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Background & objectives Medication-related harm is known to be the cause for about 1/10th of hospitalizations. Some estimates from India show that about 90 per cent of medicines consumed are inessential or irrational and contribute towards high out-of-pocket expenditure on health. In this context, the Indian Council of Medical Research in 2022 constituted a National Task Force (NTF) to explore possible solutions that could improve safe and rational use of medicines (SRUMs). The objective of this study was to identify research ideas in the field of SRUM through a survey of relevant stakeholders, and further to prioritize the research ideas using a pre-identified set of criteria. Methods The responses from the identified stakeholders were assessed using the Child Health and Nutrition Research Initiative method, which is an established research priority-setting methodology. First, the NTF asked for two to six research ideas from relevant Indian and global stakeholders on solutions to improve SRUM. The ideas were checked for duplicates, re-phrased where necessary and classified into various sub-themes. Subsequently, the research ideas were scored by Indian experts with relevant technical expertise using a pre-defined set of five criteria: innovativeness, effectiveness, translational value, answerability and applicability. Each research idea received from a stakeholder was assigned a score under each of the five criteria. The overall research priority score was calculated as a mean of all five criteria-specific scores and converted into a percentage. Results The final output of the prioritization process was a list of research ideas or questions, ranked by their scores. Total 209 unique ideas were received from 190 respondents, which were scored by 27 experts. The top three research topics on medication safety focused on cost-effective strategies for improving antimicrobial stewardship, safe use of poly-pharmacy in geriatric patients and drug take-back policy interventions. Regarding the rational use of medicine, the top three topics included testing mobile application-based antimicrobial stewardship interventions, development of diagnostics for antimicrobial resistance, and behavioural interventions. Interpretation & conclusions Several priority ideas found in this study also align with those of global priority, e.g., safe disposal practices and enhanced pharmacovigilance, rational use of medicines. Patient engagement, which underlines many of the top scoring ideas found in this study, is also inclined with the top research priorities reported by the WHO priority exercise on research into the safe use of medicines. However, to the best of our knowledge, this is the first such work from a low- and middle- income country on medication safety and rational use of medicines. The findings of this research priority-setting exercise can help to guide research for the development of policy-relevant and novel interventions to improve SRUM in India.

Myocyte fusion is a pivotal process in the development and regeneration of skeletal muscle. Failure during fusion can lead to a range of developmental as well as pathological consequences. This review aims to comprehensively explore the intricate processes underlying myocyte fusion, from the molecular to tissue scale. We shed light on key players, such as the muscle-specific fusogens - Myomaker and Myomixer, in addition to some lesser studied molecules contributing to myocyte fusion. Conserved across vertebrates, Myomaker and Myomixer play a crucial role in driving the merger of plasma membranes of fusing myocytes, ensuring the formation of functional muscle syncytia. Our multiscale approach also delves into broader cell and tissue dynamics that orchestrate the timing and positioning of fusion events. In addition, we explore the relevance of muscle fusogens to human health and disease. Mutations in fusogen genes have been linked to congenital myopathies, providing unique insights into the molecular basis of muscle diseases. We conclude with a discussion on potential therapeutic avenues that may emerge from manipulating the myocyte fusion process to remediate skeletal muscle disorders., (Copyright © 2024. Published by Elsevier Inc.)

Background: Pneumonia contributes to about 15% of child deaths globally, with 20% of the overall deaths occurring in India. Although WHO recommends the use of pulse oximeters (PO) in first-level facilities for early detection of child pneumonia in low- and middle-income countries (LMICs), this has not yet been implemented in India. We aimed to assess the feasibility and acceptability of introducing PO in integrated management of neonatal and childhood illnesses (IMNCI) services at primary health centres (PHC) in the rural Pune district., Methods: We identified medical officers (MO) and auxiliary nurse midwives (ANM) from six PHCs as study participants due to their involvement in the treatment of children. We developed in-depth interview (IDI) guides for both groups to explore their IMNCI knowledge and attitude towards the program through a qualitative study. We conducted interviews with MOs (n = 6) and ANMs (n = 6) from each PHC. The PO module was added to explore perceptions about its usefulness in diagnosing pneumonia. After baseline assessment, we conducted training sessions on adapted IMNCI services (including PO use) for MOs and ANMs. PO devices were provided at the study PHCs., Results: At baseline, no PO devices were being used at study PHCs; PHC staff demonstrated satisfactory knowledge about paediatric pneumonia management and demanded refresher IMNCI training. They also felt the need to reiterate the PO use for early diagnosis of pneumonia in children and highlighted the challenges encountered in managing pneumonia at PHCs, such as health system-related challenges and parents' attitudes towards care seeking. There was positive acceptance of training and PO started to be used immediately in PHCs. There was increased confidence in using PO at endline. PO use in examining symptomatic children increased from 26 to 85%., Conclusions: Paediatric PO implementation could be integrated successfully at PHC levels; we found pre-implementation training and provision of PO to PHCs to be helpful in achieving this goal. This intervention demonstrated that an algorithm to diagnose pneumonia in children that included PO could improve case management., Competing Interests: Disclosure of interest: The authors completed the ICMJE Disclosure of Interest Form (available upon request form the corresponding author) and declare the following activities and/or relationships: HN has received grant funding from Innovative Medicines Initiative, World Health Organisation, Bill and Melinda Gates Foundation, Pfizer and Icosavax. He has received honoraria from Sanofi, GSK, Merck, Novavax, Reviral. Other authors declare that they have no competing interests, (Copyright © 2023 by the Journal of Global Health. All rights reserved.)

Primary healthcare caters to nearly 70% of the population in India and provides treatment for approximately 80-90% of common conditions. To achieve universal health coverage (UHC), the Indian healthcare system is gearing up by initiating several schemes such as National Health Protection Scheme, Ayushman Bharat, Nutrition Supplementation Schemes, and Inderdhanush Schemes. The healthcare delivery system is facing challenges such as irrational use of medicines, over- and under-diagnosis, high out-of-pocket expenditure, lack of targeted attention to preventive and promotive health services, and poor referral mechanisms. Healthcare providers are unable to keep pace with the volume of growing new scientific evidence and rising healthcare costs as the literature is not published at the same pace. In addition, there is a lack of common standard treatment guidelines, workflows, and reference manuals from the Government of India. Indian Council of Medical Research in collaboration with the National Health Authority, Govt. of India, and the WHO India country office has developed Standard Treatment Workflows (STWs) with the objective to be utilized at various levels of healthcare starting from primary to tertiary level care. A systematic approach was adopted to formulate the STWs. An advisory committee was constituted for planning and oversight of the process. Specialty experts' group for each specialty comprised of clinicians working at government and private medical colleges and hospitals. The expert groups prioritized the topics through extensive literature searches and meeting with different stakeholders. Then, the contents of each STW were finalized in the form of single-pager infographics. These STWs were further reviewed by an editorial committee before publication. Presently, 125 STWs pertaining to 23 specialties have been developed. It needs to be ensured that STWs are implemented effectively at all levels and ensure quality healthcare at an affordable cost as part of UHC., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Grover, Bhargava, Srivastava, Sharma, Cherian, Tandon, Chandershekhar, Ofrin, Bekedam, Pandhi, Mukherjee, Dhaliwal, Singh, Rajshekhar, Roy, Rasaily, Saraf, Kumar, Parmar, Kabra, Chaudhry, Deorari, Tandon, Singh, Khaitan, Agrawala, Gupta, Goel, Bhansali, Dutta, Seth, Singh, Awasthi, Seth, Pandian, Jha, Dwivedi, Tripathi, Thakar, Jindal, Gangadhar, Bajaj, Kant and Chatterjee.)

Background: Pulmonary rehabilitation (PR) is an effective strategy to improve breathlessness, health status and exercise tolerance and to reduce readmissions and mortality. In India, there is no government health programme for chronic obstructive pulmonary disease (COPD) management while in the private sector availability of PR is limited. Most PR centres are in urban areas, with few services accessible to rural populations. We aimed to assess the need for PR from the perspective of patients with COPD and healthcare professionals (HCPs: registered medical practitioners and medical officers) in rural Maharashtra., Methodology: Between June and October 2020, we conducted semi-structured interviews with 14 patients with COPD and 9 HCPs to explore their perceptions of, and need for, PR in rural Maharashtra. Interviews were transcribed and analysed thematically., Results: We approached 14 patients with COPD and 9 HCPs practising in rural areas. Five HCPs stated that they did not advise PR for patients with COPD citing poor compliance to PR referral and follow-up of the patients. Patients with COPD had symptoms and needs that could be helped by PR but commented how transportation would be a problem for them to visit a PR centre. In contrast, they could understand the benefits of PR and expressed their willingness to join such programmes. A PR service was established that addressed these needs., Conclusion: Patients with COPD have unmet needs that could benefit from attending a PR programme, but there are barriers at both healthcare and patient levels that we addressed in a new PR service for people with chronic respiratory disease in rural Maharashtra., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, responsible for the coronavirus disease 2019 (COVID-19) pandemic, has been a major public health concern requiring continuous efforts for understanding its epidemiology. Patients infected with SARS-CoV-2 have a wide range of clinical features ranging from asymptomatic infection to mild or severe illness with fatal outcomes or recovery. Population-based seroepidemiological studies are an effective method for measuring the rapid spread of SARS-CoV-2 and monitoring the pandemic's progress., Methods: We conducted repeated cross-sectional community-based sentinel surveillance between January and June 2021 in the rural parts of the Pune district of Maharashtra, India to assess the seroprevalence against SARS-CoV-2 in three age categories. We selected 30 clusters for each round using a proportional population sampling method and 30 individuals in each of the three age groups (1-17 years, 18-49 years, and ≥50 years). We took blood samples from consenting study participants to check for the presence of Immunoglobulin G (IgG) antibodies against SARS-CoV-2 in all five rounds., Results: We included 14 274 individuals across five rounds; 29% were from the 1-17, 39% from the 18-49, and 32% from the ≥50-year-old group. Overall seroprevalence combining all rounds was 45%. There was an increase in seropositivity in rounds four (51.15%) and five (58.32%) contributed mostly by adults. We found that about 72% of elderly individuals ≥50 years in round five were seropositive. The factors strongly associated with the seropositivity were being in contact with suspected or confirmed cases of COVID-19 (odds ratio (OR) = 7.15; 95% confidence interval (CI) = 4.2-12.14), receiving at least one dose of COVID-19 vaccine (OR = 3.13 (95% CI = 0.70-14.07), being aged ≥50 years (OR = 1.97; 95% CI = 1.81-2.15), and being in an occupation belonging to a high-risk category (OR = 1.92; 95% CI = 1.65-2.26). Among 135 hospitalizations reported due to COVID-19-like illness, 91 (67%) were in the elderly age group of ≥50 and 33 (24%) were in the 18-49-year-old age group., Conclusions: Seroprevalence of SARS-CoV-2 was high in the last two rounds (April to June 2021) which coincide with the second wave of the pandemic (Delta variant B.1.617.2) in India. Overall, one in three children and one in two adults had antibodies for SARS-CoV-2. The suspected or confirmed case of COVID-19 emerged as the significant factor strongly associated with the seropositivity followed by COVID-19 vaccination., Competing Interests: Disclosure of interest: The authors completed the ICMJE Disclosure of Interest Form (available upon request from the corresponding author) and disclose the following activities and/or relationships: HN has received grant funding from Innovative Medicines Initiative, World Health Organisation, Bill and Melinda Gates Foundation, Pfizer and Icosavax. He has received honoraria from Sanofi, GSK, Merck, Novavax, Reviral. Other authors declare that they have no competing interests., (Copyright © 2023 by the Journal of Global Health. All rights reserved.)

Autosomal dominant polycystic kidney disease (ADPKD) is a life-threatening monogenic disease caused by mutations in PKD1 and PKD2 that encode polycystin 1 (PC1) and polycystin 2 (PC2). PC1/2 localize to cilia of renal epithelial cells, and their function is believed to embody an inhibitory activity that suppresses the cilia-dependent cyst activation (CDCA) signal. Consequently, PC deficiency results in activation of CDCA and stimulates cyst growth. Recently, re-expression of PCs in established cysts has been shown to reverse PKD. Thus, the mode of action of PCs resembles a 'counterbalance in cruise control' to maintain lumen diameter within a designated range. Herein we review recent studies that point to novel arenas for future PC research with therapeutic potential for ADPKD., Competing Interests: Declaration of interests The authors have no interests to declare., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Multiciliated cells (MCCs) project dozens to hundreds of motile cilia from their apical surface to promote the movement of fluids or gametes in the mammalian brain, airway or reproductive organs. Differentiation of MCCs requires the sequential action of the Geminin family transcriptional activators, GEMC1 and MCIDAS, that both interact with E2F4/5-DP1. How these factors activate transcription and the extent to which they play redundant functions remains poorly understood. Here, we demonstrate that the transcriptional targets and proximal proteomes of GEMC1 and MCIDAS are highly similar. However, we identified distinct interactions with SWI/SNF subcomplexes; GEMC1 interacts primarily with the ARID1A containing BAF complex while MCIDAS interacts primarily with BRD9 containing ncBAF complexes. Treatment with a BRD9 inhibitor impaired MCIDAS-mediated activation of several target genes and compromised the MCC differentiation program in multiple cell based models. Our data suggest that the differential engagement of distinct SWI/SNF subcomplexes by GEMC1 and MCIDAS is required for MCC-specific transcriptional regulation and mediated by their distinct C-terminal domains., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Oral-facial-digital (OFD) syndromes are a heterogeneous group of congenital disorders characterized by malformations of the face and oral cavity, and digit anomalies. Mutations within 12 cilia-related genes have been identified that cause several types of OFD, suggesting that OFDs constitute a subgroup of developmental ciliopathies. Through homozygosity mapping and exome sequencing of two families with variable OFD type 2, we identified distinct germline variants in INTS13, a subunit of the Integrator complex. This multiprotein complex associates with RNA Polymerase II and cleaves nascent RNA to modulate gene expression. We determined that INTS13 utilizes its C-terminus to bind the Integrator cleavage module, which is disrupted by the identified germline variants p.S652L and p.K668Nfs*9. Depletion of INTS13 disrupts ciliogenesis in human cultured cells and causes dysregulation of a broad collection of ciliary genes. Accordingly, its knockdown in Xenopus embryos leads to motile cilia anomalies. Altogether, we show that mutations in INTS13 cause an autosomal recessive ciliopathy, which reveals key interactions between components of the Integrator complex., (© 2022. The Author(s).)

Multiciliated cells (MCCs) in the brain reside in the ependyma and the choroid plexus (CP) epithelia. The CP secretes cerebrospinal fluid that circulates within the ventricular system, driven by ependymal cilia movement. Tumors of the CP are rare primary brain neoplasms mostly found in children. CP tumors exist in three forms: CP papilloma (CPP), atypical CPP, and CP carcinoma (CPC). Though CPP and atypical CPP are generally benign and can be resolved by surgery, CPC is a particularly aggressive and little understood cancer with a poor survival rate and a tendency for recurrence and metastasis. In contrast to MCCs in the CP epithelia, CPCs in humans are characterized by solitary cilia, frequent TP53 mutations, and disturbances to multiciliogenesis program directed by the GMNC-MCIDAS transcriptional network. GMNC and MCIDAS are early transcriptional regulators of MCC fate differentiation in diverse tissues. Consistently, components of the GMNC-MCIDAS transcriptional program are expressed during CP development and required for multiciliation in the CP, while CPC driven by deletion of Trp53 and Rb1 in mice exhibits multiciliation defects consequent to deficiencies in the GMNC-MCIDAS program. Previous studies revealed that abnormal NOTCH pathway activation leads to CPP. Here we show that combined defects in NOTCH and Sonic Hedgehog signaling in mice generates tumors that are similar to CPC in humans. NOTCH-driven CP tumors are monociliated, and disruption of the NOTCH complex restores multiciliation and decreases tumor growth. NOTCH suppresses multiciliation in tumor cells by inhibiting the expression of GMNC and MCIDAS, while Gmnc-Mcidas overexpression rescues multiciliation defects and suppresses tumor cell proliferation. Taken together, these findings indicate that reactivation of the GMNC-MCIDAS multiciliogenesis program is critical for inhibiting tumorigenesis in the CP, and it may have therapeutic implications for the treatment of CPC., (© 2022. The Author(s).)

The microtubular scaffold of motile cilia-the axoneme, is decorated with dynein arms, which are large multiprotein complexes essential for ciliary motility. Dynein arms are arranged along the length of the axoneme in a precise repeating pattern, converting chemical energy from ATP hydrolysis into ciliary mechanical movement. How these complicated molecular machines are assembled coordinately and accurately, starting from mere polypeptide chains in the cytoplasm, remains a fascinating yet perplexing question. Rapidly emerging evidence, from multiple studies carried out with different model organisms and with various methodologies, has highlighted the existence of a dedicated assembly pathway. Here, we summarize recent progress made in clarifying the axonemal dynein arm assembly process, focusing on individual assembly steps, including cytoplasmic preassembly, intraflagellar transport, and axonemal docking., (© 2022 Wiley Periodicals LLC.)

Background: Adaptation of existing guidelines can be an efficient way to develop contextualized recommendations. Transparent reporting of the adaptation approach can support the transparency and usability of the adapted guidelines., Objective: To develop an extension of the RIGHT (Reporting Items for practice Guidelines in HealThcare) statement for the reporting of adapted guidelines (including recommendations that have been adopted, adapted, or developed de novo), the RIGHT-Ad@pt checklist., Design: A multistep process was followed to develop the checklist: establishing a working group, generating an initial checklist, optimizing the checklist (through an initial assessment of adapted guidelines, semistructured interviews, a Delphi consensus survey, an external review, and a final assessment of adapted guidelines), and approval of the final checklist by the working group., Setting: International collaboration., Participants: A total of 119 professionals participated in the development process., Measurements: Participants' consensus on items in the checklist., Results: The RIGHT-Ad@pt checklist contains 34 items grouped in 7 sections: basic information (7 items); scope (6 items); rigor of development (10 items); recommendations (4 items); external review and quality assurance (2 items); funding, declaration, and management of interest (2 items); and other information (3 items). A user guide with explanations and real-world examples for each item was developed to provide a better user experience., Limitation: The RIGHT-Ad@pt checklist requires further validation in real-life use., Conclusion: The RIGHT-Ad@pt checklist has been developed to improve the reporting of adapted guidelines, focusing on the standardization, rigor, and transparency of the process and the clarity and explicitness of adapted recommendations., Primary Funding Source: None.

Introduction: Large-scale sero-prevalence studies with representation from all age groups are required to estimate the true burden of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections in the community. Serial serological surveys in fixed cohorts enable study of dynamics of viral transmission and correlates of immune response over time in the context of gradual introduction of COVID-19 vaccines and repeated upsurge of cases during the pandemic., Methods: This longitudinal study will involve follow-up of a cohort of 25,000 individuals (5,000 per site) aged 2 years and above recruited from five existing demographic surveillance sites in India. The cohort will be tested for the presence of IgG antibodies against S1/S2 spike protein subunits of SARS-CoV-2 in four rounds; once at baseline and subsequently, at intervals of 4 months for a year between January 2021 and January 2022. Neutralization assays will be carried out in a subset of seropositive samples in each round to quantify the antibody response and to estimate the durability of antibody response. Serial serological surveys will be complemented by fortnightly phone based syndromic surveillance to assess the burden of symptomatic acute febrile illness/ influenza like illness in the same cohort. A bio-repository will also be established to store the serum samples collected in all rounds of serological surveys., Discussion: The population based sero-epidemiological studies will help to determine the burden of COVID-19 at the community level in urban and rural Indian populations and guide in monitoring the trends in the transmission of SARS-CoV-2 infection. Risk factors for infection will be identified to inform future control strategies. The serial serological surveys in the same set of participants will help determine the viral transmission dynamics and durability of neutralizing immune response in participants with or without symptomatic COVID infection., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Nair, Raju, Roy, Dandge, Chethrapilly Purushothaman, Jayaraman, Kangusamy, Shrivastava, Arora, Rose, Juvekar, Jammy, Singh, Mehendale, Rajkumar and Malik.)

The vertebrate left-right axis is specified during embryogenesis by a transient organ: the left-right organizer (LRO). Species including fish, amphibians, rodents and humans deploy motile cilia in the LRO to break bilateral symmetry, while reptiles, birds, even-toed mammals and cetaceans are believed to have LROs without motile cilia. We searched for genes whose loss during vertebrate evolution follows this pattern and identified five genes encoding extracellular proteins, including a putative protease with hitherto unknown functions that we named ciliated left-right organizer metallopeptide (CIROP). Here, we show that CIROP is specifically expressed in ciliated LROs. In zebrafish and Xenopus, CIROP is required solely on the left side, downstream of the leftward flow, but upstream of DAND5, the first asymmetrically expressed gene. We further ascertained 21 human patients with loss-of-function CIROP mutations presenting with recessive situs anomalies. Our findings posit the existence of an ancestral genetic module that has twice disappeared during vertebrate evolution but remains essential for distinguishing left from right in humans., (© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Routinely children are exposed to various procedures as a part of clinical care and/or research participation. Public health strategies to contain current COVID-19 pandemic demanded massive nasopharyngeal swab testing but limited data exist to confirm the extent of the pain and distress that result from this procedure. These data could help clinicians to formulate mitigation strategies, influence public health directives, and inform review boards/ethics committees to decide on risk-benefit ratio of the procedure. Hence, an observational study to assess perceived distress was nested in a phase IV alternate and reduced dose schedule trial of the pneumococcal conjugate vaccine (PCV) in which nasopharyngeal swab (NPS) was used to collect nasopharyngeal secretions as part of the study procedure. Out of 805 infant participants enrolled in the main study, a total of 425 infants were enrolled and observed for procedural distress at 18 weeks and 10 months of age using the Face Leg Activity Cry and Consolability (FLACC) Scale. The FLACC score and duration of cry were recorded. The mean FLACC score changed substantially from preprocedural to procedure in both age groups (from 0.08 to 5.8 at 18 weeks and from 0.5 to 7.007 at 10 months. P  = <.0001). The proportion of infants experiencing higher FLACC scores (7-10) indicating severe distress increased significantly from 22% (n = 95) at 18 weeks to 61% (n = 248) at 10 months ( P  < .0001). The mean duration of cry was significantly increased from 23.03 seconds at 18 weeks to 52.6 seconds at 10 months ( P  = .00). Nasopharyngeal swab collection produced substantial distress which increased with age. Adequate training of sample collectors and supporting parent engagement during procedure could help in reducing the distress., Competing Interests: None., (© 2021 The Authors. Paediatric and Neonatal Pain published by John Wiley & Sons Ltd.)

Motile cilia defects impair cerebrospinal fluid (CSF) flow and can cause brain and spine disorders. The development of ciliated cells, their impact on CSF flow, and their function in brain and axial morphogenesis are not fully understood. We have characterized motile ciliated cells within the zebrafish brain ventricles. We show that the ventricles undergo restructuring through development, involving a transition from mono- to multiciliated cells (MCCs) driven by gmnc. MCCs co-exist with monociliated cells and generate directional flow patterns. These ciliated cells have different developmental origins and are genetically heterogenous with respect to expression of the Foxj1 family of ciliary master regulators. Finally, we show that cilia loss from the tela choroida and choroid plexus or global perturbation of multiciliation does not affect overall brain or spine morphogenesis but results in enlarged ventricles. Our findings establish that motile ciliated cells are generated by complementary and sequential transcriptional programs to support ventricular development., Competing Interests: Declaration of interests N.K., A.G., and B.S.N. are full-time employees of Resolve Biosciences GmbH., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Micronutrient deficiency is a known cause of adverse neurodevelopment and growth. Poor adherence to oral regimes of micronutrient supplements is a known challenge during the implementation of supplementation programs. The present study evaluates the benefits of liposomal encapsulated micronutrient fortified body oils (LMF oil) that can be used for infant body massage in terms of neurodevelopment and prevention of deficiency., Study Design: Double-blind randomized clinical trial., Methods: A total of 444 healthy infants aged 4-7 weeks were randomized to receive either LMF oil (containing iron, vitamin D, folate, and vitamin B12) or placebo oil for gentle body massage till 12 months of age. Blood samples were collected at 6 and 12 months for transferrin saturation (TSAT), hemoglobin, and 25-hydroxy vitamin (25-OH-D) levels. Mental and motor development was assessed at 12 months using developmental assessment for Indian Infants (DASII)., Results: A total of 391 infants completed the study. There was no significant improvement in the hemoglobin in the intervention group at 12 months of age as compared to the placebo group [- 0.50 vs.-0.54 g%]. There was a marginally significant improvement in 25-OH-D at 12 months in the LMF oil group [+ 1.46vs.-0.18 ng/ml, p = 0.049]. In the subgroup of infants with moderate anemia, the intervention prevented the decline in hemoglobin at 12 months of age [adjusted mean change + 0.11vs.-0.51 g%, p = 0.043]. The mental or motor developmental quotients in the intervention group were not significantly different from those in the placebo group., Conclusion: Use of LMF oil for prevention of nutritional deficiency did not offer significant protection against nutritional anemia but prevented vitamin D deficiency to some extent with improvement in 25-OH-D at 12 months. In the subgroup of infants with moderate anemia, the intervention prevented the decline in hemoglobin at 12 months of age. The intervention did not result in significant improvement in mental or motor development. Further evaluation with increased doses needs to be undertaken., Trial Registration: CTRI no: CTRI/2017/11/010710 ; dated 30/11/2017., (© 2021. The Author(s).)

Background: To control the transmission of the coronavirus disease 2019 (COVID-19) infection, the Government of India (GoI) had taken stringent precautionary measures during the lockdown period. This study aimed to explore determinants affecting adherence to protective measures against COVID-19 infection among rural and semi-urban settings of Maharashtra, India. Methods: A cross-sectional telephonic survey among 1,016 adults from randomly selected households was conducted between June 5 and July 16, 2020. The data were explored for knowledge, awareness, practices related to protective measures, and self-risk perception. Socio-demographic and attitudinal correlates of failure to use protective measures against COVID-19 were measured. Results: In the survey, 72% of the participants were men. The mean age was 46 years (SD: 13.8). The main source of information was television (91%); however, information from healthcare providers (65%) and mass media announcements (49%) was trustworthy. Washing hands immediately with soap after returning from outdoors was reported by 95% of the respondents, always using a mask while outdoors by 94%, never attended social gatherings by 91%, always using hand sanitizer while outside by 77%, and 68% of the respondents followed all protective measures. The knowledge score [mean score 20.3 (SD: 2.4) out of 24] was independently associated with the risk of not using protective measures, with each unit increase in knowledge score, the risk of not using protective measures reduced by 16%. No source of income was independently associated with not using protective measures [AOR 1.5 95% CI (1.01-2.3)]. Conclusions: The COVID-19 public health interventions and behavior change communication strategies should be specifically directed towards the low socio-economic populations through trusted sources. The association between knowledge and practices demonstrates the importance of accurate public health communication to optimally follow preventive measures, such as structural interventions to address poverty and employment policies to address the unemployment crisis are required. Surveillance activity is needed to understand the actual behavior change among the population., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Shewale, Sane, Ujagare, Patel, Roy, Juvekar, Kohli, Bangar, Jadhav and Sahay.)

Adolescent idiopathic scoliosis (AIS) is a common skeletal disorder, characterized by abnormal spine curvatures. In zebrafish, cilia-driven cerebrospinal fluid flow and urotensin II pathway activity are required for proper spine morphogenesis. Genetic studies with AIS patients now establish a conservation of the zebrafish findings in the etiology of the disease., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Epithelial tissues are primed to respond to insults by activating epithelial cell motility and rapid inflammation. Such responses are also elicited upon overexpression of the membrane-bound protease, Matriptase, or mutation of its inhibitor, Hai1. Unrestricted Matriptase activity also predisposes to carcinoma. How Matriptase leads to these cellular outcomes is unknown. We demonstrate that zebrafish hai1a mutants show increased H 2 O 2 , NfκB signalling, and IP 3 R -mediated calcium flashes, and that these promote inflammation, but do not generate epithelial cell motility. In contrast, inhibition of the Gq subunit in hai1a mutants rescues both the inflammation and epithelial phenotypes, with the latter recapitulated by the DAG analogue, PMA. We demonstrate that hai1a has elevated MAPK pathway activity, inhibition of which rescues the epidermal defects. Finally, we identify RSK kinases as MAPK targets disrupting adherens junctions in hai1a mutants. Our work maps novel signalling cascades mediating the potent effects of Matriptase on epithelia, with implications for tissue damage response and carcinoma progression., Competing Interests: JM, CS, YH, HM, KM, CZ, CT, SN, WZ, VT, LP, SR, EA, TC No competing interests declared, (© 2021, Ma et al.)

Introduction: Health interventions often target pregnant women and their unborn children. Interventions in rural India targeting pregnant women, however, often do not cover the critical early windows of susceptibility during the first trimester and parts of the second trimester. This pilot seeks to determine if targeting newlyweds could protect entire pregnancies with a clean stove and fuel intervention., Methods: We recruited 50 newlywed couples who use biomass as a cooking fuel into a clean cooking intervention that included a liquefied petroleum gas (LPG) stove, two gas cylinders, a table to place the stove on and health education. We first evaluated whether community health workers in this region could identify and recruit couples at marriage. We quantified how many additional days of pregnancy could be covered by an intervention if we recruited at marriage versus recruiting after detection of pregnancy., Results: On average, we identified and visited newlywed couples within 40 (SD 21) days of marriage. Of the 50 couples recruited, 25 pregnancies and 18 deliveries were identified during this 1-year study. Due to challenges securing fuel from the LPG supply system, not all couples received their intervention prior to pregnancy. Regardless, couples recruited in the marriage arm had substantially more days with the intervention than couples recruited into a similar arm recruited at pregnancy (211 SD 46 vs 120 SD 45). At scale, a stove intervention targeting new marriages would cover about twice as many weeks of first pregnancies as an intervention recruiting after detection of pregnancy., Conclusions: We were able to recruit in early marriage using existing community health workers. Households recruited early in marriage had more days with clean fuel coverage than those recruited at pregnancy. Our findings indicate that recruitment at marriage is feasible and warrants further exploration for stove and other interventions targeting pregnancy-related outcomes., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Esoteric organelles called deuterosomes have been implicated in the explosive production of hundreds of basal bodies in multiciliated cells (MCCs). A new study by Meunier, Holland, and colleagues now shows that deuterosomes are dispensable, re-igniting the quest for mechanisms driving basal body biogenesis in this specialized ciliated cell type., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

We review concepts and methods associated with quantum discord and related topics. We also describe their possible connections with other aspects of quantum information and beyond, including quantum communication, quantum computation, many-body physics, and open quantum dynamics. Quantum discord in the multiparty regime and its applications are also discussed.

In five separate families, we identified nine individuals affected by a previously unidentified syndrome characterized by growth retardation, spine malformation, facial dysmorphisms, and developmental delays. Using homozygosity mapping, array CGH, and exome sequencing, we uncovered bi-allelic loss-of-function CDK10 mutations segregating with this disease. CDK10 is a protein kinase that partners with cyclin M to phosphorylate substrates such as ETS2 and PKN2 in order to modulate cellular growth. To validate and model the pathogenicity of these CDK10 germline mutations, we generated conditional-knockout mice. Homozygous Cdk10-knockout mice died postnatally with severe growth retardation, skeletal defects, and kidney and lung abnormalities, symptoms that partly resemble the disease's effect in humans. Fibroblasts derived from affected individuals and Cdk10-knockout mouse embryonic fibroblasts (MEFs) proliferated normally; however, Cdk10-knockout MEFs developed longer cilia. Comparative transcriptomic analysis of mutant and wild-type mouse organs revealed lipid metabolic changes consistent with growth impairment and altered ciliogenesis in the absence of CDK10. Our results document the CDK10 loss-of-function phenotype and point to a function for CDK10 in transducing signals received at the primary cilia to sustain embryonic and postnatal development., (Copyright © 2017 American Society of Human Genetics. All rights reserved.)

DISRUPTED-IN-SCHIZOPHRENIA (DISC1) has been one of the most intensively studied genetic risk factors for mental illness since it was discovered through positional mapping of a translocation breakpoint in a large Scottish family where a balanced chromosomal translocation was found to segregate with schizophrenia and affective disorders. While the evidence for it being central to disease pathogenesis in the original Scottish family is compelling, recent genome-wide association studies have not found evidence for common variants at the DISC1 locus being associated with schizophrenia in the wider population. It may therefore be the case that DISC1 provides an indication of biological pathways that are central to mental health issues and functional studies have shown that it functions in multiple signalling pathways. However, there is little information regarding factors that function upstream of DISC1 to regulate its expression and function. We herein demonstrate that Sonic hedgehog (Shh) signalling promotes expression of disc1 in the zebrafish brain. Expression of disc1 is lost in smoothened mutants that have a complete loss of Shh signal transduction, and elevated in patched mutants which have constitutive activation of Shh signalling. We previously demonstrated that disc1 knockdown has a dramatic effect on the specification of oligodendrocyte precursor cells (OPC) in the hindbrain and Shh signalling is known to be essential for the specification of these cells. We show that disc1 is prominently expressed in olig2-positive midline progenitor cells that are absent in smo mutants, while cyclopamine treatment blocks disc1 expression in these cells and mimics the effect of disc1 knock down on OPC specification. Various features of a number of psychiatric conditions could potentially arise through aberrant Hedgehog signalling. We therefore suggest that altered Shh signalling may be an important neurodevelopmental factor in the pathobiology of mental illness., (© 2015. Published by The Company of Biologists Ltd.)

Over the recent years, a large number of embryological studies with the zebrafish have provided substantial evidence of its usefulness for the investigation of the genetic and cellular basis of vertebrate development. With regard to the Hedgehog (Hh) pathway, forward as well as reverse genetic approaches in this organism have not only validated the roles of evolutionarily conserved players of the signaling cascade, but have also contributed to the isolation of several novel components that had remained unidentified through screens in other animal models. Here, the author describes a whole mount antibody labeling method that allows the detection of three unique muscle cell fates in the zebrafish embryo, which are induced by distinct levels and timing of Hh-signaling activity. This technique provides a rapid and convenient assay that can be utilized for the evaluation of effects of loss- or gain-of-function of any gene on the levels of Hh pathway activation during embryogenesis.