Genomic sequencing can reveal variants with limited to no medical actionability. Previous research has assessed individuals' intentions to learn this information, but few report the decisions they ...made and why.
The North Carolina Clinical Genomic Evaluation by Next Generation Exome Sequencing (NCGENES) project evaluated adult patients randomized to learn up to six types of non-medically actionable secondary findings (NMASF). We previously found that most participants intended to request NMASF and intentions were strongly predicted by anticipated regret. Here we examine discrepancies between intentions and decisions to request NMASF, hypothesizing that anticipated regret would predict requests but that this association would be mediated by participants' intentions.
Of the 76% who expressed intentions to learn results, only 42% made one or more requests. Overall, only 32% of the 155 eligible participants requested NMASF. Analyses support a plausible causal link between anticipated regret, intentions, and requests.
The discordance between participants' expressed intentions and their actions provides insight into factors that influence patients' preferences for genomic information that has little to no actionability. These findings have implications for the timing and methods of eliciting preferences for NMASF and suggest that decisions to learn this information have cognitive and emotional components.
Abstract Objective To compare resuscitation performance on simulated in-hospital cardiac arrests after traditional American Heart Association (AHA) Healthcare Provider Basic Life Support course ...(TradBLS) versus revised course including in-hospital skills (HospBLS). Design Prospective, randomized, controlled curriculum evaluation. Setting Johns Hopkins Medicine Simulation Center. Subjects One hundred twenty-two first year medical students divided into fifty-nine teams. Intervention HospBLS course of identical length, containing additional content contextual to hospital environments, taught utilizing Rapid Cycle Deliberate Practice (RCDP). Measurements The primary outcome measure during simulated cardiac arrest scenarios was chest compression fraction (CCF) and secondary outcome measures included metrics of high quality resuscitation. Main Results Out-Of-Hospital Cardiac Arrest HospBLS teams had larger CCF: (69%(65-74) vs 58%(53-62), p < 0.001 and were faster than TradBLS at initiating compressions: median(IQR): 9 seconds(s)(7-12) vs. 22s(17.5-30.5), p < 0.001. In-Hospital Cardiac Arrest HospBLS teams had larger CCF: 73%(68-75%) vs. 50%(43-54%)), p < 0.001) and were faster to initiate compressions: 10s(6-11) vs. 36s(27-63), p < 0.001. All teams utilized the hospital AED to defibrillate within 180 seconds per AHA guidelines, HospBLS: 122s(103-149) vs. TradBLS: 139s(116-172), p = 0.09. HospBLS teams performed more hospital-specific maneuvers to optimize compressions, i.e. utilized: CPR button to flatten bed: 7/30(23%) vs. 0/29(0%), p = 0.006, backboard: 21/30(70%) vs. 5/29(17%), p < 0.001, stepstool: 28/30(93%) vs. 8/29(28%), p < 0.001, lowered bedrails: 28/30(93%) vs. 10/29(34%), p < 0.001, connected oxygen appropriately: 26/30(87%) vs. 1/29(3%), p < 0.001 and used oral airway and/or 2-person bagging when traditional bag-mask-ventilation unsuccessful: 30/30(100%) vs. 0/29(0%), p < 0.001. Conclusion A hospital focused BLS course utilizing RCDP was associated with improved performance on hospital-specific quality measures compared to the traditional AHA course.
Background: Severe organ damage from acute graft-versus-host disease (aGVHD) results in a high risk of morbidity and mortality. Treatments that focus on immunosuppression alone do not consistently ...improve long-term survival. Modalities that aid in inflammation resolution, immune tolerance, and tissue repair may improve outcomes beyond high-dose corticosteroids and other broad immunosuppressants for life-threatening aGVHD. We studied the addition of urinary-derived human chorionic gonadotropin/epidermal growth factor (uhCG/EGF, Pregnyl®, Organon, USA) to standard aGVHD therapy in a prospective Phase 2 clinical trial (NCT02525029) conducted at the University of Minnesota and Rush University, extending from our previously published Phase 1 study results (Holtan et al, Blood Advances, 2020) showing uhCG/EGF to be safe and preliminarily efficacious as aGVHD therapy.
Methods: Patients with new onset Minnesota (MN) high risk aGVHD (N=22) or with aGVHD requiring 2nd line therapy (N=22) received methylprednisolone 48 mg/m2/day plus 2,000 units/m2 of uhCG/EGF subcutaneously (SQ) every other day for 1 week (high risk arm). Patients in need of 2nd line aGVHD therapy received 2,000 - 5,000 units/m2 SQ every other day, with dose depending on organ severity, for 2 weeks plus standard of care immunosuppression (anti-thymocyte globulin (N=4), etanercept (N=1), ruxolitinib (N=5), sirolimus (N=4), steroid boost (N=8)). Patients who achieved a complete or partial response (CR/PR) after their initial course of therapy received twice weekly maintenance doses for the next 5 weeks. Exploratory metabolomic profiling was performed using mass spectrometry.
Results: The median age was 61 years (range 2 years - 72 years, 75% male). The majority of patients had stage 3-4 lower GI GVHD (52%) and overall grade III-IV aGVHD (75%) at time of enrollment, with a median baseline albumin of 2.6 g/dl (range 0.9 - 4 g/dl) and median baseline Karnofsky performance status of 50 (range 20-100). The proportion of patients with a response (CR/PR) at day 28 (primary endpoint) was 68% (57% CR, 11% PR, Figure 1A). Among MN high risk patients receiving 1st line steroids, 64% achieved a CR at day 28 (0% PR). Among patients receiving 2nd line therapy, 50% achieved a CR and 23% PR at day 28. The median overall survival for the entire cohort was 1.2 years (Figure 1B), with a 2-year survival of 67% for responders and 12% for non-responders (p<0.01). Twenty-three died; causes of death included aGVHD (n=9), relapse (n=9), infection (n=3), and organ failure (n=2). Only one dose-limiting toxicity occurred (1 cerebral venous sinus thrombosis, resolved with anticoagulation). Exploratory metabolomic analysis of plasma samples collected during the study suggest potential correlations between blood metabolites and response to therapy. Higher levels of linoleic acid were associated with greater CR/PR rates, while higher levels of lactic acid were associated with treatment failure (Figure 1C).
Conclusion: Our Phase 2 study demonstrates that uhCG/EGF is a promising addition to systemic therapy in patients with life-threatening aGVHD. The overall survival result is encouraging considering historical median survival of <0.5 years for patients with both MN high risk and steroid refractory aGVHD. As a commercially available, safe, and inexpensive drug, addition of uhCG/EGF to standard therapy may reduce morbidity and mortality from severe aGVHD. Further studies to explore its role as a steroid-sparing treatment are warranted.
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Holtan: Incyte: Consultancy, Research Funding; Generon: Consultancy. Ustun: novartis: Honoraria; Blueprint: Honoraria. Arora: Pharmacyclics: Research Funding; Syndax: Research Funding; Kadmom: Research Funding. Bachanova: Incyte: Research Funding; FATE: Membership on an entity's Board of Directors or advisory committees, Research Funding; KaryoPharma: Membership on an entity's Board of Directors or advisory committees; Gamida Cell: Membership on an entity's Board of Directors or advisory committees, Research Funding. Betts: Patent Disclosures: Patents & Royalties: B.C.B. holds a patent (WO2015120436A2) related to CD4+ T cell pSTAT3 as a marker and therapeutic target of acute GVHD. B.C.B. additionally holds a provisional patent (WO2017058950A1) related to the use of JAK inhibitors for rejection and GVHD prevention. . Vercellotti: CSL Behring: Research Funding; Mitobridge, an Astellas Company: Consultancy, Research Funding. Brunstein: GamidaCell: Research Funding; NANT: Research Funding; FATE: Research Funding; BlueRock: Research Funding; AlloVir: Consultancy. Janakiram: FATE, Nektar Therapeutics: Research Funding; Bristol Meyer Squibb, Kyowa Kirin, ADCT Therapeutics: Honoraria. Weisdorf: Fate Therapeutics: Research Funding; Incyte: Research Funding. MacMillan: Equilium: Other: DSMB member; Incyte: Consultancy; Jazz Pharmaceuticals: Consultancy.
uhCG/EGF has FDA orphan drug designation to treat acute GVHD.
Pulmonary hypertension (PH) is a well-recognized complication of interstitial lung disease, including idiopathic pulmonary fibrosis (IPF). The underlying pathogenesis was initially hypothesized to be ...inflammatory but now is characterized as an over exuberant fibroproliferative process. The prevalence of PH in the setting of IPF has not been well described in the literature, with a reported occurrence from 32% to 85%. Diagnostically, recognizing underlying PH in the setting of IPF remains challenging because of nonspecific clinical symptoms and unrevealing ancillary testing. A high degree of clinical suspicion is paramount. The only reliable diagnostic tool for PH is right heart catheterization. The treatment of PH, in patients with IPF, is based on multiple factors, including disease severity, functional status and degree of hypoxemia. Medications currently approved to treat PH have been administered for PH in the setting of IPF, such as phosphodiesterase-5 inhibitors, nonselective endothelin receptor antagonists and prostacyclin analogues. The treatment of PH in the setting of IPF may also be difficult due to worsening ventilation-perfusion mismatch induced by selective pulmonary artery vasodilator therapy. Lung transplantation should be considered with patients refractory to pharmacological treatment. Identification of PH in IPF patients is crucial, as functional status and prognosis are greatly reduced. Given the high mortality rate and propensity for acute decompensation, IPF and PH patients should be evaluated for transplant early in their disease course.
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