Long-term Healthcare Resource Utilization and Costs among Patients with Myasthenia Gravis: A Swedish Nationwide Population-based Study.

INTRODUCTION: Health care costs and societal impact of myasthenia gravis (MG), a potentially life-threatening rare, chronic neuromuscular disease are sparsely studied. We assessed healthcare resource utilization (HCRU) and associated costs among patients with newly diagnosed (ND) and pre-existing (PE) MG in Sweden. METHODS: This observational, retrospective cohort study used data from four linkable Swedish nationwide population-based registries. Adult MG patients receiving pharmacological treatment for MG and having ≥ 24-month follow-up during the period 1/1/2010 to 12/31/2017 were included. RESULTS: A total of 1,275 patients were included in the analysis, of which 554 patients were categorized into the ND MG group and 721 into the PE MG group. Mean (±SD) age was 61.3 (±17.4) years and 52.3% were female. In first year post-diagnosis, ND patients had significantly higher utilization of acetylcholinesterase inhibitors (96.0% vs 83.9%), corticosteroids (59.6% vs 45.8%), thymectomy (12.1% vs 0.7%) and plasma exchange (3.8% vs 0.6%); had higher all-cause (70.9% vs 35.8%) and MG-related (62.5% vs 18.4%) hospitalization rates with 11 more hospitalization days (all p<0.01) and an increased risk of hospitalization (odds ratio [95% CI] = 4.4 [3.43, 5.64]) than PE MG. In year 1 post-diagnosis, ND MG patients incurred €7302 (p<0.01) higher total all-cause costs than PE MG, of which 84% were estimated to be MG-related and the majority (86%) were related to inpatient care. These results remained significant also after controlling for baseline demographics and comorbidities (p<0.01). In year 2 post-diagnosis, the all-cause medical costs decreased by ~55% for ND MG from year 1 and were comparable with PE MG. CONCLUSION: In this population-based study, MG patients required significantly more healthcare resources in year 1 post-diagnosis than PE MG primarily due to more pharmacological treatments, thymectomies and associated hospitalizations. These findings highlight the need to better understand potential factors including disease characteristics associated with increased health resource use and costs and need for more efficacious treatments early in the disease course.

Effect of Concomitant Benzodiazepine Use on Efficacy and Safety of Esketamine Nasal Spray in Patients with Major Depressive Disorder and Acute Suicidal Ideation or Behavior: Pooled Randomized, Controlled Trials.

PURPOSE: The impact of benzodiazepines on the efficacy and safety of esketamine as a rapid-acting antidepressant remains unclear. MATERIALS AND METHODS: Data from two identically designed, randomized double-blind studies were pooled and analyzed on a post-hoc basis. In both studies, adults with major depressive disorder with acute suicidal ideation or behavior were randomized to placebo or esketamine 84 mg nasal spray twice-weekly for 4 weeks, each with comprehensive standard-of-care (initial hospitalization and newly initiated or optimized oral antidepressant[s]). Efficacy and safety were analyzed in two groups based on whether patients used concomitant benzodiazepines, which were prohibited within 8 hours before and 4 hours after the first dose of esketamine and within 8 hours of the primary efficacy assessment at 24 hours. The primary efficacy endpoint - change from baseline to 24 hours post-first dose in Montgomery-Asberg Depression Rating Scale (MADRS) total score - was analyzed using ANCOVA. RESULTS: Most patients (309/451, 68.5%) used concomitant benzodiazepines. Greater decrease in MADRS total score was observed with esketamine (mean [SD]: -16.1 [11.73]) versus placebo (-12.6 [10.56]) at 24 hours (least-squares mean difference: -3.7, 95% CI: -5.76, -1.59). The differences between the esketamine and placebo groups were clinically meaningful, irrespective of benzodiazepine use (benzodiazepine: -4.3 [-6.63, -1.89]; no benzodiazepine: -3.1 [-6.62, 0.45]). Among patients taking esketamine, change in MADRS total score was not significantly different between patients taking benzodiazepines (-15.8 [11.27]) versus those not taking benzodiazepines (-16.8 [12.82]) (least-squares mean difference: 1.1, [-2.24, 4.45]). Among esketamine-treated patients, the incidence of sedation was higher with benzodiazepine use, whereas dissociation was similar. CONCLUSION: Benzodiazepines do not meaningfully affect the rapid-acting antidepressant effect of esketamine at 24 hours post-first dose among patients with MDD and acute suicidal ideation or behavior.

Incremental Health Care Burden of Treatment-Resistant Depression Among Commercial, Medicaid, and Medicare Payers.

OBJECTIVE: This study compared health care use and costs among patients with treatment-resistant versus treatment-responsive depression across Medicaid, Medicare, and commercial payers. METHODS: A retrospective cohort study was conducted by using Truven Health Analytics' commercial (2006-2017; N=111,544), Medicaid (2007-2017; N=24,036), and Medicare supplemental (2006-2017; N=8,889) claims databases. Participants were adults with major depressive disorder who had received one or more antidepressant treatments. Treatment resistance was defined as failure of two or more antidepressant treatments of adequate dose and duration. Annual use (hospitalizations and outpatient and emergency department [ED] visits) and costs were compared across patients by treatment-resistant status in each payer population. Incremental burden of treatment-resistant depression was estimated with regression analyses. Monthly changes in costs during 1-year follow-up were assessed to understand differential cost trends by treatment-resistant status. RESULTS: In the three payer populations, patients with treatment-resistant depression incurred higher health care utilization than those with treatment-responsive depression (hospitalization, odds ratios [ORs]=1.32-1.76; ED visits, ORs=1.38-1.45; outpatient visits, incident rate ratio=1.29-1.54; p<0.001 for all). Compared with those with treatment-responsive depression, those with treatment resistance incurred higher annual costs (from $4,093 to $8,054 higher; p<0.001). Patients with treatment-resistant depression had higher costs at baseline compared with patients with treatment-responsive depression and incurred higher costs each month throughout follow-up. CONCLUSIONS: Treatment-resistant depression imposes a significant health care burden on insurers. Treatment-resistant depression may exist and affect health care burden before a patient is identified as having treatment-resistant depression. Findings underscore the need for effective and timely treatment of treatment-resistant depression.

Improved prediction of poor outcome after thrombolysis using conservative definitions of symptomatic hemorrhage.

BACKGROUND AND PURPOSE: Direct comparison of symptomatic intracerebral hemorrhage (sICH) rates among different thrombolysis studies is complicated by the variability of definitions of sICH. The prediction of outcome still remains unclear. METHODS: Baseline data and clinical courses of patients treated with thrombolytic therapy were collected in a prospective database. The 3-month outcome was evaluated using the modified Rankin Scale. Results of 24-hour follow-up imaging were reevaluated by at least 2 independent raters. Four common definitions of sICH (National Institute of Neurological Disorders and Stroke [NINDS], European Cooperative Acute Stroke Study [ECASS] 2, Safe Implementation of Thrombolysis in Stroke [SITS], ECASS 3) were applied. Kappa interrater statistics were calculated. Our objective was to find the sICH definition with the highest predictive value for mortality, poor (modified Rankin Scale 5 or 6) and unfavorable (modified Rankin Scale ≥3) clinical outcome after 90 days. RESULTS: The data of 314 patients were analyzed. The NINDS definition revealed the highest sICH rate (7.7%); the lowest rate was found for the ECASS 3 definition (3.2%) of sICH. The highest interrater agreement was found for the ECASS 2 definition (κ 0.85) and the lowest for the NINDS definition (κ 0.57). Patients with sICH according to the SITS definition had the highest risk for death (OR, 14.4) and poor outcome (OR, 26.6). CONCLUSIONS: None of the different definitions contains an optimal combination of prediction of mortality and outcome and a high interrater agreement rate. For the clinical evaluation of mortality, we recommend using the SITS definition; for studies needing a high interrater agreement rate, we recommend using the ECASS 2 definition. Due to the lack of 1 single optimal definition, future thrombolytic trials should preferably use different definitions.

Low hemoglobin is associated with poor functional outcome after non-traumatic, supratentorial intracerebral hemorrhage.

INTRODUCTION: The impact of anemia on functional outcome and mortality in patients suffering from non-traumatic intracerebral hemorrhage (ICH) has not been investigated. Here, we assessed the relationship between hemoglobin (HB) levels and clinical outcome after ICH. METHODS: One hundred and ninety six patients suffering from supratentorial, non-traumatic ICH were extracted from our local stroke database (June 2004 to June 2006). Clinical and radiologic computed tomography data, HB levels on admission, mean HB values and nadir during hospital stay were recorded. Outcome was assessed at discharge and 3 months using the modified Rankin score (mRS). RESULTS: Forty six (23.5%) patients achieved a favorable functional outcome (mRS

Aquaporin-4 antibody positive longitudinally extensive transverse myelitis following varicella zoster infection.

Longitudinally extensive transverse myelitis (LETM) is a condition shown to confer high risk of conversion into neuromyelitis optica (NMO). Increasing evidence from immunological and histopathological studies suggests that LETM is an autoimmune disorder caused by pathogenic antibodies to aquaporin-4 (AQP4-Ab), the most abundant water channel in the CNS, at least in a subset of patients. However, cases of infectious or parainfectious NMO/LETM (mostly associated with herpes zoster) have been repeatedly reported in the previous literature, raising the question of aetiological diversity in NMO/LETM. Here we present a case of acute LETM in a 63-year-old patient occurring two weeks after reactivation of varicella zoster virus (VZV). Serological testing revealed antibodies to AQP4. Plasma exchange was paralleled by disappearance of AQP4-Ab and sustained clinical improvement. Our observations provide further evidence for a pathogenic role of AQP4-Ab in LETM and suggest that AQP4-Ab associated auto-immunity should be considered also in apparently infectious/parainfectious settings.

Hypoxia decreases cellular ATP demand and inhibits mitochondrial respiration of a549 cells.

Hypoxia inhibits activity and expression of transporters involved in alveolar Na reabsorption and fluid clearance. We studied whether this represents a mechanism for reducing energy consumption or whether it is the consequence of metabolic dysfunction. Oxygen consumption (JO2) of A549 cells and primary rat alveolar type II cells was measured by microrespirometry during normoxia, hypoxia (1.5% O2), and reoxygenation. In both cell types, acute and 24-h hypoxia decreased total JO2 significantly and reoxygenation restored JO2 after 5 min but not after 24 h of hypoxia in A549 cells, whereas recovery was complete in type II cells. In A549 cells under normoxia Na/K-ATPase accounted for approximately 15% of JO2, whereas Na/K-ATPase-related JO2 was decreased by approximately 25% in hypoxia. Inhibition of other ion transporters did not affect JO2. Protein synthesis-related JO2 was not affected by acute hypoxia, but decreased by 30% after 24-h hypoxia. Acute and 24-h hypoxia decreased JO2 of A549 cell mitochondrial complexes I, II, and III by 30-40%. Reoxygenation restored complex I activity after acute hypoxia but not after 24-h hypoxia. ATP was decreased 30% after 24-h hypoxia, but lactate production rate was not affected. Reduced nicotinamine adenine dinucleotide was slightly elevated in acute hypoxia. Our findings indicate that inhibition of the Na/K-ATPase by hypoxia contributes little to energy preservation in hypoxia. It remains unclear to what extent hypoxic inhibition of mitochondrial metabolism affects ATP-consuming processes.