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Genetic polymorphism of genes encoding the drug metabolizing enzymes, cytochrome P450 2D6 and 2C19 (CYP2D6 and CYP2C19), is associated with treatment failure of and adverse reactions to psychotropic drugs. The clinical utility of routine CYP2D6 and CYP2C19 genotyping (CYP testing) is unclear. To estimate whether routine CYP testing effects the persistence of antipsychotic drug treatment. This single-masked, 3-group randomized clinical trial included patients aged 18 years or older who had been diagnosed within the schizophrenic spectrum (International Statistical Classification of Diseases and Related Health Problems, Tenth Revision codes, F20-F29) and not previously genotyped. A total of 669 of 1406 potentially eligible patients from 12 psychiatric outpatient clinics in Denmark were approached between July 2008 and December 2009. Overall, 528 patients were genotyped and randomly allocated to 1 of 3 study groups or exclusion in a sequence of 1:1:1:3 using a predictive enrichment design, aiming to double the proportion of poor or ultrarapid metabolizers for CYP2D6 or CYP2C19. Outcome measurements were recorded at baseline and 1-year follow-up. Data analysis was performed in December 2012 and updated March 2019. The trial included 2 intervention groups, where antipsychotic drug treatment was guided by either CYP test (CYP test-guided [CTG]) or structured clinical monitoring (SCM), in which adverse effects and factors influencing compliance were systematically recorded at least once quarterly, and 1 control group. Primary outcome was antipsychotic drug persistence, ie, days to first modification of the initial treatment. Secondary outcomes were number of drug and dose changes, adverse effects, and psychotic symptoms, ie, hallucinations and delusions. A total of 528 participants were genotyped, and 311 (median [interquartile range {IQR} age, 41 [30-50] years; 139 [45%] women; median [IQR] duration of illness, 6 [3-13] years) were randomly allocated to 1 of 3 study groups. Overall, 61 participants (20%) were extreme metabolizers. There was no difference in antipsychotic drug persistence between the CTG group and the control group (hazard ratio [HR], 1.02; 95% CI, 0.71-1.45) or SCM and the control group (HR, 0.88; 95% CI, 0.61-1.26). Subanalyses among extreme metabolizers showed similar results (CTG: HR, 0.99; 95% CI, 0.48-2.03; SCM: HR, 0.93; 95% CI, 0.44-1.96). The results of this randomized clinical trial do not support routine CYP testing in patients with schizophrenia. ClinicalTrials.gov Identifier: NCT00707382.

Purpose The aim of this randomized controlled trial (RCT) was to test the effectiveness of a post-ICU recovery program compared to standard care during the first year after ICU discharge. Methods A pragmatic, non-blinded, multicenter, parallel-group RCT was conducted between December 2012 and December 2015, at ten intensive care units (ICUs) in Denmark. We randomly assigned 386 adult patients (≥18 years) after receiving mechanical ventilation (≥48 h) to standard care (SC) plus a nurse-led intensive care recovery program or standard care alone after ICU discharge (190 intervention, 196 SC). Primary outcome was health-related quality of life (HRQOL) at 12 months. Secondary outcomes were sense of coherence (SOC), anxiety, depression, and post-traumatic stress disorder (PTSD) assessed at 3 and 12 months after ICU discharge including utilization of healthcare services at 12 months. Results At 12 months, we found no differences in HRQOL between groups (mean difference in the Physical Component Summary score, 1.41 [95 % CI, −1.53 to 4.35; p  = 0.35] ( n  = 235); and in the Mental Component Summary score, 1.92 [95 % CI, −1.06 to 4.90; p  = 0.11] ( n  = 235). No differences were found on self-reported SOC ( p  = 0.63), anxiety ( p  = 0.68), depression ( p  = 0.67), PTSD ( p  = 0.27), or the utilization of healthcare services including rehabilitation. We found a difference on anxiety, when a cut-off point ≥11 was applied, in per protocol analysis of complete cases at 3 months favoring the intervention (8.8 % vs. 16.2 %, p  = 0.04). Conclusions The tested recovery program was not superior to standard care during the first 12 months post-ICU. Trial registration The trial is registered at Clinicaltrials.gov, identification no. NCT01721239.

High-grade serous ovarian carcinoma (HGSOC) is a molecularly heterogeneous and lethal malignancy, with late-stage diagnosis contributing to high risk of recurrence and poor clinical outcomes. Although homologous recombination (HR) deficiency and retinoblastoma gene ( RB1 ) expression have been implicated in prognosis, their combined role in shaping tumor biology and survival outcomes is not well defined. To investigate the relationship between HR status and RB1 expression and explore their potential as a combined prognostic marker, we analyzed data from two cohorts: (1) 272 HGSOC cases from The Cancer Genome Atlas (TCGA) with RB1 mRNA expression data and HR status previously annotated by Takaya et al. (HR-deficient, HRD; HR-proficient, HRP), and (2) 226 clinical HGSOC cases profiled by comprehensive genomic and immune profiling (CGIP) at OmniSeq, categorized as either HR-intact (HRi) or harboring BRCA1/2 alterations (BRCAa). Cases were additionally stratified according to RB1 mRNA expression level as RB1-high (> 25th percentile; RBH) or RB1-low (≤ 25th percentile; RBL). HRP-RBH tumors ( n  = 120, 44.1%) were associated with significantly worse overall survival (OS) and progression free survival (PFS) compared to all other subgroups. Survival metrics were evaluated from the TCGA cohort and demonstrated that median OS for HRP-RBH was 35.9 mo, shorter than HRP-RBL (52.0 mo), HRD-RBL (57.1 mo), and HRD-RBH subgroups (53.3 mo; all p  < 0.0001). PFS demonstrated a similar trend (15.1 mo vs. 20.6, 20.2 and 20.4 mo, respectively, p  = 0.0021). HRP-RBH tumors also showed higher aneuploidy scores (median 18 vs. ≤ 10.5 in other subgroups, all p  < 0.01). From the OmniSeq cohort, HRi-RBH tumors exhibited a distinct immune gene signature, including elevated mRNA expression of 213 differentially expressed genes and enrichment of pathways such as EMT, PI3K/AKT signaling, and interleukin signaling. Overall, this study suggests that molecular subtyping of HGSOC based on HR status and RB1 expression may provide valuable prognostic insight. HRP tumors with high RB1 expression represent a high-risk subgroup with a distinct molecular profile and poor clinical outcomes, underscoring the need for novel therapeutic strategies targeting this aggressive subset. These findings provide a foundation for future studies aimed at developing biomarkers and treatments tailored to this challenging subset of HGSOC patients.

The Terra Sirenum region of Mars, located in the Noachian southern highlands, is mineralogically diverse, providing unique insight into ancient aqueous processes. Analyses of remote sensing data over the region indicate the presence of both Fe‐ or Mg‐rich phyllosilicates and a spectrally unique deposit interpreted to be rich in chloride salts. The stratigraphic relationships indicate that the phyllosilicates are part of the ancient highland crust and that the salts were deposited at a later time. In some instances, there is clear morphological evidence that salts were mobilized and deposited by near‐surface waters.

Background Older adults with myeloid malignancies are susceptible to treatment-related toxicities. Accelerated DNAm age, or the difference between DNA methylation (DNAm) age and chronological age, may be used as a biomarker of biological age to predict individuals at risk. In addition, cancer treatment can also lead to accelerated DNAm age. Exercise is a promising intervention to reduce or prevent functional, psychological, and cognitive impairments in older patients with myeloid malignancies, yet there is little evidence of the effects of exercise on DNAm age. We explored (1) the associations of accelerated DNAm age with physical, psychological, and cognitive functions at baseline; (2) changes in DNAm age from baseline to post-intervention; and (3) the associations of changes in accelerated DNAm age with changes in functions from baseline to post-intervention. Methods We enrolled older patients with myeloid malignancies to a single-arm pilot study testing a mobile health (mHealth) exercise intervention that combines an exercise program (EXCAP ©® ) with a mobile application over 2 cycles of chemotherapy (8–12 weeks). Patients completed measures of physical, psychological, and cognitive functions and provided blood samples for analyses of DNAm age at baseline and post-intervention. Paired t-tests or Wilcoxon signed rank tests assessed changes in DNAm ages, and Spearman’s correlation assessed the relationships between accelerated ages and functions. Results We included 20 patients (mean age: 72 years, range 62–80). Accelerated GrimAge, accelerated PhenoAge, and DunedinPACE were stable from baseline to post-intervention. At baseline, DunedinPACE was correlated with worse grip strength (r = -0.41, p = 0.08). From baseline to post-intervention, decreases in accelerated GrimAge (r = -0.50, p = 0.02), accelerated PhenoAge (r = − 0.39, p  = 0.09), and DunedinPace (r = − 0.43, p  = 0.06) were correlated with increases in distance walked on 6-min walk test. Decreases in accelerated GrimAge (r = − 0.49, p  = 0.03), accelerated PhenoAge (r = − 0.40, p  = 0.08), and DunedinPace (r = − 0.41, p  = 0.07) were correlated with increases in in grip strength. Conclusions Among older adults with myeloid malignancies receiving chemotherapy, GrimAge and PhenoAge on average are stable after a mHealth exercise intervention. Decreases in accelerated GrimAge, accelerated PhenoAge, and DunedinPACE over 8–12 weeks of exercise were correlated with increased physical performance. Future trials assessing the effects of exercise on treatment-related toxicities should evaluate DNAm age. Trial registration Clinicaltrials.gov identifier: NCT04981821.

Younger patients with non-small cell lung cancer (NSCLC) (<50 years) represent a significant patient population with distinct clinicopathological features and enriched targetable genomic alterations compared to older patients. However, previous studies of younger NSCLC suffer from inconsistent findings, few studies have incorporated sex into their analyses, and studies targeting age-related differences in the tumor immune microenvironment are lacking. We performed a retrospective analysis of 8,230 patients with NSCLC, comparing genomic alterations and immunogenic markers of younger and older patients while also considering differences between male and female patients. We defined older patients as those ≥65 years and used a 5-year sliding threshold from <45 to <65 years to define various groups of younger patients. Additionally, in an independent cohort of patients with NSCLC, we use our observations to inform testing of the combinatorial effect of age and sex on survival of patients given immunotherapy with or without chemotherapy. We observed distinct genomic and immune microenvironment profiles for tumors of younger patients compared to tumors of older patients. Younger patient tumors were enriched in clinically relevant genomic alterations and had gene expression patterns indicative of reduced immune system activation, which was most evident when analyzing male patients. Further, we found younger male patients treated with immunotherapy alone had significantly worse survival compared to male patients ≥65 years, while the addition of chemotherapy reduced this disparity. Contrarily, we found younger female patients had significantly better survival compared to female patients ≥65 years when treated with immunotherapy plus chemotherapy, while treatment with immunotherapy alone resulted in similar outcomes. These results show the value of comprehensive genomic and immune profiling (CGIP) for informing clinical treatment of younger patients with NSCLC and provides support for broader coverage of CGIP for younger patients with advanced NSCLC.

Background In a single‐arm pilot study, we assessed the feasibility and usefulness of an innovative patient‐centered communication tool (UR‐GOAL tool) that addresses aging‐related vulnerabilities, patient values, and prognostic awareness for use in treatment decision making between older adults with newly diagnosed acute myeloid leukemia (AML), their caregivers, and oncologists. Methods Primary feasibility metric was retention rate; >50% was considered feasible. We collected recruitment rate, usefulness, and outcomes including AML knowledge (range 0–14) and perceived efficacy in communicating with oncologists (range 5–25). Due to the pilot nature and small sample size, hypothesis testing was performed at α = 0.10. Results We included 15 patients (mean age 76 years, range 64–88), 12 caregivers, and 5 oncologists; enrollment and retention rates for patients were 84% and 73%, respectively. Patients agreed that the UR‐GOAL tool helped them understand their AML diagnosis and treatment options, communicate with their oncologist, and make more informed decisions. From baseline to post‐intervention, patients and caregivers scored numerically higher on AML knowledge (patients: +0.6, p = 0.22; caregivers: +1.1, p = 0.05) and perceived greater efficacy in communicating with their oncologists (patients: +1.5, p = 0.22; caregivers: +1.2, p = 0.06). Conclusion We demonstrated that it is feasible to incorporate the UR‐GOAL tool into treatment decision making for older patients with AML, their caregivers, and oncologists. We demonstrated that it is feasible to incorporate a patient‐centered communication tool (UR‐GOAL) into treatment decision making. For patients and caregivers, AML knowledge scores and perceived efficacy in communicating with the oncologist increased at post‐intervention.

Residential wood combustion (RWC) is an important contributor to air quality in numerous regions worldwide. This study is the first extensive evaluation of the influence of RWC on ambient air quality in several Nordic cities. We have analysed the emissions and concentrations of PM2.5 in cities within four Nordic countries: in the metropolitan areas of Copenhagen, Oslo, and Helsinki and in the city of Umeå. We have evaluated the emissions for the relevant urban source categories and modelled atmospheric dispersion on regional and urban scales. The emission inventories for RWC were based on local surveys, the amount of wood combusted, combustion technologies and other relevant factors. The accuracy of the predicted concentrations was evaluated based on urban concentration measurements. The predicted annual average concentrations ranged spatially from 4 to 7 µgm-3 (2011), from 6 to 10 µgm-3 (2013), from 4 to more than 13 µgm-3 (2013) and from 9 to more than 13 µgm-3 (2014), in Umeå, Helsinki, Oslo and Copenhagen, respectively. The higher concentrations in Copenhagen were mainly caused by the relatively high regionally and continentally transported background contributions. The annual average fractions of PM2.5 concentrations attributed to RWC within the considered urban regions ranged spatially from 0 % to 15 %, from 0 % to 20 %, from 8 % to 22 % and from 0 % to 60 % in Helsinki, Copenhagen, Umeå and Oslo, respectively. In particular, the contributions of RWC in central Oslo were larger than 40 % as annual averages. In Oslo, wood combustion was used mainly for the heating of larger blocks of flats. In contrast, in Helsinki, RWC was solely used in smaller detached houses. In Copenhagen and Helsinki, the highest fractions occurred outside the city centre in the suburban areas. In Umeå, the highest fractions occurred both in the city centre and its surroundings.

ObjectivesIn 2018, a nationwide mandatory switch from originator to biosimilar adalimumab was conducted in Denmark. The available biosimilar was GP2017 (Hyrimoz) in Eastern regions and SB5 (Imraldi) in Western regions. We aimed to assess the comparative effectiveness of GP2017 versus SB5 in patients with rheumatoid arthritis (RA)/psoriatic arthritis (PsA)/axial spondyloarthritis (AxSpA).MethodsObservational cohort study based on the DANBIO registry with geographical cluster pseudo-randomisation, analysed by emulating a randomised clinical trial. Main outcome was adjusted 1-year treatment retention (Cox regression). Furthermore, 6 months’ remission rates (logistic regression), reasons for withdrawal and back-switching to originator were investigated (overall and stratified by indication).ResultsOverall, of 1570 eligible patients, 1318 switched and were included (467 RA/321 PsA/530 AxSpA); 623 (47%) switched to GP2017, 695 (53%) to SB5. Baseline characteristics of the two clusters were largely similar, but some differences in registration practice were observed. The combined 1-year retention rate for the two biosimilars was 89.5%. Compared with SB5, estimated risk of withdrawal for GP2017 was lower (HR 0.60; 95% CI 0.42 to 0.86) and 6 months’ remission rate was higher (OR 1.72; 95% CI 1.25 to 2.37). Stratified analyses gave similar results (statistically significant for RA). During 1 year, 8.5% and 12.9% withdrew GP2017 and SB5, respectively (primarily lack of effect and adverse events), of whom 48 patients (3.6%) back-switched.ConclusionThis head-to-head comparison of GP2017 versus SB5 following a mandatory switch from the originator indicated differences in effectiveness in routine care. This may reflect a true difference, but other explanations, for example, differences in excipients, differences between clusters and residual confounding cannot be ruled out.