Resilience to substance use disorder following childhood maltreatment: association with peripheral biomarkers of endocannabinoid function and neural indices of emotion regulation.

Childhood maltreatment (CM) is a risk factor for substance use disorders (SUD) in adulthood. Understanding the mechanisms by which people are susceptible or resilient to developing SUD after exposure to CM is important for improving intervention. This case-control study investigated the impact of prospectively assessed CM on biomarkers of endocannabinoid function and emotion regulation in relation to the susceptibility or resilience to developing SUD. Four groups were defined across the dimensions of CM and lifetime SUD (N = 101 in total). After screening, participants completed two experimental sessions on separate days, aimed at assessing the behavioral, physiological, and neural mechanisms involved in emotion regulation. In the first session, participants engaged in tasks assessing biochemical (i.e., cortisol, endocannabinoids), behavioral, and psychophysiological indices of stress and affective reactivity. During the second session, the behavioral and brain mechanisms associated with emotion regulation and negative affect were investigated using magnetic resonance imaging. CM-exposed adults who did not develop SUD, operationally defined as resilient to developing SUD, had higher peripheral levels of the endocannabinoid anandamide at baseline and during stress exposure, compared to controls. Similarly, this group had increased activity in salience and emotion regulation regions in task-based measures of emotion regulation compared to controls, and CM-exposed adults with lifetime SUD. At rest, the resilient group also showed significantly greater negative connectivity between ventromedial prefrontal cortex and anterior insula compared to controls and CM-exposed adults with lifetime SUD. Collectively, these peripheral and central findings point to mechanisms of potential resilience to developing SUD after documented CM exposure.

Functional connectivity signatures of major depressive disorder: machine learning analysis of two multicenter neuroimaging studies.

The promise of machine learning has fueled the hope for developing diagnostic tools for psychiatry. Initial studies showed high accuracy for the identification of major depressive disorder (MDD) with resting-state connectivity, but progress has been hampered by the absence of large datasets. Here we used regular machine learning and advanced deep learning algorithms to differentiate patients with MDD from healthy controls and identify neurophysiological signatures of depression in two of the largest resting-state datasets for MDD. We obtained resting-state functional magnetic resonance imaging data from the REST-meta-MDD (N = 2338) and PsyMRI (N = 1039) consortia. Classification of functional connectivity matrices was done using support vector machines (SVM) and graph convolutional neural networks (GCN), and performance was evaluated using 5-fold cross-validation. Features were visualized using GCN-Explainer, an ablation study and univariate t-testing. The results showed a mean classification accuracy of 61% for MDD versus controls. Mean accuracy for classifying (non-)medicated subgroups was 62%. Sex classification accuracy was substantially better across datasets (73-81%). Visualization of the results showed that classifications were driven by stronger thalamic connections in both datasets, while nearly all other connections were weaker with small univariate effect sizes. These results suggest that whole brain resting-state connectivity is a reliable though poor biomarker for MDD, presumably due to disease heterogeneity as further supported by the higher accuracy for sex classification using the same methods. Deep learning revealed thalamic hyperconnectivity as a prominent neurophysiological signature of depression in both multicenter studies, which may guide the development of biomarkers in future studies.

Mapping and analysis of health financing in South Kivu province (DRC) / Cartographie et analyse du financement de la santé dans la province du Sud-Kivu (RDC)

Introduction: In South-Kivu, the health system is underfunded due to numerous constraints. Several initiatives have been tested but are insufficient for increasing and sustaining health financing. Purpose of research: Analyze the health financing system in South-Kivu, through a mapping as well as quantitative and qualitative analysis of health financing mechanisms. Results: The provincial health financing system is fragmented, with poorly coordinated mechanisms and interventions, leading to duplication of health system strengthening activities in addition to the absence of a mechanism for pooling external funding flows. Costs recovery (i.e. user fees) and external supports are the most widely used schemes while the government hardly contributes to the financing of the provincial health system. Mutual health insurance is supposed to improve access to health care, but its coverage is still extremely low. Results-Based Financing and free health care programs, fully financed by external donors, are irregular and insufficiently sustainable. Conclusions: It would be critical to implement a strategic purchasing model that is anchored in local institutions, owned by all stakeholders, and integrating all existing financing mechanisms, which could be supported by a common fund supporting the provincial health system. The "Single Contract" initiative developed to harmonize, pool, and sustain external programs, could be a good basis in this respect. This would involve strengthening policy dialogue, developing an investment case to support resource mobilization and implementing a joint monitoring and evaluation platform for disbursements led by the provincial health authorities.

Introduction: Au Sud-Kivu, en République démocratique du Congo, le système de santé est sous-financé dû à de nombreuses contraintes. Plusieurs initiatives ont été testées mais restent insuffisantes pour augmenter et pérenniser le financement de la santé. But de l'étude: Analyser le système de financement de la santé au Sud-Kivu, par une cartographie et une analyse quantitative et qualitative des mécanismes de financement. Résultats: Le système de financement de la santé de la province est fragmenté, avec des mécanismes et interventions peu coordonnés, suscitant des duplications d'activités d'appui au système de santé, en plus de la quasi-absence de mécanisme de mise en commun des appuis extérieurs. Le recouvrement des coûts et les financements extérieurs sont les mécanismes les plus utilisés alors que l'État contribue très faiblement au financement du système provincial de santé. Les mutuelles de santé sont censées améliorer l'accès aux soins, mais leur taux de couverture reste extrêmement faible. Le financement basé sur les résultats et la gratuité des soins, intégralement compensés par les donateurs extérieurs, sont irréguliers et insuffisamment pérennes. Conclusions: Il serait essentiel d'adopter au Sud-Kivu un modèle d'achat stratégique, ancré dans les institutions locales, approprié par l'ensemble des parties prenantes, qui intègre l'ensemble des mécanismes de financement existants et qui soit appuyé par un fonds commun d'appui au système provincial de santé. L'initiative du Contrat unique développée pour harmoniser, mettre en commun et pérenniser les programmes extérieurs peut servir de base pour élaborer un tel modèle. Ceci impliquerait de renforcer le dialogue politique, d'élaborer un dossier d'investissement pour soutenir la mobilisation des ressources et de créer une plateforme conjointe de suivi et d'évaluation des décaissements, pilotée par les autorités provinciales de santé.

Peripheral and central kynurenine pathway abnormalities in major depression.

Considerable data relate major depressive disorder (MDD) with aberrant immune system functioning. Pro-inflammatory cytokines facilitate metabolism of tryptophan along the kynurenine pathway (KP) putatively resulting in reduced neuroprotective and increased neurotoxic KP metabolites in MDD, in addition to modulating metabolic and immune function. This central nervous system hypothesis has, however, only been tested in the periphery. Here, we measured KP-metabolite levels in both plasma and cerebrospinal fluid (CSF) of depressed patients (n = 63/36 respectively) and healthy controls (n = 48/33). Further, we assessed the relation between KP abnormalities and brain-structure volumes, as well as body mass index (BMI), an index of metabolic disturbance associated with atypical depression. Plasma levels of picolinic acid (PIC), the kynurenic/quinolinic acid ratio (KYNA/QUIN), and PIC/QUIN were lower in MDD, but QUIN levels were increased. In the CSF, we found lower PIC in MDD. Confirming previous work, MDD patients had lower hippocampal, and amygdalar volumes. Hippocampal and amygdalar volumes were correlated positively with plasma KYNA/QUIN ratio in MDD patients. BMI was increased in the MDD group relative to the control group. Moreover, BMI was inversely correlated with plasma and CSF PIC and PIC/QUIN, and positively correlated with plasma QUIN levels in MDD. Our results partially confirm previous peripheral KP findings and extend them to the CSF in MDD. We present the novel finding that abnormalities in KP metabolites are related to metabolic disturbances in depression, but the relation between KP metabolites and depression-associated brain atrophy might not be as direct as previously hypothesized.

Évaluation de la mise en œuvre de la sécurité routière au Bénin en 2019.

OBJECTIVE: The study aims to assess the level of implementation of road safety interventions in Benin. METHOD: The research is based on an evaluative study of road safety aimed to analyze the implementation and logic of road safety interventions, conducted in Benin in 2019. It combined a review of the gray literature and a qualitative component. The data were collected through documents and interviews in structures involved in road safety management. RESULTS: Road safety was a national priority with one lead institution and several structures involved. There was a lack of consensus among stakeholders, insufficient framework documents, resources, legislative texts, and study data. Few roads were in good condition and very few allowed the separation of two-wheeled vehicles. The vehicle fleet was outdated. Various activities were carried out to raise awareness, to educate the population and to enforce the texts but they were insufficient and poorly coordinated. Reference hospitals had the minimum service to deal with trauma cases. The interventions had not yet resulted in a reduction in the number of injuries and fatalities by accidents, which was increasing. CONCLUSION: Benin has made great efforts in the area of road safety. However, there are still some shortcomings to take into account.

Misunderstandings and ambiguities in strategic purchasing in low- and middle-income countries.

Strategic purchasing is branded as an approach that is necessary for progress towards universal health coverage. While we agree that publicly purchased health services should respond to society's needs and patient expectations, and thus generally endorse strategic purchasing, here we would like to explore two emerging concerns within current discussions in low- and middle-income countries. First, there exists a great deal of misunderstanding and conceptual unclarity, within practitioner groups, around the concept of strategic purchasing and what instruments it incorporates. Second, there is a growing trend to regularly fuse strategic purchasing into a performance-based financing (PBF) discourse in ways that increasingly blur their distinctive properties and policy orientations, while perhaps too easily obfuscating potential tensions. We believe the discourse on strategic purchasing would benefit from better conceptual clarity by dissociating and prioritising its two objectives, namely: priority should be given to needs-based allocation of resources, while rewarding performance is a subsequent concern. We argue there is a need for a more thoroughgoing conceptual and empirical re-examination of strategic purchasing's priorities, its link with PBF, as well as for a wider evidence-base on what strategic purchasing tools exist and which are most appropriate for diverse contexts.

Choice for Drug or Natural Reward Engages Largely Overlapping Neuronal Ensembles in the Infralimbic Prefrontal Cortex.

Cue-reward associations form distinct memories that can drive appetitive behaviors and are involved in craving for both drugs and natural rewards. Distinct sets of neurons, so-called neuronal ensembles, in the infralimbic area (IL) of the medial prefrontal cortex (mPFC) play a key role in alcohol seeking. Whether this ensemble is specific for alcohol or controls reward seeking in general remains unclear. Here, we compared IL ensembles formed upon recall of drug (alcohol) or natural reward (saccharin) memories in male Wistar rats. Using an experimental framework that allows identification of two distinct reward-associated ensembles within the same animal, we found that cue-induced seeking of either alcohol or saccharin activated ensembles of similar size and organization, whereby these ensembles consist of largely overlapping neuronal populations. Thus, the IL seems to act as a general integration hub for reward seeking behavior, but also contains subsets of neurons that encode for the different rewards.SIGNIFICANCE STATEMENT Cue-reward associations form distinct memories that can act as drivers of appetitive behaviors and are involved in craving for natural rewards as well as for drugs. Distinct sets of neurons, so-called neuronal ensembles, in the infralimbic area of the mPFC play a key role in cue-triggered reward seeking. However, it is unclear whether these ensembles act as broadly tuned controllers of approach behavior or represent the learned associations between specific cues and rewards. Using an experimental framework that allows identification of two distinct reward-associated ensembles within the same animal we find largely overlapping neuronal populations. Repeated activation by two distinct events could reflect the linking of the two memory traces within the same neuron.

How is equity approached in universal health coverage? An analysis of global and country policy documents in Benin and Senegal.

BACKGROUND: Equity seems inherent to the pursuance of universal health coverage (UHC), but it is not a natural consequence of it. We explore how the multidimensional concept of equity has been approached in key global UHC policy documents, as well as in country-level UHC policies. METHODS: We analysed a purposeful sample of UHC reports and policy documents both at global level and in two Western African countries (Benin and Senegal). We manually searched each document for its use and discussion of equity and related terms. The content was summarised and thematically analysed, in order to comprehend how these concepts were understood in the documents. We distinguished between the level at which inequity takes place and the origin or types of inequities. RESULTS: Most of the documents analysed do not define equity in the first place, and speak about "health inequities" in the broad sense, without mentioning the dimension or type of inequity considered. Some dimensions of equity are ambiguous - especially coverage and financing. Many documents assimilate equity to an overall objective or guiding principle closely associated to UHC. The concept of equity is also often linked to other concepts and values (social justice, inclusion, solidarity, human rights - but also to efficiency and sustainability). Regarding the levels of equity most often considered, access (availability, coverage, provision) is the most often quoted dimension, followed by financial protection. Regarding the types of equity considered, those most referred to are socio-economic, geographic, and gender-based disparities. In Benin and Senegal, geographic inequities are mostly pinpointed by UHC policy documents, but concrete interventions mostly target the poor. Overall, the UHC policy of both countries are quite similar in terms of their approach to equity. CONCLUSIONS: While equity is widely referred to in global and country-specific UHC policy documents, its multiple dimensions results in a rather rhetorical utilisation of the concept. Whereas equity covers various levels and types, many global UHC documents fail to define it properly and to comprehend the breadth of the concept. Consequently, perhaps, country-specific policy documents also use equity as a rhetoric principle, without sufficient consideration for concrete ways for implementation.

Performance-based financing in the heath sector in low- and middle-income countries: Is there anything whereof it may be said, see, this is new?

Whereas performance-based financing (PBF) is now developing fast in the health sector in low- and middle-income countries and is presented an innovative approach-concomitantly, subject to a separate research stream-it shares many features of the "managing for results" (MfR) and performance-based budgeting (PBB) currents that have existed for decades. In this paper, we first argue that PBF as currently developed in the health sector in low- and middle-income countries shares many features and thus can be viewed as an avatar of MfR and more precisely PBB. Secondly, we draw lessons from the literature on MfR and PBB so as to (1) better apprehend PBF conceptually and (2) avoid pitfalls and better design PBF schemes in practice. We argue that the lessons from the theoretical and empirical literature on MfR and PBB offer interesting insights to feed into a "theory of change" of PBF, enabling to analyse critical aspects and better design PBF schemes. Moreover, it is hoped that just like MfR processes have been demonstrated as having the potential to boost individual performance not only through links with financial incentives but also through acting on other sources of motivation, one can demonstrate more accurately by which mechanisms the various elements of the PBF package can help improve health sector results.

The use of medicine retailers by people of Goma as an alternative healthcare provider: a risky but rational practice.

BACKGROUND: Medicine retailers, considered here as any person or setting dedicated to the sale of retail medicines, fill an important gap in terms of access to healthcare in areas where population are not covered by universal healthcare schemes. In Goma in the Democratic Republic of the Congo, such retailers have proliferated and are consulted as the first port of call by more than half of the population, playing therefore a key role as an alternative source of healthcare for any type of health condition. The objective of this study is to understand people of Goma's rationale for using the medicine retailers over the formal healthcare system. METHODS: Twelve focus groups, gathering 147 participants in total, were conducted in four worship communities, covering the most common faiths practised in Goma. Three focus group discussions were organised per worship community: one with fathers, another with mothers, and another with chronic patients and/or highly vulnerable people. We used a qualitative and inductive approach to analyse the participants' practices and perceptions in terms of their use of medicine retailers. We identified central categories explaining the reasons for using medicine retailers and the choice of a specific medicine retailer. RESULTS: When facing a health problem, most of the participants in our study tended to first buy medicines at medicine retailers because it was cheap, quick, and easily accessible. Most were aware of the risks and limitations of such practices and had developed a number of mitigation strategies in order to reduce those risks: evaluating medicine retailers' expertise; developing a "medical expertise"; and seeking proactively out empathetic care. CONCLUSIONS: People in Goma make a conscious and rational choice when resorting to medicine retailers as it is seen as the least-worst option in a complex situation. In order to reduce the risks, they have developed a number of mitigation strategies. Future research should focus on the organisation of medicine retailers as a professional group to improve their supervision in a sensitive context such as Goma and on modalities to articulate them to the formal health system to guarantee a financial accessibility to healthcare for all.

Which socio-economic groups benefit most from public health expenditure in Senegal? A dynamic benefit incidence analysis.

Despite efforts to enhance public investment in Senegal's health sector, the equitable distribution of benefits between socioeconomic groups remains largely unexplored. To address this gap, our study examines the progressive (or regressive) nature of public health expenditure. Utilizing data from the latest survey on household living conditions (2018-2019) in conjunction with administrative data on health expenditure from the same period (provided by the Ministry of Health of Senegal), we performed a benefit incidence analysis. This entailed segmenting the population by poverty quintiles and subsequently estimating how each group utilized and benefitted from public health expenditure, according to level of care and geographical location. Additionally, we performed a marginal benefit analysis to discern the impact of an increase in public health expenditure on various socioeconomic groups. Our findings unveil a pro-rich distribution of benefits at both primary healthcare and hospital levels, observable both at national and regional levels. Moreover, disparities in the distribution of resource allocation between Senegal's 14 administrative regions were observed. Ultimately, our results indicate that under prevailing conditions, increasing public health expenditure would not yield a pro-poor distribution of benefits. Therefore, our research underscores the imperative of better targeting populations for greater equity between regions and social groups.

Who is "anti-science"?

Objectives: "Anti-science" accusations are common in medicine and public health, sometimes to discredit scientists who hold opposing views. However, there is no such thing as "one science". Epistemology recognizes that any "science" is sociologically embedded, and therefore contextual and intersubjective. In this paper, we reflect on how "science" needs to adopt various perspectives to give a comprehensive and nuanced understanding of a phenomenon. Study design: Opinion paper. Methods: Based on a targeted literature survey, we first clarify the known limits of traditional scientific methods and then reflect on how the scientific reporting about Covid-19 mRNA vaccines has evolved. Results: The first reports of the Covid-19 mRNA vaccines randomised controlled trial results showed impressive efficacy. Nevertheless, an abundant literature has since depicted a far more nuanced picture of the effectiveness and safety of those vaccines over the medium-term. We organise them around five themes: (i) differentiating between relative and absolute reduction; (ii) taking account of time in reporting effectiveness; (iii) taking account of all outcomes, including adverse effects; (iv) stratifying effectiveness and considering other decision criteria (efficiency, equity, and acceptance); (v) changing the outcome of concern and assessing vaccines' effectiveness on mortality. Conclusions: Science offers a wide range of perspectives on a given study object. Only the process of deliberation amongst scientists and other stakeholders can result in accepted new knowledge useful to support decision-making. Unfortunately, by trying to reduce "science" to simple messages set in stone, scientists can become the worse enemies of science.

Contributions of Polygenic Risk and Disease Status to Gray Matter Abnormalities in Major Depression.

BACKGROUND: Gray matter (GM) abnormalities in depression are potentially attributable to some combination of trait, state, and illness history factors. Here, we sought to determine the contributions of polygenic risk for depression, depressive disease status, and the interaction of these factors to these GM abnormalities. METHODS: We conducted a cross-sectional comparison using a 2 × 3 factorial design examining effects of polygenic risk for depression (lower vs. upper quartile) and depression status (never depressed, currently depressed, or remitted depression) on regional GM concentration and GM volume. Participants were a subset of magnetic resonance imaging-scanned UK Biobank participants comprising 2682 people (876 men, 1806 women) algorithmically matched on 16 potential confounders. RESULTS: In women but not men, we observed that elevated polygenic risk for depression was associated with reduced cerebellar GM volume. This deficit occurred in salience and dorsal attention network regions of the cerebellum and was associated with poorer performance on tests of attention and executive function but not fluid intelligence. Moreover, in women with current depression compared to both women with remitted depression and women who never had depression, we observed GM reductions in ventral and medial prefrontal, insular, and medial temporal regions. These state-related abnormalities remained when accounting for antidepressant medication status. CONCLUSIONS: Neuroanatomical deficits attributed broadly to major depression are more likely due to an aggregation of independent factors. Polygenic risk for depression accounted for cerebellar structural abnormalities that themselves accounted for cognitive deficits observed in this disorder. Medial and ventral prefrontal, insular, and temporal cortex deficits constituted a much larger proportion of the aggregate deficit and were attributable to the depressed state.

Mandatory membership of community-based mutual health insurance in Senegal: A national survey.

With the low adherence to voluntary mutual health insurance, Senegal's policymakers have sought to understand the feasibility of compulsory health insurance membership. This study aims to measure the acceptability of mandatory membership in community-based mutual health insurance (CBHI) and to understand its possible administrative modalities. The study consists of a national survey among a representative population sample selected by marginal quotas. The survey was conducted in 2022 over the phone, with a random composition method involving 914 people. The questionnaire measured the socio-economic characteristics of households, their level of acceptability concerning voluntary and compulsory membership, and their level of confidence in CBHIs and the health system. Respondents preferred voluntary (86%) over mandatory (70%) membership of a CBHI. The gap between voluntary and compulsory membership scores was smaller among women (p = 0.040), people under 35 (p = 0.033), and people with no health coverage (p = 0.011). Voluntary or compulsory membership was correlated (p = 0.000) to trust in current CBHIs and health systems. Lack of trust in the CBHI management has been more disadvantageous for acceptance of the mandatory than the voluntary membership. No particular preference emerged as the preferred administrative channel (e.g. death certificate, identity card, etc.) to enforce the mandatory option. The results confirmed the well-known challenges of building universal health coverage based on CBHIs-a poorly appreciated model whose low performance reduces the acceptability of populations to adhere to it, whether voluntary or mandatory. Suppose Senegal persists in its health insurance approach. In that case, it will be essential to strengthen the performance and funding of CBHIs, and to gain population trust to enable a mandatory or more systemic membership.

Expectations and disappointments relative to COVID-19 passes: results from a voluntary mixed-methods study in French-speaking Belgium.

Objectives: Belgium enacted a coronavirus disease 2019 (COVID-19) pass - the 'COVID Safe Ticket' (CST) - in October 2021. This study aimed to understand the expectations and reasons given by those supporting this policy measure. Methods: This mixed methods study was based on a voluntary online survey among 9444 French-speaking residents in Belgium. Results: Most respondents were not very supportive of the CST, with only 617 respondents (7%) being pro-CST. Compared with other respondents, the pro-CST sample comprised more males, older people, people scared of COVID-19, people who had confidence in the COVID-19 vaccines, and highly educated people. A qualitative analysis was undertaken to identify the reasons why respondents supported the CST. Two lines of argument were related to personal comfort (individual protection and means of 'recovering freedom'), and two other lines were related to collective protection (controlling the pandemic and incentivizing vaccination). Pro-CST respondents also indicated some limitations of the CST. Conclusions: The expectations regarding the CST were high, diverse and not entirely rational. Some contradictions and frustration emerged from the respondents' comments. The CST may have exacerbated the social divide in society. The high expectations risk leading to comparably high levels of disappointment, resulting in potential distrust towards future public health interventions.

Human endogenous oxytocin and its neural correlates show adaptive responses to social touch based on recent social context.

Both oxytocin (OT) and touch are key mediators of social attachment. In rodents, tactile stimulation elicits the endogenous release of OT, potentially facilitating attachment and other forms of prosocial behavior, yet the relationship between endogenous OT and neural modulation remains unexplored in humans. Using a serial sampling of plasma hormone levels during functional neuroimaging across two successive social interactions, we show that contextual circumstances of social touch influence not only current hormonal and brain responses but also later responses. Namely, touch from a male to his female romantic partner enhanced her subsequent OT release for touch from an unfamiliar stranger, yet females' OT responses to partner touch were dampened following stranger touch. Hypothalamus and dorsal raphe activation reflected plasma OT changes during the initial social interaction. In the subsequent interaction, precuneus and parietal-temporal cortex pathways tracked time- and context-dependent variables in an OT-dependent manner. This OT-dependent cortical modulation included a region of the medial prefrontal cortex that also covaried with plasma cortisol, suggesting an influence on stress responses. These findings demonstrate that modulation between hormones and the brain during human social interactions can flexibly adapt to features of social context over time.

Multivariate analyses of immune markers reveal increases in plasma EN-RAGE in first-episode psychosis patients.

Immune cells and cytokines are largely recognized as significant factors in the pathophysiology of neuropsychiatric disorders. The possible role of other blood cells such as leukocytes in events of acute psychosis is in contrast only emerging. To study blood-born markers in acute psychosis we here evaluated plasma proteins in drug-naive first-episode psychosis (FEP) patients and healthy controls using a multiplex proximity extension assay technique. We analyzed a panel of 92 immune markers and plasma samples from 60 FEP patients and 50 controls and evaluated the changes obtained using multivariate statistical methods followed by protein pathway analyses. Data showed that 11 proteins are significantly different between FEP patients and healthy controls We observed increases in pro-inflammatory proteins such as interleukin-6, oncostatin-M, and transforming growth factor-alpha in FEP patients compared with controls. Likewise, the extracellular newly identified RAGE-binding protein (EN-RAGE) that regulates the expression of various cytokines was also elevated in the plasma of FEP patients. The results indicate that neutrophil-derived EN-RAGE could play an important role during the early phase of acute psychosis by stimulating cytokines and the immune response targeting thereby likely also the brain vasculature.

Towards a multilevel model of major depression: genes, immuno-metabolic function, and cortico-striatal signaling.

Biological assay and imaging techniques have made visible a great deal of the machinery of mental illness. Over fifty years of investigation of mood disorders using these technologies has identified several biological regularities in these disorders. Here we present a narrative connecting genetic, cytokine, neurotransmitter, and neural-systems-level findings in major depressive disorder (MDD). Specifically, we connect recent genome-wide findings in MDD to metabolic and immunological disturbance in this disorder and then detail links between immunological abnormalities and dopaminergic signaling within cortico-striatal circuitry. Following this, we discuss implications of reduced dopaminergic tone for cortico-striatal signal conduction in MDD. Finally, we specify some of the flaws in the current model and propose ways forward for advancing multilevel formulations of MDD most efficiently.

COVAX - Time to reconsider the strategy and its target.

COVAX, the international initiative supporting COVID-19 vaccination campaigns globally, is budgeted to be the costliest public health initiative in low- and middle-income countries, with over 16 billion US dollars already committed. While some claim that the target of vaccinating 70% of people worldwide is justified on equity grounds, we argue that this rationale is wrong for two reasons. First, mass COVID-19 vaccination campaigns do not meet standard public health requirements for clear expected benefit, based on costs, disease burden and intervention effectiveness. Second, it constitutes a diversion of resources from more cost-effective and impactful public health programmes, thus reducing health equity. We conclude that the COVAX initiative warrants urgent review.