Co-Designed Cardiac Rehabilitation for the Secondary Prevention of Stroke (CARESS): A Pilot Program Evaluation.

Structured health system-based programs, such as cardiac rehabilitation, may reduce the risk of recurrent stroke. This study aimed to co-design and evaluate a structured program of rehabilitation, developed based on insights from focus groups involving stroke survivors and health professionals. Conducted in Tasmania, Australia in 2019, the 7-week program comprised one hour of group exercise and one hour of education each week. Functional capacity (6 min walk test), fatigue, symptoms of depression (Patient Health Questionnaire), and lifestyle were assessed pre- and post-program, with a historical control group for comparison. Propensity score matching determined the average treatment effect (ATE) of the program. Key themes from the co-design focus groups included the need for coordinated care, improved psychosocial management, and including carers and peers in programs. Of the 23 people approached, 10 participants (70% men, mean age 67.4 ± 8.6 years) completed the program without adverse events. ATE analysis revealed improvements in functional capacity (139 m, 95% CI 44, 234) and fatigue (-5 units, 95% CI -9, -1), with a small improvement in symptoms of depression (-0.8 units, 95% CI -1.8, 0.2) compared to controls. The co-designed program demonstrated feasibility, acceptability, and positive outcomes, suggesting its potential to support stroke survivors.

A brainstem-hypothalamus neuronal circuit reduces feeding upon heat exposure.

Empirical evidence suggests that heat exposure reduces food intake. However, the neurocircuit architecture and the signalling mechanisms that form an associative interface between sensory and metabolic modalities remain unknown, despite primary thermoceptive neurons in the pontine parabrachial nucleus becoming well characterized1. Tanycytes are a specialized cell type along the wall of the third ventricle2 that bidirectionally transport hormones and signalling molecules between the brain's parenchyma and ventricular system3-8. Here we show that tanycytes are activated upon acute thermal challenge and are necessary to reduce food intake afterwards. Virus-mediated gene manipulation and circuit mapping showed that thermosensing glutamatergic neurons of the parabrachial nucleus innervate tanycytes either directly or through second-order hypothalamic neurons. Heat-dependent Fos expression in tanycytes suggested their ability to produce signalling molecules, including vascular endothelial growth factor A (VEGFA). Instead of discharging VEGFA into the cerebrospinal fluid for a systemic effect, VEGFA was released along the parenchymal processes of tanycytes in the arcuate nucleus. VEGFA then increased the spike threshold of Flt1-expressing dopamine and agouti-related peptide (Agrp)-containing neurons, thus priming net anorexigenic output. Indeed, both acute heat and the chemogenetic activation of glutamatergic parabrachial neurons at thermoneutrality reduced food intake for hours, in a manner that is sensitive to both Vegfa loss-of-function and blockage of vesicle-associated membrane protein 2 (VAMP2)-dependent exocytosis from tanycytes. Overall, we define a multimodal neurocircuit in which tanycytes link parabrachial sensory relay to the long-term enforcement of a metabolic code.

Novel synthetic procedures for C2 substituted imidazoquinolines as ligands for the α/ß-interface of the GABAA-receptor.

A series of substituted imidazoquinolines, a structurally related chemotype to pyrazoloquinolinones, a well-known class of GABAA ligands, was prepared via two synthetic procedures and the efficiency of these procedures were compared. One method relies on classical heterocyclic synthesis, the other one aims at late-stage decoration of a truncated scaffold via direct C-H functionalization. A pharmacological evaluation disclosed that one of the synthesized derivatives showed interesting activity on a α1ß3 containing receptor subtype. Supplementary Information: The online version contains supplementary material available at 10.1007/s00706-022-02988-8.

Is sex a predictor for delayed cerebral ischaemia (DCI) and hydrocephalus after aneurysmal subarachnoid haemorrhage (aSAH)? A systematic review and meta-analysis.

OBJECTIVES: DCI and hydrocephalus are the most common complications that predict poor outcomes after aSAH. The relationship between sex, DCI and hydrocephalus are not well established; thus, we aimed to examine sex differences in DCI and hydrocephalus following aSAH in a systematic review and meta-analysis. METHODS: A systematic search was conducted using the PubMed, Scopus and Medline databases from inception to August 2022 to identify cohort, case control, case series and clinical studies reporting sex and DCI, acute and chronic shunt-dependent hydrocephalus (SDHC). Random-effects meta-analysis was used to pool estimates for available studies. RESULTS: There were 56 studies with crude estimates for DCI and meta-analysis showed that women had a greater risk for DCI than men (OR 1.24, 95% CI 1.11-1.39). The meta-analysis for adjusted estimates for 9 studies also showed an association between sex and DCI (OR 1.61, 95% CI 1.27-2.05). For acute hydrocephalus, only 9 studies were included, and meta-analysis of unadjusted estimates showed no association with sex (OR 0.95, 95%CI 0.78-1.16). For SDHC, a meta-analysis of crude estimates from 53 studies showed that women had a somewhat greater risk of developing chronic hydrocephalus compared to men (OR 1.14, 95% CI 0.99-1.31). In meta-analysis for adjusted estimates from 5 studies, no association of sex with SDHC was observed (OR 0.87, 95% CI 0.57-1.33). CONCLUSIONS: Female sex is associated with the development of DCI; however, an association between sex and hydrocephalus was not detected. Strategies to target females to reduce the development of DCI may decrease overall morbidity and mortality after aSAH.

Sex differences in pressure and flow waveform physiology across the life course.

Cardiovascular disease (CVD) has long been deemed a disease of old men. However, in 2019 CVD accounted for 35% of all deaths in women and, therefore, remains the leading cause of death in both men and women. There is increasing evidence to show that risk factors, pathophysiology and health outcomes related to CVD differ in women compared with men, yet CVD in women remains understudied, underdiagnosed and undertreated. Differences exist between the sexes in relation to the structure of the heart and vasculature, which translate into differences in blood pressure and flow waveform physiology. These physiological differences between women and men may represent an important explanatory factor contributing to the sex disparity in CVD presentation and outcomes but remain understudied. In this review we aim to describe sex differences in arterial pressure and flow waveform physiology and explore how they may contribute to differences in CVD in women compared to men. Given that unfavourable alterations in the cardiovascular structure and function can start as early as in utero, we report sex differences in waveform physiology across the entire life course.

Barriers and facilitators to more timely treatment of aneurysmal subarachnoid haemorrhage across two tertiary referral centres in Australia: A thematic analysis.

BACKGROUND: Delays in treatment of aSAH appear to be common but the causes are not well understood. We explored facilitators and barriers to timely treatment of aSAH. METHODS: We used a multiple case study with cases of aSAH surviving> 1 day identified prospectively. We conducted semi-structured interviews with the patient, their next-of-kin and health professionals involved in the case. Within-case analysis identified barriers and facilitators in 4 phases (pre-hospital, presentation, transfer, in-hospital) followed by thematic analysis across cases using a case-study matrix. RESULTS: Twenty-seven cases with 90 interviewees yielded five themes related to facilitators or barriers of timely treatment. "Early recognition" led to urgent response. "Accessibility to health care" depended on patient's location, transport, and environmental conditions. Good "Coordination" between and within health services was a key facilitator. "Complexity" of patient's condition affected time to treatment in multiple time periods. "Availability of resources" was identified most frequently during the diagnostic and treatment phases as both barrier and facilitator. CONCLUSIONS: The identified themes may be modifiable at the patient/health professional level and health system level and may improve timely treatment of aSAH through targeted interventions, subsequently contributing to improve morbidity and mortality of patients with aSAH.

Tricyclic antipsychotics and antidepressants can inhibit α5-containing GABAA receptors by two distinct mechanisms.

BACKGROUND AND PURPOSE: Many psychotherapeutic drugs, including clozapine, display polypharmacology and act on GABAA receptors. Patients with schizophrenia show alterations in function, structure and molecular composition of the hippocampus, and a recent study demonstrated aberrant levels of hippocampal α5 subunit-containing GABAA receptors. The purpose of this study is to investigate the effects of tricyclic compounds on α5 subunit-containing receptor subtypes. EXPERIMENTAL APPROACH: Functional studies of effects by seven antipsychotic and antidepressant medications were performed in several GABAA receptor subtypes by two-electrode voltage-clamp electrophysiology using Xenopus laevis oocytes. Computational structural analysis was employed to design mutated constructs of the α5 subunit, probing a novel binding site. Radioligand displacement data complemented the functional and mutational findings. KEY RESULTS: The antipsychotic drugs clozapine and chlorpromazine exerted functional inhibition on multiple GABAA receptor subtypes, including those containing α5-subunits. Based on a chlorpromazine binding site observed in a GABA-gated bacterial homologue, we identified a novel site in α5 GABAA receptor subunits and demonstrate differential usage of this and the orthosteric sites by these ligands. CONCLUSION AND IMPLICATIONS: Despite high molecular and functional similarities among the tested ligands, they reduce GABA currents by differential usage of allosteric and orthosteric sites. The chlorpromazine site we describe here is a new potential target for optimizing antipsychotic medications with beneficial polypharmacology. Further studies in defined subtypes are needed to substantiate mechanistic links between the therapeutic effects of clozapine and its action on certain GABAA receptor subtypes.

Case-Fatality and Functional Outcome after Subarachnoid Hemorrhage (SAH) in INternational STRoke oUtComes sTudy (INSTRUCT).

BACKGROUND: There are few large population-based studies of outcomes after subarachnoid hemorrhage (SAH) than other stroke types. METHODS: We pooled data from 13 population-based stroke incidence studies (10 studies from the INternational STRroke oUtComes sTudy (INSTRUCT) and 3 new studies; N=657). Primary outcomes were case-fatality and functional outcome (modified Rankin scale score 3-5 [poor] vs. 0-2 [good]). Harmonized patient-level factors included age, sex, health behaviours (e.g. current smoking at baseline), comorbidities (e.g.history of hypertension), baseline stroke severity (e.g. NIHSS >7) and year of stroke. We estimated predictors of case-fatality and functional outcome using Poisson regression and generalized estimating equations using log-binomial models respectively at multiple timepoints. RESULTS: Case-fatality rate was 33% at 1 month, 43% at 1 year, and 47% at 5 years. Poor functional outcome was present in 27% of survivors at 1 month and 15% at 1 year. In multivariable analysis, predictors of death at 1-month were age (per decade increase MRR 1.14 [1.07-1.22]) and SAH severity (MRR 1.87 [1.50-2.33]); at 1 year were age (MRR 1.53 [1.34-1.56]), current smoking (MRR 1.82 [1.20-2.72]) and SAH severity (MRR 3.00 [2.06-4.33]) and; at 5 years were age (MRR 1.63 [1.45-1.84]), current smoking (MRR 2.29 [1.54-3.46]) and severity of SAH (MRR 2.10 [1.44-3.05]). Predictors of poor functional outcome at 1 month were age (per decade increase RR 1.32 [1.11-1.56]) and SAH severity (RR 1.85 [1.06-3.23]), and SAH severity (RR 7.09 [3.17-15.85]) at 1 year. CONCLUSION: Although age is a non-modifiable risk factor for poor outcomes after SAH, however, severity of SAH and smoking are potential targets to improve the outcomes.

Adherence to evidence-based processes of care reduces one-year mortality after aneurysmal subarachnoid hemorrhage (aSAH).

BACKGROUND: There is limited research on the provision of evidence-based care and its association with outcomes after aneurysmal subarachnoid hemorrhage (aSAH). AIMS: We examined adherence to evidence-based care after aSAH and associations with survival and discharge destination. Also, factors associated with evidence-based care including age, sex, Charlson comorbidity index, severity scores, and delayed cerebral ischemia and infarction were examined for association with survival and discharge destination. METHODS: In a retrospective cohort (2010-2016) of all aSAH cases across two comprehensive cerebrovascular centres, we extracted 3 indicators of evidence-based aSAH care from medical records: (1) antihypertensives prior to aneurysm treatment, (2) nimodipine, and (3) aneurysm treatment (coiling/clipping). We defined 'optimal care' as receiving all eligible processes of care. Survival at 1 year was obtained by data linkage. We estimated (1) proportion of patients and characteristics associated with receiving processes of care, (2) associations between processes of care with 1-year mortality using cox-proportional hazard model and discharge destination with log binomial regression adjusting for age, sex, severity of aSAH, delayed cerebral ischemia and/or cerebral infarction and comorbidities. Sensitivity analyses explored effect modification of the association between processes of care and outcome by management type (active versus comfort measures). RESULTS: Among 549 patients (69% women), 59% were managed according to the guidelines. Individual indicators were associated with lower 1-year mortality but not discharge destination. Optimal care reduced mortality at 1 year in univariable (HR 0.24 95% CI 0.17-0.35) and multivariable analyses (HR 0.51 95% CI 0.34-0.77) independent of age, sex, severity, comorbidities, and hospital network. CONCLUSION: Adherence to processes of care reduced 1-year mortality after aSAH. Many patients with aSAH do not receive evidence-based care and this must be addressed to improve outcomes.

Time and predictors of time to treatment for aneurysmal subarachnoid haemorrhage (aSAH): a systematic review.

BACKGROUND: Aneurysmal subarachnoid haemorrhage (aSAH) is a serious form of stroke, for which rapid access to specialist neurocritical care is associated with better outcomes. Delays in the treatment of aSAH appear to be common and may contribute to poor outcomes. We have a limited understanding of the extent and causes of these delays, which hinders the development of interventions to reduce delays and improve outcomes. The aim of this systematic review was to quantify and identify factors associated with time to treatment in aSAH. METHODS: This systematic review was performed according to the Preferred Reporting Items for Systematic Review and Meta-Analysis guidelines and was registered in PROSPERO (Reg. No. CRD42019132748). We searched four electronic databases (MEDLINE, EMBASE, Web of Science and Google Scholar) for manuscripts published from January 1998 using pre-designated search terms and search strategy. Main outcomes were duration of delays of time intervals from onset of aSAH to definitive treatment and/or factors related to time to treatment. RESULTS: A total of 64 studies with 16 different time intervals in the pathway of aSAH patients were identified. Measures of time to treatment varied between studies (e.g. cut-off timepoints or absolute mean/median duration). Factors associated with time to treatment fell into two categories-individual (n = 9 factors, e.g. age, sex and clinical characteristics) and health system (n = 8 factors, e.g. pre-hospital delay or presentation out-of-hours). Demographic factors were not associated with time to treatment. More severe aSAH reduced treatment delay in most studies. Pre-hospital delays (patients delay, late referral, late arrival of ambulance, being transferred between hospitals or arriving at the hospital outside of office hours) were associated with treatment delay. In-hospital factors (patients with complications, procedure before definitive treatment, slow work-up and type of treatment) were less associated with treatment delay. CONCLUSIONS: The pathway from onset to definitive treatment of patients with aSAH consists of multiple stages with multiple influencing factors. This review provides the first comprehensive understanding of extent and factors associated with time to treatment of aSAH. There is an opportunity to target modifiable factors to reduce time to treatment, but further research considering more factors are needed.

Sex differences in aneurysmal subarachnoid haemorrhage (aSAH): aneurysm characteristics, neurological complications, and outcome.

BACKGROUND: Women are over-represented in aSAH cohorts, but whether their outcomes differ to men remains unclear. We examined if sex differences in neurological complications and aneurysm characteristics contributed to aSAH outcomes. METHODS: In a retrospective cohort (2010-2016) of all aSAH cases across two hospital networks in Australia, information on severity, aneurysm characteristics and neurological complications (rebleed before/after treatment, postoperative stroke < 48 h, neurological infections, hydrocephalus, seizures, delayed cerebral ischemia [DCI], cerebral infarction) were extracted. We estimated sex differences in (1) complications and aneurysm characteristics using chi square/t-tests and (2) outcome at discharge (home, rehabilitation or death) using multinomial regression with and without propensity score matching on prestroke confounders. RESULTS: Among 577 cases (69% women, 84% treated) aneurysm size was greater in men than women and DCI more common in women than men. In unadjusted log multinomial regression, women had marginally greater discharge to rehabilitation (RRR 1.15 95% CI 0.90-1.48) and similar likelihood of in-hospital death (RRR 1.02 95% CI 0.76-1.36) versus discharge home. Prestroke confounders (age, hypertension, smoking status) explained greater risk of death in women (rehabilitation RRR 1.13 95% CI 0.87-1.48; death RRR 0.75 95% CI 0.51-1.10). Neurological complications (DCI and hydrocephalus) were covariates explaining some of the greater risk for poor outcomes in women (rehabilitation RRR 0.87 95% CI 0.69-1.11; death RRR 0.80 95% CI 0.52-1.23). Results were consistent in propensity score matched models. CONCLUSION: The marginally poorer outcome in women at discharge was partially attributable to prestroke confounders and complications. Improvements in managing complications could improve outcomes.

A novel de novo variant of GABRA1 causes increased sensitivity for GABA in vitro.

The GABRA1 gene encodes one of the most conserved and highly expressed subunits of the GABAA receptor family. Variants in this gene are causatively implicated in different forms of epilepsy and also more severe epilepsy-related neurodevelopmental syndromes. Here we study functional consequences of a novel de novo missense GABRA1 variant, p.(Ala332Val), identified through exome sequencing in an individual affected by early-onset syndromic epileptic encephalopathy. The variant is localised within the transmembrane domain helix 3 (TM3) and in silico prediction algorithms suggested this variant to be likely pathogenic. In vitro assessment revealed unchanged protein levels, regular assembly and forward trafficking to the cell surface. On the functional level a significant left shift of the apparent GABA potency in two-electrode voltage clamp electrophysiology experiments was observed, as well as changes in the extent of desensitization. Additionally, apparent diazepam potency was left shifted in radioligand displacement assays. During prenatal development mainly alpha2/3 subunits are expressed, whereas after birth a switch to alpha1 occurs. The expression of alpha1 in humans is upregulated during the first years. Thus, the molecular change of function reported here supports pathogenicity and could explain early-onset of seizures in the affected individual.

GABAA Receptor Ligands Often Interact with Binding Sites in the Transmembrane Domain and in the Extracellular Domain-Can the Promiscuity Code Be Cracked?

Many allosteric binding sites that modulate gamma aminobutyric acid (GABA) effects have been described in heteropentameric GABA type A (GABAA) receptors, among them sites for benzodiazepines, pyrazoloquinolinones and etomidate. Diazepam not only binds at the high affinity extracellular "canonical" site, but also at sites in the transmembrane domain. Many ligands of the benzodiazepine binding site interact also with homologous sites in the extracellular domain, among them the pyrazoloquinolinones that exert modulation at extracellular α+/ß- sites. Additional interaction of this chemotype with the sites for etomidate has also been described. We have recently described a new indole-based scaffold with pharmacophore features highly similar to pyrazoloquinolinones as a novel class of GABAA receptor modulators. Contrary to what the pharmacophore overlap suggests, the ligand presented here behaves very differently from the identically substituted pyrazoloquinolinone. Structural evidence demonstrates that small changes in pharmacophore features can induce radical changes in ligand binding properties. Analysis of published data reveals that many chemotypes display a strong tendency to interact promiscuously with binding sites in the transmembrane domain and others in the extracellular domain of the same receptor. Further structural investigations of this phenomenon should enable a more targeted path to less promiscuous ligands, potentially reducing side effect liabilities.

Life-long impairment of glucose homeostasis upon prenatal exposure to psychostimulants.

Maternal drug abuse during pregnancy is a rapidly escalating societal problem. Psychostimulants, including amphetamine, cocaine, and methamphetamine, are amongst the illicit drugs most commonly consumed by pregnant women. Neuropharmacology concepts posit that psychostimulants affect monoamine signaling in the nervous system by their affinities to neurotransmitter reuptake and vesicular transporters to heighten neurotransmitter availability extracellularly. Exacerbated dopamine signaling is particularly considered as a key determinant of psychostimulant action. Much less is known about possible adverse effects of these drugs on peripheral organs, and if in utero exposure induces lifelong pathologies. Here, we addressed this question by combining human RNA-seq data with cellular and mouse models of neuroendocrine development. We show that episodic maternal exposure to psychostimulants during pregnancy coincident with the intrauterine specification of pancreatic ß cells permanently impairs their ability of insulin production, leading to glucose intolerance in adult female but not male offspring. We link psychostimulant action specifically to serotonin signaling and implicate the sex-specific epigenetic reprogramming of serotonin-related gene regulatory networks upstream from the transcription factor Pet1/Fev as determinants of reduced insulin production.

Brain-wide genetic mapping identifies the indusium griseum as a prenatal target of pharmacologically unrelated psychostimulants.

Psychostimulant use is an ever-increasing socioeconomic burden, including a dramatic rise during pregnancy. Nevertheless, brain-wide effects of psychostimulant exposure are incompletely understood. Here, we performed Fos-CreERT2-based activity mapping, correlated for pregnant mouse dams and their fetuses with amphetamine, nicotine, and caffeine applied acutely during midgestation. While light-sheet microscopy-assisted intact tissue imaging revealed drug- and age-specific neuronal activation, the indusium griseum (IG) appeared indiscriminately affected. By using GAD67gfp/+ mice we subdivided the IG into a dorsolateral domain populated by γ-aminobutyric acidergic interneurons and a ventromedial segment containing glutamatergic neurons, many showing drug-induced activation and sequentially expressing Pou3f3/Brn1 and secretagogin (Scgn) during differentiation. We then combined Patch-seq and circuit mapping to show that the ventromedial IG is a quasi-continuum of glutamatergic neurons (IG-Vglut1+) reminiscent of dentate granule cells in both rodents and humans, whose dendrites emanate perpendicularly toward while their axons course parallel with the superior longitudinal fissure. IG-Vglut1+ neurons receive VGLUT1+ and VGLUT2+ excitatory afferents that topologically segregate along their somatodendritic axis. In turn, their efferents terminate in the olfactory bulb, thus being integral to a multisynaptic circuit that could feed information antiparallel to the olfactory-cortical pathway. In IG-Vglut1+ neurons, prenatal psychostimulant exposure delayed the onset of Scgn expression. Genetic ablation of Scgn was then found to sensitize adult mice toward methamphetamine-induced epilepsy. Overall, our study identifies brain-wide targets of the most common psychostimulants, among which Scgn+/Vglut1+ neurons of the IG link limbic and olfactory circuits.

Sex differences in risk factors for aneurysmal subarachnoid haemorrhage: Systematic review and meta-analysis.

BACKGROUND: Aneurysmal subarachnoid haemorrhage (aSAH) disproportionally affects women. We conducted a systematic review and meta-analysis to explore sex differences in aSAH risk factors. METHODS: Case-control/cohort studies were searched to November 2017 with sex-specific risk factors for aSAH. Meta-analysis was performed when a risk factor was reported in ≥2 studies. RESULTS: Of 31 studies, 22 were eligible for meta-analysis. Female sex was associated with greater odds of aSAH (HRadjusted 1.90 [1.47-2.46]. There was no detectable difference between the sexes for hypertension (ORadjusted: men 3.13 [2.26-4.34]; women 3.65 [2.87-4.63], p = .18), smoking (ORadjusted: men 2.96 [1.68-5.21]; women 3.11 [1.21-7.97], p = .95), aSAH family history, systolic blood pressure, age and some genetic variations. Alcohol (ORadjusted: men 1.50 [1.04-2.17]; women 0.83 [0.48-1.45], p = .003), high alanine aminotransferase levels, and some gene variants increased the risk of aSAH in men. Reproductive factors, divorce and some genetic variations increased the risk in women. High aspartate aminotransferase levels in men and, diabetes (ORadjusted: men 0.57 [0.32-1.01]; women 0.24 [0.13-0.43], p = .01) and parity in women reduced aSAH risk. CONCLUSION: We recommend sex-specific re-analysis of existing studies of aSAH risk factors. Known aSAH risk factors (hypertension, smoking and alcohol consumption) should be targeted to prevent aSAH in men and women. Registration PROSPERO (ID: CRD42018091521).

Variations on a scaffold - Novel GABAA receptor modulators.

Allosteric ligands of GABAA receptors exist in many different chemotypes owing to their great usefulness as therapeutics, with benzodiazepines being among the best known examples. Many allosteric binding sites have been described, among them a site at the extracellular interface between the alpha principal face and the beta complementary face (α+/ß-). Pyrazoloquinolinones have been shown to bind at α+/ß-binding sites of GABAA receptors, exerting chiefly positive allosteric modulation at this location. In order to further explore molecular determinants of this type of allosteric modulation, we synthesized a library of ligands based on the PQ pharmacophore employing a ring-chain bioisosteric approach. In this study we analyzed the structure-activity-relationship (SAR) of these novel ligands based on an azo-biaryl structural motif in α1ß3 GABAA receptors, indicating interesting novel properties of the compound class.

Urban-rural differences in the care and outcomes of acute stroke patients: Systematic review.

OBJECTIVE: To describe literature pertaining to urban-rural differences in both the quality of care and outcomes of acute stroke patients. METHODS: We systematically searched CINAHL, PubMed, ProQuest Dissertations & Theses, and Scopus for published and unpublished literature until 9th December 2017. Studies were included if they compared the acute care provided to, or outcomes of, patients hospitalised for stroke in urban versus rural settings. Abstract, full-text review, and data extraction were conducted in duplicate. Findings are presented in the form of narrative syntheses. RESULTS: A total of 28 studies were included in the review (16 on care, 12 on outcomes). With few exceptions, studies addressing the provision of care suggested that rural patients have less access to most aspects of acute stroke care. Studies reporting urban-rural differences in patient outcomes were inconsistent in their findings, however, few of these studies were primarily focused on the issue of urban-rural disparities. Overall, study findings did not appear to differ in line with study quality ratings, stroke subtypes included, or how inter-facility patient transfers were accounted for. CONCLUSIONS: There is convincing, albeit not unanimous, evidence to suggest that stroke patients in rural areas receive less acute care than their urban counterparts. Despite this, the available data and methodology have largely not been used to study urban-rural differences in patient outcomes. PROSPERO registration information: URL: https://www.crd.york.ac.uk/prospero. Unique identifier: CRD42017073262.

A Public Health Analysis on Gaps in Disease Monitoring and Opportunities for Improved Care for the Management of Hepatitis B and C.

Hepatitis B and Hepatitis C have been major disease-causing agents among humans since they were discovered in the 1960s. Both cause jaundice-like symptoms initially but their prognosis and treatment are somehow different and depend upon many demographic details, such as the age and susceptibility of the patients and any other comorbid conditions. They clinically present primarily with hepatitis and can have many adverse effects or even be life-threatening at times, if not treated properly. However, their epidemiological background and findings in terms of morbidity, mortality, and case fatality rates are different. The disease burden, impact on the healthcare system, and prevention of the two diseases are quite different. The treatment and management options along with the prevention and control measures share unique strategies for handling the two diseases. The purpose of this review is to highlight the gaps in disease monitoring and to find ways and opportunities that can lead to improved care and better management of Hepatitis B and C locally and globally. Online databases were searched and peer-reviewed articles were selected. Key issues identified were lack of education globally in resource-limited settings, leading to a decreased understanding of the potential hazards associated with needle sharing and lack of access to healthcare because of a lack of insurance. The failure of compliance with vaccination leads to an increase in mother-to-child transmission (MTCT)-related infections. Increased global travel demands a systematic program in most immigrant-receiving countries to screen for hepatitis B virus (HBV)/hepatitis c virus (HCV) infections. Delayed U.S. Food and Drug Administration (FDA) licensing for new drugs hampers the treatment of chronic Hepatitis-B (CHB) among children. With the advancement in science, an effective vaccine against HCV will definitely help in eradicating the infection.

Prevention of Congenital Syphilis Through Antenatal Screenings in Lusaka, Zambia: A Systematic Review.

Congenital syphilis is one of the preventable diseases caused by the gram-negative bacteria Treponema pallidum; yet, it imposes a serious global health and economic burden, with more than half of the cases resulting in serious adverse outcomes, including infant mortality. Mother-to-child transmission (MTCT) of syphilis is estimated at 3.6 million adjusted life years (DALYs) and around $309 million in medical costs. In 2006, an estimated 9.7 million children of age less than five years died in developing countries; almost four million were neonatal deaths. There were 3.2 million stillbirths globally, among whom 95% were in the developing countries. In sub-Saharan Africa, there is an estimated 2.7% (0.1%-10.3%) of pregnant women infected with syphilis, representing more than 900,000 pregnancies at risk each year. There were many non-specific and specific diagnostic tests used in the past, which required laboratory equipment and electricity, but there are many newer tests available now that provide rapid results with high sensitivity and specificity, e.g., the immunochromatographic strip (ICS) and rapid syphilis tests (RST). Early syphilis can be completely eliminated with a single injection of penicillin, which is readily available, cheap, and highly effective, and treating pregnant women with penicillin is 98% effective at preventing congenital syphilis. Targeting women at a high risk of having syphilis makes universal screening in antenatal programs the most efficacious way to prevent syphilis-associated morbidity and mortality. The potential for a program to prevent congenital syphilis in the perinatal, neonatal, and postnatal periods is evident. While considering resource allocation to child survival programs in areas where the prevalence of syphilis is high, officials need to include antenatal syphilis screening, using rapid tests and treatment at the first contact of the mother with the health care system. In countries like Zambia and other resource-limited settings, a same-day test and treatment with penicillin should be prioritized to achieve the goal of eliminating congenital syphilis. Eliminating MTCT of syphilis through screening and treatment in antenatal care (ANC) is highly cost-effective in a wide range of settings, especially in countries with a high prevalence.