Giroctocogene fitelparvovec gene therapy for severe hemophilia A: 104-week analysis of the phase 1/2 Alta study.

ABSTRACT: Patients with hemophilia A require exogenous factor VIII (FVIII) or nonfactor hemostatic agents to prevent spontaneous bleeding events. Adeno-associated virus (AAV) vector-based gene therapy is under clinical investigation to enable endogenous FVIII production. Giroctocogene fitelparvovec is a recombinant AAV serotype 6 vector containing the coding sequence for the B-domain-deleted human F8 gene. In the ongoing phase 1/2, dose-ranging Alta study, 4 sequential cohorts of male participants with severe hemophilia A received a single IV dose of giroctocogene fitelparvovec. The primary end points are safety and changes in circulating FVIII activity. Interim results up to 214 weeks after treatment for all participants are presented. Eleven participants were dosed. Increases in alanine and aspartate aminotransferases were the most common treatment-related adverse events (AEs), which resolved with corticosteroid administration. Two treatment-related serious AEs (hypotension and pyrexia) were reported in 1 participant within 6 hours of infusion and resolved within 24 hours after infusion. At the highest dose level (3 × 1013 vg/kg; n = 5), the mean circulating FVIII activity level at week 52 was 42.6% (range, 7.8%-122.3%), and at week 104 it was 25.4% (range, 0.9%-71.6%) based on a chromogenic assay. No liver masses, thrombotic events, or confirmed inhibitors were detected in any participant. These interim 104-week data suggest that giroctocogene fitelparvovec is generally well tolerated with appropriate clinical management and has the potential to provide clinically meaningful FVIII activity levels, as indicated by the low rate of bleeding events in the highest dose cohort. This trial was registered at www.clinicaltrials.gov as #NCT03061201.

Extracorporeal Membrane Oxygenation in Immunocompromised Patients With Acute Respiratory Distress Syndrome-A Retrospective Cohort Study.

Objective: Although the negative impact of immunosuppression on survival in patients with acute respiratory distress syndrome (ARDS) treated by extracorporeal membrane oxygenation (ECMO) is well known, short-term outcomes such as successful weaning rate from ECMO and subgroups benefit most from ECMO remain to be determined. The aims of this study were (1) to identify the association between immunocompromised status and weaning from ECMO in patients of ARDS, and (2) to identify subgroups of immunocompromised patients who may benefit from ECMO. Methods: This retrospective cohort study enrolled patients who received ECMO for ARDS from 2010 to 2020. Immunocompromised status was defined as having a hematological malignancy, active solid tumor, solid organ transplant, or autoimmune disease. Results: This study enrolled 256 ARDS patients who received ECMO, of whom 68 were immunocompromised. The multivariable analysis showed that immunocompromised status was not independently associated with failure to wean from ECMO. In addition, the patients with an autoimmune disease (14/24, 58.3%) and organ transplantation (3/3, 100%) had a numerically higher weaning rate from ECMO than other immunocompromised patients. For causes of ARDS, most patients with pulmonary hemorrhage (6/8, 75%) and aspiration (5/9, 55.6%) could be weaned from ECMO, compared to only a few of the patients with interstitial lung disease (2/9, 22.2%) and sepsis (1/4, 25%). Conclusions: Immunocompromised status was not an independent risk factor of failure to wean from ECMO in patients with ARDS. For patients with pulmonary hemorrhage and aspiration-related ARDS, ECMO may be beneficial as bridge therapy.

Predictors of Erectile Function Normalization in Men With Erectile Dysfunction Treated With Placebo.

BACKGROUND: Clinical study and practice data have shown sildenafil improves sexual function in men with erectile dysfunction (ED). However, some men treated with placebo in double-blind, placebo-controlled sildenafil studies also report improved erectile function as measured by International Index of Erectile Function (IIEF)-Erectile Function Domain (EFD) scores. AIM: This analysis estimated the relationship between post-baseline IIEF-EFD scores and demographic variables, including co-morbidities, in men with ED receiving placebo in flexible-dose sildenafil studies. METHODS: Placebo-treated participants in the intent-to-treat population of 42 double-blind, placebo-controlled, flexible-dose, sildenafil studies were included. A participant was classified as a placebo responder if the IIEF-EFD score was ≥26 at the last visit. OUTCOMES: Variables assessed were age (<45, 45-64, ≥65 years), race, body mass index, co-morbidities (cardiovascular disease/hypertension, diabetes mellitus, depression), date the last study dose was taken, study completion date, ED etiology (psychogenic, organic, mixed), history of cigarette smoking, ED duration, baseline IIEF-EFD score (≤10, 11-16, ≥17), and treatment duration. Stepwise multivariate logistic regression models assessed the odds of being a responder vs a non-responder for each variable. RESULTS: A total of 4,360 men were included; 13.5% were responders. Odds estimates indicated the largest likelihood of placebo response occurred in men who were black (odds = 20.2, P < .0001), were younger than 45 years (odds = 7.3, P < .0001), had mild ED (baseline IIEF-EFD ≥17; odds >100, P < .0001), and did not have diabetes (odds = 4.5, P < .0001). The likelihood of a placebo response decreased as ED duration increased (odds = 0.74, P < .0001). The frequency of common adverse events was similar between placebo responders and non-responders. CLINICAL TRANSLATION: These findings contribute to the improved understanding of predictors of placebo response in sildenafil clinical studies. Elucidation of these factors may contribute to the development of further interventions and treatment strategies and best practices for clinical trials. STRENGTHS AND CONCLUSIONS: Strengths of this analysis include the large and diverse population and the duration of follow-up. Limitations include those associated with retrospective analyses and the inability to ascertain to what extent other demographic factors might have contributed to the placebo responses or how these placebo responses might be related to the natural course of ED. CONCLUSIONS: Certain demographics, co-morbidities, and condition characteristics predicted the odds of a placebo response in sildenafil clinical studies of ED. Underlying reasons behind a placebo response warrant further evaluation. Mulhall JP, Carlsson M, Stecher V, et al. Predictors of Erectile Function Normalization in Men With Erectile Dysfunction Treated With Placebo. J Sex Med 2018;15:866-872.

Hemojuvelin Predicts Acute Kidney Injury and Poor Outcomes Following Cardiac Surgery.

Acute kidney injury (AKI) is detrimental after cardiac surgery. In this multicenter study, the novel biomarker hemojuvelin (HJV) was evaluated for AKI prediction following cardiac surgery. Urinary HJV, neutrophil gelatinase-associated lipocalin (NGAL), and urinary creatinine were measured in 151 patients after surgery. The outcomes of advanced AKI (KDIGO stages 2 and 3) and all causes of in-hospital mortality as the composite outcome were recorded. Areas under the receiver operator characteristic curves (AUC) and a multivariate generalized additive model (GAM) were applied to predict these outcomes of interest. Urinary HJV differentiated patients with/without AKI, advanced AKI or composite outcome after surgery (p < 0.001, by a generalized estimating equation) in this study. At three hours post-surgery, urinary HJV predicted advanced AKI (p < 0.001) and composite outcome (p < 0.001) with corresponding AUC values of 0.768 and 0.828, respectively. The performance of creatinine-adjusted HJV was also superior to NGAL in predicting advanced AKI (AUC = 0.784 and 0.694; p = 0.037) and composite outcome (AUC = 0.842 and 0.676; p = 0.002). The integration of HJV into the Cleveland Clinic score for advanced AKI led to a significant increase in risk stratification (net reclassification improvement [NRI] = 0.598; p < 0.001).

Perioperative body weight change is associated with in-hospital mortality in cardiac surgical patients with postoperative acute kidney injury.

BACKGROUND: Postoperative acute kidney injury (AKI) is common following cardiac surgery (CS). Body weight (BW) may be an amenable variable by representing the summation of the nutritional and the fluid status. However, the predictive role of perioperative BW changes in CS patients with severe postoperative AKI is never explored. This study aimed to evaluate this association. METHODS: This study was conducted using a prospectively collected multicenter cohort, NSARF (National Taiwan University Hospital Study Group on Acute Renal Failure) database. The adult CS patients with postoperative AKI requiring renal replacement therapy (RRT), who had clear initial consciousness, received CS within 14 days of hospitalization, and underwent RRT within seven days after CS in intensive care units from January 2001 to January 2014 were enrolled. With the endpoint of 30-day postoperative mortality, we evaluated the association between the clinical factors denoting fluid status and patients outcomes. RESULTS: A total of 188 patients (70 female, mean age 63.7 ± 15.2 years) were enrolled. Comparing with the survivors (n = 124), the non-survivors (n = 64) had a significantly higher perioperative BW change [3.6 ± 6.1% versus 0.1 ± 8.3%, p = 0.003] but not the postoperative and pre-RRT BW changes. By using multivariate Cox proportional hazards model, the independent indicators of 30-day postoperative mortality included perioperative BW change (p = 0.026) and packed red blood cells transfusion (p = 0.007), postoperative intra-aortic balloon pump (p = 0.001) and central venous pressure level (p = 0.005), as well as heart rate (p = 0.022), sequential organ failure assessment score (p < 0.001), logistic organ dysfunction score (p = 0.001), and blood total bilirubin level (p = 0.044) at RRT initiation. The generalized additive models further demonstrated, in a multivariate manner, that the mortality risk rose significantly during a perioperative BW change of 2% to 15%. CONCLUSIONS: Perioperative BW change was independently associated with an increased risk for 30-day postoperative mortality in CS patients with RRT-requiring AKI.

Urinary π-glutathione S-transferase Predicts Advanced Acute Kidney Injury Following Cardiovascular Surgery.

Urinary biomarkers augment the diagnosis of acute kidney injury (AKI), with AKI after cardiovascular surgeries being a prototype of prognosis scenario. Glutathione S-transferases (GST) were evaluated as biomarkers of AKI. Urine samples were collected in 141 cardiovascular surgical patients and analyzed for urinary alpha-(α-) and pi-(π-) GSTs. The outcomes of advanced AKI (KDIGO stage 2, 3) and all-cause in-patient mortality, as composite outcome, were recorded. Areas under the receiver operator characteristic (ROC) curves and multivariate generalized additive model (GAM) were applied to predict outcomes. Thirty-eight (26.9%) patients had AKI, while 12 (8.5%) were with advanced AKI. Urinary π-GST differentiated patients with/without advanced AKI or composite outcome after surgery (p < 0.05 by generalized estimating equation). Urinary π-GST predicted advanced AKI at 3 hrs post-surgery (p = 0.033) and composite outcome (p = 0.009), while the corresponding ROC curve had AUC of 0.784 and 0.783. Using GAM, the cutoff value of 14.7 µg/L for π-GST showed the best performance to predict composite outcome. The addition of π-GST to the SOFA score improved risk stratification (total net reclassification index = 0.47). Thus, urinary π-GST levels predict advanced AKI or hospital mortality after cardiovascular surgery and improve in SOFA outcome assessment specific to AKI.

Highlighting Indication of extracorporeal membrane oxygenation in endocrine emergencies.

Extracorporeal membrane oxygenation (ECMO) has been repeatedly used to rescue patients with cardiopulmonary arrest. However, its clinical utility in endocrine emergencies remains unclear. Herein, we describe a case series of 12 patients presenting with refractory shock secondary to endocrine emergencies who were rescued by ECMO support. Patients were identified between 2005 and 2012 from our ECMO registry. The diagnostic distribution was as follows: pheochromocytoma crisis (n = 4), thyroid storm (n = 5), and diabetic ketoacidosis (n = 3). The initial presentation of pheochromocytoma crisis was indistinguishable from acute myocardial infarction (AMI) and frequently accompanied by paroxysmal hypertension and limb ischemia. Thyroid storm was characterized by hyperbilirubinemia and severe gastrointestinal bleeding, whereas neurological symptoms were common in diabetic ketoacidosis. The clinical outcomes of patients with endocrine emergencies were compared with those of 80 cases with AMI who received ECMO because of cardiogenic shock. The cardiac function and the general conditions showed a significantly faster recovery in patients with endocrine emergencies than in those with AMI. We conclude that ECMO support can be clinically useful in endocrine emergencies. The screening of endocrine diseases should be considered during the resuscitation of patients with refractory circulatory shock.

Dissociable effect of acute varenicline on tonic versus cue-provoked craving in non-treatment-motivated heavy smokers.

RATIONALE: The effectiveness of varenicline for smoking cessation has been established, but little is known about the psychological processes that mediate this clinical outcome. OBJECTIVES: This study evaluated the effect of a single dose of varenicline on tonic and cue-provoked changes in craving, withdrawal, and affect using a randomized, double-blind, placebo-controlled, cross-over design. METHODS: Following overnight abstinence, 38 non-treatment-motivated smokers received either varenicline 2mg or matched placebo, then tonic measures of craving, withdrawal, and positive and negative affect were obtained at 30-min intervals. At 4-h post-administration, a cue exposure session obtained the same subjective measures at three time-points following the physical handling of a lit cigarette versus the sharpening and handling of a pencil. RESULTS: At 4-h post-administration, varenicline reduced tonic craving as well as craving across the smoking and neutral cue conditions, relative to placebo. By contrast, the capacity of the smoking cue to enhance craving relative to the neutral cue was unaffected by varenicline. Measures of withdrawal and positive and negative affect produced mixed results. CONCLUSIONS: Acute varenicline selectively attenuates tonic but not cue-provoked craving. This dissociation provides insight into the specific psychological processes that might mediate the effectiveness of varenicline, and highlights cue-provoked craving as a discrete target for advancing smoking cessation pharmacotherapy.

A double-blind randomized placebo-controlled pilot study of neuropsychiatric adverse events in abstinent smokers treated with varenicline or placebo.

BACKGROUND: Varenicline is an α4ß2 partial nicotinic agonist approved for smoking cessation. There have been spontaneous postmarketing reports of neuropsychiatric adverse events (NPAEs) in smokers without a history of psychiatric illness quitting with varenicline. METHODS: One hundred ten smokers without history of psychiatric illness (screened by Structured Clinical Interview for DSM-IV) were randomized to 12 weeks of varenicline 1 mg twice daily (n = 55) or placebo. Adverse events were solicited systematically. Depressive symptoms, anxiety, aggression, and irritability were measured at baseline and weekly using the Montgomery-Åsberg Depression Rating Scale (MADRS), the Hamilton Anxiety Scale (HAM-A), and the Overt Aggression Scale-Modified (OAS-M). The Profile of Mood States (POMS) was administered daily. Mixed-model analysis of repeated measures was conducted to compare mean changes in scores between groups across study periods. RESULTS: Participants' mean baseline characteristics were 33 years of age, 22 cigarettes/day and Fagerström Test for Nicotine Dependence score > 7. Reported NPAEs were similar between groups. No suicidal events were reported. There were no significant differences between groups for the MADRS (treatment difference vs. placebo = .03, 95% confidence interval [CI] -.68-.73; NS), HAM-A (treatment difference [TD] = .14, 95% CI -.62-.90; NS), OAS-M Aggression subscale (TD = .5, 95% CI -1.18-2.18; NS), OAS-M Irritability subscale (TD = .08, 95% CI -.17-.34; NS), and the POMS total scores (TD = .5, 95% CI -.52-1.53; NS). CONCLUSIONS: There were no significant differences between groups on measures of depressive symptoms, anxiety, or aggression/hostility. Systematically solicited NPAEs were similar between the varenicline and placebo groups.

Esophageal intramural pseudodiverticulosis complicated with stricture.

We report a rare case of diffuse esophageal intramural pseudodiverticulosis in a 35-year-old man complaining of severe dysphagia and vomiting for several months. The advanced morphological change in the esophagus caused irregular track formation, mimicking an ulcerative lesion on esophagogram. Endoscopic examination revealed an esophageal stricture with intact mucosa. Endoscopic ultrasonography and chest computed tomography showed multiple hyperechoic lesions of unknown nature and multiple air collection sites in the esophageal wall, respectively, making diagnosis difficult. The patient finally received a subtotal esophagectomy because of severe symptoms. The lesion was pathologically proven to be intramural pseudodiverticulosis with marked submucosal fibrosis. Our experience suggests that awareness of this rare pathology and the related image changes will be helpful for early diagnosis and treatment in the future.

Genetic variants of IL-6 and its receptor are not associated with schizophrenia in Taiwan.

The pathophysiological process of schizophrenia is still unclear. The levels of interleukine-6 (IL-6) and its receptor, soluble IL-6R, have been reported to be elevated in the plasma and cerebrospinal fluid of schizophrenic patients. In this study, we tested the association of genetic variants of IL-6 and IL-6R with schizophrenia. Genotyping of three single nucleotide polymorphisms (SNP) for each IL-6 (IL-6-1, IL-6-2, and IL-6-3) and IL-6R (rs4845617=IL-6R1, rs4553185=IL-6R2, and rs4379670=IL-6R3) gene was performed in 100 patients with schizophrenia and 113 normal controls. The polymorphisms of IL-6R2 were genotyped using Tetra-primer ARMS PCR. IL-6R3 polymorphisms were genotyped using restriction fragment length polymorphism (RFLP) with Apo I enzyme as the restriction enzyme. All other polymorphisms were genotyped using the direct sequencing method. We found a di-nucleotide haplotype block and a tri-nucleotide haplotype block in the genes of IL-6 and IL-6R, respectively. All six SNPs and their haplotypes failed to show a significant association with schizophrenia. The IL-6-2 SNP showed a nominally significant association with the positive symptoms of schizophrenia (p=0.0472). We conclude that the genetic variants of IL-6 and IL-6R are not associated with schizophrenia. In order to verify this result, further study using a larger sample size and exploring the association between the genotype of IL-6-2 and plasma level of IL-6 is recommended.

Sildenafil citrate improves erectile function and urinary symptoms in men with erectile dysfunction and lower urinary tract symptoms associated with benign prostatic hyperplasia: a randomized, double-blind trial.

PURPOSE: We evaluated sildenafil for erectile dysfunction and lower urinary tract symptoms in men with the 2 conditions. MATERIALS AND METHODS: This was a 12-week, double-blind, placebo controlled study of sildenafil in men 45 years or older who scored 25 or less on the erectile function domain of the International Index of Erectile Function and 12 or greater on the International Prostate Symptom Score. Men with confirmed or suspected prostate malignancy, or prostate specific antigen 10 ng/ml or more were excluded. End points were changes in International Index of Erectile Function domain scores, International Prostate Symptom Score (irritative, obstructive and quality of life), the Benign Prostatic Hyperplasia Impact Index, the Self-Esteem And Relationship questionnaire and Erectile Dysfunction Inventory of Treatment Satisfaction Index Score. RESULTS: The 189 men receiving sildenafil had significant improvements in erectile function domain score vs the 180 on placebo (9.17 vs 1.86, p<0.0001) and on all other International Index of Erectile Function domains. In men on sildenafil vs placebo significant improvements were observed in International Prostate Symptom Score (-6.32 vs -1.93, p<0.0001), Benign Prostatic Hyperplasia Impact Index (-2.0 vs -0.9, p<0.0001), mean International Prostate Symptom Score quality of life score (-0.97 vs -0.29, p<0.0001) and total Self-Esteem And Relationship questionnaire scores (24.6 vs 4.3, p<0.0001). There was no difference in urinary flow between the groups (p=0.08). Significantly more sildenafil vs placebo treated patients were satisfied with treatment (71.2 vs 41.7, p<0.0001). Sildenafil was well tolerated. CONCLUSIONS: Improved erectile dysfunction and lower urinary tract symptoms with sildenafil in men with the 2 conditions were associated with improved quality of life and treatment satisfaction. Daily dosing with sildenafil may improve lower urinary tract symptoms. However, the lack of effect on urinary flow rates may mean that a new basic pathophysiology paradigm is needed to explain the etiology of lower urinary tract symptoms.