Immunological and virological response to initial antiretroviral therapy among older people living with HIV in the Canadian Observational Cohort (CANOC).

OBJECTIVES: The aim of this study was to assess the adequacy of immunological recovery and virological suppression in response to antiretroviral therapy (ART) in the growing population of older people living with HIV (PLWH), as treatment regimens become more effective and tolerable. METHODS: An interprovincial Canadian cohort of treatment-naïve PLWH who initiated ART after 1 January 2000 was used and age assessed in decades. Longitudinal absolute CD4 count response to treatment was modelled using generalized estimating equations. Cumulative incidence functions and proportional hazards models with a competing risk of death were used to estimate time to: (1) CD4 ≥ 200 cells/µL, (2) CD4 ≥ 500 cells/µL, (3) virological suppression (≤ 50 copies/mL), and (4) virological failure (> 200 copies/mL). RESULTS: In all, 12 489 individuals starting ART between 2000 and 2016 with one or more post-treatment CD4 count or viral load were included in the analysis. Age > 60 years was associated with lower absolute CD4 recovery (adjusted ß = -31 cells/µL) compared with age ≤ 30 years when pre-treatment CD4 count and other covariates were accounted for. Older age groups were less likely to achieve a CD4 ≥ 500 cells/µL, with the greatest effect in the > 60 group [adjusted hazard ratio (aHR) = 0.69, 95% confidence interval (CI): 0.57-0.84 vs. age ≤ 30). Older age groups were more likely to achieve viral suppression (age > 60, aHR = 1.20, 95% CI: 1.05-1.37) and less likely to have virological failure (age > 60, aHR = 0.46, 95% CI: 0.3-0.71) compared with those aged ≤ 30 years. CONCLUSIONS: Older adults have robust virological responses to ART; however, individuals over the age 60 are more likely to experience blunted CD4 recovery.

Lost but not forgotten: A population-based study of mortality and care trajectories among people living with HIV who are lost to follow-up in Ontario, Canada.

OBJECTIVES: Selection as a consequence of volunteer participation in, and loss to follow-up from, cohort studies may bias estimates of mortality and other health outcomes. To quantify this potential, we estimated mortality and health service use among people living with HIV (PLWH) who were lost to cohort follow-up (LTCFU) from a volunteer clinical HIV-infected cohort, and compared these to mortality and health service use in active cohort participants and non-cohort-participants living with HIV in Ontario, Canada. METHODS: We analysed population-based provincial health databases from 1995 to 2014, identifying PLWH ≥ 18 years old; these included data from participants in the Ontario HIV Treatment Network Cohort Study (OCS), a volunteer, multi-site clinical HIV-infected cohort. We calculated all-cause mortality, hospitalization and emergency department (ED) visit rates per 100 person-years (PY) and estimated hazard ratios (HRs) of mortality, adjusting for age, sex, income, rurality, and immigration status. RESULTS: Among 23 043 PLWH, 5568 were OCS participants. Compared with nonparticipants, participants were younger and less likely to be female, to be an immigrant and to reside in a major urban centre, and had lower comorbidity. Mortality among active participants, participants LTCFU and nonparticipants was 2.52, 3.30 and 2.20 per 100 PY, respectively. After adjustment for covariates, mortality risk was elevated among participants LTCFU compared with active participants (HR 2.26; 95% confidence interval 1.91, 2.68). Age-adjusted hospitalization rates and ED visit rates were highest among participants LTCFU. CONCLUSIONS: Mortality risk and use of health care resources were lower among active cohort participants. Our findings may inform health outcome estimates based on volunteer cohorts, as well as quantitative bias adjustment to correct for such biases.

Late diagnosis, delayed presentation and late presentation among persons enrolled in a clinical HIV cohort in Ontario, Canada (1999-2013).

OBJECTIVES: Timely HIV diagnosis and presentation to medical care are important for treatment and prevention. Our objective was to measure late diagnosis, delayed presentation and late presentation among individuals in the Ontario HIV Treatment Network Cohort Study (OCS) who were newly diagnosed in Ontario. METHODS: The OCS is a multi-site clinical cohort study of people living with HIV in Ontario, Canada. We measured prevalence of late diagnosis [CD4 count < 350 cells/µL or an AIDS-defining condition (ADC) within 3 months of HIV diagnosis], delayed presentation (≥ 3 months from HIV diagnosis to presentation to care), and late presentation (CD4 count < 350 cells/µL or ADC within 3 months of presentation). We identified characteristics associated with these outcomes and explored their overlap. RESULTS: A total of 1819 OCS participants were newly diagnosed in Ontario from 1999 to 2013. Late diagnosis (53.0%) and presentation (54.0%) were common, and a quarter (23.1%) of participants were delayed presenters. In multivariable models, the participants of delayed presentation decreased over calendar time, but that of late diagnosis/presentation did not. Late diagnosis contributed to the majority (> 87%) of late presentation, and the prevalence of delayed presentation was similar among those diagnosed late versus early (13.4 versus 13.4%, respectively; P = 0.99). Characteristics associated with higher odds of late diagnosis/presentation in multivariable analyses included older age at diagnosis/presentation; African, Caribbean and Black race/ethnicity; Indigenous race/ethnicity; female sex; and being a male who did not report sex with men. There were lower odds of late diagnosis/presentation among participants who had ever injected drugs. In contrast, delayed presentation risk factors included younger age at diagnosis and having ever injected drugs. CONCLUSIONS: Late presentation is common in Ontario, as it is in other high-income countries. Our findings suggest that efforts to reduce late presentation should focus on facilitating earlier diagnosis for the populations identified in this analysis.

Quality of initial HIV care in Canada: extension of a composite programmatic assessment tool for HIV therapy.

OBJECTIVES: To document the quality of initial HIV care in Canada using the Programmatic Compliance Score (PCS), to explore the association of the PCS with mortality, and to identify factors associated with higher quality of care. METHODS: We analysed data from the Canadian Observational Cohort Collaboration (CANOC), a multisite Canadian cohort of HIV-positive adults initiating combination antiretroviral therapy (ART) from 2000 to 2011. PCS indicators of noncompliance with HIV treatment guidelines include: fewer than three CD4 count tests in the first year of ART; fewer than three viral load tests in the first year of ART; no drug resistance testing before initiation; baseline CD4 count < 200 cells/mm3 ; starting a nonrecommended ART regimen; and not achieving viral suppression within 6 months of initiation. Indicators are summed for a score from 0 to 6; higher scores indicate poorer care. Cox regression was used to assess the association between PCS and mortality and ordinal logistic regression was used to explore factors associated with higher quality of care. RESULTS: Of the 7460 participants (18% female), the median score was 1.0 (Q1-Q3 1.0-2.0); 21% scored 0 and 8% scored ≥ 4. In multivariable analysis, compared with a score of 0, poorer PCS was associated with mortality for scores > 1 [score = 2: adjusted hazard ratio (AHR) 1.64; 95% confidence interval (CI) 1.13-2.36; score = 3: AHR 2.02; 95% CI 1.38-2.97; score ≥ 4: AHR 2.14; 95% CI 1.43-3.21], after adjustments for age, sex, province, ART start year, hepatitis C virus (HCV) coinfection, and baseline viral load. Women, individuals with HCV coinfection, younger people, and individuals starting ART earlier (2000-2003) had poorer scores. CONCLUSIONS: Our findings further validate the PCS as a predictor of all-cause mortality. Disparities identified suggest that further efforts are needed to ensure that care is equitably accessible.

A tale of two countries: all-cause mortality among people living with HIV and receiving combination antiretroviral therapy in the UK and Canada.

OBJECTIVES: We sought to compare all-cause mortality of people living with HIV and accessing care in Canada and the UK. METHODS: Individuals from the Canadian Observational Cohort (CANOC) collaboration and UK Collaborative HIV Cohort (UK CHIC) study who were aged ≥ 18 years, had initiated antiretroviral therapy (ART) for the first time between 2000 and 2012 and who had acquired HIV through sexual transmission were included in the analysis. Cox regression was used to investigate the difference in mortality risk between the two cohort collaborations, accounting for loss to follow-up as a competing risk. RESULTS: A total of 19 960 participants were included in the analysis (CANOC, 4137; UK CHIC, 15 823). CANOC participants were more likely to be older [median age 39 years (interquartile range (IQR): 33, 46 years) vs. 36 years (IQR: 31, 43 years) for UK CHIC participants], to be male (86 vs. 73%, respectively), and to report men who have sex with men (MSM) sexual transmission risk (72 vs. 56%, respectively) (all P < 0.001). Overall, 762 deaths occurred during 98 798 person-years (PY) of follow-up, giving a crude mortality rate of 7.7 per 1000 PY [95% confidence interval (CI): 7.1, 8.3 per 1000 PY]. The crude mortality rates were 8.6 (95% CI: 7.4, 10.0) and 7.5 (95% CI: 6.9, 8.1) per 1000 PY among CANOC and UK CHIC study participants, respectively. No statistically significant difference in mortality risk was observed between the cohort collaborations in Cox regression accounting for loss to follow-up as a competing risk (adjusted hazard ratio 0.86; 95% CI: 0.72-1.03). CONCLUSIONS: Despite differences in national HIV care provision and treatment guidelines, mortality risk did not differ between CANOC and UK CHIC study participants who acquired HIV through sexual transmission.

Quantifying sympathetic neuro-haemodynamic transduction at rest in humans: insights into sex, ageing and blood pressure control.

KEY POINTS: We have developed a simple analytical method for quantifying the transduction of sympathetic activity into vascular tone. This method demonstrates that as women age, the transfer of sympathetic nerve activity into vascular tone is increased, so that for a given level of sympathetic activity there is more vasoconstriction. In men, this measure decreases with age. Test-re-test analysis demonstrated that the new method is a reliable estimate of sympathetic transduction. We conclude that increased sympathetic vascular coupling contributes to the age-related increase in blood pressure that occurs in women only. This measure is a reliable estimate of sympathetic transduction in populations with high sympathetic nerve activity. Thus, it will provide information regarding whether treatment targeting the sympathetic nervous system, which interrupts the transfer of sympathetic nerve activity into vascular tone, will be effective in reducing blood pressure in hypertensive patients. This may provide insight into which populations will respond to certain types of anti-hypertensive medication. ABSTRACT: Sex and age differences in the sympathetic control of resting blood pressure (BP) may be due to differences in the transduction of sympathetic nerve activity (SNA) into vascular tone. Current methods for dynamically quantifying transduction focus on the relationship between SNA and vasoconstriction during a pressor stimulus, which increases BP and may be contra-indicated in patients. We describe a simple analytical method for quantifying transduction under resting conditions. We performed linear regression analysis of binned muscle SNA burst areas against diastolic BP (DBP). We assessed whether the slope of this relationship reflects the transduction of SNA into DBP. To evaluate this, we investigated whether this measure captures differences in transduction in different populations. Specifically, we (1) quantified transduction in young men (YM), young women (YW), older men (OM) and postmenopausal women (PMW); and (2) measured changes in transduction during ß-blockade using propranolol in YW, YM and PMW. YM had a greater transduction vs. OM (0.10 ± 0.01 mmHg (% s)(-1) , n = 23 vs. 0.06 ± 0.01 mmHg (% s)(-1) , n = 18; P = 0.003). Transduction was lowest in YW (0.02 ± 0.01 mmHg (% s)(-1) , n = 23) and increased during ß-blockade (0.11 ± 0.01 mmHg (% s)(-1) ; P < 0.001). Transduction in PMW (0.07 ± 0.01 mmHg (% s)(-1) , n = 23) was greater compared to YW (P = 0.001), and was not altered during ß-blockade (0.06 ± 0.01 mmHg (% s)(-1) ; P = 0.98). Importantly, transduction increased in women with age, but decreased in men. Transduction in women intersected that in men at 55 ± 1.5 years. This measure of transduction captures age- and sex-differences in the sympathetic regulation of DBP and may be valuable in quantifying transduction in disease. In particular, this measure may help target treatment strategies in specific hypertensive subpopulations.

Predictors of unstructured antiretroviral treatment interruption and resumption among HIV-positive individuals in Canada.

OBJECTIVES: Sustained optimal use of combination antiretroviral therapy (cART) has been shown to decrease morbidity, mortality and HIV transmission. However, incomplete adherence and treatment interruption (TI) remain challenges to the full realization of the promise of cART. We estimated trends and predictors of treatment interruption and resumption among individuals in the Canadian Observational Cohort (CANOC) collaboration. METHODS: cART-naïve individuals ≥ 18 years of age who initiated cART between 2000 and 2011 were included in the study. We defined TIs as ≥ 90 consecutive days off cART. We used descriptive analyses to study TI trends over time and Cox regression to identify factors predicting time to first TI and time to treatment resumption after a first TI. RESULTS: A total of 7633 participants were eligible for inclusion in the study, of whom 1860 (24.5%) experienced a TI. The prevalence of TI in the first calendar year of cART decreased by half over the study period. Our analyses highlighted a higher risk of TI among women [adjusted hazard ratio (aHR) 1.59; 95% confidence interval (CI) 1.33-1.92], younger individuals (aHR 1.27; 95% CI 1.15-1.37 per decade increase), earlier treatment initiators (CD4 count ≥ 350 vs. <200 cells/µL: aHR 1.46; 95% CI 1.17-1.81), Aboriginal participants (aHR 1.67; 95% CI 1.27-2.20), injecting drug users (aHR 1.43; 95% CI 1.09-1.89) and users of zidovudine vs. tenofovir in the initial cART regimen (aHR 2.47; 95% CI 1.92-3.20). Conversely, factors predicting treatment resumption were male sex, older age, and a CD4 cell count <200 cells/µL at cART initiation. CONCLUSIONS: Despite significant improvements in cART since its advent, our results demonstrate that TIs remain relatively prevalent. Strategies to support continuous HIV treatment are needed to maximize the benefits of cART.

Characteristics and determinants of T-cell phenotype normalization in HIV-1-infected individuals receiving long-term antiretroviral therapy.

OBJECTIVES: Although combination antiretroviral therapy (cART) can restore CD4 T-cell numbers in HIV infection, alterations in T-cell regulation and homeostasis persist. We assessed the incidence and predictors of reversing these alterations with cART. METHODS: ART-naïve adults (n = 4459) followed within the Canadian Observational Cohort and exhibiting an abnormal T-cell phenotype (TCP) prior to cART initiation were studied. Abnormal TCP was defined as having (1) a low CD4 T-cell count (< 532 cells/µL), (2) lost T-cell homeostasis (CD3 < 65% or > 85%) or (3) CD4:CD8 ratio dysregulation (ratio < 1.2). To thoroughly evaluate the TCP, CD4 and CD8 T-cell percentages and absolute counts were also analysed for a median duration of 3.14 years [interquartile range (IQR) 1.48-5.47 years]. Predictors of TCP normalization were assessed using adjusted Cox proportional hazards models. RESULTS: At baseline, 96% of pateints had CD4 depletion, 32% had lost homeostasis and 99% exhibited ratio dysregulation. With treatment, a third of patients had normalized CD4 T-cell counts, but only 85 individuals (2%) had normalized their TCP. In a multivariable model adjusted for age, measurement frequency and baseline regimen, higher baseline CD4 T-cell counts and time-dependent viral suppression independently predicted TCP normalization [hazard ratio (HR) for baseline CD4 T-cell count = 1.42 (1.31-1.54) per 100 cells/µL increase; P ≤ 0.0001; HR for time-dependent suppressed viral load = 3.69 (1.58-8.61); P-value ≤ 0.01]. CONCLUSIONS: Despite effective cART, complete TCP recovery occurred in very few individuals and was associated with baseline CD4 T-cell count and viral load suppression. HIV-induced alterations of the TCP are incompletely reversed by long-term ART.

Human papillomavirus (HPV) vaccination across a cascade of knowledge, willingness, and uptake among gay, bisexual, and other men who have sex with men in Canada's three largest cities.

BACKGROUND: Some Canadian jurisdictions offer publicly funded HPV vaccine to gay, bisexual, and other men who have sex with men (GBM) aged ≤26 years. We characterized factors associated with being in different stages of HPV vaccination. METHODS: Engage is a sexual health study of GBM in the three largest Canadian cities recruited via respondent driven sampling (RDS). We categorized participants as: (1) unaware of HPV vaccine, (2) undecided/unwilling to get vaccinated, (3) willing to get vaccinated, (4) vaccinated with one or more doses. Our RDS-II weighted analyses used multinomial logistic regression to identify factors associated with being in earlier stages of the cascade compared to Stage 4. RESULTS: Across the cities, 26-40%, 7-14%, 33-39%, and 13-28% were in Stages 1 to 4, respectively. Compared to Stage 4, being in earlier stages of the cascade was associated with bisexual-identification (Stage 1: adjusted odds ratio[aOR] = 2.84, 95% confidence interval[CI] = 1.06-7.62; Stage 2: aOR = 3.09, 95%CI = 1.19-8.05), having immigrated to Canada (Stage 1: aOR = 1.79, 95%CI 1.07-2.99), preference to keep same-sex romantic relationships private (Stage 1: aOR = 1.25, 95% CI = 1.05-1.48; Stage 2: aOR = 1.24, 95%CI = 1.05-1.46), not receiving sexual health information (Stage 1: aOR = 0.31, 95% CI = 0.13-0.71; Stage 2: aOR = 0.27, 95%CI = 0.12-0.64), not accessing a health-care provider (Stage 2: aOR = 0.36, 95%CI = 0.15-0.83), and no past hepatitis A/B vaccination (Stage 1: aOR = 0.16, 95% CI = 0.09-0.30; Stage 2: aOR = 0.18, 95%CI = 0.09-0.35; Stage 3: aOR = 0.38, 95%CI = 0.21-0.61). DISCUSSION: Interventions are needed to reduce social and financial barriers, increase sexual health knowledge, and improve GBM-competent health-care access to increase vaccine uptake among GBM.

Human papillomavirus (HPV) vaccine uptake among a community-recruited sample of gay, bisexual, and other men who have sex with men in the three largest cities in Canada from 2017 to 2019.

INTRODUCTION: In 2015/2016, Canada's largest provinces implemented publicly-funded human papillomavirus (HPV) vaccination programs for gay, bisexual, and other men who have sex with men (GBM) ≤ 26 years old. We sought to describe HPV vaccine uptake among GBM and determine barriers and facilitators to vaccine initiation with a focus on healthcare access and utilization. METHODS: Engage is a cohort study among GBM aged 16 + years in three Canadian cities recruited from 2017 to 2019 via respondent driven sampling (RDS). Men completed a comprehensive questionnaire at baseline. By publicly-funded vaccine eligibility (≤26 years old = eligible for vaccination, ≥27 years old = ineligible), we described HPV vaccine uptake (initiation = 1 + dose, completion = 3 doses) and explored factors associated with vaccine initiation using Poisson regression. All analyses were weighted with the RDS-II Volz-Heckathorn estimator. RESULTS: Across the three cities, 26-35% and 14-21% of men ≤ 26 years and 7-26% and 2-9% of men ≥ 27 years initiated and completed HPV vaccination, respectively. Vaccine initiation was significantly associated with STI/HIV testing or visiting a HIV care specialist in the past six months (≤26: prevalence ratio[PR] = 2.15, 95% confidence interval[CI] 1.06-4.36; ≥27: PR = 2.73, 95%CI 1.14-6.51) and past hepatitis A or B vaccination (≤26: PR = 2.88, 95%CI 1.64-5.05; ≥27: PR = 2.03, 95%CI 1.07-3.86). Among men ≥ 27 years old, vaccine initiation was also positively associated with accessing PrEP, living in Vancouver or Toronto, but negatively associated with identifying as Latin American and increasing age. Vaccine initiation was twice as likely among men ≥ 27 years with private insurance versus no insurance. CONCLUSIONS: Sixty-five to 74% of men eligible for publicly-funded vaccine across the three cities remained unvaccinated against HPV by 2019. High vaccine cost may partly explain even lower uptake among men ≥ 27 years old. Men seeking sexual health care were more likely to initiate vaccination; bundling vaccination with these services may help improve HPV vaccine uptake.

Acceptability of anal cancer screening tests for women living with HIV in the EVVA study.

Background: Anal cancer is potentially preventable through screening. For screening to be implemented, the screening procedures must be acceptable to the affected population. The objective of the present study was to measure the acceptability of currently available anal cancer screening tests in a population of women living with hiv who had experienced the tests. Methods: The evva study ("Evaluation of Human Immunodeficiency Virus, Human Papillomavirus, and Anal Intraepithelial Neoplasia in Women") is a prospective cohort study of adult women living with hiv in Montreal, Quebec. Participants were screened with cervical or anal hpv testing and cervical or anal cytology every 6 months for 2 years. High-resolution anoscopy (hra) and digital anal rectal examination (dare) were also performed systematically, with biopsies, at baseline and at 2 years. An acceptability questionnaire was administered at the final visit or at study withdrawal. Results: Of 124 women who completed the acceptability questionnaire, most considered screening "an absolute necessity" in routine care for all women living with hiv [77%; 95% confidence interval (ci): 69% to 84%]. Yearly anal cytology or anal hpv testing was considered very acceptable by 81% (95% ci: 73% to 88%); hra every 2 years was considered very acceptable by 84% (95% ci: 77% to 90%); and yearly dare was considered very acceptable by 87% (95% ci: 79% to 92%). Acceptability increased to more than 95% with a longer proposed time interval. Pain was the main reason for lower acceptability. Conclusions: Most participating women considered anal cancer screening necessary and very acceptable. Longer screening intervals and adequate pain management could further increase the acceptability of repeated screening.

Efficacy of a Carrageenan gel Against Transmission of Cervical HPV (CATCH): interim analysis of a randomized, double-blind, placebo-controlled, phase 2B trial.

OBJECTIVES: To evaluate the efficacy of a carrageenan-based lubricant gel in reducing the risk of genital human papillomavirus (HPV) infections in women. METHODS: We conducted a planned interim analysis of a randomized, double-blind, placebo-controlled, phase 2B trial. Women aged 18 years and older were randomly assigned (1:1) to a carrageenan-based gel or a placebo gel to be self-applied every other day for the first month and before and after each intercourse during follow-up. Assessments were performed at 0.5, 1, 3, 6, 9 and 12 months. The primary outcome was incidence of a new infection by an HPV type that was not present at baseline. Intention-to-treat analyses were performed. RESULTS: Between January 2013 and June 2017, a total of 280 participants were randomly assigned to the carrageenan (n = 141) or the placebo (n = 139) arm. All participants were included in safety analyses, but three (1%) were excluded from efficacy analyses (HPV results unavailable for two participants in the carrageenan and one participant in the placebo arm). The median follow-up time was 9.2 months (interquartile range, 1.9-13.2 months). A total of 59 (42%) of 139 participants in the carrageenan arm and 78 (57%) of 138 participants in the placebo arm became infected by at least one new HPV type (hazard ratio = 0.64, 95% confidence interval = 0.45-0.89, p 0.009). A total of 62 (44%) of 141 participants in the carrageenan arm versus 43 (31%) of 139 participants in the placebo arm reported an adverse event (p 0.02), none of which was deemed related to the gels. CONCLUSIONS: Our trial's interim analysis suggests that using a carrageenan-based lubricant gel can reduce the risk of genital HPV infections in women.

Portal blood flow in cirrhosis of the liver.

Direct measurements of portal flow and pressure in a relatively large number of patients with cirrhosis show a marked reduction in flow associated with a nearly constant plateau of portal pressure. This lack of correlation indicates the complex relationships of resistances in the splanchnic, collateral, and hepatic circuits determining the division of the available splanchnic flow between the portal vein and the collateral pathways. Subtracting the measured portal flow from well-established estimates of total hepatic blood flow in cirrhosis suggests that the hepatic artery contributes more than one-half of the blood perfusing the cirrhotic liver. There was no instance of retrograde portal flow during the preshunt measurements, although such reversal was frequent after side-to-side portacaval anastomosis. Attempting to explain the plateau of portal pressure in the face of an increasing outflow resistance presumably associated with progress of the disease, we postulate that an augmented inflow resistance to the splanchnic chamber reduces splanchnic flow in cirrhosis. End-to-side portacaval anastomosis did not return normal portal flow, although it decreased pressure to accepted control levels. The assumption is that most of the splanchnic blood was flowing through the shunt, leading to a high splanchnic resistance in the immediate postshunt status. If this resistance was previously elevated, as suggested by the plateau of portal pressure, the mechanism responsible for the elevation was not immediately deactivated after the shunt, and the true effect of the operation upon splanchnic flow may not be measurable at such time. Respiratory oscillations were a significant component of portal flow in cirrhosis before and after portacaval anastomosis, indicating the limitations of any steady state analysis of the circulatory derangement in cirrhosis.

Glucocorticoid exposure in late gestation permanently programs rat hepatic phosphoenolpyruvate carboxykinase and glucocorticoid receptor expression and causes glucose intolerance in adult offspring.

Low birth weight in humans is predictive of insulin resistance and diabetes in adult life. The molecular mechanisms underlying this link are unknown but fetal exposure to excess glucocorticoids has been implicated. The fetus is normally protected from the higher maternal levels of glucocorticoids by feto-placental 11beta-hydroxysteroid dehydrogenase type-2 (11beta-HSD2) which inactivates glucocorticoids. We have shown previously that inhibiting 11beta-HSD2 throughout pregnancy in rats reduces birth weight and causes hyperglycemia in the adult offspring. We now show that dexamethasone (a poor substrate for 11beta-HSD2) administered to pregnant rats selectively in the last week of pregnancy reduces birth weight by 10% (P < 0.05), and produces adult fasting hyperglycemia (treated 5.3+/-0.3; control 4.3+/-0.2 mmol/ liter, P = 0.04), reactive hyperglycemia (treated 8.7+/-0.4; control 7.5+/-0.2 mmol/liter, P = 0.03), and hyperinsulinemia (treated 6.1+/-0.4; control 3.8+/-0.5 ng/ml, P = 0.01) on oral glucose loading. In the adult offspring of rats exposed to dexamethasone in late pregnancy, hepatic expression of glucocorticoid receptor (GR) mRNA and phosphoenolpyruvate carboxykinase (PEPCK) mRNA (and activity) are increased by 25% (P = 0.01) and 60% (P < 0.01), respectively, while other liver enzymes (glucose-6-phosphatase, glucokinase, and 11beta-hydroxysteroid dehydrogenase type-1) are unaltered. In contrast dexamethasone, when given in the first or second week of gestation, has no effect on offspring insulin/glucose responses or hepatic PEPCK and GR expression. The increased hepatic GR expression may be crucial, since rats exposed to dexamethasone in utero showed potentiated glucose responses to exogenous corticosterone. These observations suggest that excessive glucocorticoid exposure late in pregnancy predisposes the offspring to glucose intolerance in adulthood. Programmed hepatic PEPCK overexpression, perhaps mediated by increased GR, may promote this process by increasing gluconeogenesis.

Electrocardiographic detection of hypertensive left atrial enlargement in the presence of obesity: re-calibration against cardiac magnetic resonance.

Left atrial enlargement (LAE) has adverse prognostic implications in hypertension. We sought to determine the accuracy of five electrocardiogram (ECG) criteria for LAE in hypertension relative to cardiac magnetic resonance (CMR) gold standard and investigate the effect of concomitant obesity. One hundred and thirty consecutive patients (age: 51.4±15.1 years, 47% male, 51% obese, systolic blood pressure (BP): 171±29 mm Hg, diastolic BP: 97±15 mm Hg) referred for CMR (1.5 T) from a tertiary hypertension clinic were included. Patients with concomitant cardiac pathology were excluded. ECGs were assessed blindly for the following: (1) P-wave >110 ms, (2) P-mitrale, (3) P-wave axis <30°, (4) area of negative P-terminal force in V1 >40 ms.mm and (5) positive P-terminal force in augmented vector left (aVL) >0.5 mm. Left atrial volume ≥55 ml m-2, measured blindly by CMR, was defined as LAE. Sensitivity, specificity, positive predictive value, negative predictive value, accuracy and area under the receiver operator curve were calculated. The prevalence of LAE by CMR was 26%. All the individual ECG LAE criteria were more specific than sensitive, with specificities ranging from 70% (P-axis <30o) to 99% (P-mitrale). Obesity attenuated the specificity of most of the individual ECG LAE criteria. Obesity correlated with significant lower specificity (48% vs 65%, P<0.05) and a trend towards lower sensitivity (59 vs 43%, P=0.119) when ≥1 ECG LAE criteria were present. Individual ECG criteria of LAE in hypertension are specific, but not sensitive, at identifying LAE. The ECG should not be used to excluded LAE in hypertension, particularly in obese subjects.

Glucose production in the human placenta.

Glucose transfer from mother to fetus by placental facilitated diffusion is the dominant mechanism by which the fetus acquires glucose. In small for gestational age pregnancies, fetal glucose concentrations tend to be lower than normal and this persists following delivery. GLUT1 is the major glucose transporter in human placenta but there is no evidence of GLUT1 deficiency as a cause of the lower fetal glucose concentration in small for gestational age pregnancy. The physiological and pathological roles of the other glucose transporters (and there are 14 currently described) are unknown. In recent years, the possibility has been raised that the placenta is itself capable of supplying glucose for fetal needs. This hypothesis derived from glucose isotope studies in normal pregnancy, where dilution of glucose isotope was demonstrated in blood samples taken from the fetal circulation during intravenous infusion of glucose isotope in the mother. Although other gluconeogenic enzymes were known to be present, the placenta was previously considered incapable of glucose secretion because it lacked functional glucose-6-phosphatase. Recent studies, however, have suggested that specific glucose-6-phosphatase may be present in placenta but it may be the product of a different gene from conventional hepatic glucose-6-phosphatase. The presence of the specific transporters necessary for glucose-6-phosphatase activity is currently being investigated. The role of placental glucose secretion in normal and growth-restricted pregnancies is an area of current study.

The effect of obesity on electrocardiographic detection of hypertensive left ventricular hypertrophy: recalibration against cardiac magnetic resonance.

Electrocardiograph (ECG) criteria for left ventricular hypertrophy (LVH) are a widely used clinical tool. We recalibrated six ECG criteria for LVH against gold-standard cardiac magnetic resonance (CMR) and assessed the impact of obesity. One hundred and fifty consecutive tertiary hypertension clinic referrals for CMR (1.5 T) were reviewed. Patients with cardiac pathology potentially confounding hypertensive LVH were excluded (n=22). The final sample size was 128 (age: 51.0±15.2 years, 48% male). LVH was defined by CMR. From a 12-lead ECG, Sokolow-Lyon voltage and product, Cornell voltage and product, Gubner-Ungerleidger voltage and Romhilt-Estes score were evaluated, blinded to the CMR. ECG diagnostic performance was calculated. LVH by CMR was present in 37% and obesity in 51%. Obesity significantly reduced ECG sensitivity, because of significant attenuation in mean ECG values for Cornell voltage (22.2±5.7 vs 26.4±9.4 mm, P<0.05), Cornell product (2540±942 vs 3023±1185 mm • ms, P<0.05) and for Gubner-Ungerleider voltage (18.2±7.1 vs 23.3±1.2 mm, P<0.05). Obesity also significantly reduced ECG specificity, because of significantly higher prevalence of LV remodeling (no LVH but increased mass-to-volume ratio) in obese subjects without LVH (36% vs 16%, P<0.05), which correlated with higher mean ECG LVH criteria values. Obesity-specific partition values were generated at fixed 95% specificity; Cornell voltage had highest sensitivity in non-obese (56%) and Sokolow-Lyon product in obese patients (24%). Obesity significantly lowers ECG sensitivity at detecting LVH, by attenuating ECG LVH values, and lowers ECG specificity through changes associated with LV remodeling. Our obesity-specific ECG partition values could improve the diagnostic performance in obese patients with hypertension.

The mechanism of histone activation of the hepatic microsomal glucose-6-phosphatase system: a novel method to assay glucose-6-phosphatase activity.

The mechanism of activation of hepatic microsomal glucose-6-phosphatase (EC 3.1.3.9) by histone 2A has been investigated in both intact and disrupted microsomes. Histone 2A increased the Vmax and decreased the Km of glucose-6-phosphatase in intact microsomes but had no effect on glucose-6-phosphatase activity in disrupted microsomes. Histone 2A was shown to activate glucose-6-phosphatase in intact microsomes by disrupting the membrane vesicles and thereby allowing the direct measurement of the activity of the latent glucose-6-phosphatase enzyme. The study demonstrated that disrupting microsomes with histone 2A is an excellent method for directly assaying glucose-6-phosphatase activity as it poses none of the problems encountered with all of the previously used methods.

Pentamidine activates T1 the hepatic microsomal glucose 6-phosphate transport protein of the glucose-6-phosphatase system.

The mechanism of activation of hepatic microsomal glucose-6-phosphatase (EC 3.1.3.9) in vitro by pentamidine has been investigated in both intact and fully disrupted microsomes. The major effect of pentamidine is a 4.7-fold reduction in the Km of glucose-6-phosphatase activity in intact diabetic rat liver microsomes. The site of action of pentamidine is T1 the hepatic microsomal glucose 6-phosphate transport protein. The activation of T1 by pentamidine may contribute to the disturbed blood glucose homeostasis seen in many patients after the administration of the drug pentamidine.