and injuries. Interpretation & conclusions: CRS data, despite the limitations, appeared to be appropriate for all-cause excess mortality estimation by age and sex but not by cause. There was an increase in death registration in 2020 and 2021 in the district.

Estimates of major non-communicable disease risk factors for India, 2010 & 2015: A summary of evidence.

Background & objectives: The National Monitoring Framework for the prevention and control of NCDs in India has set targets for reduction of risk factors relative to the measure recorded in 2010. Estimates for 2010 and 2015 were established using meta-analyses in the absence of a national risk factor survey till 2017. Methods: We searched national survey reports and also articles published in English from India between 2008 and 2017 in PubMed, Google Scholar and Cochrane review databases for specific risk factors among 18-69 yr Indians. Quality of studies was evaluated using Joanna-Briggs tool, but all studies were included in analyses. Estimates for each of the eight strata by age, gender and place of residence, respectively, were generated. MetaXL was used to calculate the pooled estimate for 2010 and 2015 using a random effects model. Strata-specific estimates were combined to arrive at national estimate using population weight of each stratum. The credibility of the estimates was determined using four parameters - average Briggs score; representativeness of the contributing studies and precision and stability of the estimates. Results: The estimates [95% confidence interval (CI)] for 2010 for different risk factors were as follows: current alcohol use, 15.7 per cent (13.2-18.2); current tobacco use, 27 per cent (21.4-32.6); household solid fuel use, 61.5 per cent (50.2-72.5); physical inactivity, 44.2 per cent (37.8-50.6); obesity, seven per cent (3.8-10.2) and raised blood pressure, 20.2 per cent (18.4-22.1). In 2015, compared to 2010, tobacco use showed a relative decline of 18 per cent, household solid fuel use of nine per cent and physical inactivity of 15 per cent. The estimates were stable for alcohol use, raised blood pressure and obesity between 2010 and 2015. All estimates varied between moderate and high degrees of credibility. Interpretation & conclusions: The estimates are consistent with other available estimates and with current national-level initiatives focused on tobacco control and improving access to clean fuel. These estimates can be used to monitor progress on non-communicable disease risk factor targets for India.

In vitro priming response in dorsal root ganglia partially mimics injury-driven pre-conditioning response and reprograms neurons for enhanced outgrowth.

Peripheral nerve injuries have the potential to bring about long-term disabilities in individuals. The major issue in repairing nerve injuries is the poor growth rate of axons. Although several molecules have been identified as potential candidates for improving axon growth, their potential translation into clinical practice is preliminary and largely unexplored. This necessitates identifying additional molecular candidates with superior potential to improve axon growth. Lack of a simple non-surgical screening model also poses a hurdle in rapidly screening potential candidate molecules. In this work, we developed a novel, rapid screening model for nerve regeneration therapeutics that retains a focus on adult neurons. The model involves simple incubation of sensory ganglia over a period of 24 h prior to dissociation. Surprisingly, this model features unique events that reprogram both sensory neurons and supporting glia favoring axon growth. Moreover, several associated cellular and molecular changes involved in this model partially mimic classic axotomy-induced changes in sensory ganglia. Overall, this model presents with a platform that not only allows rapid screening of drug candidates but offers opportunities in studying novel intrinsic molecular changes in both neurons and glial cells directed towards improving the pace of axon growth.

Public health research priorities for WHO on COVID-19 in the South-East Asia Region: results of a prioritization survey.

BACKGROUND: Effectively addressing the coronavirus disease 2019 (COVID-19) pandemic caused by the new pathogen requires continuous generation of evidence to inform decision-making. Despite an unprecedented amount of research occurring globally, the need to identify gaps in knowledge and prioritize a research agenda that is linked to public health action is indisputable. The WHO South-East Asia Region (SEAR) is likely to have region-specific research needs. METHODS: We aimed to identify a priority research agenda for guiding the regional and national response to the COVID-19 pandemic in SEAR countries. An online, anonymous research prioritization exercise using recent WHO guidance was conducted among the technical staff of WHO's country and regional offices engaged with the national COVID-19 response during October 2020. They were each asked to contribute up to five priority research ideas across seven thematic areas. These research ideas were reviewed, consolidated and scored by a core group on six parameters: regional specificity, relevance to the COVID-19 response, feasibility within regional research capacity, time to availability for decision-making, likely impact on practice, and promoting equity and gender responsiveness. The total scores for individual suggestions were organized in descending order, and ideas in the upper tertile were considered to be of high priority. RESULTS: A total of 203 priority research ideas were received from 48 respondents, who were primarily research and emergency response focal points in country and regional offices. These were consolidated into 78 research ideas and scored. The final priority research agenda of 27 items covered all thematic areas-health system (n=10), public health interventions (n=6), disease epidemiology (n=5), socioeconomic and equity (n=3), basic sciences (n=1), clinical sciences (n=1) and pandemic preparedness (n=1). CONCLUSIONS: This exercise, a part of WHO's mandate to "shape the research agenda", can help build a research roadmap ensuring efficient use of limited resources. This prioritized research agenda can act as a catalyst for Member States to accelerate research that could impact the COVID-19 response in SEAR.

Performance of equations for estimation of 24-hour urinary sodium from morning fasting urine samples in a multisite study in India.

Background Dietary salt intake is an important modifiable risk factor for cardiovascular diseases. Estimation of 24-hour salt intake using morning urine samples needs to be validated in the Indian context. We examined the performance of INTERSALT, Tanaka and Kawasaki equations for the estimation of 24-hour urinary sodium from morning fasting urine (MFU) samples. Methods We enrolled 486 adults aged 18-69 years from four regions of India with equal rural/urban and sex representation to provide 24-hour urine samples. The next day, a MFU sample was obtained. Based on the volume and sodium content of the 24-hour urine sample, 24-hour sodium excretion (reference method) was calculated. Sodium levels in the MFU samples were measured along with other parameters required, and the above equations were used to estimate 24-hour urinary sodium levels. Intraclass correlation coefficient (ICC) was used to assess the degree of agreement between the estimates from the reference method and the three equations. Bland-Altman (BA) plots were used to identify systematic bias and limits of agreement. A difference of 1 g of salt (0.39 g of sodium) between the mean salt intake by 24-hour urine and as estimated by equations was considered acceptable. Results A total of 346 participants provided both the samples. The mean (SD) daily salt intake estimated by the 24-hour urine sample method was 9.9 (5.8) g. ICC was low for all the three equations: highest for Kawasaki (0.16; 95% CI 0.05-0.26) and least for Tanaka (0.12; 0.02-0.22). Only Tanaka equation provided estimates within 1 g of measured 24-hour salt intake (-0.36 g). BA plots showed that as the mean values increased, all the three equations provided lower estimates of salt intake. Conclusion Tanaka equation provided acceptable values of 24-hour salt intake at the population level. However, poor performance of all the equations highlights the need to understand the reasons and develop better methods for the measurement of sodium intake at the population level.