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Abstract Extracorporeal membrane oxygenation (ECMO) is a cardiopulmonary bypass device commonly used to treat cardiac arrest in children. The American Heart Association guidelines for cardiopulmonary resuscitation (CPR) and emergency cardiovascular care recommend using amiodarone as a first‐line agent to treat ventricular arrhythmias in children with cardiac arrest. However, there are no dosing recommendations for amiodarone to treat ventricular arrhythmias in pediatric patients on ECMO. Amiodarone has a high propensity for adsorption to the ECMO components due to its physicochemical properties leading to altered pharmacokinetics (PK) in ECMO patients. The change in amiodarone PK due to interaction with ECMO components may result in a difference in optimal dosing in patients on ECMO when compared with non‐ECMO patients. To address this clinical knowledge gap, a physiologically‐based pharmacokinetic model of amiodarone was developed in adults and scaled to children, followed by the addition of an ECMO compartment. The pediatric model included ontogeny functions of cytochrome P450 (CYP450) enzyme maturation across various age groups. The ECMO compartment was parameterized using the adsorption data of amiodarone obtained from ex vivo studies. Model predictions captured observed concentrations of amiodarone in pediatric patients with ECMO well with an average fold error between 0.5 and 2. Model simulations support an amiodarone intravenous (i.v) bolus dose of 22 mg/kg (neonates), 13 mg/kg (infants), 8 mg/kg (children), and 6 mg/kg (adolescents). This PBPK modeling approach can be applied to explore the dosing of other drugs used in children on ECMO.

Background: Prednisolone and prednisone are recommended treatment options for adults with congenital adrenal hyperplasia (CAH); however, there is no randomised comparison of prednis(ol)one with hydrocortisone. Design: Six-month open-label randomised phase 3 study and interim analysis of a single-arm extension study was the design of the study. Methods: The method of the study was hydrocortisone dose equivalent and 09:00-h 17-hydroxyprogesterone (17OHP) from 48 patients taking prednis(ol)one at baseline. Results: At baseline, the median hydrocortisone dose equivalent was 30 mg/day and 17OHP was < 36 nmol/L (3× upper limit of normal) in 56% of patients. Patients were randomised to continue prednis(ol)one or switch to modified-release hydrocortisone capsule (MRHC) at the same hydrocortisone-equivalent dose. At 4 weeks, 94% on MRHC and 71% on prednis(ol)one had 17OHP < 36 nmol/L. At 18 months in the extension study of MRHC, the median MRHC dose was 20 mg/day and 82% had 17OHP < 36 nmol/L. The per cent of patients with 17OHP < 36 nmol/L on a hydrocortisone dose equivalent ≤ 25 mg/day was greater at 18 months in the extension study on MRHC than while on prednis(ol)one at baseline: 57% vs 27%, P = 0.04. In the randomised study, no patients had an adrenal crisis on MRHC and one on prednisolone. In the extension study (221 patient years), there were 12 adrenal crises in 5 patients (5.4/100 patient years). Conclusion: MRHC reduces 17OHP at 09:00 h compared to prednis(ol)one and the dose of MRHC can be down-titrated over time in the majority of patients.

Abstract Background Construction workers are 3–4 times more likely than other workers to die from accidents at work—however, in the developing world, the risks associated with construction work may be 6 times greater. India does not publish occupational injury statistics, and so little is known about construction workers injured. We aimed to use Indian police records to describe the epidemiology of construction site injuries in Delhi and to thus generate knowledge that may help to control the burden of injuries to construction workers in India and in other developing countries. Methods This was a cross-sectional analysis of accident records maintained by the Delhi Police. We included all construction workers reported to have been killed or injured in construction site accidents in Delhi during the period 2016–2018. We used multivariable logistic regression models to investigate associations between injury severity (fatal vs. non-fatal injury) and exposure variables whilst adjusting for a priori risk factors. We also estimated the number of Delhi construction workers in total and by trade to generate estimates of worker injury rates per 100,000 workers per year. Results There were 929 construction site accidents within the study period, in which 1,217 workers and children were reported to have sustained injuries: 356 (29%) were fatal and 861 (71%) were non-fatal. One-eighth of injuries were sustained by females. Most occurred in the Rainy season; most were sustained during the construction of buildings. The most frequent causes were the collapse of an old building, the collapse of a new building under construction, and electric shocks. Electricians were more likely than unskilled workers to suffer a fatal injury (adjOR 2.5; 95% CI: 0.87–6.97), and there were more electrical shocks than electricians injured. The odds of a fatal injury were statistically significantly lower in Central districts than in the less developed, peripheral districts. Conclusions Construction site injuries are an unintended health impact of urbanisation. Women undertake manual work alongside men on construction sites in Delhi, and many suffer injuries as a consequence: an eighth of the injuries were sustained by females. Children accompanying their working parents on construction sites are also at risk. Two main hazards to construction workers in Delhi were building collapses and electrical shocks. Electricians were over twice as likely as unskilled workers to suffer a fatal injury, and electrical work would appear to be undertaken by a multitude of occupations. As the global urban population increases over the coming decades, so too will the burden of injuries to construction workers. The introduction and enforcement of occupational safety, health, and working conditions laws in India and in other rapidly developing countries will be necessary to help to control this injury burden to construction workers.

Summary: In this article we attempt to put forth insights into using traditional medicine (TM) systems to achieve Universal Health Coverage (UHC). We discuss the need for reimagining India's health system and the importance of an inclusive approach for UHC. We comprehend the challenges with appropriate use of TM systems and the lessons from international experience of integrating TM systems. We highlight the pathways for better utilization of TM systems for UHC in India.

Background: The use of pre- and intra-operative vasoactive agents for improved blood pressure control has transformed the outcomes following pheochromocytoma (PC) resection. The first agent utilized was phenoxybenzamine, but selective alpha-1 antagonists (SAA) and calcium channel antagonists (CCA) have also been used with success. We sought to define the relationship between pre-operative treatment and intra-operative hemodynamics associated with each of these agents in patients with PC. Methods: A retrospective, single-institution review of patients >18 years with resected PC from 1996-2020 was performed. Pre-operative blockade was at the discretion of the treating providers. Adequacy of pre-operative blockade was determined by the attending surgeon prior to proceeding with PC resection. To determine the effectiveness of pre-operative blockade during surgery, vital signs throughout the operation were examined. Results: The final dataset included 166 patients. Phenoxybenzamine (55%) and SAA (24%) were the most commonly used pre-operative medications but phenoxybenzamine use decreased over time. Patients who experienced a hypertensive crisis had a higher initial systolic blood pressure and were older. There was no predilection for developing a hypertensive crisis based on race, sex, tumor size or type of pre-operative medication used. Patients in the early group (2010-2015) were found to have more pronounced hemodynamic instability when compared to patients in the late group (2016-2020). Conclusion: Although there are no demonstrated differences between antihypertensives, the prescription pattern has evolved away from phenoxybenzamine. However, as this is transition happening, patients exhibit better hemodynamic control. We hypothesize that this is due to greater experience by the intra-operative team.

Since the release of the Oculus Rift CV1 in 2016, millions of VR headsets have made their way into consumers’ homes. Since then, users have created large quantities of data about their experiences in VR through posts made to online discussion forums. We examine this data to gain insights on what sorts of “lingering effects” users report having experienced after VR, and on the progression of these effects over time. We found three major categories of lingering effects (besides simulator sickness) during our qualitative analysis: perceptual effects, behavioral effects, and changes in dreams. The perceptual and behavioral categories were further divided into sub-themes: disruption of body ownership and proprioception, loss of a sense of depth in the real world, visual aftereffects, the need to verify the reality of the real world through touch, hesitation when moving in the real world, and attempts to apply VR interaction metaphors to real life interactions. Users were nearly unanimous that these lingering effects only occurred after spending at least 1 h in VR, and that these effects completely disappeared several weeks after they first appeared (assuming the user continued to spend time in VR). There was less agreement about how long these effects lasted after exiting a specific VR session. The results of our analysis suggest that users feel that there are no long-term side effects to the use of VR. We pair this analysis with an analysis of interviews conducted with 20 novice users who were loaned Oculus Quest HMDs to use for 4 weeks. Semi-structured interviews with participants further substantiated the findings of our analysis of online discussions.

Beta-thalassemia and particularly its transfusion-dependent form (TDT) is a demanding clinical condition, requiring life-long care and follow-up, ideally in specialized centers and by multidisciplinary teams of experts. Despite the significant progress in TDT diagnosis and treatment over the past decades that has dramatically improved patients’ prognosis, its management remains challenging. On one hand, diagnostic and therapeutic advances are not equally applied to all patients across the world, particularly in several high-prevalence eastern regions. On the other, healthcare systems in low-prevalence western countries that have recently received large numbers of migrant thalassemia patients, were not ready to address patients’ special needs. Thalassaemia International Federation (TIF), a global patient-driven umbrella federation with 232 member-associations in 62 countries, strives for equal access to quality care for all patients suffering from thalassemia or other hemoglobinopathies in every part of the world by promoting education, research, awareness, and advocacy. One of TIF’s main actions is the development and dissemination of clinical practice guidelines for the management of these patients. In 2021, the fourth edition of TIF’s guidelines for the management of TDT was published. The full text provides detailed information on the management of TDT patients and the clinical presentation, pathophysiology, diagnostic approach, and treatment of disease complications or other clinical entities that may occur in these patients, while also covering relevant psychosocial and organizational issues. The present document is a summary of the 2021 TIF guidelines for TDT that focuses mainly on clinical practice issues and recommendations.

Abstract Background In India, the construction sector provides the main alternative to agricultural work - seasonal migration to and from construction work is widespread and construction work remains the second-largest employer of women in the country behind agriculture. Occupational injuries, which kill over 300,000 people annually, are a serious public health concern. However, data on construction site injuries to women are lacking, as India does not publish statistics on occupational injuries and illnesses. Our objectives were to: Estimate the number of women injured in construction site accidents in Delhi; and to estimate and compare the annual construction site injury rates per 100,000 workers of males and females in Delhi. Methods We conducted a two-sample capture-recapture study using data for accidents reported to the Delhi Police, Employee State Insurance Corporation (ESIC), and Commissioners of Workmen Compensation (CWC) of Delhi Government. The capture-recapture method has been used in epidemiology, to estimate morbidity and mortality using multiple, overlapping, but incomplete data sources. This study is based on the injuries reported from construction site accidents in Delhi in 2017. We linked the data from each of the data sources using the name, gender, and age of each injured person, the date and place of the accident, and the name of the employer. We used the Chapman estimator to estimate the total incidence of construction injuries in Delhi. Results We estimated that there was a total of 37 female construction site workers injured (17 fatal and 20 non-fatal) in Delhi in 2017. There was a total of 1043 male construction site workers injured (236 fatal and 807 non-fatal). FIRs ascertained two-thirds (68%) of all injuries to females but only one third (34%) of those to males. The annual construction site injury rate per 100,000 workers of females was 82.26 (95%CI: 57.92 to 113.39). The annual construction site injury rate per 100,000 workers of males was 146.5 (95%CI: 137.7 to 155.6). There was strong evidence (p = 0.001) that the overall construction site injury rate per 100,000 workers of females was about one half the rate of males [rate ratio 0.56 (95%CI: 0.40 to 0.78)]. There was no evidence (p = 0.601) that the rates of fatal injuries differed in males and females (rate ratio 1.14 (95%CI: 0.70 to 1.87). Conclusions This study is the first to estimate the incidence of injuries to female construction site workers in India. The overall injury rate of female construction workers was over half as great as the rate of males. This implies that female construction workers face a not insignificant risk. Hence, safety measures (e.g., personal protective equipment) that are appropriate and culturally acceptable to Indian women are needed.

TNF can be inhibited by small molecules that stabilize the TNF trimer in an asymmetric conformation. Here, the authors develop a monoclonal antibody that selectively binds this inactive form of TNF, enabling both target engagement assessment and structural characterization of TNF binding to TNF receptor 1.

Small molecules stabilising a distorted TNF trimer can inhibit TNF signaling, but the underlying mechanism is unclear. Here, the authors characterize the inhibitor-bound TNF-receptor complex structurally and biochemically, showing that the inhibitors alter TNF-receptor binding stoichiometry and cluster formation.

Abstract Background Beta Thalassaemia Major (βTM) is a chronic genetic illness whereby the challenges faced by patients exposes them to increased risk of psychosocial issues. Despite this, a disease-specific tool to measure the impact of this illness on adult patients has yet to be developed. Methods In collaboration with βTM adult patients, this study aimed to develop a comprehensive, disease-specific, easy to use psychometrically sound tool to measure the impact of chelation and transfusion dependent βTM in a cross-cultural patient group in England.The Thalassaemia Life Index (ThALI) was developed in two stages – item generation and pre-testing and item reduction – in collaboration with service users. Recruited adult patients shaped the design of the instrument including its statements and subscales. Standard item reduction techniques were used to develop the instrument. Results The final version of the ThALI encompasses 35 statements and five sub-scales - general physical health, coping, body image, appearance and confidence, social relationships and autonomy. This endorses the multidimensionality of quality of life (QoL). The factor structure of the ThALI is highly stable and its internal consistency is high (alpha = 0.87 for the overall scale; 0.83–0.94 for its subscales). The ThALI has sound scaling assumptions, acceptability and score variability. Content validity was confirmed by experts and service user interviewees. The loadings for the items retained were adequate and the item discriminant validity sound. Conclusions The ThALI covers the impact of βTM in adult patients. Preliminary testing shows its multidimensionality to be reliable and valid. The national authentication of the tool with patients treated in Centres of Excellence will aim to provide further evidence regarding the ThALI’s psychometric properties. Once authenticated, the ThALI may be utilised in research and in clinical settings to assess the effects of new therapies and/or interventions from the patients’ perspective to inform practice and/or to identify areas of concern.

The Murray-Darling Basin (the Basin) is the largest river system in Australia, supplying about 40% of the country’s irrigated agricultural output. Associated water resource development has come with a heavy price for the Basin’s freshwater ecosystems degrading them over decades. Australian governments are attempting to achieve environmental sustainability by returning water to the environment through buy-back of irrigation licences and improved water efficiencies. To determine effectiveness, basin-wide management objectives were established for key indicators, including waterbird populations and life histories which can effectively indicate ecosystem function and condition, driven by flow and flooding regimes. Ongoing monitoring of waterbird numbers indicates continued declines. We evaluated the feasibility of meeting established waterbird objectives under existing and predicted climates. We modelled long-term waterbird numbers using one of the world’s largest ongoing waterbird surveys (1983–2020), covering about 13.5% of the area of the entire Basin. Our findings suggest that under near future climate change projections, waterbird numbers will likely continue to decline, and remain below restoration targets set for the Basin. We discuss the current policy settings for using environmental water to support waterbird populations, recommending adjustments to restore the Basin’s waterbird populations and their wetlands in order to meet Australia’s conservation targets in relation to the ongoing global crisis of biodiversity loss.

Cyclic arginyl-glycyl-aspartic acid peptide (cRGD) peptides show a high affinity towards αVβ3 integrin, a receptor overexpressed in many cancers. We aimed to combine the versatility of ultrasmall gold nanoparticles (usGNP) with the target selectivity of cRGD peptide for the directed delivery of a cytotoxic payload in a novel design. usGNPs were synthesized with a modified Brust-Schiffrin method and functionalized via amide coupling and ligand exchange and their uptake, intracellular trafficking, and toxicity were characterized. Our cRGD functionalized usGNPs demonstrated increased cellular uptake by αVβ3 integrin expressing cells, are internalized via clathrin-dependent endocytosis, accumulated in the lysosomes, and when loaded with mertansine led to increased cytotoxicity. Targeting via cRGD functionalization provides a mechanism to improve the efficacy, tolerability, and retention of therapeutic GNPs.

While biologics have been successfully applied in TNF antagonist treatments, there are no clinically approved small molecules that target TNF. Here, the authors discover potent small molecule inhibitors of TNF, elucidate their molecular mechanism, and demonstrate TNF inhibition in vitro and in vivo.

Abstract Background Current policy priorities to strengthen the nursing sector in India have focused on increasing the number of nurses in the health system. However, the nursing sector is afflicted by other, significant problems including the low status of nurses in the hierarchy of health care professionals, low salaries, and out-dated systems of professional governance, all affecting nurses’ leadership potential and ability to perform. Stronger nurse leadership has the potential to support the achievement of health system goals, especially for strengthening of primary health care, which has been recognised and addressed in several other country contexts. This research study explores the process of policy agenda-setting for nurse leadership in India, and aims to identify the structural and systemic constraints in setting the agenda for policy reforms on the issue. Methods Our methods included policy document review and expert interviews. We identified policy reforms proposed by different government appointed committees on issues concerning nurses’ leadership and its progress. Experts’ accounts were used to understand lack of progress in several nursing reform proposals and analysed using deductive thematic analysis for ‘legitimacy’, ‘feasibility’ and ‘support’, in line with Hall’s agenda setting model. Results The absence of quantifiable evidence on the nurse leadership crisis and treatment of nursing reforms as a ‘second class’ issue were found to negatively influence perceptions of the legitimacy of nurse leadership reform. Feasibility is affected by the lack of representation of nurses in key positions and the absence of a nurse-specific institution, which is seen as essential for creating visibility of the issues facing the profession, their processing and planning for policy solutions. Finally, participants noted the lack of strong support from nurses themselves for these policy reforms, which they attributed to social disempowerment, and lack of professional autonomy. Conclusions The study emphasises that the nursing empowerment needs institutional reforms to facilitate nurse’s distributed leadership across the health system and to enable their collective advocacy that questions the status quo and the structures that uphold it.

β-thalassemia, a hereditary blood disorder caused by defective synthesis of hemoglobin β globin chains, leads to ineffective erythropoiesis and chronic anemia that may require blood transfusions. Sotatercept (ACE-011) acts as a ligand trap to inhibit negative regulators of late-stage erythropoiesis in the transforming growth factor β superfamily, correcting ineffective erythropoiesis. In this phase II, open-label, dose-finding study, 16 patients with transfusion-dependent β -thalassemia and 30 patients with non-transfusion-dependent β-thalassemia were enrolled at seven centers in four countries between November 2012 and November 2014. Patients were treated with sotatercept at doses of 0.1, 0.3, 0.5, 0.75, or 1.0 mg/kg to determine a safe and effective dose. Doses were administered by subcutaneous injection every 3 weeks. Patients were treated for ≤22 months. Response was assessed as a ≥20% reduction in transfusion burden sustained for 24 weeks in transfusion-dependent β-thalassemia patients, and an increase in hemoglobin level of ≥1.0 g/dL sustained for 12 weeks in non-transfusion-dependent β-thalassemia patients. Sotatercept was well tolerated. After a median treatment duration of 14.4 months (range 0.6-35.9), no severe life-threatening adverse events were observed. Thirteen percent of patients reported serious but manageable adverse events. The active dose of sotatercept was ≥0.3 mg/kg for patients with non-transfusion-dependent β-thalassemia and ≥0.5 mg/kg for those with transfusion-dependent β-thalassemia. Of 30 non-transfusion-dependent β-thalassemia patients treated with ≥0.1 mg/kg sotatercept, 18 (60%) achieved a mean hemoglobin increase ≥1.0 g/dL, and 11 (37%) an increase ≥1.5 g/dL, sustained for ≥12 weeks. Four (100%) transfusion-dependent β-thalassemia patients treated with 1.0 mg/kg sotatercept achieved a transfusion-burden reduction of ≥20%. Sotatercept was effective and well tolerated in patients with β-thalassemia. Most patients with non-transfusion-dependent β-thalassemia treated with higher doses achieved sustained increases in hemoglobin level. Transfusion-dependent β-thalassemia patients treated with higher doses of sotatercept achieved notable reductions in transfusion requirements. This trial was registered at ClinicalTrials.gov with the number NCT01571635.