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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.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.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]).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.The Health Foundation and the National Institute for Health and Care Research.

Laura Anselmi, Victor Ruiz-Velasco, Sean D. Stocker, Shannon P. Higgins, Guillaume P. Ducrocq and Marc P. Kaufman. The role played by the transient receptor potential vallinoid-1 (TRPV1) on the endings of thin fiber muscle afferents in evoking the exercise pressor reflex is controversial. To shed light on this controversy, we used TRPV1-/- rats that were made by a CRISPR-Cas9 deletion to introduce a 26-bp frameshift deletion in exon 3. We compared the magnitude of the reflex between TRPV1 +/+ wild-type rats (WT), TRPV1+/- heterozygous rats (HET), and TRPV1-/- knockout rats (KO). The exercise pressor reflex was evoked by stimulating the tibial nerve (40Hz, 0.01ms, 1.5 times motor threshold) in precollicular decerebrated unanesthetized rats whose femoral arteries were either freely perfused or were occluded for 30 sec before the start of contraction. We found that there was no difference between the magnitude of the reflex in the three groups of rats with freely perfused hindlimbs (p=0.61). Specifically, the exercise pressor reflex averaged 16.4 ± 2.2 mmHg in WT rats (n=9), 21.1 ± 5 mmHg in HET rats (n=9), and 17.7 ± 2.3 mmHg in KO rats (n=9). No difference was also observed among the three groups of rats that received acute femoral artery occlusion (p=0.79). Specifically, the peak exercise pressor reflex averaged 15.3 ± 2.2 mmHg in WT rats (n=4), 19.8 ± 4.7 mmHg in HET rats (n=6), and 19 ± 8 mmHg in KO rats (n=3). Stimulation of the tibial nerve after paralysis of the rats with pancuronium (iv) had trivial effects on arterial pressure indicating that the pressor responses to contraction were not caused by electrical stimulation within the axon of the tibial nerve. Intra-carotid arterial injection of the TRPV1 agonist, capsaicin (0.5 mg), evoked a significant pressor response in the WT rats (34.7 ± 9.2 mmHg) and in the HET rats (36.3 ± 7.2 mmHg), but not in the KO rats (3.2 ± 0.4 mmHg). In electrophysiological studies of dorsal root ganglion cells innervating the gastrocnemius muscles, capsaicin evoked inward currents in the WT and HET rats, but not in the KO rats. Moreover, immunofluorescence revealed the presence of TRPV1 in the DRG of WT, but not in the DRG of KO rats. We conclude that TRPV1 is not needed to evoke the exercise pressor reflex either in rats whose femoral arteries were either freely perfused or were occluded. These results are consistent with our previous finding that pharmacological antagonism of TRPV1 had no effect on the exercise pressor reflex. Supported by HL156594 and HL 156513 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

We investigated the role played by lactate and H+ in evoking the exercise pressor reflex in decerebrated rats whose hindlimb muscles were either freely perfused or ischemic. Production of lactate and H+ by the contracting hindlimb muscles was manipulated with CRISPR to render the myophosphorylase gene (PYGM) non-functional with respect to its ability metabolize glycogen to glucose. Three groups of rats were studied, namely those in which both alleles of the myophosphorylase gene was non-functional (MYO -/-; n=6), one allele of the myophosphorylase gene was non-functional (MYO +/-; n=11), and those in which both alleles were functional MYO +/+ (n=11). The exercise pressor reflex was evoked by statically contracting the triceps surae muscles for 30s with or without the femoral artery occluded, the latter rendering the contracting muscles ischemic. The sensitivity of the muscle mechanoreflex was evaluated in each group of rats by passively stretching the triceps surae muscles for 30 seconds. The sensitivity of the muscle metaboreflex was evaluated by injecting lactic acid (24mM, pH=2.4, 100μL) or inorganic phosphate (24mM, pH=6.0, 100 μL) into the arterial supply of the triceps surae muscles. For each contraction, the peak pressor response, the pressor response integrated over the contraction period (i.e., blood pressure index) and the cardioaccelerator response were calculated. Lactate concentrations were measured from arterial blood samples. Static contraction of freely perfused muscles increased blood lactate concentrations in both MYO +/+ rats (1.3 ± 0.8mmol/L; P < 0.001) and MYO +/- rats (0.57 ± 0.41mmol/L; P = 0.030), but not in MYO -/- rats (0.10 ± 0.28mmol/L; P = 0.999). Despite different lactate productions, the peak pressor, the blood pressure index, and the cardioaccelerator responses to freely perfused contraction did not differ between groups (P > 0.32). Compared to contraction with freely perfused hindlimb circulation, static contraction with occluded circulation increased lactate production by 44 ± 40%, and 26 ± 60% in MYO +/+ and MYO +/- rats, respectively, whereas it had no effect on lactate production in MYO-/- rats (-0.05±0.07%). The blood pressure index calculated for ischemic contraction was greater than that calculated for freely perfused contraction in both the MYO +/+ (73 ± 50%; P < 0.001) and the MYO +/- rats (50 ± 51%; p = 0.050) but not in MYO -/- rats (-10 ± 25%; P=0.734). No difference in the pressor response to passive stretch or lactic acid injection was found between groups (P > 0.295). A greater pressor response to injection of inorganic phosphate was detected, however, in MYO -/- rats (44 ± 24 mmHg) compared to those in MYO +/+ (23 ± 12mmHg; P = 0.0271) and in MYO+/- rats (9 ± 5mmHg; P < 0.001). We conclude that lactate and/or hydrogen ion accumulation in contracting myocytes play a key role in evoking the metabolic component of the exercise pressor reflex during ischemic but not during freely perfused contractions. Supported by NIH grants HL 156594 and HL 156513. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

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, in case there is a Matthew Effect and financial bonuses are primarily captured by providers who are already better able to perform (say 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 one standard-deviation above the mean in terms of access to guidelines, earned 90 USD more per quarter than those that were one-standard deviation below the mean. Differences in bonus pay-outs for facilities that were one standard-deviation above and below the mean in terms of 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 in the richest quintile. Qualitative data confirm these findings. Respondents identified facilities’ 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. Keywords: Health financing, pay-for-performance, inequality, Zimbabwe

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.

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 Gα(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.

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.

Este manuscrito proviene de una investigación donde se pretende construir un estado del arte actual acerca de la utilización de materiales alternativos a los tradicionales por parte de diferentes empresas o marcas de diseño que buscan incorporar soluciones sustentables iniciando por el material, proponiendo modelos de producción diferentes y utilizando materias primas atípicas. En este momento histórico la creación y aplicación de nuevos materiales que colaboren a la transición ecológica son necesarios y están siendo cada vez más requeridos por la industria manufacturera de bienes. El estudio presente pretende ampliar el conocimiento bajo este enfoque.

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.

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.

BackgroundConcurrent 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 in absence of mandated policies. Their relative impact on Covid-19 attributed mortality rates, enabling policy selection for maximal benefit with minimal disruption, is not well established.MethodsWe exploited variations in nine non-pharmaceutical interventions implemented in 130 countries (3250 observations) in two periods chosen to limit reverse causality: 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, on average). We examined associations with daily deaths per million in each subsequent 24-day period (the time between virus transmission and mortality) which could only be affected by the policy period. A mean score of strictness and timeliness was coded for each intervention. Days in each country were indexed in time by first reported Covid-19 death to proxy for virus transmission rate. Multivariable linear regression models of Covid-19 mortality rates on all concurrent interventions were adjusted for seasonality, potential confounders, and potential cross-country differences in their mortality definitions. Robustness was checked by removing countries with known data reporting issues and with non-linear, negative binomial, models.ResultsAfter adjusting for multiple concurrent interventions and confounders, and accounting for both timing and strictness of interventions, earlier and stricter school (−1.23 daily deaths per million, 95% CI -2.20 -0.27) and workplace closures (−0.26, 95% CI -0.46 -0.05) were associated with lower Covid-19 mortality rates. Only controlling for strictness international travel controls, and only controlling for timing later restrictions on gatherings, were also associated with lower Covid-19 mortality. Other interventions, such as stay-at-home orders or restrictions on public transport, were not significantly associated with differences in mortality rates across countries. Findings were robust across multiple statistical approaches.ConclusionsFocusing on ‘compulsory’, particularly school closing, not ‘voluntary’ reduction of social interactions with mandated policies appears to have been the most effective strategy to mitigate early Covid-19 mortality.

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.

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., Highlights • We build a mediation framework for the cash transfer and mental health relationship. • Analyse mediation effects of the Child Support Grant (CSG) on adult mental health. • The cash transfer improves mental health by 0.7 units or 0.2 standard deviations. • Physical health and lifestyle factors mediate the CSG effect on mental health. • Physical health explains 8% and lifestyle factors explain 16% of the total effect.

Dopamine (DA)-containing fibers and neurons are embedded within the brain stem dorsal vagal complex (DVC); we have shown previously that DA modulates the membrane properties of neurons of the dorsal motor nucleus of the vagus (DMV) via DA1 and DA2 receptors. The vagally dependent modulation of gastric tone and phasic contractions, i.e., motility, by DA, however, has not been characterized. With the use of microinjections of DA in the DVC while recording gastric tone and motility, the aims of the present study were 1) assess the gastric effects of brain stem DA application, 2) identify the DA receptor subtype, and, 3) identify the postganglionic pathway(s) activated. Dopamine microinjection in the DVC decreased gastric tone and motility in both corpus and antrum in 29 of 34 rats, and the effects were abolished by ipsilateral vagotomy and fourth ventricular treatment with the selective DA2 receptor antagonist L741,626 but not by application of the selective DA1 receptor antagonist SCH 23390. Systemic administration of the cholinergic antagonist atropine attenuated the inhibition of corpus and antrum tone in response to DA microinjection in the DVC. Conversely, systemic administration of the nitric oxide synthase inhibitor nitro-l-arginine methyl ester did not alter the DA-induced decrease in gastric tone and motility. Our data provide evidence of a dopaminergic modulation of a brain stem vagal neurocircuit that controls gastric tone and motility. NEW & NOTEWORTHY Dopamine administration in the brain stem decreases gastric tone and phasic contractions. The gastric effects of dopamine are mediated via dopamine 2 receptors on neurons of the dorsal motor nucleus of the vagus. The inhibitory effects of dopamine are mediated via inhibition of the postganglionic cholinergic pathway.

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.

BackgroundEquitable access to mental healthcare is a priority for many countries. The National Health Service in England uses a weighted capitation formula to ensure that the geographical distribution of resources reflects need.AimsTo produce a revised formula for estimating local need for secondary mental health, learning disability (intellectual disability) and psychological therapies services for adults in England.MethodWe used demographic records for 43 751 535 adults registered with a primary care practitioner in England linked with service use, ethnicity, physical health diagnoses and type of household, from multiple data-sets. Using linear regression, we estimated the individual cost of care in 2015 as a function of individual- and area-level need and supply variables in 2013 and 2014. We sterilised the effects of the supply variables to obtain individual-need estimates. We aggregated these by general practitioner practice, age and gender to derive weights for the national capitation formula.ResultsHigher costs were associated with: being 30–50 years old, compared with 20–24; being Irish, Black African, Black Caribbean or of mixed ethnicity, compared with White British; having been admitted for specific physical health conditions, including drug poisoning; living alone, in a care home or in a communal environment; and living in areas with a higher percentage of out-of-work benefit recipients and higher prevalence of severe mental illness. Longer distance from a provider was associated with lower cost.ConclusionsThe resulting needs weights were higher in more deprived areas and informed the distribution of some 12% (£9 bn in 2019/20) of the health budget allocated to local organisations for 2019/20 to 2023/24.

Background: Standardized mortality rates are routinely used as measures of hospital performance and quality. Such metrics may, however, be biased if hospital admission thresholds differ and patient severity is not fully measured.Aim: To examine whether comparisons of hospital mortality rates suffer from selection bias due to variations in hospital admission rates, using the example of variations by day of the week.Data: 12,900,687 emergency department attendances and 3,418,446 unplanned admissions to all acute non-specialist hospitals of the National Health Service in England between 1 April 2013 and 28 February 2014. Methods: Population-based retrospective cohort study. Mortality within 30 days of attendance is modelled as a function of weekend or weekday attendance and hospital-level predictors of admission rates using patient-level risk-adjusted probit and bivariate Heckman selection models. Robustness is supported by the use of different hospital-level predictors. Results: When examining only the admitted population, patients admitted to hospital at weekends have a 0.206 percentage point higher risk of death within 30 days compared to patients admitted during the week. However, patients attending emergency departments at weekends have a 1.390 percentage point lower probability of being admitted to hospital. Once this selection bias is accounted for, the weekend effect in mortality is reduced by two-thirds to a 0.068 percentage point increase in the risk of death.Conclusions: Comparisons of standardized hospital mortality rates following unplanned admissions can be biased by variations in emergency department admission rates, leading to incorrect conclusions about quality. The use of mortality as a performance measure could therefore lead to misleading comparisons if admission rates vary and illness severity is not fully controlled for. Accounting for sample selection bias and dependence between admission and mortality rates is vital if accurate comparisons of hospital performance are to be made.

The majority of patients with Parkinson’s disease (PD) experience gastrointestinal dysfunction. Recently, we described a nigro-vagal pathway that uses dopaminergic (DA) inputs to the dorsal motor nucleus of the vagus (DMV) and A2 area neurons to modulate gastric motility and tone. This pathway is disrupted in a rodent model of PD. The aim of the present study was to test the hypothesis that brain-stem DA modulation of gastric tone and motility is altered in a rodent model of PD. Male Sprague-Dawley rats received three weekly intraperitoneal injections of paraquat (10 mg/kg) or saline (control). In naive conditions, microinjection of DA into the DMV induced a gastroinhibitory response in 100% of animals. In 19 of 28 PQ-treated animals, however, microinjection of DA into the DVC induced a biphasic response, with an initial increase in gastric tone and motility followed by a profound gastroinhibition. The excitatory response to DA microinjection was attenuated by a combination of DA type 1 (DA1)- and DA2-like receptor antagonists. Conversely, the inhibitory response was reduced by the DA2-like receptor antagonist only. Pretreatment with the α2-adrenoceptor antagonist yohimbine did not modulate the response to DA, thus excluding involvement of the A2 area. At the end of the experiments, induction of the Parkinson phenotype was confirmed by the presence of α-synuclein immunoreactivity in the DMV and substantia nigra pars compacta. These data suggest a maladaptive neural plasticity in brain-stem vagal circuits regulating gastric motility in PQ-treated rats that may be responsible for the gastric dysfunction observed in PD models. NEW & NOTEWORTHY After paraquat treatment and induction of Parkinson’s disease, brain-stem dopamine (DA) application induces a biphasic gastric response in the majority of rats, with an initial increase in tone and motility followed by gastroinhibition. The initial increase in gastric tone and motility is mediated via a combined activation of DA type 1 (DA1)- and DA2-like receptors. The inhibitory effects of DA are mediated by DA2-like receptors and are not affected by blockade of adrenergic inputs mediated by α2-adrenoceptors.

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., Highlights • Zimbabwe's national Results Based Financing scheme decreased under-five mortality. • Among higher wealth and education groups. • RBF increased institutional deliveries in the poorest and least educated groups and reduced the rate of c-section. • There were no programme effects on other incentivised services. • The RBF programme effects generally appear to be stronger earlier in the implementation process.

Simple Summary The use of innovative technologies has revolutionized cancer research in recent years, and in the field of pediatric oncohematology, great results have been achieved. However, within this context, acute myeloid leukemia still represents a considerable challenge for clinicians, as frequent cases of relapse or refractory disease, especially in specific subgroups, remain present. With this review, the authors aim to recapitulate the main features of this extremely heterogeneous malignancy, by highlighting the concept of clonal evolution and how, thanks also to the impact of new high throughput techniques, this could be exploited to deepen the current knowledge on molecular mechanisms driving this disease. Overall, this study will seek to pave the way for making new tools available to further improve diagnosis and treatment protocols in pediatric patients. Abstract 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.

Impairment of the axonal transport system mediated by intracellular microtubules (MTs) is known to be a major drawback in neurodegenerative processes. Due to a growing interest on the neurotoxic effects of selenium in environmental health, our study aimed to assess the relationship between selenium and MTs perturbation, that may favour disease onset over a genetic predisposition to amyotrophic lateral sclerosis. We treated a neuron-like cell line with sodium selenite, sodium selenate and seleno-methionine and observed that the whole cytoskeleton was affected. We then investigated the protein interactome of cells overexpressing αTubulin-4A (TUBA4A) and found that selenium increases the interaction of TUBA4A with DNA- and RNA-binding proteins. TUBA4A ubiquitination and glutathionylation were also observed, possibly due to a selenium-dependent increase of ROS, leading to perturbation and degradation of MTs. Remarkably, the TUBA4A mutants R320C and A383 T, previously described in ALS patients, showed the same post-translational modifications to a similar extent. In conclusion this study gives insights into a specific mechanism characterizing selenium neurotoxicity.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive disorder characterized by malignant transformation of immature progenitors primed towards T-cell development. Over the past 15 years, advances in the molecular characterization of T-ALL have uncovered oncogenic key drivers and crucial signaling pathways of this disease, opening new chances for the development of novel therapeutic strategies. Currently, T-ALL patients are still treated with aggressive therapies, consisting of high dose multiagent chemotherapy. To minimize and overcome the unfavorable effects of these regimens, it is critical to identify innovative targets and test selective inhibitors of such targets. Major efforts are being made to develop small molecules against deregulated signaling pathways, which sustain T-ALL cell growth, survival, metabolism, and drug-resistance. This review will focus on recent improvements in the understanding of the signaling pathways involved in the pathogenesis of T-ALL and on the challenging opportunities for T-ALL targeted therapies.

Increasing evidence suggests that environmental neurotoxicants or misfolded α-synuclein generated by such neurotoxicants are transported from the gastrointestinal tract to the central nervous system via the vagus nerve, triggering degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and causing Parkinson’s disease (PD). We tested the hypothesis that gastric co-administration of subthreshold doses of lectins and paraquat can recreate the pathology and behavioral manifestations of PD in rats. A solution containing paraquat + lectin was administered daily for 7 days via gastric gavage, followed by testing for Parkinsonian behavior and gastric dysmotility. At the end of the experiment, brainstem and midbrain tissues were analyzed for the presence of misfolded α-synuclein and neuronal loss in the SNpc and in the dorsal motor nucleus of the vagus (DMV). Misfolded α-synuclein was found in DMV and SNpc neurons. A significant decrease in tyrosine hydroxylase positive dopaminergic neurons was noted in the SNpc, conversely there was no apparent loss of cholinergic neurons of the DMV. Nigrovagally-evoked gastric motility was impaired in treated rats prior to the onset of parkinsonism, the motor deficits of which were improved by l-dopa treatment. Vagotomy prevented the development of parkinsonian symptoms and constrained the appearance of misfolded α-synuclein to myenteric neurons. These data demonstrate that co-administration of subthreshold doses of paraquat and lectin induces progressive, l-dopa-responsive parkinsonism that is preceded by gastric dysmotility. This novel preclinical model of environmentally triggered PD provides functional support for Braak’s staging hypothesis of idiopathic PD., Environmental triggers: a gut reaction Tube-feeding rats with low levels of the herbicide paraquat and the dietary factor lectin triggers the development of Parkinson’s disease (PD), supporting the idea that the disease can start in the gut. Two weeks after co-administration of paraquat and lectin for seven days, Alberto Travagli and colleagues at Penn State College of Medicine, Pennsylvania, found misfolded α-synuclein in both the vagal neurocircuitry, which connects the gastrointestinal tract to the central nervous system, and the substantia nigra pars compacta where there was also a loss of dopaminergic neurons. Furthermore, the rats exhibited typical PD symptoms, including reduced gastric motility and impaired motor function, that could be alleviated with l-dopa. Removing part of the vagus nerve prevented the development of disease suggesting that environmentally triggered PD spreads from the gut.