Neurosarcoidosis: Phenotypes, Approach to Diagnosis and Treatment.

PURPOSE OF REVIEW: The aim of this review is to provide an update of clinical presentation, diagnosis, differential diagnoses, and treatment according to recent evidence. RECENT FINDINGS: Neurosarcoidosis remains a diagnosis of exclusion, with infectious and malignant etiologies recognized as important mimickers. Corticosteroids remain as first-line therapy. In recent years, however, studies have demonstrated the effectiveness of anti-tumor necrosis factor (anti-TNF) therapy in the treatment of neurosarcoidosis, leading to improved outcomes. Neurosarcoidosis is a granulomatous disease with protean manifestations that may affect any part of the central and peripheral nervous system. It has many mimickers, and potentially devastating complications necessitating long-term follow-up. Early initiation of treatment, particularly with anti-TNF therapy, may lead to better outcomes and fewer relapses. There is an unmet need for randomized controlled trials that provide robust data to guide therapy and the long-term management of neurosarcoidosis patients.

Efficacy of Combination Therapy with the JAK Inhibitor Baricitinib in the Treatment of COVID-19.

Coronavirus disease-19 (COVID-19), resulting from infection with SARS-CoV-2, spans a wide spectrum of illness. In severely ill patients, highly elevated serum levels of certain cytokines and considerable cytolytic T cell infiltrates in the lungs have been observed. These same patients may bear low to negligible viral burdens suggesting that an overactive immune response, often termed cytokine storm, contributes to the severity of COVID-19. We report the safety and efficacy of baricitinib combined with remdesivir and dexamethasone in a retrospective review of 45 hospitalized patients with COVID-19 pneumonia at a tertiary academic medical center. Patients received 7-day course of baricitinib, 5-day course of remdesivir, and 10-day course of dexamethasone. Clinical status and biomarkers were obtained daily. Outcomes assessed include mortality, duration of hospitalization, presence of shock, need for supplemental oxygen, need for non-invasive ventilation, need for mechanical ventilation, and development of thrombosis. Obesity and multiple medical comorbidities were associated with hospitalization in the setting of COVID-19. Treated patients demonstrated rapid declines of C-reactive protein (CRP), ferritin and D-dimer with gradual improvement in hemoglobin, platelet counts, and clinical status. Only 2 of 45 (4.4%) treated patients required mechanical ventilation after initiating treatment, and there were six deaths (13.3%). Only 2 of 45 (4.4%) treated patients required mechanical ventilation after initiating treatment. There were six deaths (13.3%) and these were associated with lower BMI. These findings support the utility of immunosuppression via JAK inhibition in moderate to severe COVID-19 pneumonia. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s42399-022-01121-4.

Efficacy of Combination Therapy With The JAK Inhibitor Baricitinib In The Treatment of COVID-19.

BACKGROUND: Coronavirus disease-19 (COVID-19), resulting from infection with SARS-CoV-2, spans a wide spectrum of illness. In severely ill patients, highly elevated serum levels of certain cytokines and considerable cytolytic T cell infiltrates in the lungs have been observed. These same patients may bear low to negligible viral burdens suggesting that an overactive immune response, often termed cytokine storm, contributes to the severity of COVID-19. We report the safety and efficacy of baricitinib combined with remdesivir and dexamethasone in 45 hospitalized patients with COVID-19 pneumonia at a tertiary academic medical center. METHODS: Retrospective review of 45 patients hospitalized with COVID-19 pneumonia. Patients received 7-day course of baricitinib, 5-day course of remdesivir and 10-day course of dexamethasone. Clinical status and biomarkers were obtained daily. Outcomes assessed include mortality, duration of hospitalization, presence of shock, need for supplemental oxygen, need for non-invasive ventilation, need for mechanical ventilation and development of thrombosis. RESULTS: Obesity and multiple medical comorbidities were associated with hospitalization in the setting of COVID-19. Treated patients demonstrated rapid declines of C-reactive protein (CRP), ferritin and D-dimer with gradual improvement in hemoglobin, platelet counts and clinical status. Only 2 of 45 (4.4%) treated patients required mechanical ventilation after initiating treatment and there were six deaths (13.3%).Only 2 of 45 (4.4%) treated patients required mechanical ventilation after initiating treatment. There were six deaths (13.3%) and these were associated with lower BMI. CONCLUSIONS: These findings support the utility of immunosuppression via JAK inhibition in moderate to severe COVID-19 pneumonia.

Defining the Resident Continuity Clinic Panel Along Patient Outcomes: a Health Equity Opportunity.

BACKGROUND: Continuity clinics are a critical component of outpatient internal medicine training. Little is known about the population of patients cared for by residents and how these physicians perform. OBJECTIVES: To compare resident and faculty performance on standard population health measures. To identify potential associations with differences in performance, specifically medical complexity, psychosocial vulnerability, and rates of patient loss. SETTING AND PARTICIPANTS: Large academic primary care clinic caring for 40,000 patients. One hundred ten internal medicine residents provide primary care for 9,000 of these patients; the remainder are cared for by faculty. STUDY DESIGN: Descriptive analysis using review of the medical record and hospital administrative data. MAIN MEASURES: We compared resident and faculty performance on standard population health measures, including cancer screening rates, chronic disease care, acute and chronic medical complexity, psychosocial vulnerability, and rates of patient loss. We evaluated the success of resident transition by measuring rates of kept continuity visits 18 months after graduation. KEY RESULTS: Performance on all clinical outcomes was significantly better for faculty compared to residents. Despite similar levels of medical complexity compared to faculty patients, resident patients had significantly higher levels of psychosocial vulnerability across all measured domains, including health literacy, economic vulnerability, psychiatric illness burden, high-risk behaviors, and patient engagement. Resident patients experienced higher rates of patient loss than faculty patients (38.5 vs. 18.8%) with only 46.5% of resident patients with a kept continuity appointment in the practice 18 months after graduation. CONCLUSIONS: In this large academic practice, resident performance on standard population health measures was significantly lower than faculty. This may be explained in part by the burden of psychosocial vulnerability of their patients and systems that do not effectively transition patients after graduation. These findings present an opportunity to improve structural equity for these vulnerable patients and developing physicians.

TULA-2 Protein Phosphatase Suppresses Activation of Syk through the GPVI Platelet Receptor for Collagen by Dephosphorylating Tyr(P)346, a Regulatory Site of Syk.

Protein-tyrosine phosphatase TULA-2 has been shown to regulate receptor signaling in several cell types, including platelets. Platelets are critical for maintaining vascular integrity; this function is mediated by platelet aggregation in response to recognition of the exposed basement membrane collagen by the GPVI receptor, which is non-covalently associated with the signal-transducing FcRγ polypeptide chain. Our previous studies suggested that TULA-2 plays an important role in negatively regulating signaling through GPVI-FcRγ and indicated that the tyrosine-protein kinase Syk is a key target of the regulatory action of TULA-2 in platelets. However, the molecular basis of the down-regulatory effect of TULA-2 on Syk activation via FcRγ remained unclear. In this study, we demonstrate that suppression of Syk activation by TULA-2 is mediated, to a substantial degree, by dephosphorylation of Tyr(P)346, a regulatory site of Syk, which becomes phosphorylated soon after receptor ligation and plays a critical role in initiating the process that yields fully activated Syk. TULA-2 is capable of dephosphorylating Tyr(P)346 with high efficiency, thus controlling the overall activation of Syk, but is less efficient in dephosphorylating other regulatory sites of this kinase. Therefore, dephosphorylation of Tyr(P)346 may be considered an important "checkpoint" in the regulation of Syk activation process. Putative biological functions of TULA-2-mediated dephosphorylation of Tyr(P)346 may include deactivation of receptor-activated Syk or suppression of Syk activation by suboptimal stimulation.