Rates and determinants of virologic and immunological response to HAART resumption after treatment interruption in HIV-1 clinical practice.

OBJECTIVE: To describe CD4 and HIV RNA changes during treatment resumption (TR) after treatment interruption (TI) compared with response to first highly active antiretroviral therapy (HAART) and to investigate predictors. METHODS: Using Concerted Action on SeroConversion to AIDS and Death in Europe (CASCADE) data, we identified subjects who interrupted first HAART, not initiated during primary infection. We estimated rate of CD4 change during TR and time from TR to HIV RNA<500 copies per milliliter and subsequent rebound and factors associated with these outcomes. RESULTS: Of 281 persons treated for median 18.4 months before interrupting, 259 resumed HAART. CD4 increases in the first 3 months on HAART were similar pre-TI and post-TI but after 3 months were significantly higher during pre-TI HAART, with median +106 and +172 cells per microliter at 3 and 18 months, respectively, during initial HAART compared with +99 and +142 cells per microliter during post-TI HAART, respectively. Subjects with lower CD4 counts at TI, aged older than 40 years, and those resuming the same HAART as their pre-TI regimen had lower CD4 increases during the first 3 months of TR. The majority (86%) of individuals reinitiating therapy achieved HIV RNA<500 copies per milliliter. CONCLUSIONS: Immune reconstitution after TI is generally poorer than after first HAART, particularly for patients aged older than 40 years at TI and those with poorer immunological responses to pre-TI HAART. Reinitiation of the same HAART regimen as pre-TI also seems to have unfavorable outcomes.

Atrial arrhythmias in adults with congenital heart disease.

BACKGROUND: Atrial arrhythmias increase disease burden in the general adult population. Adults with congenital heart lesions constitute a rapidly growing group of patients with cardiovascular disease. We hypothesized that atrial arrhythmias increase with age and impair health outcomes in this population. METHODS AND RESULTS: We conducted a population-based analysis of prevalence, lifetime risk, mortality, and morbidity associated with atrial arrhythmias in adults with congenital heart disease from l983 to 2005. In 38 428 adults with congenital heart disease in 2005, 5812 had atrial arrhythmias. Overall, the 20-year risk of developing atrial arrhythmia was 7% in a 20-year-old subject and 38% in a 50-year-old subject. More than 50% of patients with severe congenital heart disease reaching age 18 years developed atrial arrhythmias by age 65 years. In patients with congenital heart disease, the hazard ratio of any adverse event in those with atrial arrhythmias compared with those without was 2.50 (95% confidence interval, 2.38 to 2.62; P<0.0001), with a near 50% increase in mortality (hazard ratio, 1.47; 95% confidence interval, 1.37 to 1.58; P<0.001), more than double the risk of morbidity (stroke or heart failure) (hazard ratio, 2.21; 95% confidence interval, 2.07 to 2.36; P<0.001), and 3 times the risk of cardiac interventions (hazard ratio, 3.00; 95% confidence interval, 2.81 to 3.20; P<0.001). CONCLUSIONS: Atrial arrhythmias occurred in 15% of adults with congenital heart disease. The lifetime incidence increased steadily with age and was associated with a doubling of the risk of adverse events. An increase in resource allocation should be anticipated to deal with this increasing burden.

A comparison of initial antiretroviral therapy in the Swiss HIV Cohort Study and the recommendations of the International AIDS Society-USA.

BACKGROUND: In order to facilitate and improve the use of antiretroviral therapy (ART), international recommendations are released and updated regularly. We aimed to study if adherence to the recommendations is associated with better treatment outcomes in the Swiss HIV Cohort Study (SHCS). METHODS: Initial ART regimens prescribed to participants between 1998 and 2007 were classified according to IAS-USA recommendations. Baseline characteristics of patients who received regimens in violation with these recommendations (violation ART) were compared to other patients. Multivariable logistic and linear regression analyses were performed to identify associations between violation ART and (i) virological suppression and (ii) CD4 cell count increase, after one year. RESULTS: Between 1998 and 2007, 4189 SHCS participants started 241 different ART regimens. A violation ART was started in 5% of patients. Female patients (adjusted odds ratio aOR 1.83, 95%CI 1.28-2.62), those with a high education level (aOR 1.49, 95%CI 1.07-2.06) or a high CD4 count (aOR 1.53, 95%CI 1.02-2.30) were more likely to receive violation ART. The proportion of patients with an undetectable viral load (<400 copies/mL) after one year was significantly lower with violation ART than with recommended regimens (aOR 0.54, 95% CI 0.37-0.80) whereas CD4 count increase after one year of treatment was similar in both groups. CONCLUSIONS: Although more than 240 different initial regimens were prescribed, violations of the IAS-USA recommendations were uncommon. Patients receiving these regimens were less likely to have an undetectable viral load after one year, which strengthens the validity of these recommendations.

Life-threatening versus non-life-threatening manual strangulation: are there appropriate criteria for MR imaging of the neck?

The aim of the study was to determine objective radiological signs of danger to life in survivors of manual strangulation and to establish a radiological scoring system for the differentiation between life-threatening and non-life-threatening strangulation by dividing the cross section of the neck into three zones (superficial, middle and deep zone). Forensic pathologists classified 56 survivors of strangulation into life-threatening and non-life-threatening cases by history and clinical examination alone, and two blinded radiologists evaluated the MRIs of the neck. In 15 cases, strangulation was life-threatening (27%), compared with 41 cases in which strangulation was non-life-threatening (73%). The best radiological signs on MRI to differentiate between the two groups were intramuscular haemorrhage/oedema, swelling of platysma and intracutaneous bleeding (all p = 0.02) followed by subcutaneous bleeding (p = 0.034) and haemorrhagic lymph nodes (p = 0.04), all indicating life-threatening strangulation. The radiological scoring system showed a sensitivity and specificity of approximately 70% for life-threatening strangulation, when at least two neck zones were affected. MRI is not only helpful in assessing the severity of strangulation, but is also an excellent documentation tool that is even admissible in court.

Predictors of nonresponse in a questionnaire-based outcome study of vocational rehabilitation patients.

OBJECTIVE: To identify predictors of nonresponse to a self-report study of patients with orthopedic trauma hospitalized for vocational rehabilitation between November 15, 2003, and December 31, 2005. The role of biopsychosocial complexity, assessed using the INTERMED, was of particular interest. DESIGN: Cohort study. Questionnaires with quality of life, sociodemographic, and job-related questions were given to patients at hospitalization and 1 year after discharge. Sociodemographic data, biopsychosocial complexity, and presence of comorbidity were available at hospitalization (baseline) for all eligible patients. Logistic regression models were used to test a number of baseline variables as potential predictors of nonresponse to the questionnaires at each of the 2 time points. SETTING: Rehabilitation clinic. PARTICIPANTS: Patients (N=990) hospitalized for vocational rehabilitation over a period of 2 years. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE: Nonresponse to the questionnaires was the binary dependent variable. RESULTS: Patients with high biopsychosocial complexity, foreign native language, or low educational level were less likely to respond at both time points. Younger patients were less likely to respond at 1 year. Those living in a stable partnership were less likely than singles to respond at hospitalization. Sex, psychiatric, and somatic comorbidity and alcoholism were never associated with nonresponse. CONCLUSIONS: We stress the importance of assessing biopsychosocial complexity to predict nonresponse. Furthermore, the factors we found to be predictive of nonresponse are also known to influence treatment outcome and vocational rehabilitation. Therefore, it is important to increase the response rate of the groups of concern in order to reduce selection bias in epidemiologic investigations.

Sub-cortical and brainstem sites associated with chemo-stimulated increases in ventilation in humans.

We investigated the neural basis for spontaneous chemo-stimulated increases in ventilation in awake, healthy humans. Blood oxygen level dependent (BOLD) functional MRI was performed in nine healthy subjects using T2 weighted echo planar imaging. Brain volumes (52 transverse slices, cortex to high spinal cord) were acquired every 3.9 s. The 30 min paradigm consisted of six, 5-min cycles, each cycle comprising 45 s of hypoxic-isocapnia, 45 s of isooxic-hypercapnia and 45 s of hypoxic-hypercapnia, with 55 s of non-stimulatory hyperoxic-isocapnia (control) separating each stimulus period. Ventilation was significantly (p<0.001) increased during hypoxic-isocapnia, isooxic-hypercapnia and hypoxic-hypercapnia (17.0, 13.8, 24.9 L/min respectively) vs. control (8.4 L/min) and was associated with significant (p<0.05, corrected for multiple comparisons) signal increases within a bilateral network that included the basal ganglia, thalamus, red nucleus, cerebellum, parietal cortex, cingulate and superior mid pons. The neuroanatomical structures identified provide evidence for the spontaneous control of breathing to be mediated by higher brain centres, as well as respiratory nuclei in the brainstem.

Hypertension and intra-operative incidents: a multicentre study of 125,000 surgical procedures in Swiss hospitals.

It is debated whether chronic hypertension increases the risk of cardiovascular incidents during anaesthesia. We studied all elective surgical operations performed in adults under general or regional anaesthesia between 2000 and 2004, in 24 hospitals collecting computerised clinical data on all anaesthetics since 1996. The focus was on cardiovascular incidents, though other anaesthesia-related incidents were also evaluated. Among 124,939 interventions, 27,881 (22%) were performed in hypertensive patients. At least one cardiovascular incident occurred in 7549 interventions (6% (95% CI 5.9-6.2%)). The average adjusted odds ratio of cardiovascular risk for chronic hypertension was 1.38 (95% CI 1.27-1.49). However, across hospitals, adjusted odd ratios varied from 0.41 up to 2.25. Hypertension did not increase the risk of other incidents. Hypertensive patients are still at risk of intra-operative cardiovascular incidents, while risk heterogeneity across hospitals, despite taking account of casemix and hospital characteristics, suggests variations in anaesthetic practices.

Underreporting of needlestick and sharps injuries among healthcare workers in a Swiss University Hospital.

OBJECTIVES: To determine 1) rates of needlestick and sharps injuries (NSSIs) not reported to occupational health services, 2) reasons for underreporting and 3) awareness of reporting procedures in a Swiss university hospital. MATERIALS AND METHODS: We surveyed 6,367 employees having close clinical contact with patients or patient specimens. The questionnaire covered age, sex, occupation, years spent in occupation, history of NSSI during the preceding twelve months, NSSI reporting, barriers to reporting and knowledge of reporting procedures. RESULTS: 2,778 questionnaires were returned (43.6%) of which 2,691 were suitable for analysis. 260/2,691 employees (9.7%) had sustained at least one NSSI during the preceding twelve months. NSSIs were more frequent among nurses (49.2%) and doctors performing invasive procedures (IPs) (36.9%). NSSI rate by occupation was 8.6% for nurses, 19% for doctors and 1.3% for domestic staff. Of the injured respondents, 73.1% reported all events, 12.3% some and 14.6% none. 42.7% of doctors performing invasive procedures (IPs) underreported NSSIs and represented 58.6% of underreported events. Estimation that transmission risk was low (87.1%) and perceived lack of time (34.3%) were the most common reasons for non-reporting. Regarding reporting procedures, 80.1% of respondents knew to contact occupational health services. CONCLUSION: Doctors performing IPs have high rates of NSSI and, through self-assessment that infection transmission risk is low or perceived lack of time, high rates of underreporting. If individual risk analyses underestimate the real risk, such underreporting represents a missed opportunity for post-exposure prophylaxis and identification of hazardous procedures. Doctors' training in NSSI reporting merits re-evaluation.

Characterization of pupil responses to blue and red light stimuli in autosomal dominant retinitis pigmentosa due to NR2E3 mutation.

PURPOSE: We characterized the pupil responses that reflect rod, cone, and melanopsin function in a genetically homogeneous cohort of patients with autosomal dominant retinitis pigmentosa (adRP). METHODS: Nine patients with Gly56Arg mutation of the NR2E3 gene and 12 control subjects were studied. Pupil and subjective visual responses to red and blue light flashes over a 7 log-unit range of intensities were recorded under dark and light adaptation. The pupil responses were plotted against stimulus intensity to obtain red-light and blue-light response curves. RESULTS: In the dark-adapted blue-light stimulus condition, patients showed significantly higher threshold intensities for visual perception and for a pupil response compared to controls (P = 0.02 and P = 0.006, respectively). The rod-dependent, blue-light pupil responses decreased with disease progression. In contrast, the cone-dependent pupil responses (light-adapted red-light stimulus condition) did not differ between patients and controls. The difference in the retinal sensitivity to blue and red stimuli was the most sensitive parameter to detect photoreceptor dysfunction. Unexpectedly, the melanopsin-mediated pupil response was decreased in patients (P = 0.02). CONCLUSIONS: Pupil responses of patients with NR2E3-associated adRP demonstrated reduced retinal sensitivity to dim blue light under dark adaptation, presumably reflecting decreased rod function. Rod-dependent pupil responses were quantifiable in all patients, including those with non-recordable scotopic electroretinogram, and correlated with the extent of clinical disease. Thus, the chromatic pupil light reflex can be used to monitor photoreceptor degeneration over a larger range of disease progression compared to standard electrophysiology.

Effects of the α₂-adrenergic agonist clonidine on the pharmacodynamics and pharmacokinetics of 3,4-methylenedioxymethamphetamine in healthy volunteers.

The mechanism of action of 3,4-methylenedioxymethamphetamine (MDMA; ecstasy) involves the carrier-mediated and potentially vesicular release of monoamines. We assessed the effects of the sympatholytic α₂-adrenergic receptor agonist clonidine (150 μg p.o.), which inhibits the neuronal vesicular release of norepinephrine, on the cardiovascular and psychotropic response to MDMA (125 mg p.o.) in 16 healthy subjects. The study used a randomized, double-blind, placebo-controlled crossover design with four experimental sessions. The administration of clonidine 1 h before MDMA reduced the MDMA-induced increases in plasma norepinephrine concentrations and blood pressure but only to the extent that clonidine lowered norepinephrine levels and blood pressure compared with placebo. Thus, no interaction was found between the cardiovascular effects of the two drugs. Clonidine did not affect the psychotropic effects or pharmacokinetics of MDMA. The lack of an interaction of the effects of clonidine and MDMA indicates that vesicular release of norepinephrine, which is inhibited by clonidine, does not critically contribute to the effects of MDMA in humans. Although clonidine may be used in the treatment of stimulant-induced hypertensive reactions, the present findings do not support a role for α₂-adrenergic receptor agonists in the prevention of psychostimulant dependence.

Chromatic pupil responses: preferential activation of the melanopsin-mediated versus outer photoreceptor-mediated pupil light reflex.

OBJECTIVE: To weight the rod-, cone-, and melanopsin-mediated activation of the retinal ganglion cells, which drive the pupil light reflex by varying the light stimulus wavelength, intensity, and duration. DESIGN: Experimental study. PARTICIPANTS: Forty-three subjects with normal eyes and 3 patients with neuroretinal visual loss. METHODS: A novel stimulus paradigm was developed using either a long wavelength (red) or short wavelength (blue) light given as a continuous Ganzfeld stimulus with stepwise increases over a 2 log-unit range. The pupillary movement before, during, and after the light stimulus was recorded in real time with an infrared illuminated video camera. MAIN OUTCOME MEASURES: The percent pupil contraction of the transient and sustained pupil response to a low- (1 cd/m(2)), medium- (10 cd/m(2)), and high-intensity (100 cd/m(2)) red- and blue-light stimulus was calculated for 1 eye of each subject. From the 43 normal eyes, median and 25th, 75th, 5th, and 95th percentile values were obtained for each stimulus condition. RESULTS: In normal eyes at lower intensities, blue light evoked much greater pupil responses compared with red light when matched for photopic luminance. The transient pupil contraction was generally greater than the sustained contraction, and this disparity was greatest at the lowest light intensity and least apparent with bright (100 cd/m(2)) blue light. A patient with primarily rod dysfunction (nonrecordable scotopic electroretinogram) showed significantly reduced pupil responses to blue light at lower intensities. A patient with achromatopsia and an almost normal visual field showed selective reduction of the pupil response to red-light stimulation. A patient with ganglion cell dysfunction owing to anterior ischemic optic neuropathy demonstrated global loss of pupil responses to red and blue light in the affected eye. CONCLUSIONS: Pupil responses that differ as a function of light intensity and wavelength support the hypothesis that selected stimulus conditions can produce pupil responses that reflect phototransduction primarily mediated by rods, cones, or melanopsin. Use of chromatic pupil responses may be a novel way to diagnose and monitor diseases affecting either the outer or inner retina.

Systematic evaluation of risk factors for diagnostic delay in inflammatory bowel disease.

The diagnosis of inflammatory bowel disease (IBD), comprising Crohn's disease (CD) and ulcerative colitis (UC), continues to present difficulties due to unspecific symptoms and limited test accuracies. We aimed to determine the diagnostic delay (time from first symptoms to IBD diagnosis) and to identify associated risk factors. A total of 1591 IBD patients (932 CD, 625 UC, 34 indeterminate colitis) from the Swiss IBD cohort study (SIBDCS) were evaluated. The SIBDCS collects data on a large sample of IBD patients from hospitals and private practice across Switzerland through physician and patient questionnaires. The primary outcome measure was diagnostic delay. Diagnostic delay in CD patients was significantly longer compared to UC patients (median 9 versus 4 months, P < 0.001). Seventy-five percent of CD patients were diagnosed within 24 months compared to 12 months for UC and 6 months for IC patients. Multivariate logistic regression identified age <40 years at diagnosis (odds ratio [OR] 2.15, P = 0.010) and ileal disease (OR 1.69, P = 0.025) as independent risk factors for long diagnostic delay in CD (>24 months). In UC patients, nonsteroidal antiinflammatory drug (NSAID intake (OR 1.75, P = 0.093) and male gender (OR 0.59, P = 0.079) were associated with long diagnostic delay (>12 months). Whereas the median delay for diagnosing CD, UC, and IC seems to be acceptable, there exists a long delay in a considerable proportion of CD patients. More public awareness work needs to be done in order to reduce patient and doctor delays in this target population.

Blunting the response to endotoxin in healthy subjects: effects of various doses of intravenous fish oil.

To test the dose response effect of infused fish oil (FO) rich in n-3 PUFAs on the inflammatory response to endotoxin (LPS) and on membrane incorporation of fatty acids in healthy subjects. Prospective, sequential investigation comparing three different FO doses. Three groups of male subjects aged 26.8 +/- 3.2 years (BMI 22.5 +/- 2.1). One of three FO doses (Omegaven10%) as a slow infusion before LPS: 0.5 g/kg 1 day before LPS, 0.2 g/kg 1 day before, or 0.2 g/kg 2 h before. Temperature, hemodynamic variables, indirect calorimetry and blood samples (TNF-alpha, stress hormones) were collected. After LPS temperature, ACTH and TNF-alpha concentrations increased in the three groups: the responses were significantly blunted (p < 0.0001) compared with the control group of the Pluess et al. trial. Cortisol was unchanged. Lowest plasma ACTH, TNF-alpha and temperature AUC values were observed after a single 0.2 g/kg dose of FO. EPA incorporation into platelet membranes was dose-dependent. Having previously shown that the response to LPS was reproducible, this study shows that three FO doses blunted it to various degrees. The 0.2 g/kg perfusion immediately before LPS was the most efficient in blunting the responses, suggesting LPS capture in addition to the systemic and membrane effects.

Patterns of sex work contact among men in the general population of Switzerland, 1987-2000

OBJECTIVES: To analyse the prevalence of lifetime recourse to prostitution (LRP) among men in the general population of Switzerland from a trend and cohort perspective. METHODS: Using nine repeated representative cross-sectional surveys from 1987 to 2000, age-specific estimates of LRP were computed. Trends and period effect were analysed as the evolution of cross-sectional population estimates within age groups and overall. Cohort analysis relied on cohorts constructed from the 1989 survey and followed in subsequent waves. Age and cohort effects were modelled using logistic regression and non-parametric monotone regression. RESULTS: Whereas prevalence for the younger groups was found to be logically lower, there was no consistent increasing or decreasing trend over the years; there was no significant period effect. For the 17-30 year age group, the mean estimate over 1987-2000 was 11.5% (range 8.3 to 12.7%); for the 31-45 year group, the mean was 21.5% (range over 1989-2000 20.3 to 23.0%). Regarding cohort analysis, the prevalence of LRP was found to increase steeply in the youngest ages before reaching a plateau near the age of 40 years. At the age of 43 years, the prevalence was estimated to be 22.6% (95% CI 21.1% to 24.1%). CONCLUSIONS: The steep increase in the cohort-wise prevalence of LRP in younger ages calls for a concentration of prevention activities in young people. If the plateauing at approximately 40 years of age is not followed by a further increase later in life, which is not known, then consumers of paid sex would be repeat buyers only, a fact that should be taken into account by prevention.

TGFBI (BIGH3) gene mutations in German families: two novel mutations associated with unique clinical and histopathological findings.

BACKGROUND: To report the clinical, histopathological and immunohistochemical findings of two novel mutations within the TGFBI gene. METHODS: The genotype of 41 affected members of 16 families and nine sporadic cases was investigated by direct sequencing of the TGFBI gene. Clinical, histological and immunohistochemical characteristics of corneal opacification were reported and compared with the coding region changes in the TGFBI gene. RESULTS: A novel mutation Leu509Pro was detected in one family with a geographic pattern-like clinical phenotype. Histopathologically we found amyloid together with non-amyloid deposits and immunohistochemical staining of Keratoepithelin (KE) KE2 and KE15 antibodies. In two families and one sporadic case the novel mutation Gly623Arg with a late-onset, map-like corneal dystrophy was identified. Here amyloid and immunohistochemical staining of only KE2 antibodies occurred. Further, five already known mutations are reported: Arg124Cys Arg555Trp Arg124His His626Arg, Ala546Asp in 13 families and five sporadic cases of German origin. The underlying gene defect within the TBFBI gene was not identified in any of the four probands with Thiel-Behnke corneal dystrophy. CONCLUSIONS: The two novel mutations within the TGFBI gene add another two phenotypes with atypical immunohistochemical and histopathological features to those so far reported.