Coerced consent in clinical research: study protocol for a randomized controlled trial.

BACKGROUND: Despite the low-risk nature of participation in most clinical anesthesia trials, subject recruitment on the same day as surgery is often restricted due to the concerns of researchers and local research ethics boards that same-day consent may not afford adequate time and opportunity for patients to weigh and make decisions, as well as perceptions of patient vulnerability immediately prior to surgery that could impact the voluntary nature and the rigor of the informed consent process. However, specialties such as anesthesiology, critical care, interventional radiology, and emergency medicine have a varied pattern of practice and patient acquaintance that does not typically afford the luxury of time or, in many cases, advance consent for participation in research. Indeed, the initial encounter between anesthesiologists and patients undergoing elective procedures routinely occurs on the day of surgery. Concerns of coercion related to same-day consent for clinical anesthesia research trials have not been borne out in the literature, and represent a significant obstacle to clinical researchers, as well as to the patients who are denied opportunities for potential benefit through participation in research studies. METHODS: We describe the protocol for a prospective randomized controlled trial examining the voluntariness of patient consent, solicited either in advance of surgery or on the same day, to participate in an anesthesia research study at Women's College Hospital. One hundred fourteen patients scheduled to undergo ambulatory anterior cruciate ligament repair facilitated by general anesthesia with an adductor canal block will be randomized for recruitment either (a) in the pre-operative assessment clinic before the day of surgery or (b) on the day of surgery, to be approached for consent to participate in a fabricated research study of adjunct medications in adductor canal blocks. Regardless of allocation, patients in both groups will receive the same routine standard of care and will complete a post-operative questionnaire to signal perceptions of undue influence in the process of providing informed consent for the fabricated trial. DISCUSSION: This study will inform trial design and practice guidelines surrounding the amount of time patients ought to be afforded in order to make durable decisions to participate (or not) in clinical research studies. This is expected to impact trial recruitment in a variety of clinical settings where researchers have only brief opportunities to interface with patients. TRIAL REGISTRATION: The trial was registered prospectively on the Open Science Framework (OSF), registration #46twc, on 2023-Mar-17.

Nonopioid analgesic use in older patients admitted for orthopedic rehabilitation.

BACKGROUND: Multimodal analgesia (MMA) combines opioids with nonopioid analgesics (NOAs) to mitigate opioid-related adverse events and development of opioid use disorders. Although MMA has become the standard for orthopedic perioperative pain management, guidance is less clear for the approximately 15% of patients who go on to require inpatient orthopedic rehabilitation (IOR) postoperatively. The IOR population tends to be older and frailer and hence likely more vulnerable to adverse events. Little research has been done to shed light on how NOAs are used in this population. OBJECTIVE: To characterize NOA prescribing in older versus younger adults during IOR admissions and to determine predictors of NOA prescribing in an older IOR population. DESIGN: Retrospective case-control study. SETTING: Two IOR wards at an academic rehabilitation hospital in Toronto, Canada. PATIENTS: All patients aged ≥50 years admitted for an orthopedic indication between November 2019 and June 2021; the patients aged <65 group was included for comparative characterization of NOA prescribing versus older peers. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Medication use and adverse events, pain, and rehabilitation outcomes such as the Functional Independence Measure, discharge destination, and length of stay. RESULTS: A total of 643 patient encounters were included; 48.2% used NOA. Age (odds ratio [OR]: 0.97; confidence interval [CI]: 0.95-0.99, p < .001) and prior NOA use (OR: 3.15; CI: 2.0-4.9, p < .001) were associated with NOA prescribing. Other positively associated factors included body mass index, psychiatric history, elective surgery, and admission from a specific referring hospital. Adverse events between NOA users and nonusers were similar. CONCLUSIONS: NOA prescribing is heterogeneous and declines with age in IOR. This points to an opportunity to explore integrating NOA into opioid-sparing MMA protocols tailored to older IOR patients, along with further study of the safety and benefit of these regimens.

Impact of Sugammadex Versus Neostigmine Reversal on Postoperative Recovery Time in Patients With Obstructive Sleep Apnea Undergoing Bariatric Surgery: A Double-Blind, Randomized Controlled Trial.

BACKGROUND: Residual neuromuscular blockade can be associated with serious postoperative complications. Sugammadex is a newer neuromuscular blocking drug (NMBD) reversal agent that rapidly and completely reverses rocuronium. Whether sugammadex has any advantages over neostigmine in morbidly obese patients with obstructive sleep apnea (OSA) is unclear. We investigated whether sugammadex would reduce discharge time from the operating room (OR) compared with neostigmine in morbidly obese patients with OSA undergoing bariatric surgery. METHODS: This was a prospective, double-blinded randomized controlled superiority trial with 2 parallel groups. Patients were randomized 1:1 into reversal of NMBD with sugammadex or neostigmine. Our inclusion criteria were morbidly obese adult patients with OSA undergoing elective bariatric surgery under general anesthesia. Our exclusion criteria were allergy to rocuronium, sugammadex or neostigmine, malignant hyperthermia, hepatic or renal insufficiency, neuromuscular diseases, and an inability to give consent. The primary outcome was the time from administration of the NMBD reversal agent to discharge from the OR. Secondary outcomes included the time from administration of the NMBD reversal agent to the time the patient opened eyes to command, and the time to extubation. The Mann-Whitney test was used to compare the outcomes between treatment groups. RESULTS: We randomized 120 patients into 2 groups of 60 patients. Overall median body mass index (BMI) was 48.1 kg/m2 ([interquartile range, IQR]) [43.0-53.5]. The time from drug administration to discharge from OR was 13.0 minutes [10.0-17.0] in the sugammadex group and 13.5 minutes [11.0-18.3] in the neostigmine group (P = .27). The treatment effect estimate with a bootstrapped 95% confidence interval [CI] for time from admission to discharge from OR was -0.5 [-2.5 to 3]. No differences were observed in postoperative complications and other secondary outcomes. CONCLUSIONS: No difference was observed in OR discharge time in morbidly obese patients with OSA when sugammadex was administered instead of neostigmine.

Airway pepsinogen A4 identifies lung transplant recipients with microaspiration and predicts chronic lung allograft dysfunction.

BACKGROUND: Aspiration is a known risk factor for adverse outcomes post-lung transplantation. Airway bile acids are the gold-standard biomarker of aspiration; however, they are released into the duodenum and likely reflect concurrent gastrointestinal dysmotility. Previous studies investigating total airway pepsin have found conflicting results on its relationship with adverse outcomes post-lung transplantation. These studies measured total pepsin and pepsinogen in the airways. Certain pepsinogens are constitutively expressed in the lungs, while others, such as pepsinogen A4 (PGA4), are not. We sought to evaluate the utility of measuring airway PGA4 as a biomarker of aspiration and predictor of adverse outcomes in lung transplant recipients (LTRs) early post-transplant. METHODS: Expression of PGA4 was compared to other pepsinogens in lung tissue. Total pepsin and PGA4 were measured in large airway bronchial washings and compared to preexisting markers of aspiration. Two independent cohorts of LTRs were used to assess the relationship between airway PGA4 and chronic lung allograft dysfunction (CLAD). Changes to airway PGA4 after antireflux surgery were assessed in a third cohort of LTRs. RESULTS: PGA4 was expressed in healthy human stomach but not lung. Airway PGA4, but not total pepsin, was associated with aspiration. Airway PGA4 was associated with an increased risk of CLAD in two independent cohorts of LTRs. Antireflux surgery was associated with reduced airway PGA4. CONCLUSIONS: Airway PGA4 is a marker of aspiration that predicts CLAD in LTRs. Measuring PGA4 at surveillance bronchoscopies can help triage high-risk LTRs for anti-reflux surgery.

The Impact of Infant Sex on Multiple Courses versus a Single Course of Antenatal Corticosteroids: A Secondary Analysis of a Randomized Controlled Trial.

OBJECTIVE: Animal literature has suggested that the impact of antenatal corticosteroids (ACS) may vary by infant sex. Our objective was to assess the impact of infant sex on the use of multiple courses versus a single course of ACS and perinatal outcomes. STUDY DESIGN: We conducted a secondary analysis of the Multiple Courses of Antenatal Corticosteroids for Preterm Birth trial, which randomly allocated pregnant people to multiple courses versus a single course of ACS. Our primary outcome was a composite of perinatal mortality or clinically significant neonatal morbidity (including neonatal death, stillbirth, severe respiratory distress syndrome, intraventricular hemorrhage [grade III or IV], cystic periventricular leukomalacia, and necrotizing enterocolitis [stage II or III]). Secondary outcomes included individual components of the primary outcome as well as anthropometric measures. Baseline characteristics were compared between participants who received multiple courses versus a single course of ACS. An interaction between exposure to ACS and infant sex was assessed for significance and multivariable regression analyses were conducted with adjustment for predefined covariates, when feasible. RESULTS: Data on 2,300 infants were analyzed. The interaction term between treatment status (multiple courses vs. a single course of ACS) and infant sex was not significant for the primary outcome (p = 0.86), nor for any of the secondary outcomes (p > 0.05). CONCLUSION: Infant sex did not modify the association between exposure to ACS and perinatal outcomes including perinatal mortality or neonatal morbidity or anthropometric outcomes. However, animal literature indicates that sex-specific differences after exposure to ACS may emerge over time and thus investigating long-term sex-specific outcomes warrants further attention. KEY POINTS: · We explored the impact of infant sex on perinatal outcomes after multiple versus a single course of ACS.. · Infant sex was not a significant effect modifier of ACS exposure and perinatal outcomes.. · Animal literature indicates that sex-specific differences after ACS exposure may emerge over time.. · Further investigation of long-term sex-specific outcomes is warranted..

Age-related differences in symptom distress among patients with cancer.

INTRODUCTION: Differences in symptom distress among older (age 65-74) and very old (age 75+) patients with cancer, compared to younger patients, remain to be well explored. These differences are important to understand given the heterogeneity of older populations and may have implications for age-appropriate symptom detection and management. MATERIALS AND METHODS: We examined routinely collected Edmonton Symptom Assessment System Revised (ESAS-r) scores from 9,143 patients age 40+ initiating chemotherapy for solid malignancies at a single academic cancer centre, between September 2011 and May 2019. We used multivariable logistic regression models to determine associations between the most common symptoms and age group (ages 40-64, 65-74, 75-84, and 85+), cancer site, clinical stage, sex, and income levels. We focused our findings on patients with the five most common cancers, breast (n = 1,532), prostate (n = 923), lung (n = 889), pancreatic (n = 429), and colorectal (n = 368), prior to receiving treatment. RESULTS: Within our sample, 58.0% were age 40-64, 27.3% age 65-74, 11.8% age 75-84, and 2.9% age 85+. Among the nine symptoms in the ESAS-r (anxiety, depression, tiredness, wellbeing, nausea, pain, drowsiness, appetite, and shortness of breath), the most common symptoms overall were anxiety (moderate-severe scores [ESAS-r 4 or higher] were reported by 33.8% of patients), lack of well-being (38.3%), and tiredness (38.3%). Older age was associated with lower odds of moderate/severe anxiety (odds ratio [OR] 0.81, 95% confidence interval [CI] 0.73-0.90 for age 65-74; OR 0.81, 95%CI 0.70-0.93 for age 75-84; OR 0.62, 95%CI 0.47-0.82 for age 85+; referent is 40-64-year-olds for all analyses), and increased odds of tiredness (OR 1.00, 95%CI 0.90-1.11 for age 65-74; OR 1.19, 95%CI 1.04-1.37 for age 75-84; and OR 1.34, 95%CI 1.04-1.72 for age 85+). Advanced stage, female sex, and lower income levels were associated with higher odds of moderate/severe tiredness, anxiety, and lack of well-being in adjusted models. Patients with pancreatic and lung cancers reported worse scores for these three symptoms than patients with other cancers. DISCUSSION: Older age was associated with differences in symptom experiences such as increased tiredness and reduced anxiety. Supportive care interventions and future research should focus on addressing these symptoms to improve patient quality of life.

One vs 2 courses of antenatal corticosteroids in pregnancies at risk of preterm birth: a secondary analysis of the MACS trial.

BACKGROUND: Birth is unpredictable and many patients who receive antenatal corticosteroids for preterm birth remain pregnant. Some professional societies recommend rescue antenatal corticosteroids for those who remain pregnant ≥14 days following the initial course. OBJECTIVE: This study aimed to explore a single vs a second course of antenatal corticosteroids in terms of severe neonatal morbidity and mortality. STUDY DESIGN: This is a secondary analysis of the Multiple Courses of Antenatal Corticosteroids for Preterm Birth (MACS) trial. The MACS study was a randomized clinical trial conducted in 80 centers in 20 different countries from 2001 to 2006. Participants who received only 1 course of intervention (ie, either a second course of antenatal corticosteroids or placebo) were included in this study. The primary outcome was a composite of stillbirth, neonatal mortality in the first 28 days of life or before discharge, severe respiratory distress syndrome, bronchopulmonary dysplasia, intraventricular hemorrhage stage III and IV, periventricular leukomalacia, and necrotizing enterocolitis. Two subgroup analyses were planned to address the effect of a second course of antenatal corticosteroids on infants born before 32 weeks or within 7 days from the intervention. Moreover, a sensitivity analysis was performed to assess the effect of intervention on singleton pregnancies. Baseline characteristics were compared between the groups using chi-square and Student t tests. Multivariable regression analysis was performed to adjust for confounding variables. RESULTS: There were 385 and 365 participants included in the antenatal corticosteroid and placebo groups, respectively. The composite primary outcome occurred in 24% and 20% of participants in the antenatal corticosteroid and placebo groups, respectively (adjusted odds ratio, 1.09; 95% confidence interval, 0.76-1.57). Moreover, severe respiratory distress syndrome rate was similar between the 2 groups (adjusted odds ratio, 0.98; 95% confidence interval, 0.65-1.48). Newborns exposed to antenatal corticosteroids were more likely to be small for gestational age (14.9% vs 10.6%; adjusted odds ratio, 1.63; 95% confidence interval, 1.07-2.47). These findings remained true among singleton pregnancies for the primary composite outcome and birthweight <10th percentile (adjusted odds ratio, 1.29 [0.82-2.01]; and adjusted odds ratio, 1.74 [1.06-2.87]; respectively). Subgroup analyses of infants born before 32 weeks or within 7 days from the intervention did not show any benefits in terms of the composite primary outcome with antenatal corticosteroids vs placebo (50.5% vs 41.8% [adjusted odds ratio, 1.16; 95% confidence interval, 0.78-1.72]; and 42.3% vs 37.1% [adjusted odds ratio, 1.02; 95% confidence interval, 0.67-1.57]; respectively). CONCLUSION: Neonatal mortality and severe morbidities, including severe respiratory distress syndrome, were not improved by a second course of antenatal corticosteroids. Policy makers need to be thoughtful when recommending a second course of antenatal corticosteroids and consider whether not only short-term but also long-term benefits can be gained from such administration.

Association Between the FRAIL Scale and Postoperative Complications in Older Surgical Patients: A Systematic Review and Meta-Analysis.

BACKGROUND: Several frailty screening tools have been shown to predict mortality and complications after surgery. However, these tools were developed for in-person evaluation and cannot be used during virtual assessments before surgery. The FRAIL (fatigue, resistance, ambulation, illness, and loss of weight) scale is a brief assessment that can potentially be conducted virtually or self-administered, but its association with postoperative outcomes in older surgical patients is unknown. The objective of this systematic review and meta-analysis (SRMA) was to determine whether the FRAIL scale is associated with mortality and postoperative outcomes in older surgical patients. METHODS: Systematic searches were conducted of multiple literature databases from January 1, 2008, to December 17, 2022, to identify English language studies using the FRAIL scale in surgical patients and reporting mortality and postoperative outcomes, including postoperative complications, postoperative delirium, length of stay, and functional recovery. These databases included Medline, Medline ePubs/In-process citations, Embase, APA (American Psychological Association) PsycInfo, Ovid Emcare Nursing, (all via the Ovid platform), Cumulative Index to Nursing and Allied Health Literature (CINAHL) EbscoHost, the Web of Science (Clarivate Analytics), and Scopus (Elsevier). The risk of bias was assessed using the quality in prognosis studies tool. RESULTS: A total of 18 studies with 4479 patients were included. Eleven studies reported mortality at varying time points. Eight studies were included in the meta-analysis of mortality. The pooled odds ratio (OR) of 30-day, 6-month, and 1-year mortality for frail patients was 6.62 (95% confidence interval [CI], 2.80-15.61; P < .01), 2.97 (95% CI, 1.54-5.72; P < .01), and 1.54 (95% CI, 0.91-2.58; P = .11), respectively. Frailty was associated with postoperative complications and postoperative delirium, with an OR of 3.11 (95% CI, 2.06-4.68; P < .01) and 2.65 (95% CI, 1.85-3.80; P < .01), respectively. The risk of bias was low in 16 of 18 studies. CONCLUSIONS: As measured by the FRAIL scale, frailty was associated with 30-day mortality, 6-month mortality, postoperative complications, and postoperative delirium.

Comparing vitamin B2 versus 5% dextrose in water for optimal ureteric jet visualisation at the time of pelvic reconstructive surgery: A randomised controlled trial.

OBJECTIVE: To compare preoperative vitamin B2 versus intraoperative cystoscopy distension using 5% dextrose in water (D5W) for ureteric jet visualisation during pelvic reconstructive surgery. DESIGN: Double-blinded, randomised controlled trial. SETTING: Three tertiary hospitals in Toronto, Canada. POPULATION: Adult women undergoing pelvic reconstructive surgery. METHODS: Patients were randomised to receive 100 mg of vitamin B2 preoperatively versus bladder distension with D5W intraoperatively. MAIN OUTCOMES: The primary outcome was the rate of accurate detection of bilateral ureteric jets during cystoscopy. Secondary outcomes included the time elapsed until visualisation, use of intravenous furosemide or fluorescein to assist with visualisation, surgeon satisfaction, and positive urine culture 1 week after surgery. RESULTS: The intervention was completed by 236 patients (vitamin B2 n = 117, D5W n = 119). Preoperative characteristics were similar across groups. Accurate detection of both ureteric jets was high in both groups (vitamin B2 97.4% vs. D5W 90.8%, p = 0.051). The vitamin B2 group had significantly lower use of fluorescein rescue compared with the D5W group (3.4% vs. 11.8%, respectively, p = 0.025). Surgeon satisfaction while using vitamin B2 was significantly higher (p < 0.001). There were no significant differences in the time elapsed until visualisation, the use of furosemide, or the incidence of positive urine culture at 1 week after surgery. CONCLUSIONS: Both preoperative vitamin B2 and intraoperative cystoscopy distension with D5W are highly available and inexpensive methods to detect ureteric jets with high accuracy at the time of pelvic reconstructive surgery. Vitamin B2 was shown to have lower rates of fluorescein rescue for visualisation and higher rates of surgeon satisfaction.

Pregnancy outcomes with donor oocyte embryos in patients diagnosed with adenomyosis using the Morphological Uterus Sonographic Assessment criteria.

OBJECTIVE: To use the Morphological Uterus Sonographic Assessment (MUSA) criteria to evaluate the impact of adenomyosis on the live birth rate after donor egg embryo transfer. DESIGN: Retrospective cohort study. SETTING: Tertiary fertility care center. PATIENT(S): A total of 100 patients who received 223 donor embryo transfers from January 2014-2020. All patients underwent ultrasound before their first transfer. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Our study was powered (80%) to assess the primary outcome of live birth rate; the secondary outcomes included the clinical pregnancy, biochemical pregnancy, and miscarriage rates. RESULT(S): Only 22 of 100 patients were diagnosed with adenomyosis on the original ultrasound report. When the MUSA criteria were applied, 76 patients had at least 1 possible ultrasonographic feature of adenomyosis; all 76 patients had an interrupted junctional zone. The second most common feature of adenomyosis was a globular and/or enlarged uterus (89.4%). Adjusted modeling demonstrated that a single ultrasound feature, 2 or more features, specific features, or the location of features did not affect the live birth outcome. A per-centimeter increase in the diameter of focal lesions was significantly associated with a decrease in the odds of live birth by the factor of 0.91. CONCLUSION(S): To our knowledge, our study is the first to characterize adenomyosis using the MUSA criteria in the donor oocyte population. Overall, our data were reassuring in that the ultrasonographic features of adenomyosis may not impact reproductive outcomes. However, we identified that the location and size of focal lesions may be important and should be studied further.

Infectious outcomes of fibrin sheath disruption in tunneled dialysis catheters.

BACKGROUND AND OBJECTIVES: Fibrin sheath (FS) formation around tunneled central venous catheters (CVC) increases the risk of catheter-related bloodstream infections due to bacterial adherence to a biofilm. We sought to investigate whether FS disruption (FSD) at the time of CVC removal or exchange affects infectious outcomes in patients with CVC-related infections. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS: Retrospective cohort study of 307 adult maintenance hemodialysis patients aged 18 years or older at a single center academic-based hemodialysis program (UHN, Toronto) who developed CVC-related infections requiring CVC removal or exchange between January 2000 and January 2019. Exposure was FSD at the time of CVC removal or exchange. Outcomes were infectious metastatic complications, recurrent infection with the same organism within 1 year, or death due to infection. We created a Markov Multi-State Model (MMSM) to assess patients' trajectories through time as they transitioned between states. A time-to-event analysis was performed, adjusted for clinically relevant factors. RESULTS: There was no significant relationship between FSD status at the time of CVC removal, the development of infectious complications in the multivariable model (adjusted HR = 0.71, 95% CI 0.09-5.80, p = 0.76), or mortality from infection (HR = 0.84, 95% CI 0.34-2.11, p = 0.73). CONCLUSIONS: FSD at the time of CVC removal was not associated with increased risk of infectious complications or death due to infection. Further prospective study is needed to determine whether FSD contributes to reducing CVC infectious related complications.

Risk of Perioperative Stroke in Patients With Patent Foramen Ovale: A Systematic Review and Meta-analysis.

BACKGROUND: Patent foramen ovale (PFO) is a common congenital cardiac abnormality. Risk of stroke increases perioperatively, but the association of PFO with perioperative stroke risk remains unclear. We conducted a systematic review to inform the risk of perioperative stroke in patients with PFO undergoing surgery. METHODS: Embase, MEDLINE, and Cochrane databases were searched from inception to January 2020. We described methods used for establishing PFO and perioperative stroke diagnosis. We conducted meta-analyses to obtain pooled estimates for risk of stroke in patients with and without PFO in different surgical populations. RESULTS: Ten articles with a total of 20,858,011 patients met the eligibility criteria. Prevalence of PFO ranged from 0.06% to 1.4% based on International Classification of Diseases (ICD)-code diagnosis and from 10.4% to 40.4% based on echocardiography diagnosis. Perioperative stroke was observed in 0% to 25% of patients with PFO, and 0% to 16.7% without PFO. Studies that used echocardiography to diagnose PFO found no association between PFO and perioperative stroke. Studies that used ICD codes found strong association but were highly heterogeneous. PFO was not associated with a risk of perioperative stroke in cardiac and transplantation surgeries. While the adjusted odds ratios for stroke were substantial for orthopaedic, general, genitourinary, neurologic, and thoracic surgeries (with PFO status established based on ICD codes), data heterogeneity and quality of data create significant uncertainty. CONCLUSIONS: In conclusion, PFO is likely a risk factor for perioperative stroke in selected types of surgeries. However, this is based on very low-quality evidence. Rigorous prospective studies are needed to further investigate this relationship.

In Vitro Matured Human Pluripotent Stem Cell-Derived Cardiomyocytes Form Grafts With Enhanced Structure and Function in Injured Hearts.

BACKGROUND: Human pluripotent stem cell (hPSC)-derived cardiomyocytes (hPSC-CMs) have tremendous promise for application in cardiac regeneration, but their translational potential is limited by an immature phenotype. We hypothesized that large-scale manufacturing of mature hPSC-CMs could be achieved through culture on polydimethylsiloxane (PDMS)-lined roller bottles and that the transplantation of these cells would mediate better structural and functional outcomes than with conventional immature hPSC-CM populations. METHODS: We comprehensively phenotyped hPSC-CMs after in vitro maturation for 20 and 40 days on either PDMS or standard tissue culture plastic substrates. All hPSC-CMs were generated from a transgenic hPSC line that stably expressed a voltage-sensitive fluorescent reporter to facilitate in vitro and in vivo electrophysiological studies, and cardiomyocyte populations were also analyzed in vitro by immunocytochemistry, ultrastructure and fluorescent calcium imaging, and bulk and single-cell transcriptomics. We next compared outcomes after the transplantation of these populations into a guinea pig model of myocardial infarction using end points including histology, optical mapping of graft- and host-derived action potentials, echocardiography, and telemetric electrocardiographic monitoring. RESULTS: We demonstrated the economic generation of >1×108 mature hPSC-CMs per PDMS-lined roller bottle. Compared with their counterparts generated on tissue culture plastic substrates, PDMS-matured hPSC-CMs exhibited increased cardiac gene expression and more mature structural and functional properties in vitro. More important, intracardiac grafts formed with PDMS-matured myocytes showed greatly enhanced structure and alignment, better host-graft electromechanical integration, less proarrhythmic behavior, and greater beneficial effects on contractile function. CONCLUSIONS: We describe practical methods for the scaled generation of mature hPSC-CMs and provide the first evidence that the transplantation of more mature cardiomyocytes yields better outcomes in vivo.

Factors affecting surgical decision-making in carriers of BRCA1/2 pathogenic variants undergoing risk-reducing surgery at a dedicated hereditary ovarian cancer clinic.

OBJECTIVE: Women with germline BRCA1/2 pathogenic variants have a significantly elevated lifetime risk of ovarian and fallopian tube cancer. Bilateral salpingo-oophorectomy (RRSO) is associated with a 90% reduction in the development of tubal and ovarian cancer. At our tertiary hospital, we have a dedicated clinic where women predisposed to hereditary ovarian/tubal cancer receive counseling on reproduction, risk reduction, surgical prophylaxis, and menopausal aftercare. The objective of this study was to evaluate the choices that Canadian women with BRCA1/2 pathogenic variants make regarding ovarian cancer risk reduction within this highly specialized multidisciplinary clinic. METHODS: This retrospective chart review included all women with confirmed BRCA1/2 mutations referred to the Familial Ovarian Cancer Clinic at Women's College Hospital, Toronto, Canada over a 45-month time period. Patient demographics, preoperative consultation notes and investigations, intraoperative findings, and pathology were recorded. RESULTS: A total of 191 women were included in our cohort; 140 (73.3%) underwent risk-reducing surgery and 51 (26.7%) deferred or declined surgery. In women who underwent surgical prevention (median age 45 [30-72] y), 123 (87.9%) underwent RRSO and 17 (12.1%) chose a risk-reducing bilateral salpingectomy with deferred oophorectomy. Of the women undergoing RRSO, 11 (8.9%) women chose concurrent hysterectomy. Prevalent themes affecting decision-making included fears around premature surgical menopause, family planning, and concerns around development of endometrial cancer related to tamoxifen. CONCLUSION: Women with BRCA1/2 pathogenic variants face challenging decisions regarding risk reduction and care providers must be knowledgeable and supportive in helping women make informed and individualized choices about their care.

Video Summary:http://links.lww.com/MENO/A857 .

Effects of a Resident's Reputation on Laparoscopic Skills Assessment.

OBJECTIVE: To quantify the effect of a resident's reputation on the assessment of their laparoscopic skills. METHODS: Faculty gynecologists were randomized to receive one of three hypothetical resident scenarios: a resident with high, average, or low surgical skills. All participants were then asked to view the same video of a resident performing a laparoscopic salpingo-oophorectomy that differed only by the resident description and provide an assessment using a modified OSATS (Objective Structured Assessment of Technical Skills) and a global assessment scale. RESULTS: From September 6, 2020, to October 20, 2020, a total of 43 faculty gynecologic surgeons were recruited to complete the study. Assessment scores on the modified OSATS (out of 20) and global assessment (out of 5) differed significantly according to resident description, where the high-performing resident scored highest (median scores of 15 and 4, respectively), followed by the average-performing resident (13 and 3), and finally, the low-performing resident (11 and 3) (P=.008 and .043, respectively). CONCLUSION: Faculty assessment of residents in gynecologic surgery is influenced by the assessor's knowledge of the resident's past performance. This knowledge introduces bias that artificially increases scores given to those residents with favorable reputations and decreases scores given to those with reputed surgical skill deficits. These data quantify the effect of such bias in the assessment of residents in the workplace and serve as an impetus to explore systems-level interventions to mitigate bias.

The Impact of Inadequate ("AX") Transbronchial Biopsies on Post-lung Transplant CLAD or Death.

BACKGROUND: Procuring a good quality transbronchial-biopsy sample is essential for diagnosing acute cellular rejection after lung transplantation (LT). Insufficient transbronchial-biopsy samples are graded "AX." We hypothesized that AX samples may be associated with a higher risk for chronic lung allograft dysfunction (CLAD) or death/retransplant, through a potential anatomic or physiologic underlying pulmonary process or because of undiagnosed acute cellular rejection episodes. METHODS: We conducted a single-center, retrospective, cohort study drawn from all consecutive adult, first, bilateral LT between 1999 and 2015. We reviewed all biopsies obtained within the first year posttransplant and compared outcomes of patients with ≥1 AX to patients with no AX. Association of any AX or percent AX with time to CLAD or death/retransplant was assessed using Cox Proportional Hazards models. RESULTS: The cohort consisted of 809 patients with a median of 6 (interquartile range 5-6) biopsies and 16.7% (interquartile range 0-25) AX samples within the first year posttransplant. Four hundred thirty-nine (54.3%) subjects had ≥1 AX sample obtained within the time period. Median time to CLAD or death/retransplant, from 1 year posttransplant, was 761 (320, 1587) and 1200 (662, 2308) days, respectively. In the multivariable analysis, there was no difference in risk for CLAD (hazard ratio = 1.05, 95% confidence interval, 0.87-1.28, P = 0.60), or death/retransplant (hazard ratio = 1.14, 95% confidence interval, 0.92-1.42, P = 0.24) between patients with ≥1 AX biopsy versus none. Among subjects with ≥1 AX, having >50% AX biopsies was not associated with outcome. CONCLUSIONS: This is the first study to demonstrate that AX biopsies are not associated with an increased risk of CLAD or death/retransplant after LT and may not require to repeat the biopsy.

Eosinophils in transbronchial biopsies: a predictor of chronic lung allograft dysfunction and reduced survival after lung transplantation - a retrospective single-center cohort study.

Long-term outcomes after lung transplantation remain inferior to those of other solid organ groups. The significance of eosinophils detected on transbronchial biopsies (TBBx) after lung transplantation and their relationship to long-term outcomes remain unknown. A retrospective single-center cohort study was performed of patients transplanted between January 01, 2001, and July 31, 2018, who had at least 1 TBBx with evaluable parenchymal tissue. Multivariable Cox proportional hazard models were used to assess the associations between eosinophil detection and: all-cause mortality and Chronic Lung Allograft Dysfunction (CLAD). 8887 TBBx reports from 1440 patients were reviewed for the mention of eosinophils in the pathology report. 112 (7.8%) patients were identified with eosinophils on at least one TBBx. The median (95% CI) survival time for all patients was 8.28 (7.32-9.31) years. Multivariable analysis, adjusted for clinical variables known to affect post-transplant outcomes, showed that the detection of eosinophils was independently associated with an increased risk of death (HR 1.51, 95% CI 1.24-1.85, p < 0.01) and CLAD (HR 1.35, 95% CI 1.07-1.70, P = 0.01). Eosinophils detected in TBBx are associated with an increased risk of CLAD and death. There may be benefit in specifically reporting the presence of eosinophils in TBBx reports and incorporating their presence in clinical decision-making.

Prophylactic use of tranexamic acid for prevention of bleeding during transbronchial lung biopsies - A randomized, double-blind, placebo-controlled trial.

BACKGROUND: Although massive bleeding following transbronchial lung biopsies (TBLB) is rare, even minor hemorrhage may prolong the procedure and result in inadequate sampling. Tranexamic acid (TXA) is an antifibrinolytic agent, which reduces bleeding in numerous scenarios, however, its prophylactic use in mitigating post-TBLB bleeding has not been investigated. We conducted a prospective, randomized, double-blind, placebo-controlled trial to determine whether topical infusion of TXA prior to TBLB would reduce bleeding, shorten procedure duration and increase the number of biopsies obtained. METHODS: We blindly randomized patients undergoing TBLB to receive topical TXA or placebo in the lobar bronchus prior to biopsies. Vital signs, procedure length, fluid balance (as a measure of the amount of bleeding), operator's assessment of bleeding, and number of biopsies obtained were measured. Data was analyzed using the two-tailed Student's T-Test, Chi-square or Mann-Whitney tests as appropriate. RESULTS: Fifty patients were randomized, 26 to the TXA arm. The bleeding in the TXA group was significantly lower (P = 0.0037), with more specimens being obtained (placebo 7 (6, 9) (median and interquartile range) vs. TXA 9 (8, 10), P = 0.023) and no difference in procedure length (placebo 30 min (29.3, 34.3) vs. TXA 30 (24.8, 36), P = 0.90). There were no clinically significant adverse events in any of the groups up to one month of follow up. CONCLUSION: Endobronchial installation of TXA prior to obtaining TBLB results in less bleeding and allows more biopsies to be obtained with no additional adverse events. The prophylactic use of TXA during TBLB may be considered as standard.

Bronchoalveolar bile acid and inflammatory markers to identify high-risk lung transplant recipients with reflux and microaspiration.

BACKGROUND: Gastroesophageal reflux disease (GERD) is a risk factor for chronic lung allograft dysfunction. Bile acids-putative markers of gastric microaspiration-and inflammatory proteins in the bronchoalveolar lavage (BAL) have been associated with chronic lung allograft dysfunction, but their relationship with GERD remains unclear. Although GERD is thought to drive chronic microaspiration, the selection of patients for anti-reflux surgery lacks precision. This multicenter study aimed to test the association of BAL bile acids with GERD, lung inflammation, allograft function, and anti-reflux surgery. METHODS: We analyzed BAL obtained during the first post-transplant year from a retrospective cohort of patients with and without GERD, as well as BAL obtained before and after Nissen fundoplication anti-reflux surgery from a separate cohort. Levels of taurocholic acid (TCA), glycocholic acid, and cholic acid were measured using mass spectrometry. Protein markers of inflammation and injury were measured using multiplex assay and enzyme-linked immunosorbent assay. RESULTS: At 3 months after transplantation, TCA, IL-1ß, IL-12p70, and CCL5 were higher in the BAL of patients with GERD than in that of no-GERD controls. Elevated TCA and glycocholic acid were associated with concurrent acute lung allograft dysfunction and inflammatory proteins. The BAL obtained after anti-reflux surgery contained reduced TCA and inflammatory proteins compared with that obtained before anti-reflux surgery. CONCLUSIONS: Targeted monitoring of TCA and selected inflammatory proteins may be useful in lung transplant recipients with suspected reflux and microaspiration to support diagnosis and guide therapy. Patients with elevated biomarker levels may benefit most from anti-reflux surgery to reduce microaspiration and allograft inflammation.