Rifampin monotherapy for children with idiopathic infantile hypercalcemia

Idiopathic Infantile Hypercalcemia (IIH) is characterized by hypercalcemia and hypercalciuria owing to PTH-independent increases in circulating concentrations of 1,25(OH)2D. At least 3 forms of IHH can be distinguished genetically and mechanistically: infantile hypercalcemia-1 (Hypercalcemia, Infantile, 1; HCINF1) due to CYP24A1 mutations results in decreased inactivation of 1,25(OH)2D; HCINF2 due to SLC34A1 mutations results in excessive 1,25(OH)2D production; and HCINF3 in which a variety of gene variants of uncertain significance (VUS) have been identified and where the mechanism for increased 1,25 (OH)2D is unclear. Conventional management with dietary calcium and vitamin D restriction has only limited success. Induction of the P450 enzyme CYP3A4 by rifampin can provide an alternate pathway for inactivation of 1,25(OH)2D that is useful in HCINF1 and may be effective in other forms of IIH. We sought to assess the efficacy of rifampin to decrease levels of serum 1,25(OH)2D and calcium, and urinary calcium concentrations in subjects with HCINF3, and to compare the response to a control subject with HCINF1. Four subjects with HCINF3 and the control subject with HCINF1 completed the study using rifampin 5 mg/kg/day and 10 mg/kg/day each for 2 months separated by a 2-month washout period. Patients had age-appropriate intake of dietary calcium plus 200 IU vitamin D/day. Primary outcome was efficacy of rifampin to lower serum concentrations of 1,25(OH)2D. The secondary outcomes included the reduction of serum calcium, urinary calcium excretion (as random urine calcium: creatinine (ca:cr) ratio) and serum 1,25(OH)2D/PTH ratio. Rifampin was well tolerated and induced CYP3A4 at both doses in all subjects. The control subject with HCINF1 showed significant response to both rifampin doses with decreases in the serum concentration of 1,25(OH)2D and the 1,25(OH)2D/PTH ratio while the serum and urine ca:cr levels were unchanged. The four patients with HCINF3 showed reductions in 1,25(OH)2D and urinary ca:cr after 10 mg/kg/d, but hypercalcemia did not improve and there were variable responses in 1,25(OH)2D/PTH ratios. These results support further longer-term studies to clarify the usefulness of rifampin as a medical therapy for IIH

Predictors of Urinary Arsenic Levels among Postmenopausal Danish Women

Arsenic is a risk factor for several noncommunicable diseases, even at low doses. Urinary arsenic (UAs) concentration is a good biomarker for internal dose, and demographic, dietary, and lifestyle factors are proposed predictors in nonoccupationally exposed populations. However, most predictor studies are limited in terms of size and number of predictors. We investigated demographic, dietary, and lifestyle determinants of UAs concentrations in 744 postmenopausal Danish women who had UAs measurements and questionnaire data on potential predictors. UAs concentrations were determined using mass spectrometry (ICP-MS), and determinants of the concentration were investigated using univariate and multivariate regression models. We used a forward selection procedure for model optimization. In all models, fish, alcohol, and poultry intake were associated with higher UAs concentration, and tap water, fruit, potato, and dairy intake with lower concentration. A forward regression model explained 35% (R2) of the variation in concentrations. Age, smoking, education, and area of residence did not predict concentration. The results were relatively robust across sensitivity analyses. The study suggested that UAs concentration in postmenopausal women was primarily determined by dietary factors, with fish consumption showing the strongest direct association. However, the majority of variation in UAs concentration in this study population is still unexplained

Moyo Vol. VII N 2

Durica, Paul. Editor\u27s Letter . 4. Spears, Amy L. As If Lipstick Was A Sign of My Declining Mind (How ChickRock Happened) . 5. Frey, Randall. Portrait of the Cartoonist as a Young Man . 6. Clements, Nina. Grease Me Up: One Woman\u27s Descent into the Depths of Pittsburgh Dinner Culture . 7. Levine, Robert. Under the Needle\u27s Point (The Healing Power of Acupuncture) . 8. Durica, Paul. The Glory that was/is Greek: Denison Three Years After the Decision . 12. Lamont, Jean. Smokin\u27 Joe Lights Up . 13. Durica, Paul. Ode on a Second Grecian Turn: An Interview with President Michele T. Myers . 14. Fisher, Dan. Lenane on the Social Scene . 19. Combe, Kirk. Intellectual Bio-Diversity: A Faculty Perspective on the Greek Residential Issue . 20. Williams, Adam. Elephants on the Floor Above and Brats in the Basement: Life on the North Quad . 22. Pfleeger, Jon. New Kid on the Block (Sigma Phi Epsilon\u27s President Speaks) . 23. Werne, Kirsten. Coffee Talk at the Bandersnatch (An Interview with Kevin Clay and Adam) . 29

Pre-treatment HIV-drug resistance associated with virologic outcome of first-line NNRTI-antiretroviral therapy: A cohort study in Kenya

Background: Pre-treatment HIV-drug-resistance (PDR) to WHO-recommended 1st-line non-nucleoside reverse transcriptase inhibitors (NNRTI)-based antiretroviral treatment (ART) is increasing in low-resource communities. We evaluated the risk of PDR on treatment failure if detected at single or multiple codons, at minority (2–9%) or higher (≥10%) frequencies during efavirenz- vs. nevirapine-ART. Methods: We conducted a pooled analysis across three cohorts of Kenyans initiating 1st-line NNRTI-ART between 2006 and 2014. Mutations K103N, Y181C, G190A, M184V and K65R were detected by an oligonucleotide ligation assay (OLA) and confirmed by Sanger and next-generation sequencing (NGS). PDR was defined as detection of any mutation by OLA when confirmed by NGS. Treatment failure, defined as plasma HIV RNA ≥400 copies/mL at month-12 of ART, was compared by PDR genotypes. Findings: PDR was detected in 59/1231 (4·8%) participants. Compared to wild-type genotypes, PDR in participants prescribed nevirapine-ART was associated with increased treatment failure [PDR 69·2% (27/39) vs. wild-type 10·4% (70/674); p = 0·0001], whether detected as minority [66·7% (4/6)] or higher [69·7% (23/33)] frequencies in an individual\u27s HIV quasispecies (p = 0·002 and p \u3c 0·0001, respectively), or mutations at single [50·0% (12/24)] or multiple [100·0% (15/15)] codons (p \u3c 0·0001). During efavirenz-ART, PDR was also associated with increased virologic failure [PDR 25·0% (5/20) vs. wild-type 5·0% (25/498); p = 0·005], but only if detected at multiple drug-resistant codons [50·0% (3/6); p = 0·003] or high frequencies PDR [33·3% (5/15); p = 0·001]. Interpretation: The risk that PDR confers for treatment failure varies by number of mutant codons and their frequency in the quasispecies, with a lower risk for efavirenz- compared to nevirapine-based regimens. PDR detection and management could extend the effective use of efavirenz-ART in low-resource settings. Funding: NIH, PEPFAR

Peak CO2? China's Emissions Trajectories to 2050

As a result of soaring energy demand from a staggering pace of economic growth and the related growth of energy-intensive industry, China overtook the United States to become the world's largest contributor to CO{sub 2} emissions in 2007. At the same time, China has taken serious actions to reduce its energy and carbon intensity by setting both short-term energy intensity reduction goal for 2006 to 2010 as well as long-term carbon intensity reduction goal for 2020. This study focuses on a China Energy Outlook through 2050 that assesses the role of energy efficiency policies in transitioning China to a lower emission trajectory and meeting its intensity reduction goals. In the past years, LBNL has established and significantly enhanced the China End-Use Energy Model based on the diffusion of end-use technologies and other physical drivers of energy demand. This model presents an important new approach for helping understand China's complex and dynamic drivers of energy consumption and implications of energy efficiency policies through scenario analysis. A baseline ('Continued Improvement Scenario') and an alternative energy efficiency scenario ('Accelerated Improvement Scenario') have been developed to assess the impact of actions already taken by the Chinese government as well as planned and potential actions, and to evaluate the potential for China to control energy demand growth and mitigate emissions. It is a common belief that China's CO{sub 2} emissions will continue to grow throughout this century and will dominate global emissions. The findings from this research suggest that this will not likely be the case because of saturation effects in appliances, residential and commercial floor area, roadways, railways, fertilizer use, and urbanization will peak around 2030 with slowing population growth. The baseline and alternative scenarios also demonstrate that the 2020 goals can be met and underscore the significant role that policy-driven energy efficiency improvements will play in carbon mitigation along with a decarbonized power supply through greater renewable and non-fossil fuel generation

Moyo Vol. VIII N 1

Durica, Paul Editor\u27s Letter . 4. Thackeray, Alex. Postcard from the sXe . 5. Ward, Luc. Gods & Monsters (Hook-Up at Church) . 6. Anshuman, Karan. The India Nobody Knows (Mysticism and Misconceptions Revealed) . 8. Clements, Nina and Betsy Falconer. God as One of Us: Diverse Faiths Thrive at Denison . 10. Million, Chris. Splendor in the Fall (First Year Love Bittersweet) . 16. Grindstaff, Michelle. Beer by Night, Bed by Morning . 17. Hart, Madeline and Meredith Newman. Smoke Alarm: Reading This may Cause Lung Cancer, Heart Disease, Emphysema, and Complicate Pregnancy . 21. Almirall, Sara and Kirsten Werne. 20 Best Spots to Smoke on Campus . 22. Werne, Kirsten. An Interview with Painted Thin . 23. Burt, Kara. All in All, We\u27re Just Paper o the Wall (Dorm Art Clue to Denison Identity) . 25. Levine, Robert. Less Talk, Moore Rock (Thurston\u27 Sound Uplifts Soul) . 30. Almirall, R.R. Turtles . 31. Almirall, RR. The Warthog Feels He Has Much in Common With Paul Newman, Others Don\u27t . 20

Mild Idiopathic Infantile Hypercalcemia—Part 1: Biochemical and Genetic Findings

Context: Idiopathic infantile hypercalcemia (IIH), an uncommon disorder characterized by elevated serum concentrations of 1,25 dihydroxyvitamin D (1,25(OH)2D) and low parathyroid hormone (PTH) levels, may present with mild to severe hypercalcemia during the first months of life. Biallelic variants in the CYP24A1 or SLC34A1 genes are associated with severe IIH. Little is known about milder forms. Objective: This work aims to characterize the genetic associations and biochemical profile of mild IIH. Methods: This is a cross-sectional study including children between age 6 months and 17 years with IIH who were followed in the Calcium Clinic at the Hospital for Sick Children (SickKids), Toronto, Canada. Twenty children with mild IIH on calcium-restricted diets were evaluated. We performed a dietary assessment and analyzed biochemical measures including vitamin D metabolites and performed a stepwise molecular genetic analysis. Complementary biochemical assessments and renal ultrasounds were offered to first-degree family members of positive probands. Results: The median age was 16 months. Median serum levels of calcium (2.69 mmol/L), urinary calcium:creatinine ratio (0.72 mmol/mmol), and 1,25(OH)2D (209 pmol/L) were elevated, whereas intact PTH was low normal (22.5 ng/L). Mean 1,25(OH)2D/PTH and 1,25(OH)2D/25(OH)D ratios were increased by comparison to healthy controls. Eleven individuals (55%) had renal calcification. Genetic variants were common (65%), with the majority being heterozygous variants in SLC34A1 and SLC34A3, while a minority showed variants of CYP24A1 and other genes related to hypercalciuria. Conclusion: The milder form of IIH has a distinctive vitamin D metabolite profile and is primarily associated with heterozygous SLC34A1 and SLC34A3 variants. Keywords: CYP24A1; genetic; hypercalcemia; nephrocalcinosis; nephrolithiasis; vitamin

Reducing the duration of untreated psychosis and its impact in the U.S.: the STEP-ED study

Background: Early intervention services for psychotic disorders optimally interlock strategies to deliver: (i) Early Detection (ED) to shorten the time between onset of psychotic symptoms and effective treatment (i.e. Duration of Untreated Psychosis, DUP); and (ii) comprehensive intervention during the subsequent 2 to 5 years. In the latter category, are teams (‘First-episode Services’ or FES) that integrate several empirically supported treatments and adapt their delivery to younger patients and caregivers. There is an urgent need to hasten access to established FES in the U.S. Despite improved outcomes for those in treatment, these FES routinely engage patients a year or more after psychosis onset. The Scandinavian TIPS study was able to effectively reduce DUP in a defined geographic catchment. The guiding questions for this study are: can a U.S. adaptation of the TIPS approach to ED substantially reduce DUP and improve outcomes beyond existing FES? Methods/Design The primary aim is to determine whether ED can reduce DUP in the US, as compared to usual detection. ED will be implemented by one FES (STEP) based in southern Connecticut, and usual detection efforts will continue at a comparable FES (PREPR) serving the greater Boston metropolitan area. The secondary aim is to determine whether DUP reduction can improve presentation, engagement and early outcomes in FES care. A quasi-experimental design will compare the impact of ED on DUP at STEP compared to PREPR over 3 successive campaign years. The campaign will deploy 3 components that seek to transform pathways to care in 8 towns surrounding STEP. Social marketing approaches will inform a public education campaign to enable rapid and effective help-seeking behavior. Professional outreach and detailing to a wide variety of care providers, including those in the healthcare, educational and judicial sectors, will facilitate rapid redirection of appropriate patients to STEP. Finally, performance improvement measures within STEP will hasten engagement upon referral. Discussion STEP-ED will test an ED campaign adapted to heterogeneous U.S. pathways to care while also improving our understanding of these pathways and their impact on early outcomes. Trial registration ClinicalTrials.gov: NCT02069925. Registered 20 February 2014