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AbstractBackgroundMinimally invasive repair of pectus excavatum (MIRPE) is associated with less tissue trauma; however, it may result in increased postoperative pain. Pain experience is a known risk factor for the development of posttraumatic stress symptoms, though there are little data on its relationship with long‐term psychological outcomes following major surgery in pediatric patients.AimsIn this study, we examined the relationship between immediate postoperative pain and psychological outcomes at 2 weeks and three months after discharge in a cohort of pediatric patients who underwent MIRPE. We sought to determine whether immediate postoperative pain levels were associated with ongoing distress related to aspects of surgery at both time points. We were also interested in how psychological symptoms related to persistent pain concerns.MethodsData on patients undergoing MIRPE across 14 institutions were collected as part of the Society for Pediatric Anesthesia Improvement Network (SPAIN). Patients were contacted at 2 weeks and three months following discharge to track pain levels and assess psychological distress using a self‐report questionnaire. Patients were grouped into cohorts based on self‐report of distress related to aspects of surgery, nonsurgical distress, or absence of distress.ResultsAnalysis revealed that a higher proportion of children reporting ongoing distress related to surgery at both 2 weeks and 3 months experienced higher immediate postoperative pain levels. A subset of patients with complete data sets for 2 weeks and 3 months (N = 76) was further examined. Among the 47 patients who endorsed surgical distress at 2 weeks, 25 (53.2%) continued to endorse surgical distress at 3 months. Additionally, report of surgical distress at 3 months was associated with longer‐term postoperative pain.ConclusionsOur data suggest that, in patients undergoing MIRPE, the presence of distress at 2 weeks and 3 months may be associated with higher immediate postoperative pain levels.

Abstract Introduction Sleep disordered breathing (SDB) is associated with adverse cardiovascular outcomes and decreased cardiorespiratory fitness (CRF). The risk of long-term major adverse cardiovascular events (MACE) when SDB and decreased CRF co-occur has not been determined. Methods We included consecutive patients that underwent a symptom-limited cardiopulmonary exercise test followed by first-time diagnostic polysomnography within 6 months. Patients were stratified based on the presence of moderate-severe SDB (apnea/hypopnea index ≥15/hour) and decreased CRF defined as <70% predicted peak oxygen consumption (VO2). MACE was a composite outcome of myocardial infarction (MI), coronary artery bypass graft (CABG), percutaneous coronary intervention (PCI), stroke/transient ischemic attack (TIA) and death. Cox-proportional hazard models adjusting for factors known to influence CRF and MACE were constructed. Results Of 498 included patients (60±13 years, 28.1% female), 175 (35%) had MACE (MI=17, PCI=14, CABG=13, stroke=20, TIA=12, deaths=99) at a median follow-up of 8.7 years (interquartile range=6.5-10.3 years). After adjusting for age, sex, beta-blockers, systemic hypertension, diabetes mellitus, coronary artery disease, cardiac arrhythmia, chronic obstructive pulmonary disease, smoking and positive airway pressure (PAP) usage, decreased CRF alone (HR=1.91, 95%CI=1.15-3.18, p=0.012), but not SDB alone (HR=1.26, 95%CI=0.75-2.13, p=0.389) was associated with increased risk of MACE. Those with SDB and decreased CRF had increased risk of MACE compared to patients with decreased CRF alone (HR=1.85, 95%CI=1.21-2.84, p<0.005) after accounting for these confounders; the risk was attenuated after additionally adjusting for adequate adherence to PAP (HR=1.85, 95%CI=0.99-3.05, p=0.05). Conclusion The incidence of MACE, including mortality, was high in this sample. Moderate-severe SDB with concurrent decreased CRF was associated with higher risk of MACE than decreased CRF alone. These results highlight the importance of including CRF in the risk assessment of patients with SDB, and conversely, that of screening for SDB in patients with low peak VO2. Support None.

e20004 Background: IB is a Bruton’s tyrosine kinase inhibitor that showed superior progression-free survival compared with BR in CLL patients (pts) 65 years or older in a randomized phase 3 trial (Woyach et al, NEJM 2018). Pts receiving IB had higher rates of atrial fibrillation (AFIB) and hypertension (HTN); BR pts had higher rates of hematologic toxicity. Differences in treatment duration for BR (6 cycles) and IB (until progression) complicated adverse event (AE) comparisons. Here we use an exploratory approach to compare toxicity burden between arms and provide assessment of AFIB, HTN and infections (INF). Methods: AEs were reported for each of cycles 1-6 and then every 3 cycles until progression or nonprotocol CLL therapy. Only grade (gr) 3-4 AEs were reported thereafter until death. A simple global AE score was calculated for each pt by summing grades of all gr 1-4 AEs and dividing by the number of cycles over which AEs were submitted. Results: 537 pts began therapy (176 BR, 361 IB). 68% on BR completed all 6 cycles. At a median follow-up of 38 months, 64% remained on IB. Treatment discontinuation for AE occurred in 10% and 14% of BR and IB pts. Overall, median AE score was 1.8 (interquartile range (IQR) 0.9-3.3) and 3.8 (IQR 2.3-5.9) in BR and IB arms (p < 0.01). For cycles 1-6, median AE score was 6.2 (IQR 3.8-9.0) and 4.8 (IQR 3.0-7.2) in BR and IB arms (p < 0.01). In the IB arm, median AE score post 6 cycles decreased significantly to 3.4 (IQR 1.9-5.6) (p < 0.01). Gr 3 or higher cumulative rates of AFIB, HTN, and INF over time appear in the table. 100 pts (26/176 BR, 74/361 IB) had 137 severe INF (39% respiratory: 16 BR, 37 IB; 25% skin: 3 BR, 31 IB; 12% GU: 3 BR, 13 IB; 25% other: 12 BR, 22 IB). There were 7 gr 5 INF (3 BR, 4 IB), none confirmed fungal. Conclusions: There was no difference in treatment discontinuation rates for AE. Overall toxicity burden was significantly higher for IB, although IB toxicity burden decreased after 6 cycles. Toxicity burden was significantly higher in cycles 1-6 for pts receiving BR. Risk of severe AFIB, HTN, and INF is highest in the first year of IB. A simple AE score provides valuable information, especially when evaluating regimens of varying length. Clinical trial information: NCT01886872 . Support: U10CA180821, U10CA180882, U24CA196171; https://acknowledgments.alliancefound.org ; Pharmacyclics; ClinicalTrials.gov Identifier: NCT01886872. [Table: see text]

To evaluate the effectiveness of an admixture of ketamine and propofol on peri-induction hemodynamics during airway manipulation, we searched electronic databases of randomized controlled trials from January 1, 2000, to October 17, 2018. Trial screening, selection, and data extraction were done independently by two reviewers with outcomes pooled across included trials using the random-effects model. We included 10 randomized trials (722 patients, mean age of 53.99 years, 39.96% female). American Society of Anesthesiologists physical status was reported in 9 trials with classes I and II representing the majority. Ketamine/propofol admixture was associated with a nonsignificant increase in heart rate (weighted mean difference, 3.36 beats per minute (95% CI, −0.88, 7.60), I2 = 88.6%), a statistically significant increase in systolic blood pressure (weighted mean difference, 9.67 mmHg (95% CI, 1.48, 17.86), I2 = 87.2%), a nonsignificant increase in diastolic blood pressure (weighted mean difference, 2.18 mmHg (95% CI, −2.82, 7.19), I2 = 73.1%), and a nonsignificant increase in mean arterial pressure (weighted mean difference, 3.28 mmHg (95% CI, −0.94, 7.49), I2 = 69.9%) compared to other agents. The risk of bias was high and the certainty of evidence was low. In conclusion, among patients undergoing airway manipulation and needing sedation, the use of a ketamine/propofol admixture may be associated with better hemodynamics compared to nonketamine/propofol sedation. This trial is registered with CRD42019125725.

Abstract Objective: Nonresponse to selective serotonin reuptake inhibitor and serotonin norepinephrine reuptake inhibitor treatment is common in patients with major depressive disorder (MDD), particularly in women, occurring in about 70% of patients despite adequate dosing. Well-tolerated augmentation strategies are needed, particularly ones that do not cause or exacerbate symptoms such as fatigue and sexual dysfunction. Low-dose testosterone has been shown to improve depression symptom severity, fatigue and sexual function in small studies of women not formally diagnosed with MDD. We sought to determine whether adjunctive low-dose transdermal testosterone improves depression symptom severity, fatigue, and sexual function in women with treatment-resistant MDD. A functional MRI (fMRI) substudy examined effects of testosterone on activity in the anterior cingulate cortex (ACC), a brain region important in mood regulation. Methods: Randomized, double-blind, placebo-controlled, 8-week trial of adjunctive testosterone cream (AndroFeme® 1, Lawley Pharmaceuticals, Australia) in 101 women, ages 21–70, with treatment-resistant MDD. Testosterone was titrated to achieve blood levels near the upper normal reference limit. Primary outcome measure was depression severity by Montgomery-Asberg Depression Rating Scale (MADRS). Secondary endpoints included fatigue, sexual function, and safety measures. fMRI substudy (n=20) primary outcome was change in ACC activity. Results: Mean age was 47±14 (SD) years and mean baseline MADRS score was 26.6±5.9. Eighty-seven (86%) participants completed 8 weeks of treatment. MADRS depression scores decreased in both arms [testosterone: 26.8±6.3 to 15.3±9.6; placebo: 26.3±5.4 to 14.4±9.3 (baseline to 8 weeks, respectively)], with no difference between groups (p=0.91). Fatigue and sexual function improved without differences between groups. There were no group differences in side effects. fMRI results demonstrated a relationship between ACC activation and androgen levels pretreatment but no difference in ACC activation with treatment. Conclusions: This rigorously designed, double-blinded clinical trial did not find significant group differences between adjunctive low dose transdermal testosterone and placebo for antidepressant augmentation in women with treatment-resistant MDD and had a high placebo response rate. Low-dose testosterone was well tolerated but failed to differentially impact overall depressive symptom severity, fatigue, or sexual dysfunction. Testosterone did not result in greater activity in a brain region (ACC) implicated in MDD etiopathology compared to placebo. Thus, the addition of low-dose testosterone to ineffective antidepressant treatment should not be recommended for women with MDD. Further studies using strategies designed to reduce placebo effects may be warranted.

Background and objectives Shared decision making in patients with glomerular disease remains challenging because outcomes important to patients remain largely unknown. We aimed to identify and prioritize outcomes important to patients and caregivers and to describe reasons for their choices. Design, setting, participants, & measurements We purposively sampled adult patients with glomerular disease and their caregivers from Australia, Hong Kong, the United Kingdom, and the United States. Participants identified, discussed, and ranked outcomes in focus groups using the nominal group technique; a relative importance score (between zero and one) was calculated. Qualitative data were analyzed thematically. Results Across 16 focus groups, 134 participants (range, 19–85 years old; 51% women), including 101 patients and 33 caregivers, identified 58 outcomes. The ten highest-ranked outcomes were kidney function (importance score of 0.42), mortality (0.29), need for dialysis or transplant (0.22), life participation (0.18), fatigue (0.17), anxiety (0.13), family impact (0.12), infection and immunity (0.12), ability to work (0.11), and BP (0.11). Three themes explained the reasons for these rankings: constraining day-to-day experience, impaired agency and control over health, and threats to future health and family. Conclusions Patients with glomerular disease and their caregivers highly prioritize kidney health and survival, but they also prioritize life participation, fatigue, anxiety, and family impact.

Importance Positron emission tomography (PET) may increase the diagnostic accuracy and confirm the underlying neuropathologic changes of Alzheimer disease (AD). Objective To determine the accuracy of antemortem [ 18 F]flortaucipir PET images for predicting the presence of AD-type tau pathology at autopsy. Design, Setting, and Participants This diagnostic study (A16 primary cohort) was conducted from October 2015 to June 2018 at 28 study sites (27 in US sites and 1 in Australia). Individuals with a terminal illness who were older than 50 years and had a projected life expectancy of less than 6 months were enrolled. All participants underwent [ 18 F]flortaucipir PET imaging, and scans were interpreted by 5 independent nuclear medicine physicians or radiologists. Supplemental autopsy [ 18 F]flortaucipir images and pathological samples were also collected from 16 historically collected cases. A second study (FR01 validation study) was conducted from March 26 to April 26, 2019, in which 5 new readers assessed the original PET images for comparison to autopsy. Main Outcomes and Measures [ 18 F]flortaucipir PET images were visually assessed and compared with immunohistochemical tau pathology. An AD tau pattern of flortaucipir retention was assessed for correspondence with a postmortem B3-level (Braak stage V or VI) pathological pattern of tau accumulation and to the presence of amyloid-β plaques sufficient to meet the criteria for high levels of AD neuropathological change. Success was defined as having at least 3 of the 5 readers above the lower bounds of the 95% CI for both sensitivity and specificity of 50% or greater. Results A total of 156 patients were enrolled in the A16 study and underwent [ 18 F]flortaucipir PET imaging. Of these, 73 died during the study, and valid autopsies were performed for 67 of these patients. Three autopsies were evaluated as test cases and removed from the primary cohort (n = 64). Of the 64 primary cohort patients, 34 (53%) were women and 62 (97%) were white; mean (SD) age was 82.5 (9.6) years; and 49 (77%) had dementia, 1 (2%) had mild cognitive impairment, and 14 (22%) had normal cognition. Prespecified success criteria were met for the A16 primary cohort. The flortaucipir PET scans predicted a B3 level of tau pathology, with sensitivity ranging from 92.3% (95% CI, 79.7%-97.3%) to 100.0% (95% CI, 91.0%-100.0%) and specificity ranging from 52.0% (95% CI, 33.5%-70.0%) to 92.0% (95% CI, 75.0%-97.8%). A high level of AD neuropathological change was predicted with sensitivity of 94.7% (95% CI, 82.7%-98.5%) to 100.0% (95% CI, 90.8%-100.0%) and specificity of 50.0% (95% CI, 32.1%-67.9%) to 92.3% (95% CI, 75.9%-97.9%). The FR01 validation study also met prespecified success criteria. Addition of the supplemental autopsy data set and 3 test cases, which comprised a total of 82 patients and autopsies for both the A16 and FR01 studies, resulted in improved specificity and comparable overall accuracy. Among the 156 enrolled participants, 14 (9%) experienced at least 1 treatment-emergent adverse event. Conclusions and Relevance This study’s findings suggest that PET imaging with [ 18 F]flortaucipir could be used to identify the density and distribution of AD-type tau pathology and the presence of high levels of AD neuropathological change, supporting a neuropathological diagnosis of AD.

Abstract We evaluated the joint associations between a new 313-variant PRS (PRS313) and questionnaire-based breast cancer risk factors for women of European ancestry, using 72 284 cases and 80 354 controls from the Breast Cancer Association Consortium. Interactions were evaluated using standard logistic regression and a newly developed case-only method for breast cancer risk overall and by estrogen receptor status. After accounting for multiple testing, we did not find evidence that per-standard deviation PRS313 odds ratio differed across strata defined by individual risk factors. Goodness-of-fit tests did not reject the assumption of a multiplicative model between PRS313 and each risk factor. Variation in projected absolute lifetime risk of breast cancer associated with classical risk factors was greater for women with higher genetic risk (PRS313 and family history) and, on average, 17.5% higher in the highest vs lowest deciles of genetic risk. These findings have implications for risk prevention for women at increased risk of breast cancer.

Abstract Background: Central nervous system (CNS) complications are among the most common, devastating sequelae of sickle cell disease (SCD) occurring throughout the lifespan. Objective: These evidence-based guidelines of the American Society of Hematology are intended to support the SCD community in decisions about prevention, diagnosis, and treatment of the most common neurological morbidities in SCD. Methods: The Mayo Evidence-Based Practice Research Program supported the guideline development process, including updating or performing systematic evidence reviews. The panel used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, including GRADE evidence-to-decision frameworks, to assess evidence and make recommendations. Results: The panel placed a higher value on maintaining cognitive function than on being alive with significantly less than baseline cognitive function. The panel developed 19 recommendations with evidence-based strategies to prevent, diagnose, and treat CNS complications of SCD in low-middle– and high-income settings. Conclusions: Three of 19 recommendations immediately impact clinical care. These recommendations include: use of transcranial Doppler ultrasound screening and hydroxyurea for primary stroke prevention in children with hemoglobin SS (HbSS) and hemoglobin Sβ0 (HbSβ0) thalassemia living in low-middle–income settings; surveillance for developmental delay, cognitive impairments, and neurodevelopmental disorders in children; and use of magnetic resonance imaging of the brain without sedation to detect silent cerebral infarcts at least once in early-school-age children and once in adults with HbSS or HbSβ0 thalassemia. Individuals with SCD, their family members, and clinicians should become aware of and implement these recommendations to reduce the burden of CNS complications in children and adults with SCD.