Ketamine to Prevent Endotracheal Intubation in Adults with Refractory Non-convulsive Status Epilepticus: A Case Series.

BACKGROUND: Non-convulsive status epilepticus (NCSE) is defined as status epilepticus (SE) with no obvious motor phenomenon and is diagnosed based on electroencephalogram (EEG). Refractory SE (RSE) is the persistence of seizures despite treatment with an adequately dosed first-line and second-line agents. Although guidelines for convulsive RSE include third-line agents such as intravenous anesthetic drugs (midazolam, propofol, or barbiturates), the therapeutic approach to NCSE is not well outlined. Treatment with traditional anesthetics invariably includes endotracheal intubation, which is associated with significant adverse events. Comparatively, ketamine, a non-competitive N-methyl-D-aspartate receptor antagonist is not associated with significant cardiorespiratory depression and may help in avoiding intubation. OBJECTIVE: In this case series, we describe our experience with the early use of intravenous ketamine as the first anesthetic agent in patients with refractory NCSE to avoid endotracheal intubation. METHODS: We present a case series of nine patients managed in the Neurointensive Care Unit at a university-affiliated tertiary care hospital. The study was approved by the hospital and university institutional review boards and the requirement for informed consent was waived for retrospective analysis of existing data, per institutional policy. All cases of SE were identified from a prospective database, and a subsequent retrospective chart review identified all patients with a diagnosis of refractory NCSE in whom ketamine was used as the first anesthetic agent. The primary endpoint was the avoidance of endotracheal intubation while on ketamine infusion. The secondary endpoint was defined as cessation of both clinical and electrographic seizures recorded on continuous EEG within 24 h of ketamine administration. RESULTS: A total of nine patients experiencing refractory NCSE were included in this case series, with a median age of 61 (range 26-72) years and seven patients were male. The primary endpoint, avoiding intubation, was achieved in five out of nine (55%) cases. Six patients experienced resolution of refractory NCSE with ketamine administration as the sole anesthetic agent. Four patients required endotracheal intubation and three patients had a failure of seizure cessation with ketamine. Hypersalivation and pneumonia were the most common ketamine associated adverse events. In non-intubated patients, no deaths occurred. One patient was discharged home, four to subacute rehabilitation, one to a long term acute care hospital, and one patient to hospice. CONCLUSION: The use of ketamine as the primary anesthetic agent may be a reasonable option to avoid endotracheal intubation in a subset of patients with refractory NCSE. This study is limited by its small sample size, retrospective design, and reliance on information obtained from chart review.

Loss of microRNA-21 protects against acetaminophen-induced hepatotoxicity in mice.

Acetaminophen (APAP)-induced Acute Liver Failure (ALF) is recognized as the most common cause of ALF in Western societies. APAP-induced ALF is characterized by coagulopathy, hepatic encephalopathy, multi-organ failure, and death. MicroRNAs are small, non-coding RNAs that regulate gene expression at the post-transcriptional level. MicroRNA-21 (miR-21) is dynamically expressed in the liver and is involved in the pathophysiology of both acute and chronic liver injury models. We hypothesize that miR-21genetic ablation attenuates hepatotoxicity following acetaminophen intoxication. Eight-week old miR-21knockout (miR21KO) or wild-type (WT) C57BL/6N male mice were injected with acetaminophen (APAP, 300 mg/kg BW) or saline. Mice were sacrificed 6 or 24 h post-injection. MiR21KO mice presented attenuation of liver enzymes ALT, AST, LDH compared with WT mice 24 h post-APAP treatment. Moreover, miR21KO mice had decreased hepatic DNA fragmentation and necrosis than WT mice after 24 h of APAP treatment. APAP-treated miR21KO mice showed increased levels of cell cycle regulators CYCLIN D1 and PCNA, increased autophagy markers expression (Map1LC3a, Sqstm1) and protein (LC3AB II/I, p62), and an attenuation of the APAP-induced hypofibrinolytic state via (PAI-1) compared with WT mice 24 post-APAP treatment. MiR-21 inhibition could be a novel therapeutic approach to mitigate APAP-induced hepatotoxicity and enhance survival during the regenerative phase, particularly to alter regeneration, autophagy, and fibrinolysis. Specifically, miR-21 inhibition could be particularly useful when APAP intoxication is detected at its late stages and the only available therapy is minimally effective.

Understanding the Influence of Hospital Volume on Inpatient Outcomes Following Hospitalization for Status Epilepticus.

BACKGROUND: Prior studies show hospital admission volume to be associated with poor outcomes following elective procedures and inpatient medical hospitalizations. However, it is unknown whether hospital volume impacts Inpatient outcomes for status epilepticus (SE) hospitalizations. In this study, we aimed to assess the impact of hospital volume on the outcome of patients with SE and related inpatient medical complications. METHODS: The 2005 to 2013 National Inpatient Sample database was queried using International Classification of Diseases 9th Edition diagnosis code 345.3 to identify patients undergoing acute hospitalization for SE. The National Inpatient Sample hospital identifier was used as a unique facility identifier to calculate the average volume of patients with SE seen in a year. The study cohort was divided into three groups: low volume (0-7 patients with SE per year), medium volume (8-22 patients with SE per year), and high volume (> 22 patients with SE per year). Multivariate logistic regression analyses were used to assess whether medium or high hospital volume had lower rates of inpatient medical complications compared with low-volume hospitals. RESULTS: A total of 137,410 patients with SE were included in the analysis. Most patients (n = 50,939; 37%) were treated in a low-volume hospital, 31% (n = 42,724) were treated in a medium-volume facility, and 18% (n = 25,207) were treated in a high-volume hospital. Patients undergoing treatment at medium-volume hospitals (vs. low-volume hospitals) had higher odds of pulmonary complications (odds ratio [OR] 1.18 [95% confidence interval {CI} 1.12-1.25]; p < 0.001), sepsis (OR 1.24 [95% CI 1.08-1.43] p = 0.002), and length of stay (OR 1.13 [95% CI 1.0 -1.19] p < 0.001). High-volume hospitals had significantly higher odds of urinary tract infections (OR 1.21 [95% CI 1.11-1.33] p < 0.001), pulmonary complications (OR 1.19 [95% CI 1.10-1.28], p < 0.001), thrombosis (OR 2.13 [95% CI 1.44-3.14], p < 0.001), and renal complications (OR 1.21 [95% CI 1.07-1.37], p = 0.002). In addition, high-volume hospitals had lower odds of metabolic (OR 0.81 [95% CI 0.72-0.91], p < 0.001), neurological complications (OR 0.80 [95% CI 0.69-0.93], p = 0.004), and disposition to a facility (OR 0.89 [95% CI 0.82-0.96], p < 0.001) compared with lower-volume hospitals. CONCLUSIONS: Our study demonstrates certain associations between hospital volume and outcomes for SE hospitalizations. Further studies using more granular data about the type, severity, and duration of SE and types of treatment are warranted to better understand how hospital volume may impact care and prognosis of patients.

NeuroMeasures-Implementation of a Web-Based, Real-Time Quality Metric Tool to Improve Provider Practices in an Epilepsy Clinic.

Background and Objectives: The retrospective nature of most available epilepsy quality improvement (QI) tools focuses on changing health care provider (HCP) clinical habits and documentation practices rather than a focus on real-time patient interventions. Furthermore, patient-reported outcome data are often not available to determine the efficacy of these tools. Our primary objective was to demonstrate the improvement of HCPs' documentation and review of epilepsy quality measures (EQMs) during the patient visit with the implementation of a novel web application, NeuroMeasures. Our secondary objective was to improve the percentage of point-of-care counseling and interventions based on quality measures during the patient encounter based on the results of the NeuroMeasures tool. Methods: Our QI study focused on comparing a preintervention and postintervention cohort of patients with epilepsy (PWE) before the implementation of NeuroMeasures, a web-based application that takes a self-guided patient survey through self-scoring algorithms focused on the American Academy of Neurology (AAN)'s 2017 EQMs. This e-tool then provides the HCP a tool to directly review the EQMs highlighted and perform any necessary counseling or interventions at the point-of-care visit. After intervention, EQMs were gained from the review of the NeuroMeasures HCP quality measures tool and a chart review for physician documentation. Patients with language barriers and severe cognitive disabilities were excluded from the study. Results: The preintervention cohort consisted of 150 unique PWE, and the postintervention cohort included 379 unique adult PWE and 515 total encounters. Overall percentages of review/adherence of EQMs were significantly improved between the preintervention and postintervention group for counseling for women of childbearing potential (91.7%), intractable epilepsy referral to a comprehensive epilepsy center (74%), quality of life assessment (80%), improvement of quality of life measurements (41.7%), and depression and anxiety screening (85.6%), demonstrating a significant increase when compared with the preintervention group (p < 0.00001). Discussion: A web-based point-of-care EQM application demonstrated significant improvement of the HCP's ability to perform and review EQMs at the point-of-care patient visit. Furthermore, the application was successful in creating opportunities for direct intervention based on the EQMs and chances for better patient education and provider-patient communication. Further considerations would include automated survey requests and expansion into other AAN QMs.

Are There Racial Differences in Inpatient Outcomes and Treatment Utilization following Hospitalization for Myasthenia Gravis Exacerbation?

INTRODUCTION: Little is known about racial differences in inpatient outcomes following hospitalizations for myasthenia gravis (MG). In this study, we used a claims-based database to assess racial differences in outcomes in hospitalized myasthenics. METHODS: The 2006-2014 National Inpatient Sample database was queried using the International Classification of Diseases 9th Edition diagnosis code (358.01) to identify adult patients (age >17 years) undergoing hospitalization for MG. Race was categorized into - white, black/African American (AA), Asian or Pacific Islander, Hispanic, Native American, and other. Complications assessed included urinary tract infections, acute renal failure, cardiac complications, systemic infection, deep venous thrombosis, and pulmonary embolism. Multivariate logistic regression analyses were used to assess whether race was associated with a difference in outcomes, after controlling for baseline demographics, hospital characteristics, and treatment factors. RESULTS: A total of 56,189 patient admissions, using a weighted sample, underwent hospitalization for MG between 2006 and 2014. Black/AA patients had significantly higher odds of experiencing systemic infections (odds ratio [OR] 1.35 [95% confidence intervals [CI] 1.16-1.58]; p < 0.001), deep venous thrombosis (OR 2.11 [95% CI 1.36-3.27]; p = 0.001), and renal failure (OR 1.19 [95% CI 1.05-1.35]; p = 0.005). Black/AA patients were more likely to be intubated (OR 1.09 [95% CI 1.01-1.19]; p = 0.028) and receive noninvasive mechanical ventilation (OR 1.62 [95% CI 1.46-1.79]; p < 0.001), however, were less likely to receive intravenous immunoglobulin (OR 0.77 [95% CI 0.73-0.82]; p < 0.001) and plasmapheresis (OR 0.77 [95% CI 0.72-0.82]; p < 0.001). Black/AA and Hispanic patients had lower mortality (OR 0.74 [95% CI 0.59-0.94; p = 0.012]. CONCLUSIONS: Significant racial differences exist in both treatment utilization and inpatient outcomes for patients hospitalized for MG.

Rasch analysis of fatigue severity scale in patients with epilepsy.

OBJECTIVE: To utilize the Rasch model to validate and assess the psychometric properties of the Fatigue Severity Scale (FSS) in patients with epilepsy. METHODS: A total of 307 patients (age > 18 years) with a confirmed diagnosis of epilepsy were consented to participate. Exclusion criteria included patients with psychogenic nonepileptic events, cognitive disabilities, and patients who did not speak/understand English. The nine-step FSS was programmed into software administered to patients on electronic tablets, and patient responses were auto-scored. The Rasch rating scale model (RSM) was used to evaluate the unidimensionality, reliability, and targeting of the FSS. To assess unidimensionality, we examined infit and outfit mean squares. We also assessed unidimensionality of the FSS using a principal component analysis of Rasch residuals, where residuals are understood as the difference between observed and expected data values. We evaluated the internal consistency of person and item performance by examining separation reliability estimates and separation ratio. Differential Item Functioning (DIF) was calculated for gender. RESULTS: There was mixed evidence regarding the extent to which the FSS fit the Rasch model. Outfit values ranged from 0.52 to 2.72 and infit values were 0.60 to 2.18, strongly suggesting the presence of misfitting items: Item 1 ("My motivation is lower when I am fatigued") and Item 2 ("Exercise brings on my fatigue"). SIGNIFICANCE: The nine-item FSS showed fair psychometric properties in this sample of patients with epilepsy. Our study provides unique, supportive information for the use of a modified version of the FSS, omitting the first two items, in patients with epilepsy. Given the prevalence of fatigue and other neuropsychiatric comorbidities of epilepsy, having a validated fatigue scale can aid healthcare providers to identify moderate-to-severe fatigue levels in patients with epilepsy and address the plausible risk factors.

Stroke at Moderate and High Altitude.

Syed, Maryam J., Ismail A. Khatri, Wasim Alamgir, and Mohammad Wasay. Stroke at moderate and high altitude. High Alt Med Biol. 23:1-7, 2022. Background: Stroke at high altitude is an understudied area in stroke research. With improvements in road infrastructure, access to high-altitude areas for recreation and living purposes has risen. Subsequently, it has been anticipated that due to normal physiological changes to high altitude the incidence of stroke is also likely to increase in these regions. Methods: We searched PubMed for available literature about stroke at high altitude. Cross-referencing was done from available articles and through other scientific search engines. Relevant case series and case reports were included in this review of the topic. Results: Only one review article, eight case series (including review of literature), and seven case reports were identified that could be included in this review. Most of the available data come from moderate and high altitude. Conclusions: There is limited available literature about stroke at high and extreme altitudes. Stroke at high altitude is likely to become an important subset of stroke population. Currently, there is inadequate knowledge about the incidence and prevalence, mechanisms, and stroke outcomes. Cerebral venous thrombosis is more common than arterial stroke. Stroke is probably secondary to conventional risk factors, polycythemia, and other coagulopathies. A case-control study may identify the at-risk population for stroke at moderate and high altitudes.

Did the COVID-19 pandemic impact help-seeking behavior for seizure management? A Google Trends™ study.

Google Trends™ is a popular tool for analyzing healthcare-seeking patterns based on observed changes in the relative search volume (RSV) of the queries made on the Google™ search engine. Google Trends™ was increasingly utilized during the pandemic to assess the impact on mental health, risk communication, the impact of media coverage, and preparedness prediction. The objective of this study was to evaluate the impact of the Coronavirus disease 2019 (COVID-19) pandemic on help-seeking behaviors for seizures and/or epilepsy by assessing the changes in seizure-related online queries in periods before and since the advent of the COVID-19 pandemic on Google Trends™. We compared the RSV volumes in the year prior to and during the COVID-19 pandemic against weekly COVID-19 positive cases for each state and US census regions Search terms were categorized according to seizure symptoms or seizure treatment. Our study showed no significant increase in the RSV for seizure and epilepsy-related searches during the COVID-19 pandemic via Google Trends™. Public health entities and medical systems may use Google Trends ™ as a way to predict national, regional, and local patient needs and drive resources to meet patient demands.

Changes in Mode of Oxygen Delivery and Physiological Parameters with Physiotherapy in COVID-19 Patients: A Retrospective Study.

Background: Coronavirus disease (COVID-19) is an infectious disease caused by SARS-CoV-2, clinically presenting with common symptoms of fever, dry cough, and breathlessness within 14 days of exposure. Its severity ranges from mild to severe, latter manifesting into severe acute respiratory syndrome. As a part of multidisciplinary team, physiotherapy along with medical management was administered to patients with COVID-19 in an acute care setup. This retrospective study aims to explore various patient characteristics and will aid in identifying the impairments associated with the disease, giving a direction to the physiotherapy community in planning future management strategy to improve quality of life. Patients and methods: The present study is a unicentric study wherein prospective analysis of retrospective data of patients referred for physiotherapy from May 13 to July 31, 2020, was performed. (i) Characteristics of patients, (ii) associated comorbidities, (iii) hospital course since the time of admission to discharge, (iv) mode of oxygen delivery, (v) pre- and post-physiotherapy treatment values of oxygen saturation and heart rate, and (vi) physiotherapy treatment were recorded. The archived data were analyzed using the commercially available SPSS software version 24. Wilcoxon's matched pair test was used to compare pre- and post-treatment oxygen saturation and heart rate, and McNemar's test was used to compare mode of oxygen delivery and pre- and post-physiotherapy treatment. Results: Descriptive analysis of data showed a better outcome in terms of grade of dyspnea and rate of discharge on day 14 of physiotherapy treatment. Hence, a comparative analysis of day 1 and day 14 was performed for mode of oxygen delivery, oxygen saturation, and heart rate. A statistically significant improvement was observed in the heart rate (p = 0.001) and oxygen delivery (p = 0.000). However, no significant difference in the level of oxygen saturation was found (p = 0.6433). Conclusion: Physiotherapy treatment in conjunction with medical treatment can be effectively administered in patients with COVID-19 in acute care setup taking into consideration the health status and the hemodynamic stability of the patients. It emphasizes the role of physiotherapy in the alleviation of symptoms, facilitating early weaning and recovery enabling early discharge from the hospital. How to cite this article: Verma CV, Arora RD, Mistry HM, Kubal SV, Kolwankar NS, Patil PC, et al. Changes in Mode of Oxygen Delivery and Physiological Parameters with Physiotherapy in COVID-19 Patients: A Retrospective Study. Indian J Crit Care Med 2021;25(3):317-321.

Outcomes of seizures, status epilepticus, and EEG findings in critically ill patient with COVID-19.

OBJECTIVE: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has a myriad of neurological manifestations and its effects on the nervous system are increasingly recognized. Seizures and status epilepticus (SE) are reported in the novel coronavirus disease (COVID-19), both new onset and worsening of existing epilepsy; however, the exact prevalence is still unknown. The primary aim of this study was to correlate the presence of seizures, status epilepticus, and specific critical care EEG patterns with patient functional outcomes in those with COVID-19. METHODS: This is a retrospective, multicenter cohort of COVID-19-positive patients in Southeast Michigan who underwent electroencephalography (EEG) from March 12th through May 15th, 2020. All patients had confirmed nasopharyngeal PCR for COVID-19. EEG patterns were characterized per 2012 ACNS critical care EEG terminology. Clinical and demographic variables were collected by medical chart review. Outcomes were divided into recovered, recovered with disability, or deceased. RESULTS: Out of the total of 4100 patients hospitalized with COVID-19, 110 patients (2.68%) had EEG during their hospitalization; 64% were male, 67% were African American with mean age of 63 years (range 20-87). The majority (70%) had severe COVID-19, were intubated, or had multi-organ failure. The median length of hospitalization was 26.5 days (IQR = 15 to 44 days). During hospitalization, of the patients who had EEG, 21.8% had new-onset seizure including 7% with status epilepticus, majority (87.5%) with no prior epilepsy. Forty-nine (45%) patients died in the hospital, 46 (42%) recovered but maintained a disability and 15 (14%) recovered without a disability. The EEG findings associated with outcomes were background slowing/attenuation (recovered 60% vs recovered/disabled 96% vs died 96%, p < 0.001) and normal (recovered 27% vs recovered/disabled 0% vs died 1%, p < 0.001). However, these findings were no longer significant after adjusting for severity of COVID-19. CONCLUSION: In this large multicenter study from Southeast Michigan, one of the early COVID-19 epicenters in the US, none of the EEG findings were significantly correlated with outcomes in critically ill COVID-19 patients. Although seizures and status epilepticus could be encountered in COVID-19, the occurrence did not correlate with the patients' functional outcome.

Telephone validation of an Urdu translated version of the extended disability severity scale in multiple sclerosis patients.

BACKGROUND: Expanded Disability Status Scale (EDSS) is a commonly used tool to assess the extent of functional impairment in multiple sclerosis (MS) patients for clinical and research purposes. EDSS is traditionally conducted in a face-to-face setting, however, routine in-person EDSS assessments are often difficult to perform in developing countries due to the various reasons patients are unable to access healthcare and maintain clinic visits. Hence validating a locally translated telephone-based EDSS (T-EDSS) could be potentially useful to both physicians and patients by removing the need to commute to healthcare centers for disability assessment and could lead to overall improved care for MS patients. METHODS: Firstly, the EDSS scale was translated and culturally adapted into Urdu. On enrolment, EDSS was conducted during scheduled clinic visits and forty-seven subjects with MS were henceforth included in the study. Same patients were contacted via telephone following two weeks by a different neurologist to carry out the telephone-EDSS assessment. The patients' baseline EDSS scores at enrolment were blinded to prevent interviewer bias. RESULTS: Kappa value for agreement between the two assessments for EDSS scores of more than 6 was 0.73, whereas the kappa value for EDSS score of less than 4.5 was 0.35. The intraclass correlation coefficient (ICC) for T-EDSS score < 4.5 was 1.7, and for a score > 4.5 was 4.9, with the overall ICC being 0.64. Cronbach's alpha value for T-EDSS score < 4.5 was 0.59 and for the score > 4.5 was 0.79. CONCLUSIONS: This study shows that there exists a positive correlation and substantial level of agreement between in-person EDSS and T-EDSS, especially in MS patients with higher baseline EDSS scores. Hence a locally translated T-EDSS can be used in Pakistani MS patients with reasonable confidence. T-EDSS may be more useful in MS patients with moderate to severe disability.

Use of Platelet-Rich Plasma in Treating Low Back Pain: A Review of the Current Literature.

Low back pain (LBP) is a common problem encountered by physicians. It is a considerable cause of morbidity and socioeconomic loss and is one of the most expensive musculoskeletal disorders. Conventional treatments include bed rest, analgesics, therapeutic exercises, lumbar or caudal epidural corticosteroids, and surgery. Several new biological therapies are being investigated for use in LBP and one of these is platelet-rich plasma (PRP). In this article, we summarize the current literature published on PRP concerning its composition, classification, and application in LBP. We believe our review will prove useful to clinicians and academics alike, interested in new developing therapies for LBP.

Depression and the Use of Selective Serotonin Reuptake Inhibitors in Patients with Acute Intracerebral Hemorrhage.

Introduction Depression is a common psychiatric complication associated with stroke. However, while most studies focus on post-stroke depression (PSD) subsequent to ischemic strokes, fewer studies have specifically explored depressive symptoms and the use of selective serotonin reuptake inhibitors (SSRIs) in patients with acute intracerebral hemorrhage (ICH). The aim of our study was to identify the incidence and factors associated with depression in ICH patients and the use of SSRIs as therapy by physicians at a tertiary care hospital in Karachi, Pakistan. Materials and methods A retrospective chart review was conducted to identify patients with ICH through the International Classification of Diseases, Ninth Revision (ICD-9) coding system electronic medical records of Aga Khan University Hospital, Karachi, Pakistan. Patient records spanning a period of five years at the hospital were identified and analyzed by neurology residents. Patients' clinical, laboratory, radiological, and pharmacological data were recorded and analyzed using a structured proforma. Patients with a past history of depression or those who were taking SSRIs at the time of admission were excluded from the analysis. Depression was defined as the presence of five or more symptoms according to the diagnostic criteria of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV). Results Out of the 458 patients we analyzed, 258 (56%) were men and 200 (44%) were women. The mean age was 59 years. Median National Institutes of Health Stroke Scale (NIHSS) score on admission was 13 (range: 0-42), and the median modified Rankin Scale (mRS) score was 4 (range: 0-6). On neuroimaging, sites of hemorrhage in patients were found to include the basal ganglia/thalamus in 279 (61%) patients, cerebral cortex in 105 (23%), cerebellum in 25 (5%), brain stem in 17 (4%), ventricles in 17 (4%), and multiple sites in eight (2%). We found that 48 (10%) patients had a ventricular extension, and 130 (28%) had midline shift, hydrocephalus, or both. Overall, 103 (22%) patients met the DSM-IV diagnostic criteria for depression. The most common depressive symptoms included tearfulness (67%), sadness (55%), and loss of interest or pleasure in life activities (53%). None of the patients reported suicidal ideation. Only seven patients (2%) were seen by a psychiatrist. The presence of depression was not significantly associated with hemorrhage sites [prabability value (p): 0.55] or the extent of disability (p: 0.09). Among the 103 depressed patients, only 25 (24%) received SSRIs during the hospital stay. A total of 57 (12%) received SSRIs during the hospital stay, of which only 25 had met the DSM-IV diagnostic criteria for depression. The mean duration between the diagnosis of ICH and the start of SSRIs was five days (range 3-25 days). None of the patients received any psychotherapeutic help for depression. At the time of discharge, only 13 (13%) of the 103 patients diagnosed with depression were discharged on SSRIs, while 23 that had not met the DSM-IV diagnostic criteria were discharged on SSRIs. Conclusion The present study demonstrates that depression is not uncommon in acute ICH patients, and it is both underdiagnosed and inadequately treated. Physicians should be trained to accurately identify and effectively treat depressive symptoms in ICH patients. Clear guidelines should be developed to aid the diagnosis and treatment of post-ICH depression in hospital settings.

Cerebral Venous Thrombosis at High Altitude: Analysis of 28 Cases.

OBJECTIVE: An association between cerebral venous sinus thrombosis (CVST) and high altitude has been previously proposed, but limited published data exist to support this association. We investigated 28 cases of CVST occurring at high altitude and sought to describe patient demographics, altitude and acclimatization, hematological laboratory findings, neuroimaging, treatment, and prognosis in these cases. METHODS: Twenty-eight cases of symptomatic CVST occurring at high altitude were identified between the months of August 2017 and December 2018, in collaboration with Military Hospital, Rawalpindi and Combined Military Hospital, Skardu (Pakistan). Follow-up visits were performed at 1 and 6 months. RESULTS: Twenty-seven (96%) of the patients were males, and the mean age was 33 years. In total, 32.1% were smokers. The mean NIHSS score on presentation was 5.5. 85.7% of the cases occurred at altitude higher than 8,000 feet. On average 107.8 days were spent at a high altitude prior to CVST. Totally, 71.4% had acclimatized for >2 weeks. The mean hemoglobin (Hb) value was 16.7 g/dL and 50% had d-dimer levels higher than 1,000 ng/mL. On MRI, 25% showed signs of hemorrhage and 14.3% showed infarcts. Treatments provided include low-molecular-weight heparin and Rivaroxaban and were associated with good outcomes. CONCLUSION: CVST is not uncommon at high altitude (>8,000 feet). It is predominantly a male disease. Most patients have high Hb and high D-dimer levels. The overall outcome was good.

Effect of GLP-1 Receptor Agonists in the Cardiometabolic Complications in a Rat Model of Postmenopausal PCOS.

Polycystic ovary syndrome (PCOS) is characterized by hyperandrogenism and ovulatory dysfunction. Women with PCOS have an elevated prevalence of cardiometabolic risk factors that worsen after menopause. Liraglutide (Lira), a glucagon-like peptide-1 receptor agonist, has shown beneficial metabolic effects in small clinic trials in reproductive-age women with PCOS. We have shown that chronic hyperandrogenemia in an experimental model of postmenopausal PCOS is associated with an adverse cardiometabolic profile and upregulation of the intrarenal renin-angiotensin system (RAS). We analyzed the effect of Lira in the cardiometabolic profile, intrarenal RAS, and blood pressure (BP) in postmenopausal PCOS. Four-week-old female Sprague Dawley rats were treated with DHT or placebo for 17 months. Lira administration during the last 3 weeks caused a bigger reduction in food intake, body weight, fat mass, and homeostasis model assessment of insulin resistance index in PCOS than in control rats. Moreover, Lira improved dyslipidemia and elevated leptin levels in PCOS. In contrast, Lira decreased intrarenal expression of RAS components only in the control group. Lira transiently increased heart rate and decreased BP in control rats. However, Lira did not modify BP but increased heart rate in PCOS. The angiotensin-converting-enzyme inhibitor enalapril abolished the BP differences between PCOS and control rats. However, Lira coadministration with enalapril further reduced BP only in control rats. In summary, Lira has beneficial effects for several cardiometabolic risk factors in postmenopausal PCOS. However, hyperandrogenemia blunted the BP-lowering effect of Lira in postmenopausal PCOS. Androgen-induced activation of intrarenal RAS may play a major role mediating increases in BP in postmenopausal PCOS.

YAP, but Not RSPO-LGR4/5, Signaling in Biliary Epithelial Cells Promotes a Ductular Reaction in Response to Liver Injury.

Biliary epithelial cells (BECs) form bile ducts in the liver and are facultative liver stem cells that establish a ductular reaction (DR) to support liver regeneration following injury. Liver damage induces periportal LGR5+ putative liver stem cells that can form BEC-like organoids, suggesting that RSPO-LGR4/5-mediated WNT/ß-catenin activity is important for a DR. We addressed the roles of this and other signaling pathways in a DR by performing a focused CRISPR-based loss-of-function screen in BEC-like organoids, followed by in vivo validation and single-cell RNA sequencing. We found that BECs lack and do not require LGR4/5-mediated WNT/ß-catenin signaling during a DR, whereas YAP and mTORC1 signaling are required for this process. Upregulation of AXIN2 and LGR5 is required in hepatocytes to enable their regenerative capacity in response to injury. Together, these data highlight heterogeneity within the BEC pool, delineate signaling pathways involved in a DR, and clarify the identity and roles of injury-induced periportal LGR5+ cells.

Glass confers rhabdomeric photoreceptor identity in Drosophila, but not across all metazoans.

Across metazoans, visual systems employ different types of photoreceptor neurons (PRs) to detect light. These include rhabdomeric PRs, which exist in distantly related phyla and possess an evolutionarily conserved phototransduction cascade. While the development of rhabdomeric PRs has been thoroughly studied in the fruit fly Drosophila melanogaster, we still know very little about how they form in other species. To investigate this question, we tested whether the transcription factor Glass, which is crucial for instructing rhabdomeric PR formation in Drosophila, may play a similar role in other metazoans. Glass homologues exist throughout the animal kingdom, indicating that this protein evolved prior to the metazoan radiation. Interestingly, our work indicates that glass is not expressed in rhabdomeric photoreceptors in the planarian Schmidtea mediterranea nor in the annelid Platynereis dumerilii. Combined with a comparative analysis of the Glass DNA-binding domain, our data suggest that the fate of rhabdomeric PRs is controlled by Glass-dependent and Glass-independent mechanisms in different animal clades.

Long-Lasting Androgen-Induced Cardiometabolic Effects in Polycystic Ovary Syndrome.

Polycystic ovary syndrome (PCOS), the most common endocrine disorder in women of reproductive age, is characterized by androgen excess and ovarian dysfunction and presents with increased cardiometabolic risk factors such as obesity, insulin resistance, and elevated blood pressure (BP). We previously reported that administration of dihydrotestosterone (DHT) to female rats elicits cardiometabolic derangements similar to those found in women with PCOS. In this study, we tested the hypothesis that the DHT-mediated cardiometabolic derangements observed in PCOS are long lasting despite DHT withdrawal. Four-week-old female Sprague Dawley rats were treated with DHT (7.5 mg/90 days) or placebo for 6 months. DHT was discontinued (ex-DHT), and rats were followed for 6 additional months. After 6 months of DHT withdrawal, food intake, body weight, fat and lean mass, fasting plasma insulin, leptin, and adiponectin were elevated in ex-DHT rats. BP remained significantly elevated, and enalapril, an angiotensin-converting enzyme (ACE) inhibitor, normalized BP in ex-DHT rats. Expression of components of the intrarenal renin-angiotensin system was increased in ex-DHT rats. The cardiometabolic features found in ex-DHT rats were associated with lower plasma androgen levels but increased expression of renal and adipose tissue androgen receptors. In summary, androgen-induced cardiometabolic effects persisted after DHT withdrawal in a PCOS experimental model. Activation of intrarenal renin-angiotensin system plays a major role in the androgen-mediated increase in BP in ex-DHT. Upregulation of the renal and adipose tissue androgen receptor may explain the long-lasting effects of androgens. In clinical scenarios characterized by hyperandrogenemia in women, prompt normalization of androgen levels may be necessary to prevent their long-lasting cardiometabolic effects.