Lactate and hydrogen ions play a predominant role in evoking the exercise pressor reflex during ischaemic contractions but not during freely perfused contractions.

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 31P-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.

The impact of devolution on local health systems: Evidence from Greater Manchester, England.

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.

Paradoxical potentiation of the exercise pressor reflex by endomorphin 2 in the presence of naloxone.

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.

Inhibition and potentiation of the exercise pressor reflex by pharmacological modulation of TRPC6 in male rats.

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.

Evaluating whole system reforms: A structured approach for selecting multiple outcomes.

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.

Functional knockout of the TRPV1 channel has no effect on the exercise pressor reflex in rats.

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.

Analysing changes to the flow of public funding within local health and care systems: An adaptation of the System of Health Accounts framework to a local health system in England.

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.

The impact of devolution on experienced health and well-being.

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.

Early effects of COVID-19 on maternal and child health service disruption in Mozambique.

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.

The impact of performance-based financing within local health systems: Evidence from Mozambique.

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.

Emergency department outcomes for patients experiencing homelessness in England: retrospective cross-sectional study.

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 effect of devolution on health: a generalised synthetic control analysis of Greater Manchester, England.

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.

Maternal and Child Health Care Service Disruptions and Recovery in Mozambique After Cyclone Idai: An Uncontrolled Interrupted Time Series Analysis.

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.

The relative effects of non-pharmaceutical interventions on wave one Covid-19 mortality: natural experiment in 130 countries.

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.

Role of CBL Mutations in Cancer and Non-Malignant Phenotype.

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.

Are Induced Pluripotent Stem Cells a Step towards Modeling Pediatric Leukemias?

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.

Serotonin-Mediated Activation of Serotonin Receptor Type 1 Oppositely Modulates Voltage-Gated Calcium Channel Currents in Rat Sensory Neurons Innervating Hindlimb Muscle.

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 (CaV) 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 CaV 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 CaV2.2 via Gα i/o protein subunits. Application of selective serotonin receptor type 1 (5-HT1) agonists revealed that modulation of CaV2.2 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 (CaV2.2) currents. Our findings suggest 5-HT exhibits receptor subtype selectivity, providing a complexity of cellular responses.

Who is paid in pay-for-performance? Inequalities in the distribution of financial bonuses amongst health centres in Zimbabwe.

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.

Use of past care markers in risk-adjustment: accounting for systematic differences across providers.

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 R2 = 0.007 at person level and R2 = 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 R2 = 0.275 at person level and R2 = 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 R2 = 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.

Can Results-Based Financing improve health outcomes in resource poor settings? Evidence from Zimbabwe.

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.