Predictors of mortality in patients undergoing percutaneous aortic valve implantation.

AIM: Transcatheter aortic valve implantation (TAVI) became an attractive alternative to surgery for patients with severe aortic stenosis and high operative risk. The first multicenter randomized trial, conducted in such high risk cohort, showed 20% reduction in mortality in the group treated with TAVI compared to those treated with medical therapy (30.7% vs. 50.7% P=0.001) and a non-inferiority of TAVI compared to traditional valve surgical replacement for all-cause mortality at 1 year with, similar improvement of symptoms and physical performance. However, mortality rate of TAVI remains high (20-30% at one year). The purpose of this prospective single center study was to identify predictors of mortality and adverse events in patients undergoing TAVI in order to be able to select the ones who benefit most from the procedure. METHODS: Between June 2009 and June of 2011, 118 patients with severe aortic stenosis treated with TAVI at IRCCS Humanitas Clinical Institute were included in a prospective registry. Pre procedural clinical and ecocardiographic evaluations, surgical risk estimation, and procedural complications, defined by VASC criteria, were recorded. Clinical and echocardiographic evaluations were performed at 1, 6 and 12 months after the implants. To investigate the predictors of mortality, clinical and anatomical characteristics of alive patients were compared with those of death ones at one month and one year follow-up. RESULTS: The procedural success occurred in 92.4% of procedures; vascular complications (33%), bleeding complications (22%), postimplant paravalvolar grade ≥2 AR (20.4%) a new permanent pacemaker implant (19.7%), were the most common complications. Survival for the whole cohort at 30 days was 6.8%, survival at one year was 82.2%. In the logistic regression test, one month mortality was significantly adversely affected by the renal functional status (odd ratio 0.9356), by a previous history of coronary artery bypass grafting (odd ratio 39) and by the mean aortic annular diameter (odd ratio 0.512) (P=0.0005). One year mortality was influenced by high EuroSCORE (odd ratio 1.0399) and the presence of hemodynamically significant prosthetic regurgitation (odd ratio 3.8438). CONCLUSION: TAVI procedure, in high risk patients with critical aortic stenosis, can be accomplished with low procedural mortality. The worst outcome affects particularly patients with renal insufficiency and previous coronary bypass. However, the long-term mortality remains high due to the poor baseline conditions, mainly related to co-morbidity and to the presence of residual post-procedural aortic insufficiency.

Extracorporeal photopheresis for the prevention of acute GVHD in patients undergoing standard myeloablative conditioning and allogeneic hematopoietic stem cell transplantation.

GVHD is partly mediated by host APCs that activate donor T cells. Extracorporeal photopheresis (ECP) can modulate APC function and benefit some patients with GVHD. We report the results of a study using ECP administered before a standard myeloablative preparative regimen intended to prevent GVHD. Grades II-IV acute GVHD developed in 9 (30%) of 30 recipients of HLA-matched related transplants and 13 (41%) of 32 recipients of HLA-matched unrelated or HLA-mismatched related donor transplants. Actuarial estimates of overall survival (OS) at day 100 and 1-year post transplant were 89% (95% CI, 78-94%) and 77% (95% CI, 64-86%), respectively. There were no unexpected adverse effects of ECP. Historical controls receiving similar conditioning and GVHD prophylaxis regimens but no ECP were identified from the database of the Center for International Blood and Marrow Transplant Research and multivariate analysis indicated a lower risk of grades II-IV acute GVHD in patients receiving ECP (P=0.04). Adjusted OS at 1 year was 83% in the ECP study group and 67% in the historical control group (relative risk 0.44; 95% CI, 0.24-0.80) (P=0.007). These preliminary data may indicate a potential survival advantage with ECP for transplant recipients undergoing standard myeloablative hematopoietic cell transplantation.

Anatomical patterns of patent foramen ovale (PFO): do they matter for percutaneous closure?

AIM: The aim of this study was to describe and classify the various anatomical pattern of patent foramen ovale (PFO) with transesophageal echocardiography (TEE) and to relate such classification to the selection of PFO closure devices. METHODS: This study enrolled 216 PFO patients (118 females) mostly with previous cryptogenic stroke or transitory ischemic attack (TIA) who underwent percutaneous closure of PFO with deep sedation under TEE control. Anatomical patterns were classified as follows: simple: PFO characterised by central/superior eccentric shunt or with a valve mechanism (45%); reduse: widely redundant septum primum (22%); ASA: atrial septal aneurysm (11%); EASA: entire atrial septal aneurysm (1.4%); CRIB: cribriform septum primum (9%); tunnel: tunnel between septum primum and secundum >10 mm (11%). Degree of right-to-left shunt, either at basal condition or at Valsalva manoeuvre, was classified as: 1=mild (45%); 2=moderate (42%); 3=severe (13%). Additional right-atrium anatomical features are also described. RESULTS: Procedure was successful in 100% of the cases. At follow-up recurrent TIA occurred in two patients. Residual shunts were present in 4.9% of the patients after Valsalva manoeuvre. Palpitations were reported in 4%. CONCLUSIONS: Closing the PFO choosing the device following strict anatomical criteria based on TEE assessment allowed excellent immediate and late results minimizing residual shunts.

[Predictive ability of a predischarge hour-specific serum bilirubin for hyperbilirubinemia in full term infants]. / Predittività di un algoritmo previsionale dell'iperbilirubinemia neonatale nel neonato a termine.

AIM: The aim of this paper was to assess the ability of total serum bilirubin (TSB) levels in the first 3 days of life to predict subsequent nonphysiologic hyperbilirubinemia. METHODS: The predictive ability of an hour-specific nomogram for TSB values in the first week of life was prospectively assessed in 1496 full term neonates admitted to a first level neonatal unit, using a single TSB value or two consecutive ones, when available. RESULTS: The incidence of TSB values > 12 mg/dL was 9.6%, while the incidence of TSB > 15 mg/dL was 2.6%. A sensitivity of 97.9% and a negative predictive value (NPV) of 99.6% were obtained with a single bilirubin determination applying Trend 12, while 82.5% of sensitivity and 99.4% of NPV were obtained with Trend 15. Two consecutive TSB determinations identified all infants reaching TSB values > 12 mg/dL and all neonates but 5 reaching TSB values > 15 mg/dL (92.1% of sensitivity and 99% of NPV) CONCLUSION: The hour-specific TSB determination in the first 3 days of life is able to predict all neonates at risk of nonphysiologic hyperbilirubinemia and could facilitate a safe discharge from the hospital and a targeted intervention and follow-up.

Plasma leptin concentration increases early during highly active antiretroviral therapy for acquired immunodeficiency syndrome, independent of body weight.

Leptin, the protein product of the obese gene (ob), is secreted by adipocytes. Circulating leptin levels correlate with fat mass in humans, including individuals infected with HIV. Leptin serves as an adipostatic hormone, a permissive factor for reproduction and a modulator of immune function. Leptin is a cytokine, and has been demonstrated to enhance CD4 cell proliferation and IL-2 secretion from CD4 cells in vitro. The role of leptin in HIV-positive patients treated with highly active antiretroviral therapy (HAART) has not been well defined. We haveevaluated leptin levels in HIV-infected individualsduringthe early phase of HAART. We measured plasma leptin levels in 15 antiretroviral-naive HIV positive patients at baseline and after 1 and 4 weeks of HAART. After the first week of therapy, mean leptin level and CD4 count were increased compared to baseline, 6.0 vs 7.2 ng/ml (p = 0.004) and 377 vs 432 cells/ul (p = 0.014), respectively. In contrast, mean body mass index (BMI) remained unchanged 27.0 vs 26.8 kg/m2 (p < 0.08). After four weeks of therapy, leptin and BMI values were unchanged compared to baseline, 6.0 vs 5.9 (p < 0.4) and 27.0 vs 26.9 (p < 0.5), respectively, whereas CD4 count continued to increase to 491 cells/ul (p < 0.012 compared to baseline). These data demonstrate an early transient increase in plasma leptin levels in HIV positive patients initiated on HAART, despite a lack of change in BMI. It is unclear if the transient increase in leptin is related to its role as a cytokine, a metabolic regulator, or reproductive factor.

Syphilitic hepatitis in HIV-infected patients: a report of 7 cases and review of the literature.

BACKGROUND: A recent resurgence of primary and secondary syphilis has been observed in certain population groups, particularly among persons infected with human immunodeficiency virus (HIV). Liver involvement is an infrequently recognized complication of early syphilis, with no previous reports among HIV-infected patients. METHODS: We describe 7 cases of syphilitic hepatitis in HIV-positive individuals and review the literature. RESULTS: At our institutions, all patients presented with a rash consistent with secondary syphilis. Each case was characterized by a conspicuous increase in serum alkaline phosphatase level (mean level +/- standard deviation, 905 +/- 523.6 IU/L) and milder elevations in serum transaminase levels. The mean CD4+ absolute T cell count was 317 cells/mm3, and the median rapid plasma reagin (RPR) titer was 1 : 128. There was a significant correlation between higher CD4+ cell counts and the RPR titers (R=0.93; P=.002). Symptomatic resolution and biochemical improvement, particularly a significant decrease in serum alkaline phosphatase levels (P=.02), occurred following antibiotic therapy. CONCLUSIONS: Hepatic dysfunction is not uncommon in HIV-infected persons and is attributable to multiple causes. In the appropriate clinical setting, syphilitic hepatitis is an easily diagnosed and reversible etiology of liver dysfunction. The recognition of this entity will prevent unnecessary evaluation of abnormal liver enzyme levels in HIV-positive patients.

A prospective, randomized, comparative US trial of a combination hepatitis A and B vaccine (Twinrix) with corresponding monovalent vaccines (Havrix and Engerix-B) in adults.

In an open, randomized, multicenter, controlled clinical trial in the US, 773 adults were administered either a combination hepatitis vaccine (Twinrix: 720 EL.U inactivated hepatitis A antigen and 20 mcg recombinant hepatitis B surface antigen per milliliter) on a 0, 1, 6 month schedule or corresponding monovalent vaccines concurrently (Havrix, 1440 EL.U/ml of hepatitis A antigen at 0, 6 months and Engerix-B, 20 mcg of hepatitis B surface antigen at 0, 1, 6 months). Non-inferiority testing for the primary endpoint, severe soreness, and equivalence testing for the secondary endpoints, anti-HAV seroconversion and anti-HBs seroprotection, showed that safety and immunogenicity were comparable in the two groups.

Care of HIV-infected pregnant women in maternal-fetal medicine programs.

OBJECTIVE: To survey the evolution over the past decade of attitudes and practices of obstetricians in maternal-fetal medicine fellowship programs regarding the management of human immunodeficiency virus (HIV)-infected pregnant women. METHODS: Directors of all 65 approved maternal-fetal medicine training programs were sent questionnaires, responses to which were to reflect the consensus among members of their faculties. Programs were stratified based upon the number of HIV-infected pregnant patients cared for in the previous year. RESULTS: Responses reflect experience with over 1000 infected pregnant women per year, nearly one-quarter with advanced disease. Combination antiretroviral therapy was prescribed by all respondents, universally in the 2nd and 3rd trimesters. A three-drug regimen (often containing a protease inhibitor) was used more often by those who treated at least 20 HIV-infected pregnant patients per year than by those programs seeing a lower number of patients (80 vs 59%). Despite the known and unknown risks of the use of antiretrovirals during pregnancy, only half of all responding programs report adverse events to the Antiretroviral Pregnancy Registry; reporting was more common among the institutions seeing a higher number of patients (61 vs 45%). Seventy-eight percent of higher volume programs enroll their patients in clinical studies, usually multicenter, versus 35% of lower volume programs. CONCLUSIONS: Care for HIV+ pregnant women has dramatically changed over the past decade. Antiretroviral therapy is now universally prescribed by physicians involved in maternal-fetal medicine training programs. Given limited experience with these agents in the setting of pregnancy, it is essential for maternal-fetal medicine practitioners to actively report on adverse events and participate in clinical trials.

Safety and immunogenicity of a recombinant Borrelia burgdorferi outer surface protein A vaccine against lyme disease in healthy children and adolescents: a randomized controlled trial.

OBJECTIVE: A recombinant lipoprotein outer surface protein A (OspA) Lyme disease (LD) vaccine (LYMErix) has been shown to be safe and effective in preventing LD in adults and in adolescents 15 years of age and older. Children are at risk for developing LD. This clinical study was conducted to address the safety and immunogenicity of LD vaccine in children 4 to 18 years of age. METHODS: A randomized, placebo-controlled clinical trial was conducted at 17 investigational sites in Lyme-endemic areas in the United States. Immunogenicity data from this study also were compared with data obtained from the adult efficacy study. A total of 4090 healthy children and adolescents (age range: 4-18; mean age: 10.4 years) were randomized; 4087 were vaccinated, and a subset of 301 children participated in the immunogenicity analysis. Children were randomized to receive either 30 microgram of LD vaccine (N = 3063) or placebo (N = 1024) on a 0, 1, 12-month schedule. Safety assessments evaluated both solicited (local: redness, swelling, and pain; general: fever, headache, fatigue, arthralgia, and rash) and unsolicited adverse events. Serum specimens were collected at month 0 or month 2, and months 6, 12, and 13. RESULTS: Solicited reactogenicity data revealed a higher incidence of local injection site reactions and general symptoms (fever, headache, fatigue, and arthralgia) in vaccine than placebo recipients. The majority of events were limited in duration (mean: 2-3 days) and were mild to moderate in severity. The total IgG anti-OspA geometric mean titer (GMT) in the pediatric vaccine recipients at month 13 was as good as and statistically higher than the GMT in the adult cohort at month 13 (27 485 enzyme-linked immunosorbent assay units [EL.U]/mL vs 8216 EL.U /mL). All of the pediatric vaccine recipients attained a level of antibody concentration >/=1400 EL.U/mL (proposed seroprotective level) compared with 90% of adults attaining levels >/=1400 EL.U/mL in the efficacy trial. CONCLUSIONS: LD vaccine administered on a 0, 1, 12-month schedule generally is well tolerated and immunogenic in children 4 to 18 years of age. The safety profile consists of mild to moderate local injection site reactions and flu-like symptoms of limited duration and did not worsen with subsequent injections. IgG GMT at month 13 was threefold higher than the month 13 GMT obtained in the adult efficacy study. This higher immune response in children should provide protection against LD.

A comparison of stavudine, didanosine and indinavir with zidovudine, lamivudine and indinavir for the initial treatment of HIV-1 infected individuals: selection of thymidine analog regimen therapy (START II).

OBJECTIVE: Comparison of stavudine (d4T), didanosine (ddI) and indinavir (IDV) with zidovudine (ZDV), lamivudine (3TC) and IDV in HIV-1 infected patients. DESIGN: Randomized, open-label. SETTING: Fourteen HIV Clinical Research Centers. PATIENTS: Two-hundred and five patients with less than 4 weeks antiretroviral treatment, naive to 3TC and protease inhibitors and with CD4 cell counts > or = 200 x 10(6)/l and plasma HIV-1 RNA levels > or = 10,000 copies/ml. INTERVENTIONS: Stavudine 40 mg and ddI 200 mg twice daily plus IDV 800 mg every 8 h compared with ZDV 200 mg every 8 h or 300 mg twice daily, 3TC 150 mg twice daily plus IDV. MAIN OUTCOME MEASURES: The proportion of patients with plasma HIV-1 RNA levels < 500 copies/ml and < or = 50 copies/ml and changes in CD4 cell counts were compared. RESULTS: In an analysis of the primary endpoint, 61% of patients on d4T + ddI + IDV and 45% of patients on ZDV + 3TC + IDV had all HIV-1 RNA values obtained between weeks 40 and 48 < 500 copies/ml [95% confidence interval (CI) for the difference between proportions, 1.7-30.3%; P = 0.038]. In an intent-to-treat analysis, the percentage of all patients randomized with all HIV-1 RNA levels < 500 copies/ml between 40 and 48 weeks were 53% for the d4T + ddI + IDV arm and 41% for the ZDV + 3TC + IDV arm (95% CI, -1.4% to 25.7%; P = 0.068). At 48 weeks 41% and 35% were < or = 50 copies/ml for the stavudine- and ZDV-containing arms respectively (P > 0.2). The median time-weighted average increases in CD4 cells count over 48 weeks were 150 x 10(6)/l cells for the d4T arm and 106 x 10(6)/l cells for the ZDV arm (P= 0.001). The occurrence of serious adverse events was not significantly different between arms. CONCLUSION: The combination of stavudine, ddl and IDV resulted in potent antiretroviral effects over a 48-week period, comparable or superior to zidovudine, 3TC and IDV supporting the use of stavudine, ddI and a protease inhibitor as an initial antiretroviral treatment.

Safety and immunogenicity profile of a recombinant outer-surface protein A Lyme disease vaccine: clinical trial of a 3-dose schedule at 0, 1, and 2 months.

OBJECTIVES: This study compared the tolerability of a Lyme disease vaccine administered intramuscularly at 0 and 1 months with that of a vaccine administered at 0, 1, and 2 months to determine (1) whether adding a third dose of vaccine 1 month after the second would affect the safety profile, and (2) whether a shortened vaccination schedule of 0, 1, and 2 months would provide an immune response similar to that obtained with vaccine administered at 0, 1, and 12 months. BACKGROUND: An efficacy trial of a Lyme disease vaccine had demonstrated safety and efficacy against definite (clinically manifested and laboratory-confirmed) Lyme disease after 3 doses at 0, 1, and 12 months and resulted in 90% of subjects having titers > or =1400 enzyme-linked immunosorbent assay units (EL.U)/mL (the proposed seroprotective level for 1 tick season). METHODS: This multicenter, open-label, prospective, randomized study assessed the safety and efficacy of different doses of a recombinant outer-surface protein A (OspA) vaccine in 956 volunteers aged 17 to 72 years from 3 Lyme disease-endemic sites. Blood samples were collected at months 0, 2, 3, 12, and 13 to assess total immunoglobulin-G anti-OspA titers. RESULTS: Most adverse events were transient and mild to moderate. The geometric mean antibody titer increased 2.8-fold from month 2 (1786 EL.U/mL to 4842 EL.U/mL), and approximately 90% of the volunteers had a titer > or =1400 and 99% had a titer > or =400 EL.U/mL (the mini- mum seroprotective level at any given time) after the third dose. An antibody kinetics model predicts that protection would last for a typical tick-transmission season. CONCLUSIONS: In volunteers aged 17 to 72 years, 3 doses of vaccine administered in 2 months was well tolerated, more immunogenic than 2 doses, and provided a higher probability of protection before exposure or travel to Lyme disease-endemic areas.

Immunogenicity of a recombinant Borrelia burgdorferi outer surface protein A vaccine against Lyme disease in children.

BACKGROUND AND OBJECTIVE: A recombinant lipoprotein vaccine against Lyme disease, containing 30 microg of Borrelia burgdorferi outer surface protein A (OspA) with aluminum adjuvant, has been shown in a large US field trial of subjects >/=15 years of age to offer 76% efficacy against clinical Lyme disease after 3 injections given at 0, 1, and 12 months. Lyme disease is also an important problem in children; thus, OspA vaccine trials in children are needed. The purpose of this study was to investigate the safety and immunogenicity of 2 different doses of lipoprotein OspA with aluminum adjuvant vaccine in healthy children 5 to 15 years of age in a double-blind, randomized study. STUDY DESIGN: In a double-blind study, 250 children from the Czech Republic were randomly assigned to receive 15 microg or 30 microg of OspA vaccine at 0, 1, and 2 months. Serum samples, obtained before vaccination and 1 month after the second and third doses, were analyzed for antiOspA antibody. Solicited and unsolicited symptoms were collected from diary cards. RESULTS: Local pain at the injection site was reported by approximately 76% of the 250 children. Headaches (after 5% to 18% of the injections) and malaise (after 2% to 16% of the injections) were the most frequently reported general symptoms. Local and generalized symptoms were not different between the 15 microg and 30 microg groups, and all symptoms resolved within 4 days. Both doses were highly immunogenic, with the 30 microg dose eliciting higher antibody levels. Seroconversion occurred in 99% of the 250 children. CONCLUSIONS: The OspA vaccine against Lyme disease was well tolerated and highly immunogenic in children.

Alterations in serum levels of lipids and lipoproteins with indinavir therapy for human immunodeficiency virus-infected patients.

Alterations in lipid metabolism have been associated with the use of protease inhibitors. Sequential lipid analyses were performed on serum samples from human immunodeficiency virus-infected antiretroviral-naive patients who received indinavir in combination with two nucleoside reverse transcriptase inhibitors. Serum levels of cholesterol, triglycerides, high-density lipoproteins (HDLs), and low-density lipoproteins (LDLs) were measured at baseline and at periodic intervals. After 48 weeks of indinavir therapy, mean serum levels +/- SD rose as follows: cholesterol, from 167.2 +/- 36.0 to 206.3 +/- 32.4 mg/dL (P < .0005); triglycerides, from 110.4 +/- 47.5 to 158.4 +/- 72.5 mg/dL (P < .0101); and LDLs, from 106.6 +/- 35.1 to 136.1 +/- 31.6 mg/dL (P = .0029). There was no significant change in the serum HDL fraction. Mean serum lipoprotein (a) levels +/- SD rose from 6.5 +/- 1.4 to 9.6 +/- 2.0 mg/dL after 30 weeks (P = .0695). Potential mechanisms for the noted increases include alterations in serum lipoprotein lipase activity or changes in hepatic lipid metabolism. The clinical significance of these changes remains to be determined.

Alternative vaccination schedules (0, 1, and 6 months versus 0, 1, and 12 months) for a recombinant OspA Lyme disease vaccine.

We have compared the immunogenicity profile of a recombinant lipoprotein outer-surface protein A (OspA) Lyme disease vaccine administered on schedules of 0, 1, and 6 months (group 1) or 0, 1, and 12 months (group 2) to 800 healthy subjects, aged 15-50 years. One month after the second dosing, geometric mean titers of IgG antibodies to OspA were 1,309 ELISA units (EL.U)/mL in group 1 and 1,404 EL.U/mL in group 2. One month after the third dosing, the titers were 7,205 EL.U/mL and 10,659 EL.U/mL, respectively. Using bioequivalence methodology, we showed that the two vaccination schedules elicit an equivalent immune response 1 month after administration of dose 3: at that point, 91%-93% of all subjects had titers > or =1,400 EL.U/mL, proposed to be protective for one tick season. The vast majority of local and systemic symptoms were mild to moderate and of limited duration. The 0, 1, and 6 months vaccination schedule is a viable alternative to the 0, 1, and 12 months schedule and can provide protection against Lyme disease during one tick season.