Citations

Abstract Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a life-time risk of 1 in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry GWAS in ALS including 29,612 ALS patients and 122,656 controls which identified 15 risk loci in ALS. When combined with 8,953 whole-genome sequenced individuals (6,538 ALS patients, 2,415 controls) and the largest cortex-derived eQTL dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, repeat expansions or regulatory effects. ALS associated risk loci were shared with multiple traits within the neurodegenerative spectrum, but with distinct enrichment patterns across brain regions and cell-types. Of the environmental and life-style risk factors obtained from literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. All ALS associated signals combined reveal a role for perturbations in vesicle mediated transport and autophagy, and provide evidence for cell-autonomous disease initiation in glutamatergic neurons.

Abstract Aims Acute pulmonary disorders are known physical triggers of takotsubo syndrome (TTS). This study aimed to investigate prevalence of acute pulmonary triggers in patients with TTS and their impact on outcomes. Methods and results Patients with TTS were enrolled from the International Takotsubo Registry and screened for triggering factors and comorbidities. Patients were categorized into three groups (acute pulmonary trigger, chronic lung disease, and no lung disease) to compare clinical characteristics and outcomes. Of the 1670 included patients with TTS, 123 (7%) were identified with an acute pulmonary trigger, and 194 (12%) had a known history of chronic lung disease. The incidence of cardiogenic shock was highest in patients with an acute pulmonary trigger compared with those with chronic lung disease or without lung disease (17% vs. 10% vs. 9%, P = 0.017). In-hospital mortality was also higher in patients with an acute pulmonary trigger than in the other two groups, although not significantly (5.7% vs. 1.5% vs. 4.2%, P = 0.13). Survival analysis demonstrated that patients with an acute pulmonary trigger had the worst long-term outcome (P = 0.002). The presence of an acute pulmonary trigger was independently associated with worse long-term mortality (hazard ratio 2.12, 95% confidence interval 1.33–3.38; P = 0.002). Conclusions The present study demonstrates that TTS is related to acute pulmonary triggers in 7% of all TTS patients, which accounts for 21% of patients with physical triggers. The presence of acute pulmonary trigger is associated with a severe in-hospital course and a worse long-term outcome.

Introduction: Respect for patient autonomy is critical, and patients/surrogates may have various preferences about acute stroke treatment that are not fully appreciated during a stroke code. COAST (Coordinating Options for Acute Stroke Therapy) is a stroke advance directive formalizing advanced consent for thrombolysis (tPA) and endovascular therapy (EVT). We examine the distribution of patient preferences to improve understanding and respect for patient autonomy in acute stroke. Methods: In our IRB-approved study, we collected COAST forms at UC San Diego from 12/1/2014-2/29/2020. Patients chose one of five tPA preferences: not under any circumstance (tPA 1); up to 3 hours only, based on FDA approval (tPA 2); up to 4.5 hours only, based on current guidelines (tPA 3); anytime per provider discretion (tPA 4); or other answer (tPA treatment under specific conditions written by the patient/surrogate) (tPA 5). Patients also chose one of five EVT preferences: not under any circumstance (EVT 1); up to 6 hours only (EVT 2); up to 12 hours only (EVT 3); up to 24 hours only (this option replaced "up to 12 hours only" on 3/1/2018 when the 6-24 hour window became standard of care) (EVT 4); anytime at provider discretion (EVT 5); or other answer (EVT treatment under specific conditions written by the patient/surrogate) (EVT 6). Frequency of preferences was calculated for each option. Results: In total, 342 COASTs were completed. Frequency of tPA preferences were: 3.2% for tPA 1 (11/342), 1.5% for tPA 2 (5/342), 25.7% for tPA 3 (88/342), 55.6% for tPA 4 (190/342), 14.0% for tPA 5 (48/342). Frequency of EVT preferences were: 1.8% for EVT 1 (6/342), 9.6% for EVT 2 (33/342), 3.2% for EVT 3 (11/342), 10.8% for EVT 4 (37/342), 62.3% for EVT 5 (213/342), 12.3% for EVT 6 (42/342). When the 6-24 hour window became standard of care, 0% (0/342) chose EVT 2. Total 81.6% (n=279) of COASTs had the same tPA and EVT preferences, and 18.4% (n=63) had tPA preferences that were different from EVT preferences. Conclusion: Preferences vary regarding tPA and EVT treatment. Most patients defer to provider discretion, though some patients have preferences that are different from current provider expectations and/or stroke guidelines. COAST is pivotal to inform respect for patient autonomy for acute stroke codes.

BACKGROUND: Current mechanical ventilation practice and the use of treatment adjuncts in patients requiring extracorporeal membrane oxygenation (ECMO) for refractory hypoxemia (RH) vary widely and their impact on outcomes remains unclear. In 2015, we implemented a standardized approach to protocolized ventilator settings and guide the escalation of adjunct therapies in patients with RH. This study aimed to investigate ICU mortality, its associated risk factors, and mechanical ventilation practice before and after the implementation of a standardized RH guideline in patients requiring venovenous ECMO (VV-ECMO). METHODS: This was a single-center, retrospective cohort study of patients undergoing VV-ECMO due to RH respiratory failure between January 2008 and March 2015 (before RH protocol implementation) and between April 2015 and October 2019 (after RH protocol implementation). RESULTS: A total of 103 subjects receiving VV-ECMO for RH were analyzed. After implementation of the RH protocol, more subjects received prone positioning (6.7% vs 23.3%, P = .02), and fewer received high-frequency oscillatory ventilation than before launching the RH protocol (0% vs 13.3%, P = .01). Plateau pressure was also lower before initiation of ECMO ( P = .04) and at day 1 during ECMO ( P = .045). Driving pressure was consistently lower at days 1, 2, and 3 after ECMO initiation: median 13.0 (interquartile range [IQR] 10.6–18.0) vs 16.0 (IQR 14.0–20.0) cm H 2 O at day 1 ( P = .003); 13.0 (IQR 11.0–15.9) vs 15.5 (IQR 12.0–20.0) cm H 2 O at day 2 ( P = .03); and 12.0 (IQR 10.0–14.5) vs 15.0 (IQR 12.0–19.0) cm H 2 O at day 3 ( P = .005). CONCLUSIONS: The implementation of a standardized RH guideline improved compliance with a lung-protective ventilation strategy and utilization of the prone position and was associated with lower driving pressure during the first 3 days after ECMO initiation in subjects with refractory hypoxemia.

Abstract Objectives We investigated the impact of our laboratory’s reflex testing process for resolving ERBB2 (HER2) status on breast cancer samples that require additional workup after fluorescence in situ hybridization (FISH), per guideline recommendations published in 2018 by the American Society of Clinical Oncology (ASCO) and the College of American Pathologists (CAP). Methods In total, 500 breast cancer specimens with ERBB2 FISH results in groups 2 through 4 (all reported as immunohistochemistry [IHC] equivocal [2+] at external laboratories) were resubmitted for IHC testing in our laboratory. Per the ASCO/CAP guideline, FISH was rescored when internal IHC was also equivocal (2+), targeted to tumor areas demonstrating more intense IHC staining, if observed. Results Reflex IHC/FISH testing changed the final reported ERBB2 status in 185 of 500 (37.0%) samples. Result changes included discordant IHC (n = 4 score 0, n = 132 score 1+, and n = 16 score 3+) and discordant FISH (n = 33). Numerical differences in FISH scores were comparable for targeted vs nontargeted FISH rescoring (P = .086 for ERBB2 copy number; P = .49 for ERBB2 ratio). Two cases showed larger differences in FISH scores, suggesting heterogeneity. Conclusions Retesting of breast cancer samples with equivocal IHC frequently changes IHC results, but targeted reanalysis of borderline FISH results rarely identifies significant differences in ERBB2 copy number or ratio.

Abstract Dr Thoralf Sundt III joined the department of neurosurgery at Mayo Clinic in 1969 and served as chairman from 1980 until his death in 1992. Dr Sundt was a pioneer in the field of cerebrovascular neurosurgery and among his many contributions to neurosurgical technology was the introduction of the Sundt clip graft (Codman, Raynham, Massachusetts), which was developed in partnership with Dr George Kees. This device is a vessel-encircling Teflon or Dacron graft loaded on a circular metallic spring initially designed to repair injuries to vessel walls during intracranial aneurysm surgery, 1 which was not an uncommon complication resulting from the use of contemporary aneurysm clips. 2 When used for this purpose, the clip graft has demonstrated both safety and efficacy in a modern series of surgical treatment of intracranial aneurysm. 3 An additional application of the clip graft is the direct clipping of aneurysms, particularly side-wall aneurysms, though Dr Sundt recognized that the potential to occlude perforating arteries adjacent to the aneurysm neck would limit the general use of the clip graft for aneurysm clipping. 2 In the following video, we present archival footage of Dr Sundt utilizing the Sundt clip graft during intracranial aneurysm surgery. The 3 cases are of the treatment of posterior communicating, middle cerebral, and anterior communicating artery aneurysms and depict the potential applications of the clip graft during aneurysm surgery. We also present footage of animal experiments Dr Sundt performed to validate the use of the clip graft. This footage likely represents some of the first microscopic neurosurgical recordings ever made. The patients consented to the procedure and to presentation of video recordings at the time of initial surgery. Image of Sundt at 0:11, Reproduced with permission from the American Association of Neurological Surgeons, 5550 Meadowbrook Dr, Rolling Meadows, IL 60008. Figures at 2:26 and 2:28, from Park PJ, Meyer FB, The Sundt clip graft, Neurosurgery , 2010;66(6 suppl operative):300-305, by permission of the Congress of Neurological Surgeons. Figure at 2:35, ©2009 Mayo, Clingman. Used with permission.

Abstract BackgroundCancer diagnosis and early treatment may have wide-ranging consequences for a woman’spartner (ie. spouse or significant other). In general, younger caregivers have been found to havegreater unmet needs and higher levels of distress compared to those who are older. To date,there is little known about the unmet needs and experiences of partners who care for youngwomen with breast cancer during active treatment.Trial Design: Cross-sectional survey of partners of young women with breast cancer.Eligibility Criteria: The current analysis focuses on a subset of respondent partners of womenwith breast cancer participating in the Young Womens Breast Cancer Study (NCT01468246)who met the following criteria: diagnosed at age < 40 years; time since diagnosis <12 months;and/or Stage IV disease (at diagnosis or in metastatic setting); and/or local recurrent disease< 12 months.Specific Aims: To explore the experience of partners of women in active treatment or havingvery recently completed treatment for breast cancer.Statistical Methods: We employed descriptive statistics to present sample characteristics,including means or medians for continuous variables and proportions for categorical variables.We assessed partners’ responses re: sociodemographics, perceived social support (MOS-Social Support Survey, Cancer Perceived Agents of Social Support), quality of life (QOL)(Caregiver QOL Index-Cancer), coping (Brief COPE), perceived financial security, perceivedparenting concerns (Parenting Concerns Questionnaire), anxiety and depression symptoms(Hospital Anxiety and Depression Scale), sexual satisfaction (Global Measure of SexualSatisfaction), posttraumatic growth (Posttraumatic Growth Inventory-Short Form), and an open-ended question to explore their experiences and needs.Accrual: 25 participants were included.Results: All partners were male (25/25; 100%), and most were white (n=23/25; 92%), workingfull-time (n=21/25; 91%); and college educated (n=19/25; 86%). Eighteen partners (n=18/25;72%) were parenting children <18 years old and 40% (n=10/25) were partnered with womenwith Stage 4 breast cancer. At the time of the survey, the median age of partners was 44 years(range, 28-69) and of patients was 38 years (range, 25-40). Many partners (57%) reportedsymptoms of anxiety (>8 on the HADS anxiety subscale), fewer (22%) were categorized ashaving symptoms of depression (>8 on the HADS depression subscale). Additionally, 39%reported not being sexually active; 41% reported maladaptive coping; 30% reported financialstrain;30% reported relationship strain. Reported caregiver QOL ranged from 22-116, with amean score of 52.5 (SD, 23.9), similar to population norms, with higher scores indicating lowerquality of life. Parenting concerns scores were generally low indicating less concern, with arange of 12-35, and mean of 20.5 (SD, 7.6). Post-traumatic growth ranged from 4-33, with amean score of 20.7 (SD, 7.4), with higher scores indicating greater personal growthexperienced. 44% (11/25) responded to the open-ended experiences and needs question.Common responses included feeling a lack of support, need for tailored and titrated information,and desire to connect with other men who faced similar experiences. Partners also reportedtheir struggles with uncertainty about the future. Discussion: A subset of partners of young women in active treatment for breast cancerexpressed concerns related to relationship strain, sexuality, need for support, and finances.Future work designed to meet the needs of partners of breast cancer patients includinginformational and psychosocial supports may benefit them and the patients as they manage theprocess of ongoing treatment and challenges about the future. Citation Format: Tamryn F Gray, Nancy Borstelmann, Shoshana Rosenberg, Shari Gelber, Meghan E Meyer, Kathryn J. Ruddy, Lidia Schapira, Steven Come, Virginia Borges, Tamara Cadet, Peter Maramaldi, Ann H. Partridge. The psychosocial impact of caregiving on partners of young women with breast cancer in treatment [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS9-08.

Background After critical illness, patients are often left with impairments in physical, social, emotional, and cognitive functioning. Peer support interventions have been implemented internationally to ameliorate these issues. Objective To explore what patients believed to be the key mechanisms of effectiveness of peer support programs implemented during critical care recovery. Methods In a secondary analysis of an international qualitative data set, 66 telephone interviews with patients were undertaken across 14 sites in Australia, the United Kingdom, and the United States to understand the effect of peer support during recovery from critical illness. Prevalent themes were documented with framework analysis. Results Most patients who had been involved in peer support programs reported benefit. Patients described 3 primary mechanisms: (1) sharing experiences, (2) care debriefing, and (3) altruism. Conclusion Peer support is a relatively simple intervention that could be implemented to support patients during recovery from critical illness. However, more research is required into how these programs can be implemented in a safe and sustainable way in clinical practice.