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A multi-center study was conducted to assess the clinical effectiveness and safety of high-strength capsaicin cream 0.25% in a lidocaine-containing vehicle for treatment of painful diabetic neuropathy (PDN) and postherpetic neuralgia (PHN). Eighty-three (83) patients with PDN (n = 56) or PHN (n = 27) who were already taking oral antiepileptics or tricyclic antidepressants with incomplete pain relief were enrolled. Capsaicin cream 0.25% in a lidocaine-containing vehicle was applied to painful areas three times daily for 6 weeks. Pain intensity was evaluated at Weeks 1, 3, and 6 using an Average Weekly Pain Score. At Week 6, improvement was also assessed with a Subject Global Evaluation (SGE), a Physician Global Evaluation (PGE), and a Functional Assessment Questionnaire. Following 1, 3, and 6 weeks of treatment, pain was reduced by 21%, 40%, and 50%, respectively, in patients with PDN, and by 24%, 39%, and 51%, respectively, in patients with PHN. On the SGE, 90% of patients with PDN were rated as Improved, with 58% rated as Much or Very Much Improved; 94% of patients with PHN were rated as Improved, with 56% rated as Much or Very Much Improved. On the PGE, 89% of patients with PDN were rated as Improved, with 63% rated as Much or Very Much Improved; 88% of patients with PHN were rated as Improved, with 63% rated as Much or Very Much Improved. Transient stinging/burning sensations at the application sites were the most commonly reported adverse events, while no serious adverse events related to study drug were observed. Capsaicin cream 0.25% in a lidocainecontaining vehicle was shown to be a safe, effective, and well tolerated adjunctive treatment for PDN and PHN in patients experiencing incomplete pain relief despite taking oral antiepileptics or tricyclic antidepressants. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the efficacy and safety of divalproex sodium (DVPX) when used as prophylactic monotherapy in patients with migraine. Design: Multicenter, double-blind, placebo-controlled, parallel group. Patients were previously untreated or had failed no more than two adequate trials of prophylactic therapy. During the 4-week (single-blind) baseline, patients received placebo and completed a headache diary. Patients with two or more migraine attacks during the baseline were randomized to receive a DVPX daily dose of 500, 1000, or 1500 mg, or to placebo. The experimental phase (EP) lasted 12 weeks, the first 4 weeks for dose escalation to randomized dose, and the remaining 8 weeks for maintenance at that dose. The primary efficacy variable was 4-week migraine attack frequency during the EP. Results: One-hundred-and-seventy-six patients (44 placebo, 132 DVPX) were randomized; 171 provided efficacy data and 137 completed the study. During the EP, after adjustment for differences in baseline migraine attack frequencies, mean reductions in the DVPX groups were 1.7 (500 mg), 2.0 (1000 mg) and 1.7 (1500 mg) migraine attacks per 4 weeks compared to a mean reduction of 0.5 migraine attacks in the placebo group (p 0.05 vs placebo). Forty-four to 45% of DVPX-treated patients, compared to 21% of patients in the placebo group achieved 50% reduction in their migraine attack frequencies (p 0.05 vs placebo). The recommended initial dose of DVPX in migraine prophylaxis is 500 mg per day, although some patients may benefit from higher doses. Adverse events were similar in the DVPX and placebo treatment groups except for nausea, dizziness and tremor, in which incidence rates were significantly higher in the DVPX 1500 mg group (nausea was also higher in 500 mg group) than in the placebo group. Conclusion: Divalproex sodium is an effective prophylactic treatment in migraine and is generally well tolerated. [ABSTRACT FROM AUTHOR]

Purpose Transfusion during lung transplantation (LT) is associated with worsened outcomes. When recipients require anticoagulation at listing, they are at increased risk of bleeding during LT if the drug effects are not rapidly reversed. Four-factor prothrombin complex concentrate (4-F PCC) is recently available for rapid warfarin reversal. Here we describe clinical outcomes in waitlisted recipients who were anticoagulated on warfarin and reversed with 4-F PCC at the time of LT. Methods The electronic medical records of all adult LT patients between 2/2014-8/2018 were queried. 4-F PCC became available in 2014, and routinely used for warfarin reversal in 2017. When indicated, patients were anticoagulated with warfarin at listing. During LT, 4-F PCC was administered immediately upon arrival to the OR and prior to incision, per recommended dose. We report 72-hour transfusion requirements, as well as short and long-term clinical outcomes. Results 451 LT patients' records were queried; of those, 4 patients received full dose 4-F PCC for warfarin reversal, for off pump LT. We describe clinical characteristics of the recipient, the surgery, relevant medications administered, and outcomes in Table 1 . 72-hr transfusion requirements ranged from 0 to 2 RBCs, with cryoprecipitate and platelets ranging from 0 to 2 U. FFP use varied tremendously because 1 patient required plasmapheresis perioperatively. Patient 2 had a deep vein thrombosis after 30 days during the index hospitalization. All patients were discharged home and have survived to date. Conclusion When warfarin is utilized as a therapeutic anticoagulation strategy at listing for lung transplant, 4F-PCC safely and effectively reverses its effects. [ABSTRACT FROM AUTHOR]

Arch Neurol . 2002 Jun;59(6):990-994 Objective: To evaluate the safety and efficacy of intranasal civamide solution for preventive treatment during an episodic cluster headache period. Subjects And Methods: This was a multicenter, double-blind, randomized, vehicle-controlled study with a 7-day treatment period and a 20-day posttreatment period performed at 14 headache/neurology centers in the United States. Twenty-eight subjects were randomized to receive civamide or its vehicle in a 2:1 ratio; 18 received civamide and 10 received the vehicle. Subjects received 100 microL of 0.025% civamide (25 microg) or 100 microL of the vehicle to each nostril via dropper once daily for 7 days. The total daily dose of civamide was 50 microg. Main Outcome Measures: The number of cluster headaches per week during the treatment and posttreatment periods, pain intensity, presence of associated symptoms, and the incidence of adverse events were assessed. Results: Subjects in the civamide group had a significantly greater percent decrease in the number of headaches from baseline to posttreatment during days 1 through 7 (-55.5% vs -25.9%; P = .03) and a trend toward significance during days 8 through 14 (-66.9% vs -32.3%; P = .07) and days 15 through 20 (-70.6% vs -34.9%; P = .07), as well as a near-significant decrease during the entire posttreatment period (days 1 through 20 [P = .054]) compared with the vehicle group. There were larger decreases in the number of headaches per week during the posttreatment period in the civamide-treated group, with trends toward significance during posttreatment days 8 through 14 (-8.6 vs -3.6; P = .09) and days 15 through 20 (-8.9 vs -3.6; P = .07). There were no significant differences between groups in cluster headache pain intensity, number of severe headaches, or associated symptoms. The most common adverse events included nasal burning (14 of 18 civamide-treated subjects, 1 of 10 vehicle-treated subjects; P = .001) and lacrimation (9 of 18... [ABSTRACT FROM AUTHOR]

Abstract Background Ribozymes are small catalytic RNAs that possess the dual functions of sequence-specific RNA recognition and site-specific cleavage. Trans-cleaving ribozymes can inhibit translation of genes at the messenger RNA (mRNA) level in both eukaryotic and prokaryotic systems and are thus useful tools for studies of gene function. However, identification of target sites for efficient cleavage poses a challenge. Here, we have considered a number of structural and thermodynamic parameters that can affect the efficiency of target cleavage, in an attempt to identify rules for the selection of functional ribozymes. Results We employed the Sfold program for RNA secondary structure prediction, to account for the likely population of target structures that co-exist in dynamic equilibrium for a specific mRNA molecule. We designed and prepared 15 hammerhead ribozymes to target GUC cleavage sites in the mRNA of the breast cancer resistance protein (BCRP). These ribozymes were tested, and their catalytic activities were measured in vitro. We found that target disruption energy owing to the alteration of the local target structure necessary for ribozyme binding, and the total energy change of the ribozyme-target hybridization, are two significant parameters for prediction of ribozyme activity. Importantly, target disruption energy is the major contributor to the predictability of ribozyme activity by the total energy change. Furthermore, for a target-site specific ribozyme, incorrect folding of the catalytic core, or interactions involving the two binding arms and the end sequences of the catalytic core, can have detrimental effects on ribozyme activity. Conclusion The findings from this study suggest rules for structure-based rational design of trans-cleaving hammerhead ribozymes in gene knockdown studies. Tools implementing these rules are available from the Sribo module and the Srna module of the Sfold program available through Web server at http://sfold.wadsworth.org.

Background: Cognitive impairment in Huntington's disease (HD) is a key driver of disability that can have deleterious impacts on everyday functioning. Currently available patient-reported outcome measures may not adequately capture the impact of HD-related cognitive impairment on daily life, particularly higher-order executive functioning (i.e., processing information, decision making, multi-tasking, planning, etc.)., Objective: To address the unmet need to better quantify the functional sequelae of HD-related cognitive impairment by developing the Huntington's Disease Everyday Functioning (Hi-DEF) scale., Methods: Qualitative interviews were conducted in two adult cohorts (25-65 years) with early stages of HD (i.e., huntingtin [ mHTT ] gene carriers with self-reported cognitive complaints but could still function independently). Cohort 1 included 10 dyads of participants with HD and their care partners, who completed concept elicitation interviews to identify cognitive challenges impacting everyday tasks, which was used to design a draft item-set. Cohort 2, which included 15 additional participants with HD, cognitively debriefed this item-set., Results: In Cohort 1, issues with executive functioning were reported 32 times by participants with HD and 22 times by care partners, and challenges with functioning were reported 46 times by participants with HD and 20 times by care partners. Based on these reports, the Hi-DEF scale was developed and cognitive debriefing interviews evaluated its content validity, relevance, clarity, interpretation, and acceptability. Psychometric validation of the Hi-DEF scale is reported elsewhere., Conclusions: These interviews revealed the impact of HD-related cognitive impairment on everyday functioning and supported the content validity, relevance, clarity, interpretation, and acceptability of the Hi-DEF scale.

Competing Interests: The authors reported no conflicts of interest. The Journal policy requires editors and reviewers to disclose conflicts of interest and to decline handling manuscripts for which they may have a conflict of interest. The editors and reviewers of this article have no conflicts of interest.

Objectives: The development of new human leukocyte antigens (HLAs) and donor-specific antibodies (DSAs) in patients are associated with worse outcomes following lung transplantation. The authors aimed to examine the relationship between blood product transfusion in the first 72 hours after lung transplantation and the development of HLA antibodies, including DSAs., Design: A retrospective observational study., Setting: At a single academic tertiary center., Participants: Adult lung transplant recipients who underwent transplantation between September 2014 and June 2019., Interventions: None., Measurements and Main Results: A total of 380 patients were included in this study, and 87 (23%) developed de novo donor-specific antibodies in the first year after transplantation. Eighty-five patients (22%) developed new HLA antibodies that were not donor-specific, and 208 patients (55%) did not develop new HLA antibodies in the first year after transplantation. Factors associated with increased HLA and DSA development included donor pulmonary infection, non-infectious indication for transplant, increased recipient body mass index, and a preoperative calculated panel reactive antibody value above 0. Multivariate analysis identified platelet transfusion associated with an increased risk of de novo HLA antibody development compared to the negative group (odds ratio [OR; 95% CI] 1.18 [1.02-1.36]; p = 0.025). Cryoprecipitate transfusion was associated with de novo DSA development compared to the negative group (OR [95% CI] 2.21 [1.32-3.69] for 1 v 0 units; p = 0.002)., Conclusions: Increased perioperative transfusion of platelets and cryoprecipitate are associated with de novo HLA and DSA development, respectively, in lung transplant recipients during the first year after transplantation., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 Elsevier Inc. All rights reserved.)

We present our institution's protocol for evaluating and transplanting thoracic organs from COVID-19 positive donors and report the outcomes to date. Hearts from donors testing positive for COVID-19 on any test were eligible for transplantation at our institution provided the donor exhibited no evidence of hypercoagulability or COVID-19 induced hyperinflammatory state during terminal hospitalization. Lungs were eligible if the donor first tested PCR positive on nasopharyngeal swab (NPS) for COVID-19 > 20 days prior to procurement and had a negative lower respiratory tract specimen. We performed 14 thoracic transplants in 13 recipients using organs from COVID-19 positive donors. None of the recipients or healthcare members acquired COVID-19. No recipients suffered unexpected acute rejection. Patient survival is 92% to date, with graft survival 93%. The use of hearts from COVID-19 positive donors may be safe and effective. Transplantation of lungs is unresolved but may be cautiously pursued under the restricted circumstances., (Copyright © 2022 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Objective: A small but growing proportion of lung transplant recipients survive longer than a decade post-transplant. The aim of this study was to identify factors associated with survival beyond a decade after lung transplant., Methods: We queried the United Network for Organ Sharing registry for adult (age ≥18 years) recipients undergoing first-time isolated lung transplantation between the introduction of the Lung Allocation Score in 2005 and 2009. Recipients were stratified into 3 cohorts: those who survived less than 1 year, 1 to 10 years, and greater than 10 years. Multivariable logistic regression was used to identify factors independently associated with early mortality (<1 year) and long-term (>10 years) survival., Results: A total of 5171 lung transplant recipients and their associated donors met inclusion criteria, including 964 (18.6%) with early mortality, 2843 (55.0%) with intermediate survival, and 1364 (26.3%) long-term survivors. Factors independently associated with early mortality included donor Black race, cigarette use, arterial oxygen partial pressure/fractional inspired oxygen ratio, diabetes, recipient Lung Allocation Score, total bilirubin, extracorporeal membrane oxygenation bridge requirement, single lung transplantation, and annual lung transplant center volume. The only factors independently associated with long-term survival among those who survived at least 1 year was donor age and single lung transplantation., Conclusions: Of patients undergoing lung transplantation after the implementation of the Lung Allocation Score, approximately one-quarter survived 10 years post-transplant. There was minimal overlap between the factors associated with 1-year and 10-year survival. Of note, the Lung Allocation Score was not associated with long-term survival. Further research is needed to better refine patient selection and optimize management strategies to increase the number of long-term survivors., (Copyright © 2020 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)