Impact of flight route changes on cosmic ray exposure: consequences of the conflict between Ukraine and the Russian federation.

This work investigates the impact on cosmic ray exposures to aircrew due to changing flight routes operated in the context of the recent conflict between Ukraine and the Russian Federation. All analyses were done based on Paris-Tokyo and Tokyo-Paris flights taken as examples, and differences in radiation exposures were quantified by comparing the situation before and after the beginning of the conflict. Regarding space weather scenarios, a quiet solar period and an extreme solar event (ground level enhancement (GLE) 5) were considered in the study. Analyses showed that the new Paris-Tokyo flight route established after the beginning of the conflict results in a smaller radiation dose to aircrew than that operated before the conflict, particularly during solar events. In contrast, for Tokyo-Paris flights the new high-latitude route crossing the Atlantic Ocean and North America increases the dose significantly (+ 50% in the worst case). Although this analysis is limited only to flights connecting Paris and Tokyo, it allowed for an evaluation of the consequences of new routes (particularly polar ones) on ambient dose equivalent values.

Identifying Medicine Shortages With the Twitter Social Network: Retrospective Observational Study.

BACKGROUND: Early identification is critical for mitigating the impact of medicine shortages on patients. The internet, specifically social media, is an emerging source of health data. OBJECTIVE: This study aimed to explore whether a routine analysis of data from the Twitter social network can detect signals of a medicine shortage and serve as an early warning system and, if so, for which medicines or patient groups. METHODS: Medicine shortages between January 31 and December 1, 2019, were collected from the Dutch pharmacists' society's national catalog Royal Dutch Pharmacists Association (KNMP) Farmanco. Posts on these shortages were collected by searching for the name, the active pharmaceutical ingredient, or the first word of the brand name of the medicines in shortage. Posts were then selected based on relevant keywords that potentially indicated a shortage and the percentage of shortages with at least 1 post was calculated. The first posts per shortage were analyzed for their timing (median number of days, including the IQR) versus the national catalog, also stratified by disease and medicine characteristics. The content of the first post per shortage was analyzed descriptively for its reporting stakeholder and the nature of the post. RESULTS: Of the 341 medicine shortages, 102 (29.9%) were mentioned on Twitter. Of these 102 shortages, 18 (5.3% of the total) were mentioned prior to or simultaneous to publication by KNMP Farmanco. Only 4 (1.2%) of these were mentioned on Twitter more than 14 days before. On average, posts were published with a median delay of 37 (IQR 7-81) days to publication by KNMP Farmanco. Shortages mentioned on Twitter affected a greater number of patients and lasted longer than those that were not mentioned. We could not conclusively relate either the presence or absence on Twitter to a disease area or route of administration of the medicine in shortage. The first posts on the 102 shortages were mainly published by patients (n=51, 50.0%) and health care professionals (n=46, 45.1%). We identified 8 categories of nature of content. Sharing personal experience (n=44, 43.1%) was the most common category. CONCLUSIONS: The Twitter social network is not a suitable early warning system for medicine shortages. Twitter primarily echoes already-known information rather than spreads new information. However, Twitter or potentially any other social media platform provides the opportunity for future qualitative research in the increasingly important field of medicine shortages that investigates how a larger population of patients is affected by shortages.

[Role of social medicine within the German Federal Employment Agency]. / Aufgabe des Arztes in der Sozialmedizin am Beispiel der Bundesagentur für Arbeit.

Social medicine deals with the interrelationships between health and society-as a cross-sectional subject within medicine and a bridging subject at the interfaces to other specialist disciplines. In the public and within the health system, social medicine still does not receive the attention it should be given, despite to its medical and socioeconomic importance. A significant proportion of social medicine specialists in Germany work as experts for social security providers. Using the example of the Medical Specialist Service ("Ärztlichen Dienstes", ÄD) of the German Federal Employment Agency ("Bundesagentur für Arbeit", BA), the medical tasks in social medicine are outlined. About 350 full-time medical employees nationwide as well as other contracted physicians support the specialists of the employment agencies and job centers to integrate those seeking training, jobs and employees with health restrictions into the labor market or maintaining an existing integration. In each individual case, they assess the extent of the health restrictions, the performance/earning ability, the suitability for training and professions as well as the requirement and type of vocational rehabilitation services. The ÄD's approximately 500,000 expert opinions each year are not only of far-reaching importance for the BA's affected customers, but also contribute to the responsible, effective, and accurate use of social system resources.

Successes and pitfalls in orphan drug development for sickle cell disease.

ABSTRACT: Sickle cell disease (SCD) is a hereditary red cell disorder with a large disease burden at a global level. In the United States and Europe, medicines may qualify for orphan designation (OD), a regulatory status that provides incentives to boost development. We evaluated the development of new therapies for SCD using data for OD granted in the United States and Europe over the last 2 decades (2000-2021). We analyzed their characteristics, pathophysiological targets, trends, and OD sponsors. We then investigated the approval outcomes, including the phase success rate and reasons for discontinuation across different variables. We identified 57 ODs for SCD: 43 (75.4%) small molecules, 32 (56.1%) for oral administration, and 36 (63.1%) for chronic use to prevent SCD complications. At the end of the study (2021), development of 34 of 57 ODs was completed. Four ODs were approved with a success rate of 11.8%. Products targeting upstream causative events of SCD pathophysiology had a 1.8 higher success rate compared with products targeting disease consequences. Large companies showed a fourfold higher success rate compared with small-medium enterprises. Failures in clinical development were mainly seen in phase 3 for a lack of efficacy on vaso-occlusive crisis as the primary study end point, likely related to variable definitions and heterogeneity of pain scoring and treatment. Both advances in SCD knowledge and regulatory incentives paved the way for new therapies for SCD. Our finding of high failure rates in late-stage clinical development signals the need for better early-stage predictive models, also in the context of meaningful clinical end points.

The Evolution of Drug Regulatory Sciences in the Netherlands: More than a Country Report.

In the Netherlands, drug regulatory science is a vibrant national and internationally oriented community. In this review, we present the factors that have contributed to this successful collaboration between relevant stakeholders and that led to a surge of activities around how regulatory science became embedded in the ecosystem of medicines research, clinical pharmacology, policymaking and regulation. We distinguished three pivotal episodes: (i) TI Pharma Escher-project, (ii) Dutch Medicines Evaluation Board as catalyst of the big jump, and (iii) Regulatory Science Network Netherlands and multistakeholder engagement. The research agenda has been influenced by the dynamic evolution of legal frameworks in Europe, such as the EU orphan medicines legislation of 2001 and the EU pharmacovigilance legislation of 2012. All these developments have inspired and have raised pertinent regulatory sciences questions. Furthermore, clinical pharmacology as a discipline has been very influential in shaping regulatory science, contributing to discussions on the level of clinical evidence that is necessary to justify marketing approval of a new medicine. With a growing interest of multiple parties such as academics, European Medicines Agency, national agencies, patient organizations and EFPIA, connecting regulatory science activities is key.

High-Density Lipoprotein Particles and Torque Teno Virus in Stable Outpatient Kidney Transplant Recipients.

Torque teno virus (TTV) is emerging as a potential marker for monitoring immune status. In transplant recipients who are immunosuppressed, higher TTV DNA loads are observed than in healthy individuals. TTV load measurement may aid in optimizing immunosuppressive medication dosing in solid organ transplant recipients. Additionally, there is a growing interest in the role of HDL particles in immune function; therefore, assessment of both HDL concentrations and TTV load may be of interest in transplant recipients. The objective of this study was to analyze TTV loads and HDL parameters in serum samples collected at least one year post-transplantation from 656 stable outpatient kidney transplant recipients (KTRs), enrolled in the TransplantLines Food and Nutrition Cohort (Groningen, the Netherlands). Plasma HDL particles and subfractions were measured using nuclear magnetic resonance spectroscopy. Serum TTV load was measured using a quantitative real-time polymerase chain reaction. Associations between HDL parameters and TTV load were examined using univariable and multivariable linear regression. The median age was 54.6 [IQR: 44.6 to 63.1] years, 43.3% were female, the mean eGFR was 52.5 (±20.6) mL/min/1.73 m2 and the median allograft vintage was 5.4 [IQR: 2.0 to 12.0] years. A total of 539 participants (82.2%) had a detectable TTV load with a mean TTV load of 3.04 (±1.53) log10 copies/mL, the mean total HDL particle concentration was 19.7 (±3.4) µmol/L, and the mean HDL size was 9.1 (±0.5) nm. The univariable linear regression revealed a negative association between total HDL particle concentration and TTV load (st.ß = -0.17, 95% CI st.ß: -0.26 to -0.09, p < 0.001). An effect modification of smoking behavior influencing the association between HDL particle concentration and TTV load was observed (Pinteraction = 0.024). After adjustment for age, sex, alcohol intake, hemoglobin, eGFR, donor age, allograft vintage and the use of calcineurin inhibitors, the negative association between HDL particle concentration and TTV load remained statistically significant in the non-smoking population (st.ß = -0.14, 95% CI st.ß: -0.23 to -0.04, p = 0.006). Furthermore, an association between small HDL particle concentration and TTV load was found (st.ß = -0.12, 95% CI st.ß: -0.22 to -0.02, p = 0.017). Higher HDL particle concentrations were associated with a lower TTV load in kidney transplant recipients, potentially indicative of a higher immune function. Interventional studies are needed to provide causal evidence on the effects of HDL on the immune system.

Smoking, Alcohol Intake and Torque Teno Virus in Stable Kidney Transplant Recipients.

Torque Teno Virus (TTV) is a non-pathogenic virus that is highly prevalent among kidney transplant recipients (KTRs). Its circulating load is associated with an immunological status in KTR and is considered a promising tool for guiding immunosuppression. To allow for optimal guidance, it is important to identify other determinants of TTV load. We aimed to investigate the potential association of smoking and alcohol intake with TTV load. For this cross-sectional study, serum TTV load was measured using PCR in stable kidney transplant recipients at ≥1 year after transplantation, and smoking status and alcohol intake were assessed through questionnaires and measurements of urinary cotinine and ethyl glucuronide. A total of 666 KTRs were included (57% male). A total of 549 KTR (82%) had a detectable TTV load (3.1 ± 1.5 log10 copies/mL). In KTR with a detectable TTV load, cyclosporin and tacrolimus use were positively associated with TTV load (St. ß = 0.46, p < 0.001 and St. ß = 0.66, p < 0.001, respectively), independently of adjustment for potential confounders. Current smoking and alcohol intake of >20 g/day were negatively associated with TTV load (St. ß = -0.40, p = 0.004 and St. ß = -0.33, p = 0.009, respectively), independently of each other and of adjustment for age, sex, kidney function, time since transplantation and calcineurin inhibitor use. This strong association of smoking and alcohol intake with TTV suggests a need to account for the smoking status and alcohol intake when applying TTV guided immunosuppression in KTR.

Humoral and cellular immune responses after COVID-19 vaccination of lung transplant recipients and patients on the waiting list: a 6-month follow-up.

Background: Data on cellular response and the decay of antibodies and T cells in time are scarce in lung transplant recipients (LTRs). Additionally, the development and durability of humoral and cellular immune responses have not been investigated in patients on the waitlist for lung transplantation (WLs). Here, we report our 6-month follow-up of humoral and cellular immune responses of LTRs and WLs, compared with controls. Methods: Humoral responses to two doses of the mRNA-1273 vaccination were assessed by determining spike (S)-specific IgG antibodies and neutralizing antibodies. Cellular responses were investigated by interferon gamma (IFN-γ) release assay (IGRA) and IFN-γ ELISpot assay at 28 days and 6 months after the second vaccination. Results: In LTRs, the level of antibodies and T-cell responses was significantly lower at 28 days after the second vaccination. Also, WLs had lower antibody titers and lower T-cell responses compared with controls. Six months after the second vaccination, all groups showed a decrease in antibody titers and T-cell responses. In WLs, the rate of decline of neutralizing antibodies and T-cell responses was significantly higher than in controls. Conclusion: Our results show that humoral and cellular responses in LTRs, if they develop, decrease at rates comparable with controls. In contrast, the inferior cellular responses and the rapid decay of both humoral and cellular responses in the WL groups imply that WLs may not be protected adequately by two vaccinations and repeat boostering may be necessary to induce protection that lasts beyond the months immediately post-transplantation.