Role of Primary Care Physicians in management of Schizophrenia in Low and Middle Income Countries (LMIC): A systematic review.

Many people with Schizophrenia lack the resources and access to mental health services especially in low and middle income countries. Integration of mental health into primary care services can be a cost effective way of reducing the disability associated with Schizophrenia. Our aim was to review the studies conducted on role of Primary care physicians in management of Schizophrenia in low and middle income countries. PRISMA guidelines were followed and we registered the study protocol at PROSPERO. Four Electronic Databases (Medline, Psycinfo, CINAHL and Embase) were searched in May 2022. Relevant articles after search were 504 of which 61 full text were examined. A total of 20 studies were included in the final review comprising of observational, experimental and qualitative studies. Most studies reported on abilities of Primary care physicians including their knowledge, perceptions, skills and competencies in identifying and management of Schizophrenia and related Psychosis. Findings suggest that there is considerable amount of stigma, lack of awareness and social support about people diagnosed with Schizophrenia. Significant improvement was observed in diagnosis and management of schizophrenia by Primary care physicians who received appropriate training by experts in the field. This review suggests that appropriate training of General practitioners in diagnosing and treating schizophrenia can help in reduction of huge Treatment Gap in Schizophrenia. They can also be utilised in delivering psycho social interventions to improve overall quality of patient care.

Trigeminal Nerve Stimulation: A Novel Method of Resuscitation for Hemorrhagic Shock.

OBJECTIVES: To determine if trigeminal nerve stimulation can ameliorate the consequences of acute blood loss and improve survival after severe hemorrhagic shock. DESIGN: Animal study. SETTING: University research laboratory. SUBJECTS: Male Sprague-Dawley rats. INTERVENTIONS: Severe hemorrhagic shock was induced in rats by withdrawing blood until the mean arterial blood pressure reached 27 ± 1 mm Hg for the first 5 minutes and then maintained at 27 ± 2 mm Hg for 30 minutes. The rats were randomly assigned to either control, vehicle, or trigeminal nerve stimulation treatment groups. The effects of trigeminal nerve stimulation on survival rate, autonomic nervous system activity, hemodynamics, brain perfusion, catecholamine release, and systemic inflammation after severe hemorrhagic shock in the absence of fluid resuscitation were analyzed. MEASUREMENTS AND MAIN RESULTS: Trigeminal nerve stimulation significantly increased the short-term survival of rats following severe hemorrhagic shock in the absence of fluid resuscitation. The survival rate at 60 minutes was 90% in trigeminal nerve stimulation treatment group whereas 0% in control group (p < 0.001). Trigeminal nerve stimulation elicited strong synergistic coactivation of the sympathetic and parasympathetic nervous system as measured by heart rate variability. Without volume expansion with fluid resuscitation, trigeminal nerve stimulation significantly attenuated sympathetic hyperactivity paralleled by increase in parasympathetic tone, delayed hemodynamic decompensation, and improved brain perfusion following severe hemorrhagic shock. Furthermore, trigeminal nerve stimulation generated sympathetically mediated low-frequency oscillatory patterns of systemic blood pressure associated with an increased tolerance to central hypovolemia and increased levels of circulating norepinephrine levels. Trigeminal nerve stimulation also decreased systemic inflammation compared with the vehicle. CONCLUSIONS: Trigeminal nerve stimulation was explored as a novel resuscitation strategy in an animal model of hemorrhagic shock. The results of this study showed that the stimulation of trigeminal nerve modulates both sympathetic and parasympathetic nervous system activity to activate an endogenous pressor response, improve cerebral perfusion, and decrease inflammation, thereby improving survival.

Glycemic indices predict outcomes after aneurysmal subarachnoid hemorrhage: a retrospective single center comparative analysis.

Although hyperglycemia is associated with worse outcomes after aneurysmal subarachnoid hemorrhage (aSAH), there is no consensus on the optimal glucose control metric, acceptable in-hospital glucose ranges, or suitable insulin regimens in this population. In this single-center retrospective cohort study of aSAH patients, admission glucose, and hospital glucose mean (MHG), minimum (MinG), maximum (MaxG), and variability were compared. Primary endpoints (mortality, complications, and vasospasm) were assessed using multivariate logistic regressions. Of the 217 patients included, complications occurred in 83 (38.2%), 124 (57.1%) had vasospasm, and 41 (18.9%) died. MHG was independently associated with (p < 0.001) mortality, MaxG (p = 0.017) with complications, and lower MinG (p = 0.015) with vasospasm. Patients with MHG ≥ 140 mg/dL had 10 × increased odds of death [odds ratio (OR) = 10.3; 95% CI 4.6-21.5; p < 0.0001] while those with MinG ≤ 90 mg/dL had nearly 2× increased odds of vasospasm (OR = 1.8; 95% CI 1.01-3.21; p = 0.0422). While inpatient insulin was associated with increased complications and provided no mortality benefit, among those with MHG ≥ 140 mg/dL insulin therapy resulted in lower mortality (OR = 0.3; 95% CI 0.1-0.9; p = 0.0358), but no increased complication risk. While elevated MHG and MaxG are highly associated with poorer outcomes after aSAH, lower MinG is associated with increased vasospasm risk. Future trials should consider initiating insulin therapy based on MHG rather than other hyperglycemia measures.

The Effect of Frailty versus Initial Glasgow Coma Score in Predicting Outcomes Following Chronic Subdural Hemorrhage: A Preliminary Analysis.

Background Initial Glasgow Coma Score (iGCS) is a well-known predictor of adverse outcomes following chronic subdural hemorrhage (cSDH). Frailty, i.e. a reduced physiologic reserve, is associated with poorer outcomes across the surgical literature, however, there is no consensus on the best measure of frailty. To date, no study has compared frailty's ability to predict cSDH outcomes versus iGCS. The goal of this study was to, therefore, examine the prognostic value of the 5- (mFI-5) and 11-factor (mFI-11) modified frailty index, and Charlson Comorbidity Index (CCI) versus iGCS following cSDH. Methods Between January, 2016 and June, 2018, patients who presented to the emergency department with cSDH were retrospectively identified using the International Classification of Diseases (ICD) codes. mFI-5, mFI-11, and CCI scores were calculated using patient baseline characteristics. Primary endpoints were death and discharge home and subgroup analyses were performed among operative cSDH. Univariate and multivariate logistic regressions were used to determine predictors of primary endpoints. Results Of the 109 patients identified, the average age was 72.6±1.6 years and the majority (69/109, 63.3%) were male. The average CCI, mFI-5, and mFI-11 were 4.5 ±0.2, 1.5 ±0.1, and 2.2 ±0.1, respectively. Fifty (45.9%) patients required surgical intervention, 11 (10.1%) died, and 48 (43.4%) were discharged home. In the overall cohort, while the only multivariate predictor of mortality was iGCS (OR=0.58; 95%CI:0.44-0.77; p=0.0001), the CCI (OR=0.73; 95%CI:0.58-0.92; p=0.0082) was a superior predictor of discharge home compared to iGCS (OR=1.46; 95%CI:1.13-1.90; p=0.0041). Conversely, among those who received an operative intervention, the CCI, but not iGCS, independently predicted both mortality (OR=4.24; 95%CI:1.01-17.86; p=0.0491) and discharge home (OR=0.55; 95%CI:0.33-0.90; p=0.0170). Neither mFI nor age predicted primary outcomes in multivariate analysis. Conclusion While frailty is associated with worse surgical outcomes, the clinical utility of the mFI-5, mFI-11, and CCI in cSDH is unclear. We show that the iGCS is an overall superior predictor of mortality following cSDH but is outperformed by the CCI after operative intervention. Similarly, the CCI is the superior predictor of discharge home in cSDH patients overall and following an operative intervention. These results indicate that while the iGCS best predicts mortality overall, the CCI may be considered when prognosticating post-operative course and hospital disposition.

Low total cholesterol and high density lipoprotein are independent predictors of poor outcomes following aneurysmal subarachnoid hemorrhage: A preliminary report.

INTRODUCTION: Aneurysmal subarachnoid hemorrhage (aSAH) is devastating, with delayed cerebral ischemia (DCI) significantly contributing to the high morbidity and mortality rates. Cholesterol has been studied as a measure of nutritional status in other neurological pathologies, but reports examining cholesterol's effects on aSAH outcomes are sparse. This study aimed to elucidate the effect of low total cholesterol (TC) and high density lipoprotein (HDL) on mortality and DCI following aSAH. METHODS: We performed a retrospective cohort study at a quaternary academic medical center between June 2014 and July 2018. All patients had aSAH confirmed by digital subtraction angiography and had TC measured on admission. Primary outcomes were mortality and DCI. Secondary outcome was radiographic vasospasm. Univariate and multivariate logistic regressions were performed. RESULTS: There were 75 aSAH patients, with an average age of 58.7 ±â€¯1.7 (range: 14-89) and Hunt & Hess score of 2.8 ±â€¯0.1, included for analysis. Those with a low TC < 160 mg/dL had 3 times increased odds of DCI (OR = 3.4; 95 %CI: 1.3-9.0; p = 0.0175) and a nearly 5 times increased odds of death (OR = 4.9; 95 %CI: 1.1-18.3; p = 0.0339). Low HDL < 40 mg/dL was associated with 12 times increased odds of DCI (OR = 12.3; 95 %CI: 2.7-56.4; p = 0.0003) but no significant differences in death (p = 0.2205). In multivariate analysis, low TC was an independent risk factor for increased mortality (OR = 5.6; 95 %CI: 1.2-27.6; p = 0.0335) while low HDL was associated with increased risk for DCI (OR = 17.9; 95 %CI: 3.1-104.4; p = 0.0013). There was no effect of TC or HDL on radiographic vasospasm. CONCLUSIONS: Low TC and HDL are independent predictors of increased mortality and DCI, respectively, following aSAH. Low TC and HDL may be markers of poor overall health, in addition to having some pathophysiological effect on cerebral vasculature. These results may have practical implications for the improvement of aSAH prognostication and management.

The Effect of Frailty and Patient Comorbidities on Outcomes After Acute Subdural Hemorrhage: A Preliminary Analysis.

BACKGROUND: Frailty is associated with worse outcomes across a variety of neurosurgical diseases. However, its effect on acute subdural hemorrhage (aSDH) outcomes is unclear. The goal of this study is to compare 3 measures of frailty with the gold standard (i.e., initial Glasgow Coma Scale [iGCS] score) for predicting outcomes after aSDH. METHODS: Patients who presented between January 2016 and June 2018 were retrospectively identified based on International Classification of Diseases codes for aSDH. Patients' modified Frailty Index (mFI), temporalis muscle thickness (TMT), and age-adjusted Charlson Comorbidity Index (CCI) were calculated. Primary end points were death and discharge home. RESULTS: Of 167 patients included, the mean age was 63.4 ± 1.9 years, the average CCI was 3.4 ± 0.2, mFI was 1.4 ± 0.1, TMT was 7.1 ± 0.2 mm, and iGCS score was 11.9 ± 0.3. Sixty-nine patients (41.3%) were discharged home and 32 (19.2%) died during hospitalization. In multivariate analysis, decreasing iGCS score (odds ratio [OR], 0.84; 95% confidence interval [CI], 0.74-0.96; P = 0.0112) and midline shift (OR, 1.27; 95% CI, 1.08-1.50; P = 0.0048), but not age or frailty, predicted mortality. In addition to iGCS score (OR, 1.26; 95% CI, 1.10-1.44; P = 0.0011), lower CCI (OR, 0.32; 95% CI, 0.14-0.74; P = 0.0071) and larger TMT (OR, 2.63; 95% CI, 1.16-5.99; P = 0.0210) independently predicted increased rates of discharge home. mFI was not independently associated with either primary end point in multivariate analysis. CONCLUSIONS: iGCS score predicts both mortality and discharge location after aSDH better than do age or frailty. However, CCI and TMT, but not mFI, are useful prognostic indicators of discharge to home after aSDH. The iGCS score should continue to be the primary prediction tool for patients with aSDH; however, frailty may be useful for resource allocation, especially when nearing discharge.

Supervised treatment in outpatients for schizophrenia plus (STOPS+): protocol for a cluster randomised trial of a community-based intervention to improve treatment adherence and reduce the treatment gap for schizophrenia in Pakistan.

INTRODUCTION: There is a significant treatment gap, with only a few community-based services for people with schizophrenia in low-income and middle-income countries. Poor treatment adherence in schizophrenia is associated with poorer health outcomes, suicide attempts and death. We previously reported the effectiveness of supervised treatment in outpatients for schizophrenia (STOPS) for improving treatment adherence in patients with schizophrenia. However, STOPS was evaluated in a tertiary care setting with no primary care involvement, limiting its generalisability to the wider at-risk population. We aim to evaluate the effectiveness of STOPS+ in scaling up the primary care treatment of schizophrenia to a real-world setting. METHODS AND ANALYSIS: The effectiveness of the STOPS+ intervention in improving the level of functioning and medication adherence in patients with schizophrenia in Pakistan will be evaluated using a cluster randomised controlled trial design. We aim to recruit 526 participants from 24 primary healthcare centres randomly allocated in 1:1 ratio to STOPS+ intervention and enhanced treatment as usual arms. Participants will be followed-up for 12 months postrecruitment. The sample size is estimated for two outcomes (1) the primary clinical outcome is level of functioning, measured using the Global Assessment of Functioning scale and (2) the primary process outcome is adherence to treatment regimen measured using a validated measure. An intention-to-treat approach will be used for the primary analysis. ETHICS AND DISSEMINATION: Ethical approval has been obtained from Keele University Ethical Review Panel (ref: MH-190017) and Khyber Medical University Ethical Review Board (ref: DIR-KMU-EB/ST/000648). The results of the STOPS+ trial will be reported in peer-reviewed journals and academic conferences and disseminated to local stakeholders and policymakers. TRIAL REGISTRATION NUMBER: ISRCTN93243890.

Protein misfolding and aggregation in neurodegenerative diseases: a review of pathogeneses, novel detection strategies, and potential therapeutics.

Protein folding is a complex, multisystem process characterized by heavy molecular and cellular footprints. Chaperone machinery enables proper protein folding and stable conformation. Other pathways concomitant with the protein folding process include transcription, translation, post-translational modifications, degradation through the ubiquitin-proteasome system, and autophagy. As such, the folding process can go awry in several different ways. The pathogenic basis behind most neurodegenerative diseases is that the disruption of protein homeostasis (i.e. proteostasis) at any level will eventually lead to protein misfolding. Misfolded proteins often aggregate and accumulate to trigger neurotoxicity through cellular stress pathways and consequently cause neurodegenerative diseases. The manifestation of a disease is usually dependent on the specific brain region that the neurotoxicity affects. Neurodegenerative diseases are age-associated, and their incidence is expected to rise as humans continue to live longer and pursue a greater life expectancy. We presently review the sequelae of protein misfolding and aggregation, as well as the role of these phenomena in several neurodegenerative diseases including Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, Parkinson's disease, transmissible spongiform encephalopathies, and spinocerebellar ataxia. Strategies for treatment and therapy are also conferred with respect to impairing, inhibiting, or reversing protein misfolding.

Age predicts outcomes better than frailty following aneurysmal subarachnoid hemorrhage: A retrospective cohort analysis.

OBJECTIVE: Increasing age has been associated with worse outcomes following aneurysmal subarachnoid hemorrhage (aSAH), yet frailty's effect on aSAH outcomes has never been studied. The most common frailty measurement tool is the modified frailty index (mFI). The goal of this study is to compare the effect of frailty versus age as predictors of aSAH outcomes and mortality. PATIENTS AND METHODS: Our institutional aSAH series were retrospectively identified and divided into non-frail (mFI = 0-1) and frail (mFI≥2) cohorts based on admission mFI scores. Primary outcomes were mortality and discharge location. Univariate and multivariate analysis were performed. RESULTS: There were 217 aSAH patients identified and 57 were frail (26.3%). Forty-one (18.9%) patients died and 74 (34%) were discharged home. Frail patients were significantly older (p < 0.0001) and had higher Hunt & Hess (HH) (p = 0.005) and Fisher (p = 0.0255) scores. Frail patients were less likely to receive an intervention (OR = 0.3; 95%CI:0.1-0.6); p = 0.0056), be discharged home (OR = 0.32; 95%CI:0.16-0.68; P = 0.0020), and were more likely to expire (OR = 2.4; 95%CI:1.2-5; P = 0.0183) and develop a complication (OR = 2.6; 95%CI:1.1-6.6; P = 0.0277). Multivariate regressions showed that the HH score (OR = 2.7; 95%CI: 1.9-3.0; P < 0.0001) followed by age≥65 (OR = 2.7; 95%CI:1.2-6.0; p = 0.012) were the only independent predictors of mortality. Likewise, discharge home was best predicted by HH score (OR = 0.24; 95%CI:0.15-0.37; p < 0.0001) and age (OR = 0.25; 95%CI:0.1-0.6; p = 0.003). CONCLUSION: Frailty is associated with worse aSAH grades, more complications, and increased mortality, however, increasing age and HH scores were the only independent predictors of aSAH outcomes. This study suggests that HH score and increasing patient age, and not the accumulated co-morbidities at the time of aSAH, better predict outcomes.

The molecular biology of prostate cancer: current understanding and clinical implications.

BACKGROUND: With continuous progress over the past few decades in understanding diagnosis, treatment, and genetics, much has been learned about the prostate cancer-diagnosed genome. METHODS: A comprehensive MEDLINE® and Google scholar literature search was conducted using keyword variations relating to the genetics of prostate cancer such as chromosomal alterations, androgen receptor, castration-resistant, inheritance, polymorphisms, oncogenes, metastasis, biomarkers, and immunotherapy. RESULTS: Traditionally, androgen receptors (AR) have been the focus of research. Recently, identification of recurrent chromosomal alterations that lead to either multiplication of regions (gain-of-function) or deletion of regions (loss-of-function) has opened the door to greater genetic accessibility. These chromosomal aberrations lead to variation in copy number and gene expression. Some of these chromosomal alterations are inherited, while others undergo somatic mutations during disease progression. Inherited gene mutations that make one susceptible to prostate cancer have been identified with familial-linked studies. Somatic genes that progress tumorigenesis have also been identified. Research on the molecular biology of prostate cancer has characterized these genes into tumor suppressor genes or oncogenes. Additionally, genome-wide assay studies have identified many high-risk single-nucleotide polymorphisms recurrent throughout the prostate cancer-diagnosed genome. Castration-resistant prostate cancer is the most aggressive form of prostate cancer, and its research has elucidated many types of mutations associated with AR itself, including enhanced expression and amplification, point mutations, and alternative splicing. Understanding the molecular biology of prostate cancer has permitted more accurate identification using advanced biomarkers and therapy for aggressive forms using immunotherapy. CONCLUSIONS: An age-related disease, prostate cancer commands profound attention. With increasing life expectancy and the continuous pursuit of it, prostate cancer is a powerful obstacle best defeated using targeted therapies specifically designed for the unique molecular profile of the malignancy.