App-Based Addiction Prevention at German Vocational Schools: Implementation and Reach for a Cluster-Randomized Controlled Trial.

This article examines the implementation, participation rates, and potential determinants of participation in the digital addiction prevention program "ready4life." A two-arm cluster-randomized trial recruited German vocational students via class-based strategies. Intervention group received 16 weeks of in-app coaching; the control group received health behavior information, with coaching offered after 12 months. Potential determinants of participation were analyzed based on class and individual characteristics. Out of 525 contacted schools, 35 participated, enrolling 376 classes. Implementation during the pandemic required flexible adjustments, with 49.7% of introductions conducted in person, 43.1% digitally via online streaming, and 7.2% received a video link via email. Despite challenges, 72.3% of the vocational students downloaded the app, and 46.7% gave informed consent. Participation rates were highest among (associate) professionals, vocational grammar school classes, classes introduced by females, younger individuals, members of the project team, and classes introduced face-to-face. Female gender, lower social competencies, lifetime cannabis use, higher problematic internet use, and higher perceived stress were associated with higher individual participation. The study highlights the importance of proactive outreach and personalized interventions for addiction prevention programs in vocational schools. While reached students aligned with the aims of the app, tailored recruitment strategies could enhance engagement among under-represented groups. The trial was registered in the German Clinical Trials Register (DRKS): DRKS00022328; registration date 09.10.2020.

Natural variation in response to combined water and nitrogen deficiencies in Arabidopsis.

Understanding plant responses to individual stresses does not mean that we understand real world situations, where stresses usually combine and interact. These interactions arise at different levels, from stress exposure to the molecular networks of the stress response. Here, we built an in-depth multi-omics description of plant responses to mild water (W) and nitrogen (N) limitations, either individually or combined, among five genetically different Arabidopsis (Arabidopsis thaliana) accessions. We highlight the different dynamics in stress response through integrative traits such as rosette growth and the physiological status of the plants. We also used transcriptomics and metabolomics profiling during a stage when the plant response was stabilized to determine the wide diversity in stress-induced changes among accessions, highlighting the limited reality of a 'universal' stress response. The main effect of the WxN interaction was an attenuation of the N-deficiency syndrome when combined with mild drought, but to a variable extent depending on the accession. Other traits subject to WxN interactions are often accession-specific. Multi-omics analyses identified a subset of transcript-metabolite clusters that are critical to stress responses but essentially variable according to the genotype factor. Including intra-specific diversity in our descriptions of plant stress response places our findings in perspective.

Posttranslational regulation of photosynthetic activity via the TOR kinase in plants.

Chloroplasts are the powerhouse of the plant cell, and their activity must be matched to plant growth to avoid photooxidative damage. We have identified a posttranslational mechanism linking the eukaryotic target of rapamycin (TOR) kinase that promotes growth and the guanosine tetraphosphate (ppGpp) signaling pathway of prokaryotic origins that regulates chloroplast activity and photosynthesis in particular. We find that RelA SpoT homolog 3 (RSH3), a nuclear-encoded enzyme responsible for ppGpp biosynthesis, interacts directly with the TOR complex via a plant-specific amino-terminal region which is phosphorylated in a TOR-dependent manner. Down-regulating TOR activity causes a rapid increase in ppGpp synthesis in RSH3 overexpressors and reduces photosynthetic capacity in an RSH-dependent manner in wild-type plants. The TOR-RSH3 signaling axis therefore regulates the equilibrium between chloroplast activity and plant growth, setting a precedent for the regulation of organellar function by TOR.

Resistance to Spindle Inhibitors in Glioblastoma Depends on STAT3 and Therapy Induced Senescence.

While mitotic spindle inhibitors specifically kill proliferating tumor cells without the toxicities of microtubule poisons, resistance has limited their clinical utility. Treating glioblastomas with the spindle inhibitors ispinesib, alisertib, or volasertib creates a subpopulation of therapy induced senescent cells that resist these drugs by relying upon the anti-apoptotic and metabolic effects of activated STAT3. Furthermore, these senescent cells expand the repertoire of cells resistant to these drugs by secreting an array of factors, including TGFß, which induce proliferating cells to exit mitosis and become quiescent-a state that also resists spindle inhibitors. Targeting STAT3 restores sensitivity to each of these drugs by depleting the senescent subpopulation and inducing quiescent cells to enter the mitotic cycle. These results support a therapeutic strategy of targeting STAT3-dependent therapy-induced senescence to enhance the efficacy of spindle inhibitors for the treatment of glioblastoma. Highlights: • Resistance to non-microtubule spindle inhibitors limits their efficacy in glioblastoma and depends on STAT3.• Resistance goes hand in hand with development of therapy induced senescence (TIS).• Spindle inhibitor resistant glioblastomas consist of three cell subpopulations-proliferative, quiescent, and TIS-with proliferative cells sensitive and quiescent and TIS cells resistant.• TIS cells secrete TGFß, which induces proliferative cells to become quiescent, thereby expanding the population of resistant cells in a spindle inhibitor resistant glioblastoma• Treatment with a STAT3 inhibitor kills TIS cells and restores sensitivity to spindle inhibitors.

Primary Tumor Resection in Leiomyosarcoma Patients With Synchronous Isolated Lung Metastases: A National Cancer Database Study.

INTRODUCTION: Up to half of patients with leiomyosarcoma (LMS) present with distant metastases, most commonly in the lungs. Despite guidelines around managing metachronous oligometastatic disease, limited evidence exists for synchronous isolated lung metastases (SILMs). Our histology-specific study describes management patterns and outcomes for patients with LMS and SILM across disease sites. METHODS: We used the National Cancer Database to analyze patients with LMS of the retroperitoneum, extremity, trunk/chest/abdominal wall, and pelvis with SILM. Patients with extra-pulmonary metastases were excluded. We identified factors associated with primary tumor resection and receipt of metastasectomy. Outcomes included median, 1-year, and 5-year overall survival (OS) across treatment approaches using log-rank tests, Kaplan-Meier curves, and Cox proportional hazard models. RESULTS: We identified 629 LMS patients with SILM from 2004 to 2017. Patients were more likely to have resection of their primary tumor or lung metastases if treated at an academic center compared to a community cancer center. Five year OS for patients undergoing both primary tumor resection and metastasectomy was 20.9% versus 9.2% for primary tumor resection alone, and 2.6% for nonsurgical patients. Median OS for all-comers was 15.5 mo. Community treatment site, comorbidity score, and larger primary tumors were associated with worse survival. Chemotherapy, primary resection, and curative intent surgery predicted improved survival on multivariate Cox regression. CONCLUSIONS: An aggressive surgical approach to primary LMS with SILM was undertaken for select patients in our population and found to be associated with improved OS. This approach should be considered for suitable patients at high-volume centers.

MT-125 Inhibits Non-Muscle Myosin IIA and IIB, Synergizes with Oncogenic Kinase Inhibitors, and Prolongs Survival in Glioblastoma.

We have identified a NMIIA and IIB-specific small molecule inhibitor, MT-125, and have studied its effects in GBM. MT-125 has high brain penetrance and retention and an excellent safety profile; blocks GBM invasion and cytokinesis, consistent with the known roles of NMII; and prolongs survival as a single agent in murine GBM models. MT-125 increases signaling along both the PDGFR- and MAPK-driven pathways through a mechanism that involves the upregulation of reactive oxygen species, and it synergizes with FDA-approved PDGFR and mTOR inhibitors in vitro . Combining MT-125 with sunitinib, a PDGFR inhibitor, or paxalisib, a combined PI3 Kinase/mTOR inhibitor significantly improves survival in orthotopic GBM models over either drug alone, and in the case of sunitinib, markedly prolongs survival in ∼40% of mice. Our results provide a powerful rationale for developing NMII targeting strategies to treat cancer and demonstrate that MT-125 has strong clinical potential for the treatment of GBM. Highlights: MT-125 is a highly specific small molecule inhibitor of non-muscle myosin IIA and IIB, is well-tolerated, and achieves therapeutic concentrations in the brain with systemic dosing.Treating preclinical models of glioblastoma with MT-125 produces durable improvements in survival.MT-125 stimulates PDGFR- and MAPK-driven signaling in glioblastoma and increases dependency on these pathways.Combining MT-125 with an FDA-approved PDGFR inhibitor in a mouse GBM model synergizes to improve median survival over either drug alone, and produces tumor free, prolonged survival in over 40% of mice.

Immunotherapy in Sarcoma: Current Data and Promising Strategies.

Traditionally sarcomas have been considered immunologically quiet tumours, with low tumour mutational burden (TMB) and an immunosuppressive tumour microenvironment (TME), consisting of decreased T-cell infiltration and elevated levels of H1F1α, macrophages and neutrophils.1,2 However, research has shown that a subset of sarcomas are immunologically 'hot' with either high TMB, PDL-1 expression, CD8+ T cells or presence of tertiary lymphoid structures (TLS) demonstrating sensitivity to immunotherapy.3,4 Here, we review the current evidence for immunotherapy use in bone sarcomas (BS) and soft tissue sarcomas (STS), with immune checkpoint inhibitors (ICI) and adoptive cellular therapies including engineered T-cell therapies, chimeric antigen receptor (CAR) T-cell therapies, tumour infiltrating lymphocytes (TILs) and cancer vaccines and biomarkers of response.

Value-Based Health Care for Prostate Cancer Centers by Implementing Specific Key Performance Indicators Using a Balanced Score Card.

BACKGROUND: Prostate cancer (PC) is the most common cancer in men in 112 countries, and accounts for 15% of cancers. Because it cannot be prevented, the rise in cases is inevitable, and improvements in diagnostic pathways and treatments are needed, as there is still a shortage of cost-effective diagnostics and widespread oncologically safe treatment options with measurable quality. As part of the implementation of a Full Cycle of Care, instruments have been developed to achieve value-based medicine, such as consistent commitment to measurability. One of these instruments is the Balanced Scorecard (BSC). Here, we propose the first BSC for prostate cancer (PC) treatment. METHODS: BSCs are used to assess performance in healthcare organizations across four dimensions: financial, patient and referrer, process, and learning and development. This study aimed to identify Key Performance Indicators (KPIs) for each perspective. A systematic literature search was conducted according to PRISMA guidelines using multiple databases and specific search terms to identify KPIs for PC care, excluding case reports and conference abstracts. In total, 44 reports were included in analyses and development of the PC-specific BSC. RESULTS: In the present study, a PC-specific BSC and KPIs were defined for the four classic perspectives, as well as for a newly developed PC-Specific Disease and Outcome perspective, including patient-related parameters from the German Cancer Society and the International Consortium for Health Outcomes Measurement. In addition, the Process perspective includes KPIs of fulfillment of continuing education of residents and the metrics of structured training of the radical prostatectomy procedure in the Learning and Development perspective. CONCLUSIONS: The developed BSC provides a comprehensive set of perspectives for an Integrated Practice Unit or center in PC care, ensuring that the indicators remain manageable and applicable. The BSC facilitates value creation in line with Porter's Full Cycle of Care by systematically collecting and providing economic, personnel, and medical results, actions, and indicators. In particular, this BSC includes KPIs of structured training of practitioners and metrics of the German Cancer Society, that recently proved to improve PC patients outcomes.

Phase Ib Study of Unesbulin (PTC596) Plus Dacarbazine for the Treatment of Locally Recurrent, Unresectable or Metastatic, Relapsed or Refractory Leiomyosarcoma.

PURPOSE: This multicenter, single-arm, open-label, phase Ib study was designed to determine the recommended phase II dose (RP2D) and to evaluate the safety and preliminary efficacy of unesbulin plus dacarbazine (DTIC) in patients with advanced leiomyosarcoma (LMS). PATIENTS AND METHODS: Adult subjects with locally advanced, unresectable or metastatic, relapsed or refractory LMS were treated with escalating doses of unesbulin orally twice per week in combination with DTIC 1,000 mg/m2 intravenously (IV) once every 21 days. The time-to-event continual reassessment method was used to determine the RP2D on the basis of dose-limiting toxicities (DLTs) assessed during the first two 21-day treatment cycles. All explored doses of unesbulin (200 mg up to 400 mg) were in combination with DTIC. An expansion cohort was enrolled to evaluate the safety and efficacy of unesbulin at the RP2D. RESULTS: Unesbulin 300 mg administered orally twice per week in combination with DTIC 1,000 mg/m2 IV once every 21 days was identified as the RP2D. On the basis of data from 27 subjects who were deemed DLT-evaluable, toxicity was higher in the unesbulin 400 mg group, with three of four subjects (75%) experiencing DLTs versus one of four subjects (25%) in the 200 mg group and three of 19 subjects (15.8%) in the 300 mg group. The most commonly reported DLTs and treatment-related grade 3 and 4 adverse events were thrombocytopenia and neutropenia. At the RP2D, seven subjects who were efficacy evaluable achieved partial response for an objective response rate of 24.1%. CONCLUSION: Unesbulin 300 mg twice per week plus DTIC 1,000 mg/m2 once every 21 days was identified as the RP2D, demonstrating a favorable benefit-risk profile in a heavily pretreated population of adults with advanced LMS.

Management of patients with an electrical storm or clustered ventricular arrhythmias: a clinical consensus statement of the European Heart Rhythm Association of the ESC-endorsed by the Asia-Pacific Heart Rhythm Society, Heart Rhythm Society, and Latin-American Heart Rhythm Society.

Electrical storm (ES) is a state of electrical instability, manifesting as recurrent ventricular arrhythmias (VAs) over a short period of time (three or more episodes of sustained VA within 24 h, separated by at least 5 min, requiring termination by an intervention). The clinical presentation can vary, but ES is usually a cardiac emergency. Electrical storm mainly affects patients with structural or primary electrical heart disease, often with an implantable cardioverter-defibrillator (ICD). Management of ES requires a multi-faceted approach and the involvement of multi-disciplinary teams, but despite advanced treatment and often invasive procedures, it is associated with high morbidity and mortality. With an ageing population, longer survival of heart failure patients, and an increasing number of patients with ICD, the incidence of ES is expected to increase. This European Heart Rhythm Association clinical consensus statement focuses on pathophysiology, clinical presentation, diagnostic evaluation, and acute and long-term management of patients presenting with ES or clustered VA.

Incidence of typhoid fever in Burkina Faso, Democratic Republic of the Congo, Ethiopia, Ghana, Madagascar, and Nigeria (the Severe Typhoid in Africa programme): a population-based study.

BACKGROUND: Typhoid Fever remains a major cause of morbidity and mortality in low-income settings. The Severe Typhoid in Africa programme was designed to address regional gaps in typhoid burden data and identify populations eligible for interventions using novel typhoid conjugate vaccines. METHODS: A hybrid design, hospital-based prospective surveillance with population-based health-care utilisation surveys, was implemented in six countries in sub-Saharan Africa. Patients presenting with fever (≥37·5°C axillary or ≥38·0°C tympanic) or reporting fever for three consecutive days within the previous 7 days were invited to participate. Typhoid fever was ascertained by culture of blood collected upon enrolment. Disease incidence at the population level was estimated using a Bayesian mixture model. FINDINGS: 27 866 (33·8%) of 82 491 participants who met inclusion criteria were recruited. Blood cultures were performed for 27 544 (98·8%) of enrolled participants. Clinically significant organisms were detected in 2136 (7·7%) of these cultures, and 346 (16·2%) Salmonella enterica serovar Typhi were isolated. The overall adjusted incidence per 100 000 person-years of observation was highest in Kavuaya and Nkandu 1, Democratic Republic of the Congo (315, 95% credible interval 254-390). Overall, 46 (16·4%) of 280 tested isolates showed ciprofloxacin non-susceptibility. INTERPRETATION: High disease incidence (ie, >100 per 100 000 person-years of observation) recorded in four countries, the prevalence of typhoid hospitalisations and complicated disease, and the threat of resistant typhoid strains strengthen the need for rapid dispatch and implementation of effective typhoid conjugate vaccines along with measures designed to improve clean water, sanitation, and hygiene practices. FUNDING: The Bill & Melinda Gates Foundation.

Clinical outcomes of patients with CIC-rearranged sarcoma: a single institution retrospective analysis.

PURPOSE: CIC-rearranged sarcomas represent a type of undifferentiated small round cell sarcoma (USRCS) characterized by poor survival, rapid development of chemotherapy resistance, and high rates of metastasis. We aim to contribute to the growing body of knowledge regarding diagnosis, treatment, clinical course, and outcomes for these patients. METHODS: This case series investigates the clinical courses of ten patients with CIC-rearranged sarcoma treated at the Johns Hopkins Hospital from July 2014 through January 2024. Clinical data were retrospectively extracted from electronic medical records. RESULTS: Patients ranged from 10 to 67 years of age at diagnosis, with seven patients presenting with localized disease and three with metastatic disease. Tumors originated from soft tissues of various anatomic locations. Mean overall survival (OS) was 22.1 months (10.6-52.2), and mean progression-free survival (PFS) was 16.7 months (5.3-52.2). Seven patients received intensive systemic therapy with an Ewing sarcoma-directed regimen or a soft tissue sarcoma-directed regimen. Three patients experienced prolonged disease-free survival without systemic treatment. CONCLUSION: Most patients in this case series demonstrated aggressive clinical courses consistent with those previously described in the literature, although we note a spectrum of clinical outcomes not previously reported. The diversity of clinical courses underscores the need for an improved understanding of individual tumor biology to enhance clinical decision-making and patient prognosis. Despite its limitations, this article broadens the spectrum of reported clinical outcomes, providing a valuable addition to the published literature on this rare cancer.

In-Hospital Pulmonary Arterial Embolism after Catheter Ablation of Over 45,000 Cardiac Arrhythmias: Individualized Case Analysis of Multicentric Data.

OBJECTIVE AND BACKGROUND: Data on incidence of in-hospital pulmonary embolisms (PE) after catheter ablation (CA) are scarce. To gain further insights, we sought to provide new findings through case-based analyses of administrative data. METHODS: Incidences of PE after CA of supraventricular tachycardias (SVT), atrial fibrillation (AF), atrial flutter (AFlu), and ventricular tachycardias (VT) in three German tertiary centers between 2005 and 2020 were determined and coded by the G-DRG (German Diagnosis Related Groups System) and OPS (German Operation and Procedure Classification) systems. An administrative search was performed with a consecutive case-based analysis. RESULTS: Overall, 47,344 ablations were analyzed (10,037 SVT; 28,048 AF; 6,252 AFlu; 3,007 VT). PE occurred in 14 (0.03%) predominantly female (n = 9; 64.3%) patients with a mean age of 55.3 ± 16.9 years, body mass index 26.2 ± 5.1 kg/m2, and left ventricular ejection fraction of 56 ± 13.6%. PE incidences were 0.05% (n = 5) for SVT, 0.02% (n = 5) for AF, and 0.13% (n = 4) for VT ablations. No patient suffered PE after AFlu ablation. Five patients (35.7%) with PE after CA had no prior indication for oral anticoagulation (OAC). Preprocedural international normalized ratio in PE patients was 1.2 ± 0.5. Most patients with PE following CA presented with symptoms the day after the procedure (n = 9) after intraprocedural heparin application of 12,943.2 ± 5,415.5 IU. PE treatment included anticoagulation with either phenprocoumon (n = 5) or non-vitamin K-dependent OAC (n = 9). Two patients with PE died after VT/AF ablation, respectively. The remaining patients were discharged without sequels. CONCLUSION: Over a 15-year period, incidence of PE after ablation is low, particularly low in patients with ablation for AF/AFlu. This is most likely due to stricter anticoagulation management in these patients compared with those receiving SVT/VT ablation procedures and could argue for continuation of OAC prior to ablation. Optimizing periprocedural anticoagulation management should be subject of further prospective trials.

Sensing and regulation of C and N metabolism - novel features and mechanisms of the TOR and SnRK1 signaling pathways.

Carbon (C) and nitrogen (N) metabolisms are tightly integrated to allow proper plant growth and development. Photosynthesis is dependent on N invested in chlorophylls, enzymes, and structural components of the photosynthetic machinery, while N uptake and assimilation rely on ATP, reducing equivalents, and C-skeletons provided by photosynthesis. The direct connection between N availability and photosynthetic efficiency allows the synthesis of precursors for all metabolites and building blocks in plants. Thus, the capacity to sense and respond to sudden changes in C and N availability is crucial for plant survival and is mediated by complex yet efficient signaling pathways such as TARGET OF RAPAMYCIN (TOR) and SUCROSE-NON-FERMENTING-1-RELATED PROTEIN KINASE 1 (SnRK1). In this review, we present recent advances in mechanisms involved in sensing C and N status as well as identifying current gaps in our understanding. We finally attempt to provide new perspectives and hypotheses on the interconnection of diverse signaling pathways that will allow us to understand the integration and orchestration of the major players governing the regulation of the CN balance.

Effect of SGLT-2 inhibitors on arrhythmia events: insight from an updated secondary analysis of > 80,000 patients (the SGLT2i-Arrhythmias and Sudden Cardiac Death).

OBJECTIVE: We aimed to assess the effect of SGLT2i on arrhythmias by conducting a meta-analysis using data from randomized controlled trials(RCTs). BACKGROUND: Sodium-glucose co-transporter 2 inhibitors (SGLT2i) have shown cardioprotective effects via multiple mechanisms that may also contribute to decrease arrhythmias risk. METHODS: We searched in databases (PubMed, Embase, Cochrane Library, and clinicaltrials.gov) up to April 2023. RCTs comparing SGLT2i with placebo were included. The effects of SGLT2i on atrial fibrillation(AF), atrial flutter(AFL), composite AF/AFL, ventricular fibrillation(VF), ventricular tachycardia(VT), ventricular extrasystoles(VES), sudden cardiac death(SCD) and composite VF/VT/SCD were evaluated. RESULTS: 33 placebo-controlled RCTs were included, comprising 88,098 patients (48,585 in SGLT2i vs. 39,513 in placebo). The mean age was 64.9 ± 9.4 years, 63.0% were male. The mean follow-up was 1.4 ± 1.1 years. The pooled-results showed that SGLT2i was associated with a significantly lower risk of AF [risk ratio(RR): 0.88, 95% confidence interval(CI) 0.78-1.00, P = 0.04] and composite AF/AFL (RR: 0.86, 95%CI 0.77-0.96, P = 0.01). This favorable effect appeared to be substantially pronounced in patients with HFrEF, male gender, dapagliflozin, and > 1 year follow-up. For SCD, only in heart failure patients, SGLT2i were found to be associated with a borderline lower risk of SCD (RR: 0.67, P = 0.05). No significant effects of SGLT2i on other ventricular arrhythmic outcomes were found. CONCLUSIONS: SGLT2i lowers the risks of AF and AF/AFL, and this favorable effect appeared to be particularly pronounced in patients with HFrEF, male gender, dapagliflozin, and longer follow-up (> 1 year). SGLT2i lowers the risk of SCD only in heart failure patients.

Treatment patterns and outcomes for primary uterine leiomyosarcoma with synchronous isolated lung metastases: A National Cancer Database study of primary resection and metastasectomy.

Background: One third of patients with uterine leiomyosarcomas (uLMS) present with distant metastases. Current guidelines do not include recommendations around surgery for metastatic uLMS. Patients with distant metastases commonly receive primary tumor resection for symptoms and so oncologic outcomes after surgery warrant exploration. We describe treatment patterns and outcomes for uLMS patients with synchronous isolated lung metastases (SILM). Methods: This retrospective analysis of the National Cancer Database identified patients with uLMS and SILM. Patients with non-pulmonary metastases were excluded. We collected demographic, disease, and treatment characteristics and assessed clinicopathologic factors associated with the receipt of surgery on multivariate regression. Median, 1-year, and 5-year overall survival (OS) across treatment approaches were compared using Kaplan-Meier curves and log-rank tests. Multivariate Cox proportional hazard regressions identified independent predictors of survival. Results: We identified 905 patients with uLMS and SILM between 2004 and 2017. 600 patients had primary tumor resection; 63 also had curative intent surgery with metastasectomy. Patients who did not receive chemotherapy were older (p<0.01) with a higher comorbidity index (p<0.05). Women with private health insurance were more likely to receive chemotherapy (p<0.01) and primary tumor resection (p<0.01). Patients who underwent curative intent surgery had 1-year OS of 71.2% and 5-year survival of 18% compared to 1-year survival of 35.6 % and 5-year survival of 5.16 % for patients who had no surgery. Black women had poorer survival on multivariate regression. Conclusions: Primary tumor resection and curative intent surgery are associated with improved OS in uLMS with SILM and may be a reasonable treatment option in appropriately selected patients.

Early detection of malignant and pre-malignant peripheral nerve tumors using cell-free DNA fragmentomics.

Early detection of neurofibromatosis type 1 (NF1) associated peripheral nerve sheath tumors (PNST) informs clinical decision-making, potentially averting deadly outcomes. Here, we describe a cell-free DNA (cfDNA) fragmentomic approach which distinguishes non-malignant, pre-malignant and malignant forms of NF1 PNST. Using plasma samples from a novel cohort of 101 NF1 patients and 21 healthy controls, we validated that our previous cfDNA copy number alteration (CNA)-based approach identifies malignant peripheral nerve sheath tumor (MPNST) but cannot distinguish among benign and premalignant states. We therefore investigated the ability of fragment-based cfDNA features to differentiate NF1-associated tumors including binned genome-wide fragment length ratios, end motif analysis, and non-negative matrix factorization deconvolution of fragment lengths. Fragmentomic methods were able to differentiate pre-malignant states including atypical neurofibromas (AN). Fragmentomics also adjudicated AN cases suspicious for MPNST, correctly diagnosing samples noninvasively, which could have informed clinical management. Overall, this study pioneers the early detection of malignant and premalignant peripheral nerve sheath tumors in NF1 patients using plasma cfDNA fragmentomics. In addition to screening applications, this novel approach distinguishes atypical neurofibromas from benign plexiform neurofibromas and malignant peripheral nerve sheath tumors, enabling more precise clinical diagnosis and management.

Behavior-related risk factors and time to death among persons with alcohol consumption versus persons without: A general population study with mortality follow-up after 20 years.

BACKGROUND: Evidence shows that low to moderate alcohol consumers seem to live longer than abstainers. Insufficient consideration of subgroups among abstainers and of further behavior-related risk factors for death might be reasons. The aim of this study was to compare alcohol lifetime abstainers, former drinkers, and current consumers with regard to mortality considering tobacco smoking, body overweight, and physical inactivity. METHODS: A general adult population sample of residents aged 18 to 64 had been drawn at random in northern Germany. Among eligible persons, 4093 (70.2%) participated. Assessments included alcohol consumption by the Alcohol Use Disorders Identification Test Consumption in addition to lifetime alcohol abstinence and former drinking. A score of behavior-related risk factors was built from tobacco smoking, body overweight, and physical inactivity. Twenty years later, a mortality follow-up was conducted. Data of 4028 study participants were analyzed. RESULTS: At baseline, former alcohol consumers but not current low to moderate alcohol drinkers had more behavior-related risk factors than lifetime abstainers. At follow-up, former alcohol drinkers with two or more behavior-related risk factors had a shorter time to death than lifetime abstainers with 0 or one behavior-related risk factor (hazard ratio 3.43, 95% confidence interval: 1.63-7.20). Low to moderate alcohol drinkers did not survive longer than lifetime alcohol abstainers with 0 or one behavior-related risk factor. CONCLUSION: The results provide evidence against the assumption that alcohol consumption has a beneficial effect on health and longevity.