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In Latin America, little is known about the involvement of private health-care providers in tuberculosis (TB) detection and management. We sought to gain a better understanding of current and potential roles of the private sector in delivering TB services in Peru. We conducted a mixed-methods study in North Lima, Peru. The quantitative component comprised a patient pathway analysis assessing the alignment of TB services with patient care-seeking behavior. The qualitative component comprised in-depth interviews with 18 private health-care providers and 5 key informants. We estimated that 77% of patients sought care initially at a facility with TB diagnostic capacity and 59% at a facility with TB treatment capacity. Among private facilities, 43% offered smear microscopy, 13% offered radiography, and none provided TB treatment. Among public-sector facilities, 100% offered smear microscopy, 26% offered radiography, and 99% provided TB treatment. Private providers believed they offered shorter wait times and a faster diagnosis, but they struggled with a lack of referral systems and communication with the public sector. Nonrecognition of private-sector tests by the public sector led to duplicate testing of referred patients. Although expressing willingness to collaborate with public-sector programs for diagnosis and referral, private providers had limited interest in treating TB. This study highlights the role of private providers in Peru as an entry point for TB care. Public-private collaboration is necessary to harness the potential of the private sector as an ally for early diagnosis.

Background: Mental health disorders (MHDs) are associated with physical health disparities, but underlying excess risk and health burden have not yet been comprehensively assessed., Objective: To assess the burden of comorbid physical health conditions (PHCs) across serious MHDs in Europe., Methods: We estimated the relative prevalence risk of PHCs associated with alcohol use disorders (AUD), bipolar disorder (BD), depressive disorders (DD) and schizophrenia (SZ) across working-age populations of 32 European countries in 2019 based on a targeted literature review. Excess physical health burden was modelled using population-attributable fractions and country-level prevalence data., Findings: We screened 10 960 studies, of which 41 were deemed eligible, with a total sample size of over 18 million persons. Relative prevalence of PHCs was reported in 54%, 20%, 15%, 5% and 7% of studies, respectively, for SZ, DD, BD, AUD or mixed. Significant relative risk estimates ranged from 1.44 to 3.66 for BD, from 1.43 to 2.21 for DD, from 0.81 to 1.97 for SZ and 3.31 for AUD. Excess physical health burden ranged between 27% and 67% of the total, corresponding to 84 million (AUD), 67 million (BD), 66 million (DD) and 5 million (SZ) PHC diagnoses in Europe. A 1% reduction in excess risk assuming causal inference could result in two million fewer PHCs across investigated MHDs., Conclusions: This is the first comprehensive study of the physical health burden of serious MHDs in Europe. The methods allow for updates, refinement and extension to other MHDs or geographical areas., Clinical Implications: The results indicate potential population health benefits achievable through more integrated mental and physical healthcare and prevention approaches., Competing Interests: Competing interests: CA has been a consultant to or has received honoraria or grants from Acadia, Angelini, Biogen, Boehringer, Gedeon Richter, Janssen Cilag, Lundbeck, Medscape, Menarini, Minerva, Otsuka, Pfizer, Roche, Sage, Servier, Shire, Schering-Plough, Sumitomo Dainippon Pharma, Sunovion and Takeda. GMK has received honoraria as a speaker or consultant for Angelini, Gilgamesh, H Lundbeck, Onsero, Pangea, Sage and Sanos. GMG is Chief Medical Officer at Compass Pathways, holds shares and share options at Compass Pathways, and has served as consultant, advisor or CME speaker in the last 3 years for Beckley Psytech, Boehringer Ingelheim, Clerkenwell Health, Compass Pathways, Evapharma, Janssen, Lundbeck, Medscape, Novartis, Ocean Neuroscience, P1Vital, Servier and Takeda. JS has received honoraria as academic advisor from the European Brain Council., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. Published by BMJ.)

Objective: Pancreatic ductal adenocarcinoma (PDAC) displays a remarkable propensity towards therapy resistance. However, molecular epigenetic and transcriptional mechanisms enabling this are poorly understood. In this study, we aimed to identify novel mechanistic approaches to overcome or prevent resistance in PDAC., Design: We used in vitro and in vivo models of resistant PDAC and integrated epigenomic, transcriptomic, nascent RNA and chromatin topology data. We identified a JunD-driven subgroup of enhancers, called interactive hubs (iHUBs), which mediate transcriptional reprogramming and chemoresistance in PDAC., Results: iHUBs display characteristics typical for active enhancers (H3K27ac enrichment) in both therapy sensitive and resistant states but exhibit increased interactions and production of enhancer RNA (eRNA) in the resistant state. Notably, deletion of individual iHUBs was sufficient to decrease transcription of target genes and sensitise resistant cells to chemotherapy. Overlapping motif analysis and transcriptional profiling identified the activator protein 1 (AP1) transcription factor JunD as a master transcription factor of these enhancers. JunD depletion decreased iHUB interaction frequency and transcription of target genes. Moreover, targeting either eRNA production or signaling pathways upstream of iHUB activation using clinically tested small molecule inhibitors decreased eRNA production and interaction frequency, and restored chemotherapy responsiveness in vitro and in vivo. Representative iHUB target genes were found to be more expressed in patients with poor response to chemotherapy compared with responsive patients., Conclusion: Our findings identify an important role for a subgroup of highly connected enhancers (iHUBs) in regulating chemotherapy response and demonstrate targetability in sensitisation to chemotherapy., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Individuals with mental health disorders (MHDs) have worse physical health than the general population, utilise healthcare resources more frequently and intensively, incurring higher costs. We provide a first comprehensive overview and quantitative synthesis of literature on the magnitude of excess resource use and costs for those with MHDs and comorbid physical health conditions (PHCs). This systematic review (PROSPERO CRD42017075319) searched studies comparing resource use or costs of individuals with MHDs and comorbid PHCs versus individuals without comorbid conditions published between 2007 and 2021. We conducted narrative and quantitative syntheses, using random-effects meta-analyses to explore ranges of excess resource use and costs across care segments, comparing to MHD only, PHC only, or general population controls (GPC). Of 20,075 records, 228 and 100 were eligible for narrative and quantitative syntheses, respectively. Most studies were from the US, covered depression or schizophrenia, reporting endocrine/metabolic or circulatory comorbidities. Frequently investigated healthcare segments were inpatient, outpatient, emergency care and medications. Evidence on lost productivity, long-term and informal care was rare. Substantial differences exist between MHDs, with depressive disorder tending towards lower average excess resource use and cost estimates, while excess resource use ranges between +6% to +320% and excess costs between +14% to +614%. PHCs are major drivers of resource use and costs for individuals with MHDs, affecting care segments differently. Significant physical health gains and cost savings are potentially achievable through prevention, earlier identification, management and treatment, using more integrated care approaches. Current international evidence, however, is heterogeneous with limited geographical representativeness and comparability., Competing Interests: Declaration of Competing Interest JS has received academic expert honoraria from the European Brain Council. ALP and DM have received support from the ECNP. GG has received royalties or licenses from Oxford University Press and Oxford University, payment or honoraria for lecture fees from Evopharma and Johnson & Johnson, provided expert testimony for Johnson & Johnson, participated in the advisory board for H Lundbeck, Medscape, Sage, Johnson & Johnson, Novartis, Beckley Psytech, Clerkenwell Health, Ocean neuroscience, and Boehringer Ingelheim, co-chairs the Bipolar Commission of Bipolar-UK, and has stock and/or stock options for P1vital, P1vital products, and Compass pathways. GG is a NIHR Emeritus Senior Investigator and Chief Medical Officer of Compass pathways. All other authors declare no competing interests. The views expressed are those of the authors and not necessarily those of the ECNP, the NHS, the NIHR or the Department of Health., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

A man in his 70s with a history of fatigue, abdominal pain, and a palpable abdominal mass was found to have a peritoneal desmoid tumour. One year after diagnosis, he was prescribed sorafenib to limit tumour growth. Two months later, he developed dyspnoea on exertion and lower extremity weakness and was reported to have supine hypertension and orthostatic hypotension. On formal autonomic testing, he was noted to have severely impaired sympathetic responses and marked orthostatic hypotension without appropriate chronotropic response. A decision to hold sorafenib was made, and treatment was started with graduated compression stockings, liberal fluid and sodium intake, and midodrine. The patient had a modest and gradual improvement in his symptoms. To our knowledge, this is the first reported case of orthostatic hypotension related to sorafenib or any vascular endothelial growth factor inhibitors., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Several preclinical and epidemiologic studies have indicated tumour-promoting effects of thyroid hormones (THs). However, very limited knowledge exists on the prognostic impact of thyroid function in metastatic cancer., Methods: We compiled a discovery cohort of 1692 patients with newly diagnosed brain metastases (BMs) of solid cancers treated at the Medical University of Vienna and an independent validation cohort of 191 patients with newly diagnosed BMs treated at the University Hospital Zurich., Results: Hypothyroidism before diagnosis of cancer was evident in 133 of 1692 (7.9%) patients of the discovery, and in 18 of 191 (9.4%) patients of the validation cohort. In the discovery cohort, hypothyroidism was statistically significantly associated with favourable survival prognosis from diagnosis of cancer (31 vs. 21 months; p = 0.0026) and with survival prognosis from diagnosis of BMs (12 vs. 7 months; p = 0.0079). In multivariate analysis including the diagnosis-specific graded prognostic assessment score, primary tumour type and sex, hypothyroidism was an independent factor associated with survival after diagnosis of BMs (hazard ratio: 0.76; 95% confidence interval [CI]: (0.63; 0.91; p = 0.0034). In the validation cohort, the association of hypothyroidism and favourable survival prognosis from diagnosis of cancer (55 vs. 11 months; p = 0.00058), as well as from diagnosis of BMs (40 vs. 10 months; p = 0.0036) was confirmed., Conclusion: Pre-existing hypothyroidism was strongly and independently associated with prognosis in patients with newly diagnosed BMs, supporting the evidence from preclinical data that THs may indeed have a tumour-promoting effect. Further investigation of the underlying pathobiological mechanism and potential therapeutic implications are required., Competing Interests: Conflict of interest statement A.S.B. has received research support from Daiichi Sankyo (≤10000€), Roche (>10000€); has received honoraria for lectures;has been a member of the consultation or advisory board participation from Roche Bristol-Meyers Squibb, Merck, Daiichi Sankyo (all < 5000€), has received travel support from Roche, Amgen and AbbVie. M.K. has received research support from Sanofi, AstraZeneca and Ipsen; served as a speaker and received consulting fees from AstraZeneca, Novartis, Novo Nordisk, Lilly, Merck, Böhringer, Roche and Sanofi. M.W. has received research grants from Abbvie, Adastra, Bristol Meyer Squibb (BMS), Dracen, Merck, Sharp & Dohme (MSD), Merck (EMD), Novocure, Piqur and Roche; has received honoraria for lectures or served as a member of advisory board participation or consulting from Abbvie, Basilea, Bristol Meyer Squibb (BMS), Celgene, Merck, Sharp & Dohme (MSD), Merck (EMD), Novocure, Orbus, Roche and Tocagen. M.P. has received research support from Böhringer-Ingelheim, GlaxoSmithKline, Merck Sharp & Dome and Roche; has received honoraria for lectures; served as a member of the consultation or advisory board participation (all < 5000€) from Bristol-Myers Squibb, Novartis, Gerson Lehrman Group (GLG), CMC Contrast, GlaxoSmithKline, Mundipharma, Roche, Astra Zeneca, AbbVie, Lilly, Medahead, Daiichi Sankyo, Merck Sharp & Dome. All the other authors have no conflicts of interest to declare., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Forty-three out of 53 of the WHO European Member States have set up political and institutional mechanisms to implement the United Nations (UN) 2030 Agenda for Sustainable Development. This includes governance and institutional mechanisms, engaging stakeholders, identifying targets and indicators, setting governmental and sectoral priorities for action and reporting progress regularly. Still, growing evidence suggests that there is room for advancing implementation of some of the Sustainable Development Goals (SDGs) and targets at a higher pace in the WHO European Region. This article proposes the E4A approach to support WHO European Member States in their efforts to achieve the health-related SDG targets., Methods: The E4A approach was developed through a 2-year, multi-stage process, starting with the endorsement of the SDG Roadmap by all WHO European Member States in 2017. This approach resulted from a mix of qualitative methods: a semi-structured desk review of existing committal documents and tools; in-country policy dialogs, interviews and reports; joint UN missions and discussion among multi-lateral organizations; consultation with an advisory group of academics and health policy experts across countries., Results: The E-engage-functions as the driver and pace-maker; the 4 As-assess, align, accelerate and account-serve as building blocks composed of policies, processes, activities and interventions operating in continuous and synchronized action. Each of the building blocks is an essential part of the approach that can be applied across geographic and institutional levels., Conclusion: While the E4A approach is being finalized, this article aims to generate debate and input to further refine and test this approach from a public health and user perspective., (© World Health Organization, 2020. All rights reserved. The World Health Organization has granted the Publisher permission for the reproduction of this article.)

Background: Platelets store large amounts of serotonin that they release during thrombus formation or acute inflammation. This facilitates hemostasis and modulates the inflammatory response., Methods: Infarct size, heart function, and inflammatory cell composition were analyzed in mouse models of myocardial reperfusion injury with genetic and pharmacological depletion of platelet serotonin. These studies were complemented by in vitro serotonin stimulation assays of platelets and leukocytes in mice and men, and by measuring plasma serotonin levels and leukocyte activation in patients with acute coronary syndrome., Results: Platelet-derived serotonin induced neutrophil degranulation with release of myeloperoxidase and hydrogen peroxide (H 2 O 2 ) and increased expression of membrane-bound leukocyte adhesion molecule CD11b, leading to enhanced inflammation in the infarct area and reduced myocardial salvage. In patients hospitalized with acute coronary syndrome, plasmatic serotonin levels correlated with CD11b expression on neutrophils and myeloperoxidase plasma levels. Long-term serotonin reuptake inhibition-reported to protect patients with depression from cardiovascular events-resulted in the depletion of platelet serotonin stores in mice. These mice displayed a reduction in neutrophil degranulation and preserved cardiac function. In line, patients with depression using serotonin reuptake inhibition, presented with suppressed levels of CD11b surface expression on neutrophils and lower myeloperoxidase levels in blood., Conclusions: Taken together, we identify serotonin as a potent therapeutic target in neutrophil-dependent thromboinflammation during myocardial reperfusion injury.

The eukaryotic actin cytoskeleton is an evolutionarily well-established pathogen target, as a large number of bacterial factors disturb its dynamics to alter the function of the host cells. These pathogenic factors modulate or mimic actin effector proteins or they modify actin directly, leading to an imbalance of the precisely regulated actin turnover. Here, we show that the pore-forming, cholesterol-dependent cytolysin pneumolysin (PLY), a major neurotoxin of Streptococcus pneumoniae, has the capacity to bind actin directly and to enhance actin polymerisation in vitro. In cells, the toxin co-localised with F-actin shortly after exposure, and this direct interaction was verified by Förster resonance energy transfer. PLY was capable of exerting its effect on actin through the lipid bilayer of giant unilamellar vesicles, but only when its pore competence was preserved. The dissociation constant of G-actin binding to PLY in a biochemical environment was 170-190 nM, which is indicative of a high-affinity interaction, comparable to the affinity of other intracellular actin-binding factors. Our results demonstrate the first example of a direct interaction of a pore-forming toxin with cytoskeletal components, suggesting that the cross talk between pore-forming cytolysins and cells is more complex than previously thought., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Streptococcus pneumoniae (pneumococcal) meningitis is a common bacterial infection of the brain. The cholesterol-dependent cytolysin pneumolysin represents a key factor, determining the neuropathogenic potential of the pneumococci. Here, we demonstrate selective synaptic loss within the superficial layers of the frontal neocortex of post-mortem brain samples from individuals with pneumococcal meningitis. A similar effect was observed in mice with pneumococcal meningitis only when the bacteria expressed the pore-forming cholesterol-dependent cytolysin pneumolysin. Exposure of acute mouse brain slices to only pore-competent pneumolysin at disease-relevant, non-lytic concentrations caused permanent dendritic swelling, dendritic spine elimination and synaptic loss. The NMDA glutamate receptor antagonists MK801 and D-AP5 reduced this pathology. Pneumolysin increased glutamate levels within the mouse brain slices. In mouse astrocytes, pneumolysin initiated the release of glutamate in a calcium-dependent manner. We propose that pneumolysin plays a significant synapto- and dendritotoxic role in pneumococcal meningitis by initiating glutamate release from astrocytes, leading to subsequent glutamate-dependent synaptic damage. We outline for the first time the occurrence of synaptic pathology in pneumococcal meningitis and demonstrate that a bacterial cytolysin can dysregulate the control of glutamate in the brain, inducing excitotoxic damage.

Astrocytes represent a major component of brain tissue and play a critical role in the proper functioning and protection of the brain. Streptococcus pneumoniae, the most common cause of bacterial meningitis, has a high lethality and causes serious disabilities in survivors. Pneumolysin (PLY), a member of the cholesterol-dependent cytolysin group and a major S. pneumoniae neurotoxin, causes deterioration over the course of experimental S. pneumoniae meningitis. At disease-relevant sub-lytic concentrations, PLY produces actin and tubulin reorganization and astrocyte cell shape changes in vitro. In this article, we show that sub-lytic amounts of PLY remodel brain tissue and produce astrocytic process retraction, cortical astroglial reorganization and increased interstitial fluid retention, which is manifested as tissue edema. These changes caused increased tissue permeability to macromolecules and bacteria. The pore-forming capacity of PLY remained necessary for these changes because none of the nonpore-forming mutants were capable of producing similar effects. We suggest that PLY can increase the permeability of brain tissue toward pathogenic factors and bacteria in the course of meningitis, thus contributing to the deterioration caused by the disease., (Copyright © 2011 Wiley Periodicals, Inc.)

Background: Streptococcus pneumoniae causes serious diseases such as pneumonia and meningitis. Its major pathogenic factor is the cholesterol-dependent cytolysin pneumolysin, which produces lytic pores at high concentrations. At low concentrations, it has other effects, including induction of apoptosis. Many cellular effects of pneumolysin appear to be calcium dependent., Methods: Live imaging of primary mouse astroglia exposed to sublytic amounts of pneumolysin at various concentrations of extracellular calcium was used to measure changes in cellular permeability (as judged by lactate dehydrogenase release and propidium iodide chromatin staining). Individual pore properties were analyzed by conductance across artificial lipid bilayer. Tissue toxicity was studied in continuously oxygenated acute brain slices., Results: The reduction of extracellular calcium increased the lytic capacity of the toxin due to increased membrane binding. Reduction of calcium did not influence the conductance properties of individual toxin pores. In acute cortical brain slices, the reduction of extracellular calcium from 2 to 1 mM conferred lytic activity to pathophysiologically relevant nonlytic concentrations of pneumolysin., Conclusions: Reduction of extracellular calcium strongly enhanced the lytic capacity of pneumolysin due to increased membrane binding. Thus, extracellular calcium concentration should be considered as a factor of primary importance for the course of pneumococcal meningitis.