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Background:Micronutrient deficiencies due to malabsorption, gut infections, and altered gut barrier function are common in children living with HIV (CLHIV) and may worsen with severe acute malnutrition (SAM).Methods:This secondary analysis of IMPAACT P1092, a Phase IV, multicenter, open label, non-randomized study of zidovudine (ZDV), lamivudine (3TC), and lopinavir/ritonavir (LPV/r) pharmacokinetics, safety, and tolerability enrolled SAM and non-SAM CLHIV age 6 to ResultsFifty-two participants, 25 SAM and 27 non-SAM, of median (Q1,Q3) age 19 (13,25) and 18 (12,25) months respectively, were enrolled. Zinc deficiency was present at entry in 2/27 (8%) from the SAM cohort. Mean (SD) baseline zinc levels for the SAM and non-SAM cohort [52.2(15.3), 54.7(12.2) µg/dL] and selenium [92.9(25.0), 84.3(29.2) µg/L] were similar, and there was no difference in change from study entry to week 48 for both: mean (95% CI) difference SAM minus non-SAM of -0.3 (-11.2,10.5) µg/dL and -5.1 (-20.1,9.8) µg/L for zinc and selenium respectively. Mean (SD) baseline total protein levels [75.2(13.2), 77.3(9.4) g/L] and mean change from entry to 48 weeks were similar between cohorts (mean difference (95% CI) (4.6 (-2.4,11.6). The SAM cohort had significantly lower serum albumin levels at entry compared to the non-SAM cohort (mean difference (95% CI) 6.2 (-10.1, -2.4) g/L) and levels were similar after 48 weeks (mean difference (95% CI) 0.4 (-2.2, 2.9) g/L). Mean increase in albumin at 48 weeks was greater in the SAM cohort (mean difference (95% CI) 6.3 (1.9, 10.7) g/L). ConclusionsThese children who were on highly active combination antiretroviral therapy and had malnutrition showed normal levels of selenium and zinc after 10-18 days of nutritional rehabilitation. Entry albumin levels were lower in SAM compared to non-SAM, with normalization to non-SAM levels by 48 weeks. Total protein levels were similar at entry and week 48.Trial RegistrationThe study was registered with ClinicalTrials.gov Identifier NCT01818258 26/03/2013

BackgroundPregnancy is accompanied by immune suppression. We hypothesized that Mycobacterium tuberculosis-specific inflammatory responses used to identify latent tuberculosis infection (LTBI) lose positivity during pregnancy. We also hypothesized that isoniazid preventive therapy (IPT) may revert LTBI diagnoses because of its sterilizing activity.Methods944 women with human immunodeficiency virus infection (HIV) participating in a randomized, double-blind, placebo-controlled study comparing 28 weeks of IPT antepartum versus postpartum, were tested by QuantiFERON-gold-in-tube (QGIT) antepartum and by QGIT and tuberculin skin test (TST) at delivery and postpartum. Serial QGIT positivity was assessed by logistic regression using generalized estimating equations.ResultsFrom entry to delivery, 68 (24%) of 284 QGIT-positive women reverted to QGIT-negative or indeterminate. Of these, 42 (62%) recovered QGIT positivity postpartum. The loss of QGIT positivity during pregnancy was explained by decreased interferon gamma (IFNγ) production in response to TB antigen and/or mitogen. At delivery, LTBI was identified by QGIT in 205 women and by TST in 113 women. Corresponding numbers postpartum were 229 and 122 women. QGIT and TST kappa agreement coefficients were 0.4 and 0.5, respectively. Among QGIT-positive women antepartum or at delivery, 34 (12%) reverted to QGIT-negative after IPT. There were no differences between women who initiated IPT antepartum or postpartum.ConclusionsDecreased IFNγ responses in pregnancy reduced QGIT positivity, suggesting that this test cannot reliably rule out LTBI during pregnancy. TST was less affected by pregnancy, but had lower positivity compared to QGIT at all time points. IPT was associated with loss of QGIT positivity, the potential clinical consequences of which need to be investigated.

BACKGROUND: The safety, efficacy, and appropriate timing of isoniazid therapy to prevent tuberculosis in pregnant women with human immunodeficiency virus (HIV) infection who are receiving antiretroviral therapy are unknown. METHODS: In this multicenter, double-blind, placebo-controlled, noninferiority trial, we randomly assigned pregnant women with HIV infection to receive isoniazid preventive therapy for 28 weeks, initiated either during pregnancy (immediate group) or at week 12 after delivery (deferred group). Mothers and infants were followed through week 48 after delivery. The primary outcome was a composite of treatment-related maternal adverse events of grade 3 or higher or permanent discontinuation of the trial regimen because of toxic effects. The noninferiority margin was an upper boundary of the 95% confidence interval for the between-group difference in the rate of the primary outcome of less than 5 events per 100 person-years. RESULTS: A total of 956 women were enrolled. A primary outcome event occurred in 72 of 477 women (15.1%) in the immediate group and in 73 of 479 (15.2%) in the deferred group (incidence rate, 15.03 and 14.93 events per 100 person-years, respectively; rate difference, 0.10; 95% confidence interval [CI], −4.77 to 4.98, which met the criterion for noninferiority). Two women in the immediate group and 4 women in the deferred group died (incidence rate, 0.40 and 0.78 per 100 person-years, respectively; rate difference, −0.39; 95% CI, −1.33 to 0.56); all deaths occurred during the postpartum period, and 4 were from liver failure (2 of the women who died from liver failure had received isoniazid [1 in each group]). Tuberculosis developed in 6 women (3 in each group); the incidence rate was 0.60 per 100 person-years in the immediate group and 0.59 per 100 person-years in the deferred group (rate difference, 0.01; 95% CI, −0.94 to 0.96). There was a higher incidence in the immediate group than in the deferred group of an event included in the composite adverse pregnancy outcome (stillbirth or spontaneous abortion, low birth weight in an infant, preterm delivery, or congenital anomalies in an infant) (23.6% vs. 17.0%; difference, 6.7 percentage points; 95% CI, 0.8 to 11.9). CONCLUSIONS: The risks associated with initiation of isoniazid preventive therapy during pregnancy appeared to be greater than those associated with initiation of therapy during the postpartum period. (Funded by the National Institutes of Health; IMPAACT P1078 TB APPRISE ClinicalTrials.gov number, .)

The World Health Organization guidelines recommend that individuals living with HIV receive ≥ 6 months of isoniazid preventive therapy, including pregnant women. Yet, plasma isoniazid exposure during pregnancy, in the antiretroviral therapy era, has not been well-described. We investigated pregnancy-induced and pharmacogenetic-associated pharmacokinetic changes and drug-drug interactions between isoniazid and efavirenz in pregnant women. Eight hundred forty-seven women received isoniazid for 28 weeks, either during pregnancy or at 12 weeks postpartum, and 786 women received efavirenz. After adjusting for NAT2 and CYP2B6 genotype and weight, pregnancy increased isoniazid and efavirenz clearance by 26% and 15%, respectively. Isoniazid decreased efavirenz clearance by 7% in CYP2B6 normal metabolizers and 13% in slow and intermediate metabolizers. Overall, both isoniazid and efavirenz exposures were reduced during pregnancy, but the main determinants of drug concentration were NAT2 and CYP2B6 genotypes, which resulted in a five-fold difference for both drugs between rapid and slow metabolizers.

Background TB is the most common opportunistic infection in PLWH. IPT is recommended for PLWH in endemic areas and for those with LTBI diagnosed by Quantiferon gold-in-tube (QGIT) or tuberculin skin test (TST) in other areas. We report on the performance of QGIT and TST in pregnant WLWH who received IPT antepartum (AP) or postpartum (PP). Methods WLWH participating in IMPAACT P1078, a randomized, double-blind, placebo-controlled study comparing 28 weeks of IPT AP vs. PP, were tested by QGIT at entry (14–34 weeks gestation) and by QGIT and TST at delivery (L&D) and 44 weeks PP. Serial QGIT positivity was assessed by logistic regression using generalized estimating equations. Results Among 944 women with study entry mean (SD) of 29 (6) years of age, 521 (245) CD4+ cells/µL, on ART, including 63% with undetectable HIV plasma RNA, 284/944 (30%) were QGIT+ AP, 215/862 (25%) at L&D and 246/764 (32%) PP (P < 0.001), while 127 (15%) were TST+ at L&D and 126 (17%) PP. QGIT was more likely positive than TST at L&D (Odds ratio = 4.3; 95% CI = 2.8–6.8) and PP (6.4; 3.9–10.7; P < 0.001). QGIT and TST agreement coefficients (95% CI) were 0.4 (0.3–0.5) at L&D and 0.5 (0.4–0.5) PP. Among women QGIT+ AP, 59 (24%) reverted to QGIT- or indeterminate at L&D. However, 37 (63%) reverters recovered QGIT+ results PP, suggesting transient suppression of IFNg responses during pregnancy. Responses to the mitogen-positive QGIT kit control were absent in 60 (7%) women AP, 116 (16%) at L&D, but only 3 (0.4%) PP (P < 0.01), supporting the notion of transient immune suppression during pregnancy. Among women QGIT- AP, 33 (7%) converted to QGIT+ PP. Among AP QGIT+ women, 24 (11%) reverted to QGIT- PP after finishing IPT. None of the results differed between treatment arms (P ≥ 0.13). Conclusion In WLWH on ART, the loss of IFNγ responses to TB antigen and mitogen in pregnancy decreased the diagnostic value of QGIT. TST was similar at L&D and PP but was less sensitive than QGIT. QGIT conversions likely resulted from a combination of PP immune reconstitution and new TB infections. QGIT reversions might represent a change in TB-specific immunity in response to IPT. Reversions have been reported in adults without HIV after treatment of active TB. The clinical significance of QGIT reversions in PLWH needs further investigation. Disclosures All authors: No reported disclosures.

Climate change has focussed global attention on reducing greenhouse gas (GHG) emissions, particularly through energy eficient technological innovation. In Australia energy policy incentives include increasing the contribution of renewable energy sources along with energy eficient behaviours. InWestern Australia an Energy Utility has embraced the principle of community engagement to inform corporate strategies toward sustainable green energy visions. This paper evaluates the process of citizen involvement in promoting community acceptance of green energy technologies at the community level. This qualitative study examines the role of community governance in planning the sustainable energy needs of regional communities. While it is promising to observe the emergence of lexible institutional responses to community energy visions, this energy governance network is a work in progress as it struggles to gain community consensus to site a small community-owned wind farm. To address community polarisation over the costs and beneits of community energy, attention must be paid to issues of inclusive representation along with mechanisms of accountability that assesses the social and economic impacts of green energy initiatives. This study highlights that an effective governance process would incorporate the principles of sustainability, procedural and distributive justice to enhance community transitions toward a more environmentally benign economy and electricity system.

Summary The Council of Australian University Librarians, constituted in 1965 for the purposes of cooperative action and the sharing of information, assumed the role of consortial purchasing agent in 1996 on behalf of its members and associate organisations in Australia and New Zealand. This role continues to grow in tandem with the burgeoning of electronic publication and the acceptance of publishers of the advantages of dealing with consortia. The needs of the Australian university community overlap significantly with consortia in North America and Europe, but important differences are highlighted.

Members celebrated the first meeting of the Conference of Australian University Librarians held 70 years ago in Melbourne in August 1928. Five of New Zealand's seven university librarians joined CAUL for both the meeting and the celebratory dinner. Also attending the dinner were Warren Horton, Director-General of the National Library, and several former members of CAUL: Harrison Bryan, Judith Edwards, Ted Flowers, Jeff Hazell, Bill Linklater, James O'Brien, Eric Wainwright and Neil Radford. Neil Radford's special contribution to the festivities was the lead article in the CAUL Memoir published as a special issue of AARL, copies of which were distributed at the dinner. The first day of the meeting consisted of a series of discussion sessions and presentations: • State-based collaborative models (Chris Mulder) • PANDORA demonstration (Margaret Phillips and Jasmine Cameron, National Library of Australia) • Convergence-Library & IT Services (Lois Jennings) • Quality of Offshore Education Policy (Vicki Williamson) • Industrial relations, contracts, etc (John Shipp). The second day was CAUL's business meeting, looking at such issues as: • CAUL's contributions to the development of government and AVCC policies • CAUL's applications for research funding • CAUL's relationships with other organisations, global and national • CAUL's role as a purchasing consortium. Alex Byrne was applauded for his leadership during the term of his Presidency. Members elected Helen Hayes (University of Melbourne) as President and Chris Mulder (Edith Cowan University) as Executive Committee member for 1999-2000. Linda O'Brien was attending her first meeting as CAUL member for the University of Newcastle.

We examined the effects of several muscarinic agonists and antagonists on phosphoinositide breakdown (PI) and adenylate cyclase (AC) inhibition in rat cerebral cortex and heart, respectively. Acetylcholine, carbachol and methacholine behaved as full agonists in both systems. In contrast, oxotremorine and arecoline failed to stimulate PI turnover but were potent and efficacious at inhibiting AC. Among the antagonists, pirenzepine, dicyclomine, telenzepine and (R)-QNA were both potent (Ki approximately 0.5-7.5 nM) and selective (90- to 8,500-fold) for the PI-linked (putatively M1) brain receptor. In contrast, the cardioselective and ileal-selective M2 antagonists, AF-DX 116 and hexahydrosiladifenidol, were equipotent, competitive inhibitors of both responses. The selectivity of these drugs in terms of their biochemical responses is described.