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There is concern that basing healthcare budgets on risk adjustment estimates derived from historical utilisation data may reinforce patterns of unmet need. We propose a method to avoid this, based on a measure of how closely local health organisations align resources to the needs of their populations. We refer to this measure as the 'responsiveness of expenditure to need' and estimate it using national person-level data on use of acute hospital and secondary mental health services in England. We find large variation in responsiveness in both services and show that higher expenditure responsiveness in mental health is associated with fewer suicides. We then re-estimate the national risk-adjustment model removing the data from the organisations with the lowest expenditure responsiveness to need. As expected, higher need individuals are estimated to have higher expenditure needs when less responsive organisations are removed from the estimation of the risk-adjustment. Removal of organisations with below-average responsiveness results in the neediest deciles of individuals having an extra £163 (7%) annual need for acute hospital care and an additional £79 (27%) annual need for mental health services. The application of this approach to risk adjustment would result in more resources being directed towards organisations serving higher-need populations., (Crown Copyright © 2024. Published by Elsevier Ltd. All rights reserved.)

Background: The process of grading and stratifying evidence in the extensive literature on neurosurgical guidelines has evolved significantly, ranging from high-quality standards to suggested options. However, the methodology for guideline development has become increasingly complex, leading to challenges in their application across various neurosurgical specialties and settings. This mini review aims to explore the practical implications of published suggestions for managing neurosurgical patients., Methods: A critical and focused collection of published literature concerning guidelines in different neurosurgical topics, from Pubmed and other sources formed the basis of this non-systematic narrative review. Only guidelines produced by neurosurgeons in the era of evidence based medicine (after 1996) were included., Results: Neurosurgical guidelines often rely on a limited number of Randomized Controlled Trials (RCTs) and Class I evidence, particularly in surgical and emergency contexts where randomization of patient treatments may conflict with established clinical practices. Challenges also include the timely update of guidelines, which sometimes lags behind rapid shifts in evidence, and varying methodologies in guideline production that can result in divergent recommendations. Geographical disparities in disease burden and literature production further influence guideline applicability, suggesting a need for greater inclusion of authors from Low- and Middle-Income Countries (LMICs) to enhance realism and global relevance. Consensus conferences and expert reviews may serve as viable alternatives to address these challenges., Conclusion: While Evidence-Based Medicine remains pivotal, critical appraisal and practical application of guidelines must consider these complexities to optimize patient care and outcomes., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

Background: Managing pain and distress in children experiencing procedural pain is a priority in pediatric care. Nitrous oxide (pre-mixed formulation of 50% nitrous oxide to 50% oxygen) is widely used to alleviate anxiety or pain during care procedures in various medical domains. This pharmacological intervention is safe to administer to children. Administration by non-anesthesiologist personnel is widespread throughout the world, though it is almost exclusively performed by doctors and nurses. The purpose of this study is to describe the experience of nitrous oxide (N 2 O) use by medical assistants and safe handling during the performance of painful procedures., Methods: A retrospective study was conducted in a pediatric outpatient unit of a regional hospital, including medical and surgical consultations., Results: Nitrous oxide was administered by medical assistants to 324 children aged 3 to 19 years. No respiratory and/or cardiovascular problems were noted. Most patients were calm and relaxed., Discussion: The use of N 2 O for minor procedures in children in a pediatric outpatient unit improved pain management through administration by medical assistants with a high level of satisfaction from patients, parents and health professionals., Conclusions: This study suggests that the use of nitrous oxide by trained medical assistants can be safe, feasible and effective within the specific context of this study.

Objective: To quantify the distribution of cauda equina nerve roots in supine and upright positions using manual measurements and radiomics features both in normal subjects and in lumbar spinal canal stenosis (LSCS) patients., Methods: We retrospectively recruited patients who underwent weight-bearing MRI in supine and upright positions for back pain. 3D T2-weighted isotropic acquisition (3D-HYCE) sequences were used to develop a 3D convolutional neural network for identification and segmentation of lumbar vertebrae. Para-axial reformatted images perpendicular to the spinal canal and parallel to each vertebral endplate were automatically extracted. From each level, we computed the maximum antero-posterior (AP) and latero-lateral (LL) dispersion of nerve roots; further, radiomics features were extracted to quantify standardized metrics of nerve root distribution., Results: We included 16 patients with LSCS and 20 normal subjects. In normal subjects, nerve root AP dispersion significantly increased from supine to upright position (p < 0.001, L2-L5 levels), and radiomics features showed an increase in non-uniformity. In LSCS subjects, in the upright position AP dispersion of nerve roots and entropy-related features increased caudally to the stenosis level (p < 0.001) and decreased cranially (p < 0.001). Moreover, entropy-related radiomics features negatively correlated with pre-operative Pain Numerical Rating Scale. Comparison between normal subjects and LSCS patients showed a difference in AP dispersion and increase of variance cranially to the stenosis level (p < 0.001) in the upright position., Conclusions: Nerve root distribution inside the dural sac changed between supine and upright positions, and radiomics features were able to quantify the differences between normal and LSCS subjects., Clinical Relevance Statement: The distribution of cauda equina nerve roots and the redundant nerve root sign significantly varies between supine and upright positions in normal subjects and spinal canal stenosis patients, respectively. Radiomics features quantify nerve root dispersion and correlates with pain severity., Key Points: • Weight-bearing MRI depicts spatial distribution of the cauda equina in both supine and upright positions in normal subjects and spinal stenosis patients. • Radiomics features can quantify the effects of spinal stenosis on the dispersion of the cauda equina in the dural sac. • In the orthostatic position, dispersion of nerve roots is different in lumbar spinal stenosis patients compared to that in normal subjects; entropy-related features negatively correlated with pre-operative Pain Numerical Rating Scale., (© 2023. The Author(s), under exclusive licence to European Society of Radiology.)

The purpose of this study is to evaluate the intracellular and extracellular volume before and after anesthesia in order to ascertain their variations and determine the potential utility of this information in optimizing intraoperative fluid administration practices. A bioimpedance spectroscopy device (body composition monitor, BCM) was used to measure total body fluid volume, extracellular volume, and intracellular volume. BCM measurements were performed before and after general anesthesia in unselected healthy children and adolescents visiting the Pediatric Institute of Southern Switzerland for low-risk surgical procedures hydrated with an isotonic solution. In 100 children and adolescents aged 7.0 (4.8-11) years (median and interquartile range), the average total body water increased perioperatively with a delta value of 182 (0-383) mL/m 2 from pre- to postoperatively, as well as the extracellular water content, which had a similar increase with a delta value of 169 (19-307) mL/m 2 . The changes in total body water and extracellular water content significantly correlated with the amount of fluids administered. The intracellular water content did not significantly change.   Conclusion: Intraoperative administration of isotonic solutions results in a significant fluid accumulation in low-risk schoolchildren during general anesthesia. The results suggest that children without major health problems undergoing short procedures do not need any perioperative intravenous fluid therapy, because they are allowed to take clear fluids up to 1 h prior anesthesia. In future studies, the use of BCM measurements has the potential to be valuable in guiding intraoperative fluid therapy. What is Known: • Most children who undergo common surgical interventions or investigations requiring anesthesia are nowadays hydrated at a rate of 1700 mL/m 2 /day with an isotonic solution. • The use bioimpedance spectroscopy for the assessment of fluid status in healthy children has already been successfully validated. • The bioimpedance spectroscopy is already currently widely used in various nephrological settings to calculate fluid overload and determine patient's optimal fluid status. What is New: • Routine intraoperative fluid administration results in a significant fluid accumulation during general anesthesia in low-risk surgical procedures. • This observation might be relevant for children and adolescents with conditions predisposing to fluid retention. • In future studies, the use of BCM measurements has the potential to be valuable in guiding intraoperative fluid therapy., (© 2024. The Author(s).)

When contracting muscles are freely perfused, the acid-sensing ion channel 3 (ASIC3) on group IV afferents plays a minor role in evoking the exercise pressor reflex. We recently showed in isolated dorsal root ganglion neurons innervating the gastrocnemius muscles that two mu opioid receptor agonists, namely endomorphin 2 and oxycodone, potentiated the sustained inward ASIC3 current evoked by acidic solutions. This in vitro finding prompted us to determine whether endomorphin 2 and oxycodone, when infused into the arterial supply of freely perfused contracting hindlimb muscles, potentiated the exercise pressor reflex. We found that infusion of endomorphin 2 and naloxone in decerebrated rats potentiated the pressor responses to contraction of the triceps surae muscles. The endomorphin 2-induced potentiation of the pressor responses to contraction was prevented by infusion of APETx2, an ASIC3 antagonist. Specifically, the peak pressor response to contraction averaged 19.3 ± 5.6 mmHg for control ( n = 10), 27.2 ± 8.1 mmHg after naloxone and endomorphin 2 infusion ( n = 10), and 20 ± 8 mmHg after APETx2 and endomorphin 2 infusion ( n = 10). Infusion of endomorphin 2 and naloxone did not potentiate the pressor responses to contraction in ASIC3 knockout rats ( n = 6). Partly similar findings were observed when oxycodone was substituted for endomorphin 2. Oxycodone infusion significantly increased the exercise pressor reflex over its control level, but subsequent APETx2 infusion failed to restore the increase to its control level ( n = 9). The peak pressor response averaged 23.1 ± 8.6 mmHg for control ( n = 9), 33.2 ± 11 mmHg after naloxone and oxycodone were infused ( n = 9), and 27 ± 8.6 mmHg after APETx2 and oxycodone were infused ( n = 9). Our data suggest that after opioid receptor blockade, ASIC3 stimulation by the endogenous mu opioid, endomorphin 2, potentiated the exercise pressor reflex. NEW & NOTEWORTHY This paper provides the first in vivo evidence that endomorphin 2, an endogenous opioid peptide, can paradoxically increase the magnitude of the exercise pressor reflex by an ASIC3-dependent mechanism even when the contracting muscles are freely perfused.

Devolution and decentralisation policies involving health and other government sectors have been promoted with a view to improve efficiency and equity in local service provision. Evaluations of these reforms have focused on specific health or care measures, but little is known about their full impact on local health systems. We evaluated the impact of devolution in Greater Manchester (England) on multiple outcomes using a whole system approach. We estimated the impact of devolution until February 2020 on 98 measures of health system performance, using the generalised synthetic control method and adjusting for multiple hypothesis testing. We selected measures from existing monitoring frameworks to populate the WHO Health System Performance Assessment framework. The included measures captured information on health system functions, intermediatory objectives, final goals, and social determinants of health. We identified which indicators were targeted in response to devolution from an analysis of 170 health policy intervention documents. Life expectancy (0.233 years, S.E. 0.012) and healthy life expectancy (0.603 years, S.E. 0.391) increased more in GM than in the estimated synthetic control group following devolution. These increases were driven by improvements in public health, primary care, hospital, and adult social care services as well as factors associated with social determinants of health, including a reduction in alcohol-related admissions (-110.1 admission per 100,000, S.E. 9.07). In contrast, the impact on outpatient, mental health, maternity, and dental services was mixed. Devolution was associated with improved population health, driven by improvements in health services and wider social determinants of health. These changes occurred despite limited devolved powers over health service resources suggesting that other mechanisms played an important role, including the allocation of sustainability and transformation funding and the alignment of decision-making across health, social care, and wider public services in the region., Competing Interests: Declaration of competing interest We declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

We investigated the role played by lactate and hydrogen in evoking the exercise pressor reflex (EPR) in decerebrated rats whose hindlimb muscles were either freely perfused or ischaemic. Production of lactate and hydrogen by the contracting hindlimb muscles was manipulated by knocking out the myophosphorylase gene (pygm). In knockout rats (pygm -/- ; n = 13) or wild-type rats (pygm +/+ ; n = 13), the EPR was evoked by isometrically contracting the triceps surae muscles. Blood pressure, tension, blood flow, renal sympathetic nerve activity and blood lactate concentrations were measured. Intramuscular metabolites and pH changes induced by the contractions were quantified by 31 P-magnetic resonance spectroscopy (n = 5). In a subset of pygm -/- rats (n = 5), contractions were evoked with prior infusion of lactate (pH 6.0) in an attempt to restore the effect of lactate and hydrogen ions. Contraction of freely perfused muscles increased blood lactate and decreased muscle pH in pygm +/+ rats only. Despite these differences, the reflex pressor and sympathetic responses to freely perfused contraction did not differ between groups (P = 0.992). During ischaemia, contraction increased muscle lactate and hydrogen ion production in pygm +/+ rats (P < 0.0134), whereas it had no effect in pygm -/- rats (P > 0.783). Likewise, ischaemia exaggerated the reflex pressor, and sympathetic responses to contraction in pygm +/+ but not in pygm -/- rats. This exaggeration was restored when a solution of lactate (pH 6.0) was infused prior to the contraction in pygm -/- rats. We conclude that lactate and hydrogen accumulation in contracting myocytes play a key role in evoking the metabolic component of the EPR during ischaemic but not during freely perfused contractions. KEY POINTS: Conflicting results exist about the role played by lactate and hydrogen ions in evoking the exercise pressor reflex. Using CRISP-Cas9, we rendered the myophosphorylase gene non-functional to block the production of lactate and hydrogen ions. The exercise pressor reflex was evoked in decerebrated rats by statically contracting the triceps surae muscles with or without muscle ischaemia. Static contraction elevated the concentration of lactate and hydrogen ions in pygm +/+ but not in pygm -/- rats. Despite these differences, the exercise pressor reflex was not different between groups. Acute muscle ischaemia exaggerated the concentration of lactate and hydrogen ions in pygm +/+ but not in pygm -/- rats. Likewise, acute muscle ischaemia exaggerated the exercise pressor reflex in pygm +/+ but not in pygm -/- rats. We conclude that lactate and hydrogen play a key role in evoking the exercise pressor reflex during ischaemic but not during freely perfused contractions., (© 2024 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

Background and Aims: The Utstein Based-ROSC (UB-ROSC) score has been developed to predict ROSC in OHCA victims. Aim of the study was to validate the UB-ROSC score using two Utstein-based OHCA registries: the SWiss REgistry of Cardiac Arrest (SWISSRECA) and the Lombardia Cardiac Arrest Registry (Lombardia CARe), northern Italy., Methods: Consecutive patients with OHCA of any etiology occurring between January 1st, 2019 and December 31st 2021 were included in this retrospective validation study. UB-ROSC score was computed for each patient and categorized in one of three subgroups: low, medium or high likelihood of ROSC according to the UB-ROSC cut-offs (≤-19; -18 to 12; ≥13). To assess the performance of the UB-ROSC score in this new cohort, we assessed both discrimination and calibration. The score was plotted against the survival to hospital admission., Results: A total of 12.577 patients were included in the study. A sustained ROSC was obtained in 2.719 patients (22%). The UB-ROSC model resulted well calibrated and showed a good discrimination (AUC 0.71, 95% CI 0.70-0.72). In the low likelihood subgroup of UB-ROSC, only 10% of patients achieved ROSC, whereas the proportion raised to 36% for a score between -18 and 12 (OR 5.0, 95% CI 2.9-8.6, p < 0.001) and to 85% for a score ≥13 (OR 49.4, 95% CI 14.3-170.6, p < 0.001)., Conclusions: UB-ROSC score represents a reliable tool to predict ROSC probability in OHCA patients. Its application may help the medical decision-making process, providing a realistic stratification of the probability for ROSC., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

We determined the role played by the transient receptor potential canonical 6 (TRPC6) channel in evoking the mechanical component of the exercise pressor reflex in male decerebrated Sprague-Dawley rats. TRPC6 channels were identified by quadruple-labelled (DiI, TRPC6, neurofilament-200 and peripherin) immunohistochemistry in dorsal root ganglion (DRG) cells innervating the triceps surae muscles (n = 12). The exercise pressor reflex was evoked by statically contracting the triceps surae muscles before and after injection of the TRPC6 antagonist BI-749327 (n = 11; 12 μg kg -1 ) or SAR7334 (n = 11; 7 μg kg -1 ) or the TRPC6 positive modulator C20 (n = 11; 18 μg kg -1 ). Similar experiments were conducted while the muscles were passively stretched (n = 8-12), a manoeuvre that isolated the mechanical component of the reflex. Blood pressure, tension, renal sympathetic nerve activity (RSNA) and blood flow were recorded. Of the DRG cells innervating the triceps surae muscles, 85% stained positive for the TRPC6 antigen, and 45% of those cells co-expressed neurofilament-200. Both TRPC6 antagonists decreased the reflex pressor responses to static contraction (-32 to -42%; P < 0.05) and to passive stretch (-35 to -52%; P < 0.05), whereas C20 increased these responses (55-65%; P < 0.05). In addition, BI-749327 decreased the peak and integrated RSNA responses to both static contraction (-39 to -43%; P < 0.05) and passive stretch (-56 to -62%; P < 0.05), whereas C20 increased the RSNA to passive stretch only. The onset latency of the decrease or increase in RSNA occurred within 2 s of the onset of the manoeuvres (P < 0.05). Collectively, our results show that TRPC6 plays a key role in evoking the mechanical component of the exercise pressor reflex. KEY POINTS: The exercise pressor reflex plays a key role in the sympathetic and haemodynamic responses to exercise. This reflex is composed of two components, namely the mechanoreflex and the metaboreflex. The receptors responsible for evoking the mechanoreflex are poorly documented. A good candidate for this function is the transient receptor potential canonical 6 (TRPC6) channel, which is activated by mechanical stimuli and expressed in dorsal root ganglia of rats. Using two TRPC6 antagonists and one positive modulator, we investigated the role played by TRPC6 in evoking the mechanoreflex in decerebrated rats. Blocking TRPC6 decreased the renal sympathetic and the pressor responses to both contraction and stretch, the latter being a manoeuvre that isolates the mechanoreflex. In contrast, the positive modulator increased the pressor reflex to contraction and stretch, in addition to the sympathetic response to stretch. Our results provide strong support for a role played by the TRPC6 channel in evoking the mechanoreflex., (© 2024 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

The role played by the transient receptor potential vanilloid 1 (TRPV1) channel on the thin fibre afferents evoking the exercise pressor reflex is controversial. To shed light on this controversy, we compared the exercise pressor reflex between newly developed TRPV1 +/+ , TRPV1 +/- and TRPV1 -/- rats. Carotid arterial injection of capsaicin (0.5 μg), evoked significant pressor responses in TRPV1 +/+ and TRPV1 +/- rats, but not in TRPV1 -/- rats. In acutely isolated dorsal root ganglion neurons innervating the gastrocnemius muscles, capsaicin evoked inward currents in neurons isolated from TRPV1 +/+ and TRPV1 +/- rats but not in neurons isolated from TRPV1 -/- rats. The reflex was evoked by stimulating the tibial nerve in decerebrated rats whose femoral artery was either freely perfused or occluded. We found no difference between the reflex in the three groups of rats regardless of the patency of the femoral artery. For example, the peak pressor responses to contraction in TRPV1 +/+ , TRPV1 +/- and TRPV1 -/- rats with patent femoral arteries averaged 17.1 ± 7.2, 18.9 ± 12.4 and 18.4 ± 8.6 mmHg, respectively. Stimulation of the tibial nerve after paralysis with pancuronium had no effect on arterial pressure, findings which indicated that the pressor responses to contraction were not caused by electrical stimulation of afferent tibial nerve axons. We also found that expression levels of acid-sensing ion channel 1 and endoperoxide 4 receptor in the L4 and 5 dorsal root ganglia were not upregulated in the TRPV1 -/- rats. We conclude that TRPV1 is not needed to evoke the exercise pressor reflex in rats whose contracting muscles have either a patent or an occluded arterial blood supply. KEY POINTS: A reflex arising in contracting skeletal muscle contributes to the increases in arterial blood pressure, cardiac output and breathing evoked by exercise. The sensory arm of the reflex comprises both mechanoreceptors and metaboreceptors, of which the latter signals that blood flow to exercising muscle is not meeting its metabolic demand. The nature of the channel on the metaboreceptor sensing a mismatch between supply and demand is controversial; some believe that it is the transient receptor potential vanilloid 1 (TRPV1) channel. Using genetically engineered rats in which the TRPV1 channel is rendered non-functional, we have shown that it is not needed to evoke the metaboreflex., (© 2023 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

Whole-system reforms, including devolution and integration of health and social care services, have the potential to impact multiple dimensions of health system performance. Most evaluations focus on a single or narrow subsets of outcomes amenable to change. This approach may not: (i) capture the overall effect of the reform, (ii) identify the mechanisms through which system-wide changes may have occurred, (iii) prevent post-hoc selection of outcomes based on significant results; and (iv) facilitate comparisons across settings. We propose a structured approach for selecting multiple quantitative outcome measures, which we apply for evaluating health and social care devolution in Greater Manchester, England. The approach consists of five-steps: (i) defining outcome domains based on a framework, in our case the World Health Organisation's Health System Performance Assessment Framework; (ii) reviewing performance metrics from national monitoring frameworks; (iii) excluding similar and condition specific outcomes; (iv) excluding outcomes with insufficient data; and (v) mapping implemented policies to identify a subset of targeted outcomes. We identified 99 outcomes, of which 57 were targeted. The proposed approach is detail and time-intensive, but useful for both researchers and policymakers to promote transparency in evaluations and facilitate the interpretation of findings and cross-settings comparisons., Competing Interests: Declaration of Competing Interest We declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Financial flows relating to health care are routinely analysed at national and international level. They have rarely been systematically analysed at local level, despite sub-national variation due to population needs and decisions enacted by local organisations. We illustrate an adaptation of the System of Health Accounts framework to map the flow of public health and care funding within local systems, with an application for Greater Manchester (GM), an area in England which agreed a health and social care devolution deal with the central government in 2016. We analyse how financial flows changed in GM during the four years post-devolution, and whether spending was aligned with local ambitions to move towards prevention of ill-health and integration of health and social care. We find that GM decreased spending on public health by 15%, and increased spending on general practice by 0.1% in real terms. The share of total local expenditure paid to NHS Trusts for general and acute services increased from 70.3% to 71.6%, while that for community services decreased from 11.7% to 10.3%. Results suggest that GM may have experienced challenges in redirecting resources towards their goals. Mapping financial flows at a local level is a useful exercise to examine whether spending is aligned with system goals and highlight areas for further investigation., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflict of interest., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Devolution of health systems from national to local levels is a common focus of policymakers across the world. The overarching aim is to improve population health by better meeting the specific needs of local citizens. We examine the case of a coordinated devolution across several public service sectors in Greater Manchester, England, in 2016. We estimate the impact on experienced health and well-being using Short-Form 12 scores from 13,938 adult respondents to the UK Household Longitudinal Survey between 2012 and 2020. We use difference-in-differences and lagged-dependent variable regressions to compare Greater Manchester to the rest of England. We find no statistically significant changes in experienced health and well-being over the four years following the start of devolution. Our findings suggest that devolving population health management alone without budgetary powers and local accountability mechanisms may not be effective in improving experienced health and well-being in the relatively short-term., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Most evidence on Performance Based Financing (PBF) in low-income settings has focused on services delivered by providers in targeted health administrations, with limited understanding of how effects on health and care vary within them. We evaluated the population effects of a program implemented in two provinces in Mozambique, focusing on child, maternal and HIV/AIDS care and knowledge. We used a difference-in-difference estimation strategy applied to data on mothers from the Demographic Health Surveys, linked to information on their closest health facility. The impact of PBF was limited. HIV testing during antenatal care increased, particularly for women who were wealthier, more educated, or residing in Gaza Province. Knowledge about transmission of HIV from mother-to-child, and its prevention, increased, particularly for women who were less wealthy, less educated, or residing in Nampula Province. Exploiting the roll-out by facility, we found that the effects were concentrated on less wealthy and less educated women, whose closest facility was in the referral network of a PBF facility. Results suggest that HIV testing and knowledge promotion increased in the whole district, as a strategy to boost referral for highly incentivized HIV services delivered in PBF facilities. However, demand-side constraints may prevent the use of those services., (© 2023 The Authors. Health Economics published by John Wiley & Sons Ltd.)

Background and Objectives: Contribution margin per hour (CMH) has been proposed in healthcare systems to increase the profitability of operating suites. The aim of our study is to propose a simple and reproducible model to calculate CMH and to increase cost-effectiveness., Methods: For the ten most commonly performed surgical procedures at our Institution, we prospectively collected their diagnosis-related group (DRG) reimbursement, variable costs and mean procedural time. We quantified the portion of total staffed operating room time to be reallocated with a minimal risk of overrun. Moreover, we calculated the total CMH with a random reallocation on a first come-first served basis. Finally, prioritizing procedures with higher CMH, we ran a simulation by calculating the total CMH., Results: Over a two-months period, we identified 14.5 hours of unutilized operating room to reallocate. In the case of a random "first come-first serve" basis, the total earnings were 87,117 United States dollars (USD). Conversely, with a reallocation which prioritized procedures with a high CMH, it was possible to earn 140,444 USD (p < 0.001)., Conclusion: Surgical activity may be one of the most profitable activities for hospitals, but a cost-effective management requires a comprehension of its cost profile. Reallocation of unused operating room time according to CMH may represent a simple, reproducible and reliable tool for elective cases on a waiting list. In our experience, it helped improving the operating suite cost-effectiveness., (Copyright © 2021 Sociedade Brasileira de Anestesiologia. Published by Elsevier España, S.L.U. All rights reserved.)

Background and Objectives: In this systematic review, we carried out an assessment of perioperative costs of local or regional anesthesia versus general anesthesia in the ambulatory setting., Methods: A systematic literature search was conducted to find relevant data on costs and cost-effectiveness analyses of anesthesia regimens in outpatients, regardless of the medical procedure they underwent. The hypothesis was that local or regional anesthesia has a lower economic impact on hospital costs in the outpatient setting. The primary outcome was the average total cost of anesthesia calculated on perioperative costs (drugs, staff, resources used)., Results: One-thousand-six-hundred-ninety-eight records were retrieved, and 28 articles including 27,581 patients were selected after reviewing the articles. Data on the average total costs of anesthesia and other secondary outcomes (anesthesia time, recovery time, time to home readiness, hospital stay time, complications) were retrieved. Taken together, these findings indicated that local or regional anesthesia is associated with lower average total hospital costs than general anesthesia when performed in the ambulatory setting. Reductions in operating room time and postanesthesia recovery time and a lower hospital stay time may account for this result., Conclusions: Despite the limitations of this systematic review, mainly the heterogeneity of the studies and the lack of cost-effectiveness analysis, the economic impact of the anesthesia regimes on healthcare costs appears to be relevant and should be further evaluated., (Copyright © 2021 Sociedade Brasileira de Anestesiologia. Published by Elsevier España, S.L.U. All rights reserved.)

This article is part of the Research Topic 'Health Systems Recovery in the Context of COVID-19 and Protracted Conflict'., Introduction: After the World Health Organization declared COVID-19 a pandemic, more than 184 million cases and 4 million deaths had been recorded worldwide by July 2021. These are likely to be underestimates and do not distinguish between direct and indirect deaths resulting from disruptions in health care services. The purpose of our research was to assess the early impact of COVID-19 in 2020 and early 2021 on maternal and child healthcare service delivery at the district level in Mozambique using routine health information system data, and estimate associated excess maternal and child deaths., Methods: Using data from Mozambique's routine health information system (SISMA, Sistema de Informação em Saúde para Monitoria e Avaliação), we conducted a time-series analysis to assess changes in nine selected indicators representing the continuum of maternal and child health care service provision in 159 districts in Mozambique. The dataset was extracted as counts of services provided from January 2017 to March 2021. Descriptive statistics were used for district comparisons, and district-specific time-series plots were produced. We used absolute differences or ratios for comparisons between observed data and modeled predictions as a measure of the magnitude of loss in service provision. Mortality estimates were performed using the Lives Saved Tool (LiST)., Results: All maternal and child health care service indicators that we assessed demonstrated service delivery disruptions (below 10% of the expected counts), with the number of new users of family planing and malaria treatment with Coartem (number of children under five treated) experiencing the largest disruptions. Immediate losses were observed in April 2020 for all indicators, with the exception of treatment of malaria with Coartem. The number of excess deaths estimated in 2020 due to loss of health service delivery were 11,337 (12.8%) children under five, 5,705 (11.3%) neonates, and 387 (7.6%) mothers., Conclusion: Findings from our study support existing research showing the negative impact of COVID-19 on maternal and child health services utilization in sub-Saharan Africa. This study offers subnational and granular estimates of service loss that can be useful for health system recovery planning. To our knowledge, it is the first study on the early impacts of COVID-19 on maternal and child health care service utilization conducted in an African Portuguese-speaking country., 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 Augusto, Roberton, Fernandes, Chicumbe, Manhiça, Tembe, Wagenaar, Anselmi, Wakefield and Sherr.)

Introduction: There are limited data on sex-related differences in out-of hospital cardiac arrests (OHCAs) with refractory ventricular arrhythmias (VA) and, in particular, about their relationship with cardiovascular risk profile and severity of coronary artery disease (CAD)., Purpose: Aim of this study was to characterize sex-related differences in clinical presentation, cardiovascular risk profile, CAD prevalence, and outcome in OHCA victims presenting with refractory VA., Methods: All OHCAs with shockable rhythm that occurred between 2015 and 2019 in the province of Pavia (Italy) and in the Canton Ticino (Switzerland) were included., Results: Out of 680 OHCAs with first shockable rhythm, 216 (33%) had a refractory VA. OHCA patients with refractory VA were younger and more often male. Males with refractory VA had more often a history of CAD (37% vs. 21%, p 0.03). In females, refractory VA were less frequent (M : F ratio 5 : 1) and no significant differences in cardiovascular risk factor prevalence or clinical presentation were observed. Male patients with refractory VA had a significantly lower survival at hospital admission and at 30 days as compared to males without refractory VA (45% vs. 64%, p  < 0.001 and 24% vs. 49%, p  < 0.001, respectively). Whereas in females, no significant survival difference was observed., Conclusions: In OHCA patients presenting with refractory VA the prognosis was significantly poorer for male patients. The refractoriness of arrhythmic events in the male population was probably due to a more complex cardiovascular profile and in particular due to a pre-existing CAD. In females, OHCA with refractory VA were less frequent and no correlation with a specific cardiovascular risk profile was observed., 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., (© 2023 Caputo, Baldi, Krüll, Pongan, Cresta, Benvenuti, Cianella, Primi, Currao, Bendotti, Compagnoni, Gentile, Anselmi, Savastano, Klersy and Auricchio.)

Background: Emergency departments (EDs) are an important point of access to health care for people experiencing homelessness. Evidence suggests that ED attendances by homeless people are more likely to result in leaving the ED without treatment, or dying in the ED. We investigate which diagnoses and patterns of health care use are associated with these (and other) discharge destinations and re-attendance within 7 days among homeless patients., Methods: We used national hospital data to analyze attendances of all 109 254 people experiencing homelessness who presented at any Type 1 ED in England over 2013-18. We used logistic regression to estimate the association of each outcome with primary diagnosis and patterns of healthcare use., Results: Compared with patients with no past ED use, patients with a high frequency of past ED use were more likely to leave without treatment and re-attend within 7 days. Patients not registered at a general practice were likelier to leave without treatment or die in the ED and had lower odds of unplanned re-attendance. A primary diagnosis of 'social problems' was associated with being discharged without follow-up. Patients with a psychiatric primary diagnosis were disproportionately likely to be referred to another health care professional/provider or an outpatient clinic., Conclusions: Further research is needed to understand why some homeless patients leave the ED without treatment and whether their healthcare needs are being met. Some patients may be attending the ED frequently due to poor access to other services, such as primary care and social welfare., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Public Health Association.)

Background: Over 250 million children under 5 years, globally, are at risk of developmental delay. Interventions during the first 2 years of life have enduring positive effects if children at risk are identified, using standardized assessments, within this window. However, identifying developmental delay during infancy is challenging and there are limited infant development assessments suitable for use in low- and middle-income (LMIC) settings. Here, we describe a new tool, the Oxford Neurodevelopment Assessment (OX-NDA), measuring cognition, language, motor, and behaviour, outcomes in 1-year-old children. We present the results of its evaluation against the Bayley Scales of Infant Development IIIrd edition (BSID-III) and its psychometric properties., Methods: Sixteen international tools measuring infant development were analysed to inform the OX-NDA's construction. Its agreement with the BSID-III, for cognitive, motor and language domains, was evaluated using intra-class correlations (ICCs, for absolute agreement), Bland-Altman analyses (for bias and limits of agreement), and sensitivity and specificity analyses (for accuracy) in 104 Brazilian children, aged 12 months (SD 8.4 days), recruited from the 2015 Pelotas Birth Cohort Study. Behaviour was not evaluated, as the BSID-III's adaptive behaviour scale was not included in the cohort's protocol. Cohen's kappas and Cronbach's alphas were calculated to determine the OX-NDA's reliability and internal consistency respectively., Results: Agreement was moderate for cognition and motor outcomes (ICCs 0.63 and 0.68, p < 0.001) and low for language outcomes (ICC 0.30, p < 0.04). Bland-Altman analysis showed little to no bias between measures across domains. The OX-NDA's sensitivity and specificity for predicting moderate-to-severe delay on the BSID-III was 76, 73 and 43% and 75, 80 and 33% for cognition, motor and language outcomes, respectively. Inter-rater (k = 0.80-0.96) and test-rest (k = 0.85-0.94) reliability was high for all domains. Administration time was < 20 minutes., Conclusion: The OX-NDA shows moderate agreement with the BSID-III for identifying infants at risk of cognitive and motor delay; agreement was low for language delay. It is a rapid, low-cost assessment constructed specifically for use in LMIC populations. Further work is needed to evaluate its use (i) across domains in populations beyond Brazil and (ii) to identify language delays in Brazilian children., (© 2022. The Author(s).)

Background: The devolution of public services from central to local government can increase sensitivity to local population needs but might also reduce the expertise and resources available. Little evidence is available on the impact of devolution on population health. We evaluated the effect of devolution affecting health services and wider determinants of health on life expectancy in Greater Manchester, England., Methods: We estimated changes in life expectancy in Greater Manchester relative to a control group from the rest of England (excluding London), using a generalised synthetic control method. Using local district-level data collected between Jan 1, 2006 and Dec 31, 2019, we estimated the effect of devolution on the whole population and stratified by sex, district, income deprivation, and baseline life expectancy., Findings: After devolution, from November, 2014, life expectancy in Greater Manchester was 0·196 years (95% CI 0·182-0·210) higher than expected when compared with the synthetic control group with similar pre-devolution trends. Life expectancy was protected from the decline observed in comparable areas in the 2 years after devolution and increased in the longer term. Increases in life expectancy were observed in eight of ten local authorities, were larger among men than women (0·338 years [0·315-0·362] for men; 0·057 years [0·040-0·074] for women), and were larger in areas with high income deprivation (0·390 years [0·369-0·412]) and lower life expectancy before devolution (0·291 years [0·271-0·311])., Interpretation: Greater Manchester had better life expectancy than expected after devolution. The benefits of devolution were apparent in the areas with the highest income deprivation and lowest life expectancy, suggesting a narrowing of inequalities. Improvements were likely to be due to a coordinated devolution across sectors, affecting wider determinants of health and the organisation of care services., Funding: The Health Foundation and the National Institute for Health and Care Research., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Climate change-related extreme weather events have increased in frequency and intensity, threatening people's health, particularly in places with weak health systems. In March 2019, Cyclone Idai devastated Mozambique's central region, causing infrastructure destruction, population displacement, and death. We assessed the impact of Idai on maternal and child health services and recovery in the Sofala and Manica provinces., Methods: Using monthly district-level routine data from November 2016 to March 2020, we performed an uncontrolled interrupted time series analysis to assess changes in 10 maternal and child health indicators in all 25 districts before and after Idai. We applied a Bayesian hierarchical negative binomial model with district-level random intercepts and slopes to estimate Idai-related service disruptions and recovery., Results: Of the 4.44 million people in Sofala and Manica, 1.83 (41.2%) million were affected. Buzi, Nhamatanda, and Dondo (all in Sofala province) had the highest proportion of people affected. After Idai, all 10 indicators showed an abrupt substantial decrease. First antenatal care visits per 100,000 women of reproductive age decreased by 23% (95% confidence interval [CI]=0.62, 0.96) in March and 11% (95% CI=0.75, 1.07) in April. BCG vaccinations per 1,000 children under age 5 years declined by 21% (95% CI=0.69, 0.90) and measles vaccinations decreased by 25% (95% CI=0.64, 0.87) in March and remained similar in April. Within 3 months post-cyclone, almost all districts recovered to pre-Idai levels, including Buzi, which showed a 22% and 13% relative increase in the number of first antenatal care visits and BCG, respectively., Conclusion: We found substantial health service disruptions immediately after Idai, with greater impact in the most affected districts. The findings suggest impressive recovery post-Idai, emphasizing the need to build resilient health systems to ensure quality health care during and after natural disasters., (© Fernandes et al.)

Background: Non-pharmaceutical interventions have been implemented around the world to control Covid-19 transmission. Their general effect on reducing virus transmission is proven, but they can also be negative to mental health and economies, and transmission behaviours can also change voluntarily, without mandated interventions. Their relative impact on Covid-19 attributed mortality, enabling policy selection for maximal benefit with minimal disruption, is not well established due to a lack of definitive methods., Methods: We examined variations in timing and strictness of nine non-pharmaceutical interventions implemented in 130 countries and recorded by the Oxford COVID-19 Government Response Tracker (OxCGRT): 1) School closing; 2) Workplace closing; 3) Cancelled public events; 4) Restrictions on gatherings; 5) Closing public transport; 6) Stay at home requirements ('Lockdown'); 7) Restrictions on internal movement; 8) International travel controls; 9) Public information campaigns. We used two time periods in the first wave of Covid-19, chosen to limit reverse causality, and fixed country policies to those implemented: i) prior to first Covid-19 death (when policymakers could not possibly be reacting to deaths in their own country); and, ii) 14-days-post first Covid-19 death (when deaths were still low, so reactive policymaking still likely to be minimal). We then examined associations with daily deaths per million in each subsequent 24-day period, which could only be affected by the intervention period, using linear and non-linear multivariable regression models. This method, therefore, exploited the known biological lag between virus transmission (which is what the policies can affect) and mortality for statistical inference., Results: After adjusting, earlier and stricter school (- 1.23 daily deaths per million, 95% CI - 2.20 to - 0.27) and workplace closures (- 0.26, 95% CI - 0.46 to - 0.05) were associated with lower Covid-19 mortality rates. Other interventions were not significantly associated with differences in mortality rates across countries. Findings were robust across multiple statistical approaches., Conclusions: Focusing on 'compulsory', particularly school closing, not 'voluntary' reduction of social interactions with mandated interventions appears to have been the most effective strategy to mitigate early, wave one, Covid-19 mortality. Within 'compulsory' settings, such as schools and workplaces, less damaging interventions than closing might also be considered in future waves/epidemics., (© 2022. The Author(s).)

Background: Inflammation-related proteins constitute a promising avenue in studying biological correlates of major depressive disorder (MDD). However, MDD is a heterogeneous condition - a crucial aspect to be considered in association studies. We examined whether inflammatory proteins are associated with categorical diagnosis, a dimensional total sum-score, and specific depressive symptoms among youths., Methods: We analyzed data from the 1993 Pelotas Birth Cohort, a population-based study in Brazil that followed individuals up to age 22 years. Categorical psychiatric diagnoses were derived using adapted modules of the Mini International Neuropsychiatric Interview (MINI). Dimensional symptomatology was assessed using the Brazilian Portuguese version of the Center for Epidemiological Studies-Depression Scale-Revised (CESD-R). We estimated network structures that included individual depressive symptoms as measured by CESD-R items, peripheral inflammatory markers (C-Reactive Protein [CRP] and Interleukin-6 [IL-6]), as well as relevant covariates., Results: We evaluated 2586 participants (mean age = 22.5[SD = 0.33]) There were no associations between concentrations of inflammatory proteins and categorical diagnosis of MDD or with CESD-R total sum-scores. In symptom-specific analysis, CRP and IL-6 were positively connected to somatic and cognitive items., Discussion: We found cross-sectional connections of two commonly studied inflammatory proteins and specific depressive symptoms. Conducting symptom-specific analyses in relation to biological markers might advance our understanding of the heterogeneity of MDD., (Copyright © 2022. Published by Elsevier Ltd.)

Serotonin (5-HT) is a multifaceted neurotransmitter that has been described to play a role as a peripheral inflammatory mediator when released in ischemic or injured muscle. Dorsal root ganglia (DRG) neurons are key sensors of noxious stimuli that are released under inflammatory conditions or mechanical stress. Little information is available on the specific 5-HT receptor subtypes expressed in primary afferents that help regulate reflex pressor responses. In the present study, the whole-cell patch-clamp technique was employed to examine the modulation of voltage-gated calcium channel (Ca V ) 2.2 currents by 5-HT and to identify the 5-HT receptor subtype(s) mediating this response in acutely dissociated rat DRG neurons innervating triceps surae muscle. Our results indicate that exposure of 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI)-labeled DRG neurons to 5-HT can exert three modulatory effects on Ca V currents: high inhibition, low inhibition, and enhancement. Both 5-HT-mediated inhibition responses were blocked after pretreatment with pertussis toxin (PTX), indicating that 5-HT receptors are coupled to Ca V 2.2 via G α i/o protein subunits. Application of selective serotonin receptor type 1 (5-HT1) agonists revealed that modulation of Ca V 2.2 currents occurs primarily after 5-HT1A receptor subtype stimulation and minimally from 5-HT1D activation. Finally, the intrathecal administration of the selective 5-HT1A receptor agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), significantly ( P < 0.05) decreased the pressor response induced by intra-arterial administration of lactic acid. This suggests that 5-HT1A receptors are expressed presynaptically on primary afferent neurons innervating triceps surae muscle. Our findings indicate that preferential stimulation of 5-HT1 receptors, expressed on thin fiber muscle afferents, serves to regulate the reflex pressor response to metabolic stimuli. SIGNIFICANCE STATEMENT: The monoamine serotonin (5-HT), released under ischemic conditions, can contribute to the development of inflammation that negatively affects the exercise pressor reflex. The 5-HT receptor subtype and signaling pathway that underlies calcium channel modulation in dorsal root ganglia afferents, innervating hindlimb muscles, are unknown. We show that 5-HT can either block (primarily via serotonin receptor type 1 (5-HT1)A subtypes) or enhance voltage-gated calcium channel (Ca V 2.2) currents. Our findings suggest 5-HT exhibits receptor subtype selectivity, providing a complexity of cellular responses., (Copyright © 2022 by The American Society for Pharmacology and Experimental Therapeutics.)

Although pay-for-performance (P4P) schemes have been implemented across low- and middle-income countries (LMICs), little is known about their distributional consequences. A key concern is that financial bonuses are primarily captured by providers who are already better able to perform (for example, those in wealthier areas), P4P could exacerbate existing inequalities within the health system. We examine inequalities in the distribution of pay-outs in Zimbabwe's national P4P scheme (2014-2016) using quantitative data on bonus payments and facility characteristics and findings from a thematic policy review and 28 semi-structured interviews with stakeholders at all system levels. We found that in Zimbabwe, facilities with better baseline access to guidelines, more staff, higher consultation volumes and wealthier and less remote target populations earned significantly higher P4P bonuses throughout the programme. For instance, facilities that were 1 SD above the mean in terms of access to guidelines, earned 90 USD more per quarter than those that were 1 SD below the mean. Differences in bonus pay-outs for facilities that were 1 SD above and below the mean in terms of the number of staff and consultation volumes are even more pronounced at 348 USD and 445 USD per quarter. Similarly, facilities with villages in the poorest wealth quintile in their vicinity earned less than all others-and 752 USD less per quarter than those serving villages in the richest quintile. Qualitative data confirm these findings. Respondents identified facility baseline structural quality, leadership, catchment population size and remoteness as affecting performance in the scheme. Unequal distribution of P4P pay-outs was identified as having negative consequences on staff retention, absenteeism and motivation. Based on our findings and previous work, we provide some guidance to policymakers on how to design more equitable P4P schemes., (© The Author(s) 2022. Published by Oxford University Press in association with The London School of Hygiene and Tropical Medicine.)

Maternal smoking during pregnancy causes several harmful effects, including deficits in the intelligence quotient (IQ), a measure associated with academic achievements and higher socioeconomic position. We aimed to measure the association between maternal smoking during pregnancy and offspring's IQ in two birth cohorts from Pelotas, Brazil. Data from the 1982 and 1993 birth cohorts were analyzed. Smoking during pregnancy was ascertained at the perinatal follow-up, and IQ was measured at 30 years (1982) and 18 years (1993). Simple and multiple linear regressions were used for crude and adjusted analysis. Mediation analysis was performed using birth weight and breastfeeding as possible mediators. Data analysis was conducted in 2020. There were 3611 and 4050 participants from the 1982 and 1993 cohorts, respectively. After adjustment for potential confounders, the inverse association between smoking during pregnancy and children's IQ remained significant in both cohorts. Offspring of mothers who smoked during pregnancy had an average of 1.32 less IQ points (95%CI: -2.23, -0.242) in the 1982 cohort, and an average of 1.66 less IQ points (95%CI: -2.42, -0.90) in the 1993 cohort. Neither cohort showed association with paternal smoking (negative controls) after adjustment. Breastfeeding's mediated effects accounted for 26.2% and 23.9% of the association in the 1982 and 1993 cohorts, respectively, while birth weight's accounted for 6.8% and 30.1%, respectively; indirect effects were not significant. The inverse association between maternal smoking and IQ and the lack of association with paternal smoking reinforces our findings of a negative association between exposure and outcome., (Copyright © 2022 Elsevier Inc. All rights reserved.)

CBL plays a key role in different cell pathways, mainly related to cancer onset and progression, hematopoietic development and T cell receptor regulation. Somatic CBL mutations have been reported in a variety of malignancies, ranging from acute myeloid leukemia to lung cancer. Growing evidence have defined the clinical spectrum of germline CBL mutations configuring the so-called CBL syndrome; a cancer-predisposing condition that also includes multisystemic involvement characterized by variable phenotypic expression and expressivity. This review provides a comprehensive overview of the molecular mechanisms in which CBL exerts its function and describes the clinical manifestation of CBL mutations in humans.

Risk-adjustment models are used to predict the cost of care for patients based on their observable characteristics, and to derive efficient and equitable budgets based on weighted capitation. Markers based on past care contacts can improve model fit, but their coefficients may be affected by provider variations in diagnostic, treatment and reporting quality. This is problematic when distinguishing need and supply influences on costs is required.We examine the extent of this bias in the national formula for mental health care using administrative records for 43.7 million adults registered with 7746 GP practices in England in 2015. We also illustrate a method to control for provider effects.A linear regression containing a rich set of individual, GP practice and area characteristics, and fixed effects for local health organisations, had goodness-of-fit equal to R 2  = 0.007 at person level and R 2  = 0.720 at GP practice level. The addition of past care markers changed substantially the coefficients on the other variables and increased the goodness-of-fit to R 2  = 0.275 at person level and R 2  = 0.815 at GP practice level. The further inclusion of provider effects affected the coefficients on GP practice and area variables and on local health organisation fixed effects, increasing goodness-of-fit at GP practice level to R 2  = 0.848.With adequate supply controls, it is possible to estimate coefficients on past care markers that are stable and unbiased. Nonetheless, inconsistent reporting may affect need predictions and penalise populations served by underreporting providers., (© 2021. The Author(s).)

Despite enormous improvements in pre-clinical and clinical research, acute leukemia still represents an open challenge for pediatric hematologists; both for a significant relapse rate and for long term therapy-related sequelae. In this context, the use of an innovative technology, such as induced pluripotent stem cells (iPSCs), allows to finely reproduce the primary features of the malignancy and can be exploited as a model to study the onset and development of leukemia in vitro. The aim of this review is to explore the recent literature describing iPSCs as a key tool to study different types of hematological malignancies, comprising acute myeloid leukemia, non-down syndrome acute megakaryoblastic leukemia, B cell acute lymphoblastic leukemia, and juvenile myelomonocytic leukemia. This model demonstrates a positive impact on pediatric hematological diseases, especially in those affecting infants whose onsets is found in fetal hematopoiesis. This evidence highlights the importance of achieving an in vitro representation of the human embryonic hematopoietic development and timing-specific modifications, either genetic or epigenetic. Moreover, further insights into clonal evolution studies shed light in the way of a new precision medicine era, where patient-oriented decisions and therapies could further improve the outcome of pediatric cases. Nonetheless, we will also discuss here the difficulties and limitations of this model.

Background: We aimed to examine the occurrence of major depressive disorder (MDD) in a population-based youth sample, assessing both categorical and dimensional presentations of the disorder and its clinical and sociodemographic correlates., Methods: We analyzed cross-sectional data from the latest assessment of the 1993 Pelotas Birth Cohort (n = 3,780), a population-based study from Brazil that followed individuals up to age 22 years. We estimated point-prevalence for categorical diagnosis of MDD and comorbid diagnoses using DSM criteria in a structured interview by trained psychologists. Dimensional symptomatology was assessed with the Brazilian Portuguese version of the Center for Epidemiological Studies-Depression Scale-Revised (CES-D-R)., Results: Point-prevalence of a current unipolar major depressive episode was 2.85% (95%CI 2.37-3.43%). The CES-D-R showed a mean of 9.20 (SD=9.72), with an area under the curve of 0.93 (95%CI 0.91 to 0.95) for the categorical diagnosis of MDD using a cutoff point of 16. Sad mood and somatic symptoms were the most frequent, and also had lower levels of latent values required for endorsement. Sad mood and anhedonia items were the most central items in the network structure., Conclusions: In a population-based sample of youths from a middle-income country, MDD prevalence estimates and comorbidity profile were consistent with previous global literature. A focus on symptoms might advance our understanding about MDD among youths by disentangling the heterogeneity of the disorder., (Copyright © 2021. Published by Elsevier B.V.)

Background: An increase in the time from the symptoms onset to first medical contact and to primary percutaneous coronary intervention (pPCI) has been observed in countries with high-incidence of COVID-19 cases. We aimed to verify if there was any change in the patient delay and in the EMS response times up to the pPCI for STEMI patients in Swiss Ticino Canton., Methods: We assessed STEMI management including time from symptoms onset to EMS call, time of EMS response, time to pPCI in Swiss Canton Ticino. Data were retrieved from the Acute-Coronary-Syndrome-Ticino-Registry. We considered the patients included in the registry from March to May 2020 (pandemic period) and then from June to August 2020 (post-pandemic period) in whom a pPCI was performed. We compared these patients to those undergoing a pPCI in the same months in the year 2016-2019., Results: During the pandemic period, the time from symptoms onset to pPCI significantly increased compared to non-pandemic periods. This was due to a significant prolongation of the time from symptoms onset to EMS call, that nearly tripled. In contrast, after the pandemic period, there was a significantly shorter time from symptom onset to EMS call compared to non-pandemic years, whereas all other times remained unchanged., Conclusion: Patients delay the call to EMS despite symptoms of myocardial infarction during the COVID-19 pandemic also in a region with a relatively low incidence of COVID-19., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 The Author(s).)

Result Based Financing (RBF) has been implemented in health systems across low and middle-income countries (LMICs), with the objective of improving population health. Most evaluations of RBF schemes have focused on average programme effects for incentivised services. There is limited evidence on the potential effect of RBF on health outcomes, as well as on the heterogeneous effects across socio-economic groups and time periods. This study analyses the effect of Zimbabwe's national RBF scheme on neonatal, infant and under five mortality, using Demographic and Health Survey data from 2005, 2010 and 2015. We use a difference in differences design, which exploits the staggered roll-out of the scheme across 60 districts. We examine average programme effects and perform sub-group analyses to assess differences between socio-economic groups. We find that RBF reduced under-five mortality by two percentage points overall, but that this decrease was only significant for children of mothers with above median wealth (2.7 percentage points) and education (2.1 percentage points). RBF increased institutional delivery by seven percentage points - with a statistically significant effect for poorer socio-economic groups and least educated. We also find that RBF reduced c-section rates by three percentage points. We find no detectable effect of RBF on other incentivised services. When considering programme effects over time, we find that effects were only observed during the second phase of the programme (March 2012) with the exception of c-sections, which only reduced in the longer term. Further research is needed to examine whether these findings can be generalised to other settings., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Despite improvements in therapeutic protocols and in risk stratification, acute myeloid leukemia (AML) remains the leading cause of childhood leukemic mortality. Indeed, the overall survival accounts for ~70% but still ~30% of pediatric patients experience relapse, with poor response to conventional chemotherapy. Thus, there is an urgent need to improve diagnosis and treatment efficacy prediction in the context of this disease. Nowadays, in the era of high throughput techniques, AML has emerged as an extremely heterogeneous disease from a genetic point of view. Different subclones characterized by specific molecular profiles display different degrees of susceptibility to conventional treatments. In this review, we describe in detail this genetic heterogeneity of pediatric AML and how it is linked to relapse in terms of clonal evolution. We highlight some innovative tools to characterize minor subclones that could help to enhance diagnosis and a preclinical model suitable for drugs screening. The final ambition of research is represented by targeted therapy, which could improve the prognosis of pediatric AML patients, as well as to limit the side toxicity of current treatments.

Objective: Prediction models have become frequent in the medical literature, but most published studies are conducted in a single setting. Heterogeneity between development and validation samples has been posited as a major obstacle for the generalization of models. We aimed to develop a multivariable prognostic model using sociodemographic variables easily obtainable from adolescents at age 15 to predict a depressive disorder diagnosis at age 18 and to evaluate its generalizability in 2 samples from diverse socioeconomic and cultural settings., Method: Data from the 1993 Pelotas Birth Cohort were used to develop the prediction model, and its generalizability was evaluated in 2 representative cohort studies: the Environmental Risk (E-Risk) Longitudinal Twin Study and the Dunedin Multidisciplinary Health and Development Study., Results: At age 15, 2,192 adolescents with no evidence of current or previous depression were included (44.6% male). The apparent C-statistic of the models derived in Pelotas ranged from 0.76 to 0.79, and the model obtained from a penalized logistic regression was selected for subsequent external evaluation. Major discrepancies between the samples were identified, impacting the external prognostic performance of the model (Dunedin and E-Risk C-statistics of 0.63 and 0.59, respectively). The implementation of recommended strategies to account for this heterogeneity among samples improved the model's calibration in both samples., Conclusion: An adolescent depression risk score comprising easily obtainable predictors was developed with good prognostic performance in a Brazilian sample. Heterogeneity among settings was not trivial, but strategies to deal with sample diversity were identified as pivotal for providing better risk stratification across samples. Future efforts should focus on developing better methodological approaches for incorporating heterogeneity in prognostic research., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Population studies have suggested that most adults with attention-deficit hyperactivity disorder (ADHD) did not have the disorder in childhood, challenging the neurodevelopmental conceptualisation of ADHD. Arbitrary definitions of age at onset and lack of defined trajectories were accounted for the findings., Aims: The objective of this study was to assess the proportion of individuals presenting with either a neurodevelopmental trajectory or late-onset disorder, and to assess risk factors associated with them., Method: Data of 4676 individuals from the 1993 Pelotas birth cohort at 11, 15, 18 and 22 years of age were used. Polythetic and latent class mixed model analyses were performed to define ADHD trajectories from childhood to adulthood, and characterise the neurodevelopmental or late-onset courses. Regression models were applied to assess factors associated with different trajectories., Results: Classical polythetic analyses showed that 67% of those with ADHD at 22 years of age had a neurodevelopmental course of the disorder. Latent class mixed model analysis indicated that 78% of adults with ADHD had a trajectory of persistent symptoms, more common in males. The remaining adults with ADHD had an ascending symptom trajectory that occurred after puberty, with late-onset ADHD associated with female gender and higher IQ., Conclusions: Both polythetic and latent trajectories analyses provided empirical evidence supporting that the large majority of adults with ADHD had a neurodevelopmental disorder.

Crowding in emergency departments (EDs) is increasing in many health systems. Previous studies of the relationship between crowding and care quality are limited by the use of data from single hospitals, a focus on particular patient groups, a focus on a narrow set of quality measures, and use of crowding measures which induce bias from unobserved hospital and patient characteristics. Using data from 139 hospitals covering all major EDss in England, we measure crowding using quasi-exogenous variation in the volume of EDs attendances and examine its impacts on indicators of performance across the entire EDs care pathway. We exploit variations from expected volume estimated using high-dimensional fixed effects capturing hospital-specific variation in attendances by combinations of month and hour-of-the-week. Unexpected increases in attendance volume result in substantially longer waiting times, lower quantity and complexity of care, more patients choosing to leave without treatment, changes in referral and discharge decisions, but only small increases in reattendances and no increase in mortality. Causal bounds under potential omitted variable bias are narrow and exclude zero for the majority of outcomes. Results suggest that physician and patient responses may largely mitigate the impacts of demand increases on patient outcomes in the short-run., (© 2020 The Authors. Health Economics published by John Wiley & Sons Ltd.)

Background: Over the past decade, targeting acute kidney injury (AKI) has become a priority to improve patient safety and health outcomes. Illness complicated by AKI is common and is associated with adverse outcomes including high rates of unplanned hospital readmission. Through national patient safety directives, NHS England has mandated the implementation of an AKI clinical decision support system in hospitals. In order to improve care following AKI, hospitals have also been incentivised to improve discharge summaries and general practices are recommended to establish registers of people who have had an episode of illness complicated by AKI. However, to date, there is limited evidence surrounding the development and impact of interventions following AKI., Design: We conducted a quality improvement project in primary care aiming to improve the management of patients following an episode of hospital care complicated by AKI. All 31 general practices within a single NHS Clinical Commissioning Group were incentivised by a locally commissioned service to engage in audit and feedback, education training and to develop an action plan at each practice to improve management of AKI., Results: AKI coding in general practice increased from 28% of cases in 2015/2016 to 50% in 2017/2018. Coding of AKI was associated with significant improvements in downstream patient management in terms of conducting a medication review within 1 month of hospital discharge, monitoring kidney function within 3 months and providing written information about AKI to patients. However, there was no effect on unplanned hospitalisation and mortality., Conclusion: The findings suggest that the quality improvement intervention successfully engaged a primary care workforce in AKI-related care, but that a higher intensity intervention is likely to be required to improve health outcomes. Development of a real-time audit tool is necessary to better understand and minimise the impact of the high mortality rate following AKI., Competing Interests: Competing interests: Between 2014 and 2017, TB was a member of the NHS England Think Kidneys Programme. The authors declare no other competing interests., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)

Poor mental health is a pressing global health problem, with high prevalence among poor populations from low-income countries. Existing studies of conditional cash transfer (CCT) effects on mental health have found positive effects. However, there is a gap in the literature on population-wide effects of cash transfers on mental health and if and how these vary by the severity of mental illness. We use the Malawian Longitudinal Study of Family and Health containing 790 adult participants in the Malawi Incentive Programme, a year-long randomized controlled trial. We estimate average and distributional quantile treatment effects and we examine how these effects vary by gender, HIV status and usage of the cash transfer. We find that the cash transfer improves mental health on average by 0.1 of a standard deviation. The effect varies strongly along the mental health distribution, with a positive effect for individuals with worst mental health of about four times the size of the average effect. These improvements in mental health are associated with increases in consumption expenditures and expenditures related to economic productivity. Our results show that CCTs can improve adult mental health for the poor living in low-income countries, particularly those with the worst mental health., (© The Author(s) 2020. Published by Oxford University Press in association with The London School of Hygiene and Tropical Medicine.)

Background and Aims: Longitudinal cohort studies examining different generations can explain how health problems can be transmitted through genetic and environmental mechanisms and their effects on the health of offspring. This study aimed to present the design and to describe the characteristics of the baseline sample of a second generation cohort., Methods: The 93Cohort-II is a dynamic prospective cohort composed of a second generation from the original 1993 Pelotas Birth Cohort (offspring), whose parents had their last follow-up at 22 years old. Biological parents were asked to answer questions addressing the type of birth, general health status, family composition, dietary habits, breastfeeding habits, and child-caregiver(s), among others, and the children's anthropometric measurements were evaluated., Results: Of 1650 children identified, 1212 were evaluated (response rate, 73.4%), and 21 died before the baseline assessment. The age of the offspring ranged from 0 to 10 years (mean [±SD], 2.9 ± 2.1 years); most children (65.6%) lived with both parents and were born to young mothers and poor families. One-third of the children were breastfed until 6 months of age, one-half were born by cesarean section, 63.9% had used medication in the previous 15 days, 26.4% experienced hospitalization at least once since birth, and 14% had no updated vaccination; asthma/bronchitis (20.4%) and bronchiolitis (13.4%) were the most frequently reported diseases. More than 60% consumed ultra-processed foods, and the prevalence of overweight among those <5 and ≥6 years of age was 10.2% and 18.9%, respectively. The mean total Child Behavior Checklist score was 44.1 ± 23.61 (≥16 months), and the mean intellectual quotient score in children ≥6 years of age was 97.9 ± 15.4., Conclusion: Despite the difficulties in conducting intergenerational cohort studies, the results of the present investigation provide evidence supporting the feasibility of performing these types of studies in middle-income countries., Competing Interests: The authors declare no conflicts of interest., (© 2020 The Authors. Health Science Reports published by Wiley Periodicals LLC.)

Objective: To investigate the incidence and homotypic and heterotypic continuity of psychiatric disorders between ages 6 and 11., Methods: In 2004, all live births in the city of Pelotas, Brazil, were recorded (n=4,231). Psychiatric disorders were assessed by the Strengths and Difficulties Questionnaire (SDQ). SDQ subscale scores (emotional symptoms, conduct problems, hyperactivity/inattention, and peer relationship problems) were categorized as normal or abnormal. To examine associations between problems over time, odds ratios were computed using logistic regression., Results: Any SDQ difficulty was observed in 350 children (10.4%, 95%CI 9.4-11.5) at age 6 and 476 (14.2%, 95%CI 13.0-15.4) at age 11, with a higher prevalence among boys at both ages. Between ages 6 and 11, there was a 50 and a 45% increase in the prevalence of emotional and hyperactivity/inattention symptoms, respectively. Among those who had any SDQ difficulty at age 6, that status persisted in 81% at age 11. We found homotypic continuity of emotional symptoms, conduct problems, hyperactivity/inattention, and peer relationship problems., Conclusions: Our results indicate an increasing incidence of psychiatric disorders in this age group, with rates of disorders and continuity patterns similar to those observed in other studies.

Pay-for-performance (P4P) is the provision of financial incentives to healthcare providers based on pre-specified performance targets. P4P has been used as a policy tool to improve healthcare provision globally. However, researchers tend to cluster into those working on high or low- and middle-income countries (LMICs), with still limited knowledge exchange, potentially constraining opportunities for learning from across income settings. We reflect here on some commonalities and differences in the design of P4P schemes, research questions, methods and data across income settings. We highlight how a global perspective on knowledge synthesis could lead to innovations and further knowledge advancement., (© 2020 The Author(s); Published by Kerman University of Medical Sciences. This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/ licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.)

There is a gap in the literature in understanding how cash transfer programmes affect mental health. We aim to fill this gap by conceptualising and estimating the mediation effects of an unconditional cash transfer programme on mental health. We use a sample of 4,535 adults living below the South African poverty line in four waves (2008-2014) of the South African National Income Dynamics Study. We use information on individual exposure to South Africa's largest unconditional cash transfer programme, the Child Support Grant. Mental health is measured by the 10-item version of the Centre for Epidemiological Depression Scale. We use the product of the coefficient method for the mediation analysis in combination with instrumental variable estimation. We find that physical health and lifestyle factors mediate the relationship of the unconditional cash transfer programme, each explaining about eight percent and 16% of the total positive effect. Our findings show that individuals living in poverty make investment decisions that are positive for their mental health, which has strong implications for policy makers., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Nowadays, thanks to extensive studies and progress in precision medicine, pediatric leukemia has reached an extremely high overall survival rate. Nonetheless, a fraction of relapses and refractory cases is still present, which are frequently correlated with poor prognosis. Although several molecular features of these diseases are known, still the field of energy metabolism, which is widely studied in adult, has not been frequently explored in childhood leukemias. Metabolic reprogramming is a hallmark of cancer and is deeply connected with other genetic and signaling aberrations generally known to be key features of both acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). This review aims to clear the current knowledge on metabolic rewiring in pediatric ALL and AML, also highlighting the influence of the main signaling pathways and suggesting potential ideas to further exploit this field to discover new prognostic biomarkers and, above all, beneficial therapeutic options.