Expansion of Electronic Health Record-Based Screening, Prevention, and Management of Diabetes in New York City

To address the increasing burden of diabetes in New York City, we designed 2 electronic health records (EHRs)-facilitated diabetes management systems to be implemented in 6 primary care practices on the West Side of Manhattan, a standard system and an enhanced system. The standard system includes screening for diabetes. The enhanced system includes screening and ensures close patient follow-up; it applies principles of the chronic care model, including community–clinic linkages, to the management of patients newly diagnosed with diabetes and prediabetes through screening. We will stagger implementation of the enhanced system across the 6 clinics allowing comparison, through a quasi-experimental design (pre–post difference with a control group), of patients treated in the enhanced system with similar patients treated in the standard system. The findings could inform health system practices at multiple levels and influence the integration of community resources into routine diabetes care

A large data resource of genomic copy number variation across neurodevelopmental disorders

Copy number variations (CNVs) are implicated across many neurodevelopmental disorders (NDDs) and contribute to their shared genetic etiology. Multiple studies have attempted to identify shared etiology among NDDs, but this is the first genome-wide CNV analysis across autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), schizophrenia (SCZ), and obsessive-compulsive disorder (OCD) at once. Using microarray (Affymetrix CytoScan HD), we genotyped 2,691 subjects diagnosed with an NDD (204 SCZ, 1,838 ASD, 427 ADHD and 222 OCD) and 1,769 family members, mainly parents. We identified rare CNVs, defined as those found in \u3c0.1% of 10,851 population control samples. We found clinically relevant CNVs (broadly defined) in 284 (10.5%) of total subjects, including 22 (10.8%) among subjects with SCZ, 209 (11.4%) with ASD, 40 (9.4%) with ADHD, and 13 (5.6%) with OCD. Among all NDD subjects, we identified 17 (0.63%) with aneuploidies and 115 (4.3%) with known genomic disorder variants. We searched further for genes impacted by different CNVs in multiple disorders. Examples of NDD-associated genes linked across more than one disorder (listed in order of occurrence frequency) are NRXN1, SEH1L, LDLRAD4, GNAL, GNG13, MKRN1, DCTN2, KNDC1, PCMTD2, KIF5A, SYNM, and long non-coding RNAs: AK127244 and PTCHD1-AS. We demonstrated that CNVs impacting the same genes could potentially contribute to the etiology of multiple NDDs. The CNVs identified will serve as a useful resource for both research and diagnostic laboratories for prioritization of variants

AGRICULTURAL POLICY REFORM IN THE WTO: THE ROAD AHEAD

Agricultural trade barriers and producer subsidies inflict real costs, both on the countries that use these policies and on their trade partners. Trade barriers lower demand for trade partners' products, domestic subsidies can induce an oversupply of agricultural products which depresses world prices, and export subsidies create increased competition for producers in other countries. Eliminating global agricultural policy distortions would result in an annual world welfare gain of $56 billion. High protection for agricultural commodities in the form of tariffs continues to be the major factor restricting world trade. In 2000, World Trade Organization (WTO) members continued global negotiations on agricultural policy reform. To help policymakers and others realize what is at stake in the global agricultural negotiations, this report quantifies the costs of global agricultural distortions and the potential benefits of their full elimination. It also analyzes the effects on U.S. and world agriculture if only partial reform is achieved in liberalizing tariffs, tariff-rate quotas (limits on imported goods), domestic support, and export subsidies.Agricultural and Food Policy, International Relations/Trade,

538 A.D. and the Transition from Pagan Roman Empire to Holy Roman Empire: Justinian’s Metamorphosis from Chief of Staffs to Theologian

The year 538 A.D. became the turning point in the history of the Roman Empire since so many aspects on political, administrative and economical levels were already switched off that when Justinian declared himself to be a theologian from this year and no longer a soldier, he crossed the barrier of his mandate between what is purely civil obligation and what is religious obligation, similarly to Constantine before, and entered in competition with the papal function and this role is evidence of Justinian’s ongoing caesaro-papism. The quest for unification of the empire by unification of the church, the fever for church-building projects with his wife Theodora, the persecution of enemies of the church and heretics, his disdain with the Sabbath although his second name was Sabbatini, his support for suppressing any eschatological fever in line with the church fathers and Oecumenius and yet trying to build the ‘Kingdom of God’ on earth, all this indicate the problem 538 was for the Roman Empire and the Catholic Church. Archaeological and historical original sources of Justinian and contemporaries of popes, biographer of Justinian and a commentator on Revelation (Oecumenius) are very revealing of these times and the shift or transition of what belonged to the Roman Empire handed over since 538 A.D. to the church and the papal function. The Code of Justinian was a persecuting instrument. Justinian upheld the supremacy of the papacy. He permitted through the Council of Orleans actions to be done on Sunday that Constantine prohibited like travel and preparation of food and cleaning the house. In Novellae CXLIV Justinian instituted a Seventh-day Sabbath persecution. He changed the times and laws ad hoc as his Novellae XLVI and coins of 538 A.D. (XII year) indicate. Private gatherings were persecuted. He had church-manual laws. Justinian studied Systematic Theology on the nature of Christ and wrote homiletical rules for preachers. He gave textcritical advice to Jews and condemned their doctrinal deviations. This theological hobby of the ruler of the once mighty Roman Empire was to be taken over by a more theological competent power that would eventually lead to papal-caesarism until the unsettling of this new aggrandizing paradigm in 1798 by Napoleon. The prophetic embedding of the 1260 days as “years” prophecies in both Daniel 7 and Revelation 12 definitely started in 538 A.D. contrary to W. Spicer’s (1918) suggestion of 533 or 538 as two alternative dates or any other dates suggested by other scholars in the history of interpretation in historicism. It is also not just a case of history of interpretation hermeneutics but data solidly supported by archaeology, iconography and original historical sources that coincides with the parameters provided by exegesis of the rest of the Books of Daniel and Revelation added with the exegesis of the detail of the passages under consideration. A necessary ingredient for the historical researcher remains to be the faith that God can predict the future and He did and that the data as well as the prophecies of the Biblical Text are evidence of that

Dietary iron intakes based on food composition data may underestimate the contribution of potentially exchangeable contaminant iron from soil

Iron intakes calculated from one-day weighed records were compared with those from same day analyzed duplicate diet composites collected from 120 Malawian women living in two rural districts with contrasting soil mineralogy and where threshing may contaminate cereals with soil iron. Soils and diet composites from the two districts were then subjected to a simulated gastrointestinal digestion and iron availability in the digests measured using a Caco-2 cell model. Median analyzed iron intakes (mg/d) were higher (p < 0.001) than calculated intakes in both Zombwe (16.6 vs. 10.1 mg/d) and Mikalango (29.6 vs. 19.1 mg/d), attributed to some soil contaminant iron based on high Al and Ti concentrations in diet composites. A small portion of iron in acidic soil from Zombwe, but not Mikalango calcareous soil, was bioavailable, as it induced ferritin expression in the cells, and may have contributed to higher plasma ferritin and total body iron for the Zombwe women reported earlier, despite lower iron intakes. In conclusion, iron intakes calculated from food composition data were underestimated, highlighting the importance of analyzing duplicate diet composites where extraneous contaminant iron from soil is likely. Acidic contaminant soil may make a small but useful contribution to iron nutrition

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

Association between Hypertension and Retinal Vascular Features in Ultra-Widefield Fundus Imaging

Objective: Changes to the retinal vasculature are known to be associated with hypertension independently of traditional risk factors. We investigated whether measurements of retinal vascular calibre from ultra-widefield fundus imaging were associated with hypertensive status.Methods: We retrospectively collected and semiautomatically measured ultra-widefield retinal fundus images from a subset of participants enrolled in an ongoing population study of ageing, categorised as normotensive or hypertensive according to thresholds on systolic/diastolic blood pressure (140/90 mm Hg) measured in a clinical setting. Vascular calibre in the peripheral retina was measured to calculate the nasal-annular arteriole:venule ratio (NA-AVR), a novel combined parameter.Results: Left and right eyes were analysed from 440 participants (aged 50-59 years, mean age of 54.6±2.9 years, 247, 56.1% women), including 151 (34.3%) categorised as hypertensive. Arterioles were thinner and the NA-AVR was smaller in people with hypertension. The area under the receiver operating characteristic curve of NA-AVR for hypertensive status was 0.73 (95% CI 0.68 to 0.78) using measurements from left eyes, while for right eyes, it was 0.64 (95% CI 0.59 to 0.70), representing evidence of a statistically significant difference between the eyes (p=0.020).Conclusions: Semiautomated measurements of NA-AVR in ultra-widefield fundus imaging were associated with hypertension. With further development, this may help screen people attending routine eye health check-ups for high blood pressure. These individuals may then follow a care pathway for suspected hypertension. Our results showed differences between left and right eyes, highlighting the importance of investigating both eyes of a patient.</p

Enhanced prefrontal serotonin 5-HT1A currents in a mouse model of Williams-Beuren syndrome with low innate anxiety

Williams-Beuren syndrome (WBS) is a neurodevelopmental disorder caused by the hemizygous deletion of 28 genes on chromosome 7, including the general transcription factor GTF2IRD1. Mice either hemizygously (Gtf2ird1+/−) or homozygously (Gtf2ird1−/−) deleted for this transcription factor exhibit low innate anxiety, low aggression and increased social interaction, a phenotype that shares similarities to the high sociability and disinhibition seen in individuals with WBS. Here, we investigated the inhibitory effects of serotonin (5-HT) on the major output neurons of the prefrontal cortex in Gtf2ird1−/− mice and their wildtype (WT) siblings. Prefrontal 5-HT receptors are known to modulate anxiety-like behaviors, and the Gtf2ird1−/− mice have altered 5-HT metabolism in prefrontal cortex. Using whole cell recording from layer V neurons in acute brain slices of prefrontal cortex, we found that 5-HT elicited significantly larger inhibitory, outward currents in Gtf2ird1−/− mice than in WT controls. In both genotypes, these currents were resistant to action potential blockade with TTX and were suppressed by the selective 5-HT1A receptor antagonist WAY-100635, suggesting that they are mediated directly by 5-HT1A receptors on the recorded neurons. Control experiments suggest a degree of layer and receptor specificity in this enhancement since 5-HT1A receptor-mediated responses in layer II/III pyramidal neurons were unchanged as were responses mediated by two other inhibitory receptors in layer V pyramidal neurons. Furthermore, we demonstrate GTF2IRD1 protein expression by neurons in layer V of the prefrontal cortex. Our finding that 5-HT1A-mediated responses are selectively enhanced in layer V pyramidal neurons of Gtf2ird1−/− mice gives insight into the cellular mechanisms that underlie reduced innate anxiety and increased sociability in these mice, and may be relevant to the low social anxiety and disinhibition in patients with WBS and their sensitivity to serotonergic medicines