Consistent survival in consecutive cases of life-supporting porcine kidney xenotransplantation using 10GE source pigs.

Xenotransplantation represents a possible solution to the organ shortage crisis and is an imminent clinical reality with long-term xenograft survival in pig-to-nonhuman primate (NHP) heart and kidney large animal models, and short-term success in recent human decedent and clinical studies. However, concerns remain about safe clinical translation of these results, given the inconsistency in published survival as well as key differences between preclinical procurement and immunosuppression and clinical standards-of-care. Notably, no studies of solid organ pig-to-NHP transplantation have achieved xenograft survival longer than one month without CD40/CD154 costimulatory blockade, which is not currently an FDA-approved immunosuppression strategy. We now present consistent survival in consecutive cases of pig-to-NHP kidney xenotransplantation, including long-term survival after >3 hours of xenograft cold preservation time as well as long-term survival using FDA-approved immunosuppression. These data provide critical supporting evidence for the safety and feasibility of clinical kidney xenotransplantation. Moreover, long-term survival without CD40/CD154 costimulatory blockade may provide important insights for immunosuppression regimens to be considered for first-in-human clinical trials.

Physiological Basis for Xenotransplantation from Genetically-Modified Pigs to Humans: A Review.

The collective efforts of scientists over multiple decades have led to advancements in molecular and cellular biology-based technologies including genetic engineering and animal cloning, that are now being harnessed to enhance the suitability of pig organs for xenotransplantation into humans. Using organs sourced from pigs with multiple gene deletions and human transgene insertions, investigators have overcome formidable immunological and physiological barriers in pig-to-non-human primate (NHP) xenotransplantation and achieved prolonged pig xenograft survival. These studies informed the design of Revivicor's (Revivicor Inc, Blacksburg, VA) genetically engineered pig with 10 genetic modifications (10 GE) (including the inactivation of 4 endogenous porcine genes and insertion of 6 human transgenes) whose hearts and kidneys have now been studied in preclinical human xenotransplantation models using brain-dead recipients. Additionally, the first two clinical cases of pig-to-human heart xenotransplantation were recently performed using hearts from this 10 GE pig at the University of Maryland. While this review focuses on xenotransplantation of hearts and kidneys, multiple organs, tissues, and cell-types from genetically engineered pigs will provide much-needed therapeutic interventions in the future.

Study design and rationale for the TETON phase 3, randomised, controlled clinical trials of inhaled treprostinil in the treatment of idiopathic pulmonary fibrosis.

INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) greatly impacts quality of life and eventually leads to premature death from respiratory failure. Inhaled treprostinil was associated with improvements in forced vital capacity (FVC) and reduced exacerbations of underlying lung disease in post hoc analyses from a phase 3 study in patients with precapillary pulmonary hypertension due to interstitial lung disease. These results, combined with preclinical evidence of treprostinil's antifibrotic activity, support its investigation in the treatment of IPF. METHODS AND ANALYSIS: The TETON programme consists of two replicate, 52-week, randomised, double-blind placebo-controlled, phase 3 studies, each enrolling 396 subjects (NCT04708782, NCT05255991). Eligible subjects must have a diagnosis of IPF confirmed by central imaging review, along with an FVC ≥45%. Stable background use of pirfenidone or nintedanib is allowed. The primary endpoint is change in absolute FVC at week 52. Secondary endpoints include time to clinical worsening (first event of death, respiratory hospitalisation or ≥10% decline in % predicted FVC), time to first acute exacerbation of IPF, overall survival, change in % predicted FVC and change in the King's Brief Interstitial Lung Disease Questionnaire at week 52. Safety parameters include adverse events, hospitalisations, oxygenation and laboratory parameters. Patients who complete week 52 will be eligible to enter an open-label extension study. ETHICS AND DISSEMINATION: Studies will be conducted in accordance with the International Conference on Harmonisation Guideline for Good Clinical Practice, Declaration of Helsinki principles, and local regulatory, ethical and legal requirements. Results will be published in a peer-reviewed publication.

Inhaled Treprostinil in Pulmonary Hypertension Due to Interstitial Lung Disease.

BACKGROUND: No therapies are currently approved for the treatment of pulmonary hypertension in patients with interstitial lung disease. The safety and efficacy of inhaled treprostinil for patients with this condition are unclear. METHODS: We enrolled patients with interstitial lung disease and pulmonary hypertension (documented by right heart catheterization) in a multicenter, randomized, double-blind, placebo-controlled, 16-week trial. Patients were assigned in a 1:1 ratio to receive inhaled treprostinil, administered by means of an ultrasonic, pulsed-delivery nebulizer in up to 12 breaths (total, 72 µg) four times daily, or placebo. The primary efficacy end point was the difference between the two groups in the change in peak 6-minute walk distance from baseline to week 16. Secondary end points included the change in N-terminal pro-B-type natriuretic peptide (NT-proBNP) level at week 16 and the time to clinical worsening. RESULTS: A total of 326 patients underwent randomization, with 163 assigned to inhaled treprostinil and 163 to placebo. Baseline characteristics were similar in the two groups. At week 16, the least-squares mean difference between the treprostinil group and the placebo group in the change from baseline in the 6-minute walk distance was 31.12 m (95% confidence interval [CI], 16.85 to 45.39; P<0.001). There was a reduction of 15% in NT-proBNP levels from baseline with inhaled treprostinil as compared with an increase of 46% with placebo (treatment ratio, 0.58; 95% CI, 0.47 to 0.72; P<0.001). Clinical worsening occurred in 37 patients (22.7%) in the treprostinil group as compared with 54 patients (33.1%) in the placebo group (hazard ratio, 0.61; 95% CI, 0.40 to 0.92; P = 0.04 by the log-rank test). The most frequently reported adverse events were cough, headache, dyspnea, dizziness, nausea, fatigue, and diarrhea. CONCLUSIONS: In patients with pulmonary hypertension due to interstitial lung disease, inhaled treprostinil improved exercise capacity from baseline, assessed with the use of a 6-minute walk test, as compared with placebo. (Funded by United Therapeutics; INCREASE ClinicalTrials.gov number, NCT02630316.).

Long-term results of the DelIVery for Pulmonary Arterial Hypertension trial.

BACKGROUND: The DelIVery for Pulmonary Arterial Hypertension clinical trial was a multi-center, prospective, single arm, Investigational Device Exemption study utilizing a fully implantable, programmable intravascular delivery system consisting of a pump and a catheter for intravenous treprostinil. The study met its primary endpoint and demonstrated that the intravascular delivery system significantly reduced catheter related complications at 22,000 subject-days of follow-up compared with a predefined objective performance criterion. Here we summarize the results obtained during a 6.4-year follow-up period. METHODS: Throughout study follow-up, participants had clinic visits and medication refills at least every 12 weeks (dependent on the subjects' dose). All adverse events and intravascular delivery system complications were evaluated and recorded. RESULTS: Sixty pulmonary arterial hypertension subjects were followed post device implantation for approximately 282 patient-years (range 87 days to 6.4 years). Of the 60 subjects, 14 died (1 related to intravascular delivery system pump failure), 2 withdrew after lung transplants, and 2 withdrew due to pump pocket infection. No catheter-related bloodstream infections, catheter thrombosis or occlusions, or catheter kinks occurred through 282 patient-years. Two participants had adverse events of abdominal pain, rash, due to subcutaneous treprostinil "leaks" after one catheter puncture and one catheter laceration during pump refill and replacement, respectively. Eight pump failure events occurred: seven pump motor stalls and one early replacement (faulty battery). CONCLUSION: Delivery of treprostinil with an intravascular delivery system is a safe alternative to an external delivery system, while providing enhanced life experiences. To preserve the risk-benefit ratio, treatment at specialized pulmonary arterial hypertension centers is recommended until training is disseminated at other sites.

Nutrient Deficiencies Are Common Prior to Bariatric Surgery.

Obesity, defined as a body mass index >30 kg/m2, is a growing worldwide epidemic currently effecting 1 in 10 adults, with rates as high as 40% in the United States. The only proven long-term treatment of severe obesity on a population level is surgical modification of the gastrointestinal anatomy to induce weight loss, termed bariatric surgery. With adequate physician guidance and appropriate candidate criteria, bariatric surgery is an option for effective long-term treatment of obesity and its related comorbidities. Complications of bariatric surgery can be seen in patients who are not compliant to the recommended lifestyle and dietary changes required following bariatric surgery, including nausea, vomiting, dumping syndrome, acid reflux, and nutrition deficiencies. Despite caloric density, the diet of patients prior to bariatric surgery is often of poor nutrition quality and does not meet recommended dietary guidelines for micronutrient intake, making this an at-risk population for micronutrient malnutrition. Currently, improvements are needed in standardization of nutrition assessment as well as micronutrient cutoffs for deficiency and insufficiency. In the meantime, utilizing our current tools to conduct nutrition assessment at baseline and implement supplementation where necessary may improve the nutrition status of patients undergoing bariatric surgery, both before and after surgery, which may improve their surgical outcomes.

Totally Implantable IV Treprostinil Therapy in Pulmonary Hypertension Assessment of the Implantation Procedure.

BACKGROUND: Prostacyclins improve symptoms and survival in pulmonary arterial hypertension (PAH). In response to risks associated with external delivery systems, an implantable IV infusion system was developed. A multicenter, prospective, single-arm, clinical trial (DelIVery for PAH) was conducted to evaluate this system for treprostinil in PAH. This analysis describes the findings related to the implant procedure. METHODS: Patients (N = 64) with PAH (World Health Organization group 1) receiving stable IV treprostinil were enrolled. Patients were transitioned to a temporary peripheral IV infusion catheter prior to the procedure. System implantation was performed at 10 centers under general anesthesia or deep IV sedation by clinicians from various specialties. Central venous access was via the cephalic, subclavian, jugular, or axillary vein. Using an introducer and fluoroscopic guidance, the distal tip of the infusion catheter was placed at the superior caval-atrial junction. The catheter was tunneled from the venous access site to an abdominal subcutaneous pocket, where the pump was placed. RESULTS: Of the 64 patients enrolled, four exited prior to implantation. All 60 implant procedures were successful. At baseline, all patients were receiving treprostinil via an external pump at a mean dose of 71.4 ± 27.8 ng/kg/min (range: 22-142 ng/kg/min). The implant averaged 102 ± 32 min (range: 47-184 min). Clinically significant implant procedure-related complications included one pneumothorax, two infections, and one episode of atrial fibrillation. There were three postimplantation catheter dislocations in two patients. Common implant-related events that were not complications included implant site pain (83%) and bruising (17%). CONCLUSIONS: The procedure for inserting a fully implantable system for treprostinil was successfully performed, with few complications. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01321073; URL: www.clinicaltrials.gov.

Treprostinil Administered to Treat Pulmonary Arterial Hypertension Using a Fully Implantable Programmable Intravascular Delivery System: Results of the DelIVery for PAH Trial.

BACKGROUND: The use of systemic prostanoids in severe pulmonary arterial hypertension (PAH) is often limited by patient/physician dissatisfaction with the delivery methods. Complications associated with external pump-delivered continuous therapy include IV catheter-related bloodstream infections and subcutaneous infusion site pain. We therefore investigated a fully implantable intravascular delivery system for treprostinil infusion. METHODS: A multicenter, prospective, single-arm, clinical trial (DelIVery for Pulmonary Arterial Hypertension) was conducted by using an implantable intravascular delivery system. The implanted pumps were refilled percutaneously at least every 12 weeks. The primary end point was the rate of catheter-related complications using the new model 10642 catheter compared with a predefined objective performance criterion of 2.5 per 1,000 patient-days based on the literature. RESULTS: Patients (n = 60) with severe PAH (World Health Organization group 1) receiving a stable dose of IV treprostinil for at least 4 weeks received an implant device and were followed up for 12.1 ± 4.4 months. Six catheter-related complications occurred, corresponding to a complication rate of 0.27 per 1,000 patient-days. The 97.5% upper one-sided confidence bound of 0.59 was less than the predefined criterion of 2.5 per 1,000 patient-days (P < .0001). Plasma treprostinil levels at 1 week postimplantation were highly correlated with baseline levels (r = 0.91; P < .0001). The delivery system management time as reported by the patients was 2.5 ± 1.7 hours per week preimplantation, and this time decreased to 0.6 ± 0.8 hour per week at 6 months' postimplantation (P < .0001). All patients rated overall satisfaction with the implantable system as good, very good, or excellent at 6 weeks and 6 months. There were no catheter-related bloodstream infections or catheter occlusions. CONCLUSIONS: The implantable intravascular delivery system delivered treprostinil to patients with PAH with a low rate of catheter-related complications and a high rate of patient satisfaction. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01321073; URL: www.clinicaltrials.gov.

Bariatric surgery and vitamin D: key messages for surgeons and clinicians before and after bariatric surgery.

Obesity is the most widespread nutritional problem globally. Bariatric surgery is the preeminent long-term obesity treatment. Bariatric procedures manipulate the intestines to produces malabsorption and/or restrict the size of the stomach. The most enduring bariatric procedure is the Roux-en-Y gastric bypass, which utilizes both restriction (small stomach pouch) and malabsorption (duodenum bypass). The in-vogue procedure is the vertical sleeve gastrectomy - resection of the greater curvature of the stomach (predominantly restrictive). Malabsorptive procedures function by decreasing nutrient absorption, primarily fat and fat-soluble nutrients (vitamins A, D, E, and K). Most studies of vitamin D status in bariatric surgery candidates reported a prevalence of over 50% vitamin D deficiency (<50 nmol/L), enduring post-operatively with one study reporting 65% deficient at 10 years post-bariatric surgery. Obesity is associated with chronic inflammation, which may contribute to adverse surgical outcomes, e.g. poor healing and infection. Since vitamin D deficiency is also associated with chronic inflammation, obese individuals with vitamin D deficiency have extraordinary risk of adverse surgical outcomes, particularly delayed wound healing and infection due to the role of vitamin D in re-epithelialization and innate immunity. When the risk of adverse surgical outcomes in obesity is combined with that of vitamin D deficiency, there is likely an additive or potentially a synergistic effect. Furthermore, deficiency in fat-soluble vitamins, such as vitamin D, is considered a metabolic complication of bariatric surgery. Thus, determining the vitamin D status of bariatric surgery candidates and amending it preoperatively may prove greatly beneficial acutely and lifelong.

Vitamin D status and supplementation before and after bariatric surgery: a comprehensive literature review.

BACKGROUND: Bariatric surgery is the most effective long-term weight loss method. The most common procedures are Roux-en-Y gastric bypass (RYGB) and vertical sleeve gastrectomy (VSG). Bariatric patients are at high risk of vitamin D deficiency (VDD) and insufficiency (VDI), which are associated with skeletal and nonskeletal ailments. There is no consensus regarding the optimal treatment for VDD/VDI in bariatric patients. OBJECTIVES: To critically examine the literature on vitamin D status (serum 25[OH]D concentrations) pre- and postbariatric surgery as well as supplementation regimens currently used. METHODS: We searched PubMed, Embase, and Cochrane from inception to May 2015 for articles relating to vitamin D, RYGB, and VSG. Of 208 citations retrieved, 30 were included. RESULTS: Preoperative VDD (<20 ng/mL) ranged from 13% to 90%, while VDI (<30 ng/mL) was found in up to 98%. Prevalence remained similar postoperatively and was highest after RYGB. Most studies found dosages<800 IU daily insufficient postbariatric surgery. Other studies examined the effectiveness of dosages between 1000 and 5000 IU daily, reaching similar conclusions. Several studies suggested using 50,000 IU weekly plus a daily dose. No studies reported optimization. CONCLUSIONS: It is widely accepted that serum 25(OH)D concentrations above 30 ng/mL are optimal; however, current postbariatric vitamin D supplementation fails to raise 25(OH)D above that level universally. This review highlights both the great need and the lack of consensus on the optimal supplementation regimen (dosage and frequency) for pre- and postbariatric patients. Future studies should investigate multiple regimens and attempt to identify methods for personalizing these regimens if found necessary.

Treatment for Vitamin D Deficiency Prior to Bariatric Surgery: a Prospective Cohort Study.

BACKGROUND: Since obesity increases vitamin D deficiency (VDD) risk, bariatric surgery candidates are high-risk. Previously, we documented 71.4% VDD at our center. OBJECTIVES: To investigate diagnosis and treatment for VDD in our bariatric candidates. METHODS: 25(OH)D, if pending, and supplementation (form, dosing, frequency) were prospectively documented in 265 candidates. RESULTS: Candidates were 83.0% female, 48.9% white, age 43 ± 13 years and BMI 46.3 ± 10.5 kg/m(2). 25(OH)D was available for 18.5%: 35.7% VDD 39.3% insufficiency. VDD history did not differ by demographics or procedure, as with those tested versus not. CONCLUSION: VDD testing was lower than clinically-indicated. Of those tested, 35.7% were deficient and 39.3% insufficient. We previously reported higher rates: 71.4% deficiency, 92.9% insufficiency. Thus, many candidates are untested but high-risk.

C1q/TNF-Related Protein-9 (CTRP9) Levels Are Associated With Obesity and Decrease Following Weight Loss Surgery.

CONTEXT: C1q/TNF-related protein-9 (CTRP9) is a novel adipokine that has beneficial metabolic and cardiovascular effects in various animal models. Alterations in circulating CTRP9 have also been observed in patients with cardiovascular disease and diabetes, but little is known about the impact of obesity and bariatric surgery on CTRP9 concentrations. OBJECTIVE: The aim of this study was to compare CTRP9 levels in obese and lean subjects and to determine whether circulating CTRP9 levels in morbidly obese patients are altered by bariatric surgery. DESIGN, SETTING, AND PARTICIPANTS: Fifty-nine obese bariatric surgical patients and 62 lean controls were recruited to participate in a cross-sectional study at an academic medical center. The obese patients were further invited to participate in a cohort study, and 21 returned for analysis at 3 and 6 months postsurgery. INTERVENTION: Bariatric surgery (Roux-en-Y gastric bypass and vertical sleeve gastrectomy) was the intervention for this study. MAIN OUTCOME MEASURES: Fasting serum was obtained from all subjects on entry to the study and was analyzed in the core laboratory for hemoglobin A1c, glucose, aspartate aminotransferase, alanine aminotransferase, total cholesterol, high- and low-density lipoprotein cholesterol, and triglycerides; CTRP9, insulin, adiponectin, and leptin were measured by ELISA. Serum from the patients in the cohort study was also analyzed at 3 and 6 months. RESULTS: Serum CTRP9 was significantly higher in the obese group compared to the lean group. CTRP9 was associated with obesity, even after controlling for age, gender, and ethnicity. Following bariatric surgery, there was a significant decrease in weight at 3 and 6 months postprocedure, accompanied by decreases in CTRP9, hemoglobin A1c and leptin, and an increase in serum adiponectin. CONCLUSIONS: CTRP9 levels are elevated in obesity and significantly decrease following weight loss surgery. Our data suggest that CTRP9 may play a compensatory role in obesity, similar to that of insulin, and is down-regulated following weight loss surgery.

Malnutrition in Bariatric Surgery Candidates: Multiple Micronutrient Deficiencies Prior to Surgery.

BACKGROUND: Over 78 million American adults have obesity. Bariatric surgery is the leading means of durable weight loss. Nutritional deficiencies are commonly treated post-operatively but are often undiagnosed pre-operatively. Malnutrition is correlated with adverse surgical outcomes. OBJECTIVES: The aim of this study is to assess pre-operative nutritional status in our bariatric surgery candidates in a cross-sectional study. METHODS: We recruited 58 bariatric candidates approved to undergo the Roux-en Y gastric bypass. Nutritional status was determined for vitamins A, B12, D, E-α, and E-ß/γ as well as thiamine, folate, and iron. We used clinical as well as frank deficiency cut-offs based on the Institute of Medicine and the World Health Organization guidelines. RESULTS: This cohort was largely female (77.6%) and white (63.8%). Median age was 42.2 years. Median body mass index (BMI) was 46.3 kg/m(2). Multiple comorbidities (MCM) were present in 41.4%, 54.0% hypertension, 42.0% diabetic, 34.0% sleep apnea. Men had more comorbidities, 69.2 % with MCM. Folate and iron saturation varied significantly by sex. Vitamins A, D, E-α, and thiamine significantly varied by race. Vitamin D negatively correlated with BMI (p = 0.003) and age (p = 0.030). Vitamin A negatively correlated with age (p = 0.001) and number of comorbidities (p = 0.003). These pre-operative bariatric candidates had significant malnutrition, particularly in vitamin D (92.9%) and iron (36.2 to 56.9 %). Multiple micronutrient deficiency (MMND) was more common in blacks (50.0 versus 39.7% overall). Number of comorbidities did not correlate with MMND. CONCLUSIONS: Malnutrition in one or multiple micronutrients is pervasive in this pre-operative bariatric cohort. The effect of pre-operative supplementation, especially vitamin D and iron, should be explored.

Lower Circulating C1q/TNF-Related Protein-3 (CTRP3) Levels Are Associated with Obesity: A Cross-Sectional Study.

PURPOSE: C1q/TNF-related protein-3 (CTRP3) is a novel adipokine that lowers blood glucose levels, reduces liver triglyceride synthesis, and is protective against hepatic steatosis in diet-induced obese mouse models. We hypothesized that higher circulating serum levels of CTRP3 would be associated with a lean body mass index (BMI) and a more favorable metabolic profile in humans. The aim of this study was to investigate CTRP3 levels in lean individuals compared to obese individuals. METHODS: This was a cross-sectional study of obese (n=44) and lean control patients (n=60). Fasting metabolic parameters were measured in all patients and serum CTRP3 levels were measured by ELISA. RESULTS: BMI of the lean group was 21.9 ± 0.2 kg/m2 and obese group was 45.2 ± 1.1 kg/m2. We found significantly lower circulating levels of CTRP3 in obese individuals (405 ± 8.3 vs. 436 ± 6.7 ng/mL, p=0.004) compared to the lean group. Serum CTRP3 levels were inversely correlated with BMI (p=0.001), and triglycerides (p<0.001), and significantly associated with gender (p<0.01), ethnicity (p=0.05), HDL-cholesterol (p<0.01), and adiponectin (p<0.01). We found BMI (p<0.01), gender (p<0.01), and ethnicity (p<0.05) to be significant predictors of CTRP3 levels when controlling for age in multiple regression analysis. CONCLUSIONS: CTRP3 is a beneficial adipokine whose circulating levels are significantly lower in obese individuals. Obesity causes dysregulation in adipokine production, including the down-regulation of CTRP3. Lower CTRP3 levels may contribute to the pathophysiology of metabolic disorders associated with obesity. Optimizing CTRP3 levels through novel therapies may improve obesity and its comorbidities.

Effect of Mandatory Centers of Excellence Designation on Demographic Characteristics of Patients Who Undergo Bariatric Surgery.

IMPORTANCE: From February 21, 2006, through September 24, 2013, the Centers for Medicare & Medicaid Services (CMS) required, via the National Coverage Determination manual, that bariatric surgery be performed only in hospitals that had been designated as a Center of Excellence (COE). The effect of this certification requirement on access to bariatric surgery has been reported only anecdotally. OBJECTIVE: To investigate whether the COE certification requirement proved to be a barrier to patients' access to bariatric surgical procedures. DESIGN, SETTING, AND PARTICIPANTS: Using the National Inpatient Sample, we retrospectively identified patients who underwent bariatric surgery from January 1, 2006, through December 31, 2011. EXPOSURE: Bariatric surgery. MAIN OUTCOMES AND MEASURES: Logistic regression and χ² tests were used to examine differences in patients' sociodemographic characteristics over time. RESULTS: A total of 134,227 bariatric surgical patients were identified. The proportion of the population who were older than 64 years increased from 2.9% in 2006 to 7.0% in 2011 (P < .001) and there was a decrease in the proportion of patients who were 49 years and younger (P < .001). The percentage of female patients who underwent bariatric surgery decreased from 80.4% to 78.1% (P < .001) and the percentage of patients who were classified as black, Hispanic, or Asian or Pacific Islander increased from 12.3% to 15.1% (P < .001), 9.7% to 12.5% (P < .001), and 0.3% to 0.4% (P < .001), respectively. The proportion of patients with Medicare increased from 8.5% to 16.3% (P < .001) and those with Medicaid from 6.6% to 11.8% (P < .001). The percentage of patients with private insurance declined from 72.4% to 63.3% (P < .001). The proportion of patients in the lowest income quartile increased from 20.7% to 22.9% (P < .001) while those in the highest income quartile decreased from 25.8% to 23.9% (P < .001). CONCLUSIONS AND RELEVANCE: The COE certification requirement by CMS did not appear to limit access to bariatric surgery. Future studies should determine whether CMS's recent (2013) change in policy (ie, removing the mandatory COE certification for bariatric surgical insurance coverage) might sacrifice patient safety without addressing the real cause of limited access to health care.

An eHealth Intervention for Patients in Rural Areas: Preliminary Findings From a Pilot Feasibility Study.

BACKGROUND: eHealth facilitation of chronic disease management has potential to increase engagement and effectiveness and extend access to care in rural areas. OBJECTIVE: The objective of this study was to demonstrate the feasibility and acceptability of an eHealth system for the management of chronic conditions in a rural setting. METHODS: We developed an online management program which incorporated content from the Flinders Chronic Condition Management Program (Flinders Program) and used an existing software platform (goACT), which is accessible by patients and health care workers using either Web-enabled mobile phone or Internet, enabling communication between patients and clinicians. We analyzed the impact of this eHealth system using qualitative and simple quantitative methods. RESULTS: The eHealth system was piloted with 8 recently hospitalized patients from rural areas, average age 63 (SD 9) years, each with an average of 5 chronic conditions and high level of psychological distress with an average K10 score of 32.20 (SD 5.81). Study participants interacted with the eHealth system. The average number of logins to the eHealth system by the study participants was 26.4 (SD 23.5) over 29 weeks. The login activity was higher early in the week. CONCLUSIONS: The pilot demonstrated the feasibility of implementing and delivering a chronic disease management program using a Web-based patient-clinician application. A qualitative analysis revealed burden of illness and low levels of information technology literacy as barriers to patient engagement.

Performance characteristics of upper airway critical collapsing pressure measurements during sleep.

OBJECTIVE: The critical pressure (P(CRIT)), a measurement of upper airway collapsibility, is a determinant of the severity of upper airway obstruction during sleep. We examined the performance characteristics of the passive and active P(CRIT) by examining both within-night and between-night variability in the measurements. METHODS: We studied 54 sleep apnea patients (39 men, 15 women) and 34 normal subjects (20 men, 14 women) on either 1 or 2 nights during sleep. The P(CRIT) was measured during relative hypotonia ("passive" state) or during periods of sustained upper airway obstruction used to recruit upper airway neuromuscular responses ("active" state) within- and between-nights. In a subgroup of 10 normal subjects, we performed repeated measurements during hypnotic-induced sleep. Bland-Altman analyses were used to determine the within-night and between-night reliability of the P(CRIT) measurements. RESULTS: There were no significant within-night or between-night differences for the mean passive P(CRIT). The active P(CRIT) was ∼1 cm H(2)O more collapsible on the second night than on the first night. The limits of agreement, which bound the passive and active P(CRIT), was ∼ ± 3 cm H(2)O and was reduced to ∼ ± 1 cm H(2)O for the passive P(CRIT) with hypnotic-induced sleep. CONCLUSION: Passive and active P(CRIT) measurements are reasonably reliable within and between nights. An approximately 3 cm H(2)O change in passive or active P(CRIT) appears to represent the minimally significant change in P(CRIT) necessary to assess the effect of an intervention (e.g., positional therapy, surgical interventions, oral appliance effects, and pharmacotherapy) on upper airway mechanical loads or neuromuscular responses.

Risk factors for incidence of sexually transmitted infections among women in South Africa, Tanzania, and Zambia: results from HPTN 055 study.

OBJECTIVE: To determine risk factors for sexually transmitted infections (STIs) among women in Durban and Hlabisa (South Africa), Moshi (Tanzania), and Lusaka (Zambia). STUDY DESIGN: Between 2003 and 2004, 958 women at risk of STIs were enrolled in a 1-year prospective study. They were interviewed at each monthly visit, and samples for STI testing were collected during quarterly and other visits when clinically indicated. RESULTS: The incidence of infections as measured in person-years at risk (PYAR) was as follows: overall trichomoniasis, 31.9/100 PYAR; chlamydial infection in South Africa, 19.5/100 PYAR; chlamydial infection in Tanzania and Zambia, 4.9/100 PYAR; gonorrhea in South Africa, 16.5/100 PYAR; gonorrhea in Tanzania and Zambia, 5.3/100 PYAR; overall syphilis, 7.5/100 PYAR; and overall HIV, 3.8/100 PYAR. The incidence of most STIs was highest among the South African sites, where chlamydial infection and gonorrhea were detected by using a more sensitive assay. Independent risk factors included age, hormonal contraceptive methods, and measures of sexual behavior, including number of sex partners and occurrence of anal sex in the past 3 months. Women with incident HIV infection were at increased risk of chlamydial infection [odds ratio (OR) = 5.5, 95% confidence interval (CI): 2.0-15.2]and gonorrhea (OR = 5.7, 95% CI: 1.9-17.0) in South African sites. Despite ongoing counseling during the study, high-risk sexual behaviors were common, and consistent condom use remained low. CONCLUSIONS: The incidence of STIs, including HIV, was high among women in this study. These findings highlight the urgent need for effective HIV/STI prevention programs in this population.

The value of site preparedness studies for future implementation of phase 2/IIb/III HIV prevention trials: experience from the HPTN 055 study.

OBJECTIVES: To evaluate the preparedness for phase 2/IIb/III microbicide trials at 4 clinical trial sites: Durban and Hlabisa (South Africa), Lusaka (Zambia), and Moshi (Tanzania). DESIGN: A prospective cohort study was undertaken to assess site suitability for microbicide efficacy studies. Study objectives included assessing sites' ability to recruit and retain high-risk women with the appropriate HIV incidence rates needed to conduct microbicide efficacy studies. METHODS: Nine hundred fifty-eight consenting women were enrolled and followed for up to 1 year. Demographic, behavioral, laboratory, and clinical data were collected to determine the incidence rates of HIV, sexually transmitted infections, and pregnancy. RESULTS: Accrual was completed in 6.3, 6.7, 7.1, and 8.3 months in Durban, Hlabisa, Moshi, and Lusaka, respectively. The highest month 12 participant retention rate was recorded in Durban (97%), followed by Hlabisa (94%), Moshi (86%), and Lusaka (93%). Mean overall age of enrolled participants was 28.6 years (ranging from 27.0 to 32.2 years) across sites. Despite condom counseling, rates of condom use were slightly lower at study end. Pregnancy incidence in the study as a whole was 20.2 per 100 women-years (wy). Overall HIV prevalence was 32.5%, and overall HIV incidence was 3.8 per 100 wy (95% confidence interval [CI]: 2.6 to 5.2). HIV incidence per site was 5.3 per 100 wy in Durban (95% CI: 2.7 to 9.2), 6.2 per 100 wy in Hlabisa (95% CI: 3.4 to 10.5); 2.6 per 100 wy in Lusaka (95% CI: 1.0 to 5.8), and 1.4 per 100 wy in Moshi (95% CI: 0.3 to 4.0). CONCLUSIONS: Preparatory studies provide accurate local estimates of HIV incidence, recruitment and retention rates, and behavioral characteristics of targeted populations for large-scale clinical trials. Determining these factors allows for better preparation for design, sample size, and appropriate population for future selection of trial sites. Because of the lower than expected HIV incidence observed at the Moshi site, only the South African and Zambian sites were selected for the phase 2/IIb trial.

SAVVY (C31G) gel for prevention of HIV infection in women: a Phase 3, double-blind, randomized, placebo-controlled trial in Ghana.

OBJECTIVE: The objective of this trial was to determine the effectiveness of 1.0% C31G (SAVVY) in preventing male-to-female vaginal transmission of HIV infection among women at high risk. METHODOLOGY/PRINCIPAL FINDINGS: This was a Phase 3, double-blind, randomized, placebo-controlled trial. Participants made up to 12 monthly visits for HIV testing, adverse event reporting, and study product supply. The study was conducted between March 2004 and February 2006 in Accra and Kumasi, Ghana. We enrolled 2142 HIV-negative women at high risk of HIV infection, and randomized them to SAVVY or placebo gel. Main outcome measures were the incidence of HIV-1 and HIV-2 infection as determined by detection of HIV antibodies from oral mucosal transudate specimens and adverse events. We accrued 790 person-years of follow-up in the SAVVY group and 772 person-years in the placebo group. No clinically significant differences in the overall frequency of adverse events, abnormal pelvic examination findings, or abnormal laboratory results were seen between treatment groups. However, more participants in the SAVVY group reported reproductive tract adverse events than in the placebo group (13.0% versus 9.4%). Seventeen HIV seroconversions occurred; eight in participants randomized to SAVVY and nine in participants receiving placebo. The Kaplan-Meier estimates of the cumulative probability of HIV infection through 12 months were 0.010 in the SAVVY group and 0.011 in the placebo group (p = 0.731), with a hazard ratio (SAVVY versus placebo) of 0.88 (95% confidence interval 0.33, 2.27). Because of a lower-than-expected HIV incidence, we were unable to achieve the required number of HIV infections (66) to obtain the desired study power. CONCLUSIONS/SIGNIFICANCE: SAVVY was not associated with increased adverse events overall, but was associated with higher reporting of reproductive adverse events. Our data are insufficient to conclude whether SAVVY is effective at preventing HIV infection relative to placebo. TRIAL REGISTRATION: ClinicalTrials.gov NCT00129532.