The comorbidity profiles and medication issues of patients with multiple system atrophy: a systematic cross-sectional analysis.

BACKGROUND: Multiple system atrophy (MSA) is a complex and fatal neurodegenerative movement disorder. Understanding the comorbidities and drug therapy is crucial for MSA patients' safety and management. OBJECTIVES: To investigate the pattern of comorbidities and aspects of drug therapy in MSA patients. METHODS: Cross-sectional data of MSA patients according to Gilman et al. (2008) diagnostic criteria and control patients without neurodegenerative diseases (non-ND) were collected from German, multicenter cohorts. The prevalence of comorbidities according to WHO ICD-10 classification and drugs administered according to WHO ATC system were analyzed. Potential drug-drug interactions were identified using AiDKlinik®. RESULTS: The analysis included 254 MSA and 363 age- and sex-matched non-ND control patients. MSA patients exhibited a significantly higher burden of comorbidities, in particular diseases of the genitourinary system. Also, more medications were prescribed MSA patients, resulting in a higher prevalence of polypharmacy. Importantly, the risk of potential drug-drug interactions, including severe interactions and contraindicated combinations, was elevated in MSA patients. When comparing MSA-P and MSA-C subtypes, MSA-P patients suffered more frequently from diseases of the genitourinary system and diseases of the musculoskeletal system and connective tissue. CONCLUSIONS: MSA patients face a substantial burden of comorbidities, notably in the genitourinary system. This, coupled with increased polypharmacy and potential drug interactions, highlights the complexity of managing MSA patients. Clinicians should carefully consider these factors when devising treatment strategies for MSA patients.

The comorbidity and co-medication profile of patients with progressive supranuclear palsy.

BACKGROUND: Progressive supranuclear palsy (PSP) is usually diagnosed in elderly. Currently, little is known about comorbidities and the co-medication in these patients. OBJECTIVES: To explore the pattern of comorbidities and co-medication in PSP patients according to the known different phenotypes and in comparison with patients without neurodegenerative disease. METHODS: Cross-sectional data of PSP and patients without neurodegenerative diseases (non-ND) were collected from three German multicenter observational studies (DescribePSP, ProPSP and DANCER). The prevalence of comorbidities according to WHO ICD-10 classification and the prevalence of drugs administered according to WHO ATC system were analyzed. Potential drug-drug interactions were evaluated using AiDKlinik®. RESULTS: In total, 335 PSP and 275 non-ND patients were included in this analysis. The prevalence of diseases of the circulatory and the nervous system was higher in PSP at first level of ICD-10. Dorsopathies, diabetes mellitus, other nutritional deficiencies and polyneuropathies were more frequent in PSP at second level of ICD-10. In particular, the summed prevalence of cardiovascular and cerebrovascular diseases was higher in PSP patients. More drugs were administered in the PSP group leading to a greater percentage of patients with polypharmacy. Accordingly, the prevalence of potential drug-drug interactions was higher in PSP patients, especially severe and moderate interactions. CONCLUSIONS: PSP patients possess a characteristic profile of comorbidities, particularly diabetes and cardiovascular diseases. The eminent burden of comorbidities and resulting polypharmacy should be carefully considered when treating PSP patients.

What do older patients know about their medication? A cross-sectional, interview-based pilot study.

PURPOSE: This study sought to analyze the medication knowledge and awareness of medication adjustment options during intercurrent illness (sick day rules) of patients ≥ 70 years treated at a hospital for geriatric medicine in northern Germany. METHODS: The study was designed as a cross-sectional, interview-based pilot study, was approved by the Ethics Committee of Hannover Medical School (No. 10274_BO_K_2022; date of approval: 11 March 2022), and enrolled a convenience sample of 100 patients between May and December 2022. RESULTS: The median of the average medication knowledge score in the study population (median age 82 years (IQR 75-87); 71% female) was 5 on a scale from 0 to 6 (IQR 3.8-5.6). Women achieved higher average medication knowledge scores than men (median 5.1 (IQR 4-5.6) vs. median 4.3 (IQR 3.6-5.1); p = 0.012), and patients < 80 years achieved higher average medication knowledge scores than patients ≥ 80 years (median 5.4 (IQR 4.9-5.7) vs. median 4.3 (IQR 3.2-5.3); p < 0.001). Sick day rules were known for only 1.1% of drugs for which sick day rules were applicable. Fifty-two percent of the patients reported that their general practitioner contributed most to their medication knowledge, and 66% considered their daily number of drugs to take adequate. CONCLUSION: Our study showed that medication knowledge of older patients was overall satisfying. Awareness of sick day rules, however, was poor. Future studies should evaluate the clinical benefits of sick day rules and ways of better communicating sick day rules to patients. In this regard, general practitioners may play a decisive role.

Patient Safety in a Box: Implementation and Evaluation of the Emergency Box in Geriatric and Parkinson Patients.

In an industrial society, the proportion of geriatric people increases with rising age. These people are likely to use polypharmacy and experience medical emergencies. However, their emergency care can be complicated by unclear comorbidities and medication. The aim of this prospective interventional study was to assess the demand for a drug safety tool in clinical practice and to analyze whether the emergency box can improve acute care in a geriatric cohort. Therefore, emergency room (ER) doctors in a German tertiary hospital recorded the number of geriatric patients lacking medical information and its impact on diagnostics/treatment. Furthermore, the emergency box was distributed to patients on the neurological ward and their current drug safety concepts were assessed. After 6 months, we evaluated in a follow-up whether the tool was helpful in emergency cases. Our study revealed that 27.4% (n = 28) of the patients came to the ER without their medical information, which caused a relevant delay or possible severe complications in 11.8% (n = 12). The emergency box was perceived as easily manageable and 87.9% (n = 109) of the participants wanted to keep it after the study. Subjectively, participants benefitted in emergencies. In conclusion, the emergency box is a cheap tool that is easy to use. It can save valuable time in emergencies and increases the safety of geriatric patients.

Validation of the Parkinson's Disease Caregiver Burden Questionnaire in Progressive Supranuclear Palsy.

Progressive supranuclear palsy (PSP) is an atypical Parkinson syndrome with axial akinetic-rigid symptoms, early postural instability, and ocular motor impairments. Patients experience a rapid loss of autonomy and care dependency; thus, caregivers must assist in the activities of daily living early in the course of the disease. Caregiver burden is an extremely important factor in disease management. However, there are no specific questionnaires for assessment of caregiver burden in PSP. This study aims to validate the Parkinson's disease caregiver burden questionnaire (PDCB) as a specific measure of caregiver burden in PSP. PSP patients were assessed by the PSP rating scale, PSP quality-of-life questionnaire (PSP-QoL), Montreal cognitive assessment test (MoCA), and geriatric depression scale (GDS-15). Caregivers filled out the short form 36-health survey, GDS-15, PDCB, and the caregiver burden inventory (CBI). 22 patient caregiver pairs completed the study. PDCB showed a highly significant correlation with the CBI (r 0.911; p < 0.001). Internal reliability of the PDCB measured by Cronbach's alpha was favourable at 0.803. These data support the specificity of the PDCB in PSP caregivers. Future studies with larger sample sizes of PSP patients and caregivers and a multicentric longitudinal design should be performed to gain further insight of caregiver burden in PSP.

Advanced Single-Cell Mapping Reveals that in hESC Cardiomyocytes Contraction Kinetics and Action Potential Are Independent of Myosin Isoform.

Human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) represent an attractive model to investigate CM function and disease mechanisms. One characteristic marker of ventricular specificity of human CMs is expression of the ventricular, slow ß-myosin heavy chain (MyHC), as opposed to the atrial, fast α-MyHC. The main aim of this study was to investigate at the single-cell level whether contraction kinetics and electrical activity of hESC-CMs are influenced by the relative expression of α-MyHC versus ß-MyHC. For effective assignment of functional parameters to the expression of both MyHC isoforms at protein and mRNA levels in the very same hESC-CMs, we developed a single-cell mapping technique. Surprisingly, α- versus ß-MyHC was not related to specific contractile or electrophysiological properties of the same cells. The multiparametric cell-by-cell analysis suggests that in hESC-CMs the expression of genes associated with electrical activity, contraction, calcium handling, and MyHCs is independently regulated.

Mindfulness and Psychological Flexibility are Inversely Associated with Caregiver Burden in Parkinson's Disease.

Parkinson's disease (PD) is a neurodegenerative movement disorder with progressive impairments in activities of daily living. With disease progression, people with PD (PwP) need more help and care from their spouses or professional caregivers. Identifying factors that help caregivers to cope with their burden is needed to frame future interventions for PwP caregivers. Mindfulness and psychological flexibility might be factors contributing to resilience against the burden of giving care. In this cross-sectional questionnaire-based study, 118 PwP and their respective primary caregivers were included. Caregivers reported moderate burden and only mild depressive symptoms. Mindfulness measured by the Mindfulness Attention and Awareness scale (p 0.003) and psychological flexibility measured by Acceptance and Actions Questionnaire II (p0.001) correlated negatively with caregiver burden. Data from this study indicate mindfulness and psychological flexibility are factors contributing to resilience against caregiver burden. Future interventions to reduce burden in PwP caregivers might be improved by the inclusion of mindfulness training programs.

Safety and Tolerability of Pharmacotherapies for Parkinson's Disease in Geriatric Patients.

Parkinson's disease is a chronic neurodegenerative movement disorder affecting people mainly beyond their 50s. Geriatric patients with Parkinson's disease experience a specific profile of comorbidities. Multimorbidity and resulting polypharmacotherapy are frequent at this age. Comorbid diseases, widely spread, involve arterial hypertension, ischemic heart disease, heart failure, atrial fibrillation, polyneuropathy, diabetes mellitus, cerebrovascular disease, sarcopenia, and frailty. Following years of drug development, levodopa is still the most effective drug for the treatment of motor symptoms. However, a wide range of other drugs are available with specific effects, contraindications, and complications. The treatment of geriatric patients with Parkinson's disease is challenging and requires the cooperation of multidisciplinary teams. A careful assessment of a patient's Parkinson's disease symptoms, comorbidities, medication, vital signs, and resources is crucial for an effective and safe therapy. Laboratory tests can assist in the identification of contraindications for specific treatments. Identifying potentially inadequate drugs from prescription lists can lead to a better targeted treatment for geriatric patients with Parkinson's disease. Future research should help develop a more evidence-based therapy of geriatric patients with Parkinson's disease. For this purpose, randomized controlled trials of geriatric patients are urgently needed. An international register concerning issues of safer drug application and monitoring could help to implement a better treatment.

Differences in Contractile Function of Myofibrils within Human Embryonic Stem Cell-Derived Cardiomyocytes vs. Adult Ventricular Myofibrils Are Related to Distinct Sarcomeric Protein Isoforms.

Characterizing the contractile function of human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) is key for advancing their utility for cellular disease models, promoting cell based heart repair, or developing novel pharmacological interventions targeting cardiac diseases. The aim of the present study was to understand whether steady-state and kinetic force parameters of ß-myosin heavy chain (ßMyHC) isoform-expressing myofibrils within human embryonic stem cell-derived cardiomyocytes (hESC-CMs) differentiated in vitro resemble those of human ventricular myofibrils (hvMFs) isolated from adult donor hearts. Contractile parameters were determined using the same micromechanical method and experimental conditions for both types of myofibrils. We identified isoforms and phosphorylation of main sarcomeric proteins involved in the modulation of force generation of both, chemically demembranated hESC-CMs (d-hESC-CMs) and hvMFs. Our results indicate that at saturating Ca2+ concentration, both human-derived contractile systems developed forces with similar rate constants (0.66 and 0.68 s-1), reaching maximum isometric force that was significantly smaller for d-hESC-CMs (42 kPa) than for hvMFs (94 kPa). At submaximal Ca2+-activation, where intact cardiomyocytes normally operate, contractile parameters of d-hESC-CMs and hvMFs exhibited differences. Ca2+ sensitivity of force was higher for d-hESC-CMs (pCa50 = 6.04) than for hvMFs (pCa50 = 5.80). At half-maximum activation, the rate constant for force redevelopment was significantly faster for d-hESC-CMs (0.51 s-1) than for hvMFs (0.28 s-1). During myofibril relaxation, kinetics of the slow force decay phase were significantly faster for d-hESC-CMs (0.26 s-1) than for hvMFs (0.21 s-1), while kinetics of the fast force decay were similar and ~20x faster. Protein analysis revealed that hESC-CMs had essentially no cardiac troponin-I, and partially non-ventricular isoforms of some other sarcomeric proteins, explaining the functional discrepancies. The sarcomeric protein isoform pattern of hESC-CMs had features of human cardiomyocytes at an early developmental stage. The study indicates that morphological and ultrastructural maturation of ßMyHC isoform-expressing hESC-CMs is not necessarily accompanied by ventricular-like expression of all sarcomeric proteins. Our data suggest that hPSC-CMs could provide useful tools for investigating inherited cardiac diseases affecting contractile function during early developmental stages.

Stiff matrix induces switch to pure ß-cardiac myosin heavy chain expression in human ESC-derived cardiomyocytes.

Human pluripotent stem cell (hPSC)-derived cardiomyocytes hold great potential for in vitro modeling of diseases like cardiomyopathies. Yet, knowledge about expression and functional impact of sarcomeric protein isoforms like the myosin heavy chain (MyHC) in hPSC-cardiomyocytes is scarce. We hypothesized that ventricular ß-MyHC expression alters contraction and calcium kinetics and drives morphological and electrophysiological differentiation towards ventricular-like cardiomyocytes. To address this, we (1) generated human embryonic stem cell-derived cardiomyocytes (hESC-CMs) that switched towards exclusive ß-MyHC, and (2) functionally and morphologically characterized these hESC-CMs at the single-cell level. MyHC-isoforms and functional properties were investigated during prolonged in vitro culture of cardiomyocytes in floating cardiac bodies (soft conditions) vs. culture on a stiff matrix. Using a specific anti-ß-MyHC and a newly generated anti-α-MyHC-antibody, we found individual cardiomyocytes grown in cardiac bodies to mostly express both α- and ß-MyHC-protein isoforms. Yet, 35 and 75 days of cultivation on laminin-coated glass switched 66 and 87 % of all cardiomyocytes to exclusively express ß-MyHC, respectively. Twitch contraction and calcium transients were faster for CMs on laminin-glass. Surprisingly, both parameters were only little affected by the MyHC-isoform, although hESC-CMs with only ß-MyHC had much lower ATP-turnover and tension cost, just as in human ventricular cardiomyocytes. Spontaneous contractions and no strict coupling of ß-MyHC to ventricular-like action potentials suggest that MyHC-isoform expression does not fully determine the hESC-CM differentiation status. Stiff substrate-induced pure ß-MyHC-protein expression in hESC-CMs, with several contractile parameters close to ventricular cardiomyocytes, provides a well-defined in vitro system for modeling of cardiomyopathies and drug screening approaches.