There are multiple methods for calculating the minimal clinically important difference (MCID) threshold, and previous reports highlight heterogeneity and limitations of anchor-based and ...distribution-based analyses. The Warfighter Readiness Survey assesses the perception of a military population’s fitness to deploy and may be used as a functional index in anchor-based MCID calculations. The purpose of the current study in a physically demanding population undergoing shoulder surgery was to compare the yields of two different anchor-based methods of calculating MCID for a battery of PROMs, a standard receiver operator curve (ROC) -based MCIDs and baseline-adjusted ROC MCIDs.
All service members enrolled prospectively in a multicenter database with prior shoulder surgery that completed pre- and postoperative PROMs at a minimum of 12 months were included. The PROMs battery included Single Assessment Numeric Evaluation (SANE), American Shoulder and Elbow Surgeons score (ASES), Patient Reported Outcome Management Information System (PROMIS) Physical Function (PF), PROMIS Pain Interference (PI), and the Warfighter Readiness survey. Standard anchor-based and baseline-adjusted ROC MCIDs were employed to determine if the calculated MCIDs were both statistically and theoretically valid (95% confidence interval either completely negative or positive).
There were 117 patients (136 operations) identified, comprised of 83% males with a mean age of 35.7 ± 10.4 years and 47% arthroscopic labral repair/capsulorrhaphy. Using the standard, anchor-based ROC MCID calculation, the area under the curve (AUC) for SANE, ASES, PROMIS PF, and PROMIS PI were greater than 0.5 (statistically valid). For ASES, PROMIS PF, and PROMIS PI, the calculated MCID 95% CI all crossed 0 (theoretically invalid). Using the baseline-adjusted ROC MCID calculation, the MCID estimates for SANE, ASES, and PROMIS PI were both statistically and theoretically valid if the baseline score was less than 70.5, 69, and 65.7.
When MCIDs were calculated and anchored to the results of standard, anchor-based MCID, a standard ROC analysis did not yield statistically or theoretically valid results across a battery of PROMs commonly used to assess outcomes after shoulder surgery in the active duty military population. Conversely, a baseline-adjusted ROC method was more effective at discerning changes across a battery of PROMs among the same cohort.
INTRODUCTION The two main subtypes of pediatric glioblastoma (GBM) are marked by highly conserved somatic H3-3A gene mutations. The H3.3G34R/V GBM occurs in children and young adults, is typically ...lobar in location, and frequently harbor concurrent TP53, ATRX/DAXX, and PDGFRA alterations. H3.3G34 alterations appear to dysregulate specific alternative splicing events. We hypothesize that the H3.3G34R/V mutation in GBM results in tumor-specific neoantigens targetable by T cell receptor (TCR)-engineered cytotoxic T lymphocytes. METHODS We used NetMHC to identify peptide sequences encompassing H3.3G34R/V predicted to show strong human leukocyte antigen (HLA)-major histocompatibility complex (MHC) binding; GATK-Mutect2, to identify neoantigens called from somatic variants; and IRIS to identify neoantigens derived from alternative splicing variants. RESULTS Clonally expanded populations of T cells demonstrated binding affinity for mutation-derived neoantigen targets, and activation in response to patient-derived H3.3G34R GBM cells in vitro. These TCRs were then cloned in a retroviral expression vector. To isolate TCRs mediating HLA-specific binding of the peptides encompassing the H3.3G34R mutation predicted to bind with strong affinity, HLA-A*03:01 specific oligomeric class I MHC molecules were designed for high-value predicted peptides encompassing the H3.3G34R mutation, according to NetMHC predicted strong binders. We created a patient-derived xenograft cell line from an HLA-A*02:01 patient harboring H3.3G34R GBM. Patient CD3+ T cells were expanded in the presence of synthetic long peptides encompassing predicted neoantigens, and sorted for CD8+ populations. The peptides were synthesized and used in an indirect HLA binding assay. HLA-specific CD8+ T cell binding was tested to confirm T cell binding of identified neoantigen candidates using oligomeric MHC I molecules. Serial oligomer selection was performed to expand the T cell population selectively binding the target peptide sequence. Jurkat cells were transfected to express the neoantigen-specific TCRab chains, and confirmed antigen-specific binding. CONCLUSION We have confirmed a small number of candidate neoantigens present within H3.3G34R GBM. Re-stimulated T cells expanded against these peptides demonstrated high binding affinity for the two splice variant-derived neoantigen targets, and activation in response to patient-derived H3.3G34R GBM cells in vitro.
BACKGROUND
The optimal method of providing transfusion medicine (TM) education has not been determined. Transfusion Camp was established in 2012 at the University of Toronto as a centrally delivered ...TM education program for postgraduate trainees. The impact of Transfusion Camp on knowledge, attitudes, and self‐reported behavior was evaluated.
METHODS
Didactic lectures (delivered locally, by webinar, or recorded) and locally facilitated team‐based learning seminars were delivered over 5 days during the academic year to 8 sites: 7 in Canada and 1 in the United Kingdom. Knowledge assessment using a validated 20‐question multiple‐choice exam was conducted before and after Transfusion Camp. Attitudes and self‐reported behavior were collected through a survey.
RESULTS
Over 2 academic years (July 2016 to June 2018), 390 trainees from 16 different specialties (predominantly anesthesia, 41%; hematology, 14%; and critical care, 7%) attended at least 1 day of Transfusion Camp. The mean pretest score was 10.3 of 20 (±2.9; n = 286) compared with posttest score of 13.0 (±2.8; n = 194; p < 0.0001). Lower pretest score and greater attendance (4–5 days compared with 1–3 days) were associated with larger improvement in posttest score; delivery format, specialty, and postgraduate year were not. Trainees reported an improvement in self‐rated abilities to manage TM scenarios; 95% rated TM knowledge as very or extremely important in providing patient care; and 81% indicated that they had applied learning from Transfusion Camp into clinical practice.
CONCLUSIONS
Transfusion Camp increased TM knowledge, fostered a positive attitude toward TM, and enabled a self‐reported positive impact on transfusion practice in postgraduate trainees. It is a novel and scalable approach to delivering TM education.
BACKGROUND: LMNA ( lamin A/C )-related dilated cardiomyopathy is a rare genetic cause of heart failure. In a phase 2 trial and long-term extension, the selective p38α MAPK (mitogen-activated protein ...kinase) inhibitor, ARRY-371797 (PF-07265803), was associated with an improved 6-minute walk test at 12 weeks, which was preserved over 144 weeks. METHODS: REALM-DCM (NCT03439514) was a phase 3, randomized, double-blind, placebo-controlled trial in patients with symptomatic LMNA -related dilated cardiomyopathy. Patients with confirmed LMNA variants, New York Heart Association class II/III symptoms, left ventricular ejection fraction ≤50%, implanted cardioverter-defibrillator, and reduced 6-minute walk test distance were randomized to ARRY-371797 400 mg twice daily or placebo. The primary outcome was a change from baseline at week 24 in the 6-minute walk test distance using stratified Hodges-Lehmann estimation and the van Elteren test. Secondary outcomes using similar methodology included change from baseline at week 24 in the Kansas City Cardiomyopathy Questionnaire-physical limitation and total symptom scores, and NT-proBNP (N-terminal pro-B-type natriuretic peptide) concentration. Time to a composite outcome of worsening heart failure or all-cause mortality and overall survival were evaluated using Kaplan-Meier and Cox proportional hazards analyses. RESULTS: REALM-DCM was terminated after a planned interim analysis suggested futility. Between April 2018 and October 2022, 77 patients (aged 23–72 years) received ARRY-371797 (n=40) or placebo (n=37). No significant differences ( P >0.05) between groups were observed in the change from baseline at week 24 for all outcomes: 6-minute walk test distance (median difference, 4.9 m 95% CI, −24.2 to 34.1; P =0.82); Kansas City Cardiomyopathy Questionnaire-physical limitation score (2.4 95% CI, −6.4 to 11.2; P =0.54); Kansas City Cardiomyopathy Questionnaire-total symptom score (5.3 95% CI, −4.3 to 14.9; P =0.48); and NT-proBNP concentration (−339.4 pg/mL 95% CI, −1131.6 to 452.7; P =0.17). The composite outcome of worsening heart failure or all-cause mortality (hazard ratio, 0.43 95% CI, 0.11–1.74; P =0.23) and overall survival (hazard ratio, 1.19 95% CI, 0.23–6.02; P =0.84) were similar between groups. No new safety findings were observed. CONCLUSIONS: Findings from REALM-DCM demonstrated futility without safety concerns. An unmet treatment need remains among patients with LMNA -related dilated cardiomyopathy. REGISTRATION: URL: https://classic.clinicaltrials.gov ; Unique Identifiers: NCT03439514, NCT02057341, and NCT02351856.
Study objective We determine the impact of a screening, brief intervention, and referral for treatment (SBIRT) program in reducing alcohol consumption among emergency department (ED) patients. ...Methods Patients drinking above National Institute of Alcohol Abuse and Alcoholism low-risk guidelines were recruited from 14 sites nationwide from April to August 2004. A quasiexperimental comparison group design was used in which control and intervention patients were recruited sequentially at each site. Control patients received a written handout. The intervention group received the handout and a brief intervention, the Brief Negotiated Interview, to reduce unhealthy alcohol use. Follow-up surveys were conducted at 3 months by telephone using an interactive voice response system. Results Of 7,751 patients screened, 2,051 (26%) exceeded the low-risk limits set by National Institute of Alcohol Abuse and Alcoholism; 1,132 (55%) of eligible patients consented and were enrolled (581 control, 551 intervention). Six hundred ninety-nine (62%) completed a 3-month follow-up survey, using the interactive voice response system. At follow-up, patients receiving a Brief Negotiated Interview reported consuming 3.25 fewer drinks per week than controls (coefficient B −3.25; 95% confidence interval CI −5.76 to −0.75), and the maximum number of drinks per occasion among those receiving Brief Negotiated Interview was almost three quarters of a drink less than controls (B −0.72; 95% CI −1.42 to −0.02). At-risk drinkers (CAGE <2) appeared to benefit more from a Brief Negotiated Interview than dependent drinkers (CAGE >2). At 3-month follow-up, 37.2% of patients with CAGE less than 2 in the intervention group no longer exceeded National Institute of Alcohol Abuse and Alcoholism low-risk limits compared with 18.6% in the control group (Δ 18.6%; 95% CI 11.5% to 25.6%). Conclusion SBIRT appears effective in the ED setting for reducing unhealthy drinking at 3 months.
Understanding what matters most to patients can help guide research in a direction that is best situated to provide evidence that is responsive to their core concerns. This can better inform the ...treatment decision-making process for patients and their physicians. The Aortic Dissection (AD) Collaborative built a collaborative AD research infrastructure involving patients and other stakeholders to facilitate patient-centered outcomes research training, support, and networking among those affected by AD. Two surveys and semi-structured interviews were conducted between January and October 2020 to gather information from people with and at risk for AD and their family members to better understand their experiences and needs. Discussion of survey and interview results were then articulated as seven key topics for future research to meet the needs of the AD community. Working groups were assembled to address each of the key topics. The groups conducted landscape reviews that were focused on providing guidance for future research that directly addresses the needs identified by the AD community. Recommendations for future research generated by the working groups were compiled by the Aortic Dissection Collaborative. From these recommendations, the Aortic Dissection Collaborative advisors and stakeholders identified high-priority research questions. The research questions form the basis for a third survey, disseminated to the Virtual Research Network between November 2021 and February 2022. Final analysis of the survey will identify top ranked research questions and assess willingness to participate. These results will inform the development of future patient-centered outcomes research and comparative effectiveness research proposals.
The mental health impact of aortic dissection Ilonzo, Nicole; Taubenfeld, Ella; Yousif, Maisoon D. ...
Seminars in vascular surgery,
March 2022, 2022-Mar, 2022-03-00, 20220301, Letnik:
35, Številka:
1
Journal Article
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Although the topics of surgical techniques and medical therapies have been widely studied in aortic dissection (AD), studies examining the short- and long-term impact of this event on mental health ...are largely lacking. Many of the studies have used the 36-Item Short Form Survey at variable time points after the event. However, AD as medical trauma has a complex impact on a person's identity. Its implications for emotional, mental, social, existential, and self-concept could be explored more robustly. This topic was identified as a topic of interest by the AD Collaborative. The AD Collaborative Mental Health Working Group was formed and performed a landscape review to summarize current literature surrounding quality of life research in those who have experienced AD, identify gaps in knowledge, and to outline future research questions.
Aortic dissection in pregnancy and the postpartum period Russo, Melissa; Boehler-Tatman, Mattie; Albright, Catherine ...
Seminars in vascular surgery,
March 2022, 2022-Mar, 2022-03-00, 20220301, Letnik:
35, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Pregnancy-associated aortic dissection (AD) is a rare event, with an incidence of 0.0004% per pregnancy. The work of the Aortic Dissection Collaborative identified pregnancy-associated AD as a ...high-priority topic, despite its rarity. The Pregnancy Working Group, which included physicians and patient stakeholders, performed a systematic literature review of pregnancy-associated AD from 1960 to 2021 and identified 6,333 articles through PubMed, OVID MEDLINE, Cochrane, Embase, CINAHL and Web of Science. The inclusion criterion was AD in pregnant populations and exclusion criteria were case reports, conference abstracts, and languages other than English. Assessment of full-text articles for eligibility after removal of duplicates from all databases yielded 68 articles to be included in the final review. Topics included were timing of AD in pregnancy, type of AD, and management considerations of pregnancy-associated AD. The Pregnancy Working Group identified gaps in knowledge and future areas of research for pregnancy-associated AD, including clinical management, mental health outcomes post AD, reproductive and genetic counseling, and contraception after AD. Future collaborative projects could be a multicenter, international registry for all pregnancy-associated AD to refine the risk factors, best practice and management of AD in pregnancy. In addition, future mixed methodology studies may be useful to explore social, mental, and emotional factors related to pregnancy-associated AD and to determine support groups’ effect on anxiety and depression related to these events in the pregnancy and postpartum period.
Potato spindle tuber viroid (PSTVd) is currently widespread in seed potatoes grown in Russia. Characterization of 39 PSTVd isolates collected over a 15-year period from widely separated areas in ...Russia revealed the presence of 17 different sequence variants, all but one of which were previously unknown. Most variants were recovered only once, but two were more widely distributed; one of these was a mild variant previously isolated in Germany, the second was a novel variant inducing symptoms similar to those of the type strain in tomato. Despite this apparent lack of population diversity, several informative PSTVd variants were recovered. Sequence changes in the pathogenicity and variable domains were particularly common, but previously unknown changes were also detected within the loop E motif in the central domain, a structural motif known to play a key role in PSTVd replication and host range determination.
Aims: This study aims to determine the impact of Screening, Brief Intervention and Referral for Treatment (SBIRT) in reducing alcohol consumption in emergency department (ED) patients at 3, 6, and 12 ...months following exposure to the intervention. Methods: Patients drinking above the low-risk limits (at-risk to dependence), as defined by National Institute of Alcohol Abuse and Alcoholism (NIAAA), were recruited from 14 sites nationwide from April to August 2004. A quasi-experimental comparison group design included sequential recruitment of intervention and control patients at each site. Control patients received a written handout. The Intervention group received the handout and participated in a brief negotiated interview with direct referral for treatment if indicated. Follow-up surveys were conducted at 3, 6, and 12 months by telephone using an Interactive Voice Response (IVR) system. Results: Of the 1132 eligible patients consented and enrolled (581 control, 551 intervention), 699 (63%), 575 (52%) and 433 (38%) completed follow-up surveys via IVR at 3, 6, and 12 months, respectively. Regression analysis adjusting for the clustered sampling design and using multiple imputation procedures to account for subject attrition revealed that those receiving SBIRT reported roughly three drinks less per week than controls (B = −3.00, SE = 1.06, P < 0.05) and the level of maximum drinks per occasion was approximately three-fourths of a drink less than controls (B = -0.76, SE = 0.29, P < 0.05) at 3 months. At 6 and 12 months post-intervention, these effects had weakened considerably and were no longer statistically or substantively significant. Conclusion: SBIRT delivered by ED providers appears to have short-term effectiveness in reducing at-risk drinking, but multi-contact interventions or booster programs may be necessary to maintain long-term reductions in risky drinking.
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