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EFFICACY AND SAFETY OF SELADELPAR IN PATIENTS WITH PRIMARY BILIARY CHOLANGITIS PREVIOUSLY TREATED WITH FIBRATES OR OBETICHOLIC ACID
No full textSeladelpar is a first-in-class delpar (selective PPAR-delta agonist) indicated in the UK for the treatment of primary biliary cholangitis including pruritus in combination with ursodeoxycholic acid (UDCA) in adults with an inadequate response to UDCA or as monotherapy in patients unable to tolerate UDCA. RESPONSE was a Phase 3, randomised, placebo-controlled clinical trial of seladelpar in patients with inadequate response or intolerance to UDCA. Patients completing RESPONSE were eligible to roll over into ASSURE (NCT03301506), an ongoing, open-label, long-term, Phase 3 safety trial. Here, we describe data from month 18 (month 6 of ASSURE) in patients with or without prior use of fibrates or obeticholic acid (OCA) who rolled over from RESPONSE into ASSURE. Patients received 10 mg seladelpar orally daily or placebo in RESPONSE; patients received open-label 10 mg seladelpar in ASSURE. Fibrates and OCA were prohibited during the study period and a 6-week washout was required prior to entry in RESPONSE. Data were described for patients in ASSURE with or without prior use of fibrates OCA and based on whether they received seladelpar (continuous seladelpar patients) or placebo (crossover patients) in RESPONSE. Efficacy included the percentage of patients achieving a composite biochemical response (CBR; alkaline phosphatase [ALP] \u3c1.67 × upper limit of normal [ULN], ALP decrease \u3e15%, and total bilirubi
Small extracellular vesicles derived from cerebral endothelial cells with elevated microRNA 27a promote ischemic stroke recovery
No full textAxonal remodeling is a critical aspect of ischemic brain repair processes and contributes to spontaneous functional recovery. Our previous in vitro study demonstrated that exosomes/small extracellular vesicles (sEVs) isolated from cerebral endothelial cells (CEC-sEVs) of ischemic brain promote axonal growth of embryonic cortical neurons and that microRNA 27a (miR-27a) is an elevated miRNA in ischemic CEC-sEVs. In the present study, we investigated whether normal CEC-sEVs engineered to enrich their levels of miR-27a (27a-sEVs) further enhance axonal growth and improve neurological outcomes after ischemic stroke when compared with treatment with non-engineered CEC-sEVs. 27a-sEVs were isolated from the conditioned medium of healthy mouse CECs transfected with a lentiviral miR-27a expression vector. Small EVs isolated from CECs transfected with a scramble vector (Scra-sEVs) were used as a control. Adult male mice were subjected to permanent middle cerebral artery occlusion and then were randomly treated with 27a-sEVs or Scra-sEVs. An array of behavior assays was used to measure neurological function. Compared with treatment of ischemic stroke with Scra-sEVs, treatment with 27a-sEVs significantly augmented axons and spines in the peri-infarct zone and in the corticospinal tract of the spinal grey matter of the denervated side, and significantly improved neurological outcomes. In vitro studies demonstrated that CEC-sEVs carrying reduced miR-27a abolished 27a-sEV-augmented axonal growth. Ultrastructural analysis revealed that 27a-sEVs systemically administered preferentially localized to the pre-synaptic active zone, while quantitative reverse transcription-polymerase chain reaction and Western Blot analysis showed elevated miR-27a, and reduced axonal inhibitory proteins Semaphorin 6A and Ras Homolog Family Member A in the peri-infarct zone. Blockage of the Clathrin-dependent endocytosis pathway substantially reduced neuronal internalization of 27a-sEVs. Our data provide evidence that 27a-sEVs have a therapeutic effect on stroke recovery by promoting axonal remodeling and improving neurological outcomes. Our findings also suggest that suppression of axonal inhibitory proteins such as Semaphorin 6A may contribute to the beneficial effect of 27a-sEVs on axonal remodeling
Infusion Reactions with Alternative Therapies During the National Shortage of Iron Dextran
No full textPrior to the national shortage of iron dextran in early 2023, it was the most commonly administered intravenous iron infusion at our institution. After the shortage impacted the health system, alternatives such as iron sucrose and sodium ferric gluconate/sucrose were required that utilized lower doses given at more frequent patient visits. Coinciding with their more prevalent use, an increase in iron infusion reactions was observed. Our study analyzed 880 patients who received iron infusions in three Henry Ford Hospital clinics in metropolitan Detroit, Michigan, from July 2022-June 2023. The 74 reactions that occurred were most commonly associated with iron sucrose at the 500 mg dose (41/74, 55.41%, p \u3c 0.0001). Most reactions observed across all iron formulations and doses were mild, with 83.7% being Grade 0 or 1 as defined by the United States Drug Allergy Registry (USDAR) grading scale for immediate reactions. Patients who experienced an infusion reaction were less likely to complete their infusion plans (OR 0.004 for iron dextran, OR 0.128 for iron sucrose, p \u3c 0.0001), with infusions most commonly being completely discontinued thereafter, with a minority pursuing alternative options. More patients with lower number of doses scheduled for iron dextran completed their infusion schedules than those with more doses, but the opposite was seen for iron sucrose. We assessed the impact of the national shortage of iron dextran examining infusion reactions with various iron infusions and doses
Recognition of the Large Ambulatory C2D Stage of Advanced Heart Failure-A Call to Action
No full textIMPORTANCE: The advanced ambulatory heart failure (HF) population comprises patients who have progressed beyond the pillars of recommended stage C HF therapies but can still find meaningful life-years ahead. Although these patients are commonly encountered in practice, national databases selectively capture the small groups accepted for heart transplant listing or left ventricular assist devices. The epidemiology, trajectories, and therapies for other ambulatory patients with advanced HF are poorly understood.
OBSERVATIONS: In December 2022, the National Heart, Lung and Blood Institute convened a team of experts to identify knowledge gaps and research priorities for the ambulatory population with limiting daily symptoms and transition toward refractory end-stage D HF, designated as stage C2D. This article summarizes the findings from that 3-day workshop. Workshop participants surveyed the initial challenges and knowledge gaps for (1) recognition of ambulatory C2D HF, (2) estimation of the magnitude of the affected population and identifiable subpopulations, and (3) physiologic phenotypes, such as low cardiac output, right HF, cardiorenal syndromes, congestive hepatopathy and frailty, which offer distinct targets for existing and emerging therapies. Social drivers of HF and patient preferences for quality/length of survival were highlighted as essential modifiers for personalization of therapies.
CONCLUSIONS AND RELEVANCE: Ten key points summarized workshop findings, with target cohorts for study proposed as a crucial next step. This workshop summary is intended as a call for action to address knowledge gaps and develop new strategies to improve outcomes in the large ambulatory population with C2D HF
Patient outcomes and health care resource utilization in acute pancreatitis-related central nervous system complications: insights from a national cohort study
No full textOBJECTIVES: Central nervous system complications of acute pancreatitis (AP) can result in cerebral edema (CE). We assessed the risk of serious outcomes and health care features associated with CE in patients hospitalized with AP.
METHODS: We conducted a retrospective cohort study using the National Inpatient Sample database. Patients were divided into the AP-CE group that developed CE and the AP-only group that did not. Outcome data were analyzed using Stata software.
RESULTS: Among 543,464 patients hospitalized with AP, 220 (0.04%) developed CE. In multivariate analysis, primary outcomes included increased length of hospital stay (adjusted odds ratio [aOR] 10.1; 95% confidence interval [CI] 0.50-19.70), hospital charges (aOR USD 208,713; 95% CI 27,095-390,330), and risk of death (aOR 17.17; 95% CI 5.88-50.07) in the AP-CE group. Secondary outcomes showed patients with AP-CE had a significantly increased risk of serious complications, particularly cardiac arrest (aOR 64.24; 95% CI 24.27-170.02), and higher hospital resource utilization.
CONCLUSION: Patients with AP who develop CE face worse outcomes, including increased mortality risk, prolonged hospital stay, and greater resource utilization. Timely identification and effective management of CE in AP may reduce mortality and ease the health care burden associated with this neurological complication
Response to: Enhancing Clinical Practice: Critical Insights for Medical Workers in Applying Pembrolizumab for Metastatic NSCLC and Pembrolizumab, Chemotherapy and Metastatic Non-Small Cell Lung Cancer
No full textDepression, non-medical pain prescriptions, and suicidal behavior in cancer survivors
No full textPURPOSE: A cancer diagnosis results in significant distress and adverse psychosocial sequelae, including suicide, the 10th leading cause of death in the USA. Primary risks for death by suicide include depression and opioid abuse, which are prevalent among cancer survivors. Yet, it remains unclear whether they are also associated with other suicidal outcomes, such as ideation, planning, and suicidal attempt.
METHODS: We used cross-sectional data from the National Survey on Drug Use and Health (2015-2019, N = 214,271), a nationwide study in the USA that provides data on mental health and other health concerns. Outcome of interest was suicidality (suicidal ideation, planning, and attempt). Main exposures were history of depression and non-medical use of pain prescriptions. Using weighted logistic regression analyses adjusted for sociodemographic factors and substance use, we estimated odds of suicidal ideation, planning, and attempt.
RESULTS: There were 7635 cancer survivors in our study, which was our analytic sample. We found an associations between a history of cancer and suicidal ideation (aOR = 1.32, 95% CI 1.10, 1.58). Among cancer survivors, depression and non-medical use of pain prescriptions were consistently associated with suicidal ideation (aOR(depression) = 7.37, 95% CI 4.52, 12.03; aOR(pain prescriptions) = 3.36, 95% CI 1.27, 8.91, planning (aOR(depression) = 10.31, 95% CI 5.79, 18.34; and aOR(pain prescriptions) = 3.77, 95% CI 1.20, 11.85), and attempt (aOR(depression) = 4.29, 95% CI 1.41, 13.06).
CONCLUSION: Both depression and non-medical pain prescriptions are independently associated with increased odds of suicidal behavior among cancer survivors. Routinely assessing for depression and history of non-medical use of pain prescriptions could be an important suicide prevention strategy in oncology.
IMPLICATIONS FOR CANCER SURVIVORS: Given the increased risk of suicide mortality among cancer survivors, it is critical that risk factors for suicidal behavior, such as depression and use of non-medical pain prescriptions, are routinely screened for as part of cancer care
Evaluation and Management of the External Nasal Valve
No full textThe external nasal valve is the anatomic structure formed by the caudal septum, alar rim, medial crura of the lower lateral cartilage, and nasal sill at the level of the nasal vestibule. Evaluation of external nasal valve dysfunction is dependent upon a thorough history and physical examination. Symptoms and quality of life impact are the main drivers for patients to seek out clinical evaluation. It is paramount that surgeons are familiar with available nonsurgical and surgical options for the management of external nasal valve dysfunction
Parotidectomy Trends Toward Outpatient for Benign Disease
No full textOBJECTIVE: We evaluate the safety of outpatient parotidectomy. We evaluate factors that lead to planned admission and compare costs. We evaluate trends toward outpatient, and the outcomes of switching admission status, total versus superficial approach, and ambulatory versus hospital site.
STUDY DESIGN: Retrospective cohort study.
SETTING: Single tertiary academic center.
METHODS: Retrospective review of patients who underwent parotidectomy for benign tumors from 2018 to 2023.
RESULTS: Of 370 parotidectomies performed, there were a planned 162 admissions and 208 outpatient procedures. A travel time \u3e 60 minutes (odds ratio [OR] = 0.487, confidence interval [CI]: 0.296-0.803, P = .005) and total parotidectomy (OR = 0.448, CI: 0.226-0.89, P = .022) decreased the odds of a planned outpatient procedure. In a multivariable model, longer operative time increased the odds of switching to inpatient (n = 29, OR = 1.02, CI: 1.007-1.033, P = .002) and drain placement decreased the odds of switching to outpatient (n = 15, OR = 0.035, CI: 0.004-0.298, P = .002). There was no significant difference in surgical complications, phone calls, clinic visits, readmission rates, or recurrence between outpatient and inpatient. This remained true when comparing surgical facility and superficial versus total parotidectomy. After COVID was declared an emergency, there was a trend toward outpatient parotidectomy (72.7% vs 48.9%, P \u3c .001), but no change in complication rates. At our institution, outpatient parotidectomy saved $3838 compared to overnight admission.
CONCLUSION: This study supports that outpatient parotidectomy is safe. This remained true for patients switching admission status, undergoing superficial or total parotidectomy, and having their operation at an ambulatory site. We demonstrate that institutions can safely increase outpatient parotidectomy rates and outpatient parotidectomy is cost effective
Self-perceived importance and confidence of adolescents transitioning to adult care
No full textPURPOSE: Motivational interviewing (MI) techniques are used by health care teams to engage adolescents and young adults (AYAs) in health care self-management and pediatric to adult health care transition (HCT) planning efforts. The aim of this study was to assess the initial level of motivation of AYAs prior to receipt of HCT anticipatory guidance and to determine associations with demographic and health coverage factors.
METHODS: This retrospective study included 5112 AYAs, aged 12-26 years, from four health systems. All AYAs completed the Got Transition readiness assessment that includes MI questions on importance and confidence related to the move to an adult provider. Independent variables included demographic and health coverage factors: age, sex, race, ethnicity, language, and insurance type. The statistical approach included summary statistics, chi-square tests of independence and log-likelihood ratio tests, and generalized linear models and contrasts.
RESULTS: The study results demonstrate initial trends in importance and confidence scores for AYAs before they became part of a HCT planning process. Importance scores increased from 12-14 through 18-20 years of age, then decreased in the 21-26-year group. Confidence scores increased from the 12-14 through the 21-26-year group. Confidence scores were generally higher than importance scores and were accompanied by smaller standard deviations. Ethnicity and insurance type also demonstrated an association with MI scoring.
DISCUSSION: This study provides baseline scores on two key MI importance and confidence questions that can facilitate clinician understanding of AYA engagement in discussing the changes needed to move to adult care and guides the clinician to start earlier than just before transfer that often occurs around age 21