Factors determining social participation in the first year after kidney transplantation: a prospective study

BACKGROUND: This study describes changes in social participation in the first year after kidney transplantation and examines the influence of clinical factors, health status, transplantation-related symptoms, and psychological characteristics on change in social participation. METHODS: A prospective study was performed on a cohort of primary kidney transplant recipients, transplanted between March 2002 and March 2003. Data on participation in obligatory activities (i.e., employment, education, household tasks) and leisure activities (i.e., volunteer work, assisting others, sports, clubs/associations, recreation, socializing, going out) were collected by in-home interviews (n=61) at 3 months (T1) and 1 year posttransplantation (T2). Analysis of covariance was performed. RESULTS: Data showed an increase in participation in obligatory activities and diversity of leisure participation between T1 and T2, although pre-end-stage renal disease level was not regained and differed from the general population. On T1, the majority of employed recipients were on sick leave, but returned to work on T2. Employment rate remained stable. An increase in obligatory participation was predicted by clinical factors (i.e., peritoneal dialysis, initial hospitalization), whereas change in leisure participation was related to serum albumin and cognitive capacity. No effects were found for type of donation, comorbidity, and renal function. CONCLUSIONS: We found that mainly clinical factors were associated with an increase in participation in society. Although health-status related factors and the psychological attribute self-efficacy may be related to recovery of social participation, their effect was outweighed by the strength of clinical predictors in multivariate analysis

Formation of Millisecond Pulsars from Accretion Induced Collapse and Constraints on Pulsar Gamma Ray Burst Models

We study accretion induced collapse of magnetized white dwarfs as an origin of millisecond pulsars. We apply magnetized accretion disk models to the pre-collapse accreting magnetic white dwarfs and calculate the white dwarf spin evolution. If the pulsar magnetic field results solely from the flux-frozen fossil white dwarf field, a typical millisecond pulsar is born with a field strength $\sim 10^{11}-10^{12}G$. The uncertainty in the field strength is mainly due to the uncertain physical parameters of the magnetized accretion disk models. A simple correlation between the pulsar spin $\Omega_*$ and the magnetic field $B_*$, $(\Omega_*/10^4s^{-1})\sim (B_{*}/10^{11}G)^{-4/5}$, is derived for a typical accretion rate \sim 5\times 10^{-8}M_{\sun}/yr. This correlation remains valid for a wide pre-collapse physical conditions unless the white dwarf spin and the binary orbit are synchronized prior to accretion induced collapse. We critically examine the possibility of spin-orbit synchronization in close binary systems. Using idealized homogeneous ellipsoid models, we compute the electromagnetic and gravitational wave emission from the millisecond pulsars and find that electromagnetic dipole emission remains nearly constant while millisecond pulsars may spin up rather than spin down as a result of gravitational wave emission. We also derive the physical conditions under which electromagnetic emission from millisecond pulsars formed by accretion induced collapse can be a source of cosmological gamma-ray bursts. We find that relativistic beaming of gamma-ray emission and precession of gamma-ray emitting jets are required unless the dipole magnetic field strengths are $>10^{15}$G; such strong dipole fields are in excess of those allowed from the accretion induced collapse formation process except in spin-orbit synchronization.Comment: 36 pages, AASLATEX, 4 ps figures, Ap

TRIM33 switches off Ifnb1 gene transcription during the late phase of macrophage activation

Despite its importance during viral or bacterial infections, transcriptional regulation of the interferon-β gene (Ifnb1) in activated macrophages is only partially understood. Here we report that TRIM33 deficiency results in high, sustained expression of Ifnb1 at late stages of toll-like receptor-mediated activation in macrophages but not in fibroblasts. In macrophages, TRIM33 is recruited by PU.1 to a conserved region, the Ifnb1 Control Element (ICE), located 15 kb upstream of the Ifnb1 transcription start site. ICE constitutively interacts with Ifnb1 through a TRIM33-independent chromatin loop. At late phases of lipopolysaccharide activation of macrophages, TRIM33 is bound to ICE, regulates Ifnb1 enhanceosome loading, controls Ifnb1 chromatin structure and represses Ifnb1 gene transcription by preventing recruitment of CBP/p300. These results characterize a previously unknown mechanism of macrophage-specific regulation of Ifnb1 transcription whereby TRIM33 is critical for Ifnb1 gene transcription shutdown

A Systematic Evaluation of Cost-Saving Dosing Regimens for Therapeutic Antibodies and Antibody-Drug Conjugates for the Treatment of Lung Cancer

Background: Expensive novel anticancer drugs put a serious strain on healthcare budgets, and the associated drug expenses limit access to life-saving treatments worldwide. Objective: We aimed to develop alternative dosing regimens to reduce drug expenses. Methods: We developed alternative dosing regimens for the following monoclonal antibodies used for the treatment of lung cancer: amivantamab, atezolizumab, bevacizumab, durvalumab, ipilimumab, nivolumab, pembrolizumab, and ramucirumab; and for the antibody-drug conjugate trastuzumab deruxtecan. The alternative dosing regimens were developed by means of modeling and simulation based on the population pharmacokinetic models developed by the license holders. They were based on weight bands and the administration of complete vials to limit drug wastage. The resulting dosing regimens were developed to comply with criteria used by regulatory authorities for in silico dose development. Results: We found that alternative dosing regimens could result in cost savings that range from 11 to 28%, and lead to equivalent pharmacokinetic exposure with no relevant increases in variability in exposure. Conclusions: Dosing regimens based on weight bands and the use of complete vials to reduce drug wastage result in less expenses while maintaining equivalent exposure. The level of evidence of our proposal is the same as accepted by regulatory authorities for the approval of alternative dosing regimens of other monoclonal antibodies in oncology. The proposed alternative dosing regimens can, therefore, be directly implemented in clinical practice.</p

Pulmonary artery pressure monitoring in chronic heart failure:effects across clinically relevant subgroups in the MONITOR-HF trial

Background and Aims:In patients with chronic heart failure (HF), the MONITOR-HF trial demonstrated the efficacy of pulmonary artery (PA)-guided HF therapy over standard of care in improving quality of life and reducing HF hospitalizations and mean PA pressure. This study aimed to evaluate the consistency of these benefits in relation to clinically relevant subgroups. Methods: The effect of PA-guided HF therapy was evaluated in the MONITOR-HF trial among predefined subgroups based on age, sex, atrial fibrillation, diabetes mellitus, left ventricular ejection fraction, HF aetiology, cardiac resynchronization therapy, and implantable cardioverter defibrillator. Outcome measures were based upon significance in the main trial and included quality of life-, clinical-, and PA pressure endpoints, and were assessed for each subgroup. Differential effects in relation to the subgroups were assessed with interaction terms. Both unadjusted and multiple testing adjusted interaction terms were presented. Results: The effects of PA monitoring on quality of life, clinical events, and PA pressure were consistent in the predefined subgroups, without any clinically relevant heterogeneity within or across all endpoint categories (all adjusted interaction P-values were non-significant). In the unadjusted analysis of the primary endpoint quality-of-life change, weak trends towards a less pronounced effect in older patients (Pinteraction = .03; adjusted Pinteraction = .33) and diabetics (Pinteraction = .01; adjusted Pinteraction = .06) were observed. However, these interaction effects did not persist after adjusting for multiple testing. Conclusions: This subgroup analysis confirmed the consistent benefits of PA-guided HF therapy observed in the MONITOR-HF trial across clinically relevant subgroups, highlighting its efficacy in improving quality of life, clinical, and PA pressure endpoints in chronic HF patients.</p

Serial cardiac biomarkers, pulmonary artery pressures and traditional parameters of fluid status in relation to prognosis in patients with chronic heart failure:Design and rationale of the BioMEMS study

AimsHeart failure (HF), a global pandemic affecting millions of individuals, calls for adequate predictive guidance for improved therapy. Congestion, a key factor in HF-related hospitalizations, further underscores the need for timely interventions. Proactive monitoring of intracardiac pressures, guided by pulmonary artery (PA) pressure, offers opportunities for efficient early-stage intervention, since haemodynamic congestion precedes clinical symptoms.MethodsThe BioMEMS study, a substudy of the MONITOR-HF trial, proposes a multifaceted approach integrating blood biobank data with traditional and novel HF parameters. Two additional blood samples from 340 active participants in the MONITOR-HF trial were collected at baseline, 3-, 6-, and 12-month visits and stored for the BioMEMS biobank. The main aims are to identify the relationship between temporal biomarker patterns and PA pressures derived from the CardioMEMS-HF system, and to identify the biomarker profile(s) associated with the risk of HF events and cardiovascular death.ConclusionSince the prognostic value of single baseline measurements of biomarkers like N-terminal pro-B-type natriuretic peptide is limited, with the BioMEMS study we advocate a dynamic, serial approach to better capture HF progression. We will substantiate this by relating repeated biomarker measurements to PA pressures. This design rationale presents a comprehensive review on cardiac biomarkers in HF, and aims to contribute valuable insights into personalized HF therapy and patient risk assessment, advancing our ability to address the evolving nature of HF effectively.Design and rationale of the BioMEMS study. QoL, quality of life. Graphical abstract is created with BioRender.com imag

Use of Sodium Thiosulfate as an Otoprotectant in Patients With Cancer Treated With Platinum Compounds: A Review of the Literature

PURPOSE Hearing loss occurs in 50%-70% of children treated with cisplatin. Scientific efforts have led to the recent approval of a pediatric formula of intravenous sodium thiosulfate (STS) for otoprotection by the US Food and Drug Administration, the European Medicines Agency, and the Medicines and Health Regulatory Authority in the United Kingdom. To inform stakeholders regarding the clinical utility of STS, the current review summarizes available literature on the efficacy, pharmacokinetics (PK), and safety of systemic STS to minimize cisplatin-induced hearing loss (CIHL). DESIGN A comprehensive narrative review is presented. RESULTS Thirty-one articles were summarized. Overall, systemic STS effectively reduces CIHL in the preclinical and controlled clinical study settings, in both adults and children with cancer. The extent of CIHL reduction depends on the timing and dosing of STS in relation to cisplatin. Both preclinical and clinical data suggest that systemic STS may affect plasma platinum levels, but studies are inconclusive. Delayed systemic administration of STS, at 6 hours after the cisplatin infusion, does not affect cisplatin-induced inhibition of tumor growth or cellular cytotoxicity in the preclinical setting, nor affect cisplatin efficacy and survival in children with localized disease in the clinical setting. CONCLUSION Systemic administration of STS effectively reduces the development and degree of CIHL in both the preclinical and clinical settings. More studies are needed on the PK of STS and cisplatin drug combinations, the efficacy and safety of STS in patients with disseminated disease, and the ability of STS to prevent further deterioration of pre-established hearing loss

A Comprehensive Study of Neutron Star Retention in Globular Clusters

(abridged) Observations of very high speeds among pulsars in the Galactic disk present a puzzle regarding neutron stars in globular clusters. The inferred characteristic speed of single pulsars in the Galaxy is $\sim 5-10$ times as large as the central escape speed from the most massive globular clusters. It is then reasonable to ask why any pulsars are seen in globular clusters, whereas, in fact, quite a large number have been detected and as many as $\sim 1000$ are thought to be present in some of the richest clusters. We use a Monte Carlo approach to generate a population of massive primordial binaries. If we utilize the convention assumptions regarding mass transfer and neutron star kicks, we find that < 5% of the neutron stars initially formed in a massive cluster can be retained. We suggest that this fraction is too low to account for what is observed, and we speculate on possible alternative solutions to the retention problem

A New Class of High-Mass X-ray Binaries: Implications for Core Collapse and Neutron-Star Recoil

We investigate an interesting new class of high-mass X-ray binaries (HMXBs) with long orbital periods (P_orb > 30 days) and low eccentricities (e <~ 0.2). The orbital parameters suggest that the neutron stars in these systems did not receive a large impulse, or ``kick,'' at the time of formation. We develop a self-consistent phenomenological picture wherein the neutron stars born in the observed wide HMXBs receive only a small kick (<~ 50 km/s), while neutron stars born in isolation, in the majority of low-mass X-ray binaries, or in many of the well-known HMXBs with P_orb <~ 30 days receive the conventional large kicks, with a mean speed of ~ 300 km/s. We propose that the magnitude of the natal kick to a neutron star born in a binary system depends on the rotation rate of the pre-collapse core. We further suggest that the rotation rate of the core is a strong, well-defined function of the evolutionary path of the progenitor star.Comment: 13 pages, 5 figures (2 color), submitted to Ap

Developmental course of conversational behaviour of children with 22q11.2 deletion syndrome and Williams syndrome

This study investigated three conversational subskills in children with 22q11.2 deletion syndrome (22q11.2DS, n = 8, ages 7–13) and Williams syndrome (WS, n = 8, ages 6–12). We re-evaluated these subskills after 18 to 24 months and compared them to those of peers with idiopathic intellectual disability (IID) and IID and comorbid autism spectrum disorders (IID+ASD). Children with 22q11.2DS became less actively involved over time. Lower assertiveness than in children with IID was demonstrated. They seemed less impaired in terms of accounting for listener’s knowledge than children with IID+ASD. Children with WS showed greater difficulties with discourse management compared to children with IID and 22q11.2DS. They had similar levels of conversational impairments to children with IID+ASD but these were caused by different shortcomings. Over time taking account of listener’s knowledge became challenging for them. Findings suggest that children with 22q11.2DS and those with WS would benefit from conversational skills support and that regular re-evaluation is needed to anticipate conversational challenges