Centre Hospitalier Universitaire de Saint-Pierre

Liver biopsy remains the gold standard in the assessment of severity of liver disease. Noninvasive tests have gained popularity to predict histology in view of the associated risks of biopsy. However, many models include tests not readily available, and there are limited data from patients with HIV/hepatitis C virus (HCV) coinfection. We aimed to develop a model using routine tests to predict liver fibrosis in patients with HIV/HCV coinfection. A retrospective analysis of liver histology was performed in 832 patients. Liver fibrosis was assessed via Ishak score; patients were categorized as 0-1, 2-3, or 4-6 and were randomly assigned to training (n = 555) or validation (n = 277) sets. Multivariate logistic regression analysis revealed that platelet count (PLT), age, AST, and INR were significantly associated with fibrosis. Additional analysis revealed PLT, age, AST, and ALT as an alternative model. Based on this, a simple index (FIB-4) was developed: age ([yr] x AST [U/L]) / ((PLT [10(9)/L]) x (ALT [U/L])(1/2)). The AUROC of the index was 0.765 for differentiation between Ishak stage 0-3 and 4-6. At a cutoff of <1.45 in the validation set, the negative predictive value to exclude advanced fibrosis (stage 4-6) was 90% with a sensitivity of 70%. A cutoff of >3.25 had a positive predictive value of 65% and a specificity of 97%. Using these cutoffs, 87% of the 198 patients with FIB-4 values outside 1.45-3.25 would be correctly classified, and liver biopsy could be avoided in 71% of the validation group. In conclusion, noninvasive tests can accurately predict hepatic fibrosis and may reduce the need for liver biopsy in the majority of HIV/HCV-coinfected patients.

BACKGROUND: In the Strategies for Management of Anti-Retroviral Therapy trial, all-cause mortality was higher for participants randomized to intermittent, CD4-guided antiretroviral treatment (ART) (drug conservation [DC]) than continuous ART (viral suppression [VS]).We hypothesized that increased HIV-RNA levels following ART interruption induced activation of tissue factor pathways, thrombosis, and fibrinolysis. METHODS AND FINDINGS: Stored samples were used to measure six biomarkers: high sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6), amyloid A, amyloid P, D-dimer, and prothrombin fragment 1+2. Two studies were conducted: (1) a nested case-control study for studying biomarker associations with mortality, and (2) a study to compare DC and VS participants for biomarker changes. For (1), markers were determined at study entry and before death (latest level) for 85 deaths and for two controls (n = 170) matched on country, age, sex, and date of randomization. Odds ratios (ORs) were estimated with logistic regression. For each biomarker, each of the three upper quartiles was compared to the lowest quartile. For (2), the biomarkers were assessed for 249 DC and 250 VS participants at study entry and 1 mo following randomization. Higher levels of hsCRP, IL-6, and D-dimer at study entry were significantly associated with an increased risk of all-cause mortality. Unadjusted ORs (highest versus lowest quartile) were 2.0 (95% confidence interval [CI], 1.0-4.1; p = 0.05), 8.3 (95% CI, 3.3-20.8; p < 0.0001), and 12.4 (95% CI, 4.2-37.0; p < 0.0001), respectively. Associations were significant after adjustment, when the DC and VS groups were analyzed separately, and when latest levels were assessed. IL-6 and D-dimer increased at 1 mo by 30% and 16% in the DC group and by 0% and 5% in the VS group (p < 0.0001 for treatment difference for both biomarkers); increases in the DC group were related to HIV-RNA levels at 1 mo (p < 0.0001). In an expanded case-control analysis (four controls per case), the OR (DC/VS) for mortality was reduced from 1.8 (95% CI, 1.1-3.1; p = 0.02) to 1.5 (95% CI, 0.8-2.8) and 1.4 (95% CI, 0.8-2.5) after adjustment for latest levels of IL-6 and D-dimer, respectively. CONCLUSIONS: IL-6 and D-dimer were strongly related to all-cause mortality. Interrupting ART may further increase the risk of death by raising IL-6 and D-dimer levels. Therapies that reduce the inflammatory response to HIV and decrease IL-6 and D-dimer levels may warrant investigation.

Via its interaction in several pathways, normal thyroid function is important to maintain normal reproduction. In both genders, changes in SHBG and sex steroids are a consistent feature associated with hyper- and hypothyroidism and were already reported many years ago. Male reproduction is adversely affected by both thyrotoxicosis and hypothyroidism. Erectile abnormalities have been reported. Thyrotoxicosis induces abnormalities in sperm motility, whereas hypothyroidism is associated with abnormalities in sperm morphology; the latter normalize when euthyroidism is reached. In females, thyrotoxicosis and hypothyroidism can cause menstrual disturbances. Thyrotoxicosis is associated mainly with hypomenorrhea and polymenorrhea, whereas hypothyroidism is associated mainly with oligomenorrhea. Thyroid dysfunction has also been linked to reduced fertility. Controlled ovarian hyperstimulation leads to important increases in estradiol, which in turn may have an adverse effect on thyroid hormones and TSH. When autoimmune thyroid disease is present, the impact of controlled ovarian hyperstimulation may become more severe, depending on preexisting thyroid abnormalities. Autoimmune thyroid disease is present in 5-20% of unselected pregnant women. Isolated hypothyroxinemia has been described in approximately 2% of pregnancies, without serum TSH elevation and in the absence of thyroid autoantibodies. Overt hypothyroidism has been associated with increased rates of spontaneous abortion, premature delivery and/or low birth weight, fetal distress in labor, and perhaps gestation-induced hypertension and placental abruption. The links between such obstetrical complications and subclinical hypothyroidism are less evident. Thyrotoxicosis during pregnancy is due to Graves' disease and gestational transient thyrotoxicosis. All antithyroid drugs cross the placenta and may potentially affect fetal thyroid function.

OBJECTIVE: The objective is to provide clinical guidelines for the management of thyroid problems present during pregnancy and in the postpartum. PARTICIPANTS: The Chair was selected by the Clinical Guidelines Subcommittee (CGS) of The Endocrine Society. The Chair requested participation by the Latin American Thyroid Society, the Asia and Oceania Thyroid Society, the American Thyroid Association, the European Thyroid Association, and the American Association of Clinical Endocrinologists, and each organization appointed a member to the task force. Two members of The Endocrine Society were also asked to participate. The group worked on the guidelines for 2 yr and held two meetings. There was no corporate funding, and no members received remuneration. EVIDENCE: Applicable published and peer-reviewed literature of the last two decades was reviewed, with a concentration on original investigations. The grading of evidence was done using the United States Preventive Services Task Force system and, where possible, the GRADE system. CONSENSUS PROCESS: Consensus was achieved through conference calls, two group meetings, and exchange of many drafts by E-mail. The manuscript was reviewed concurrently by the Society's CGS, Clinical Affairs Committee, members of The Endocrine Society, and members of each of the collaborating societies. Many valuable suggestions were received and incorporated into the final document. Each of the societies endorsed the guidelines. CONCLUSIONS: Management of thyroid diseases during pregnancy requires special considerations because pregnancy induces major changes in thyroid function, and maternal thyroid disease can have adverse effects on the pregnancy and the fetus. Care requires coordination among several healthcare professionals. Avoiding maternal (and fetal) hypothyroidism is of major importance because of potential damage to fetal neural development, an increased incidence of miscarriage, and preterm delivery. Maternal hyperthyroidism and its treatment may be accompanied by coincident problems in fetal thyroid function. Autoimmune thyroid disease is associated with both increased rates of miscarriage, for which the appropriate medical response is uncertain at this time, and postpartum thyroiditis. Fine-needle aspiration cytology should be performed for dominant thyroid nodules discovered in pregnancy. Radioactive isotopes must be avoided during pregnancy and lactation. Universal screening of pregnant women for thyroid disease is not yet supported by adequate studies, but case finding targeted to specific groups of patients who are at increased risk is strongly supported.

Graves' disease (GD) is a systemic autoimmune disorder characterized by the infiltration of thyroid antigen-specific T cells into thyroid-stimulating hormone receptor (TSH-R)-expressing tissues. Stimulatory autoantibodies (Ab) in GD activate the TSH-R leading to thyroid hyperplasia and unregulated thyroid hormone production and secretion. Diagnosis of GD is straightforward in a patient with biochemically confirmed thyrotoxicosis, positive TSH-R-Ab, a hypervascular and hypoechoic thyroid gland (ultrasound), and associated orbitopathy. In GD, measurement of TSH-R-Ab is recommended for an accurate diagnosis/differential diagnosis, prior to stopping antithyroid drug (ATD) treatment and during pregnancy. Graves' hyperthyroidism is treated by decreasing thyroid hormone synthesis with the use of ATD, or by reducing the amount of thyroid tissue with radioactive iodine (RAI) treatment or total thyroidectomy. Patients with newly diagnosed Graves' hyperthyroidism are usually medically treated for 12-18 months with methimazole (MMI) as the preferred drug. In children with GD, a 24- to 36-month course of MMI is recommended. Patients with persistently high TSH-R-Ab at 12-18 months can continue MMI treatment, repeating the TSH-R-Ab measurement after an additional 12 months, or opt for therapy with RAI or thyroidectomy. Women treated with MMI should be switched to propylthiouracil when planning pregnancy and during the first trimester of pregnancy. If a patient relapses after completing a course of ATD, definitive treatment is recommended; however, continued long-term low-dose MMI can be considered. Thyroidectomy should be performed by an experienced high-volume thyroid surgeon. RAI is contraindicated in Graves' patients with active/severe orbitopathy, and steroid prophylaxis is warranted in Graves' patients with mild/active orbitopathy receiving RAI.

BACKGROUND: Dolutegravir (S/GSK1349572), a once-daily, unboosted integrase inhibitor, was recently approved in the United States for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in combination with other antiretroviral agents. Dolutegravir, in combination with abacavir-lamivudine, may provide a simplified regimen. METHODS: We conducted a randomized, double-blind, phase 3 study involving adult participants who had not received previous therapy for HIV-1 infection and who had an HIV-1 RNA level of 1000 copies per milliliter or more. Participants were randomly assigned to dolutegravir at a dose of 50 mg plus abacavir-lamivudine once daily (DTG-ABC-3TC group) or combination therapy with efavirenz-tenofovir disoproxil fumarate (DF)-emtricitabine once daily (EFV-TDF-FTC group). The primary end point was the proportion of participants with an HIV-1 RNA level of less than 50 copies per milliliter at week 48. Secondary end points included the time to viral suppression, the change from baseline in CD4+ T-cell count, safety, and viral resistance. RESULTS: A total of 833 participants received at least one dose of study drug. At week 48, the proportion of participants with an HIV-1 RNA level of less than 50 copies per milliliter was significantly higher in the DTG-ABC-3TC group than in the EFV-TDF-FTC group (88% vs. 81%, P=0.003), thus meeting the criterion for superiority. The DTG-ABC-3TC group had a shorter median time to viral suppression than did the EFV-TDF-FTC group (28 vs. 84 days, P<0.001), as well as greater increases in CD4+ T-cell count (267 vs. 208 per cubic millimeter, P<0.001). The proportion of participants who discontinued therapy owing to adverse events was lower in the DTG-ABC-3TC group than in the EFV-TDF-FTC group (2% vs. 10%); rash and neuropsychiatric events (including abnormal dreams, anxiety, dizziness, and somnolence) were significantly more common in the EFV-TDF-FTC group, whereas insomnia was reported more frequently in the DTG-ABC-3TC group. No participants in the DTG-ABC-3TC group had detectable antiviral resistance; one tenofovir DF-associated mutation and four efavirenz-associated mutations were detected in participants with virologic failure in the EFV-TDF-FTC group. CONCLUSIONS: Dolutegravir plus abacavir-lamivudine had a better safety profile and was more effective through 48 weeks than the regimen with efavirenz-tenofovir DF-emtricitabine. (Funded by ViiV Healthcare; SINGLE ClinicalTrials.gov number, NCT01263015 .).

BACKGROUND: The clinical presentation of European patients with mild-to-moderate COVID-19 infection is still unknown. OBJECTIVE: To study the clinical presentation of COVID-19 in Europe. METHODS: Patients with positive diagnosis of COVID-19 were recruited from 18 European hospitals. Epidemiological and clinical data were obtained through a standardized questionnaire. Bayesian analysis was used for analysing the relationship between outcomes. RESULTS: A total of 1,420 patients completed the study (962 females, 30.7% of healthcare workers). The mean age of patients was 39.17 ± 12.09 years. The most common symptoms were headache (70.3%), loss of smell (70.2%), nasal obstruction (67.8%), cough (63.2%), asthenia (63.3%), myalgia (62.5%), rhinorrhea (60.1%), gustatory dysfunction (54.2%) and sore throat (52.9%). Fever was reported by 45.4%. The mean duration of COVID-19 symptoms of mild-to-moderate cured patients was 11.5 ± 5.7 days. The prevalence of symptoms significantly varied according to age and sex. Young patients more frequently had ear, nose and throat complaints, whereas elderly individuals often presented fever, fatigue and loss of appetite. Loss of smell, headache, nasal obstruction and fatigue were more prevalent in female patients. The loss of smell was a key symptom of mild-to-moderate COVID-19 patients and was not associated with nasal obstruction and rhinorrhea. Loss of smell persisted at least 7 days after the disease in 37.5% of cured patients. CONCLUSION: The clinical presentation of mild-to-moderate COVID-19 substantially varies according to the age and the sex characteristics of patients. Olfactory dysfunction seems to be an important underestimated symptom of mild-to-moderate COVID-19 that needs to be recognized as such by the WHO.

BACKGROUND: CC chemokine receptor 5 antagonists are a new class of antiretroviral agents. METHODS: We conducted two double-blind, placebo-controlled, phase 3 studies--Maraviroc versus Optimized Therapy in Viremic Antiretroviral Treatment-Experienced Patients (MOTIVATE) 1 and MOTIVATE 2--with patients who had R5 human immunodeficiency virus type 1 (HIV-1) only. They had been treated with or had resistance to three antiretroviral-drug classes and had HIV-1 RNA levels of more than 5000 copies per milliliter. The patients were randomly assigned to one of three antiretroviral regimens consisting of maraviroc once daily, maraviroc twice daily, or placebo, each of which included optimized background therapy (OBT) based on treatment history and drug-resistance testing. Safety and efficacy were assessed after 48 weeks. RESULTS: A total of 1049 patients received the randomly assigned study drug; the mean baseline HIV-1 RNA level was 72,400 copies per milliliter, and the median CD4 cell count was 169 per cubic millimeter. At 48 weeks, in both studies, the mean change in HIV-1 RNA from baseline was greater with maraviroc than with placebo: -1.66 and -1.82 log(10) copies per milliliter with the once-daily and twice-daily regimens, respectively, versus -0.80 with placebo in MOTIVATE 1, and -1.72 and -1.87 log(10) copies per milliliter, respectively, versus -0.76 with placebo in MOTIVATE 2. More patients receiving maraviroc once or twice daily had HIV-1 RNA levels of less than 50 copies per milliliter (42% and 47%, respectively, vs. 16% in the placebo group in MOTIVATE 1; 45% in both maraviroc groups vs. 18% in MOTIVATE 2; P<0.001 for both comparisons in each study). The change from baseline in CD4 counts was also greater with maraviroc once or twice daily than with placebo (increases of 113 and 122 per cubic millimeter, respectively, vs. 54 in MOTIVATE 1; increases of 122 and 128 per cubic millimeter, respectively, vs. 69 in MOTIVATE 2; P<0.001 for both comparisons in each study). Frequencies of adverse events were similar among the groups. CONCLUSIONS: Maraviroc, as compared with placebo, resulted in significantly greater suppression of HIV-1 and greater increases in CD4 cell counts at 48 weeks in previously treated patients with R5 HIV-1 who were receiving OBT. (ClinicalTrials.gov numbers, NCT00098306 and NCT00098722.)

Ovarian hyperstimulation syndrome (OHSS) is a rare iatrogenic complication of ovarian stimulation occurring during the luteal phase or during early pregnancy. Fortunately, the reported prevalence of the severe form of OHSS is small, ranging from 0.5 to 5%. Nevertheless, as this is an iatrogenic complication of a non-vital treatment with a potentially fatal outcome, the syndrome remains a serious problem for specialists dealing with infertility. The aim of this literature review was to determine whether it is possible to identify patients at risk, and which preventive method should be applied when an exaggerated ovarian response occurs. Data pertaining to the epidemiology and prevention of OHSS in women were searched using Medline, Current Contents and PubMed, and are summarized. Preventive strategies attempt either to limit the dose or concentration of hCG or to find a way to induce luteolysis without inducing a detrimental effect on endometrial and oocyte quality. The following particular preventive strategies were reviewed: cancelling the cycle; coasting; early unilateral ovarian follicular aspiration (EUFA); modifying the methods of ovulation triggering; administration of glucocorticoids, macromolecules and progesterone; cryopreservation of all embryos; and electrocautery or laser vaporization of one or both ovaries.

In the WHO European Region, COVID-19 surveillance was implemented 27 January 2020. We detail the first European cases. As at 21 February, nine European countries reported 47 cases. Among 38 cases studied, 21 were linked to two clusters in Germany and France, 14 were infected in China. Median case age was 42 years; 25 were male. Late detection of the clusters' index cases delayed isolation of further local cases. As at 5 March, there were 4,250 cases.

Background. The risk of myocardial infarction (MI) in patients with human immunodeficiency virus (HIV) infection has been assessed in 13 anti-HIV drugs in the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) study. Methods. Poisson regression models were adjusted for cardiovascular risk factors, cohort, calendar year, and use of other antiretroviral drugs and assessed the association between MI risk and cumulative (per year) or recent (current or in the past 6 months) use of antiretroviral drugs, with 130,000 person-years of exposure. Results. Over 178,835 person-years, 580 patients developed MI. There were no associations between use of tenofovir, zalcitabine, zidovudine, stavudine, or lamivudine and MI risk. Recent exposure to abacavir or didanosine was associated with an increased risk of MI. No association was found between MI risk and cumulative exposure to nevirapine, efavirenz, nelfinavir, or saquinavir. Cumulative exposure to indinavir and lopinavir-ritonavir was associated with an increased risk of MI (relative rate [RR] per year, 1.12 and 1.13, respectively). These increased risks were attenuated slightly (RR per year, 1.08 [95% confidence interval {CI}, 1.02–1.14] and 1.09 [95% CI, 1.01–1.17], respectively) after adjustment for lipids but were not altered further after adjustment for other metabolic parameters. Conclusions. Of the drugs considered, only indinavir, lopinavir-ritonavir, didanosine, and abacavir were associated with a significantly increased risk of MI. As with any observational study, our findings must be interpreted with caution (given the potential for confounding) and in the context of the benefits that these drugs provide.

This paper reviews present knowledge on the etiology, pathophysiology, complications, prevention, and therapy of the disorders induced by iodine deficiency. The recommended dietary allowances of iodine are 100 μg/day for adults and adolescents, 60–100 μg/day for children aged 1 to 10 years, and 35–40 μg/day in infants aged less than 1 year. When the physiological requirements of iodine are not met in a given population, a series of functional and developmental abnormalities occur including thyroid function abnormalities and, when iodine deficiency is severe, endemic goiter and cretinism, endemic mental retardation, decreased fertility rate, increased perinatal death, and infant mortality. These complications, which constitute a hindrance to the development of the affected populations, are grouped under the general heading of iodine deficiency disorders (IDD). At least one billion people are at risk of IDD. Iodine deficiency, therefore, constitutes one of the most common preventable causes of mental deficiency in the world today. Most of the affected populations live in montainous areas in preindustrialized countries, but 50 to 100 million people are still at risk in Europe. The most important target groups to the effects of iodine deficiency from a public health point of view are pregnant mothers, fetuses, neonates, and young infants because the main complication of IDD, i.e., brain damage resulting in irreversible mental retardation, is the consequence of thyroid failure occurring during pregnancy, fetal, and early postnatal life. The main cause of endemic goiter and cretinism is an insufficient dietary supply of iodine. The additional role of naturally occurring goitrogens has been documented in the case of certain foods (milk, cassava, millet, nuts) and bacterial and chemical water polluants. The mechanism by which the thyroid gland adapts to an insufficient iodine supply is to increase the trapping of iodide as well as the subsequent steps of the intrathyroidal metabolism of iodine leading to preferential synthesis and secretion of triiodotyronine (T3). They are triggered and maintained by increased secretion of TSH, which is ultimately responsible for the development of goiter. The acceleration of the main steps of iodine kinetics and the degree of hyperstimulation by TSH are much more marked in the pediatric age groups, including neonates, than in adults, and the development of goiter appears as an unfavorable side effect in the process of adaptation to iodine deficiency during growth. The most serious complication of iodine deficiency is endemic cretinism, a syndrome characterized by irreversible mental retardation together with either a predominant neurological syndrome or predominant hypothyroidism, or a combination of both syndromes. The prophylactic action of iodine on the incidence of both types of cretinism demonstrates the fundamental etiological role of iodine deficiency. The possible additional roles of thyroid growth-blocking immunoglobulins and of selenium deficiency have been suggested. The pathogenic roles of maternal and fetal hypothyroidism or a combination of both as well as of hypothyroidism present during the postnatal period are clearly established, but the relative importance of the three mechanisms in the pathogenesis of the various clinical manifestations of endemic cretinism is not entirely clearly established. A particularly important issue established both in severe and moderate conditions of iodine deficiency is that obvious neurointellectual deficits due to the deficiency are also frequently observed in individuals who do not present any of the other signs of endemic cretinism. The status of iodine nutrition was recently reevaluated in all European countries, including those in the Eastern part of the continent. Iodine deficiency is presently under control in only 5 countries (Austria, Finland, Norway, Sweden, and Switzerland). All other countries are still affected to varying degrees, especially in the southern and central parts of the continent. The public health consequences of iodine deficiency in Europe are an elevated thyroidal uptake of radioiodine that aggravates the risk of thyroid cancer in case of a nuclear accident, the occasional presence of neurointellectual deficits in schoolchildren, elevated frequencies of transient primary hypothyroidism and of transient hyperthyrotropinemia in young infants. Neonatal screening for congenital hypothyroidism using serum TSH as primary screening test appears as a particularly sensitive index of the effects of iodine deficiency at a population level and as a monitoring tool in the evaluation of the effects of iodine prophylaxis. Although theoretically entirely preventable, IDD still prevail in the world because of various socioeconomical, cultural, and political limitations to adequate programs of iodine supplementation, especially in Europe. Prevention of iodine deficiency in Western countries is most efficiently achieved by programs of salt iodization at the level of one part of iodide to 10,000–50,000 parts salt, depending on the degree of the deficiency and on salt intake. Iodized salt should be made available not only for household salt but also in industrial food production including cheese and bread as well as for animal consumption. As a matter of fact, milk appears as the main source of iodine in many industrialized countries. In preindustrialized countries where food fortification with iodine is impossible to organize, prophylaxis and therapy of IDD can be achieved extremely efficiently by the administration of large quantities of iodine (20-960 mg) in the form of slowly resorbable iodized oil administered by intramuscular injections or orally. This approach not only corrected thyroid function on a long-term basis with progressive disappearance of goiter but also prevented the occurrence of endemic cretinism and endemic mental retardation.

This study reports the in vitro influence of morphine, dextromoramide, levomoramide, and methionine-enkephalin upon normal human T blood lymphocytes by using the active and total rosette tests. Morphine and dextromoramide inhibited the percentage of active T rosettes. This effect was completely reversed in the presence of naloxone, their specific antagonist. The specificity was further demonstrated by the absence of the effect of levomoramide, the inactive enantiomere, upon the rosette system. Methionine-enkephalin increased the percentage of active T rosettes. This effect was specifically inhibited by naloxone. These observations suggest that normal human blood T lymphocytes bear surface receptor-like structures for morphine, dextromoramide, and methionine-enkephalin. Such findings may provide a link between the central nervous system and the immune system.

In sensitized subjects, exposure to the mite allergen appears to be only one of several factors leading to asthma. We hypothesized that in association with allergen exposure, endotoxin, a proinflammatory agent present in house dust (HD), influences the severity of asthma. Using a cross-sectional study design, we investigated a group of 69 consecutive dust mite (HDM)-sensitized subjects defined as having rhinitis (n = 20) or asthma (n = 49); the latter were evaluated functionally and clinically by three different scores and by their need for daily medication. Concentrations of Dermatophagoides pteronyssinus p I allergen (Der p I) (by two-site monoclonal antibody enzyme-linked immunosorbent assay [ELISA]), guanine (by high-pressure liquid chromatography [HPLC]), and endotoxin (by modified Limulus. amebocyte lysate assay) were measured in HD collected in duplicate from the mattresses and floors in each subject's home. The concentrations of Der p I and of guanine in HD collected from mattresses were significantly higher in asthmatic subjects than in those with rhinitis (p < 0.05 and < 0.04, respectively). In subjects (n = 37) exposed to a high level of HDM allergen (i.e., Der p I > or = 10 micrograms/g HD and/or guanine > or = 0.10 mg/100 mg HD), the severity of asthma was unrelated to mite allergen concentration in HD. On the contrary, the severity of asthma was related to concomitant exposure to endotoxin in HD, since the concentration of HD endotoxin was significantly and inversely correlated with FEV1 (p < 0.05), FEV1/FVC (p < 0.02), daily need for oral (p < 0.01) and inhaled (p < 0.01) corticosteroids, daily need for beta 2 agonists (p < 0.001) and xanthines (p < 0.01), and clinical scores such as the modified Aas score (p < 0.01). In HDM-sensitized subjects exposed to a high level of allergen, the concentration of endotoxin measured in HD is an important determinant of asthma severity.

BACKGROUND: Whether hepatitis B (HBV) coinfection affects outcome in HIV-1-infected patients remains unclear. OBJECTIVE: To assess the prevalence of HBV (assessed as HBsAg) coinfection and its possible impact on progression to AIDS, all-cause deaths, liver-related deaths and response to highly active antiretroviral therapy (HAART) in the EuroSIDA cohort. METHODS: Data on 9802 patients in 72 European HIV centres were analysed. Incidence rates of AIDS, global mortality and liver-related mortality, time to 25% CD4 cell count increase and time to viral load < 400 copies/ml after starting HAART were calculated and compared between HBsAg-positive and HBsAg-negative patients. RESULTS: HBsAg was found in 498 (8.7%) patients. The incidence of new AIDS diagnosis was similar in HBsAg-positive and HBsAg-negative patients (3.3 and 3.4/100 person-years, respectively) even after adjustment for potential confounders: the incidence rate ratio (IRR) was 0.94 [95% confidence interval (CI), 0.74-1.19; P = 0.61]. The incidences of all-cause and liver-related mortalities were significantly higher in HBsAg-positive subjects (3.7 and 0.7/100 person-years, respectively) compared with HBsAg-negative subjects (2.6 and 0.2/100 person-years, respectively). The adjusted IRR values were 1.53 for global (95% CI, 1.23-1.90; P = 0.0001) and 3.58 for liver-related (95% CI, 2.09-6.16; P < 0.0001) mortality. HBsAg status did not influence viral or immunological responses among the 1679 patients starting HAART. CONCLUSIONS: The prevalence of HBV coinfection was 9% in the EuroSIDA cohort. Chronic HBV infection significantly increased liver-related mortality in HIV-1-infected patients but did not impact on progression to AIDS or on viral and immunological responses to HAART.

UNLABELLED: Beta-blockers may have a negative impact on survival in patients with cirrhosis and refractory ascites. The aim of this study was to evaluate the effect of the administration of beta-blockers on long-term survival in patients with cirrhosis and refractory ascites. We performed a single-center, observational, case-only, prospective study of patients with cirrhosis and refractory ascites who did or did not receive beta-blockers for the prevention of gastrointestinal bleeding; 151 patients were included. The mean Model for End-Stage Liver Disease score was 18.8 +/- 4.1. All patients regularly underwent large-volume paracentesis and intravenous albumin administration. Seventy-seven patients (51%) were treated with propranolol (113 +/- 46 mg/day). The median follow-up for the whole group was 8 months. The median survival time was 10 months [95% confidence interval (CI) = 8-12 months]. The probability of survival at 1 year was 41% (95% CI = 33%-49%). The clinical characteristics and laboratory values at enrolment were not significantly different between patients who were receiving propranolol and those who were not. The median survival time was 20.0 months (95% CI = 4.8-35.2 months) in patients not treated with propranolol and 5.0 months (95% CI = 3.5-6.5 months) in those treated with propranolol (P = 0.0001). The 1-year probability of survival was significantly lower in patients who received propranolol [19% (95% CI = 9%-29%)] versus those who did not [64% (95% CI = 52%-76%), P < 0.0001]. The independent variables of mortality were Child-Pugh class C, hyponatremia and renal failure as causes of refractory ascites, and beta-blocker therapy. CONCLUSION: The use of beta-blockers is associated with poor survival in patients with refractory ascites. These results suggest that beta-blockers should be contraindicated in these patients.

BACKGROUND: The SMART study was a trial of intermittent use of antiretroviral therapy (ART) (drug conservation [DC]) versus continuous use of ART (viral suppression [VS]) as a strategy to reduce toxicities, including cardiovascular disease (CVD) risk. We studied the predictive value of high sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6) and D-dimer with CVD morbidity and mortality in HIV-infected patients who were enrolled in SMART beyond other measured CVD risk factors. METHODS: A blood sample was available in 5098 participants who were enrolled in the SMART study for the measurement of IL-6, hsCRP and D-dimer. Hazard ratios (HR) with 95% CI for CVD events were estimated for each quartile (Q) for each biomarker vs the 1(st) quartile and for 1 SD higher levels. For both treatment groups combined, unadjusted and adjusted HRs were determined using Cox regression models. RESULTS: There were 252 participants who had a CVD event over a median follow-up of 29 months. Adjusted HRs (95% CI) for CVD for Q4 vs Q1 were 4.65 (2.61, 8.29), 2.10 (1.40, 3.16), and 2.14 (1.38, 3.33) for IL-6, hsCRP and D-dimer, respectively. Associations were similar for the DC and VS treatment groups (interaction p-values were >0.30). The addition of the three biomarkers to a model that included baseline covariates significantly improved model fit (p<0.001). Area under the curve (AUC) estimates improved with inclusion of the three biomarkers in a model that included baseline covariates corresponding to other CVD risk factors and HIV factors (0.741 to 0.771; p<0.001 for difference). CONCLUSIONS: In HIV-infected individuals, IL-6, hsCRP and D-dimer are associated with an increased risk of CVD independent of other CVD risk factors. Further research is needed to determine whether these biomarkers can be used to improve CVD risk prediction among HIV positive individuals.

OBJECTIVE: The aims of this study were to determine the incidence of diabetes among HIV-infected patients in the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) cohort, to identify demographic, HIV-related, and combination antiretroviral therapy (cART)-related factors associated with the onset of diabetes, and to identify possible mechanisms for any relationships found. RESEARCH DESIGN AND METHODS: D:A:D is a prospective observational study of 33,389 HIV-infected patients; diabetes is a study end point. Poisson regression models were used to assess the relation between diabetes and exposure to cART after adjusting for known risk factors for diabetes, CD4 count, lipids, and lipodystrophy. RESULTS: Over 130,151 person-years of follow-up (PYFU), diabetes was diagnosed in 744 patients (incidence rate of 5.72 per 1,000 PYFU [95% CI 5.31-6.13]). The incidence of diabetes increased with cumulative exposure to cART, an association that remained significant after adjustment for potential risk factors for diabetes. The strongest relationship with diabetes was exposure to stavudine; exposures to zidovudine and didanosine were also associated with an increased risk of diabetes. Time-updated measurements of total cholesterol, HDL cholesterol, and triglycerides were all associated with diabetes. Adjusting for each of these variables separately reduced the relationship between cART and diabetes slightly. Although lipodystrophy was significantly associated with diabetes, adjustment for this did not modify the relationship between cART and diabetes. CONCLUSION: Stavudine and zidovudine are significantly associated with diabetes after adjustment for risk factors for diabetes and lipids. Adjustment for lipodystrophy did not modify the relationship, suggesting that the two thymidine analogs probably directly contribute to insulin resistance, potentially through mitochondrial toxicity.

A semi-quantitative and non-invasive method for scoring embryos obtained after in-vitro fertilization (IVF) has been defined, aiming at selection of embryos before transfer and at prognostic evaluation of IVF trials. Grading of embryos observed on the inverted microscope was essentially based on the amount of anucleate fragments expelled during early cleavage and on developmental speed. Embryos endowed with a high score were more often associated with pregnancy and in particular with the occurrence of multiple pregnancy. No difference was observed between scores attributed to embryos related to ongoing, aborted or chemical pregnancies. Average embryonic scores corresponding to double and triple transfers differed significantly in failures as well as pregnancies. The better quality of embryos replaced in triple transfers was also apparent from the significantly higher implantation rate per embryo observed in this group. From our results, five criteria including clinical data and embryonic scores can be derived for defining a high risk of multiple pregnancy prior to transfer. It might be warranted to replace only two embryos when these conditions are fulfilled.

Theoretically, in laparoscopic surgery, a computer interface in command of a mechanical system (robot) allows the surgeon: (1) to recover a number a number of lost degrees of freedom, thanks to intra‐abdominal articulations; (2) to obtain better visual control of instrument manipulation, thanks to three‐dimensional vision; (3) to modulate the amplitude of surgical motions by downscaling and stabilization; (4) to work at a distance from the patient. These advances improve the quality of surgical tasks in a perfect ergonomic position. The purpose of this paper is to evaluate the feasibility of utilizing a robot in laparoscopic surgery. The first robot‐assisted procedure in humans was performed in March 1997 by our team. One hundred forty‐six patients underwent robot‐assisted laparoscopic surgery. Between March 1997 and February 2001 a nonconsecutive series was performed of 39 antireflux procedures, 48 cholecystectomies, 28 tubal reanastomoses, 10 gastroplasties for obesity, 3 inguinal hernias, 3 intrarectal procedures, 2 hysterectomies, 2 cardiac procedures, 2 prostactectomies, 2 arteriovenous fistulas, 1 lumbar sympathectomy, 1 appendectomy, 1 laryngeal exploration, 1 varicocele ligation, 1 endometriosis cure, 1 neosalpingostomy, 1 deferent canal. The robot (Da Vinci system, Intuitive Surgical, Mountain View, CA), consists of a console and a cart with three articulated robot arms. The surgeon sits in front of the console, manipulating joysticklike handles while observing the operative field through binoculars that provide a three‐dimensional picture. This computer is capable of modulating these data by eliminating physiologic tremor and by downscaling the amplitude of motions by a factor 5 or 3 to one. This study has demonstrated the feasibility of several laparoscopic robotic procedures. There is no morbidity related to the system. Operating time and the hospital stay were within acceptable limits. The system seems most beneficial in intra‐abdominal microsurgery or for manipulations in a very small space. Optimized ergonomics and increased mobility of the instrument tips are beneficial in many steps of abdominal surgical procedures.