Risk factors for SARS transmission from patients requiring intubation: a multicentre investigation in Toronto, Canada.

BACKGROUND: In the 2003 Toronto SARS outbreak, SARS-CoV was transmitted in hospitals despite adherence to infection control procedures. Considerable controversy resulted regarding which procedures and behaviours were associated with the greatest risk of SARS-CoV transmission. METHODS: A retrospective cohort study was conducted to identify risk factors for transmission of SARS-CoV during intubation from laboratory confirmed SARS patients to HCWs involved in their care. All SARS patients requiring intubation during the Toronto outbreak were identified. All HCWs who provided care to intubated SARS patients during treatment or transportation and who entered a patient room or had direct patient contact from 24 hours before to 4 hours after intubation were eligible for this study. Data was collected on patients by chart review and on HCWs by interviewer-administered questionnaire. Generalized estimating equation (GEE) logistic regression models and classification and regression trees (CART) were used to identify risk factors for SARS transmission. RESULTS: 45 laboratory-confirmed intubated SARS patients were identified. Of the 697 HCWs involved in their care, 624 (90%) participated in the study. SARS-CoV was transmitted to 26 HCWs from 7 patients; 21 HCWs were infected by 3 patients. In multivariate GEE logistic regression models, presence in the room during fiberoptic intubation (OR = 2.79, p = .004) or ECG (OR = 3.52, p = .002), unprotected eye contact with secretions (OR = 7.34, p = .001), patient APACHE II score > or = 20 (OR = 17.05, p = .009) and patient Pa0(2)/Fi0(2) ratio < or = 59 (OR = 8.65, p = .001) were associated with increased risk of transmission of SARS-CoV. In CART analyses, the four covariates which explained the greatest amount of variation in SARS-CoV transmission were covariates representing individual patients. CONCLUSION: Close contact with the airway of severely ill patients and failure of infection control practices to prevent exposure to respiratory secretions were associated with transmission of SARS-CoV. Rates of transmission of SARS-CoV varied widely among patients.

Perinatal exposure to antiretroviral therapy is associated with increased blood mitochondrial DNA levels and decreased mitochondrial gene expression in infants.

BACKGROUND: The effects of perinatal antiretroviral therapy (ART) on infant mitochondrial function are not well known. We compared blood mitochondrial DNA (mtDNA) levels and mtDNA gene expression (mtRNA) in human immunodeficiency virus (HIV)-uninfected, ART-exposed infants born to HIV-positive mothers with mtDNA levels and mtDNA gene expression in control infants born to uninfected women. METHODS: In this prospective cohort study, longitudinal mtDNA:nuclear DNA and mtRNA:beta-actin mRNA ratios were compared in blood samples obtained at various time points from birth to 8 months, using generalized estimating equation linear regression models. RESULTS: Log(10) mtDNA levels at birth were higher in ART-exposed infants, compared with levels in control infants, although the difference did not reach statistical significance (P = .07 for comparison of samples obtained 0-3 days after birth). ART-exposed infants' mtDNA levels increased further during the zidovudine prophylaxis period-from age 4 days to age 6 weeks-(P = .001) and remained significantly higher than the levels observed in control infants until the end of the study. In contrast, log(10) mtRNA levels at birth were lower in ART-exposed infants than in control infants (P = .03), but were not statistically different later. CONCLUSIONS: When control infants and ART-exposed infants were compared, the mtDNA level was increased but mitochondrial gene expression was decreased in ART-exposed infants. These differences persisted after zidovudine was discontinued, suggesting that changes in mitochondrial proliferation and/or expression take place during and after ART exposure. These changes are likely the effects of the antiretroviral drugs on mitochondria. The clinical relevance and long-term impact of these alterations must be studied.

Hyperbolic relationship between insulin secretion and sensitivity on oral glucose tolerance test.

The utility of the disposition index as a measure of beta-cell compensatory capacity rests on the established hyperbolic relationship between its component insulin secretion and sensitivity measures as derived from the intravenous glucose tolerance test (IVGTT). If one is to derive an analogous measure of beta-cell compensation from the oral glucose tolerance test (OGTT), it is thus necessary to first establish the existence of this hyperbolic relationship between OGTT-based measures of insulin secretion and insulin sensitivity. In this context, we tested five OGTT-based measures of secretion (insulinogenic index, Stumvoll first phase, Stumvoll second phase, ratio of total area-under-the-insulin-curve to area-under-the-glucose-curve (AUC(ins/gluc)), and incremental AUC(ins/gluc)) with two measures of sensitivity (Matsuda index and 1/Homeostasis Model of Assessment for insulin resistance (HOMA-IR)). Using a model of log(secretion measure) = constant + beta x log(sensitivity measure), a hyperbolic relationship can be established if beta is approximately equal to -1, with 95% confidence interval (CI) excluding 0. In 277 women with normal glucose tolerance (NGT), the pairing of total AUC(ins/gluc) and Matsuda index was the only combination that satisfied these criteria (beta = -0.99, 95% CI (-1.66, -0.33)). This pairing also satisfied hyperbolic criteria in 53 women with impaired glucose tolerance (IGT) (beta = -1.02, (-1.72, -0.32)). In a separate data set, this pairing yielded distinct hyperbolae for NGT (n = 245) (beta = -0.99, (-1.67, -0.32)), IGT (n = 116) (beta = -1.18, (-1.84, -0.53)), and diabetes (n = 43) (beta = -1.37, (-2.46, -0.29)). Moreover, the product of AUC(ins/gluc) and Matsuda index progressively decreased from NGT (212) to IGT (193) to diabetes (104) (P < 0.001), consistent with declining beta-cell function. In summary, a hyperbolic relationship can be demonstrated between OGTT-derived AUC(ins/gluc) and Matsuda index across a range of glucose tolerance. Based on these findings, the product of these two indices emerges as a potential OGTT-based measure of beta-cell function.

A randomized, placebo-controlled trial of rosiglitazone for HIV-related lipoatrophy.

BACKGROUND: Thiazolidinediones such as rosiglitazone may have benefit in ameliorating human immunodeficiency virus (HIV) lipoatrophy. METHODS: HIV-positive patients receiving stable, protease inhibitor-containing highly active antiretroviral therapy with HIV lipodystrophy were prospectively randomized to rosiglitazone (4 mg/day) or placebo. The primary end point was the 24-week percentage change in arm fat by dual-energy x-ray absorptiometry (DEXA). Clinical and anthropometric evaluations, fasting lipid parameters, oral glucose tolerance testing, CD36 expression, quality of life measures, and DEXA scanning were performed at baseline and week 24. RESULTS: Seventy-eight of the 96 enrolled patients were evaluated. Median age was 46.8 years, 97.4% were male, and 54% were treated with thymidine analogues. Median baseline limb fat was 3.76 and 2.99 kg in the rosiglitazone and control groups, respectively. Median changes in arm, leg, trunk, and total body fat at 24 weeks were not significantly different between groups (7.1% vs. 5.0% [P=.94]; 0.1% vs. -2.4% [P=.90]; 1.2% vs. -1.4% [P=.81]; and 1.7% vs. 0.4% [P=.76]). There were no significant changes in secondary end points. There was no correlation between changes in body fat or treatment-arm and CD36 expression. CONCLUSIONS: This randomized, placebo-controlled trial did not show benefit of 4 mg/day of rosiglitazone on lipoatrophy or metabolic parameters in patients with HIV lipodystrophy.

Immediate versus delayed polyalkylimide gel injections to correct facial lipoatrophy in HIV-positive patients.

OBJECTIVE: To evaluate the safety and efficacy of polyalkylimide gel (PAIG) in the treatment of HIV-associated facial lipoatrophy. DESIGN: A randomized, open-label, single-centre study. METHODS: HIV-positive individuals with facial lipoatrophy (based on physician assessment) were randomly assigned to immediate (weeks 0 and 6) or delayed (weeks 12 and 18) PAIG injections administered into the subcutaneous plane. Outcome measures included a change in facial lipoatrophy severity scores (five-point scale), adverse events, photographic assessment, and changes in quality of life (QoL), depression and anxiety using validated surveys. RESULTS: Thirty-one patients (median age 48 years, 97% male) were enrolled and completed 48 weeks of follow-up. Overall, the median volume of product injected bilaterally was 16.0 ml. Adverse events, including swelling, redness, bruising and pain, were mild, and resolved after a median of 3 days. There were no cases of necrosis, nodules or infection. Compared with patients randomly assigned to delayed treatment, patients in the immediate therapy group had significantly lower physician-rated facial lipoatrophy scores (0 versus 2; P < 0.0001), improved QoL (P = 0.01), and lower anxiety (P = 0.02) at week 12. At week 48, median physician and patient facial lipoatrophy scores were 0 and 1, respectively, for the entire cohort, and were not significantly different between the groups. Significant improvements in patient anxiety (P = 0.001) and depression (P = 0.01) were observed from baseline to week 48. CONCLUSION: Treatment with PAIG was effective and safe and led to improvements in facial lipoatrophy grading, QoL, anxiety and depression scores in HIV-infected patients with facial lipoatrophy.

Mild to moderate symptoms do not correlate with lactate levels in HIV-positive patients on nucleoside reverse transcriptase inhibitors.

PURPOSE: Nucleoside reverse transcriptase inhibitors (NRTIs) are associated with mitochondrial toxicities ranging from asymptomatic hyperlactatemia to fatal lactic acidosis. It is uncertain whether mild clinical symptoms predict hyperlactatemia and the need to consider changes in antiretroviral therapy. This cross-sectional study evaluated whether an association exists between mild symptoms and lactate levels. METHOD: HIV-positive patients on NRTIs attending routine clinic visits were surveyed about symptoms associated with hyperlactatemia. Symptom severity was quantified using Likert scales, and the sum was converted into a symptom score ranging from 0 to 30. Tourniquet-free blood specimens were collected simultaneously to measure serum lactate. Symptom scores were compared between patients with normal and elevated lactates. RESULTS: 284 individuals were included. The most common NRTIs used included lamivudine (79%), zidovudine (50%), abacavir (39%), and stavudine (24%). Twenty-two patients (8%) had increased lactates (mean = 2.7 mmol/L; range, 2.1-4.5 mmol/L), while 262 patients (92%) had normal lactates (mean = 1.2 mmol/L, range, 0.1-2.0 mmol/L). Median symptom scores were similar between groups (3 vs. 2, p = .23). Spearman's correlation coefficient for lactate and symptom score was 0.07 (p = .22). CONCLUSIONS: Mild symptoms did not correlate with lactate levels, and symptoms alone should not trigger clinicians to measure serum lactates and stop NRTIs if the levels are elevated.

Long-term follow-up of a cohort of HIV-infected patients who discontinued maintenance therapy for cytomegalovirus retinitis.

PURPOSE: To determine the long-term safety of discontinuation of maintenance therapy for cytomegalovirus retinitis (CMVR) and to identify predictors for relapse. METHOD: This was a prospective cohort study. Patients with treated CMVR who responded to HAART were followed by ophthalmologic assessment, markers for CMV replication (blood and urine cultures, CMV antigenemia, CMV DNA by PCR), and in vitro lymphoproliferative responses to CMV and other antigens after discontinuation of CMVR maintenance therapy. RESULTS: 23 patients were followed a median of 34 (range, 5-61) months. Median CD4 count was 321/mm3 at enrollment and 395/mm3 at last follow-up. HIV RNA was <50 copies/mL in 78% of patients at enrollment and 65% at last follow-up. One CMVR reactivation occurred at 12 months at a CD4 count of 395/mm3 (21%) and HIV RNA <50 copies/mL. Urine cultures were a poor predictive marker for reactivation. Other CMV replication markers had good negative predictive value. 96% of patients had a good lymphoproliferative response to CMV antigen in vitro. CONCLUSION: Maintenance therapy for CMVR can safely be discontinued in patients who have responded to HAART. Combining our results with the published literature, the risk of reactivation is estimated at 0.016 per person year of follow-up. Markers to predict relapse and the need for re-initiation of maintenance therapy are not yet identified.