The natural history of primary progressive multiple sclerosis: insights from the German NeuroTransData registry.

BACKGROUND: Primary progressive multiple sclerosis (PPMS) is characterised by gradual worsening of disability from symptom onset. Knowledge about the natural course of PPMS remains limited. METHODS: PPMS patients from the German NeuroTransData (NTD) MS registry with data from 56 outpatient practices were employed for retrospective cross-sectional and longitudinal analyses. The cross-sectional analysis included a contemporary PPMS cohort with a documented visit within the last 2 years before index date (1 Jan 2021). The longitudinal analysis included a disease modifying therapy (DMT)-naïve population and focused on the evolution of expanded disability status scale (EDSS) from the first available assessment at or after diagnosis within the NTD registry to index date. Outcome measures were estimated median time from first EDSS assessment to first 24-week confirmed EDSS ≥ 4 and ≥ 7. Besides EDSS change, the proportion of patients on disability pension were described over time. RESULTS: The cross-sectional analysis included 481 PPMS patients (59.9% female, mean [standard deviation, SD] age 60.5 [11.5] years, mean [SD] EDSS 4.9 [2.1]). Estimated median time from first EDSS assessment after diagnosis to reach 24-week confirmed EDSS ≥ 4 for DMT-naïve patients was 6.9 years. Median time to EDSS ≥ 7 was 9.7 years for 25% of the population. Over a decade mean (SD) EDSS scores increased from 4.6 (2.1) to 5.7 (2.0); the proportion of patients on disability pension increased from 18.9% to 33.3%. CONCLUSIONS: This study provides first insights into the German NTD real-world cohort of PPMS patients. Findings confirm the steadily deteriorating course of PPMS accompanied by increasingly limited quality of life.

Outcomes of a Delirium Prevention Program in Older Persons After Elective Surgery: A Stepped-Wedge Cluster Randomized Clinical Trial.

Importance: Delirium significantly worsens elective surgery outcomes and costs. Delirium risk is highest in elderly populations, whose surgical health care resource consumption (50%) exceeds their demographic proportion (15% to 18%) in high-resource countries. Effective nonpharmacologic delirium prevention could safely improve care in these vulnerable patients, but data from procedure-specific studies are insufficiently compelling to drive changes in practice. Delirium prevention approaches applicable to different surgical settings remain unexplored. Objective: To examine whether a multifaceted prevention intervention is effective in reducing postoperative delirium incidence and prevalence after various major surgical procedures. Design, Setting, and Participants: This stepped-wedge cluster randomized trial recruited 1470 patients 70 years and older undergoing elective orthopedic, general, or cardiac surgery from November 2017 to April 2019 from 5 German tertiary medical centers. Data were analyzed from December 2019 to July 2021. Interventions: First, structured delirium education was provided to clinical caregivers at each site. Then, the study delirium prevention team assessed patient delirium risk factors and symptoms daily. Prevention was tailored to individual patient needs and could include: cognitive, motor, and sensory stimulation; meal companionship; accompaniment during diagnostic procedures; stress relaxation; and sleep promotion. Main Outcomes and Measures: Postoperative delirium incidence and duration. Results: Of 1470 included patients, 763 (51.9%) were male, and the median (IQR) age was 77 (74-81) years. Overall, the intervention reduced postoperative delirium incidence (odds ratio, 0.87; 95% CI, 0.77-0.98; P = .02) and percentage of days with delirium (intervention, 5.3%; control, 6.9%; P = .03). The effect was significant in patients undergoing orthopedic or abdominal surgery (odds ratio, 0.59; 95% CI, 0.35-0.99; P = .047) but not cardiac surgery (odds ratio, 1.18; 95% CI, 0.70-1.99; P = .54). Conclusions and Relevance: This multifaceted multidisciplinary prevention intervention reduced postoperative delirium occurrence and days with delirium in older patients undergoing different elective surgical procedures but not cardiac procedures. These results suggest implementing this delirium prevention program will improve care and outcomes in older patients undergoing elective general and orthopedic procedures.

Non-genomic effects of androgens on isolated human vascular and nonvascular penile erectile tissue.

OBJECTIVES: To evaluate non-genomic effects of testosterone and dihydrotestosterone (DHT) on isolated human cavernosal arteries (HCA) and corpus cavernosum (HCC) using organ-bath studies and radio-immunoassays (RIA), as non-genomic effects of androgens are reported for vascular smooth musculature and there is evidence that the relaxant response involves a modulation of cyclic nucleotide tissue levels. MATERIALS AND METHODS: The relaxation induced by the cumulative addition of testosterone and DHT (0.01-10 microm) was studied using circular segments of HCA and strip preparations of HCC. To evaluate the effects of testosterone and DHT on tissue levels of cAMP and cGMP, specimens were exposed to increasing concentrations of the hormones. Forskolin and sodium nitroprusside (SNP) served as reference compounds. RESULTS: Testosterone and DHT dose-dependently reversed the noradrenaline-induced tension of vascular segments and HCC strips. At the maximum concentration, testosterone and DHT reduced the mean (sd) tension to 79.8 (4.43)% and 83.9 (10.94)%, respectively. SNP and forskolin significantly stimulated the production of cGMP and cAMP. No effects of testosterone and DHT on cGMP and cAMP levels were detected. CONCLUSION: Rapid androgen-induced relaxation of HCA and HCC occurs via non-genomic mechanisms. In penile erectile tissue, non-genomic relaxant effects of testosterone and DHT are not mediated via modulation of cyclic nucleotide tissue levels. Additional studies are required to establish if non-genomic relaxant effects are important in ensuring a basal level of perfusion to maintain overall penile function.