Guselkumab demonstrates long-term efficacy and maintenance of treatment response postwithdrawal in systemic treatment-naïve patients and nonresponders to fumaric acid esters: results from parts II and III of a randomized active-comparator-controlled phase IIIb trial (POLARIS).

BACKGROUND: The anti-interleukin-23 antibody guselkumab (GUS) demonstrated favourable week 24 efficacy and safety over fumaric acid esters (FAE) in systemic treatment-naïve patients with moderate-to-severe plaque psoriasis (study part I). OBJECTIVES: To compare, in study part II, the sustainability of treatment responses (weeks 24-32) in GUS- and FAE-treated patients and treatment responses (weeks 32-56) in patients treated with GUS and FAE and in FAE nonresponders switching to GUS; and, in part III, to investigate the maintenance of response through week 100 in patients withdrawn from GUS at week 56. METHODS: At week 0, systemic treatment-naïve patients were randomized 1 : 1 to GUS or FAE as per label. At week 32, patients with a Psoriasis Area and Severity Index (PASI) 75 (≥ 75% improvement in PASI score) response (r) continued assigned treatment (GUSr-GUS; FAEr-FAE), whereas nonresponders (nr) received GUS (FAEnr-GUS; GUSnr-GUS). GUS-treated patients with a week 56 PASI 90 response (≥ 90% improvement in PASI score) were withdrawn (w) and followed until loss of response or week 100. RESULTS: At week 32, 98% (n = 54/55) of GUS- and 41% (n = 14/34) of FAE-treated patients were PASI 75 responders. At week 56, 91%, 50% and 80% of GUSr-GUS, FAEr-FAE and FAEnr-GUS patients, respectively, achieved a PASI 90 response; 72%, 29% and 45%, respectively, achieved a Dermatology Life Quality Index score of 0/1. At week 100, 44 weeks postwithdrawal, 47% (n = 17/36) and 25% (n = 3/12) of GUS-GUSw and FAE-GUSw patients, respectively, maintained a PASI score ≤ 5. Overall, the adverse event and discontinuation rates were lower for GUS than FAE. CONCLUSIONS: In these exploratory analyses, GUS, as a first-line systemic treatment or second-line systemic treatment in FAE nonresponders, was associated with long-term clinical efficacy up to week 100, including a withdrawal period.

Molecular pathways in post-colonoscopy versus detected colorectal cancers: results from a nested case-control study.

BACKGROUND: Post-colonoscopy colorectal cancers (PCCRCs) pose challenges in clinical practice. PCCRCs occur due to a combination of procedural and biological causes. In a nested case-control study, we compared clinical and molecular features of PCCRCs and detected CRCs (DCRCs). METHODS: Whole-genome chromosomal copy number changes and mutation status of genes commonly affected in CRC were examined by low-coverage WGS and targeted sequencing, respectively. MSI and CIMP status was also determined. RESULTS: In total, 122 PCCRCs and 98 DCRCs with high-quality DNA were examined. PCCRCs were more often located proximally (P < 0.001), non-polypoid appearing (P = 0.004), early stage (P = 0.009) and poorly differentiated (P = 0.006). PCCRCs showed significantly less 18q loss (FDR < 0.2), compared to DCRCs. No significant differences in mutations were observed. PCCRCs were more commonly CIMP high (P = 0.014) and MSI (P = 0.029). After correction for tumour location, only less 18q loss remained significant (P = 0.005). CONCLUSION: Molecular features associated with the sessile serrated lesions (SSLs) and non-polypoid colorectal neoplasms (CRNs) are more commonly seen in PCCRCs than in DCRCs. These together with the clinical features observed support the hypothesis that SSLs and non-polypoid CRNs are contributors to the development of PCCRCs. The future focus should be directed at improving the detection and endoscopic removal of these non-polypoid CRN and SSLs. CLINICAL TRIAL REGISTRATION: NTR3093 in the Dutch trial register ( www.trialregister.nl ).

Proteins in stool as biomarkers for non-invasive detection of colorectal adenomas with high risk of progression.

Screening to detect colorectal cancer (CRC) in an early or premalignant state is an effective method to reduce CRC mortality rates. Current stool-based screening tests, e.g. fecal immunochemical test (FIT), have a suboptimal sensitivity for colorectal adenomas and difficulty distinguishing adenomas at high risk of progressing to cancer from those at lower risk. We aimed to identify stool protein biomarker panels that can be used for the early detection of high-risk adenomas and CRC. Proteomics data (LC-MS/MS) were collected on stool samples from adenoma (n = 71) and CRC patients (n = 81) as well as controls (n = 129). Colorectal adenoma tissue samples were characterized by low-coverage whole-genome sequencing to determine their risk of progression based on specific DNA copy number changes. Proteomics data were used for logistic regression modeling to establish protein biomarker panels. In total, 15 of the adenomas (15.8%) were defined as high risk of progressing to cancer. A protein panel, consisting of haptoglobin (Hp), LAMP1, SYNE2, and ANXA6, was identified for the detection of high-risk adenomas (sensitivity of 53% at specificity of 95%). Two panels, one consisting of Hp and LRG1 and one of Hp, LRG1, RBP4, and FN1, were identified for high-risk adenomas and CRCs detection (sensitivity of 66% and 62%, respectively, at specificity of 95%). Validation of Hp as a biomarker for high-risk adenomas and CRCs was performed using an antibody-based assay in FIT samples from a subset of individuals from the discovery series (n = 158) and an independent validation series (n = 795). Hp protein was significantly more abundant in high-risk adenoma FIT samples compared to controls in the discovery (p = 0.036) and the validation series (p = 9e-5). We conclude that Hp, LAMP1, SYNE2, LRG1, RBP4, FN1, and ANXA6 may be of value as stool biomarkers for early detection of high-risk adenomas and CRCs. © 2019 Authors. Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Molecular characterization of colorectal adenomas reveals POFUT1 as a candidate driver of tumor progression.

Removal of colorectal adenomas is an effective strategy to reduce colorectal cancer (CRC) mortality rates. However, as only a minority of adenomas progress to cancer, such strategies may lead to overtreatment. The present study aimed to characterize adenomas by in-depth molecular profiling, to obtain insights into altered biology associated with the colorectal adenoma-to-carcinoma progression. We obtained low-coverage whole genome sequencing, RNA sequencing and tandem mass spectrometry data for 30 CRCs, 30 adenomas and 18 normal adjacent colon samples. These data were used for DNA copy number aberrations profiling, differential expression, gene set enrichment and gene-dosage effect analysis. Protein expression was independently validated by immunohistochemistry on tissue microarrays and in patient-derived colorectal adenoma organoids. Stroma percentage was determined by digital image analysis of tissue sections. Twenty-four out of 30 adenomas could be unambiguously classified as high risk (n = 9) or low risk (n = 15) of progressing to cancer, based on DNA copy number profiles. Biological processes more prevalent in high-risk than low-risk adenomas were related to proliferation, tumor microenvironment and Notch, Wnt, PI3K/AKT/mTOR and Hedgehog signaling, while metabolic processes and protein secretion were enriched in low-risk adenomas. DNA copy number driven gene-dosage effect in high-risk adenomas and cancers was observed for POFUT1, RPRD1B and EIF6. Increased POFUT1 expression in high-risk adenomas was validated in tissue samples and organoids. High POFUT1 expression was also associated with Notch signaling enrichment and with decreased goblet cells differentiation. In-depth molecular characterization of colorectal adenomas revealed POFUT1 and Notch signaling as potential drivers of tumor progression.

Prescribing medications of questionable benefit prior to death: a retrospective study on older nursing home residents with and without dementia in Germany.

PURPOSE: We studied the prevalence of medications of questionable benefit in the last 6 months of life among older nursing home residents with and without dementia in Germany. METHODS: A retrospective cohort study was conducted on claims data from 67,328 deceased nursing home residents aged 65+ years who were admitted between 2010 and 2014. We analyzed prescription regimens of medications of questionable benefit in the 180-91-day period and the 90-day period prior to death for residents with dementia (n = 29,052) and without dementia (n = 38,276). Factors associated with new prescriptions of medications of questionable benefit prior to death were analyzed using logistic regression models among all nursing home residents and stratified by dementia. RESULTS: A higher proportion of nursing home residents with dementia were prescribed at least one medication of questionable benefit in the 180-91-day (29.6%) and 90-day (26.8%) periods prior to death, compared with residents without dementia (180-91 days, 22.8%; 90 days, 20.1%). Lipid-lowering agents were the most commonly prescribed medications. New prescriptions of medications of questionable benefit were more common among residents with dementia (9.8% vs. 8.7%). When excluding anti-dementia medication, new prescriptions of these medications were more common among residents without dementia (6.4% vs. 8.0%). The presence of dementia (odds ratio [OR] 1.40, 95% confidence interval [95%CI] 1.32-1.48) and excessive polypharmacy were associated with new prescriptions of medications of questionable benefit prior to death (OR 4.74, 95%CI 4.15-5.42). CONCLUSION: Even when accounting for anti-dementia prescriptions, the prevalence of nursing home residents with dementia receiving medications of questionable benefit is considerable and may require further attention.

Consensus molecular subtype classification of colorectal adenomas.

Consensus molecular subtyping is an RNA expression-based classification system for colorectal cancer (CRC). Genomic alterations accumulate during CRC pathogenesis, including the premalignant adenoma stage, leading to changes in RNA expression. Only a minority of adenomas progress to malignancies, a transition that is associated with specific DNA copy number aberrations or microsatellite instability (MSI). We aimed to investigate whether colorectal adenomas can already be stratified into consensus molecular subtype (CMS) classes, and whether specific CMS classes are related to the presence of specific DNA copy number aberrations associated with progression to malignancy. RNA sequencing was performed on 62 adenomas and 59 CRCs. MSI status was determined with polymerase chain reaction-based methodology. DNA copy number was assessed by low-coverage DNA sequencing (n = 30) or array-comparative genomic hybridisation (n = 32). Adenomas were classified into CMS classes together with CRCs from the study cohort and from The Cancer Genome Atlas (n = 556), by use of the established CMS classifier. As a result, 54 of 62 (87%) adenomas were classified according to the CMS. The CMS3 'metabolic subtype', which was least common among CRCs, was most prevalent among adenomas (n = 45; 73%). One of the two adenomas showing MSI was classified as CMS1 (2%), the 'MSI immune' subtype. Eight adenomas (13%) were classified as the 'canonical' CMS2. No adenomas were classified as the 'mesenchymal' CMS4, consistent with the fact that adenomas lack invasion-associated stroma. The distribution of the CMS classes among adenomas was confirmed in an independent series. CMS3 was enriched with adenomas at low risk of progressing to CRC, whereas relatively more high-risk adenomas were observed in CMS2. We conclude that adenomas can be stratified into the CMS classes. Considering that CMS1 and CMS2 expression signatures may mark adenomas at increased risk of progression, the distribution of the CMS classes among adenomas is consistent with the proportion of adenomas expected to progress to CRC. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Prevalence, trend and contributing factors of geriatric syndromes among older Swedes: results from the Stockholm County Council Public Health Surveys.

BACKGROUND: Evidence is scarce on the trend in prevalence of geriatric syndromes (GS). This study assesses how GS prevalence changes over time in Swedish older community-dwellers by socio-demography, and attempts to highlight factors that may contribute to explain the trend. METHODS: Data from Stockholm County Council Public Health Surveys in 2006, 2010 and 2014 were used. Old adults, aged 65-84 years, with measurements on GS items were identified. Thus, a total of 17,560 participants were selected in 2006 (n = 6295), 2010 (n = 6733) and 2014 (n = 4532). Data on socio-demographics, lifestyles and health status were collected through questionnaires. GS was defined as having at least one of the following: insomnia, urinary incontinence, severe hearing/vision problem, functional decline, fall and depressive disorder. Logistic regression was performed to assess the prevalence trend as well as the change in the associations of sociodemographic factors, health behaviors and chronic disease with GS. RESULTS: From 2006 to 2014, the prevalence of GS remained stable (Ptrend = 0.54). However, among old adults born outside Nordic countries, it increased significantly from 73.0% in 2006, 78.0% in 2010 to 83.0% in 2014 (Ptrend < 0.001). Furthermore, the association with GS became stronger for born outside Nordic counties (Ptrend < 0.001) and weaker for sedentary lifestyles (Ptrend = 0.004), whereas the association did not change for other sociodemographic factors, health behaviors and chronic disease (all Ptrend > 0.05). CONCLUSIONS: At population level, GS prevalence remained stable at a high level among Swedish old community-dwellers. There are noteworthy differences in GS trend between population groups, in particular to the detriment of older adults born outside Nordic countries.

Number of medications and adverse drug events by unintentional poisoning among older adults in consideration of inappropriate drug use: a Swedish population-based matched case-control study.

PURPOSE: This national, population-based study aims to determine the association between the number of prescribed medications and adverse drug events (ADE) by unintentional poisoning and examine this risk when known indicators of inappropriate drug use (IDU) are accounted for. METHODS: We employed a matched case-control design among people living in Sweden who were 50 years and older. Cases experiencing an ADE by unintentional poisoning resulting in hospitalization or death (n = 5336) were extracted from the National Health and Death Registers from January 2006 to December 2009. Four controls per case matched by age, sex and residential area were randomly selected among those without an ADE (n = 21,344). Prescribed medications dispensed during the 4-month period prior to the ADE were identified via the Swedish Prescribed Drug Register and coded according to the number of different dispensed medications (NDDM) (0 to 10 medications) and IDU indicators (one single-drug, and three drug-combinations). Conditional logistic regression was used. RESULTS: Each of the IDU indicators was significantly associated with very high risks of ADE. For NDDM, we found a lower but graded positive association from two to ten or more medications (adjusted OR, 1.5; 95% CI, 1.2-1.8). Exclusion of IDU from the NDDM decreased the risk of ADE, but the effects remained significant for three or more medications (adjusted OR excl. IDU, 1.5; 95% CI, 1.2-2.0). CONCLUSION: At population level, the number of different dispensed medications starting from three or more remains associated with ADE even after adjusting for known IDUs. Clinicians and patients need to be made aware of the increased likelihood of serious ADE, not only in case of documented inappropriate medications but also in the case of an increasing number of medications.

New opioid analgesic use and the risk of injurious single-vehicle crashes in drivers aged 50-80 years: A population-based matched case-control study.

BACKGROUND: the increasing trend in opioid analgesic use among older drivers has raised concerns about their risk of being involved in car crashes. AIM: to investigate if older drivers who started using opioid analgesics have a higher probability of being involved in injurious crashes. METHODS: population-based matched case-control study. Data from population registers were merged using a personal identity number. Cases were drivers aged 50-80 years responsible for a single vehicle crash between 01.07.05 and 31.12.09 that led to at least one injured passenger (n = 4,445). Four controls were randomly matched to each case by sex, birth month/year, and residence area from persons holding a valid driving license who did not crash during the study period. New use was defined as at least one dispensation within 1-30 days prior to the crash, but none within the previous 31-180 days; frequent use when ≥3 dispensations were given within 0-180 days, with at least one within 31-180 days. Individuals using 1-2 non-opioid analgesic medications were used as reference category. Conditional logistic regression was used to estimate odds ratios (OR; 95% CI) adjusting for benzodiazepine use, co-morbidity, civil status and occupation. RESULTS: adjusted odds for new use were two-fold that of drivers using 1-2 non-opioid analgesics medications (2.0; 1.6-2.5). For frequent use, adjusted odds were also increased regardless of number of dispensations (3-4 = 1.7; 1.3-2.1, 5-6 = 1.6; 1.2-2.3, and ≥7 = 1.7; 1.3-2.1). CONCLUSION: new, but also frequent opioid analgesic use, resulted in an increased probability of single vehicle crashes. While more epidemiologic evidence is needed, patients could be advised to refrain from driving when using opioid analgesics.

Crystal structure of the ω-aminotransferase from Paracoccus denitrificans and its phylogenetic relationship with other class III aminotransferases that have biotechnological potential.

Apart from their crucial role in metabolism, pyridoxal 5'-phosphate (PLP)-dependent aminotransferases (ATs) constitute a class of enzymes with increasing application in industrial biotechnology. To provide better insight into the structure-function relationships of ATs with biotechnological potential we performed a fundamental bioinformatics analysis of 330 representative sequences of pro- and eukaryotic Class III ATs using a structure-guided approach. The calculated phylogenetic maximum likelihood tree revealed six distinct clades of which the first segregates with a very high bootstrap value of 92%. Most enzymes in this first clade have been functionally well characterized, whereas knowledge about the natural functions and substrates of enzymes in the other branches is sparse. Notably, in those clades 2-6 members of the peculiar class of ω-ATs prevail, many of which have proven useful for the preparation of chiral amines or artificial amino acids. One representative is the ω-AT from Paracoccus denitrificans (PD ω-AT) which catalyzes, for example, the transamination in a novel biocatalytic process for the production of L-homoalanine from L-threonine. To gain structural insight into this important enzyme, its X-ray analysis was carried out at a resolution of 2.6 Å, including the covalently bound PLP as well as 5-aminopentanoate as a putative amino donor substrate. On the basis of this crystal structure in conjunction with our phylogenetic analysis, we have identified a generic set of active site residues of ω-ATs that are associated with a strong preference for aromatic substrates, thus guiding the discovery of novel promising enzymes for the biotechnological production of corresponding chiral amines.

NRPSpredictor2--a web server for predicting NRPS adenylation domain specificity.

The products of many bacterial non-ribosomal peptide synthetases (NRPS) are highly important secondary metabolites, including vancomycin and other antibiotics. The ability to predict substrate specificity of newly detected NRPS Adenylation (A-) domains by genome sequencing efforts is of great importance to identify and annotate new gene clusters that produce secondary metabolites. Prediction of A-domain specificity based on the sequence alone can be achieved through sequence signatures or, more accurately, through machine learning methods. We present an improved predictor, based on previous work (NRPSpredictor), that predicts A-domain specificity using Support Vector Machines on four hierarchical levels, ranging from gross physicochemical properties of an A-domain's substrates down to single amino acid substrates. The three more general levels are predicted with an F-measure better than 0.89 and the most detailed level with an average F-measure of 0.80. We also modeled the applicability domain of our predictor to estimate for new A-domains whether they lie in the applicability domain. Finally, since there are also NRPS that play an important role in natural products chemistry of fungi, such as peptaibols and cephalosporins, we added a predictor for fungal A-domains, which predicts gross physicochemical properties with an F-measure of 0.84. The service is available at http://nrps.informatik.uni-tuebingen.de/.

The Association between Birthweight and Use of Cardiovascular Medications: The Role of Health Behaviors.

BACKGROUND: There is limited evidence on the effect of low birthweight on the use of cardiovascular medications and the role of health behaviors. This study aims to determine the independent effect of low birthweight and its combination with adult health behaviors on the number of dispensed cardiovascular medications. METHODS: We included 15618 participants with information on birthweight and self-reported health behaviors. Dispensed cardiovascular medications were identified from the Prescribed Drug Register based on a three-digit level Anatomical Therapeutic Chemical classification code (C01 to C10 and B01) and categorized into 0, 1, and ≥2 different types of medications. We applied multinomial logistic regression models estimating odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Participants with low birthweight had a higher estimated OR of using ≥2 types of cardiovascular medications (OR = 1.46, 95% CI = 1.06, 2.01). Further, an increased risk for using ≥2 types of cardiovascular medications was found in participants with poor health behaviors for normal (OR = 2.17, 95% CI = 1.80, 2.62) and high (OR = 1.84, 95% CI = 1.29, 2.62) birthweight. The strongest effect on using ≥2 types of cardiovascular medications was found for low birthweight and poor health behaviors (OR = 3.14, 95% CI = 1.80, 5.50). CONCLUSION: This cohort study provides evidence that low birthweight increases the risk of using more types of cardiovascular medications in adulthood. This study also suggests that ideal health behaviors reduce this risk.

Modeling early treatment response in AML from cell-free tumor DNA.

Monitoring disease response after intensive chemotherapy for acute myeloid leukemia (AML) currently requires invasive bone marrow biopsies, imposing a significant burden on patients. In contrast, cell-free tumor DNA (ctDNA) in peripheral blood, carrying tumor-specific mutations, offers a less-invasive assessment of residual disease. However, the relationship between ctDNA levels and bone marrow blast kinetics remains unclear. We explored this in 10 AML patients with NPM1 and IDH2 mutations undergoing initial chemotherapy. Comparison of mathematical mixed-effect models showed that (1) inclusion of blast cell death in the bone marrow, (2) transition of ctDNA to peripheral blood, and (3) ctDNA decay in peripheral blood describes kinetics of blast cells and ctDNA best. The fitted model allows prediction of residual bone marrow blast content from ctDNA, and its scaling factor, representing clonal heterogeneity, correlates with relapse risk. Our study provides precise insights into blast and ctDNA kinetics, offering novel avenues for AML disease monitoring.

Validation and refinement of the 2022 European LeukemiaNet genetic risk stratification of acute myeloid leukemia.

The revised 2022 European LeukemiaNet (ELN) AML risk stratification system requires validation in large, homogeneously treated cohorts. We studied 1118 newly diagnosed AML patients (median age, 58 years; range, 18-86 years) who received cytarabine-based induction chemotherapy between 1999 and 2012 and compared ELN-2022 to the previous ELN-2017 risk classification. Key findings were validated in a cohort of 1160 mostly younger patients. ELN-2022 reclassified 15% of patients, 3% into more favorable, and 12% into more adverse risk groups. This was mainly driven by patients reclassified from intermediate- to adverse-risk based on additional myelodysplasia-related mutations being included as adverse-risk markers. These patients (n = 79) had significantly better outcomes than patients with other adverse-risk genotypes (5-year OS, 26% vs. 12%) and resembled the remaining intermediate-risk group. Overall, time-dependent ROC curves and Harrel's C-index controlling for age, sex, and AML type (de novo vs. sAML/tAML) show slightly worse prognostic discrimination of ELN-2022 compared to ELN-2017 for OS. Further refinement of ELN-2022 without including additional genetic markers is possible, in particular by recognizing TP53-mutated patients with complex karyotypes as "very adverse". In summary, the ELN-2022 risk classification identifies a larger group of adverse-risk patients at the cost of slightly reduced prognostic accuracy compared to ELN-2017.

Geriatric syndromes and subsequent health-care utilization among older community dwellers in Stockholm.

Little is known about the long-term effect of geriatric syndromes on health-care utilization. This study aims to determine the association between geriatric syndromes and health-care utilization during a four-year period among older community dwellers. Based on the Stockholm Public Health Cohort study, a total number of 6700 community dwellers aged ≥65 years were included. From a baseline survey in 2006, geriatric syndromes were defined as having at least one of the following: insomnia, functional decline, urinary incontinence, depressive symptoms and vision impairment. Health-care utilization was identified by linkages at individual level with register data with a four-year follow-up. Cox regression was performed to estimate the associations. Compared to those without geriatric syndromes, participants with any geriatric syndromes had a higher prevalence of frequent hospitalizations, long hospital stays, frequent outpatient visits and polypharmacy in each of the follow-up years. After controlling for covariates, having any geriatric syndromes was associated with higher levels of utilization of inpatient and outpatient care as well as polypharmacy. The association was stable over time, and the fully adjusted hazard ratio (95% confidence interval) remained stable in frequent hospitalizations (from 1.89 [1.31, 2.73] in year 1 to 1.70 [1.23, 2.35] in year 4), long hospital stay (from 1.75 [1.41, 2.16] to 1.49 [1.24, 1.78]), frequent outpatient visits (from 1.40 [1.26, 1.54] to 1.33 [1.22, 1.46]) and polypharmacy (from 1.63 [1.46, 1.83] to 1.53 [1.37, 1.71]). Having any geriatric syndromes is associated with higher levels of health-care utilization among older community dwellers, and the impact of geriatric syndromes is stable over a four-year period. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at. 10.1007/s10433-021-00600-2.

Newly initiated cardiovascular medication and short-term risk of unintentional poisoning among Swedish middle-aged and older adults: A national register-based case-crossover study.

BACKGROUND: Although some studies have shown the average side effects of cardiovascular medication, the short-term effect after newly initiated cardiovascular medications has not been studied in any detail. We aim to determine the effect of newly initiated cardiovascular medications resulting in unintentional poisoning and to identify those at high risk. METHODS: A case-crossover design was used. From the Swedish National Patient Register, a total of 9,354 persons aged ≥ 50 and hospitalized with a first event of unintentional poisoning between July 2006 and September 2018 were identified. Through linkage to the Prescribed Drug Register, exposure to newly initiated cardiovascular medication during the case period (1-28 days prior to the onset date of unintentional poisoning) was compared with that in a corresponding control period (113-140 days prior to the onset date). Conditional logistic regression was used to determine the associations in total, for different time periods as well as by age, sex, underlying comorbidity, and use of other medications. RESULTS: Newly initiated cardiovascular medications were associated with a higher risk of unintentional poisoning, especially during the first week after initiation (odds ratio [OR]=1.39), (95% confidence interval [CI]=1.08-1.79). The risk of unintentional poisoning was comparable across age groups, sex, underlying comorbidities, and medications with OR (95% CI) ranging from 1.15 (0.75-1.74) to 2.00 (1.15-3.47). CONCLUSION: This large population-based case-crossover study showed that newly initiated cardiovascular medication is associated with an increased risk of unintentional poisoning, particularly during the first week after initiation. The risk is comparable across age, sex, underlying comorbidity, and medications.

Short-Term Risk of Unintentional Poisoning After New Initiation of Central Nervous System Medications in Swedish Older Adults: A Register-Based Case-Crossover Study.

INTRODUCTION: Medications acting on the central nervous system (CNS) are common causes of medication-related unintentional poisoning. Little is known about the short-term effects of CNS medications on unintentional poisoning. OBJECTIVE: This study aims to determine the short-term association between newly prescribed CNS drugs and unintentional poisoning. METHODS: We conducted a register-based case-crossover study of 9354 patients (age ≥ 50 years) with first-time hospitalization for unintentional poisoning in Sweden between 1 July, 2006 and 30 September, 2018. Newly initiated CNS medication was identified based on dispensations from the Swedish Prescribed Drug Register during 28 days prior to the unintentional poisoning event and compared with dispensations during an equally long control period. Conditional logistic regression was used to estimate the odds ratio and 95% confidence intervals. RESULTS: After a newly initiated CNS treatment, we found an increased risk of unintentional poisoning during the following 2 weeks with an odds ratio (95%) being 2.52 (1.98-3.21) and 1.47 (1.08-2.00) for the first and second week, respectively. The risk was elevated in all sub-groups but to a different degree with odds ratio ranges of 1.73-2.47 by age, 1.91-2.21 by sex, 1.40-2.30 by Charlson Comorbidity Index, 2.00-2.07 by neuropsychiatric comorbidity, and 1.63-2.82 by number of other medications. CONCLUSIONS: The risk of unintentional poisoning doubles in 2 weeks following a new initiation of CNS drugs and the risk is increased across a range of population groups. Clinicians should carefully monitor signs of poisoning after such initiation among not only multimorbid older adults but also those with less comorbidity and polypharmacy.

[Acute Myeloid Leukemia - Update 2022]. / Akute Myeloische Leukämien ­ Update 2022.

The suspicion of acute myeloid leukemia (AML) is a haematological emergency that requires a rapid diagnostic workup. Symptoms are usually caused by cytopenias of all blood cell lines. The differentiation of acute promyelocytic leukemia (APL) is important because of the early death rate caused by thrombembolic and bleeding events. Rapid immunophenotypic and genetic characterization is necessary for risk stratification and therapy selection. For this purpose, a center with appropriate expertise should be contacted. Therapy has become more complex due to numerous new approvals. For certain patients, the established intensive induction therapy with cytarabine and anthracycline is now combined with targeted agents, like the antibody conjugate Gemtuzumab-Ozogamicin or the FLT3 inhibitor Midostaurin. Patients with secondary AML benefit from the liposomal chemotherapy combination CPX-351. Therapy with the hypomethylating agent Azacitidine and the BCL2-inhibitor Venetoclax (Aza/Ven) represents the standard for patients who are not fit for intensive therapy. Here, it is important to consider interactions with CYP3A4-effective drugs.In most cases, APL is treated "chemotherapy-free" with all-trans retinoic acid (ATRA) and arsenic trioxide (ATO). In high-risk patients, the combination of chemotherapy and ATRA is still standard.Moreover, maintenance therapies were (re)established as an important therapeutic element of post-remission therapy. For example, Midostaurin is used in patients with FLT3 mutations, as is the multikinase inhibitor sorafenib after allogeneic stem cell transplantation. In addition, oral azacitidine is available for non-allogeneic transplant eligible patients in first complete remission. These new drugs have improved prognosis and resulted in a more individualized therapy mostly driven by genetic aberrations. This development will continue in the next years and will significantly improve treatment options, especially for older patients.

Combining BeEAM with Brentuximab Vedotin for High-Dose Therapy in CD30 Positive Lymphomas before Autologous Transplantation-A Phase I Study.

The prognosis for patients with CD30+ lymphomas (Hodgkin lymphoma and various T-cell lymphomas) relapsing after autologous stem cell transplantation (ASCT) is critical. Brentuximab vedotin (BV), an ADC targeting CD30, is an obvious candidate for inclusion into high-dose chemotherapy (HDCT) regimens to improve outcomes. This single center phase I trial investigated 12 patients with CD30+ lymphoma (AITL: n = 5; relapsed HL: n = 7; median of two previous treatment lines) undergoing ASCT. In a 3 + 3 dose escalation design, 12 patients received a single BV dose at three dose levels (DL) (0.9/1.2/1.8 mg/kg b.w.) prior to standard BeEAM. All patients were treated as planned; no dose limiting toxicities (DLTs) occurred at DL 1 and 2. At DL 3, one DLT (paralytic ileus, fully recovering) occurred. Grade III febrile neutropenia occurred in one patient, and two others had septic complications, all fully recovering. Median hospitalization was 23 days. Hematologic recovery was normal. Six of twelve (50%) patients achieved CR. PFS and OS at 1 year were 67% (n = 8/12) and 83% (n = 10/12), respectively. The addition of brentuximab to standard BeEAM HDCT seems to be safe. We observed a CR rate of 75% post-ASCT in a highly pretreated population. The efficacy of this novel HDCT combination with BV at a 1.8 mg/kg dose level needs to be explored in larger studies.

Geriatric Syndromes and Incident Chronic Health Conditions Among 9094 Older Community-Dwellers: Findings from the Lifelines Cohort Study.

OBJECTIVES: To determine the association between geriatric syndromes and any specific incident chronic health conditions among older community-dwellers. DESIGN: Population-based cohort study over a median follow-up period of 43 months. SETTING AND PARTICIPANTS: Participants from the Lifelines Cohort Study aged 60 years and older without presence of the studied chronic health conditions at baseline (n = 9094). METHODS: Baseline assessment took place between November 2006 and December 2013 and included information on socioeconomic (age, sex, level of education and income), social contact, and health-related factors [eg, self-rated health, body mass index, chronic health conditions, and health behavior (alcohol consumption and smoking)]. Participants also reported the presence of geriatric syndromes (ie, included falls, incontinence, vision impairment, hearing impairment, depressive symptoms, and frailty at baseline). Three follow-up questionnaires were used to examine the incidence of any and specific chronic health conditions (ie, pulmonary and cardiovascular diseases, diabetes, cancer, and neurological diseases). Cox regression was used to analyze the longitudinal associations between geriatric syndromes and incident chronic health conditions. RESULTS: Older community-dwelling individuals with at least one geriatric syndrome (44.7%, n = 4038) had an increased risk of developing any new chronic health condition [hazard ratio (HR) 1.35; 95% confidence interval (CI) 1.21-1.51]. The association was attenuated but remained significant after adjustment for socioeconomic factors, social contact, health status, and health behavior (HR 1.27; 95% CI 1.12-1.43). Analyses for specific chronic health conditions showed that compared with older community-dwellers without geriatric syndromes, those with geriatric syndromes had an increased risk to develop a cardiovascular health condition (HR 1.42; 95% CI 1.13-1.79) or diabetes (HR 1.53; 95% CI 1.11-2.11). They had no increased risk to develop pulmonary conditions, cancer, or neurological conditions. CONCLUSION AND IMPLICATIONS: The presence of geriatric syndromes is associated with incident chronic health conditions, specifically cardiovascular conditions and diabetes. Increased awareness is needed among older people with geriatric syndromes and their physicians. Comprehensive assessments of geriatric syndromes may help to prevent or at least delay the development of chronic health conditions.