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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.

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.

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.

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.

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.

Aiming at the design of an allosteric modulator of the neonatal Fc receptor (FcRn)-Immunoglobulin G (IgG) interaction, we developed a new methodology including NMR fragment screening, X-ray crystallography, and magic-angle-spinning (MAS) NMR at 100 kHz after sedimentation, exploiting very fast spinning of the nondeuterated soluble 42 kDa receptor construct to obtain resolved proton-detected 2D and 3D NMR spectra. FcRn plays a crucial role in regulation of IgG and serum albumin catabolism. It is a clinically validated drug target for the treatment of autoimmune diseases caused by pathogenic antibodies via the inhibition of its interaction with IgG. We herein present the discovery of a small molecule that binds into a conserved cavity of the heterodimeric, extracellular domain composed of an α-chain and β2-microglobulin (β2m) (FcRnECD, 373 residues). X-ray crystallography was used alongside NMR at 100 kHz MAS with sedimented soluble protein to explore possibilities for refining the compound as an allosteric modulator. Proton-detected MAS NMR experiments on fully protonated [13C,15N]-labeled FcRnECD yielded ligand-induced chemical-shift perturbations (CSPs) for residues in the binding pocket and allosteric changes close to the interface of the two receptor heterodimers present in the asymmetric unit as well as potentially in the albumin interaction site. X-ray structures with and without ligand suggest the need for an optimized ligand to displace the α-chain with respect to β2m, both of which participate in the FcRnECD-IgG interaction site. Our investigation establishes a method to characterize structurally small molecule binding to nondeuterated large proteins by NMR, even in their glycosylated form, which may prove highly valuable for structure-based drug discovery campaigns.

For reasons of time, this short talk will be confined to the optimal frequency, timing, indications and dosing of blood transfusion. Blood transfusion protocols in thalassaemia syndromes are more widely agreed (1) than for sickle disorders but questions still remain about optimal Hb levels, timing and frequency. In transfusion thalassaemia thalassaemias (TDT) , the purpose of blood transfusion is to maximise quality of life by correcting anaemia and suppressing ineffective erythropoiesis, whilst minimising the complications of the transfusion itself. Under-transfusion will limit growth and physical activity while increasing intramedullary and extra-medullary erythroid expansion. Over transfusion may cause unnecessary iron loading and increased risk of extra-hepatic iron deposition however. Although guidelines imply a ‘one size fits all’ approach to transfusion, in reality this is not be the case. Indeed a flexible approach crafted to the patient’s individual requirements and to the local availability of safe blood products is needed for optimal outcomes. For example in HbEβ thalassaemias, the right shifted oxygen dissociation curve tends to lead to better oxygen delivery per gram of Hb than in β thalassaemia intermedia with high Hb F. Patients with Eβthal therefore tend to tolerate lower Hb values than β thalassaemia intermedia. Guidelines aim to balance the benefits of oxygenation and suppression of extra-medullary expansion with those of excessive iron accumulation from overtransfusion. In an Italian TDT population, this balance was optimised with pre-transfusion values of 9.5-10.5g/dl (2). However this may not be universally optimal because of different levels of endogenous erythropoiesis with different genotypes in different populations. Recent work by our group (3) suggests that patients with higher levels of endogenous erythropoiesis, marked by higher levels of soluble transferrin receptors, at significantly lower risk of cardiac iron deposition than in those where endogenous erythropoiesis is less active, as would be the case in transfusion regimes achieving higher levels of pre-transfusion Hb. In sickle cell disorders, the variability in the phenotype between patients and also within a single patient at any given time means that the need for transfusion also varies. A consideration in sickle disorders, not usually applicable to thalassaemia syndromes, is that of exchange transfusion versus simple top up transfusion. Exchanges have the advantages of lower iron loading rates and more rapid lowering of HbS%. Disadvantages of exchange transfusion are of increased exposure to blood products with inherent increased risk of allo-immunisation or infection, requirement for better venous access for adequate blood flow, and requirements for team of operators capable of performing either manual or automated apheresis, often at short notice. Some indications for transfusion in sickle disorders are backed up by randomised controlled data, such as for primary and secondary stroke prevention, or prophylaxis of sickle related complications for high-risk operations (4). Others are widely practiced as standard of care without randomised data, such as treatment of acute sickle chest syndrome. Other indications for transfusion, not backed up by randomised studies, but still widely practiced in selected cases, include the management of pregnancy, leg ulceration or priapism and repeaed vaso-occlusive crises. Allo-immunisation is more common in sickle patients than in thalassaemia disorders and hyper-haemolysis is a rare but growing serious problem in sickle disorders. It is arguable that increased use of transfusion early in life, is indicated to decrease silent stroke rates and that early exposure to blood will decease red cell allo-immunisation rates.

Recent years have seen accelerating advances in the treatment, monitoring and potential cures for haemoglobin disorders, as the interaction between basic science, pharmaceutical research, and practical medicine intensifies. In order to appreciate how close to the end we may have reached, it is helpful to consider the journey thus far. For thalassaemia syndromes, advances with non-curative treatment began with the establishment of the principles of blood transfusion and their application in the 1950s both to treat anaemia and suppress erythropoietic expansion. The consequences of transfusional iron overload soon became a problem however, with patients dying in their late teens and early 20s, typically with cardiomyopathy. The introduction of desferrioxamine infusions in the 1970s, led to gradual improvement in outcome and the subsequent introduction and licensing of orally active chelation has contributed to improved treatment adherence and improved survival. Morbidity from iron overload, particularly hypogonadotrophic hypogonadism remains a serious issue and emergence of new pathologies in older patients, such as in the liver, is a cause for concern. Curative treatment with allogeneic stem cell transplantation was introduced in the 1980s but is only available to a minority of patients and is still associated with significant morbidity and mortality. Novel approaches aimed at decreasing transfusion requirements by improving the efficiency of erythropoiesis, such as with activin receptor traps, may prove useful in both transfusion dependent and non-transfusion dependent thalassaemias. Gene therapy is now a reality for a small number of patients and has the potential for application to many patients in whom allogeneic transplant was precluded by lack of a suitable donors, or was too risky for other reasons such increasing as age. For sickle cell disorders, advances have included the setting up of specialist clinics, pneumococcal septicaemia prevention programs, the application of blood transfusion for the prevention and treatment of disease complications, the use of hydroxyurea for prevention of painful crises and chest syndrome and allogeneic transplantation for carefully selected patients. New pharmacological agents with novel mechanisms of action are being evaluated at a hitherto unprecidented rate. However thus far, the impact of these advances on survival and quality of life in patients as a whole often lags somewhat behind those of thalassaemia. Disease prevention is a key element to management of both sickle and thalassaemia syndromes but implementation has been highly variable both geographically and even between these conditions at a local level. Prevention of births with sickle cell disorders have been less effective than for thalassaemia, even in countries such as the UK which share the same prevention programs for these conditions. The perceived variability and unpredictability of sickle cell disease is part of the reason for this: if all patients had a uniformly fatal outcome without transfusion, blood transfusion would be more uniformly applied, as with TDT , from an early age with perhaps better overall quality of life and survival. In order approach “the end,’’ advances in therapy will need to be more affordable and deliverable to populations where the conditions are most prevalent. It is anticipated in the next decade that blood transfusion safety will improve, the cost of chelation will fall, the safety and applicability of allogeneic stem cell transplantation with increase, and with further scientific advances such as CRISPR technology, the cost of gene therapy fall. In the meantime, to paraphrase a well-known quotation, “this is not the end, it is not even at the beginning of the end, but it is perhaps the end of the beginning”.

Summary: Background: The burden of end-stage kidney disease (ESKD) in sub-Saharan Africa is unknown but is probably high. Access to dialysis for ESKD is limited by insufficient infrastructure and catastrophic out-of-pocket costs. Most patients remain undiagnosed, untreated, and die. We did a systematic literature review to assess outcomes of patients who reach dialysis and the quality of dialysis received. Methods: We searched PubMed, African Journals Online, WHO Global Health Library, and Web of Science for articles in English or French from sub-Saharan Africa reporting dialysis outcomes in patients with ESKD published between Jan 1, 1990, and Dec 22, 2015. No studies were excluded to best represent the current situation in sub-Saharan Africa. Outcomes of interest included access to dialysis, mortality, duration of dialysis, and markers of dialysis quality in patients with ESKD. Data were analysed descriptively and reported using narrative synthesis. Findings: Studies were all of medium to low quality. We identified 4339 studies, 68 of which met inclusion criteria, comprising 24 456 adults and 809 children. In the pooled analysis, 390 (96%) of 406 adults and 133 (95%) of 140 children who could not access dialysis died or were presumed to have died. Among those dialysed, 2747 (88%) of 3122 adults in incident ESKD cohorts, 496 (16%) of 3197 adults in prevalent ESKD cohorts, and 107 (36%) of 294 children with ESKD died or were presumed to have died. 2508 (84%) of 2990 adults in incident ESKD cohorts discontinued dialysis compared with 64 (5%) of 1364 adults in prevalent ESKD cohorts. 41 (1%) of 4483 adults in incident ESKD cohorts, 2280 (19%) of 12 125 adults in prevalent ESKD cohorts, and 71 (19%) of 381 children with ESKD received transplants. 16 studies reported on management of anaemia, 17 on dialysis frequency, eight on dialysis accuracy, and 22 on vascular access for dialysis Interpretation: Most patients with ESKD starting dialysis in sub-Saharan Africa discontinue treatment and die. Further work is needed to develop equitable and sustainable strategies to manage individuals with ESKD in sub-Saharan Africa. Funding: None.

OBJECTIVE: To explore whether adding a gender and HIV training programme to microfinance initiatives can lead to health and social benefits beyond those achieved by microfinance alone. METHODS: Cross-sectional data were derived from three randomly selected matched clusters in rural South Africa: (i) four villages with 2-year exposure to the Intervention with Microfinance for AIDS and Gender Equity (IMAGE), a combined microfinance-health training intervention; (ii) four villages with 2-year exposure to microfinance services alone; and (iii) four control villages not targeted by any intervention. Adjusted risk ratios (aRRs) employing village-level summaries compared associations between groups in relation to indicators of economic well-being, empowerment, intimate partner violence (IPV) and HIV risk behaviour. The magnitude and consistency of aRRs allowed for an estimate of incremental effects. FINDINGS: A total of 1409 participants were enrolled, all female, with a median age of 45. After 2 years, both the microfinance-only group and the IMAGE group showed economic improvements relative to the control group. However, only the IMAGE group demonstrated consistent associations across all domains with regard to women's empowerment, intimate partner violence and HIV risk behaviour. CONCLUSION: The addition of a training component to group-based microfinance programmes may be critical for achieving broader health benefits. Donor agencies should encourage intersectoral partnerships that can foster synergy and broaden the health and social effects of economic interventions such as microfinance.

Dryland rivers have considerable flow variability, producing complex ecosystems, processes, and communities of organisms that vary over space and time. They are also among the more vulnerable of the world's ecosystems. A key strategy for conservation of dryland rivers is identifying and maintaining key sites for biodiversity conservation, particularly protecting the quantity and quality of flow and flooding regimes. Extreme variability considerably challenges freshwater conservation planning. We systematically prioritised wetlands for waterbirds (simultaneously for 52 species), across about 13.5% of the Murray-Darling Basin (1,061,469 km2), using a 30-year record of systematic aerial surveys of waterbird populations. Nine key wetlands in this area, primarily lakes, floodplains, and swamps, consistently contributed to a representation target (80%) of total abundances of all 52 waterbird species. The long temporal span of our data included dramatic availability (i.e., booms) and scarcity (i.e., busts) of water, providing a unique opportunity to test prioritisation at extremes of variation. These extremes represented periods when waterbirds were breeding or concentrating on refugia, varying wetland prioritisation. In dry years, important wetlands for waterbirds were riverine and lacustrine (12 wetlands) but this changed in wet years to lacustrine and palustrine (8 wetlands). Such variation in ecosystem condition substantially changes the relative importance of individual wetlands for waterbirds during boom and bust phases. Incorporating this variability is necessary for effective conservation of Murray-Darling Basin waterbirds, with considerable generality for other similarly variable systems around the world.

Iron overload in haemoglobinopathies and rare anaemias may develop from increased iron absorption secondary to hepcidin suppression, and/or from repeated blood transfusions. While the accumulation of body iron load from blood transfusion is inevitable and predictable from the variable rates of transfusion in the different conditions, there are some important differences in the distribution of iron overload and its consequences between these. Transfusion-dependent thalassaemia (TDT) is the best described condition in which transfusional overload occurs. Initially iron loads into macrophages, subsquently hepatocytes, and then the endocrine system including the anterior pituiatry and finally the myocardium. The propensity to extrahepatic iron spread increases with rapid transfusion and with inadequate chelation therapy but there is considerable interpatient and interpopulation variability in this tendency. The conduits though which iron is delivered to tissues is through non transferrin iron species (NTBI) which are taken into liver, endocrine tissues and myocardium through L-type calcium channells and possibly through other channells. Recent work by the MSCIO group1 suggests that levels of NTBI are determined by three mechanisms: i) increasing with iron overload; ii) increasing with ineffective erythropoieis; iii) and decreasing when level of transferrin iron utilisation is high. In TDT all three mechanisms increase NTBI levels because transferrin iron utilisation is suppressed by hypertransfusion. It is hypothesized that the transfusion regimen and target mean Hb may have a key impact on NTBI levels because high transfusion regimes may suppress the ‘sink’ effect of the erythron though decreased clearance of transferrin iron. In sickle cell disease (SCD) without blood transfusion the anaemia results mainly from haemolysis rather than from ineffective erythropoiesis.2 Thus there is a tendency to iron depletion because of urinary iron loss from intrascular haemolysis outweighs any increased iron absortion from hepcidin suppression. These effects result in a low trasferrin saturation and NTBI levels and a low tendency from extrahepatic iron distribution. In rare anaemias that result from low production of red cells such as Diamond Blackfan Anaemia (DBA) there is little or no clearance of transferrin iron by the erythron. This leads to high NTBI and a high tendency to extrahepatic iron distribution in DBA. These differences potentially impact on strategies for monitoring and treatment of iron overload in these different conditions.

Oral presentation is available online

Oral presentation is available online