Haemophilia B, or factor IX deficiency, is a X-linked recessive disorder that occurs in about one in 25,000 males, and severely affected people are at risk for spontaneous bleeding into numerous ...organs. Bleeding can be life-threatening or lead to chronic disabilities with haemophilic arthropathy. The severity of the bleeding tendency varies among patients and is related to the concentration of functional plasma factor IX. Patients with 5-30% of the normal factor IX have mild haemophilia that may not be recognized until adulthood or after heavy trauma or surgery. Therapy for acute bleeding consists of the transfusion of clotting-factor concentrates prepared from human blood and recombinant clotting factors that are currently in clinical trials. Both recombinant retroviral and adenoviral vectors have successfully transferred factor IX cDNA into the livers of dogs with haemophilia B. Recombinant retroviral-mediated gene transfer results in persistent yet subtherapeutic concentrations of factor IX and requires the stimulation of hepatocyte replication before vector administration. Recombinant adenoviral vectors can temporarily cure the coagulation defect in the canine haemophilia B model; however, an immune response directed against viral gene products made by the vector results in toxicity and limited gene expression. The use of recombinant adeno-associated virus (rAAV) vectors is promising because the vector contains no viral genes and can transduce non-dividing cells. The efficacy of in vivo transduction of non-dividing cells has been demonstrated in a wide variety of tissues. In this report, we describe the successful transduction of the liver in vivo using r-AAV vectors delivered as a single administration to mice and demonstrate that persistent, curative concentrations of functional human factor IX can be achieved using wild-type-free and adenovirus-free rAAV vectors. This demonstrates the potential of treating haemophilia B by gene therapy at the natural site of factor IX production.
Hypertension after treatment with vascular endothelial growth factor (VEGF) receptor inhibitors is associated with superior treatment outcomes for advanced cancer patients. To determine whether ...increased sorafenib doses cause incremental increases in blood pressure (BP), we measured 12‐h ambulatory BP in 41 normotensive advanced solid tumor patients in a randomized dose‐escalation study. After 7 days’ treatment (400 mg b.i.d.), mean diastolic BP (DBP) increased in both study groups. After dose escalation, group A (400 mg t.i.d.) had marginally significant further increase in 12‐h mean DBP (P = 0.053), but group B (600 mg b.i.d.) did not achieve statistically significant increases (P = 0.25). Within groups, individuals varied in BP response to sorafenib dose escalation, but these differences did not correlate with changes in steady‐state plasma sorafenib concentrations. These findings in normotensive patients suggest BP is a complex pharmacodynamic biomarker of VEGF inhibition. Patients have intrinsic differences in sensitivity to sorafenib's BP‐elevating effects.
Clinical Pharmacology & Therapeutics (2014); 96 1, 27–35. doi:10.1038/clpt.2014.63
Sexual and physical abuse predict cardiovascular disease (CVD) among women in the general population. Women living with HIV (WLWH) report more abuse and have higher CVD risk compared with other ...women, yet associations between abuse history and CVD have not been considered among WLWH. This study fills this gap, and describes possible pathways linking abuse to CVD risk among WLWH and women living without HIV (WLWOH).
Using 25 years of data from the Women's Interagency HIV Study (WIHS; n = 2734; WLWH n = 1963; WLWOH n = 771), we used longitudinal generalized estimating equations (GEE) to test associations between sexual and physical abuse with CVD risk. Framingham (FRS-H) and the American College of Cardiology/American Heart Association-Pooled Cohort Equation (ACC/AHA-PCE) scores were examined. Analyses were stratified by HIV-serostatus.
Among WLWH, childhood sexual abuse was associated with higher CVD risk ( βFRS-H = 1.25, SE = 1.08, P = 0.005; βACC/AHA-PCE = 1.14, SE = 1.07, P = 0.04) compared with no abuse. Adulthood sexual abuse was associated with higher CVD risk for WLWH ( βFRS-H = 1.39, SE = 1.08, P < 0.0001) and WLWOH ( βFRS-H = 1.58, SE = 1.14, P = 0.0006). Childhood physical abuse was not associated with CVD risk for either group. Adulthood physical abuse was associated with CVD risk for WLWH ( βFRS-H = 1.44, SE = 1.07; P < 0.0001, βACC/AHA-PCE = 1.18, SE = 1.06, P = 0.002) and WLWOH ( βFRS-H = 1.68, SE = 1.12, P < 0.0001; βACC/AHA-PCE = 1.24, SE = 1.11, P = 0.03). Several pathway factors were significant, including depression, smoking, and hepatitis C infection.
Life course abuse may increase CVD risk among WLWH and women at high risk of acquiring HIV. Some comorbidities help explain the associations. Assessing abuse experiences in clinical encounters may help contextualize cardiovascular risk among this vulnerable population and inform intervention.
AGA Institute Review of Endoscopic Sedation Cohen, Lawrence B; DeLegge, Mark H; Aisenberg, James ...
Gastroenterology (New York, N.Y. 1943),
08/2007, Letnik:
133, Številka:
2
Journal Article
More than 90,000 patients with ESRD die annually in the United States, yet advance care planning (ACP) is underutilized. Understanding patients' and families' diverse needs can strengthen systematic ...efforts to improve ACP.
In-depth interviews were conducted with a purposive sample of patients and family/friends from dialysis units at two study sites. Applying grounded theory, interviews were audiotaped, professionally transcribed, and analyzed in an iterative process. Emergent themes were identified, discussed, and organized into major themes and subthemes.
Thirteen patients and nine family/friends participated in interviews. The mean patient age was 63 years (SD 14) and five patients were women. Participants identified as black (n=1), Hispanic (n=4), Native American (n=4), Pacific Islander (n=1), white (n=11), and mixed (n=1). Three major themes with associated subthemes were identified. The first theme, "Prior experiences with ACP," revealed that these discussions rarely occur, yet most patients desire them. A potential role for the primary care physician was broached. The second theme, "Factors that may affect perspectives on ACP," included a desire for more of a connection with the nephrologist, positive and negative experiences with the dialysis team, disenfranchisement, life experiences, personality traits, patient-family/friend relationships, and power differentials. The third theme, "Recommendations for discussing ACP," included thoughts on who should lead discussions, where and when discussions should take place, what should be discussed and how.
Many participants desired better communication with their nephrologist and/or their dialysis team. A number expressed feelings of disenfranchisement that could negatively impact ACP discussions through diminished trust. Life experiences, personality traits, and relationships with family and friends may affect patient perspectives regarding ACP. This study's findings may inform clinical practice and will be useful in designing prospective intervention studies to improve patient and family experiences at the end of life.
Background Transradial access is a recently developed alternative for diagnostic cardiac catheterization. Its effects on quality of life after the procedure, patient preference, and cost are unknown.
...Methods and Results We performed a randomized single-center trial in which 99 patients underwent transfemoral and 101 underwent transradial diagnostic cardiac catheterization. Quality of life was measured with the SF-36 and visual analog scales at baseline, 1 day, and 1 week. Patients were examined at 1 day and at 1 week after for complications. Costs were measured prospectively. One patient in the femoral group and 2 in the radial group crossed over to the alternative access site. There were no major access site complications. One patient in the transfemoral group had a minor stroke. Transradial catheterization significantly reduced median length of stay (3.6 vs 10.4 hours,
P < .0001). Over the first day after the procedure, measures of bodily pain, back pain, and walking ability favored the transradial group (
P <.05 for all comparisons). Over the week after the procedure, changes in role limitations caused by physical health, bodily pain, and back pain favored the transradial group (
P < .05 for all comparisons). There was a strong patient preference for transradial catheterization as well (
P < .0001). Transradial catheterization led to significant reductions in bed, pharmacy, and total hospital costs ($2010 vs $2299,
P < .0001).
Conclusions Among patients undergoing diagnostic cardiac catheterization, transradial access leads to improved quality of life after the procedure, is strongly preferred by patients, and reduces hospital costs. (Am Heart J 1999;138:430-6.)
Identifying novel molecular drivers of disease progression in heart failure (HF) is a high-priority goal that may provide new therapeutic targets to improve patient outcomes. The authors investigated ...the relationship between plasma proteins and adverse outcomes in HF and their putative causal role using Mendelian randomization.
The authors measured 4776 plasma proteins among 1964 participants with HF with a reduced left ventricular ejection fraction enrolled in PHFS (Penn Heart Failure Study). Assessed were the observational relationship between plasma proteins and (1) all-cause death or (2) death or HF-related hospital admission (DHFA). The authors replicated nominally significant associations in the Washington University HF registry (N=1080). Proteins significantly associated with outcomes were the subject of 2-sample Mendelian randomization and colocalization analyses. After correction for multiple testing, 243 and 126 proteins were found to be significantly associated with death and DHFA, respectively. These included small ubiquitin-like modifier 2 (standardized hazard ratio sHR, 1.56;
<0.0001), growth differentiation factor-15 (sHR, 1.68;
<0.0001) for death, A disintegrin and metalloproteinase with thrombospondin motifs-like protein (sHR, 1.40;
<0.0001), and pulmonary-associated surfactant protein C (sHR, 1.24;
<0.0001) for DHFA. In pathway analyses, top canonical pathways associated with death and DHFA included fibrotic, inflammatory, and coagulation pathways. Genomic analyses provided evidence of nominally significant associations between levels of 6 genetically predicted proteins with DHFA and 11 genetically predicted proteins with death.
This study implicates multiple novel proteins in HF and provides preliminary evidence of associations between genetically predicted plasma levels of 17 candidate proteins and the risk for adverse outcomes in human HF.
Investigate whether adjuvant everolimus, an mTOR inhibitor, improves progression-free survival (PFS) in advanced-stage head and neck squamous cell carcinoma (HNSCC) and provide outcomes related to ...correlative biological factors associated with disease control.
This was a prospective, randomized, double-blind phase II trial of patients with advanced-stage HNSCC from 13 institutions who were confirmed disease-free post-definitive therapy and enrolled between December 2010 and March 2015. Patients received adjuvant everolimus or placebo daily (10 mg, oral) for a maximum of 1 year. p16 IHC as a surrogate marker for human papillomavirus infection and whole-exome sequencing were performed. Cox proportional hazard models estimated hazard rates. Log-rank tests evaluated differences in survival. The primary endpoint was PFS. Secondary endpoints and objectives included overall survival (OS) and toxicity assessment.
52 patients median (range) age, 58 (37-76) years; 43 men (83%), 9 women (17%) were randomized to placebo (n = 24) or everolimus (n = 28). PFS favored everolimus, but was not significant log-rank P = 0.093; HR = 0.44; 95% confidence interval (CI), 0.17-1.17. There was no difference in OS (P = 0.29; HR = 0.57; 95% CI, 0.20-16.2). Everolimus resulted in significant improvement in PFS for p16-negative patients (n = 31; P = 0.031; HR = 0.26; 95% CI, 0.07-0.97), although subgroup analysis showed no difference for p16-positive patients (n = 21; P = 0.93). Further, PFS was significantly higher in TP53-mutated (TP53mut) patients treated with everolimus compared with placebo (log-rank P = 0.027; HR = 0.24; 95% CI, 0.06-0.95). No treatment difference was seen in patients with TP53 wild-type tumors (P = 0.79).
p16-negative and TP53mut patients may benefit from adjuvant treatment with everolimus.
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