Using Patient Blogs on Social Media to Assess the Content Validity of Patient-Reported Outcome Measures:Qualitative Analysis of Patient-Written Blogs

Background: Patient-reported outcome measures (PROMs) are questionnaires that measure patient outcomes related to quality of life, health, and functioning, and are increasingly used to assess important outcomes from the patient's perspective. For PROMs to contribute to better health and better care, it is vital that their content validity be adequate. This requires patient involvement in various steps of PROM development. PROM developers not only recognize the benefits of patient involvement but also report difficulties in recruiting patients and experience patient involvement as time-consuming, logistically challenging, and expensive. Objective: This study seeks to explore different strategies for disclosing the experiential knowledge of patients, namely through analyzing patient stories on the web and social media. The research questions are as follows: (1) how do bloggers living with a disease experience their health-related quality of life? (2) How are these experiences reflected in the domains and items of PROMs related to their disease? Methods: First, a qualitative analysis of blogs written by patients was performed. Second, subthemes and underlying codes resulting from this qualitative analysis were systematically compared with the domains and items in PROMs for the respective diseases that the bloggers write about. Blogs were identified via the Google search engine between December 2019 and May 2021. Results: Bloggers describe a wide range of experiences regarding their physical functioning and health; mental well-being; social network and support; daily life, education, work, and leisure; coping; and self-management. Bloggers also write about their positive and negative experiences with health care delivery, the organization of health care, and health care professionals. In general, patients' experiences as described in blogs were reflected in the domains and items of the PROMs related to their disease. However, except for diabetes mellitus, in all the sets of PROMs, potentially missing topics could be identified. Similarly, with the exception of Parkinson disease, all PROMs address issues that patients did not write about in their blogs and that might therefore be redundant. Conclusions: Web-based patient stories in the form of blogs reveal how people living with a certain disease experience their health-related quality of life. These stories enable analyses of patients' experiences that can be used to assess the content validity of PROMs. This can be a useful step for researchers who are looking for sets of measuring instruments that match their purposes.</p

Smokers’ responses to being addressed when smoking in an outdoor voluntary smoke-free zone:An observational study

INTRODUCTION: Addressing smokers who smoke in a voluntary smoke-free area is vital to its successful implementation. Many people perceive barriers in addressing smokers due to fear of negative responses. Insights in actual responses are currently lacking. METHODS: This is an observational field study at the voluntary smoke-free zone surrounding the Erasmus MC and two schools in Rotterdam, the Netherlands. In the first month after implementing the zone, Erasmus MC representatives performed rounds to address smokers who were smoking inside the zone. Four people observed addressors for two weeks then they also addressed the smokers. Smokers were classified as employees, patients, students, or other. We noted whether smokers were addressed directly or indirectly, and their verbal and behavioral responses to being addressed. Differences between the responses of the groups were assessed using chi-squared tests. RESULTS: In all, 331 smokers were observed of whom 73% were addressed directly. Most verbal reactions were positive (46%) or neutral (18%). Employees were more likely to respond guiltily, whereas patients more often responded angrily than the others. After being addressed, the majority of smokers either extinguished their cigarette (41%) or left to continue smoking outside the smoke-free zone (34%). CONCLUSIONS: Most smokers showed a positive or neutral response when being addressed about smoking inside the smoke-free zone and the majority adapted their behavior to comply with the policy. These findings may help decrease barriers for those in doubt about addressing smokers that fail to comply with a smoke-free policy

Preclinical characterization and target validation of the antimalarial pantothenamide MMV693183.

Drug resistance and a dire lack of transmission-blocking antimalarials hamper malaria elimination. Here, we present the pantothenamide MMV693183 as a first-in-class acetyl-CoA synthetase (AcAS) inhibitor to enter preclinical development. Our studies demonstrate attractive drug-like properties and in vivo efficacy in a humanized mouse model of Plasmodium falciparum infection. The compound shows single digit nanomolar in vitro activity against P. falciparum and P. vivax clinical isolates, and potently blocks P. falciparum transmission to Anopheles mosquitoes. Genetic and biochemical studies identify AcAS as the target of the MMV693183-derived antimetabolite, CoA-MMV693183. Pharmacokinetic-pharmacodynamic modelling predict that a single 30 mg oral dose is sufficient to cure a malaria infection in humans. Toxicology studies in rats indicate a \u3e 30-fold safety margin in relation to the predicted human efficacious exposure. In conclusion, MMV693183 represents a promising candidate for further (pre)clinical development with a novel mode of action for treatment of malaria and blocking transmission

Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy

AbstractDevelopmental epileptic encephalopathies are devastating disorders characterized by intractable epileptic seizures and developmental delay. Here, we report an allelic series of germline recessive mutations in UGDH in 36 cases from 25 families presenting with epileptic encephalopathy with developmental delay and hypotonia. UGDH encodes an oxidoreductase that converts UDP-glucose to UDP-glucuronic acid, a key component of specific proteoglycans and glycolipids. Consistent with being loss-of-function alleles, we show using patients’ primary fibroblasts and biochemical assays, that these mutations either impair UGDH stability, oligomerization, or enzymatic activity. In vitro, patient-derived cerebral organoids are smaller with a reduced number of proliferating neuronal progenitors while mutant ugdh zebrafish do not phenocopy the human disease. Our study defines UGDH as a key player for the production of extracellular matrix components that are essential for human brain development. Based on the incidence of variants observed, UGDH mutations are likely to be a frequent cause of recessive epileptic encephalopathy.</jats:p

Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy

Developmental epileptic encephalopathies are devastating disorders characterized by intractable epileptic seizures and developmental delay. Here, we report an allelic series of germline recessive mutations in UGDH in 36 cases from 25 families presenting with epileptic encephalopathy with developmental delay and hypotonia. UGDH encodes an oxidoreductase that converts UDP-glucose to UDP-glucuronic acid, a key component of specific proteoglycans and glycolipids. Consistent with being loss-of-function alleles, we show using patients’ primary fibroblasts and biochemical assays, that these mutations either impair UGDH stability, oligomerization, or enzymatic activity. In vitro, patient-derived cerebral organoids are smaller with a reduced number of proliferating neuronal progenitors while mutant ugdh zebrafish do not phenocopy the human disease. Our study defines UGDH as a key player for the production of extracellular matrix components that are essential for human brain development. Based on the incidence of variants observed, UGDH mutations are likely to be a frequent cause of recessive epileptic encephalopathy

Modifying effect of dual antiplatelet therapy on incidence of stent thrombosis according to implanted drug-eluting stent type

Aim To investigate the putative modifying effect of dual antiplatelet therapy (DAPT) use on the incidence of stent thrombosis at 3 years in patients randomized to Endeavor zotarolimus-eluting stent (E-ZES) or Cypher sirolimus-eluting stent (C-SES). Methods and results Of 8709 patients in PROTECT, 4357 were randomized to E-ZES and 4352 to C-SES. Aspirin was to be given indefinitely, and clopidogrel/ticlopidine for ≥3 months or up to 12 months after implantation. Main outcome measures were definite or probable stent thrombosis at 3 years. Multivariable Cox regression analysis was applied, with stent type, DAPT, and their interaction as the main outcome determinants. Dual antiplatelet therapy adherence remained the same in the E-ZES and C-SES groups (79.6% at 1 year, 32.8% at 2 years, and 21.6% at 3 years). We observed a statistically significant (P = 0.0052) heterogeneity in treatment effect of stent type in relation to DAPT. In the absence of DAPT, stent thrombosis was lower with E-ZES vs. C-SES (adjusted hazard ratio 0.38, 95% confidence interval 0.19, 0.75; P = 0.0056). In the presence of DAPT, no difference was found (1.18; 0.79, 1.77; P = 0.43). Conclusion A strong interaction was observed between drug-eluting stent type and DAPT use, most likely prompted by the vascular healing response induced by the implanted DES system. These results suggest that the incidence of stent thrombosis in DES trials should not be evaluated independently of DAPT use, and the optimal duration of DAPT will likely depend upon stent type (Clinicaltrials.gov number NCT00476957

Ultrathin Bioresorbable Polymer Sirolimus-Eluting Stents Versus Thin Durable Polymer Everolimus-Eluting Stents

BACKGROUND: Coronary drug-eluting stent development has introduced new metal alloys, changes in stent architecture, and bioresorbable polymers. Whether these advancements improve long-term clinical safety and efficacy has been inconsistent in prior studies. OBJECTIVES: The authors sought to compare late-term clinical outcomes among patients treated with an ultrathin strut (60 μm) bioresorbable polymer sirolimus-eluting stent (BP SES) and a thin strut (81 μm) durable polymer everolimus-eluting stent (DP EES) in a large randomized trial. METHODS: BIOFLOW V (Biotronik Prospective Randomized Multicenter Study to Assess the Safety and Effectiveness of the Orsiro Sirolimus Eluting Coronary Stent System in the Treatment of Subjects with Up to Three De Novo or Restenotic Coronary Artery Lesions V) was an international randomized trial comparing coronary revascularization with BP SES and DP EES regarding the primary endpoint of 12-month target lesion failure (TLF). Analysis of pre-specified 2-year clinical outcomes was performed. RESULTS: Among 1,334 patients randomized to treatment with BP SES (n = 884) or DP EES (n = 450), the 2-year TLF rate was 7.5% for BP SES and 11.9% for DP EES (-4.33% treatment difference; 95% confidence interval: -8.16% to -0.91%; p = 0.015), driven by differences in target vessel myocardial infarction (MI) (5.3% vs. 9.5%; p = 0.01) and ischemia-driven target lesion revascularization (2.6% vs. 4.9%; p = 0.04). Rates of cardiac death or MI were 7.0% versus 10.4% for BP SES and DP EES, respectively (p = 0.047). Late/very late definite stent thrombosis was statistically lower for BP SES compared with DP EES (0.1% vs. 1.0%; p = 0.045). CONCLUSIONS: In a large randomized trial, significant differences in both TLF and target vessel-related MI persisted through 2 years, favoring treatment with BP SES over DP EES. Significantly lower cumulative target lesion revascularization and late/very late stent thrombosis were also observed with BP SES. (Safety and Effectiveness of the Orsiro Sirolimus Eluting Coronary Stent System in Subjects With Coronary Artery Lesions [BIOFLOW-V]; NCT02389946).status: publishe

Effects of the Moderate CYP3A4 Inhibitor Erythromycin on the Pharmacokinetics of Palbociclib: A Randomized Crossover Trial in Patients With Breast Cancer

Palbociclib is an oral inhibitor of cyclin-dependent kinases 4 and 6 used in the treatment of locally advanced and metastatic breast cancer, and is extensively metabolized by cytochrome P450 enzyme 3A4 (CYP3A4). A pharmacokinetic/pharmacodynamic relationship between palbociclib exposure and neutropenia is well known. This study aimed to investigate the effects of the moderate CYP3A4 inhibitor erythromycin on the pharmacokinetics of palbociclib. We performed a randomized crossover trial comparing the pharmacokinetics of palbociclib monotherapy 125 mg once daily (q.d.) with palbociclib 125 mg q.d. plus oral erythromycin 500 mg three times daily for seven days. Pharmacokinetic sampling was performed at steady-state for both dosing schedules. Eleven evaluable patients have been enrolled. For palbociclib monotherapy, geometric mean area under the plasma concentration-time curve from zero to infinity (AUC0–24h), maximum plasma concentration (Cmax), and minimum plasma concentration (Cmin) were 1.46 × 103 ng•h/mL (coefficient of variation (CV) 45.0%), 80.5 ng/mL (CV 48.5%), and 48.4 ng/mL (CV 38.8%), respectively, compared with 2.09 × 103 ng•h/mL (CV 49.3%, P = 0.000977), 115 ng/mL (CV 53.7%, P = 0.00562), and 70.7 ng/mL (CV 47.5%, P = 0.000488) when palbociclib was administered concomitantly with erythromycin. Geometric mean ratios (90% confidence intervals) of AUC0–24h, Cmax, and Cmin for palbociclib plus erythromycin vs. palbociclib monotherapy were 1.43 (1.24–1.66), 1.43 (1.20–1.69), and 1.46 (1.30–1.63). Minor differences in adverse events were observed, and only one grade ≥ 3 toxicity was observed in this short period of time. To conclude, concomitant intake of palbociclib with the moderate CYP3A4 inhibitor erythromycin resulted in an increase in palbociclib AUC0–24h and Cmax of both 43%. Therefore, a dose reduction of palbociclib to 75 mg q.d. is rational, when palbociclib and moderate CYP3A4 inhibitors are used concomitantly