Showing papers by "David Cohen published in 2023"

Search for gravitational-lensing signatures in the full third observing run of the LIGO-Virgo network

Abstract: Gravitational lensing by massive objects along the line of sight to the source causes distortions of gravitational wave-signals; such distortions may reveal information about fundamental physics, cosmology and astrophysics. In this work, we have extended the search for lensing signatures to all binary black hole events from the third observing run of the LIGO--Virgo network. We search for repeated signals from strong lensing by 1) performing targeted searches for subthreshold signals, 2) calculating the degree of overlap amongst the intrinsic parameters and sky location of pairs of signals, 3) comparing the similarities of the spectrograms amongst pairs of signals, and 4) performing dual-signal Bayesian analysis that takes into account selection effects and astrophysical knowledge. We also search for distortions to the gravitational waveform caused by 1) frequency-independent phase shifts in strongly lensed images, and 2) frequency-dependent modulation of the amplitude and phase due to point masses. None of these searches yields significant evidence for lensing. Finally, we use the non-detection of gravitational-wave lensing to constrain the lensing rate based on the latest merger-rate estimates and the fraction of dark matter composed of compact objects.

Trimethylamine-N-oxide is associated with cardiovascular mortality and vascular brain lesions in patients with atrial fibrillation

Abstract: Objective Trimethylamine-N-oxide (TMAO) is a metabolite derived from the microbial processing of dietary phosphatidylcholine and carnitine and the subsequent hepatic oxidation. Due to its prothrombotic and inflammatory mechanisms, we aimed to assess its role in the prediction of adverse events in a susceptible population, namely patients with atrial fibrillation. Methods Baseline TMAO plasma levels were measured by liquid chromatography-tandem mass spectrometry in 2379 subjects from the ongoing Swiss Atrial Fibrillation cohort. 1722 underwent brain MRI at baseline. Participants were prospectively followed for 4 years (Q1–Q3: 3.0–5.0) and stratified into baseline TMAO tertiles. Cox proportional hazards and linear and logistic mixed effect models were employed adjusting for risk factors. Results Subjects in the highest TMAO tertile were older (75.4±8.1 vs 70.6±8.5 years, p<0.01), had poorer renal function (median glomerular filtration rate: 49.0 mL/min/1.73 m2 (35.6–62.5) vs 67.3 mL/min/1.73 m2 (57.8–78.9), p<0.01), were more likely to have diabetes (26.9% vs 9.1%, p<0.01) and had a higher prevalence of heart failure (37.9% vs 15.8%, p<0.01) compared with patients in the lowest tertile. Oral anticoagulants were taken by 89.1%, 94.0% and 88.2% of participants, respectively (from high to low tertiles). Cox models, adjusting for baseline covariates, showed increased total mortality (HR 1.65, 95% CI 1.17 to 2.32, p<0.01) as well as cardiovascular mortality (HR 1.86, 95% CI 1.21 to 2.88, p<0.01) in the highest compared with the lowest tertile. When present, subjects in the highest tertile had more voluminous, large, non-cortical and cortical infarcts on MRI (log-transformed volumes; exponentiated estimate 1.89, 95% CI 1.11 to 3.21, p=0.02) and a higher chance of small non-cortical infarcts (OR 1.61, 95% CI 1.16 to 2.22, p<0.01). Conclusions High levels of TMAO are associated with increased risk of cardiovascular mortality and cerebral infarction in patients with atrial fibrillation. Trial registration number NCT02105844.

Hypotension-Avoidance Versus Hypertension-Avoidance Strategies in Noncardiac Surgery

Abstract: BACKGROUND Among patients having noncardiac surgery, perioperative hemodynamic abnormalities are associated with vascular complications. Uncertainty remains about what intraoperative blood pressure to target and how to manage long-term antihypertensive medications perioperatively. OBJECTIVE To compare the effects of a hypotension-avoidance and a hypertension-avoidance strategy on major vascular complications after noncardiac surgery. DESIGN Partial factorial randomized trial of 2 perioperative blood pressure management strategies (reported here) and tranexamic acid versus placebo. (ClinicalTrials.gov: NCT03505723). SETTING 110 hospitals in 22 countries. PATIENTS 7490 patients having noncardiac surgery who were at risk for vascular complications and were receiving 1 or more long-term antihypertensive medications. INTERVENTION In the hypotension-avoidance strategy group, the intraoperative mean arterial pressure target was 80 mm Hg or greater; before and for 2 days after surgery, renin-angiotensin-aldosterone system inhibitors were withheld and the other long-term antihypertensive medications were administered only for systolic blood pressures 130 mm Hg or greater, following an algorithm. In the hypertension-avoidance strategy group, the intraoperative mean arterial pressure target was 60 mm Hg or greater; all antihypertensive medications were continued before and after surgery. MEASUREMENTS The primary outcome was a composite of vascular death and nonfatal myocardial injury after noncardiac surgery, stroke, and cardiac arrest at 30 days. Outcome adjudicators were masked to treatment assignment. RESULTS The primary outcome occurred in 520 of 3742 patients (13.9%) in the hypotension-avoidance group and in 524 of 3748 patients (14.0%) in the hypertension-avoidance group (hazard ratio, 0.99 [95% CI, 0.88 to 1.12]; P = 0.92). Results were consistent for patients who used 1 or more than 1 antihypertensive medication in the long term. LIMITATION Adherence to the assigned strategies was suboptimal; however, results were consistent across different adherence levels. CONCLUSION In patients having noncardiac surgery, our hypotension-avoidance and hypertension-avoidance strategies resulted in a similar incidence of major vascular complications. PRIMARY FUNDING SOURCE Canadian Institutes of Health Research, National Health and Medical Research Council (Australia), and Research Grant Council of Hong Kong.

Profils cliniques et prise en charge des enfants et adolescents transgenres dans une consultation spécialisée d’Île-de-France

Abstract: Il existe très peu de données cliniques françaises sur les modalités de prise en charge médicale des enfants et adolescents transgenres alors que le sujet vient très régulièrement sur le devant de la scène médiatique. Nous proposons dans cet article de décrire de manière rétrospective l’ensemble des enfants et adolescents reçus depuis 2012 dans la plus importante consultation spécialisée identité de genre enfants et adolescents d’Île-de-France. Outre leurs caractéristiques sociodémographiques, nous étudions la présence ou non d’une incongruence de genre selon les critères de la CIM 11, les vulnérabilités psychiatriques et sociales des sujets et décrivons les principales modalités de prise en charge proposées : la transition sociale, le blocage pubertaire, les transitions hormonales et/ou les rares transitions chirurgicales. Ces trois dernières propositions sont discutées en réunion de concertation pluridisciplinaire (RCP). Nous avons colligé 239 jeunes âgés de 3 à 20 ans. L’âge moyen auquel les jeunes et leur famille sont vus au premier rendez-vous est de 14,5 ans (± 3,16). Au total, 91 % de l’échantillon présentent une incongruence de genre, 32 % ayant exprimé cette incongruence avant la puberté. Deux-tiers sont des jeunes assignés de sexe féminin à la naissance (p < 0,05). En termes de psychopathologie, les troubles dépressifs et anxieux, ainsi que la suicidalité arrivent largement avant les autres cooccurrences psychiatriques. L’ostracisme et le rejet scolaire sont fréquents. Par rapport à la population adolescente générale, les jeunes de la consultation spécialisée sont beaucoup plus exposés aux discriminations et aux insultes, voire aux agressions sexuelles dans l’espace public, que leurs pairs et l’internalisation de la transphobie par ces jeunes est particulièrement importante. Au total, 40 % des jeunes ont effectué une transition sociale avant le premier rendez-vous et 74 % et 61 % d’entre elles/eux l’on fait au sein de la famille et à l’école (l’âge moyen de la transition sociale à l’école = 15,13 ans). Au total, 35 % des jeunes ont officialisé en mairie le changement de prénom (l’âge moyen = 16,26 ans). La prise de bloqueurs de puberté concerne 11 % des jeunes qui ont atteint la puberté (âge moyen = 13,9 ans, délai moyen avant instauration du traitement = 10 mois). Au total, moins de la moitié des jeunes (44 %) ont reçu un traitement hormonal masculinisant ou féminisant par hormones sexuelles (âge moyen = 16,9 ans, délai moyen avant l’instauration = 14 mois). Au total, 8,7 % des jeunes ayant reçu un traitement hormonal par hormones sexuelles ont réalisé une préservation de fertilité. Les demandes de chirurgie avant 18 ans restent très rares. Les plus fréquentes sont les torsoplasties (20 %) réalisées à l’âge moyen de 18,44 ans et jamais avant 16 ans. Les résultats de cette cohorte sont proches de ceux rapportés par d’autres centres européens pour ce qui concerne la proportion plus élevée de jeunes assignés de genre féminin à la naissance. En revanche, ils diffèrent avec des chiffres plus bas en termes de recours à des traitements hormonaux. La transition sociale est dans notre centre la demande la plus fréquente mais elle n’est pas systématique. Nous discuterons la place de la parole dans notre accompagnement pour expliquer ces différences. French clinical data on the medical management of transgender children and adolescents are scarce. Yet, the topic regularly comes to the forefront of the media. In this article, we propose to retrospectively describe all the children and adolescents received since 2012 in the largest specialized gender identity consultation for children and adolescents in Île-de-France. In addition to their sociodemographic characteristics, we study the presence or not of gender incongruence according to the ICD 11 criteria, the psychiatric and social vulnerabilities, and describe the main management modalities proposed: social transition, puberty blockage, hormonal transitions and/or rare surgical transitions. These last three proposals were discussed in multidisciplinary concertation meetings. We collected 239 youths aged 3 to 20 years. The mean age at which youth and their families were seen at the first appointment was 14.5 years (± 3.16). In all, 91% of the sample had gender incongruence, with 32% expressing gender incongruence before puberty. Two-thirds were youth assigned female at birth (P < 0.05). In terms of psychopathology, depressive and anxiety disorders, as well as suicidality, came well ahead of other psychiatric co-occurrences. School ostracism and rejection were common. Compared to the general adolescent population, the young people in the specialized consultation are much more exposed to discrimination and insults, and even sexual aggression in the public space, than their peers, and the internalization of transphobia by these young people is particularly important. In all, 40% of the young people made a social transition before the first consultation and 74% and 61% of them did so within the family and at school (the average age of social transition at school = 15.13 years). In all, 35% of the young people made the name change official at the town hall (the average age = 16.26 years). Puberty blockers were used by 11% of the youths who had reached puberty (mean age = 13.9 years, mean time to initiation = 10 months). In total, fewer than half of the youths (44%) received masculinizing or feminizing sex hormone treatment (mean age = 16.9 years, mean time to initiation = 14 months). In all, 8.7% of the young people who received sex hormone treatment underwent fertility preservation. Requests for surgery before the age of 18 remain very rare. The most frequent are torsoplasties (20%) performed at a mean age of 18.44 years and never before 16 years. The results of this cohort are close to those reported by other European centers in terms of the higher proportion of young people assigned female at birth. However, they differ with a lower proportion of hormonal treatment. Social transition is the most frequent request in our center, but it is not systematic. We wonder whether the place of narration while in our care may explain these differences.

Natural Antibodies Are Associated With Rejection and Long-term Renal Allograft Loss in a Multicenter International Cohort

Abstract: Background. Potentially harmful nonhuman leukocyte antigen antibodies have been identified in renal transplantation, including natural immunoglobulin G antibodies (Nabs) reactive to varied antigenic structures, including apoptotic cells. Methods. In this retrospective, multicenter study, we assessed Nabs by reactivity to apoptotic cells in sera collected from 980 kidney transplant recipients across 4 centers to determine their association with graft outcomes. Results. Elevated pretransplant Nabs were associated with graft loss (hazard ratio [HR] 2.71; 95% confidence interval [CI], 1.15-6.39; P = 0.0232), the composite endpoint of graft loss or severe graft dysfunction (HR 2.40; 95% CI, 1.13-5.10; P = 0.0232), and T cell–mediated rejection (odds ratio [OR] 1.77; 95% CI, 1.07-3.02; P = 0.0310). High pretransplant Nabs together with donor-specific antibodies (DSAs) were associated with increased risk of composite outcomes (HR 6.31; 95% CI, 1.81-22.0; P = 0.0039). In patients with high pretransplant Nabs, the subsequent development of posttransplant Nabs was associated with both T cell–mediated rejection (OR 3.64; 95% CI, 1.61-8.36; P = 0.0021) and mixed rejection (OR 3.10; 95% CI, 1.02-9.75; P = 0.0473). Finally, elevated pre- and posttransplant Nabs combined with DSAs were associated with increased risk of composite outcomes (HR 3.97; 95% CI, 1.51-10.43; P = 0.0052) and T cell–mediated rejection (OR 7.28; 95% CI, 2.16-25.96; P = 0.0016). Conclusions. The presence of pre- and posttransplant Nabs, together with DSAs, was associated with increased risk of poor graft outcomes and rejection after renal transplantation.

Diagnosis and Management of Pineal Germinoma: From Eye to Brain.

Abstract: Pineal germinomas can be very complex in terms of presentation, diagnosis, and management. This review attempts to simplify this complexity in an organized manner, addressing the anatomic relationships that provide the basis for the uniqueness of pineal germinoma. Ocular findings and signs and symptoms of elevated intracranial pressure are the keys to suspecting the diagnosis and obtaining the necessary imaging and cerebrospinal fluid studies. Other symptoms can suggest spread beyond the pineal region. Surgery may only be needed to obtain tissue for a definitive diagnosis, as germinoma is highly responsive to chemotherapy and focused radiation therapy. Hydrocephalus, usually related to tumor obstruction of the cerebral aqueduct, may also need to be addressed. Outcome for pineal germinoma is usually excellent, but relapse can occur and may require additional intervention. These issues are detailed in this review.

High-sensitivity Troponin I Predicts Major Cardiovascular Events after Non-Cardiac Surgery: A Vascular Events in Non-Cardiac Surgery Patients Cohort Evaluation (VISION) Substudy.

Abstract: BACKGROUND Myocardial injury after non-cardiac surgery (MINS), based on measurement of troponin T, is associated with perioperative major adverse cardiovascular events (MACE). We therefore determined the high-sensitivity troponin I (hsTnI) thresholds associated with 30 day MACE after non-cardiac surgery. METHODS We performed a nested biobank cohort study of 4553 patients from the Vascular Events in Non-Cardiac Surgery Patients Cohort Evaluation (VISION) Study. We measured hsTnI (ADVIA Centaur® hsTnI assay) on postoperative days 1 to 3 in patients ≥45 years undergoing non-cardiac surgery. An iterative Cox proportional hazard model determined peak postoperative hsTnI thresholds independently associated with MACE (i.e., death, myocardial infarction occurring on postoperative day 4 or after, non-fatal cardiac arrest, or congestive heart failure) within 30 days after surgery. RESULTS MACE occurred in 89/4545 (2.0%) patients. Peak hsTnI values of <75 ng/L, 75 ng/L to <1000 ng/L, and ≥1000 ng/L were associated with 1.2% (95% CI, 0.9-1.6), 7.1% (95% CI, 4.8-10.5), and 25.9% (95% CI, 16.3-38.4) MACE, respectively. Compared to peak hsTnI <75 ng/L, values 75 ng/L to <1000 ng/L and ≥1000 ng/L were associated with adjusted hazard ratios (aHR) of 4.53 (95% CI, 2.75-7.48) and 16.17 (95% CI, 8.70-30.07), respectively. MACE was observed in 9% of patients with peak hsTnI ≥75 ng/L vs 1% in patients with peak hsTnI <75 ng/L (aHR 5.76; 95% CI, 3.64-9.11). A peak hsTnI ≥75 ng/L was associated with MACE in the presence (aHR 9.35; 95% CI, 5.28-16.55) or absence (aHR 3.99; 95% CI, 2.19-7.25) of ischemic features of myocardial injury. CONCLUSION A peak postoperative hsTnI ≥75 ng/L was associated with >5-fold increase in the risk of 30 days MACE compared to levels <75 ng/L. This threshold could be used for MINS diagnosis when the ADVIA Centaur hsTnI assay is used. Clinicaltrials.gov Registration Number: NCT00512109.

Abstract LB156: Identified the ISG15 mediated extracellular vesicles drives ovarian cancer progression and metastasis: extracellular vesicular ISG15 is a potential biomarker and therapeutic target

Abstract: Background & Objective: High-grade serous ovarian cancer (HGSOC) accounts for over 80% of all epithelial ovarian cancer (OC) diagnoses, and the majority of patients with HGSOC are diagnosed with advanced metastatic disease. Aberrant expression of interferon stimulated gene 15 (ISG15) has been demonstrated in human malignancies, and we have identified that ISG15 is highly expressed in HGSOC tumors and peritoneal ascites. This study seeks to determine whether ISG15 contributes to HGSOC progression and metastasis through extracellular vesicle (EVs) secretion. Method: ISG15 expression was analyzed in ascites samples and primary ovarian cancer cells (POCC) from different patients by ELISA and WB. Cell surface biotinylation assay was done to show the modulation of endo and exocytosis by ISG15 and STAT3. Immunoprecipitation pull down assay was done to demonstrate the interaction of ISG15 with activated STAT3. Confocal microscopy showed the co-localization of STAT3 with the endosome marker TSG101. In-vivo studies were done using bio-luminescence imaging in orthotopic ovarian tumor mouse models to measure tumor progression and metastasis. Results: ISG15 was found to be significantly elevated in HGSOC metastases (pelvic, mesenteric and diaphragmatic samples) as compared to primary ovarian tumors or benign samples. We observed that ISGylation was increased in POCC cells derived from ascites with increased USP18 expression. Our results confirmed a significant decrease in EV’s secretion in ISG15 KD POCC cells. Mice injected with ISG15 OE -POCC cells showed increased tumor burden when compared to the ISG15Kd cells in mice. Furthermore, we observed a significant reduction of ovarian tumor growth and metastasis in an orthotopic mouse model treated with a small molecule inhibitor-DAP5 that targeted ISG15 or exosome blocker (Amiloride) compared to untreated mice. In addition, we found the expression of ISG15 within the EVs represents a promising development in elucidating prognostic markers for HGSOC patients. Conclusion: Based on our results, ISG15 expression is elevated in HGSOC patient ascites and metastatic disease sites. The aberrant expression of ISG15 in patient ascites plays a key role in the secretion of EVs carrying ISG15, which contributes to HGSOC progression and metastases. Our study provides the pre-clinical evidence regarding new molecular targets, novel prognostic markers, and innovative therapeutic strategies for HGSOC, aiming to ultimately improve the survival of patients suffering from this disease. Citation Format: Kalpana Deepa Priya Dorayappan, Vincent Wagner, Dongju Park, Meghan M. Newcomer, Michelle DS Lightfoot, Deepika Kalaiyarasan, Takahiko Sakaue, Wafa Khadraoui, Casey Cosgrove, Larry J. Maxwell, Qi-En Wang Wang, David O’Malley, Raphael E. Pollock, David E. Cohn, Selvendiran Karuppaiyah. Identified the ISG15 mediated extracellular vesicles drives ovarian cancer progression and metastasis: extracellular vesicular ISG15 is a potential biomarker and therapeutic target [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB156.

Omega-3 Fatty Acids and Heart Rhythm, Rate, and Variability in Atrial Fibrillation.

Abstract: Background Previous randomized control trials showed mixed results concerning the effect of omega-3 fatty acids (n-3 FAs) on atrial fibrillation (AF). The associations of n-3 FA blood levels with heart rhythm in patients with established AF are unknown. The goal of this study was to assess the associations of total and individual n-3 FA blood levels with AF type (paroxysmal versus nonparoxysmal), heart rate (HR), and HR variability in patients with AF. Methods and Results Total n-3 FAs, eicosapentaenoic acid, docosahexaenoic acid, docosapentaenoic acid, and alpha-linolenic acid blood levels were determined in 1969 patients with known AF from the SWISS-AF (Swiss Atrial Fibrillation cohort). Individual and total n-3 FAs were correlated with type of AF, HR, and HR variability using standard logistic and linear regression, adjusted for potential confounders. Only a mild association with nonparoxysmal AF was found with total n-3 FA (odds ratio [OR], 0.97 [95% CI, 0.89-1.05]) and docosahexaenoic acid (OR, 0.93 [95% CI, 0.82-1.06]), whereas other individual n-3 FAs showed no association with nonparoxysmal AF. Higher total n-3 FAs (estimate 0.99 [95% CI, 0.98-1.00]) and higher docosahexaenoic acid (0.99 [95% CI, 0.97-1.00]) tended to be associated with slower HR in multivariate analysis. Docosapentaenoic acid was associated with a lower HR variability triangular index (0.94 [95% CI, 0.89-0.99]). Conclusions We found no strong evidence for an association of n-3 FA blood levels with AF type, but higher total n-3 FA levels and docosahexaenoic acid might correlate with lower HR, and docosapentaenoic acid with a lower HR variability triangular index.

Bone morphogenetic protein 10 as a predictor for recurrent atrial fibrillation after catheter ablation

Abstract: Abstract Funding Acknowledgements Type of funding sources: None. Background Atrial fibrillation (AF) recurrence after catheter ablation (CA) poses a major challenge. The novel atrial-specific biomarker, bone morphogenetic protein 10 (BMP10), might aid in the selection of appropriate patients for CA. Purpose We aimed to assess the predictive value BMP10 for AF recurrence after CA in a large cohort of AF patients. Methods We measured baseline BMP10 concentrations in AF patients who underwent elective CA for the first time. Patients were enrolled in a single-center prospective cohort study. The primary outcome variable was AF recurrence during 12 months’ follow-up using 2 x 24h and 1 x at least 4-day Holter. We constructed Cox proportional hazard models to determine the association of BMP10 and AF recurrence. The multivariable model was adjusted for age, sex, body mass index, and cardiovascular risk factors. Results A total of 1,112 AF patients (74% male) with a mean age of 61 ± 10 years were included in our analysis (60% paroxysmal AF, 40% persistent AF). The 12-month follow-up examination revealed that AF recurred in 374 (33.6%) patients. Kaplan-Meier curves for recurrent AF according to BMP10 quartiles are shown in the Figure (BMP10 quartile I: 0.76-1.50 ng/mL, quartile II: 1.50-1.72 ng/mL, quartile III: 1.72-1.99 ng/mL, quartile IV: 1.99-3.75 ng/mL). In the unadjusted Cox proportional hazard model, a per-unit increase in log transformed BMP10 was associated with a hazard ratio (HR) of 2.28 (95% CI 1.43, 3.62; p < 0.001) for AF recurrence. After multivariable adjustment, the HR of BMP10 was 1.98 (95% CI 1.14; 3.42, p = 0.01) for AF recurrence. Conclusion The novel atrial-specific biomarker BMP10 was associated with AF recurrence after CA in our large cohort of AF patients. Kaplan Meier Curve

Effect of Colchicine on the Risk of Perioperative Acute Kidney Injury: Clinical Protocol of a Substudy of the Colchicine for the Prevention of Perioperative Atrial Fibrillation Randomized Clinical Trial

Abstract: Background: Inflammation during and after surgery can lead to organ damage including acute kidney injury. Colchicine, an established inexpensive anti-inflammatory medication, may help to protect the organs from pro-inflammatory damage. This protocol describes a kidney substudy of the colchicine for the prevention of perioperative atrial fibrillation (COP-AF) study, which is testing the effect of colchicine versus placebo on the risk of atrial fibrillation and myocardial injury among patients undergoing thoracic surgery. Objective: Our kidney substudy of COP-AF will determine whether colchicine reduces the risk of perioperative acute kidney injury compared with a placebo. We will also examine whether colchicine has a larger absolute benefit in patients with pre-existing chronic kidney disease, the most prominent risk factor for acute kidney injury. Design and Setting: Randomized, superiority clinical trial conducted in 40 centers in 11 countries from 2018 to 2023. Patients: Patients (~3200) aged 55 years and older having major thoracic surgery. Intervention: Patients are randomized 1:1 to receive oral colchicine (0.5 mg tablet) or a matching placebo, given twice daily starting 2 to 4 hours before surgery for a total of 10 days. Patients, health care providers, data collectors, and outcome adjudicators will be blinded to the randomized treatment allocation. Methods: Serum creatinine concentrations will be measured before surgery and on postoperative days 1, 2, and 3 (or until hospital discharge). The primary outcome of the substudy is perioperative acute kidney injury, defined as an increase (from the prerandomization value) in serum creatinine concentration of either ≥26.5 μmol/L (≥0.3 mg/dL) within 48 hours of surgery or ≥50% within 7 days of surgery. The primary analysis (intention-to-treat) will examine the relative risk of acute kidney injury in patients allocated to receive colchicine versus placebo. We will repeat the primary analysis using alternative definitions of acute kidney injury and examine effect modification by pre-existing chronic kidney disease, defined as a prerandomization estimated glomerular filtration rate (eGFR) <60 mL/min per 1.73 m2. Limitations: The substudy will be underpowered to detect small effects on more severe forms of acute kidney injury treated with dialysis. Results: Substudy results will be reported in 2024. Conclusions: This substudy will estimate the effect of colchicine on the risk of perioperative acute kidney injury in older adults undergoing major thoracic surgery. Clinical trial registration number: NCT03310125

Recurrence rate in early-stage epithelial ovarian cancer: Is there a role for upfront maintenance with PARP inhibitors in stages I and II?

Abstract: To determine the recurrence rate and survival among early-stage epithelial ovarian cancer cases considering homologous recombination deficiency (HRD) status.Single institution retrospective study of stage I/II EOC patients from 2017 to 2020. HRD was defined as evidence of germline or somatic BRCA mutation, or loss of heterozygosity (LOH)/genomic instability (GIS) as determined by companion diagnostic tests. Kaplan-Meier analyses were performed.89 stage I/II cases were included. 4/89 (4.5%) had a germline BRCA1/2 mutation, 8 (9%) were germline negative but had a somatic BRCA mutation, and 8 (9%) were BRCA wild-type but had evidence of LOH/GIS on somatic testing; these 20/89 (22%) cases comprised the HRD group. The remaining tumors were confirmed homologous recombination proficient (HRP, 35/89, 39%) or homologous recombination unknown (HRU, 34/89, 38%). The overall recurrence rate was 33/89 (37%). There were more recurrences among HRD cases (14/20, 70%) compared to HRP/HRU cases (19/69, 27.5%, p = 0.0012). Median Recurrence-Free Survival (RFS) was 35 months for HRD cases and 225 months for HRP/HRU cases (p = 0.001). At 2 years, there were 60% HRD cases and 88% HRP/HRU cases recurrence-free. At 5 years there were 29% HRD and 69% HRP/HRU cases recurrence-free (p = 0.001).Despite a high rate of complete surgical staging and six cycles of adjuvant chemotherapy, recurrence rate was high in this early-stage cohort. Higher recurrence rates were seen in the HRD group, however these data are likely biased by the clinical practice of tumor testing primarily at the time of recurrence rather than the upfront setting. RFS was significantly lower for HRD cases.

Bone Morphogenetic Protein 10-A Novel Biomarker to Predict Adverse Outcomes in Patients With Atrial Fibrillation.

Abstract: Background Patients with atrial fibrillation (AF) face an increased risk of death and major adverse cardiovascular events (MACE). We aimed to assess the predictive value of the novel atrial-specific biomarker BMP10 (bone morphogenetic protein 10) for death and MACE in patients with AF in comparison with NT-proBNP (N-terminal prohormone of B-type natriuretic peptide). Methods and Results BMP10 and NT-proBNP were measured in patients with AF enrolled in Swiss-AF (Swiss Atrial Fibrillation Study), a prospective multicenter cohort study. A total of 2219 patients were included (median follow-up 4.3 years [interquartile range 3.9, 5.1], mean age 73±9 years, 73% male). In multivariable Cox proportional hazard models, the adjusted hazard ratio (aHR) associated with 1 ng/mL increase of BMP10 was 1.60 (95% CI, 1.37-1.87) for all-cause death, and 1.54 (95% CI, 1.35-1.76) for MACE. For all-cause death, the concordance index was 0.783 (95% CI, 0.763-0.809) for BMP10, 0.784 (95% CI, 0.765-0.810) for NT-proBNP, and 0.789 (95% CI, 0.771-0.815) for both biomarkers combined. For MACE, the concordance index was 0.732 (95% CI, 0.715-0.754) for BMP10, 0.747 (95% CI, 0.731-0.768) for NT-proBNP, and 0.750 (95% CI, 0.734-0.771) for both biomarkers combined. When grouping patients according to NT-proBNP categories (<300, 300-900, >900 ng/L), higher aHRs were observed in patients with high BMP10 in the categories of low NT-proBNP (all-cause death aHR, 2.28 [95% CI, 1.15-4.52], MACE aHR, 1.88 [95% CI, 1.07-3.28]) and high NT-proBNP (all-cause death aHR, 1.61 [95% CI, 1.14-2.26], MACE aHR, 1.38 [95% CI, 1.07-1.80]). Conclusions BMP10 strongly predicted all-cause death and MACE in patients with AF. BMP10 provided additional prognostic information in low- and high-risk patients according to NT-proBNP stratification. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT02105844.

The role of serum brain injury biomarkers in individuals with a mild-to-moderate COVID infection and Long-COVID - results from the prospective population-based COVI-GAPP study

Abstract: Background: During and after mild (no hospitalization) or moderate (hospitalization without ICU) SARS-CoV-2 infections, a wide range of symptoms, including neurological disorders have been reported. It is, however, unknown if these neurological symptoms are associated with brain injury and whether brain injury and related symptoms also emerge in patients suffering from Long-COVID. Neuronal biomarkers such as serum neurofilament light chain and glial fibrillary acidic protein can be used to elucidate neuro-axonal and astroglial injuries. We therefore investigated whether these biomarkers are associated with the COVID-19 infection status (mild-to-moderate), the associated symptoms and Long-COVID. Methods: From 146 individuals of the general population with a post-acute, mild-to-moderate SARS-CoV-2 infection, serum neurofilament light chain (sNfL; marker of intra-axonal neuronal injury) and serum glial fibrillary acidic protein (sGFAP; marker of astrocytic activation/injury) were measured. Samples were taken before, during and after (five and ten months) a SARS-CoV-2 infection. Individual symptoms and Long-COVID status were assessed using questionnaires. Results: Neurological symptoms were described for individuals after a mild and moderate COVID-19 infection, however, serum markers of brain injury (sNfL/sGFAP) did not change after an infection (sNfL: P = 0.74; sGFAP: P = 0.24) and were not associated with headache (P = 0.51), fatigue (P = 0.93), anosmia (P = 0.77) and ageusia (P = 0.47). In participants with Long-COVID, sGFAP (P = 0.038), but not sNfL (P = 0.58) significantly increased but was not associated with neurological symptoms. Conclusion: Neurological symptoms in individuals after a mild-to-moderate SARS-CoV-2 infection with and without Long-COVID were not associated with brain injury, although there was some astroglial injury observed in Long-COVID patients. Funding: The COVI-GAPP study received grants from the Innovative Medicines Initiative (IMI grant agreement number 101005177), the Princely House of Liechtenstein, the government of the Principality of Liechtenstein, and the Hanela Foundation (Switzerland). None of the funders played a role in the study design, data collection, data analysis, data interpretation, writing of the report, or decision to publish.

Severe self-injurious behaviors in an autistic child with sensory seeking, depressive disorder and anxiety disorder: A focus on the therapeutic interventions

Abstract: We report the case of a 12-year-old boy with nonverbal autism, intellectual disability, and hypermobility spectrum disorder. The patient was hospitalized in a French multidisciplinary neurobehavioral inpatient unit due to extreme self-harming behaviors. This major self-aggression led to a multi-fractured nose and to a growing risk of life-threatening traumatic injuries (risk of cervical fracture and spinal cord injury caused by forceful headbanging). These challenging behaviors required for a time the day-to-day skills of at least four caregivers and resulted in a rare escalation of restraint measures and in exceptional adaptations by our psychoeducational team. Clinical improvement was obtained after managing all causes of somatic pain and discomfort, as well as stabilizing the patient's mood and anxiety. We offered both sensorimotor developmental approaches with proprioceptive compressive garment and therapeutic body wrap, as well as protective equipment and specific psychoeducational interventions adapted to his severe self-injurious behaviors and to his developmental abilities. Nous rapportons la situation clinique d’un garçon de 12 ans présentant un trouble du spectre autistique non verbal, associé à une déficience intellectuelle et un trouble du spectre de l’hypermobilité articulaire. Le patient a été hospitalisé en pédopsychiatrie dans une unité d’hospitalisation française neurocomportementale spécialisée, du fait de comportements d’auto-agressivité extrême. Cette auto-agressivité majeure a conduit à des fractures nasales multiples et à un risque important de blessures traumatiques mettant en jeu le pronostic vital (risque de fracture cervicale et de lésion de la moelle épinière suite à des coups de tête en hyperextension violents et répétés). Ces comportements-défis ont nécessité durant une période les compétences d’au moins quatre soignants au quotidien, et ont été à l’origine d’une escalade inhabituelle des mesures de contrainte, ainsi que d’adaptations exceptionnelles de l’équipe psychoéducative. L’amélioration clinique a été obtenue sur le plan médical après prise en charge des causes de douleur et d’inconfort somatiques, d’une part, et de l’humeur et de l’anxiété du patient, d’autre part. Nous avons également proposé une approche développementale sensorimotrice avec vêtement proprioceptif compressif et enveloppements corporels thérapeutiques, ainsi qu’une approche psychoéducative, intégrant des équipements de protection, basée sur des interventions adaptées à ses comportements d’automutilations sévères et à ses capacités développementales.

Physician Practices in the Management of Myocardial Injury after Non-Cardiac Surgery

Abstract: Objective: To describe how physicians manage patients with myocardial injury (i.e., a troponin elevation of presumed ischemic origin) after non-cardiac surgery (MINS). Methods: Web-based survey to physicians distributed between December 2020 and September 2021, including a case scenario of asymptomatic MINS. Results: Of 103 respondents, 94% were practicing in Canada and 65% were general internists. 97% of respondents would order an ECG; following a normal ECG, 46% of would order an echocardiogram; following a normal echocardiogram, 42% would order myocardial perfusion imaging. Of the respondents, 91% and 90% would initiate ASA and a statin, respectively; 24%, 21%, and 7% would initiate an ACE inhibitor, a beta-blocker, and dabigatran, respectively. Most participants indicated that outpatient follow-up with a medicine specialist within 1–2 months (90%) and 1 year (68%) was appropriate. Conclusion: Respondents generally agreed that ASA and statins should be prescribed for MINS, and that post-discharge specialist follow-up is warranted. However, opinions regarding the role of cardiac imaging varied. RésuméObjectif: Décrire la manière dont les médecins prennent en charge les patients atteints d’une lésion myo-cardique (c’est-à-dire une élévation de la troponine d’origine ischémique présumée) à la suite d’une intervention chirurgicale non cardiaque (MINS pour myocardial injury after non-cardiac surgery). Méthodologie: Enquête en ligne menée auprès de médecins et distribuée entre décembre 2020 et septembre 2021 et comprenant un scénario de cas de MINS asymptomatique. Résultats: Sur les 103 répondants au sondage, 94% pratiquent au Canada et 65% sont des internistes généralistes. Une proportion de 97% des répondants demanderaient un ECG; si l’ECG s’avère normal, 46% demanderaient un échocardiogramme; s’il s’avère normal, 42% demanderaient une imagerie de perfusion myocardique. Une proportion de 90 à 91% des répondants prescriraient un traitement par l’acide acétylsalicylique (ASA) ou une statine; 24% un traitement par un inhibiteur de l’enzyme de conversion de l’angioten-sine (IECA), 21% un traitement par un bêtabloquant et 7% un traitement par le dabigatran. La plupart des participants indiquent qu’il est approprié d’assurer un suivi en consultation externe par un spécialiste dans le mois ou les deux mois (90%) et un an (68%) suivant l’intervention. Conclusion: Les répondants au sondage sont généralement d’avis que l’ASA et les statines devraient être prescrits pour la MINS et qu’il est justifié d’assurer un suivi par un spécialiste après la sortie de l’hôpital. Les avis concernant le rôle de l’imagerie cardiaque varient.

Association of Preoperative Growth Differentiation Factor-15 Concentrations and Postoperative Cardiovascular Events after Major Noncardiac Surgery

Abstract: Background: The association between growth differentiation factor-15 concentrations and cardiovascular disease has been well described. The study hypothesis was that growth differentiation factor-15 may help cardiac risk stratification in noncardiac surgical patients, in addition to clinical evaluation. Methods: The objective of the study was to determine whether preoperative serum growth differentiation factor-15 is associated with the composite primary outcome of myocardial injury after noncardiac surgery and vascular death at 30 days and can improve cardiac risk prediction in noncardiac surgery. This is a prospective cohort study of patients 45 yr or older having major noncardiac surgery. The association between preoperative growth differentiation factor-15 and the primary outcome was determined after adjusting for the Revised Cardiac Risk Index. Preoperative N-terminal-pro hormone brain natriuretic peptide was also added to compare predictive performance with growth differentiation factor-15. Results: Between October 27, 2008, and October 30, 2013, a total of 5,238 patients were included who had preoperative growth differentiation factor-15 measured (median, 1,325; interquartile range, 880 to 2,132 pg/ml). The risk of myocardial injury after noncardiac surgery and vascular death was 99 of 1,705 (5.8%) for growth differentiation factor-15 less than 1,000 pg/ml, 161 of 1,332 (12.1%) for growth differentiation factor-15 1,000 to less than 1,500 pg/ml, 302 of 1476 (20.5%) for growth differentiation factor-15 1,500 to less than 3,000 pg/ml, and 247 of 725 (34.1%) for growth differentiation factor-15 concentrations 3,000 pg/ml or greater. Compared to patients who had growth differentiation factor-15 concentrations less than 1,000 pg/ml, the corresponding adjusted hazard ratio for each growth differentiation factor-15 category was 1.93 (95% CI, 1.50 to 2.48), 3.04 (95% CI, 2.41 to 3.84), and 4.8 (95% CI, 3.76 to 6.14), respectively. The addition of growth differentiation factor-15 improved cardiac risk classification by 30.1% (301 per 1,000 patients) compared to Revised Cardiac Risk Index alone. It also provided additional risk classification beyond the combination of preoperative N-terminal-pro hormone brain natriuretic peptide and Revised Cardiac Risk Index (16.1%; 161 per 1,000 patients). Conclusions: Growth differentiation factor-15 is strongly associated with 30-day risk of major cardiovascular events and significantly improved cardiac risk prediction in patients undergoing noncardiac surgery. This study used clinical data and serum samples from 5,238 patients enrolled in a multisite cohort study (Vascular Events in Noncardiac Surgery Evaluation study; VISION). The authors assessed the association between increased preoperative serum growth differentiation factor-15 and the primary study outcome of 30-day risk of myocardial injury after noncardiac surgery and vascular death. A preoperative growth differentiation factor-15 concentration 1,500 pg/ml or greater was associated with a 24.9% risk of myocardial injury after noncardiac surgery and vascular death. In the subset of patients who had preoperative N-terminal-pro hormone brain natriuretic peptide results available (n = 4,246), the incidence of myocardial injury after noncardiac surgery and vascular death was 606 patients (14.3%). In a multivariable model that included preoperative Revised Cardiac Risk Index score and preoperative N-terminal-pro hormone brain natriuretic peptide categories, both preoperative growth differentiation factor-15 and N-terminal-pro hormone brain natriuretic peptide remained independently associated with myocardial injury after noncardiac surgery and vascular death and vascular mortality at 30 days.

Use of the Khorana score to predict venous thromboembolism in patients undergoing chemotherapy for uterine cancer

Abstract: Gynecologic cancers are associated with a high risk of venous thromboembolism (VTE). The Khorana score is a validated tool to assess risk of VTE in cancer patients. The purpose of this study is to determine if the Khorana score can be used as a risk stratification tool for VTE in patients with uterine cancer undergoing chemotherapy.A retrospective cohort study of patients with newly diagnosed uterine cancer receiving chemotherapy over a 4-year period was conducted. The patients were stratified based on their Khorana score as well as their chemotherapy sequence, neoadjuvant or definitive versus adjuvant.A total of 276 patients were included: 40 received neoadjuvant or definitive, 236 adjuvant chemotherapy. Most patients had advanced stage disease (64.5%). 18 (6.5%) patients developed VTE within 180 days of initiating chemotherapy. High Khorana score was associated with a non-significant increase in VTE (K ≥ 2 OR 1.17, CI 0.40-3.39, K ≥ 3 OR 1.69, CI 0.61-4.69) but had poor predictive accuracy based on area under the curve (K ≥ 2 0.51, K ≥ 3 0.55). The VTE rate was higher in the neoadjuvant/definitive chemotherapy group to adjuvant (12.5% vs 5.5%, p = 0.11). While the former group had a higher average Khorana score (2.35 vs 1.93, p = 0.0048), this was not predictive of VTE.While validated in other cancer types, the Khorana score was found to be a poor predictor of VTE in patients with uterine cancer. The use of the Khorana score to guide routine thromboprophylaxis in these patients should be used with caution and further investigation is warranted.

Brain lesions and cognitive decline in patients with atrial fibrillation

Abstract: Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): Swiss National Science Foundation, Swiss Heart Foundation Background In addition to clinical stroke, atrial fibrillation (AF) is associated with a high burden of various vascular brain lesions, the majority of which are silent. However, the impact of these lesions on cognitive performance remains unclear. Purpose Our aim was to assess the association between vascular brain lesions and cognitive decline in clinically asymptomatic AF patients. Methods In a prospective multicentre cohort trial, we included 1536 clinically stable AF patients aged ≥65 years and a limited number of patients aged 45–64 years (90% on oral anticoagulation therapy). Patients underwent brain magnetic resonance imaging (bMRI) for the detection of any brain lesions at baseline (ischemic brain lesions and microbleeds) and yearly cognitive assessment using different standardized tests. Cognitive decline was defined as a measurement >1 standard deviation of the age-education standardized baseline population, compared with individual baseline levels. Multivariable adjusted Cox regression analyses were performed to assess the relationship of baseline brain lesions presence with cognitive decline during follow-up. Results At the time of inclusion, 1030 (67%) of 1536 patients (mean age 72±8 years, 73% male) had one or more vascular brain lesions on baseline MRI. Based on the Montreal Cognitive Assessment score (MoCA), cognitive decline developed in 159 (10%) patients during a mean follow-up of 4.8 years. The incidence rate (per 100 person-years) for cognitive decline (MoCA score) was 3.64 and 1.82 in patients with and without brain lesions, respectively. After multivariable adjustment, the hazard ratio (95% CI) for cognitive decline (MoCA score) was 1.29 (0.85-1.96). The association of brain lesions with cognitive decline was 1.57 (1.02-2.40) for the Digit Symbol Substitution Test (DSST), 1.28 (1.01 to 1.63) for the semantic fluency test (SFT), and 0.91 (0.69-1.21) for the Trail Making Test Part A (TMT-A). Conclusion In our contemporary AF cohort, two thirds of patients had brain lesions on baseline MRI, and these lesions were predictive of worse cognitive outcomes in the mid-term on some of the tests used. The full effects on cognitive outcome will be obtained during even longer follow-up.

Epigenetic MMR defect identifies a risk group not accounted for through traditional risk stratification algorithms in endometrial cancer

Abstract: Purpose We sought to evaluate the contribution of mismatch repair (MMR) status to traditional risk stratification algorithms used to predict nodal involvement and recurrence in a large single-institution cohort. Methods Endometrioid endometrial cancer (EC) cases from 2014-2020 were evaluated. MMR immunohistochemistry (IHC) was performed universally. Uterine factors assessed in the Mayo criteria were used to retrospectively classify patients as low or high risk for lymphatic spread. Patients were classified according to risk for recurrence using GOG 99 and PORTEC criteria. Associations were evaluated using chi-square and t-tests and contributing factors assessed using logistic regression models. Results 1,514 endometrioid EC were evaluated; 392 (25.9%) were MMR (MMR) deficient of which 80.4% of MMR defects were associated with epigenetic silencing of MLH1. Epigenetic MMR defects were significantly more likely to be high risk for lymph node (LN) metastasis based on Mayo criteria (74.9% vs 60.6%, p=<0.001) and with the presence of LN metastasis (20.3 vs 10.5%, p=0.003) compared to MMR proficient tumors. Tumors with epigenetic MMR defects were significantly more likely to be classified as high or high intermediate risk using GOG99 and PORTEC criteria. Furthermore, cases with epigenetic MMR defects classified as low or low intermediate risk were significantly more likely to recur (GOG99 p=0.013; PORTEC p=0.008) and independently associated with worse disease-free survival (DFS). MMR status was found to be independently associated with worse DFS (HR 1.90; 95% CI 1.34-2.70; p=0.003) but not overall survival. Conclusion While MMR deficient EC has been associated with poor prognostic features in prior reports; we demonstrate that only epigenetic MMR defects have poorer outcomes. Epigenetic MMR defect were independently associated with lymph node metastasis after controlling for risk criteria. Epigenetic MMR deficiency was found to be an independent predictor of recurrence beyond the factors considered in traditional risk stratification algorithms. Traditional uterine-based risk stratification algorithms may not fully reflect the risk for recurrence in MMR deficient tumors. Consideration should be given to implementing MMR status and MLH1 hypermethylation alongside traditional risk stratification algorithms. Performing MMR IHC on preoperative pathologic specimens may aid in risk stratification and patient counseling.

Genetic architecture of spatial electrical biomarkers for cardiac arrhythmia and relationship with cardiovascular disease

Abstract: The 3-dimensional spatial and 2-dimensional frontal QRS-T angles are measures derived from the vectorcardiogram. They are independent risk predictors for arrhythmia, but the underlying biology is unknown. Using multi-ancestry genome-wide association studies we identify 61 (58 previously unreported) loci for the spatial QRS-T angle (N = 118,780) and 11 for the frontal QRS-T angle (N = 159,715). Seven out of the 61 spatial QRS-T angle loci have not been reported for other electrocardiographic measures. Enrichments are observed in pathways related to cardiac and vascular development, muscle contraction, and hypertrophy. Pairwise genome-wide association studies with classical ECG traits identify shared genetic influences with PR interval and QRS duration. Phenome-wide scanning indicate associations with atrial fibrillation, atrioventricular block and arterial embolism and genetically determined QRS-T angle measures are associated with fascicular and bundle branch block (and also atrioventricular block for the frontal QRS-T angle). We identify potential biology involved in the QRS-T angle and their genetic relationships with cardiovascular traits and diseases, may inform future research and risk prediction.