Sympathetic hyper-excitation in obesity and pulmonary hypertension: physiological relevance to the 'obesity paradox'.

BACKGROUND: Within the lung, sympathetic nerve activity (SNA) has an important role in facilitating pulmonary vasodilation. As SNA is elevated in obesity, we aimed to assess the impact of sympathetic hyper-excitation on pulmonary vascular homeostasis in obesity, and its potential role in ameliorating the severity of pulmonary hypertension (PH); the well-documented 'obesity paradox' phenomenon. METHODS: Zucker obese and lean rats were exposed to normoxia or chronic hypoxia (CH-10% O2) for 2 weeks. Subsequently, pulmonary SNA (pSNA) was recorded (electrophysiology), or the pulmonary microcirculation was visualized using Synchrotron microangiography. Acute hypoxic pulmonary vasoconstriction (HPV) was assessed before and after blockade of ß1-adrenergic receptors (ARs) (atenolol, 3 mg kg(-1)) and ß1+ß2-adrenergic (propranolol, 2 mg kg(-1)). RESULTS: pSNA of normoxic obese rats was higher than lean counterparts (2.4 and 0.5 µV s, respectively). SNA was enhanced following the development of PH in lean rats, but more so in obese rats (1.7 and 6.8 µV s, respectively). The magnitude of HPV was similar for all groups (for example, ~20% constriction of the 200-300 µm vessels). Although ß-blockade did not modify HPV in lean rats, it significantly augmented the HPV in normoxic obese rats (ß1 and ß2 blockade), and more so in obese rats with PH (ß2-blockade alone). Western blots showed, while the expression of pulmonary ß1-ARs was similar for all rats, the expression of ß2-ARs was downregulated in obesity and PH. CONCLUSIONS: This study suggests that sympathetic hyper-excitation in obesity may have an important role in constraining the severity of PH and, thus, contribute in part to the 'obesity paradox' in PH.

High prevalence of unintended pregnancies in HIV-positive women of reproductive age in Ontario, Canada: a retrospective study.

OBJECTIVES: There is speculation, but there are few data, on the high rates of unintended pregnancies in HIV-positive women. We investigated rates and correlates of unintended pregnancies among HIV-positive women of reproductive age. METHODS: A cross-sectional study was conducted with recruitment stratified to match the geographical distribution of HIV-positive women of reproductive age (18-52 years) living in Ontario, Canada. Women, recruited from 38 sites between October 2007 and April 2009, were invited to complete a 189-item self-administered survey. This analysis focused on questions relating to pregnancy and whether the last pregnancy was intended. Logistic regression models were fitted to calculate unadjusted and adjusted odds ratios of correlates of unintended pregnancies occurring after HIV diagnosis. Happiness with unintended pregnancies was also assessed. RESULTS: The median age at the time of the survey of the 416 participating HIV-positive women who were previously pregnant (53% before and 47% after HIV diagnosis) was 38 years [interquartile range (IQR) 33-44 years] and their last pregnancy was a median of 8 years (IQR 3-14 years) prior to the survey (n=283). Fifty-nine per cent were born outside Canada and 47% were of African ethnicity. Of the 416, 56% [95% confidence interval (CI) 51-61%] identified that their last pregnancy was unintended (57% before and 54% after HIV diagnosis). In the multivariable model, significant correlates of unintended pregnancy after HIV diagnosis were: marital status (P=0.01) and never having given birth (P=0.01). Women were less happy if their pregnancy was unintended (P<0.01). CONCLUSIONS: The prevalence of unintended pregnancy was high in this cohort. Pregnancy planning programmes are needed for this population to decrease fetal and maternal complications and reduce vertical and horizontal transmission.

Opioid Use After Nephrectomy for Kidney Cancer in Ontario: A Population-Based Study.

OBJECTIVE: To compare the odds of early and prolonged post-operative opioid use in patients undergoing minimally invasive surgery (MIS) vs open surgery for nephrectomy. METHODS: For opioid-naïve patients in Ontario who underwent nephrectomy for kidney cancer (1994-2017, n = 7900), post-discharge opioid use was determined by prescriptions in the Ontario Drug Benefit database (age ≥65 years) and the Narcotics Monitoring System (all patients from 2012). Early opioid use was defined as ≥1 prescription 1-90 days after surgery. Two separate definitions of prolonged opioid use were examined: (1) prescription(s) for ≥60 days during post-operative days 90-365; (2) ≥1 prescriptions between both of: 1-90 days AND 91-180 days after surgery. Predictors of opioid use were assessed using multivariable generalized estimating equation logistic regression, accounting for surgeon clustering. RESULTS: Overall, 67.4% of patients received early opioid prescriptions; however, prolonged use was low, ranging from 1.6 to 4.4% of patients depending on the definition. In multivariable analysis, open nephrectomy was associated with higher odds of early opioid use compared to MIS nephrectomy (Odds Ratio [OR] 1.36, 95% Confidence Interval [CI] 1.19-1.55). Surgery type was not significantly associated with prolonged opioid use for either definition (OR 1.22, CI 0.79-1.89 and OR 1.06, CI 0.83-1.35). CONCLUSIONS: In this population-level study of patients undergoing nephrectomy for kidney cancer, patients who received open surgery were at increased odds of receiving early post-operative opioids compared to MIS. Prolonged opioid use was low overall and was not significantly with associated with type of surgery.

HIV/hepatitis C virus and HIV/hepatitis B virus coinfections protect against antiretroviral-related hyperlipidaemia.

INTRODUCTION: Hyperlipidaemia is a recognized complication of HIV antiretroviral therapy. The interactions among HIV, viral hepatitis, antiretroviral therapies and lipids are poorly understood. METHODS: Ontario HIV Treatment Network Cohort Study participants with at least one lipid level after highly active antiretroviral therapy (HAART) initiation were assessed. Hepatitis B virus (HBV)- and hepatitis C virus (HCV)-coinfected patients were identified by serology or chart review. HCV antiviral recipients, diabetics and those on lipid-lowering drugs at baseline were excluded from the study. Factors associated with a decreased risk of grade 3 or 4 hyperlipidaemia or lipid-lowering drug use were assessed by multivariate logistic regression. RESULTS: A total of 1587 HIV-monoinfected, 190 HIV/HBV-coinfected and 255 HIV/HCV-coinfected patients were evaluated. Most were male (85-92% for the 3 groups evaluated: HIV, HIV/HBV, HIV/HCV). The median [interquartile range (IQR)] age at HAART initiation was 48 (44-56) years and was similar between groups. The median (IQR) CD4 count at HAART initiation was 245 (120-370) cells/µL in HIV-monoinfected participants, 195 (110-330) cells/µL in HIV/HBV-coinfected participants and 268 (140-409) cells/µL in HIV/HCV-coinfected participants. Factors associated with a decreased risk of grade 3 or 4 hyperlipidaemia or lipid-lowering drug use included HIV/HCV coinfection [odds ratio (OR) 0.46; 95% confidence interval (CI) 0.34, 0.61; P<0.0001], HIV/HBV coinfection (OR 0.74; 95% CI 0.55, 0.99; P=0.04), year of starting HAART after 2004 vs. 1997 or earlier (OR 0.37; 95% CI 0.29, 0.48; P<0.0001) and year of starting HAART between 1998 and 2003 vs. 1997 or earlier (OR 0.75; 95% CI 0.61, 0.92; P<0.01). Factors associated with increased risk included age (OR 1.55; 95% CI 1.39, 1.72; per 10 years, P<0.0001) and male gender (OR 1.84; 95% CI 1.36, 2.48; P<0.0001). CONCLUSIONS: HIV/HCV and to a lesser extent HIV/HBV coinfections are protective against HAART-related hyperlipidaemia.

Virologic and immunologic effectiveness of tipranavir/ritonavir (TPV/r)- versus darunavir/ritonavir (DRV/r)-based regimens in clinical practice.

BACKGROUND: Although both tipranavir and darunavir are important options for the management of patients with multidrug resistant HIV, there are at present no studies comparing the effectiveness and safety of these 2 antiretroviral drugs in this population of patients. OBJECTIVE: To compare the effectiveness and safety of ritonavir (TPV/r)- and darunavir/ritonavir (DRV/ r)-based therapies in treatment-experienced patients (n = 38 and 47, respectively). METHODS: Multicenter, retrospective cohort study. RESULTS: The median baseline viral load and CD4 count were 4.7 copies/mL (interquartile range [IQR] 4.3, 5.2) and 168 cells/mm( 3) (IQR 80, 252) for TPV/r patients and 4.7 copies/mL (IQR 3.7, 5.1) and 171 cells/mm(3) (IQR 92, 290) for DRV/r patients. The median number of years on antiretroviral therapy (ART) prior to starting DRV/r or TPV/r were 12.7 (10.2-15.5) and 10.5 (8.4-12.6), respectively (P < .01). Current raltegravir (RAL) use (odds ratio [OR] 5.53, 95% CI 1.08-28.34) was significantly associated with virologic suppression at week 24 in multivariable logistic regression models, whereas the use of TPV/r was not significantly associated with virologic suppression compared to DRV/r (OR 0.93, 95% CI 0.27-3.18, P = .91). CONCLUSION: No significant difference was observed between DRV/r and TPV/r in terms of virologic suppression.

Virologic and immunologic impact and durability of enfuvirtide-based antiretroviral therapy in HIV-infected treatment-experienced patients in a clinical setting.

OBJECTIVE: To evaluate the effectiveness and safety of enfuvirtide-based therapy in treatment-experienced patients in a clinical setting. METHOD: Retrospective study of treatment-experienced patients receiving enfuvirtide-based therapy for a minimum of 2 months. Endpoints included virologic suppression, virologic rebound, immunologic response, and adverse events. RESULTS: Sixty-four patients were eligible for inclusion in the analysis. Median baseline viral load and CD4+ count were 4.7 log10 copies/mL (interquartile range [IQR], 4.0-5.2) and 150 cells/mm3 (IQR, 60-250), respectively. At month 12, viral load declined by a median of 2.53 log10 copies/mL (IQR, 0.97-3.12). The unadjusted median time to virologic suppression was 7.7 months (95% CI 4.1-10.4 months). Baseline viral load and number of protease inhibitors in the current regimen were significantly associated with virologic suppression following multivariate analysis (hazard ratio [HR] 0.45, 95% CI 0.31-0.63, p < .0001, and HR 0.51, 95% CI 0.27-0.94, p = .03, respectively). Among the 42 patients who attained sustained virologic suppression, 10 experienced virologic rebound during a median follow-up of 13.3 months (IQR, 7.0-19.1). Injection site reactions were reported in 33 (52%) patients, resulting in treatment discontinuation in nine patients. CONCLUSION: Enfuvirtide-based therapy provides durable antiretroviral activity for treatment-experienced patients in a clinical setting.

An exploration of the applicability of the refined disease risk index and its integration with other independent risk factors for individualized prognostication.

The refined disease risk index (DRI) is a powerful prognostic model based solely on the disease type and stage for predicting survival outcomes of various hematological malignancies after allogeneic transplant. Here, we analyzed our series of 690 patients transplanted over the past 15 years, and showed that besides overall survival (OS), the refined DRI is also able to segregate event-free survival and relapse mortality in our cohort of largely Southeast Asian patients with a long and complete follow-up. Stratification by refined DRI remains statistically significant even when broken down by specific diseases each with a smaller number of patients, as well as for a small subset of patients younger than 18 years old, providing a robust model for prognostication. Multivariable analysis shows that refined DRI, age, year of transplant and donor type are independent risk factors for OS. We further demonstrated here that prognostication for a given patient with a specific disease can be made more discriminating by integrating independent risk factors such as age and donor type with the refined DRI. The future development of prognostic system incorporating the refined DRI with patient- and transplant-related risk factors will provide a more precise estimate of transplant outcome.

Two new coccidian parasites from the grand anglehead lizard, Gonocephalus grandis from Peninsular Malaysia.

During 3 collecting expeditions between October 1996 and December 1996, fecal samples were obtained from 43 adult Gonocephalus grandis from Tanah Rata and the Cameron Highlands in Peninsular Malaysia. Two species of coccidia (Isospora gonocephali n. sp. [9/43, 23%] and Eimeria cameronensis n. sp. [3/43, 7%]) were discovered. Sporulated oocysts of I. gonocephali are subspherical to ovoidal, 22.3 x 18.7 (19-25 x 17-23) microm with a bilayered wall composed of a thin inner wall and a striated outer wall with a pitted surface; oocyst residuum absent; 1 polar granule present; sporocysts are almond-shaped, 13.5 x 9.2 (12-15 x 8.5-10) microm, Stieda body broad, domelike, substieda body fanlike, sporocyst residuum consisting of coarse, nonuniform granules in an amorphous cluster; sporozoites sausage-shaped with 1 large terminal, refractile body and lay randomly in the sporocyst. Sporulated oocysts of E. cameronensis are bilayered, smooth-walled, ellipsoidal, 26.5 x 12.4 (25-28 x 12-13) microm; with 1, small, polar granule composed of 2-3 splinter-like structures fused together; oocyst residuum absent; sporocysts ovoidal, almost rectangular-shaped 8.8 x 6.6 (8-9 x 5-7) microm, with no Stieda or substieda bodies, containing scattered residuum and 2 sausage-shaped sporozoites with 1 terminal, ovoidal refractile body. No individual lizard was host to both coccidian species.

Single center retrospective analysis of BU-based conditioning regimens in allogeneic transplantation.

We performed a single institution retrospective analysis of 114 patients treated with BU-based pretransplant conditioning regimens. Oral BU was administered to 76 patients (total dose 16 mg/kg or 8 mg/kg) and i.v. BU to 38 others (total dose 12.8 mg/kg or 6.4 mg/kg). Either CY (n=74) or fludarabine (n=40) was given in combination with BU. Median age was 35 years in the oral BU group and 48.5 years with i.v. BU (P<0.001). OS and PFS rates at 3-years post HSCT were not different in patients who received either i.v. or oral BU (OS: 41.3 vs 44.0% (P=0.981); PFS: 52.7 vs 54.7% (P=0.526), respectively). The i.v. BU, however, was associated with a significantly shorter time to engraftment (13.5 days vs 16 days, respectively; P<0.001). There were no significant differences in survival or 100-day mortality for patients who received either CY or fludarabine, in combination with BU. After adjustment for confounders, multivariate analysis showed that age of transplant (P=0.002), donor type (sibling or unrelated; P=0.003), GVHD (P<0.05) and route of administration (P=0.023) were significant risk factors for OS. The i.v. BU used in an older age group yielded equivalent survival compared with oral BU used in a younger population.

High-sensitivity and specificity of laser-induced autofluorescence spectra for detection of colorectal cancer with an artificial neural network.

An artificial neural network (ANN) has been used in various clinical research for the prediction and classification of data in cancer disease. Previous research in this direction focused on the correlation between various input parameters such as age, antigen, and size of tumor growth. Recently, laser-induced autofluorescence (LIAF) techniques have been shown to be a useful noninvasive early diagnostic tool for various cancer diseases. We report on a successful application of ANN to in vitro LIAF spectra. We show that classification of tumor samples with ANN can be done with high sensitivity, specificity, and accuracy. Thus a combination of LIAF techniques and ANN can provide a robust method for clinical diagnosis.