Search

PurposeTo assess the safety and efficacy of the third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor osimertinib as neoadjuvant therapy in patients with surgically resectable stage I-IIIA EGFR-mutated non-small cell lung cancer (NSCLC).Patients and methodsThis was a multi-institutional phase II trial of neoadjuvant osimertinib for patients with surgically resectable stage I-IIIA (American Joint Committee on Cancer [AJCC] V7) EGFR-mutated (L858R or exon 19 deletion) NSCLC (ClinicalTrials.gov identifier: NCT03433469). Patients received osimertinib 80 mg orally once daily for up to two 28-day cycles before surgical resection. The primary end point was major pathological response (MPR) rate. Secondary safety and efficacy end points were also assessed. Exploratory end points included pretreatment and post-treatment tumor mutation profiling.ResultsA total of 27 patients were enrolled and treated with neoadjuvant osimertinib for a median 56 days before surgical resection. Twenty-four (89%) patients underwent subsequent surgery; three (11%) patients were converted to definitive chemoradiotherapy. The MPR rate was 14.8% (95% CI, 4.2 to 33.7). No pathological complete responses were observed. The ORR was 52%, and the median DFS was 40.9 months. One treatment-related serious adverse event (AE) occurred (3.7%). No patients were unable to undergo surgical resection or had surgery delayed because of an AE. The most common co-occurring tumor genomic alterations were in TP53 (42%) and RBM10 (21%).ConclusionTreatment with neoadjuvant osimertinib in surgically resectable (stage IA-IIIA, AJCC V7) EGFR-mutated NSCLC did not meet its primary end point for MPR rate. However, neoadjuvant osimertinib did not lead to unanticipated AEs, surgical delays, nor result in a significant unresectability rate.

BACKGROUND: Cardiac arrest is a common and devastating emergency of both the heart and brain. More than 380,000 patients suffer out-of-hospital cardiac arrest annually in the USA. Induced cooling of comatose patients markedly improved neurological and functional outcomes in pivotal randomized clinical trials, but the optimal duration of therapeutic hypothermia has not yet been established. METHODS: This study is a multi-center randomized, response-adaptive, duration (dose) finding, comparative effectiveness clinical trial with blinded outcome assessment. We investigate two populations of adult comatose survivors of cardiac arrest to ascertain the shortest duration of cooling that provides the maximum treatment effect. The design is based on a statistical model of response as defined by the primary endpoint, a weighted 90-day mRS (modified Rankin Scale, a measure of neurologic disability), across the treatment arms. Subjects will initially be equally randomized between 12, 24, and 48 h of therapeutic cooling. After the first 200 subjects have been randomized, additional treatment arms between 12 and 48 h will be opened and patients will be allocated, within each initial cardiac rhythm type (shockable or non-shockable), by response adaptive randomization. As the trial continues, shorter and longer duration arms may be opened. A maximum sample size of 1800 subjects is proposed. Secondary objectives are to characterize: the overall safety and adverse events associated with duration of cooling, the effect on neuropsychological outcomes, and the effect on patient-reported quality of life measures. DISCUSSION: In vitro and in vivo studies have shown the neuroprotective effects of therapeutic hypothermia for cardiac arrest. We hypothesize that longer durations of cooling may improve either the proportion of patients that attain a good neurological recovery or may result in better recovery among the proportion already categorized as having a good outcome. If the treatment effect of cooling is increasing across duration, for at least some set of durations, then this provides evidence of the efficacy of cooling itself versus normothermia, even in the absence of a normothermia control arm, confirming previous RCTs for OHCA survivors of shockable rhythms and provides the first prospective controlled evidence of efficacy in those without initial shockable rhythms. TRIAL REGISTRATION: ClinicalTrials.gov NCT04217551. Registered on 30 December 2019.

BACKGROUND: Patients with telomere biology disorders (TBD) develop hepatic disease, including hepatitis, cirrhosis, and hepatopulmonary syndrome. No specific treatment exists for TBD-related liver disease, and the role of liver transplantation (LT) remains controversial. Our study objectives were to describe the clinical characteristics, management, and outcomes in patients with TBD-related liver disease, and their LT outcomes. METHODS: Data from 83 patients with TBD-associated liver disease were obtained from 17 participating centers in the Clinical Care Consortium of Telomere-Associated Ailments and by self-report for our retrospective, multicenter, international cohort study. RESULTS: Group A (Advanced) included 40 patients with advanced liver disease. Of these, 20 underwent LT (Group AT). Group M (Mild) included 43 patients not warranting LT evaluation, none of whom were felt to be medically unfit for liver transplantation. Supplemental oxygen requirement, pulmonary arteriovenous malformation, hepatopulmonary syndrome, and higher bilirubin and international normalized ratio values were associated with Group A. Other demographics, clinical manifestations, and laboratory findings were similar between groups. Six group A patients were declined for LT; 3 died on the waitlist. Median follow-up post-LT was 2.9 years (range 0.6-13.2 y). One-year survival post-LT was 73%. Median survival post-LT has not been reached. Group AT patients had improved survival by age compared to all nontransplant patients (log-rank test p = 0.02). Of 14 patients with pretransplant hypoxemia, 8 (57%) had improved oxygenation after transplant. CONCLUSIONS: LT recipients with TBD do not exhibit excessive posttransplant mortality, and LT improved respiratory status in 57%. A TBD diagnosis should not exclude LT consideration.

Teaching statistics to undergraduate business students is an enduring challenge, often due to student apprehension and low understanding of relevance. The Data to Decision Project is an approach designed to address this challenge. At the onset of an introductory statistics course, fifty-two students received instruction on the Define, Collect, Organize, Visualize and Analyze (DCOVA) framework to integrate data with business-related decision-making. Concurrent with this instruction, students selected and completed individual projects, using the DCOVA framework to explore their individual decisions. Quantitative and qualitative methods indicated that this approach positively impacted the students' ability to apply statistics, as well as their attitudes regarding their statistics abilities.

Abstract Background Cardiac arrest is a common and devastating emergency of both the heart and brain. More than 380,000 patients suffer out-of-hospital cardiac arrest annually in the USA. Induced cooling of comatose patients markedly improved neurological and functional outcomes in pivotal randomized clinical trials, but the optimal duration of therapeutic hypothermia has not yet been established. Methods This study is a multi-center randomized, response-adaptive, duration (dose) finding, comparative effectiveness clinical trial with blinded outcome assessment. We investigate two populations of adult comatose survivors of cardiac arrest to ascertain the shortest duration of cooling that provides the maximum treatment effect. The design is based on a statistical model of response as defined by the primary endpoint, a weighted 90-day mRS (modified Rankin Scale, a measure of neurologic disability), across the treatment arms. Subjects will initially be equally randomized between 12, 24, and 48 h of therapeutic cooling. After the first 200 subjects have been randomized, additional treatment arms between 12 and 48 h will be opened and patients will be allocated, within each initial cardiac rhythm type (shockable or non-shockable), by response adaptive randomization. As the trial continues, shorter and longer duration arms may be opened. A maximum sample size of 1800 subjects is proposed. Secondary objectives are to characterize: the overall safety and adverse events associated with duration of cooling, the effect on neuropsychological outcomes, and the effect on patient-reported quality of life measures. Discussion In vitro and in vivo studies have shown the neuroprotective effects of therapeutic hypothermia for cardiac arrest. We hypothesize that longer durations of cooling may improve either the proportion of patients that attain a good neurological recovery or may result in better recovery among the proportion already categorized as having a good outcome. If the treatment effect of cooling is increasing across duration, for at least some set of durations, then this provides evidence of the efficacy of cooling itself versus normothermia, even in the absence of a normothermia control arm, confirming previous RCTs for OHCA survivors of shockable rhythms and provides the first prospective controlled evidence of efficacy in those without initial shockable rhythms. Trial registration ClinicalTrials.gov NCT04217551. Registered on 30 December 2019.

Abstract Backgrounds Team leadership skills of physicians working in high-performing medical teams are directly related to outcome. It is currently unclear how these skills can best be developed. Therefore, in this multi-national cross-sectional prospective study, we explored the development of these skills in relation to physician-, organization- and training characteristics of Helicopter Emergency Medicine Service (HEMS) physicians from services in Europe, the United States of America and Australia. Methods Physicians were asked to complete a survey regarding their HEMS service, training, and background as well as a full Leader Behavior Description Questionnaire (LBDQ). Primary outcomes were the 12 leadership subdomain scores as described in the LBDQ. Secondary outcome measures were the association of LBDQ subdomain scores with specific physician-, organization- or training characteristics and self-reported ways to improve leadership skills in HEMS physicians. Results In total, 120 HEMS physicians completed the questionnaire. Overall, leadership LBDQ subdomain scores were high (10 out of 12 subdomains exceeded 70% of the maximum score). Whereas physician characteristics such as experience or base-specialty were unrelated to leadership qualities, both organization- and training characteristics were important determinants of leadership skill development. Attention to leadership skills during service induction, ongoing leadership training, having standards in place to ensure (regular) scenario training and holding structured mission debriefs each correlated with multiple LBDQ subdomain scores. Conclusions Ongoing training of leadership skills should be stimulated and facilitated by organizations as it contributes to higher levels of proficiency, which may translate into a positive effect on patient outcomes. Trial registration Not applicable.

Long noncoding RNA (lncRNA) genes outnumber protein coding genes in the human genome and the majority remain uncharacterized. A major difficulty in generalizing understanding of lncRNA function is the dearth of gross sequence conservation, both for lncRNAs across species and for lncRNAs that perform similar functions within a species. Machine learning based methods which harness vast amounts of information on RNAs are increasingly used to impute certain biological characteristics. This includes interactions with proteins that are important mediators of RNA function, thus enabling the generation of knowledge in contexts for which experimental data are lacking. Here, we applied a natural language-based machine learning approach that enabled us to identify RNA binding protein interactions in lncRNA transcripts, using only RNA sequence as an input. We found that this predictive method is a powerful approach to infer conserved binding across species as distant as human and opossum, even in the absence of sequence conservation, thus informing on sequence-function relationships for these poorly understood RNAs.

BackgroundCognitive dysfunction is a common problem in multiple sclerosis (MS). Progress toward understanding and treating cognitive dysfunction is thwarted by the limitations of traditional cognitive tests, which demonstrate poor sensitivity and ecological validity. Ambulatory methods of assessing cognitive function in the lived environment may improve the detection of subtle changes in cognitive function and the identification of predictors of cognitive changes and downstream effects of cognitive change on other functional domains. ObjectiveThis paper describes the study design and protocol for the Optimizing Detection and Prediction of Cognitive Function in Multiple Sclerosis (CogDetect-MS) study, a 2-year longitudinal observational study designed to examine short- and long-term changes in cognition, predictors of cognitive change, and effects of cognitive change on social and physical function in MS. MethodsParticipants—ambulatory adults with medically documented MS—are assessed over the course of 2 years on an annual basis (3 assessments: T1, T2, and T3). A comprehensive survey battery, in-laboratory cognitive and physical performance tests, and 14 days of ambulatory data collection are completed at each annual assessment. The 14-day ambulatory data collection includes continuous wrist-worn accelerometry (to measure daytime activity and sleep); ecological momentary assessments (real-time self-report) of somatic symptoms, mood, and contextual factors; and 2 brief, validated cognitive tests, administered by smartphone app 4 times per day. Our aim was to recruit 250 participants. To ensure standard test protocol administration, all examiners passed a rigorous examiner certification process. Planned analyses include (1) nonparametric 2-tailed t tests to compare in-person to ambulatory cognitive test scores; (2) mixed effects models to examine cognitive changes over time; (3) mixed effects multilevel models to evaluate whether ambulatory measures of physical activity, sleep, fatigue, pain, mood, and stress predict changes in objective or subjective measures of cognitive functioning; and (4) mixed effects multilevel models to examine whether ambulatory measures of cognitive functioning predict social and physical functioning over short (within-day) and long (over years) time frames. ResultsThe study was funded in August 2021 and approved by the University of Michigan Medical Institutional Review Board on January 27, 2022. A total of 274 adults with MS (first participant enrolled on May 12, 2022) have been recruited and provided T1 data. Follow-up data collection will continue through March 2026. ConclusionsResults from the CogDetect-MS study will shed new light on the temporal dynamics of cognitive function, somatic and mood symptoms, sleep, physical activity, and physical and social function. These insights have the potential to improve our understanding of changes in cognitive function in MS and enable us to generate new interventions to maintain or improve cognitive function in those with MS. Trial RegistrationClinicalTrials.gov NCT05252195; https://clinicaltrials.gov/study/NCT05252195 International Registered Report Identifier (IRRID)DERR1-10.2196/59876

Abstract Although classically recognized as a neurotransmitter, gamma aminobutyric acid (GABA) has also been identified in colonic tumors. Moreover, the gut microbiome represents another potential source of GABA. Both GABAA and GABAB receptors have been implicated in contributing to the effects of GABA in colorectal cancer, with both pro‐ and anti‐tumorigenic functions identified. However, their subunit composition is often overlooked. Studies to date have not addressed whether the GABA‐producing potential of the microbiome changes over the course of colon tumor development or whether receptor subunit expression patterns are altered in colon cancer. Therefore, we investigated the clusters of orthologous group frequencies of glutamate decarboxylase (GAD) in feces from two murine models of colon cancer and found that the frequency of microbial GAD was significantly decreased early in the tumorigenic process. We also determined that microbial‐derived GABA inhibited proliferation of colon cancer cells in vitro and that this effect of GABA on SW480 cells involved both GABAA and GABAB receptors. GABA also inhibited prostaglandin E2 (PGE2)‐induced proliferation and interleukin‐6 (IL‐6) expression in these cells. Gene expression correlations were assessed using the “Cancer Exploration” suite of the TIMER2.0 web tool and identified that GABA receptor subunits were differentially expressed in human colon cancer. Moreover, GABAA receptor subunits were predominantly positively associated with PGE2 synthase, cyclooxygenase‐2 and IL‐6. Collectively, these data demonstrate decreased potential of the microbiome to produce GABA during tumorigenesis, a novel anti‐tumorigenic pathway for GABA, and that GABA receptor subunit expression adds a further layer of complexity to GABAergic signaling in colon cancer.

Abstract Constitutional heterozygous pathogenic variants in genes coding for some components of the Fanconi anemia-BRCA signaling pathway, which repairs DNA interstrand crosslinks, represent risk factors for common cancers, including breast, ovarian, pancreatic and prostate cancer. A high cancer risk is also a main clinical feature in patients with Fanconi anemia (FA), a rare condition characterized by bone marrow failure, endocrine and physical abnormalities. The mainly recessive condition is caused by germline pathogenic variants in one of 21 FA-BRCA pathway genes. Among patients with FA, the highest cancer risks are observed in patients with biallelic pathogenic variants in BRCA2 or PALB2. These patients develop a range of embryonal tumors and leukemia during the first decade of life, however, little is known about specific clinical, genetic and pathologic features or toxicities. Here, we present genetic, clinical, pathological and treatment characteristics observed in an international cohort of eight patients with FA due to biallelic BRCA2 pathogenic variants and medulloblastoma (MB), an embryonal tumor of the cerebellum. Median age at MB diagnosis was 32.5 months (range 7–58 months). All patients with available data had sonic hedgehog-MB. Six patients received chemotherapy and one patient also received proton radiation treatment. No life-threatening toxicities were documented. Prognosis was poor and all patients died shortly after MB diagnosis (median survival time 4.5 months, range 0–21 months) due to MB or other neoplasms. In conclusion, MB in patients with biallelic BRCA2 pathogenic variants is a lethal disease. Future experimental treatments are necessary to help these patients.

Abstract Background A frequent complication of Fontan operations is unilateral diaphragmatic paresis, which leads to hemodynamic deterioration of the Fontan circulation. A potential new therapeutic option is the unilateral diaphragmatic pacemaker. In this study, we investigated the most effective stimulation location for a potential fully implantable system in a porcine model. Methods Five pigs (20.8 ± 0.95 kg) underwent implantation of a customized cuff electrode placed around the right phrenic nerve. A bipolar myocardial pacing electrode was sutured adjacent to the motor point and peripherally at the costophrenic angle (peripheral diaphragmatic muscle). The electrodes were stimulated 30 times per minute with a pulse duration of 200 µs and a stimulation time of 300 ms. Current intensity was the only variable changed during the experiment. Results Effective stimulation occurred at 0.26 ± 0.024 mA at the phrenic nerve and 7 ± 1.22 mA at the motor point, a significant difference in amperage (p = 0.005). Even with a maximum stimulation of 10 mA at the peripheral diaphragm muscle, however, no effective stimulation was observed. Conclusion The phrenic nerve seems to be the best location for direct stimulation by a unilateral thoracic diaphragm pacemaker in terms of the required amperage level in a porcine model.

Shailey Gale Twamley,1– 3 Niclas Gimber,4 Héctor Eduardo Sánchez-Ibarra,1,2 Tobias Christaller,1,2 Victoria Isakzai,1,2 Harald Kratz,5 Ronodeep Mitra,6 Lena Kampen,1– 3 Anke Stach,1,2 Heike Heilmann,7 Berit Söhl-Kielczynski,8 Eno Essien Ebong,6,9,10 Jan Schmoranzer,4 Agnieszka Münster-Wandowski,7,* Antje Ludwig1– 3,* 1Department of Cardiology, Angiology and Intensive Care Medicine, Deutsches Herzzentrum der Charité, Berlin, Germany; 2Department of Cardiology, Angiology and Intensive Care Medicine, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität Zu Berlin, Berlin, Germany; 3DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Berlin, Germany; 4Advanced Medical Bioimaging Core Facility (AMBIO), Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany; 5Department of Radiology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany; 6Department of Chemical Engineering, Northeastern University, Boston, MA, USA; 7Institute of Integrative Neuroanatomy, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany; 8Institute for Integrative Neurophysiology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Zu Berlin, and Berlin Institute of Health, Berlin, Germany; 9Department of Bioengineering, Northeastern University, Boston, MA, USA; 10Department of Neuroscience, Albert Einstein College of Medicine, New York, NY, USA*These authors contributed equally to this workCorrespondence: Shailey Gale Twamley; Antje Ludwig, Tel +49-30-450-528455 ; +49-30-450-513196, Fax +49-30-450-528922 ; +49-30-450941, Email shailey.twamley@charite.de; antje.ludwig@dhzc-charite.dePurpose: To study whether the absence of laminar shear stress (LSS) enables the uptake of very small superparamagnetic iron oxide nanoparticles (VSOP) in endothelial cells by altering the composition, size, and barrier function of the endothelial surface layer (ESL).Methods and Results: A quantitative particle exclusion assay with living human umbilical endothelial cells using spinning disc confocal microscopy revealed that the dimension of the ESL was reduced in cells cultivated in the absence of LSS. By combining gene expression analysis, flow cytometry, high pressure freezing/freeze substitution immuno-transmission electron microscopy, and confocal laser scanning microscopy, we investigated changes in ESL composition. We found that increased expression of the hyaluronan receptor CD44 by absence of shear stress did not affect the uptake rate of VSOPs. We identified collagen as a previously neglected component of ESL that contributes to its barrier function. Experiments with inhibitor halofuginone and small interfering RNA (siRNA) demonstrated that suppression of collagen expression facilitates VSOP uptake in endothelial cells grown under LSS.Conclusion: The absence of laminar shear stress disturbs the barrier function of the ESL, facilitating membrane accessibility and endocytic uptake of VSOP. Collagen, a previously neglected component of ESL, contributes to its barrier function. Keywords: citrate coated nanoparticles, atherosclerosis, blood flow, endothelial barrier, permeability, internalization

Katarzyna Sołkiewicz,1 Izabela Kokot,1 Violetta Dymicka-Piekarska,2 Justyna Dorf,2 Ewa Maria Kratz1 1Department of Laboratory Diagnostics, Division of Laboratory Diagnostics, Faculty of Pharmacy, Wroclaw Medical University, Wroclaw, Poland; 2Department of Clinical Laboratory Diagnostics, Medical University of Bialystok, Bialystok, PolandCorrespondence: Ewa Maria Kratz; Katarzyna Sołkiewicz, Email ewa.kratz@umw.edu.pl; katarzyna.solkiewicz@umw.edu.plIntroduction: Immunoglobulin G (IgG) glycosylation affects its effector functions and is essential in many steps of the inflammatory cascade. Therefore, it may be an important parameter for assessing the body’s immune response during the course of COVID-19 (Coronavirus disease 2019).Methods: The N- and O-glycosylation of serum IgG in severe COVID-19 patients (n=87), convalescents (n=50), and healthy subjects (n=65) were examined using a modified lectin-ELISA method with specific biotinylated lectins. The obtained data were analyzed using STATISTICA 13.3PL software.Results: We showed significantly higher expression of Lewisx oligosaccharide structures in severe COVID-19 patients than in the other two groups. Moreover, significantly lower expression of Lewisy sugar structures in IgG glycans was observed in the convalescents when compared with COVID-19 patients and healthy subjects. The lowest expression of highly branched N-glycans in cases of severe COVID-19 indicates that the development of the disease is associated with the presence of typical IgG biantennary N-glycans. The lack of significant differences in the expression of Tn antigen in IgG between studied groups and the significantly lower expression of T antigen in convalescents compared to the patients with severe COVID-19 and healthy subjects indicates a decrease in the content of the T antigen in IgG O-glycans in subjects recovered from COVID-19. Substantially higher reactivities of IgG O-glycans with Jacalin observed in COVID-19 patients and convalescents in comparison to the control group were most probably caused by increased expression of core 3 O-glycans in IgG.Conclusion: Severe COVID-19 is accompanied by the expression in serum IgG of sialylated biantennary and highly branched N-glycans, decorated by fucose of Lewisx and Lewisy structures. The higher reactivity of IgG O-glycans with Jacalin in severe COVID-19 patients and convalescents indicates that the disease development and the recovery process are most probably accompanied by increased expression of the core 3 O-glycans.Keywords: serum IgG, glycosylation, SARS-CoV-2, COVID-19, inflammation

Abstract Background Low-dose computed tomography (lung cancer screening) can reduce lung cancer-specific mortality by 20–24%. Based on this evidence, the United States Preventive Services Task Force recommends annual lung cancer screening for asymptomatic high-risk individuals. Despite this recommendation, utilization is low (3–20%). Lung cancer screening may be particularly beneficial for African American patients because they are more likely to have advanced disease, lower survival, and lower screening rates compared to White individuals. Evidence points to multilevel approaches that simultaneously address multiple determinants to increase screening rates and decrease lung cancer burden in minoritized populations. This study will test the effects of provider- and patient-level strategies for promoting equitable lung cancer screening utilization. Methods Guided by the Health Disparities Research Framework and the Practical, Robust Implementation and Sustainability Model, we will conduct a quasi-experimental study with four primary care clinics within a large health system (MedStar Health). Individuals eligible for lung cancer screening, defined as 50–80 years old, ≥ 20 pack-years, currently smoking, or quit

Epidemiology of carbapenem-resistant organisms (CRO) has focused on transmission in acute care hospital or long-term care facility (LTCF) settings. Few investigations have examined community-associated (CA)-CRO, with no consensus about common exposures. To explore possible exposures, the New York City (NYC) Department of Health and Mental Hygiene investigated suspected CA-CRO cases through routine surveillance among NYC residents with specimens collected during December 2020-May 2023. CA-CRO cases were defined as urine or skin specimens with bacterial cultures exhibiting carbapenem resistance, among individuals aged ≤70 years with no international travel, hospitalization, or LTCF stays within 12 months before specimen collection. Inclusion was determined by reviewing data from health information exchanges, when available electronic medical records, and telephone screening for those not excluded through record review. We identified 426 suspected cases for review, those not meeting the case definition were excluded; 44 individuals were not reached for screening. A preliminary questionnaire was fielded with 12 individuals and then refined to capture additional potential exposures. Analyses were completed with 23 individuals interviewed with the refined questionnaire. Of the 23, 70% were female; 39% were Hispanic, 17% Black, and 17% White; their median age was 60 years (range: 26-70 years). Further, 83% reported an outpatient appointment, 48% reported an outpatient procedure/surgery, and 9% reported having a hospitalized household member, all within 12 months before specimen collection; 26% had a urinary catheter or indwelling device within 2 days of specimen collection. Additionally, 30% reported taking antibiotics within 3 months of specimen collection, 52% denied taking antibiotics, 9% were unsure about antibiotic use, and 9% did not answer the question. Whole genome sequencing (WGS) was performed on 14 available isolates from CA-CRO cases by the NYC Public Health Laboratory or Wadsworth Center (WC), of which only 7 could be compared with isolates previously sequenced at WC (2017-2023). Six isolates were separated by >50 mutation events, suggesting no close genomic relationship. One isolate from 2021 was 11 mutation events from a 2018 isolate from the same individual, consistent with the expected evolutionary rate. While infrequent, CA-CRO cases occur in NYC. Outpatient healthcare, antibiotic use, and urinary catheters or indwelling devices were common self-reported exposures. Analyses were limited by screening non-response. Increased specimen availability for WGS could enhance investigation of CA-CRO exposure patterns. Health information exchange data were often incomplete and future surveillance could benefit from healthcare and public health partnerships and better documentation for more complete electronic medical histories.

Background:. A person diagnosed with gender dysphoria who was assigned female at birth (AFAB) may request a vaginectomy as part of gender-affirming treatment. The aim of this study was to investigate the impact of vaginectomy on symptoms of pelvic floor dysfunction (PFD). Methods:. This is a cohort study on patient-reported symptoms of PFD in patients who were AFAB, diagnosed with gender dysphoria, and undergoing vaginectomy in a single surgical center. Patients responded to a questionnaire preoperatively and 1 year postoperatively. The questionnaire consisted of 33 questions, including a modified short-form version of the Pelvic Floor Distress Inventory (PFDI-20). Results:. Twenty-three consecutive patients were included in the study and 20 patients (87%) completed the 1-year follow-up. The preoperative median PFDI-20 score was 24 (0–114) compared with 32 (0–168) at the 1-year follow-up (P = 0.07). Patients who had previously undergone neophallus construction with a metoidioplasty (n = 15) had no significant change between the preoperative and the 1-year postoperative PFDI-20 score [median 17.5 (0–114) and 27.5 (0–145) (P = 0.65), respectively]; whereas those with a groin flap phalloplasty (n = 5) had a significant increase in reported symptoms [median 37 (10–95) and 124 (45–168), respectively (P = 0.04)]. Conclusions:. Overall, vaginectomy could be performed without any major impact on symptoms of PFD. However, this seemed to be true mainly for patients with previous metoidioplasty, whereas patients with previous groin flap phalloplasty reported worsening of symptoms.

Purpose: Many publications address the epidemiology of secondary osteosarcomas following retinoblastoma. Treatment- and outcome-related information is, however, scarce. We used a large cooperative group’s database to study this issue. Patients and methods: The database Cooperative Osteosarcoma Study Group COSS was searched for patients with osteosarcoma following a previous retinoblastoma. Patients were then analyzed for demographic factors, local/systemic treatments received, and outcomes. Results: 28 eligible patients were identified. Median age at retinoblastoma was .5 years, 89% occurred bilaterally. Retinoblastoma-therapy was by surgery in 26/27, radiotherapy in 26/27, chemotherapy in 10/26 (rest unknown). Osteosarcoma was diagnosed after 13.7 (3.1 – 36.1) years, extremities and head/neck affected in 14/28, each. Four/28 patients had primary metastases. Osteosarcoma treatment included chemotherapy in all cases, local therapy surgery in 27/28. Histological response was good in 9/16 evaluable cases. Surgery of all sites was macroscopically complete in 23/27 operated tumors and microscopically complete in 17/26 (1 unknown). Radiotherapy was administered to 3 craniofacial tumors. Median follow-up was 3.5 (.4 – 30.1) years from osteosarcoma diagnosis, 8/28 patients remaining event-free. Altogether, five patients suffered further secondary malignancies. Actuarial overall and event-free survival at 2 and 5 years from osteosarcoma were 73% (standard error: 8%) / 50% (10%) and 47% (10%) / 22% (9%), respectively. Conclusion: This comparatively large cohort of osteosarcomas after retinoblastoma proves that the latter may be treated curatively. While their prognosis is far worse than that of primary osteosarcomas, partly due to a predilection for craniofacial involvement, selected patients may still become long-term survivors with appropriate therapies.

Immigration, particularly forced immigration, has a profound impact on every aspect of immigrants’ lives. One such aspect is their religious convictions and practices. Nowadays, Migration Studies is a major academic field that produces many books and articles each year. This article examines the impact of forced immigration on the daily practices and internal relationships between leaders and followers of a specific religious group—Hassidism, in one particular period—the early second half of the 20th century. It does so by examining how two Hassidic leaders, the Satmar Rebbe in America and the Viznitzer Rebbe in Israel, established their communities after the Holocaust. This is one of only a few academic studies that explore post-Holocaust Hassidism, with a specific focus on the effects of forced immigration on its development. Throughout Jewish history, large-scale immigration and the inevitable need to adapt to new political, religious, and cultural circumstances had a profound influence on the way Jews conducted their religious affairs. This article explores how the uprooting of Hassidism from Eastern Europe after the Holocaust and its transplantation in countries that were new to them prompted Hassidic leaders who wanted to reestablish their communities to adopt a new set of leadership priorities. The result was that despite bearing the same title, Hassidic communities that were established after the Holocaust were very different from those that operated in Europe previously.

This paper proposes a fault detection method for multivariate statistical process control. The proposed method combines the Forward-Backward Hidden Semi-Markov Model (HSMM) and Principal Component Analysis (PCA). A stochastic automaton was used for multi-mode detection with many observation sequences. We used agglomerative clusters to find the initial parameters of HSMM. We allocated an adaptive threshold and a fixed threshold in each mode for fault detection with PCA, including Hotelling T2 statistic and squared predictive error (Q statistic). We simulated this method on the Tennessee Eastman Process (TEP). Some faults were designed with various runs and times of occurrence. The experimental results were compared with the Mixture Bayesian PCA, Hidden Markov Model (HMM), and HSMM methods. The results are robust with an efficient detection rate. This activity recommends ways to find action plans for multi-mode process monitoring in chemical plants.

Introduction Patients with a first venous thromboembolism (VTE) are at risk of recurrence. Recurrent VTE (rVTE) can be prevented by extended anticoagulant therapy, but this comes at the cost of an increased risk of bleeding. It is still uncertain whether patients with an intermediate recurrence risk or with a high recurrence and high bleeding risk will benefit from extended anticoagulant treatment, and whether a strategy where anticoagulant duration is tailored on the predicted risks of rVTE and bleeding can improve outcomes. The aim of the Leiden Thrombosis Recurrence Risk Prevention (L-TRRiP) study is to evaluate the outcomes of tailored duration of long-term anticoagulant treatment based on individualised assessment of rVTE and major bleeding risks.Methods and analysis The L-TRRiP study is a multicentre, open-label, cohort-based, randomised controlled trial, including patients with a first VTE. We classify the risk of rVTE and major bleeding using the L-TRRiP and VTE-BLEED scores, respectively. After 3 months of anticoagulant therapy, patients with a low rVTE risk will discontinue anticoagulant treatment, patients with a high rVTE and low bleeding risk will continue anticoagulant treatment, whereas all other patients will be randomised to continue or discontinue anticoagulant treatment. All patients will be followed up for at least 2 years. Inclusion will continue until the randomised group consists of 608 patients; we estimate to include 1600 patients in total. The primary outcome is the combined incidence of rVTE and major bleeding in the randomised group after 2 years of follow-up. Secondary outcomes include the incidence of rVTE and major bleeding, functional outcomes, quality of life and cost-effectiveness in all patients.Ethics and dissemination The protocol was approved by the Medical Research Ethics Committee Leiden-Den Haag-Delft. Results are expected in 2028 and will be disseminated through peer-reviewed journals and during (inter)national conferences.Trial registration number NCT06087952.