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Abstract Background Despite recent advances, optimal therapeutic approaches applicable to subpopulations with primary central nervous system (CNS) lymphoma outside of clinical trials remain to be determined. Methods We performed a retrospective study of immunocompetent, adult patients with histologically confirmed diffuse large B‐cell lymphoma of the CNS (PCNSL). 190/204 (93%) patients (median age: 65) received one of five high‐dose methotrexate (HD‐MTX) containing chemotherapy regimens: MPV/Ara‐C (HD‐MTX, procarbazine, and vincristine, followed by cytarabine [Ara‐C]) (n = 94, 50%), MATRix (HD‐MTX, Ara‐C, thiotepa, and rituximab) (n = 19, 10%), HD‐MTX/Ara‐C (n = 31, 16%), HD‐MTX monotherapy (n = 35, 18%) and MBVP (HD‐MTX, carmustine, teniposide, prednisolone) (n = 11, 6%). Results Cumulative median HD‐MTX and Ara‐C doses were 17 g/m2 (range: 1–64 g/m2) and 12 g/m2 (0–32 g/m2) respectively. Using 14 g/m2 as the reference dose, the median HD‐MTX relative dose intensity (HD‐MTX‐RDI) was 1.25 (0.27‐4.57) with 84% receiving > 0.75. The overall response rate (ORR) was 72% (complete response: 50%) after completing HD‐MTX. At a median follow‐up of 3.41 years (0.06–9.42), progression‐free survival (PFS) and overall survival (OS) were different between chemotherapy cohorts, with the best outcomes achieved in the MPV/Ara‐C cohort (2‐year PFS 74%, 2‐year OS 82%; p = 0.0001 and p = 0.0024 respectively). On multivariate analysis, MPV/Ara‐C administration and HD‐MTX‐RDI > 0.75 were associated with longer PFS and OS. Conclusion Sequential, response‐adapted approaches can improve outcomes, even in older patients who are ineligible for a high‐intensity concurrent chemotherapy approach and do not undergo traditional consolidative strategies.

Introduction: High dropout and low treatment attendance rates among patients with posttraumatic stress disorder (PTSD) and personality disorders (PDs) continue to pose a significant challenge. Despite numerous studies focusing on enhancing treatment attendance, the identification of consistent and reliable predictors in patients with PTSD and comorbid PDs remains limited. Objectives: This study aims to investigate a wide range of potential predictors of treatment attendance, encompassing demographic, patient-severity, treatment, and therapist-related variables in patients with PTSD and comorbid borderline and/or cluster C PDs. Methods: Utilizing data from 255 patients participating in two randomized controlled trials comparing trauma-focused treatment with or without concurrent PD treatment, candidate predictors were individually analyzed in univariate regression models. Significant predictors were then combined in a multiple ordinal regression model. Results: In total, 40% of patients attended fewer trauma-focused treatment sessions than the minimum recommended in treatment guidelines. Out of the 38 candidate predictors examined, five significant, independent predictors of treatment attendance emerged in a multiple ordinal regression model. Higher baseline PTSD severity (OR = 1.04, p = .036), higher education level (OR = 1.22, p = .009) and a stronger patient-rated working alliance (OR = 1.72, p = .047) with the therapist predicted higher treatment attendance. Conversely, inadequate social support from friends (OR = 0.90, p = .042) and concurrent PD treatment and trauma-focused treatment (OR = 0.52, p = .022) were associated with lower treatment attendance. Conclusions: In conclusion, this constitutes the first study investigating predictors of treatment attendance in patients with PTSD and comorbid PDs. The results highlight the complexity of pinpointing reliable predictors. Nevertheless, the identification of five predictors provides valuable insights, aiding clinicians in customizing treatment strategies for individual patients and enhancing overall treatment attendance.

Objectives: In March 2023, all societal-level COVID-19 control measures were lifted by the Dutch government. This study was performed to understand the self-experienced burden of this new phase of COVID-19 on the perspectives and behaviors of severely immunocompromised individuals. Methods: This is an observational, descriptive, cross-sectional study in The Netherlands. An online survey was completed by severely immunocompromised individuals, to capture their general well-being (score from 1 = worst to 10 = best), mental and physical health, and daily and social activities during survey conduct and retrospectively for before onset of COVID-19. The survey was open for completion from May 24th until August 7nd, 2023. Results: Of the 236 respondents, 96.6 % had been vaccinated against COVID-19 and 24.6 % were shielding to avoid COVID-19 during survey conduct. The general well-being score for all respondents was 7.5 (±1.2 SD) before onset of the COVID-19 pandemic and 6.9 (±1.6 SD) during survey conduct (P

Abstract BackgroundEvery month, around 3800 people complete an anonymous self-test for suicidal thoughts on the website of the Dutch suicide prevention helpline. Although 70% score high on the severity of suicidal thoughts,

Abstract Background There is divergence in the rate at which people age. The concept of biological age is postulated to capture this variability, and hence to better represent an individual’s true global physiological state than chronological age. Biological age predictors are often generated based on cross-sectional data, using biochemical or molecular markers as predictor variables. It is assumed that the difference between chronological and predicted biological age is informative of one’s chronological age-independent aging divergence ∆. Methods We investigated the statistical assumptions underlying the most popular cross-sectional biological age predictors, based on multiple linear regression, the Klemera-Doubal method or principal component analysis. We used synthetic and real data to illustrate the consequences if this assumption does not hold. Results The most popular cross-sectional biological age predictors all use the same strong underlying assumption, namely that a candidate marker of aging’s association with chronological age is directly informative of its association with the aging rate ∆. We called this the identical-association assumption and proved that it is untestable in a cross-sectional setting. If this assumption does not hold, weights assigned to candidate markers of aging are uninformative, and no more signal may be captured than if markers would have been assigned weights at random. Conclusions Cross-sectional methods for predicting biological age commonly use the untestable identical-association assumption, which previous literature in the field had never explicitly acknowledged. These methods have inherent limitations and may provide uninformative results, highlighting the importance of researchers exercising caution in the development and interpretation of cross-sectional biological age predictors.

Background: Aging triggers intricate physiological changes, particularly in whole-body fat-free mass (FFM) and handgrip strength, affecting overall health and independence. Despite existing research, the broader significance of how muscle health is affected by the intricate interplay of lifestyle factors simultaneously during aging needs more exploration. This study aims to examine how nutrition, physical activity, and sleep impact on FFM and handgrip strength in middle-aged men and women, facilitating future personalized recommendations for preserving muscle health. Methods: The cross-sectional analysis of the UK Biobank involved 45,984 individuals (54 % women) aged 40–70 years with a complete dataset. Multiple linear regression explored determinants of FFM and handgrip strength, considering traditional, socio-demographics, medication use and smoking as covariates, with sex and age (younger and older than 55 years) stratifications. Results: In older men and women, higher physical activity beneficially affect both FFM (respectively Β = 3.36 × 10−3, p-value = 1.66 × 10−3; Β = 2.52 × 10−3, p-value = 3.57 × 10−4) and handgrip strength (Β = 6.05 × 10−3, p-value = 7.99 × 10−5, Β = 8.98 × 10−3, p-value = 2.95 × 10−15). Similar results were found in fiber intake for FFM in older men and women (respectively B = 3.00 × 10−2, p-value = 2.76 × 10−5; B = 2.68 × 10−2, p-value = 1.78 × 10−9) and handgrip strength (Β = 3.27 × 10−2, p-value = 1.40 × 10−3; Β = 3.12 × 10−2, p-value = 1.34 × 10−5). Other lifestyle factors influence FFM and handgrip strength differently. Key determinants influencing handgrip strength included higher protein intake, lower water intake, higher alcohol intake, and extended sleep duration whereas mainly higher water intake is associated with higher FFM. Conclusions: In both men and women, the main factors associated with FFM and handgrip strength are physical activity and fiber intake, which may underlie a connection between gut and muscle health. Given the observed complexity of muscle health in the age and sex strata, further longitudinal research is needed to provide personalized lifestyle recommendations.

The gut microbiome is a dynamic ecosystem shaped by various factors, including diet, sex, and environment. This system plays a crucial role in host health, such that perturbation in the form of antibiotics can lead to a vast array of negative outcomes. Accordingly, a growing body of work seeks to develop interventions to protect the microbiome during antibiotic exposure. While it is well established that antibiotics can disrupt the microbiome in the short term, how the impact of antibiotics is modulated by factors such as diet, sex, and environment is poorly understood. In this study, we analyzed how sex, diet and early life environment (vendor of origin) modulate the impact and recovery of the microbiome in mice treated with oral amoxicillin. Utilizing 16S rRNA gene sequencing and bioinformatic analyses, we looked at the microbiome response to antibiotics under high-sugar and high-fat (Western) and standard high-fiber mouse (Chow) diets in male and female C57BL/6 from Jackson Laboratory, and female mice from Charles River Laboratories. The microbiome composition of each set of mice had a distinct pre-antibiotic starting point, depending on vendor, sex, and diet. These differences were further exacerbated by antibiotic exposure and revealed that each group responded differently to this perturbation. In particular, we found that the Western diet microbiome had an exacerbated response to antibiotics with greater changes in alpha, and beta diversity, and microbial composition when compared to the antibiotic-treated Chow diet cohort. In particular, we detected blooms in Enterobacteriaceae, Streptococcaceae, and Peptostreptococcaceae that were not found in the Chow diet. The response to antibiotics on each diet also appeared to be vendor and sex dependent. Charles River female mice had less Bifidobacteriaceae, Clostridia_UCG.014, and Clostridiaceae compared to Jackson Laboratory females in a Western diet, while female mice had more Bacteroides, Bilophila, and Parasutterella compared to male mice. In a narrow sense, these findings underscore the importance of considering vendor source, diet, and sex when examining antibiotics’ impact on mice. The broader implications suggest that we will likely need to utilize patient-specific microbiome-informed approaches in the development of human therapeutics to safeguard the microbiome during antibiotic exposure.

IntroductionAlthough some adults with autism spectrum disorder (ASD) require intensive and specialized ASD treatment, there is little research on how these adults experience the recovery process. Recovery is defined as the significant improvement in general functioning compared to the situation prior to treatment.MethodsThis qualitative study describes the recovery process from the perspective of adults on the autism spectrum during intensive inpatient treatment. Semi-structured interviews (n = 15) were carried out and analyzed according to the principles of grounded theory.ResultsOur results indicate that, given the specific characteristics of autism, therapeutic interventions and goal-oriented work cannot be carried out successfully, and the recovery process cannot begin, if no good working relationship has been established, and if care is not organized in ways that a person on the autism spectrum finds clear and predictable.

Abstract Trimethylamine N‐oxide (TMAO) is a circulating microbiome‐derived metabolite implicated in the development of atherosclerosis and cardiovascular disease (CVD). We investigated whether plasma levels of TMAO, its precursors (betaine, carnitine, deoxycarnitine, choline), and TMAO‐to‐precursor ratios are associated with clinical outcomes, including CVD and mortality. This was followed by an in‐depth analysis of their genetic, gut microbial, and dietary determinants. The analyses were conducted in five Dutch prospective cohort studies including 7834 individuals. To further investigate association results, Mendelian Randomization (MR) was also explored. We found only plasma choline levels (hazard ratio [HR] 1.17, [95% CI 1.07; 1.28]) and not TMAO to be associated with CVD risk. Our association analyses uncovered 10 genome‐wide significant loci, including novel genomic regions for betaine (6p21.1, 6q25.3), choline (2q34, 5q31.1), and deoxycarnitine (10q21.2, 11p14.2) comprising several metabolic gene associations, for example, CPS1 or PEMT. Furthermore, our analyses uncovered 68 gut microbiota associations, mainly related to TMAO‐to‐precursors ratios and the Ruminococcaceae family, and 16 associations of food groups and metabolites including fish‐TMAO, meat‐carnitine, and plant‐based food‐betaine associations. No significant association was identified by the MR approach. Our analyses provide novel insights into the TMAO pathway, its determinants, and pathophysiological impact on the general population.

Objectives To evaluate asthma characteristics and treatment patterns, including short-acting β2-agonist (SABA) prescriptions, in primary and specialist care in the Singapore cohort of the SABA use IN Asthma (SABINA III) study.Design Cross-sectional, observational study.Setting Multicentre study conducted at five sites across Singapore.Methods In patients with asthma (aged ≥12 years), data on demographics, disease characteristics and asthma treatment prescriptions were collected using electronic case report forms. Patients were classified by investigator-defined asthma severity (guided by 2017 Global Initiative for Asthma recommendations) and practice type (primary/specialist care).Results Of the 205 patients analysed (mean (SD) age, 53.6 (16.8) years; female, 62%), 55.9% were enrolled by specialists and 44.1% by primary care physicians. Most study patients (80.5%) had moderate-to-severe asthma (86.0% in specialist care and 74.4% in primary care). In the 12 months before study enrolment, 18.0% of patients experienced ≥1 severe exacerbation. Asthma was well or partly controlled in 78.0% of patients. Overall, 17.1% of all patients were overprescribed SABA (≥3 SABA canisters/year) in the preceding 12 months, and overprescription was greater in specialist versus primary care (26.3% vs 5.6%). Only 2.9% of patients were prescribed SABA monotherapy, while 41.0% received SABA in addition to maintenance therapy. Among the latter, 40.5% were overprescribed SABA. Overall, a higher percentage of patients prescribed ≥3 SABA canisters (vs 0–2 SABA canisters) were assessed as having uncontrolled asthma during the study visit (42.9% vs 17.6%). Maintenance therapy in the form of inhaled corticosteroids (ICS) or ICS/long-acting β2 agonist fixed-dose combinations were prescribed to 14.1% and 84.9% of patients, respectively, in the 12 months before enrolment.Conclusions In this Singapore cohort, ~17% of all patients and more than 40% of patients prescribed SABA in addition to maintenance therapy were overprescribed SABA. These findings emphasise the need to align clinical practices with the latest evidence-based treatment recommendations.Trial registration NCT03857178.