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Objective To evaluate the long-term stone free rate (SFR) of retrograde intra-renal surgery (RIRS) in the treatment of lower pole renal calculi using only basket relocation and identify independent predictors of stone-free status. All consecutive patients treated with RIRS lower pole renal calculi in a single high-volume tertiary center. Methods All consecutive patients underwent RIRS lower pole renal calculi at a single high-volume tertiary center were analyzed retrospectively. Lower pole stones were relocated to the upper pole, where laser lithotripsy was performed. All patients were followed up in the clinic following the surgery and yearly thereafter. The stone-free status was assessed with a combination of an abdominal ultrasound and abdominal X-ray (KUB), or an abdominal non-contrast computed tomography (NCCT) if the stones were known to be radiolucent. Results A total of 480 consecutive patients who underwent RIRS for treatment of lower pole renal calculi, between January 2012 and December 2018, were analyzed from a prospectively maintained database of 3000 ureteroscopies. With a median follow-up time of 18.6 months, the mean SFR was 94%. The procedures were unsuccessful in 26 (5.4%) due to unreachable stones. The median stone size of the unreachable stones was 12 mm (range 10–30 mm). Multivariable logistic regression analysis revealed two predictors of SFR for lower pole stones: A small cumulative stone burden (Odds Ratio [OR]: 0.881, 95% confidence interval [CI]: 0.731–1.062, p Conclusions The long-term SFR of RIRS for the treatment of lower pole stones with basket displacement with appropriate patient selection is high. In our study, the SFR, at a median follow up of 18.6 months (range 6–161 months), was 94%.

We report detailed functional analyses and genotype-phenotype correlations in 392 individuals carrying disease-causing variants in SCN8A, encoding the voltage-gated Na+ channel Nav1.6, with the aim of describing clinical phenotypes related to functional effects. Six different clinical subgroups were identified: Group 1, benign familial infantile epilepsy (n = 15, normal cognition, treatable seizures); Group 2, intermediate epilepsy (n = 33, mild intellectual disability, partially pharmaco-responsive); Group 3, developmental and epileptic encephalopathy (n = 177, severe intellectual disability, majority pharmaco-resistant); Group 4, generalized epilepsy (n = 20, mild to moderate intellectual disability, frequently with absence seizures); Group 5, unclassifiable epilepsy (n = 127); and Group 6, neurodevelopmental disorder without epilepsy (n = 20, mild to moderate intellectual disability). Those in Groups 1–3 presented with focal or multifocal seizures (median age of onset: 4 months) and focal epileptiform discharges, whereas the onset of seizures in patients with generalized epilepsy was later (median: 42 months) with generalized epileptiform discharges. We performed functional studies expressing missense variants in ND7/23 neuroblastoma cells and primary neuronal cultures using recombinant tetrodotoxin-insensitive human Nav1.6 channels and whole-cell patch-clamping. Two variants causing developmental and epileptic encephalopathy showed a strong gain-of-function (hyperpolarizing shift of steady-state activation, strongly increased neuronal firing rate) and one variant causing benign familial infantile epilepsy or intermediate epilepsy showed a mild gain-of-function (defective fast inactivation, less increased firing). In contrast, all three variants causing generalized epilepsy induced a loss-of-function (reduced current amplitudes, depolarizing shift of steady-state activation, reduced neuronal firing). Functional effects were known for 170 individuals. All 136 individuals carrying a functionally tested gain-of-function variant had either focal (n = 97, Groups 1–3) or unclassifiable (n = 39) epilepsy, whereas 34 individuals with a loss-of-function variant had either generalized (n = 14), no (n = 11) or unclassifiable (n = 6) epilepsy; only three had developmental and epileptic encephalopathy. Computational modelling in the gain-of-function group revealed a significant correlation between the severity of the electrophysiological and clinical phenotypes. Gain-of-function variant carriers responded significantly better to sodium channel blockers than to other anti-seizure medications, and the same applied for all individuals in Groups 1–3. In conclusion, our data reveal clear genotype-phenotype correlations between age at seizure onset, type of epilepsy and gain- or loss-of-function effects of SCN8A variants. Generalized epilepsy with absence seizures is the main epilepsy phenotype of loss-of-function variant carriers and the extent of the electrophysiological dysfunction of the gain-of-function variants is a main determinant of the severity of the clinical phenotype in focal epilepsies. Our pharmacological data indicate that sodium channel blockers present a treatment option in SCN8A-related focal epilepsy with onset in the first year of life.

Background: Despite advances in surgery and pharmacotherapy, there remains significant residual ischemic risk after coronary artery bypass grafting surgery. Methods: In REDUCE-IT (Reduction of Cardiovascular Events With Icosapent Ethyl–Intervention Trial), a multicenter, placebo-controlled, double-blind trial, statin-treated patients with controlled low-density lipoprotein cholesterol and mild to moderate hypertriglyceridemia were randomized to 4 g daily of icosapent ethyl or placebo. They experienced a 25% reduction in risk of a primary efficacy end point (composite of cardiovascular death, myocardial infarction, stroke, coronary revascularization, or hospitalization for unstable angina) and a 26% reduction in risk of a key secondary efficacy end point (composite of cardiovascular death, myocardial infarction, or stroke) when compared with placebo. The current analysis reports on the subgroup of patients from the trial with a history of coronary artery bypass grafting. Results: Of the 8179 patients randomized in REDUCE-IT, a total of 1837 (22.5%) had a history of coronary artery bypass grafting, with 897 patients randomized to icosapent ethyl and 940 to placebo. Baseline characteristics were similar between treatment groups. Randomization to icosapent ethyl was associated with a significant reduction in the primary end point (hazard ratio [HR], 0.76 [95% CI, 0.63–0.92]; P =0.004), in the key secondary end point (HR, 0.69 [95% CI, 0.56–0.87]; P =0.001), and in total (first plus subsequent or recurrent) ischemic events (rate ratio, 0.64 [95% CI, 0.50–0.81]; P =0.0002) compared with placebo. This yielded an absolute risk reduction of 6.2% (95% CI, 2.3%–10.2%) in first events, with a number needed to treat of 16 (95% CI, 10–44) during a median follow-up time of 4.8 years. Safety findings were similar to the overall study: beyond an increased rate of atrial fibrillation/flutter requiring hospitalization for at least 24 hours (5.0% vs 3.1%; P =0.03) and a nonsignificant increase in bleeding, occurrences of adverse events were comparable between groups. Conclusions: In REDUCE-IT patients with a history of coronary artery bypass grafting, treatment with icosapent ethyl was associated with significant reductions in first and recurrent ischemic events. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01492361.

International audience; There is currently no consensus regarding preferred clinical outcome measures following image-guided tumor ablation or clear definitions of oncologic end points. This consensus document proposes standardized definitions for a broad range of oncologic outcome measures with recommendations on how to uniformly document, analyze, and report outcomes. The initiative was coordinated by the Society of Interventional Oncology in collaboration with the Definition for the Assessment of Time-to-Event End Points in Cancer Trials, or DATECAN, group. According to predefined criteria, based on experience with clinical trials, an international panel of 62 experts convened. Recommendations were developed using the validated three-step modified Delphi consensus method. Consensus was reached on when to assess outcomes per patient, per session, or per tumor; on starting and ending time and survival time definitions; and on time-to-event end points. Although no consensus was reached on the preferred classification system to report complications, quality of life, and health economics issues, the panel did agree on using the most recent version of a validated patient-reported outcome questionnaire. This article provides a framework of key opinion leader recommendations with the intent to facilitate a clear interpretation of results and standardize worldwide communication. Widespread adoption will improve reproducibility, allow for accurate comparisons, and avoid misinterpretations in the field of interventional oncology research. Published under a CC BY 4.0 license. Online supplemental material is available for this article. See also the editorial by Liddell in this issue.

We report a simplified Zone 2 arch repair using a trifurcated graft for acute type A aortic dissection. The right axillary artery is cannulated. After completion of proximal aortic repair using a one-branched graft, a trifurcated graft is anastomosed to the ascending graft just above the proximal suture line or coronary buttons in case of Bentall procedure. Distal aortic anastomosis is performed at the Zone 2 level under unilateral antegrade cerebral perfusion. Full cardiopulmonary bypass flow is resumed via the right axillary and ascending graft using both Y-shaped arterial limbs. The left common carotid and innominate artery are sequentially anastomosed.

Background : Lefamulin, a pleuromutilin antibiotic approved for community-acquired bacterial pneumonia (CABP), was evaluated for microbiological efficacy in a prespecified pooled analysis of LEAP 1 and 2 phase 3 clinical trial data in patients with CABP. Methods : In LEAP 1, adults (Pneumonia Outcomes Research Team [PORT] risk class III‒V) received intravenous (IV) lefamulin 150 mg every 12 hours (q12h; 5‒7 days) or moxifloxacin 400 mg every 24 hours (q24h; 7 days), with optional IV-to-oral switch. In LEAP 2, adults (PORT II‒IV) received oral lefamulin 600 mg q12h (5 days) or moxifloxacin 400 mg q24h (7 days). Primary outcomes were early clinical response (ECR) 96±24 hours after treatment start and investigator assessment of clinical response (IACR) 5‒10 days after last dose. Secondary outcomes included ECR and IACR in patients with a baseline CABP pathogen (detected via culture, urinary antigen test, serology, and/or real-time PCR). Results : Baseline CABP pathogens were detected in 709/1289 patients (55.0% [microbiological intent-to-treat population]). The most frequently identified pathogens in this population were Streptococcus pneumoniae (61.9% of patients) and Haemophilus influenzae (29.9%); 25.1% had atypical pathogens and 33.1% had polymicrobial infections. Pathogens were identified most frequently by PCR from sputum, followed by culture from respiratory specimens. In patients with baseline CABP pathogens, ECR rates were 89.3% (lefamulin) and 93.0% (moxifloxacin); IACR success rates were 83.2% and 86.7%, respectively. Results were consistent across CABP pathogens, including drug-resistant isolates and polymicrobial infections. Conclusions : Lefamulin is a valuable IV and oral monotherapy option for empiric and directed CABP treatment in adults.

Objectives The aim of this study was to evaluate clinical characteristics, mechanisms of failure, and outcomes of transcatheter aortic valve replacement (TAVR) explantation. Background Surgical explantation following TAVR may be required for structural valve degeneration, paravalvular leak, infection, or other reasons. However, in-depth data on indications and outcomes are lacking. Methods Data from a multicenter, international registry (EXPLANT-TAVR) of patients who underwent TAVR explantation were reviewed retrospectively. Explantations performed during the same admission as initial TAVR were excluded. Clinical and echocardiographic outcomes were evaluated. Median follow-up duration was 6.7 months (interquartile range [IQR]: 1.0-18.8 months) after TAVR explantation and was 97.7% complete at 30 days and 86.1% complete at 1 year. Results From November 2009 to September 2020, 269 patients across 42 centers with a mean age of 72.7 ± 10.4 years underwent TAVR explantation. About one quarter (25.9%) were deemed low surgical risk at index TAVR, and median Society of Thoracic Surgeons risk at TAVR explantation was 5.6% (IQR: 3.2%-9.6%). The median time to explantation was 11.5 months (IQR: 4.0-32.4 months). Balloon-expandable and self-expanding or mechanically expandable valves accounted for 50.9% and 49.1%, respectively. Indications for explantation included endocarditis (43.1%), structural valve degeneration (20.1%), paravalvular leak (18.2%), and prosthesis-patient mismatch (10.8%). Redo TAVR was not feasible because of unfavorable anatomy in 26.8% of patients. Urgent or emergency cases were performed in 53.1% of patients, aortic root replacement in 13.4%, and 54.6% had concomitant cardiac procedures. Overall survival at last follow-up was 76.1%. In-hospital, 30-day, and 1-year mortality rates were 11.9%, 13.1%, and 28.5%, respectively, and stroke rates were 5.9%, 8.6%, and 18.7%, respectively. Conclusions The EXPLANT-TAVR registry reveals that surgical risks associated with TAVR explantation are not negligible and should be taken into consideration in the lifetime management of aortic stenosis.

Key Points Question Are alcohol-induced loss of consciousness and heavy weekly alcohol consumption associated with increased risk of future dementia? Findings In this multicohort study of 131 415 adults, a 1.2-fold excess risk of dementia was associated with heavy vs moderate alcohol consumption. Those who reported having lost consciousness due to alcohol consumption, regardless of their overall weekly consumption, had a 2-fold increased risk of dementia compared with people who had not lost consciousness and were moderate drinkers. Meaning The findings of this study suggest that alcohol-induced loss of consciousness is a long-term risk factor for dementia among both heavy and moderate drinkers., Importance Evidence on alcohol consumption as a risk factor for dementia usually relates to overall consumption. The role of alcohol-induced loss of consciousness is uncertain. Objective To examine the risk of future dementia associated with overall alcohol consumption and alcohol-induced loss of consciousness in a population of current drinkers. Design, Setting, and Participants Seven cohort studies from the UK, France, Sweden, and Finland (IPD-Work consortium) including 131 415 participants were examined. At baseline (1986-2012), participants were aged 18 to 77 years, reported alcohol consumption, and were free of diagnosed dementia. Dementia was examined during a mean follow-up of 14.4 years (range, 12.3-30.1). Data analysis was conducted from November 17, 2019, to May 23, 2020. Exposures Self-reported overall consumption and loss of consciousness due to alcohol consumption were assessed at baseline. Two thresholds were used to define heavy overall consumption: greater than 14 units (U) (UK definition) and greater than 21 U (US definition) per week. Main Outcomes and Measures Dementia and alcohol-related disorders to 2016 were ascertained from linked electronic health records. Results Of the 131 415 participants (mean [SD] age, 43.0 [10.4] years; 80 344 [61.1%] women), 1081 individuals (0.8%) developed dementia. After adjustment for potential confounders, the hazard ratio (HR) was 1.16 (95% CI, 0.98-1.37) for consuming greater than 14 vs 1 to 14 U of alcohol per week and 1.22 (95% CI, 1.01-1.48) for greater than 21 vs 1 to 21 U/wk. Of the 96 591 participants with data on loss of consciousness, 10 004 individuals (10.4%) reported having lost consciousness due to alcohol consumption in the past 12 months. The association between loss of consciousness and dementia was observed in men (HR, 2.86; 95% CI, 1.77-4.63) and women (HR, 2.09; 95% CI, 1.34-3.25) during the first 10 years of follow-up (HR, 2.72; 95% CI, 1.78-4.15), after excluding the first 10 years of follow-up (HR, 1.86; 95% CI, 1.16-2.99), and for early-onset (, This cohort study examines the association of overall consumption of alcohol and resultant loss of consciousness with risk for dementia.

Background & Aims There is significant variability in county-level rates of liver disease–related mortality. Although this variability is explained partly by demographics, risk factors for liver disease, and access to specialty liver care, little is known about temporal changes in mortality, and its association with economic prosperity. Therefore, we sought to explore the association between changes in county-level economic prosperity and liver disease–related mortality. Methods We performed a retrospective cohort study using county-level mortality data from the Centers for Disease Control and Prevention, economic prosperity measures from the Distressed Communities Index, and county-level markers of demographics, risk factors for liver disease, and access to health care. Primary analyses focused on adults aged 20 to 64 years of age. We used generalized linear mixed models (outcome = annual percentage change in age-adjusted liver disease–related mortality), with the primary exposure being an interaction between year and change in economic prosperity. Results There was an inverse relationship between county-level changes in economic prosperity and changes in county-level age-adjusted liver disease–related mortality rates (eg, counties with the smallest increase in economic prosperity had the biggest annual increase in liver disease–related mortality). In generalized linear mixed models accounting for county-level covariates, there was a significant association between economic prosperity and liver disease–related mortality, that is, for every 10-point higher mean rank for change in economic prosperity, there was an additional 0.65% decrease (95% CI, 0.19%–1.10%; P = .006) in mortality per year. Conclusions County-level changes in economic prosperity, independent of other county-level clinical, demographic, and access-to-care variables, may play a role in population-level trends in liver disease–related deaths among the working age population.

Background Researchers take different positions when describing the effects of infrasound on the human body. Although several studies investigated the likely harmful effects of infrasound exposure from wind turbines a significant connection has not been found yet. There is evidence that infrasound interacts with cell metabolism and may disrupt cell membrane integrity. Objectives The suggested impairment of the cells’ ultrastructure by infrasound leads to the question of whether infrasound can be therapeutically used, for instance in cancer therapy. This review provides the current state of the literature. Method Current literature on infrasound in cancer therapy including all studies with the search terms ‘cancer’ and ‘infrasound’ were identified and reviewed until the year 2020. Results The present state of research reveals promising effects of targeted infrasound in cancer therapy. Infrasound directly affects the tumor cells’ ultrastructure and seems to sensitize several types of cancer to chemotherapy, presumably due to membrane permeabilization. The application of infrasound on tumor cells without other therapeutic agents demonstrates different effects that probably depend on the type of cells, the applied frequency and sound pressure level as well as the time of exposure. Conclusions The mechanism of infrasound on cancer cells is not completely understood yet, hence, further studies have to be conducted to clarify the ultrastructural and metabolic changes inside the tumor cells. The development of suitable infrasound generators for the application in a clinical setting would be an important course of action.

Background: Cardiac autonomic neuropathy (CAN) is a complication of diabetes mellitus (DM) that is associated with increased mortality. Exercise-based assessment of autonomic function has identified diminished parasympathetic reactivation after exercise in type 2 DM. It is postulated herein, that this would be more prominent among those with type 1 DM. Methods: Sixteen subjects with type 1 DM (age 32.9 ± 10.1 years), 18 subjects with type 2 DM (55.4 ± 8.0 years) and 30 controls (44.0 ± 11.6 years) underwent exercise-based assessment of autonomic function. Two 16-min submaximal bicycle tests were performed followed by 45 min of recovery. On the 2 nd test, atropine (0.04 mg/kg) was administered near end-exercise so that all of the recovery occurred under parasympathetic blockade. Plasma epinephrine and norepinephrine levels were measured at rest, during exercise, and during recovery. Results: There were no differences in resting or end-exercise heart rates in the three groups. Parasympathetic effect on RR-intervals during recovery (p < 0.03) and heart rate recovery (p = 0.02) were blunted in type 2 DM. Type 1 DM had higher baseline epinephrine and norepinephrine levels (p < 0.03), and exhibited persistent sympathoexcitation during recovery. Conclusions: Despite a longer duration of DM in the study patients with type 1 versus type 2 DM, diminished parasympathetic reactivation was not noted in type 1 DM. Instead, elevation in resting plasma catecholamines was noted compared to type 2 DM and controls. The variable pathophysiology for exercise-induced autonomic abnormalities in type 1 versus type 2 DM may impact prognosis.

BACKGROUND Emerging data suggest increased arterial thrombosis risk in the months preceding a cancer diagnosis. OBJECTIVES Assess whether patients without documented vascular risk factors or pre-existent cardiovascular disease have a higher relative risk of cancer 12 months after arterial thrombotic events (ATE), compared to unselected patients. PATIENTS/METHODS A population-based cohort study of Clalit Health Services (CHS) database included CHS members ≥25 years without prior cancer or ATE (n=2804584). An iterative matching process selected 10 potential controls chronologically for each consecutive exposed, age- and sex-matched (actual controls drawn 1:1 from a lot). Study exposure, ATE, was defined as ischemic stroke, transient ischemic attack, myocardial infarction or systemic arterial thromboembolism during hospitalization. The outcome was newly-diagnosed cancer within 12 months, based on Israeli national cancer registry. Cox proportional hazards multivariate regression calculated hazard ratio (HR) for outcomes, adjusted for cancer risk factors. Analysis also performed for 3 subgroups: age≤50 years; no cardiovascular risk factors; no prior cardiovascular disease. RESULTS The full ATE and matched control cohorts included 43108 patients. The 12-month cumulative incidence of cancer (95% confidence interval) was 0.020 (0.019-0.022) in the ATE cohort and 0.012 (0.011-0.013) in controls, corresponding to an adjusted HR of 1.665 (1.489-1.862). The relative risk of cancer was high in all subgroups up to a HR of 3.754 (1.912-7.372) in patients without cardiovascular risk factors. CONCLUSION There is an increased risk of previously undiagnosed cancer at 12 months after ATE, especially in patients without documented vascular risk factors or pre-existent cardiovascular disease.

Peripheral artery disease (PAD) has high morbidity and mortality rates. A metabolomics approach was employed to determine whether consumption of bean-rich diets for 8 weeks would impact the metabolomic profile of individuals with PAD. Serum and urine, collected from 54 participants with clinical PAD at baseline and after 8 weeks on 0.3 cups beans/day (n = 19), 0.6 cups beans/day (n = 20), or control (n = 23) diet, and the beans were extracted and analyzed using LC-QTOF-MS. As a result, PGE2 p-acetamidophenyl ester, PGF2α diethyl amide and 5-l-glutamyl-l-alanine were significantly changed in the serum or urine of bean groups compared with control. Significant changes (P < 0.05) in the profile and/or levels of 22 flavonoids present in bean extracts showed the potential importance of the mixture of beans used in this study. In a subset of participants taking metoprolol, after 8 weeks the bean-rich diets significantly elevated metoprolol in the serum while reducing it in urine compared with baseline. In addition, the diets significantly enhanced the urinary excretion of metformin. In conclusion, several biochemical pathways including prostaglandins and glutathione were affected by bean consumption. Significant changes in the metabolism of metoprolol and metformin with bean consumption suggested the presence of diet-drug interactions that may require adjustment of the prescribed dose. ClinicalTrials.gov Identifier: NCT01382056. Novelty: Bean consumption by people with PAD alters the levels of certain metabolites in serum and urine. Different bean types (black, red kidney, pinto, navy) have unique flavonoid profiles. Metabolomics revealed potential diet–drug interactions as serum and/or urinary levels of metoprolol and metformin are modified by bean consumption.

Kidney transplantation (KT) from deceased donors with hepatitis C virus (HCV) into HCV-negative recipients has become more common. However, the risk of complications such as BK polyomavirus (BKPyV) remains unknown. We assembled a retrospective cohort at four centers. We matched recipients of HCV-viremic kidneys to highly similar recipients of HCV-aviremic kidneys on established risk factors for BKPyV. To limit bias, matches were within the same center. The primary outcome was BKPyV viremia ≥1000 copies/ml or biopsy-proven BKPyV nephropathy; a secondary outcome was BKPyV viremia ≥10 000 copies/ml or nephropathy. Outcomes were analyzed using weighted and stratified Cox regression. The median days to peak BKPyV viremia level was 119 (IQR 87-182). HCV-viremic KT was not associated with increased risk of the primary BKPyV outcome (HR 1.26, p = .22), but was significantly associated with the secondary outcome of BKPyV ≥10 000 copies/ml (HR 1.69, p = .03). One-year eGFR was similar between the matched groups. Only one HCV-viremic kidney recipient had primary graft loss. In summary, HCV-viremic KT was not significantly associated with the primary outcome of BKPyV viremia, but the data suggested that donor HCV might elevate the risk of more severe BKPyV viremia ≥10 000 copies/ml. Nonetheless, one-year graft function for HCV-viremic recipients was reassuring.

Introduction: Transplanting kidneys from hepatitis C virus (HCV) viremic donors into HCV-negative patients (HCV D-RNA-positive/R-negative) has evolved from experimental to “standard-of-care” at many centers. Nevertheless, most data derive from single centers and provide only short-term follow-up. Methods: The Multicenter Study to Transplant Hepatitis C-Infected Kidneys (MYTHIC) study was a multicenter (7 sites) trial of HCV D-RNA-positive/R-negative kidney transplantation (KT) followed by 8 weeks of glecaprevir/pibrentasvir (G/P) initiated 2 to 5 days post-KT. Prespecified outcomes included probability of KT (vs. matched waitlist comparators) and 1-year safety outcomes, allograft function, and survival. Results: Among 63 enrolled patients, 1-year cumulative incidence of KT was approximately 3.5-fold greater for the MYTHIC cohort versus 2055 matched United Network for Organ Sharing (UNOS) comparators who did not opt-in to receive a kidney from an HCV-viremic donor (68% vs. 19%, P < 0.0001). Of 30 HCV D-RNA-positive/R-negative KT recipients, all achieved HCV cure. None developed clinically significant liver disease or HCV-related kidney injury. Furthermore, 1-year survival was 93% and 1-year graft function was excellent (median creatinine 1.17; interquartile range [IQR]: 1.02–1.38 mg/dl). There were 4 cases of cytomegalovirus (CMV) disease among 10 CMV-negative patients transplanted with a kidney from an HCV-viremic/CMV-positive donor. Conclusion: The 1-year findings from this multicenter trial suggest that opting-in for HCV-viremic KT offers can increase probability of KT with excellent 1-year outcomes. Trial Registration: NCT03781726

On March 10, 2021, the FDA granted regular approval to tivozanib for treatment of patients with relapsed or refractory (R/R) advanced renal cell carcinoma (RCC) following two or more prior systemic therapies. Approval was based on the TIVO-3 study, a randomized trial of tivozanib versus sorafenib in patients with R/R advanced RCC. In TIVO-3, patients were randomized to receive either tivozanib 1.34 mg orally once daily for 21 consecutive days of every 28-day cycle or sorafenib 400 mg orally twice daily continuously. The primary endpoint was progression-free survival (PFS) per RECIST v1.1. Tivozanib demonstrated efficacy compared with sorafenib with an improvement in PFS [HR, 0.73; 95% confidence interval (CI), 0.56–0.95; P = 0.016]. The estimated median PFS was 5.6 months and 3.9 months in the tivozanib and sorafenib arms, respectively. There was no evidence of a detrimental effect on overall survival: HR, 0.97 (95% CI, 0.75–1.24). The most common grade 3 to 4 adverse reaction on the tivozanib arm was hypertension (24%). Compared with sorafenib, tivozanib was associated with lower rates of grade 3 to 4 diarrhea, rash, and palmar-plantar erythrodysesthesia. Patients receiving tivozanib in TIVO-3 had lower rates of dose reduction, interruption, or permanent discontinuation than those receiving sorafenib.

STUDY OBJECTIVES: Geriatric impairments and obstructive sleep apnea (OSA) are prevalent among older patients with atrial fibrillation (AF). Little is known about the association between OSA and geriatric impairments, including frailty, cognitive performance, and AF-related quality of life. The objective of this study was to examine the associations of OSA with frailty, cognitive performance, and AF-related quality of life among older adults with AF. METHODS: Data from the Systemic Assessment of Geriatrics Elements-AF study were used, which included AF participants 65 years and older and with a CHA(2)DS(2)-VASc ≥ 2. The STOP-BANG questionnaire was used to assess the risk of OSA. Multivariable logistic regression models were used to examine the association between risk of OSA and geriatric impairments, adjusting for sociodemographic, geriatric, and clinical characteristics. RESULTS: A total of 970 participants (mean age 75 years; 51% male) were studied. Of the 680 participants without a medical history of OSA, 26% (n = 179) of participants had a low risk of OSA, 53% (n = 360) had an intermediate risk, and 21% (n = 141) had a high risk for OSA. Compared to those with low risk of OSA, participants with an intermediate or high risk of OSA were more likely to be frail (adjusted odds ratio = 1.67, 95% confidence interval: 1.08–2.56; adjusted odds ratio = 3.00, 95% confidence interval: 1.69–5.32, respectively) in the fully adjusted models. CONCLUSIONS: Our findings identify a group of patients at high risk who would benefit from early screening for OSA. Future longitudinal studies are needed to assess the effect of OSA treatment on frailty, physical functioning, and quality of life among patients with AF. CITATION: Mehawej J, Saczynski JS, Kiefe CI, et al. Association between risk of obstructive sleep apnea and cognitive performance, frailty, and quality of life among older adults with atrial fibrillation. J Clin Sleep Med. 2022;18(2):469–475.

End stage ankle joint arthritis is a debilitating condition. Surgical treatment, most commonly ankle arthrodesis or fusion, can be highly effective. The authors outline the nature and prevalence of ankle arthritis and show that the frequency of each type of procedure varies geographically. They present data supporting the hypothesis that units performing ankle replacement more frequently tend to have better outcomes, both clinically and financially. Adoption of country-wide Ankle Arthritis Networks is proposed, ensuring that every patient seeing a foot and ankle orthopaedic surgeon has potential access to all treatment options whether their surgeon chooses to perform replacement or not. The case is made that establishment of Ankle Arthritis Networks will avoid the need for units to perform a low number of replacements per year, homogenise treatment availability across the country and enables the right patient to receive the right treatment first time. LEVEL OF EVIDENCE: IV.

Background This study reviews the outcomes of our reoperative total arch repair technique using a trifurcated graft and selective antegrade cerebral perfusion. Methods Fifty patients underwent reoperative total arch repair from January 2005 to September 2020, with either a one-stage repair (n = 9) or two-stage repair (n = 41). The two-stage technique includes minimal dissection of the mediastinal structures, an arch-first technique using a trifurcated graft, and construction of a classical elephant trunk through a partial transverse incision distally in the old graft or in the aorta just distal to the old graft. Results The median age was 63 years. Chronic dissection was the most frequent indication (88%), and 98% had undergone a previous proximal aortic repair at a median interval of 3 years. The median cardiopulmonary bypass, myocardial ischemic, selective antegrade cerebral perfusion, and lower body circulatory arrest times were 226, 103, 97, and 98 minutes, respectively. The minimum nasopharyngeal and bladder temperature were 16.5°C and 20.0°C, respectively. Operative mortality was 2%, the incidence of stroke was 2%, and the incidence of spinal cord injury was 0%. Stage II repair was performed in 37 patients (open, 33 patients; endovascular, 4 patients), with 2 mortalities and no spinal cord injury. The median duration between stage I and II was 63 days. Survival and aortic event free rates at 3 years were 88.4% ± 4.9%, and 89.8% ± 5%, respectively. Conclusions We report a reoperative total arch repair technique that minimizes dissection of the cardiac structures, simplifies the distal anastomosis, and protects vital organs, such as the brain, heart, and spinal cord.

Purpose No approved therapies directly target retinal ganglion cells (RGCs) for neuroprotection or neuroenhancement in glaucoma. Recombinant human nerve growth factor (rhNGF) has been shown to promote RGC survival and function in animal models of optic neuropathy. Here we evaluate safety, tolerability, and efficacy of short-term, high-dose rhNGF eye drops versus placebo in a cohort of glaucoma patients. Methods This study is a single-center, randomized, double-masked, vehicle-controlled, parallel group study designed to assess safety and tolerability as well as short-term neuroenhancement of structure and function (Clinicaltrials.gov NCT02855450). Sixty open-angle glaucoma patients were randomized 40:20 to receive either 180 μg/ml rhNGF or vehicle control eye drops in both eyes, three times daily for 8 weeks, with a 24-week post-treatment follow-up. One eye was officially selected as the study eye, although both eyes were studied and dosed. Primary endpoints were safety, as assessed through adverse events, and tolerability, as assessed through patient reported outcomes. Secondary outcome measures included best corrected visual acuity (BCVA), Humphrey visual field (HVF), electroretinogram (ERG), and optical coherence tomography (OCT) of retinal nerve fiber layer (RNFL) thickness at baseline, after 8 weeks of treatment, and at 4 and 24 weeks after treatment (12- and 32-weeks total). Results Of the 60 randomized subjects, 23 were female (38%) and the average age was 66.1 years. Through week 32, there were no treatment-related serious adverse events, including no unexpectedly severe progression of optic neuropathy, no adverse events affecting ocular function or pressure, and no drug-related systemic toxicity. Topical high-dose rhNGF was tolerated well, with low level of symptom burden mainly eliciting periocular ache (in 52% of treated, 5% of placebo) and only 3 patients (7.5%) discontinuing treatment due to discomfort, out of whom 1 patient (2.5%) prematurely withdrawing from the study. There were no statistically significant differences in global indices of HVF, and no meaningful differences in total, quadrant, or clock-hour mean RNFL thickness between the groups, although both of these function and structure measures showed non-significant trends towards significance in favor of rhNGF. Real-world participant data was used to generate an estimate of cohort size needed to power subsequent studies. Conclusions rhNGF is safe and tolerable in a topical 180 μg/ml formulation. Although no statistically significant short-term neuroenhancement was detected in this trial, given the strong effects of NGF in preclinical models and trends detected in this study, analysis for efficacy in a neuroprotection trial is warranted.

The FDA approved capmatinib and tepotinib on May 6, 2020, and February 3, 2021, respectively. Capmatinib is indicated for patients with metastatic non–small cell lung cancer (mNSCLC) whose tumors have a mutation leading to mesenchymal–epithelial transition (MET) exon 14 skipping as detected by an FDA-approved test. Tepotinib is indicated for mNSCLC harboring MET exon 14 skipping alterations. The approvals were based on trials GEOMETRY mono-1 (capmatinib) and VISION (tepotinib). In GEOMETRY mono-1, overall response rate (ORR) per Blinded Independent Review Committee (BIRC) was 68% [95% confidence interval (CI), 48–84] with median duration of response (DoR) 12.6 months (95% CI, 5.5–25.3) in 28 treatment-naïve patients and 41% (95% CI: 29, 53) with median DoR 9.7 months (95% CI, 5.5–13) in 69 previously treated patients with NSCLC with mutations leading to MET exon 14 skipping. In VISION, ORR per BIRC was 43% (95% CI: 32, 56) with median DoR 10.8 months (95% CI, 6.9–not estimable) in 69 treatment-naïve patients and 43% (95% CI, 33–55) with median DoR 11.1 months (95% CI, 9.5–18.5) in 83 previously-treated patients with NSCLC harboring MET exon 14 alterations. These are the first two therapies to be FDA approved specifically for patients with metastatic NSCLC with MET exon 14 skipping.

Saroglitazar is a novel peroxisome proliferator-activated receptor (PPAR) agonist with dual agonistic properties (α/γ). Due to a strong mechanistic rationale, we aimed to test the safety and efficacy of saroglitazar in patients with primary biliary cholangitis (PBC) who were either ursodeoxycholic acid (UDCA) resistant or intolerant.In this double-blind, phase II proof-of-concept trial, 37 patients with PBC were randomized to saroglitazar 4 mg (n = 13), saroglitazar 2 mg (n = 14), or placebo (n = 10) daily for 16 weeks. The primary efficacy endpoint was the reduction in alkaline phosphatase (ALP) level at Week 16.A significant reduction of mean ALP levels was observed at Week 16 relative to baseline in both the saroglitazar 4 mg (least-squares [LS] mean =-163.3 U/L, SE = 25.1, p0.001) and 2 mg (LS mean =-155.8 U/L, SE = 24.4, p0.001) groups, compared with placebo (LS mean =-21.1 U/L, SE = 28.9). Treatment with saroglitazar resulted in a rapid reduction of ALP concentration at Week 4 that was sustained through the study duration. At least 1 treatment-emergent adverse event occurred in 11 (84.6%) patients in the saroglitazar 4 mg group, in 12 (85.7%) patients in the 2 mg group and in 8 (80%) patients in the placebo group. Study drug was discontinued in 4 patients (3 patients in the 4 mg group and 1 patient in the 2 mg group) due to aminotransferase increases that promptly returned to baseline values after drug discontinuation.Saroglitazar at 2 mg and 4 mg daily was tolerated and resulted in rapid and sustained improvements in ALP. Further studies are underway at a daily dose of 2 mg and 1 mg due to the higher incidence of elevated liver enzymes observed with the 4 mg dose. CLINICALTRIALS.NCT03112681 LAY SUMMARY: Saroglitazar resulted in a rapid and sustained improvement in alkaline phosphatase levels in patients with primary biliary cholangitis. The mean percentage reductions in alkaline phosphatase levels were 49% and 51% in the saroglitazar 4 mg and 2 mg groups compared to 3% in the placebo group.

Itch pathogenesis is broadly characterized into histaminergic and nonhistaminergic pathways and transmitted via 2 main receptor families: G protein-coupled receptors and transient receptor potential channels. In the skin, itch is primarily transmitted by unmyelinated type C and thinly myelinated type Aδ nerve fibers. Crosstalk between the immune and neural systems modulates itch transmission at the skin, spinal cord, and brain. Among the many known pruritogens, Th2 cytokines, such as interleukin-4, interleukin-13, interleukin-31, and thymic stromal lymphopoietin, are particularly important mediators that signal through shared Janus kinase pathways, representing novel targets for novel itch therapeutics. Emerging evidence has also revealed that the opioidergic system is a potent modulator of itch transmission, with increased μ-opioid activity and decreased κ-opioid activity contributing to itch pathogenesis. Optimal management of itch requires that treatment approaches be tailored to specific etiologic itch subtypes. When the etiology is unknown and patients are given a diagnosis of chronic pruritus of unknown origin, treatment should be guided by the presence of Th2 polarization, often reflected by increased blood eosinophils. In the second article of this 2-part series, we outline our current understanding of itch pathogenesis and discuss available and emerging treatments for itch.

Massive pulmonary embolism (MPE) is associated with a 20-50% mortality rate with guideline directed therapy. MPE treatment with surgical embolectomy (SE) or venoarterial extracorporeal membrane oxygenation (VA-ECMO) have shown promising results. In the context of a surgical management strategy for MPE, a comparison of outcomes associated with VA-ECMO or SE was performed. A retrospective review of a single institution cardiac surgery database was performed, identifying MPE treated with SE or VA-ECMO between 2005-2020. Primary outcome was in-hospital survival. 59 MPE [27 (46.8%) VA-ECMO vs 32 (54.2%) SE] were identified. All presented with elevated cardiac biomarkers, tachycardia (mean heart rate 113 ± 20 beats/minute), hypotension (mean systolic blood pressure 85 ± 22 mm Hg) and vasopressors requirement, without significant differences between cohorts. Preoperative CPR was performed in 37.3% (22/59), without a significant difference between cohorts. More VA-ECMO presented with questionable neurologic status (GCS ≤ 4) [9/27 (33.3%) vs 2/32 (6.2%), P = 0.008] and more VA-ECMO failed thrombolysis [8/27 (29.6) vs 2/32 (6.3), P = 0.014]. All presented with severe RV dysfunction, by discharge all had normalization of echocardiographic RV function. Overall mortality was 10.2%, with a trend toward higher mortality among VA-ECMO [14.9% (4/27) vs 6.3% (2/32) P = 0.14]. CPR was independently associated with death (OR 10.8, P = 0.02) whereas treatment modality was not (OR 0.24). In an extremely unstable MPE population VA-ECMO and SE were safely performed with low mortality while achieving RV recovery. Adverse outcomes were more closely associated with preoperative CPR than with treatment modality.

Study Objective Myomectomy is the gold standard treatment for patients with symptomatic fibroids who desire fertility preservation. Given the relatively recent application of robotic surgery in the field of gynecology, there is only a small amount of data describing fertility outcomes after robotic-assisted laparoscopic myomectomy (RALM). The objective of this study was to determine the pregnancy rate in patients trying to conceive after RALM. Design A single-center, retrospective case series. Setting Department of Obstetrics and Gynecology, St. Michael's Hospital, Toronto, Ontario, Canada. Patients All patients who underwent RALM between October 2008 and September 2015 and who consented to a telephone interview were included. Intervention None. The primary outcome was pregnancy rate after RALM. Secondary outcomes included whether patients underwent fertility treatment, rate of live births after RALM, rate of spontaneous abortion mode of delivery in pregnancies following RALM, obstetric complications, and symptoms experienced postoperatively. Measurements and Main Results A total of 123 patients underwent RALM between 2008 and 2015. Of them, 101 consented to be interviewed. Average age ± standard deviation was 34.4 ± 4.4 years. Average myoma size was 8.9 ± 2.2 cm. Of all myomas, 64 (63.4%) were intramural, 35 (34.7%) were subserosal, and 2 (2%) were submucosal according to preoperative imaging. The pregnancy rate after RALM was 42/60 (70.0%). Three additional patients became pregnant who were not trying to conceive. Of the 45 patients who became pregnant, 38 (84.4%) successfully delivered or were pregnant at the time of data collection. Conclusion The pregnancy rate after RALM was 70.0%, which is similar to that reported in previous studies. Future research should aim to conduct larger, prospective studies investigating fertility outcomes after RALM and should aim to identify variables that predict pregnancy.

Multiparametric magnetic resonance imaging (mpMRI)-ultrasound (US) fusion-guided biopsy may improve prostate cancer (PCa) detection and reduce grade misclassification. We compared PCa detection rates on systematic, magnetic resonance imaging-targeted, and combined biopsy with evaluation of important subgroups.Men with clinical suspicion of harboring PCa from 2 institutions with visible Prostate Imaging-Reporting and Data System (PI-RADSOf 1,236 patients (647 biopsy-naïve) included, 626 (50.6%) harbored PCa and 412 (33.3%) had csPCa on combined biopsy. Detection of csPCa was 27.9% vs 23.3% (+4.6%) and GG1 PCa was 11.3% vs 17.8% (-6.5%) for targeted vs systematic cores. Benefit in csPCa detection was higher in the prior negative than biopsy-naïve setting (+7.8% [p0.0001] vs +1.7% [p=0.3]) while reduction in GG1 PCa detection remained similar (-5.6% [p=0.0002] vs -7.3% [p=0.0001]). Targeted biopsy showed increased csPCa detection for PI-RADS 5, decrease in GG1 for PI-RADS 3, and both for PI-RADS 4 relative to systematic biopsy. Combined biopsy detected more csPCa (+10.0%) and slightly fewer GG1 PCa (-0.5%) compared to systematic alone. Upgrading to ≥GG2 by targeted biopsy occurred in 9.8% with no cancer and 23.6% with GG1 on systematic biopsy.Combined biopsy doubled the benefit of targeted biopsy alone in detection of csPCa without increasing GG1 PCa diagnoses relative to systematic biopsy. Utility of targeted biopsy was higher in the prior negative biopsy cohort, but advantages of combined biopsy were maintained regardless of biopsy history.

Objectives Low-grade serous ovarian cancer (LGSC) is a relatively chemo-resistant disease with limited effective treatment options for patients with recurrence. Secondary cytoreductive surgery (SCS) is commonly offered at recurrence, although any benefit this has on survival is not fully determined. This review evaluates the impact of SCS, including residual disease, on progression-free survival (PFS) and overall survival (OS) in recurrent LGSC. Methods A comprehensive search of Medline ALL, Embase Classic + Embase, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Web of Science was conducted to obtain studies evaluating optimal or complete SCS versus suboptimal SCS and the amount of residual disease in recurrent LGSC. Meta-analysis was performed and PFS and OS outcomes were calculated. Results 1Of 5296 studies screened, 350 progressed to full-text review, with 9 ultimately selected for inclusion in the systematic review. Two studies met criteria for meta-analysis of PFS and of OS. The presence of visible residual disease at the conclusion of SCS negatively impacted PFS (HR = 3.51, 95% CI = 1.72-7.14), whereas SCS with no residual disease significantly improved OS (HR = 0.4, 95% CI = 0.23-0.7) in patients with recurrent LGSC. Diffuse and extensive disease distribution was inversely linked to survival. In addition, SCS as an initial treatment for recurrent LGSC was associated with superior survival in comparison to chemotherapy. A short platinum-free interval was not associated with worse survival in this cohort. Conclusions Complete SCS, and to a lesser extent optimal SCS, are associated with improved PFS and OS in patients with recurrent LGSC. SCS may be a better initial treatment strategy than systemic chemotherapy for recurrent disease. Patients with recurrent LGSC should be evaluated for the role of SCS based on disease distribution and functional status, irrespective of the platinum-free interval. Prospective studies are needed to further study the role of SCS in patients with recurrent LGSC.

The tricuspid valve often is referred to as "the forgotten valve" because it frequently is managed conservatively due to poor prognostic outcomes with conventional surgical intervention, in particular, in high-risk patients. Nevertheless, a paradigm shift has occurred in recent years, due to a growing evidence base supporting the independent prognostic influence of severe tricuspid regurgitation (TR) on patient outcomes. Both transcatheter valve replacement and valve repair have emerged as feasible and efficacious interventions for TR correction. Novel transcatheter repair techniques that replicate surgical annuloplasty are evolving as potentially lower-risk alternatives.

The prevalence of homologous recombination–DNA damage response (HR-DDR) genetic alterations is of therapeutic interest in gastroesophageal cancers. This study is a comprehensive assessment of HR-DDR mutation prevalence across gastroesophageal adenocarcinomas and squamous cell carcinomas. Here we investigate the association of HR-DDR mutations with known predictors for immune-checkpoint inhibition [deficiency in mismatch-repair (dMMRP), tumor mutational burden (TMB), and programmed death ligand 1 (PD-L1)]. We confirmed HR-DDR mutations are present in a subset of gastroesophageal adenocarcinomas (23%) and gastroesophageal squamous cell carcinomas (20%). Biomarker expression of dMMRP (18% vs. 1%) and TMB-high with a cutoff of ≥10 mt/MB (27% vs. 9%) was significantly more prevalent in the DDR-mutated cohort compared with the non-DDR-mutated cohort. Mean combined positive score for PD-L1 in the total adenocarcinoma cohort was significantly higher in the DDR-mutated cohort compared with the non–DDR-mutated cohort (10.1 vs. 5.8). We demonstrated that alterations in ARID1A, BRCA2, PTEN, and ATM are correlated with dMMRP, TMB-high, and increased PD-L1 expression in gastroesophageal adenocarcinomas. Our findings show that a subset of gastroesophageal tumors harbor HR-DDR mutations correlated with established immune biomarkers. By better understanding the relationship between HR-DDR mutations and immune biomarkers, we may be able to develop better immunotherapy combination strategies to target these tumors.

Introduction Root resorption may occur in traumatized necrotic teeth that have undergone apexification after orthodontic treatment. This study examined the effects of orthodontic treatment on the outcome of apexification. Methods This retrospective study included 36 children presenting with anterior permanent traumatized teeth with immature roots who were treated by apexification and root canal treatment. The orthodontic group consisted of 17 children with 24 teeth that were subjected to orthodontic treatment after apexification. The control group consisted of 19 children with 21 teeth that underwent only apexification without orthodontic treatment. Almost half of the teeth in both groups underwent apexification with calcium hydroxide, whereas the other half were treated with mineral trioxide aggregate. The effects of sex, stage of root development, and apexification material on the outcomes of apexification were analyzed and compared between the 2 groups. Results Apexification was successful in 88% of cases after at least 5 years of follow-up. Neither apexification technique nor sex had a significant effect on treatment outcome. The stage of root development had a positive effect on outcome, although it was not statistically significant. Some root resorption (average = 0.3 mm) was observed after orthodontic treatment, whereas teeth that underwent apexification without orthodontic treatment exhibited some root elongation (average = 0.1 mm). This difference was highly significant. Conclusions Minor root resorption was observed in the orthodontic group compared with a minor increase in root length in the control group. Orthodontic movement of immature traumatized teeth after apexification appears to be safe.

Introduction Trends on glycemic control and diabetes complications are known for high-income countries, but comprehensive data from low- and middle-income countries (LMIC) are lacking. Methods This is an expert opinion based on two retrospective studies. Here we examine the recent subset analysis of relevant data from the IDMPS Wave 7 (International Diabetes Management-Practices Study, 2015-2016) and the GOAL study conducted in multiple LMICs. Results Wave 7 sub-analysis was performed in 6113 people with type 2 diabetes from 24 LMIC. Poorly controlled diabetes (hemogloblin A1c [HbA1c] >= 7%) was found in 58.6, 73.0 and 78.3% of participants with diabetes duration of < 5, 5-12 and > 12 years, respectively (in association with a high prevalence of macro- and microvascular complications). Moreover, 37.7% of participants with diabetes duration of 5-12 years were treated only with oral antihyperglycemic drugs. The GOAL study investigated the efficacy of insulin in 2704 poorly controlled participants (mean HbA1c 9.7%; diabetes duration 10.1 +/- 6.7 years; 10 LMIC). A significant 2% reduction in mean HbA1c levels was observed after 12 months of treatment. Only 7.2% of participants experienced a symptomatic episode of hypoglycemia (nocturnal or severe hypoglycemia events were infrequent). Conclusion The rate of well-controlled participants (HbA1c < 7.0%) in the Wave 7 sub-analysis was lower than that observed in the USA (NHANES survey) or in European countries (GUIDANCE study), and the incidence of microvascular complications was higher. The GOAL study showed that insulin treatment improves glycemic control and reduces this gap. The Expert Panel recommends intensifying diabetes treatment as soon as possible, as well as patients' education and other preventive measures, initiatives which require modest costs compared to hospitalization and treatment of diabetes complications.

Direct oral anticoagulants (DOACs) have become the treatment of choice in thromboembolism prophylaxis for non-valvular atrial fibrillation, surpassing warfarin. While interruption of DOAC therapy for various reasons is a common eventuality, the body of data from real-world clinical practice on the implications of such interruptions in different clinical settings is still limited. We assessed complication rates from DOAC (apixaban, rivaroxaban, dabigatran) interruption compared with warfarin in hospitalized patients. We performed a retrospective cohort analysis of electronic records of patients hospitalized in Rabin Medical Center between 2010 and 2017. Incidents of anticoagulation interruptions for various reasons (including unintended interruptions) were collected. DOAC-treated patients were excluded if they reported non-compliance, and warfarin-treated patients were excluded if their international normalized ratio measurement on admission was subtherapeutic. Outcomes included ischemic stroke, systemic thromboembolism, myocardial infarction, and all-cause mortality within 90 days of anticoagulation interruption. The median CHA2DS2-VASc score was 5.0 (IQR 4.0–6.0) in both treatment groups. The associated risk of stroke, thromboembolic complications, myocardial infarction, and all-cause mortality after interruption of anticoagulation was not significantly different between the 2 treatment groups. Selective comparison of patients who were well balanced on warfarin before treatment interruption to DOAC-treated patients did not significantly influence the outcomes. This study did not find a significant difference in the complication rate after interruption of DOAC therapy compared with interruption of warfarin therapy in hospitalized patients with a high risk of thromboembolism.

Although primary cutaneous B-cell lymphomas (PCBCL) comprise 25% of all cutaneous lymphomas, their incidence in the pediatric population is unknown, and the information on pediatric PCBCL has mostly been gathered from individual case reports or series from single centers.This was a population-based, retrospective cohort study of patients in 18 cancer registries in the United States diagnosed between 2000 to 2016 through the Surveillance, Epidemiology, and End Results (SEER) program. Age-adjusted incidence rates were calculated for PCBCL in pediatric (20 years) and adult (≥20 years) populations. Demographic, clinical, and pathological characteristics of PCBCL were compared between the two groups.A total of 48 pediatric and 5128 adult PCBCL cases were included. Median age at diagnosis was 16.5 years and 65 years in the two groups, respectively. The major histologic subtypes of pediatric cases were marginal zone lymphoma (77.1%), followed by diffuse large B-cell lymphoma (12.5%) and follicle center lymphoma (10.4%), which were equally distributed in adults. The age-adjusted pediatric PCBCL incidence rate (per 1,000,000 person-years) was 0.12 (95% CI 0.09-0.16). The incidence in the adult population was approximately 40-fold higher than the one observed in the pediatric group (IRR 41.4, 95% CI 31.2-56.2). All 48 pediatric cases were alive during a median follow-up time of 48 months.Pediatric PCBCL is a very rare disease affecting mostly adolescents of both sexes. The major histologic subtype is marginal zone lymphoma, and the prognosis is favorable.

Research question What are the reproductive choices and retrospective reflections of women at least 4 years after planned oocyte cryopreservation (POC)? Design This was an internet survey, using the REDCap application, of women who underwent POC, at a single-centre university-affiliated IVF unit, 4–8 years before the survey. The questionnaire addressed reproductive choices and outcomes following POC. Results Seventy-nine women who underwent POC during 2011–2014 were invited to participate, and 70 (89%) responded. Mean age at cryopreservation was 37.1 ± 2.4 (range 30–41) years, mean age at study participation 42.6 ± 2.6 (range 35–48) years, and mean time from first cryopreservation cycle to study participation 5.5 ± 1.3 (range 4–8) years. The main retrospectively reported reason for POC was not wanting to become pregnant without a partner (59, 84%). During the follow-up period, 44 women (63%) attempted to conceive either naturally or by assisted reproductive technology using fresh or cryopreserved oocytes. Of those, 28 women achieved a live birth (64% of those who tried to conceive). Fourteen respondents (20% of all respondents) reported using their cryopreserved oocytes, and three (21%) achieved a birth using those oocytes. Fifteen women (34%) of those who tried to conceive used donor spermatozoa. Conclusions The most common reasons for not using frozen oocytes were achieving pregnancy without frozen oocytes or preferring not to have a child without a partner. A considerable proportion of women who had POC and were not interested in being a single parent by choice eventually try to conceive using donor spermatozoa several years later.

Background and aims Glucagon Like Peptide-1 Receptor (GLP-1R) activation reduces pro-inflammatory responses of human monocytes, their accumulation in the vascular wall and foam cell formation inhibiting atherosclerogenesis. This suggests that reduction of circulating GLP-1-1R positive monocytes may have pro-atherogenic effects. It is unknown whether different CD14/CD16 monocytes subsets display GLP-1R and whether their relative proportions correlate with atherosclerosis severity. We evaluated the association between GLP-1R positivity in different CD14/CD16 monocyte subsets and coronary atherosclerosis severity. Methods Relative amounts of classical (CD14+/CD16-), intermediate pro-inflammatory (CD14+/CD16+) and non-classical patrolling (CD14-/CD16+) subsets of total circulating monocytes and the proportions of GLP-1R positive monocytes in these subsets were determined in 13 control subjects and 10 dyslipidemic ischemic heart disease (IHD) patients with severe angiographic proven coronary atherosclerosis using flow cytometry analysis. Atherosclerosis severity was calculated by SYNTAX score. Results In univariable analysis, severe atherosclerosis was associated with decreased proportion of classical monocytes and two fold increased CD16+ pro-inflammatory and patrolling subsets as compared with controls (p = 0.01, p = 0.02 and p = 0.01, respectively). Frequency of GLP-1R positive monocytes was decreased in both CD16+ subsets (p = 0.02 and p = 0.05, respectively) and negatively correlated with atherosclerosis severity (r = −0.65, p = 0.005 and r = −0.44, p = 0.05, respectively). Conclusions Increased skewing of the classical monocyte population toward CD16+ pro-inflammatory and patrolling subsets accompanied by decreased in GLP-1R positivity are associated with coronary atherosclerosis severity in IHD patients with dyslipidemia. Although the effect of potential confounders cannot be ruled out, our data suggest that failure of GLP-1R-dependent anti-inflammatory/anti-atherogenic control results in innate immune system dysfunction and can promote atherosclerogenesis.

Objective The surgical closure of septal perforations is a challenging procedure. Various techniques exist. Each perforation proves that there is not the one precise procedure for all perforations. Nevertheless, success rates of about 90% are reported, although the procedure for closing the defect is challenging. Our goal was to evaluate the existing data. Methods We performed a contemporary review of published closure rates of septal perforations on order to compare the present results in the literature. The limitations of the respective studies were analyzed. Results We found closure rates from 30 to 100%. Numerous procedures were described and combined. Prospective studies comparing different techniques are missing. The follow-up time in studies was quite short or not even specified. Studies on long-term success rates are rare. Conclusion The closure of septal defects is one of the most challenging rhinosurgical interventions. Closure rates ≥90% as described in literature seem relatively high. One reason might be short follow-ups and retrospective study designs. Frequently, precise information on the follow-up and the method of follow up is missing. Thoroughly designed prospective studies are absent. Longer follow-up times are associated with lower complete closure rates. A long-term success rate between 70 and 80% seems realistic.

Implantation is a critical step in human reproduction. The success of this step is dependent on a competent blastocyst, receptive endometrium, and successful cross talk between the embryonic and maternal interfaces. Recurrent implantation failure is the lack of implantation after the transfer of several embryo transfers. As the success of in vitro fertilization has increased and failures have become more unacceptable for patients and providers, the literature on recurrent implantation failure has increased. While this clinical phenomenon is often encountered, there is not a universally agreed-on definition—something addressed in an earlier portion of this Views and Reviews. Implantation failure can result from several different factors. In this review, we discuss factors including the maternal immune system, genetics of the embryo and parents, anatomic factors, hematologic factors, reproductive tract microbiome, and endocrine milieu, which factors into embryo and endometrial synchrony. These potential causes are at various stages of research and not all have clear implications or immediately apparent treatment.

The safety and efficacy of direct-acting antiviral therapies have allowed the transplantation of organs from hepatitis C virus (HCV)-viremic donors into uninfected recipients. This novel strategy contrasts with the previous standard-of-care practice of limiting the transplantation of HCV infected-donor organs to HCV-infected recipients, or all too often, discarding viable organs. In this review, we summarize the published literature about the safety and feasibility of transplanting organs from HCV-viremic donors, the challenges that hinder wider adoption of this strategy, and future research needs.

Objective Static endoscopic evaluation of swallowing (SEES) is an instrumental evaluation developed for in‐office identification of patients who may benefit from a modified barium swallow study (MBSS). We aim to determine the predictive value of SEES for evaluating dysphagia. Methods A retrospective case series was performed on adults evaluated for dysphagia using SEES followed by MBSS at a single tertiary care center. Studies were evaluated by two blinded expert raters. Results Fifty‐eight patients were included. Thin liquid penetration on SEES had a sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of 0.86 (95% CI 0.70‐0.95), 0.63 (95% CI 0.24‐0.91), 0.91 (95% CI 0.76‐0.98), and 0.5 (0.19‐0.81), respectively, for predicting thin liquid penetration on MBSS, and 1.0 (95% CI 0.59‐1.0), 0.29 (95% CI 0.15‐0.47), 0.23 (95% CI 0.10‐0.41), and 1.0 (95% CI 0.69‐1.0) for predicting thin liquid aspiration on MBSS. Thin liquid aspiration on SEES had a sensitivity, specificity, PPV, and NPV of 0.67 (95% CI 0.09‐0.99), 0.85 (95% CI 0.66‐0.96), 0.33 (95% CI 0.04‐0.78), and 0.96 (95% CI 0.79‐1.0), respectively, for predicting thin liquid aspiration on MBSS. Conclusions SEES may be used as an objective in‐office test to screen for aspiration and penetration. Thin liquid penetration on SEES is moderately sensitive for predicting penetration on MBSS. Absence of thin liquid penetration or aspiration on SEES has a high NPV for excluding aspiration on MBSS. Abnormalities on SEES or the need to view the entire swallowing mechanism should prompt an MBSS for a more complete evaluation of dysphagia. Level of Evidence: 4, Static endoscopic evaluation of swallowing (SEES) is an instrumental evaluation developed for in‐office identification of patients who may benefit from a modified barium swallow study (MBSS). SEES may be used as an objective in‐office test to screen for aspiration and penetration. Absence of thin liquid penetration or aspiration on SEES has a high NPV for excluding aspiration on MBSS.

OBJECTIVE Chronic subdural hematoma (cSDH) is a common and challenging pathology to treat due to both the historically high recurrence rate following surgical evacuation and the medical comorbidities inherent in the aging patient population that it primarily affects. Middle meningeal artery (MMA) embolization has shown promise in the treatment of cSDHs, most convincingly to avoid surgical evacuation in relatively asymptomatic patients. Symptomatic patients requiring surgical evacuation may also benefit from perioperative MMA embolization to prevent cSDH recurrence. The goal of this study was to determine the utility of perioperative MMA embolization for symptomatic cSDH requiring surgical evacuation and to assess if there is a decrease in the cSDH recurrence rate compared to historical recurrence rates following surgical evacuation alone. METHODS Symptomatic cSDHs were evacuated using a subdural evacuating port system (SEPS) with 5-mm twist-drill craniostomy in an intensive care unit or by performing a craniotomy in the operating room, using either a small (silver dollar, < 4 cm) or large (≥ 4 cm) craniotomy. MMA embolization was performed perioperatively using angiography, selective catheterization of the MMA, and infusion of polyvinyl particles. Outcomes were assessed clinically and radiographically with interval head CT imaging. RESULTS There were 44 symptomatic cSDHs in 41 patients, with 3 patients presenting with bilateral symptomatic cSDH. All cSDHs were evacuated using an SEPS (n = 18), a silver-dollar craniotomy (n = 16), or a large craniotomy (n = 10). Prophylactic MMA embolization was performed successfully in all cSDHs soon after surgical evacuation. There were no deaths and no procedural complications. There was an overall reduction of greater than 50% or resolution of cSDH in 40/44 (90.9%) cases, regardless of the evacuation procedure used. Of the 44 prophylactic cases, there were 2 (4.5%) cases of cSDH recurrence that required repeat surgical evacuation at the 1-year follow-up. These 2 cSDHs were initially evacuated using an SEPS and subsequently required a craniotomy, thereby representing an overall 4.5% recurrence rate of treated cSDH requiring repeat evacuation. Most notably, of the 26 patients who underwent surgical evacuation with a craniotomy followed by MMA embolization, none had cSDH recurrence requiring repeat intervention. CONCLUSIONS Perioperative prophylactic MMA embolization in the setting of surgical evacuation, via either craniotomy or SEPS, may help to lower the recurrence rate of cSDH.

Patients with dextro-transposition of the great arteries (d-TGA) require surgical repair as neonates. These patients are at risk for post-operative chylothorax. We sought to describe the presentation, imaging, and outcomes after intervention for patients with d-TGA with post-operative chylothorax. A retrospective chart review was performed in patients with repaired d-TGA who were referred from 1/1/2013 to 4/1/2020 for evaluation of chylothorax. Patient history, lymphatic imaging, and interventional data were collected. Impact of intervention on lymphatic drainage was evaluated with a student’s t-test. Eight patients met inclusion criteria for this study. Five patients had a history of central venous thrombus leading to thoracic duct outlet occlusion. Five patients underwent intervention, two were managed conservatively, and one was not a candidate for intervention. Chylothorax resolved in six patients. There was a significant difference in output from 7 days prior to first intervention (114 mL/kg/day) compared to 28 days following final intervention (27 mL/kg/day, p = 0.034). There were no procedural complications. Chylothorax in patients with repaired transposition of the great arteries is often amenable to intervention. Early surveillance and management of central venous thrombosis may reduce the burden of lymphatic disease in these patients.

The Jewish Farmer Network (JFN) is a North American grassroots organization that mobilizes Jewish agricultural wisdom to build a more just and regenerative food system for all. This paper pre­sents methodological findings and reflections from the initial stages of a participatory action research (PAR) collaboration led by the authors and JFN organizers centered on Cultivating Culture, JFN’s inaugural conference in February 2020. For this early iterative phase, we used a PAR approach to guide event ethnography to both facilitate and understand collective movement building and action. This work included pre-conference collabo­rative research design, a participatory reflection and action workshop with roughly 90 participants, eval­uative surveys, short ethnographic interviews, and ongoing post-conference analysis with researchers and movement organizers. While this data was first analyzed and organized for JFN’s use, we present findings to demonstrate the effectiveness of fore­grounding event ethnography within a PAR re­search design at an early stage of movement for­mation, especially how elements of event ethnogra­phy can address some of the limitations of using PAR with a nascent network of farmers. Our work revealed themes in the movement of Jewish farm­ing: the politics of identity in movement building, the tensions around (de)politicization, and the production of Jewish agroecological knowledge. We reflect on the utility of using PAR to frame scholar-activism and propose future inquires for Jewish agrarianism.

The Freiburg index of post-TIPS survival (FIPS) score was recently demonstrated to improve prediction of post-TIPS mortality relative to existing standards. As this score was derived from a German cohort over an extended time period, it is unclear if performance will translate well to other settings. This study aimed to externally validate the FIPS score in a large Veterans Affairs (VA) cohort over two separate eras of TIPS-related care. This was a retrospective cohort study of patients with cirrhosis who underwent TIPS placement in the VA from 2008 to 2020. Cox regression models for post-TIPS survival were constructed using FIPS, MELD, MELD-Na, or CTP scores as predictors. Discrimination (Harrell’s C) and calibration (joint tests of calibration curve slope and intercept) were evaluated for each score. A stratified analysis was performed for time periods between 2008–2013 and 2014–2020. The cohort of 1,274 patients was 97.3% male with mean age 60.9 years and mean MELD-Na 14. The FIPS score demonstrated the highest overall discrimination versus MELD, MELD-Na, and CTP (0.634 vs. 0.585, 0.626, 0.612, respectively). However, in the modern treatment era (2014–2020), the FIPS score performed similarly to MELD-Na. Additionally, the FIPS score demonstrated poor calibration at one-month and six-month post-TIPS timepoints (joint p = 0.04 and 0.004, respectively). MELD, MELD-Na, and CTP were well-calibrated at each timepoint (each joint p > 0.05). The FIPS score performed similarly to MELD-Na in the modern TIPS treatment era and demonstrated regions of poor calibration. Future models derived with contemporary data may improve prediction of post-TIPS mortality.

Articular facet morphology plays a fundamental role in subtalar joint biomechanics and stability, and likely influences the development of hindfoot osteoarthritis. While multiple anatomical studies have shown wide variation in articular facet configuration, the clinico-radiological findings are rarely presented. We illustrate a case of bilateral subtalar joint middle facet agenesis in a 45-year-old woman, which was missed despite several presentations. We demonstrate the imaging findings to enable clinicians to distinguish this from the more common middle facet coalition. We summarise the developmental anatomy and discuss the potential implications on biomechanical function. Recognition of middle facet agenesis within the complex subtalar joint is important to prevent misdiagnosis and unnecessary surgery.

PURPOSE Treatment for orbital venolymphatic malformations (VLMs) commonly includes 3 major options: sclerotherapy, surgery, and embolization followed by surgical excision. Each has certain advantages, although it is not clear whether all are effective. The authors characterize the clinical course for a series of patients with distensible orbital venous-dominant VLM treated with sclerotherapy and/or embolization with excision. METHODS In this cross-sectional cohort study, patients affected by distensible orbital venous-dominant VLM presenting to the orbital and ophthalmic plastic surgery service from 2014 to 2020 were identified. Patients were included if they presented with a moderate-flow, distensible venous-dominant malformation associated with Valsalva-related symptoms (e.g., pain, proptosis, and diplopia). RESULTS Six cases were treated with sclerotherapy. Four underwent multiple treatments, with a mean ± SD of 3.5 ± 2.3 (range 1-7). All patients in this group failed to improve or experienced recurrence of symptoms after sclerotherapy. Twelve cases were treated with embolization and excision. Resolution of symptoms in all 12 cases was noted and maintained for a mean of 3.4 ± 2.1 years. There have been no cases of recurrence. Patients treated with sclerotherapy were more likely to experience recurrence of symptoms compared to those treated with embolization and excision (p < 0.001). CONCLUSIONS Treatment of distensible venous-dominant moderate-flow orbital VLM with sclerotherapy may provide temporary improvement in some cases. However, in the medium to long term, recurrence was universal in this series. Embolization with excision appears to provide more definitive management, avoiding recurrence in all cases for a mean follow-up of 3 years.

Point-of-care ultrasound (POCUS) has been described as a useful tool for identification of coronavirus disease 2019 (COVID-19) in adults and children. Although several case reports describe POCUS findings in children with COVID-19, to our knowledge, there have been no published multicenter case series describing the large heterogeneity in lung POCUS findings in pediatric COVID-19. This series includes 7 symptomatic patients with COVID-19 who had a lung POCUS performed at 6 institutions by pediatric emergency attendings and fellows. The findings were variable, ranging from no findings to the appearance of B-lines, pleural abnormalities, consolidations, and a pleural effusion. Further studies are needed to improve our understanding, characterization, and prognostic correlation of POCUS findings in this novel disease in children.

The controversial account of Jesus in Josephus’s Jewish Antiquities 18.63–64, known as the Testimonium Flavianum, has puzzling similarities to Luke 24.18–24, a portion of the Emmaus narrative. This article proposes an explanation based on established research into Josephus’s methods of composition. Through a phrase-by-phrase study, this article finds that the Testimonium can be derived from the Emmaus narrative using transformations Josephus is demonstrated to have employed in paraphrasing known sources for the Antiquities. Precedents are identified in word adoption/substitution and content modification. Consequently, I submit that the Testimonium is Josephus’s paraphrase of a Christian source. This result also resolves the difficulties that have raised doubts about the Testimonium’s authenticity, with implications for the understanding of the historical Jesus.

BACKGROUND The authors' purpose was to create a nomogram using machine learning models predicting risk of breast reconstruction complications with or without postmastectomy radiation therapy. METHODS Between 1997 and 2017, 1617 breast cancer patients undergoing mastectomy and breast reconstruction were analyzed. Those with autologous, tissue expander/implant, and single-stage direct-to-implant reconstruction were included. Postmastectomy radiation therapy was delivered either with three-dimensional conformal photon or proton therapy. Complication endpoints were defined based on surgical reintervention operative notes as infection/necrosis requiring debridement. For implant-based patients, the authors studied capsular contracture requiring capsulotomy and implant failure. For each complication endpoint, least absolute shrinkage and selection operator-penalized regression was used to select the subset of predictors associated with the smallest prediction error from 10-fold cross-validation. Nomograms were built using the least absolute shrinkage and selection operator-selected predictors, and internal validation using cross-validation was performed. RESULTS Median follow-up was 6.6 years. Among 1617 patients, 23 percent underwent autologous reconstruction, 39 percent underwent direct-to-implant reconstruction, and 37 percent underwent tissue expander/implant reconstruction. Among 759 patients who received postmastectomy radiation therapy, 8.3 percent received proton-therapy to the chest wall and nodes and 43 percent received chest wall boost. Internal validation for each model showed an area under the receiver operating characteristic curve of 73 percent for infection, 75 percent for capsular contracture, 76 percent for absolute implant failure, and 68 percent for overall implant failure. Periareolar incisions and complete implant muscle coverage were found to be important predictors for infection and capsular contracture, respectively. In a multivariable analysis, we found that protons compared to no postmastectomy radiation therapy significantly increased capsular contracture risk (OR, 15.3; p < 0.001). This was higher than the effect of photons with electron boost versus no postmastectomy radiation therapy (OR, 2.5; p = 0.01). CONCLUSION Using machine learning, these nomograms provided prediction of postmastectomy breast reconstruction complications with and without radiation therapy. CLINICAL QUESTION/LEVEL OF EVIDENCE Risk, III.

OBJECTIVE Management of a patient presenting with a first seizure depends on the risk of additional seizures. In clinical practice, the recurrence risk is estimated by the treating physician using the neurological examination, brain imaging, a thorough history for risk factors, and routine scalp electroencephalogram (EEG) to detect abnormal epileptiform activity. The decision to use antiseizure medication can be challenging when objective findings are missing. There is a need for new biomarkers to better diagnose epilepsy following a first seizure. Recently, an EEG-based novel analytical method was reported to detect paroxysmal slowing in the cortical network of patients with epilepsy. The aim of our study is to test this method's sensitivity and specificity to predict epilepsy following a first seizure. METHODS We analyzed interictal EEGs of 70 patients admitted to the emergency department of a tertiary referral center after a first seizure. Clinical data from a follow-up period of at least 18 months were available. EEGs of 30 healthy controls were also analyzed and included. For each EEG, we applied an automated algorithm to detect paroxysmal slow wave events (PSWEs). RESULTS Of patients presenting with a first seizure, 40% had at least one additional recurring seizure and were diagnosed with epilepsy. Sixty percent did not report additional seizures. A significantly higher occurrence of PSWEs was detected in the first interictal EEG test of those patients who were eventually diagnosed with epilepsy. Conducting the EEG test within 72 h after the first seizure significantly increased the likelihood of detecting PSWEs and the predictive value for epilepsy up to 82%. SIGNIFICANCE The quantification of PSWEs by an automated algorithm can predict epilepsy and help the neurologist in evaluating a patient with a first seizure.

In the USA, the COVID-19 pandemic has created challenges beyond the direct consequences of the infection. Because of shifting resources in response to need, many domains within the healthcare sector unrelated to COVID-19 have had interrupted abilities to provide care. In the current study, we focus on preventative sexual health care during the pandemic. In a sample of 511 (mean age = 27.7) people, we examined quantitative data regarding continuation and discontinuation of birth control and PrEP during the pandemic, along with qualitative data illustrating the underlying reasons for participants' (dis)continuation. Results showed that most (92.5%) of birth control users reported continuation of their birth control, with the predominant reasons reported being use for health reasons, long-acting reversible contraceptive use, access to remote healthcare services, and increased vigilance over pregnancy prevention. Conversely, around half (52.6%) of PrEP-using participants reported already discontinuing or planning to discontinue their PrEP regimen. Temporary abstinence and concerns about accessing in-person health care were the predominant reasons for PrEP discontinuation. These results have implications for both researchers and sexual healthcare providers. Disruptions to preventative sexual health care should be considered in ongoing research about patient needs, and healthcare providers may wish to consider particular challenges faced by PrEP users concerning re-start and continuation.