During evolution from the earliest tetrapoda, newly-recruited genes are increasingly paralogues of existing genes and distribute non-randomly among the chromosomes.

BACKGROUND: The present availability of full genome sequences of a broad range of animal species across the whole range of evolutionary history enables one to ask questions as to the distribution of genes across the chromosomes. Do newly recruited genes, as new clades emerge, distribute at random or at non-random locations? RESULTS: We extracted values for the ages of the human genes and for their current chromosome locations, from published sources. A quantitative analysis showed that the distribution of newly-added genes among and within the chromosomes appears to be increasingly non-random if one observes animals along the evolutionary series from the precursors of the tetrapoda through to the great apes, whereas the oldest genes are randomly distributed. CONCLUSIONS: Randomization will result from chromosome evolution, but less and less time is available for this process as evolution proceeds. Much of the bunching of recently-added genes arises from new gene formation as paralogues in gene families, near the location of genes that were recruited in the preceding phylostratum. As examples we cite the KRTAP, ZNF, OR and some minor gene families. We show that bunching can also result from the evolution of the chromosomes themselves when, as for the KRTAP genes, blocks of genes that had previously been on disparate chromosomes become linked together.

Development and validation of novel algorithms to identify patients with inflammatory bowel diseases in Israel: an epi-IIRN group study.

BACKGROUND: Before embarking on administrative research, validated case ascertainment algorithms must be developed. We aimed at developing algorithms for identifying inflammatory bowel disease (IBD) patients, date of disease onset, and IBD type (Crohn's disease [CD] vs ulcerative colitis [UC]) in the databases of the four Israeli Health Maintenance Organizations (HMOs) covering 98% of the population. METHODS: Algorithms were developed on 5,131 IBD patients and 2,072 controls, following independent chart review (60% CD and 39% UC). We reviewed 942 different combinations of clinical parameters aided by mathematical modeling. The algorithms were validated on an independent cohort of 160,000 random subjects. RESULTS: The combination of the following variables achieved the highest diagnostic accuracy: IBD-related codes, alone if more than five to six codes or combined with purchases of IBD-related medications (at least three purchases or ≥3 months from the first to last purchase) (sensitivity 89%, specificity 99%, positive predictive value [PPV] 92%, negative predictive value [NPV] 99%). A look-back period of 2-5 years (depending on the HMO) without IBD-related codes or medications best determined the date of diagnosis (sensitivity 83%, specificity 68%, PPV 82%, NPV 70%). IBD type was determined by the majority of CD/UC codes of the three recent contacts or the most recent when less than three contacts were recorded (sensitivity 92%, specificity 97%, PPV 97%, NPV 92%). Applying these algorithms, a total of 38,291 IBD patients were residing in Israel, corresponding to a prevalence rate of 459/100,000 (0.46%). CONCLUSION: The application of the validated algorithms to Israel's administrative databases will now create a large and accurate ongoing population-based cohort of IBD patients for future administrative studies.

Cancer prevalence in Israeli men and women with schizophrenia.

The aim of this cross-sectional study was to compare cancer prevalence rates among patients with schizophrenia to those of the non-schizophrenia population. The study population included members of Clalit Health Services aged 25 to 74 years and all data was taken from patients' electronic health records. Of the 2,060,314 members who were included in the study, 32,748 had a diagnosis of schizophrenia. Cancer prevalence rates in women with and without schizophrenia were 491 per 10,000 and 439 per 10,000, respectively; in men, cancer prevalence rates were 226 per 10,000 and 296 per 10,000, respectively. The age-adjusted prevalence rate of all-type cancer was significantly lower among men with schizophrenia, compared to men without schizophrenia; specifically, men with schizophrenia had a lower rate of prostate cancer, and of cancers in the "other" category, compared to men without schizophrenia. Reduced cancer rates in men with schizophrenia may reflect under-diagnosis of some cancer types, likely due to insufficient medical attention. An effort to improve screening regimes should be made.

Stimulant use for ADHD and relative age in class among children in Israel.

BACKGROUND: Diagnosis of children with attention-deficit/hyperactivity disorder (ADHD) is increasing. The present study sought to identify characteristics and medication treatment patterns of children with ADHD and compare them by relative age in class, sex, ethnicity, family size, sibling order, and other socioeconomic status, as well as find trends in disparity of pharmacotherapy. METHODS: This study was based on data from 1 013 149 Clalit Health Services members aged 6-17 years during 2006-2011. Centrally acting sympathomimetic drug purchases were compared according to children's estimated relative age in class; youngest third (born August to November), middle third (born April to July), and oldest third (born December to March). Treatment trends were determined and compared according to sociodemographic and family-related factors. RESULTS: The overall prevalence of stimulant use in the population was 2.6% in 2006 and 4.9% in 2011. The annual incidence of stimulant use increased from 0.75% to 1.36%, rising more sharply among children in the older age groups (≥12) than among younger ones. Moreover, the youngest third of children in class was more likely to use medication than the oldest third (risk ratio (RR) 1.17, confidence interval (CI) 1.12-1.23) or the middle third (RR 1.06, CI 1.01-1.11). Of the different ethnic sectors, incidence of stimulant use was highest among general Jewish (1.8% in 2011) and lowest among Arabs (0.37% in 2011). CONCLUSIONS: The use of stimulant medication is growing among children in Israel. Although the overall use does not exceed the estimated prevalence of ADHD among children, the appropriateness of prescribing to the Israeli pediatric population, especially to the youngest children in class, may be questionable. Copyright © 2016 John Wiley & Sons, Ltd.

Defining the role of medication adherence in poor glycemic control among a general adult population with diabetes.

AIMS: This study assesses the attributable impact of adherence to oral glucose medications as a risk factor for poor glycemic control in population subgroups of a large general population, using an objective medication adherence measure. METHODS: Using electronic health records data, adherence to diabetes medications over a two-year period was calculated by prescription-based Medication Possession Ratios for adults with diabetes diagnosed before January 1, 2010. Glycemic control was determined by the HbA1c test closest to the last drug prescription during 2010-2012. Poor control was defined as HbA1c>75 mmol/mol (9.0%). Medication adherence was categorized as "good" (>80%), "moderate" (50-80%), or "poor" (<50%). Logistic regression models assessed the role medication adherence plays in the association between disease duration, age, and poor glycemic control. We calculated the change in the attributable fraction of glucose control if the non-adherent diabetic medication population would become adherent by age-groups. RESULTS: Among 228,846 diabetes patients treated by oral antiglycemic medication, 46.4% had good, 28.8% had moderate, and 24.8% had poor adherence. Good adherence rates increased with increasing disease duration, while glycemic control became worse. There was a strong inverse association between adherence level and poor control (OR = 2.50; CI = 2.43-2.58), and adherence was a significant mediator between age and poor control. CONCLUSIONS: A large portion of the diabetes population is reported to have poor adherence to oral diabetes medications, which is strongly associated with poor glycemic control in all disease durations. While poor adherence does not mediate the poorer glycemic control seen in patients with longer-standing disease, it is a significant mediator of poor glycemic control among younger diabetes patients. A greater fraction of poorly controlled younger patients, compared to older patients, could be prevented if at least 80% adherence to their medications was achieved. Therefore, our results suggest that interventions to improve adherence should focus on this younger sub-group.

Vitamin D and risk of cause specific death: systematic review and meta-analysis of observational cohort and randomised intervention studies.

OBJECTIVE: To evaluate the extent to which circulating biomarker and supplements of vitamin D are associated with mortality from cardiovascular, cancer, or other conditions, under various circumstances. DESIGN: Systematic review and meta-analysis of observational studies and randomised controlled trials. DATA SOURCES: Medline, Embase, Cochrane Library, and reference lists of relevant studies to August 2013; correspondance with investigators. STUDY SELECTION: Observational cohort studies and randomised controlled trials in adults, which reported associations between vitamin D (measured as circulating 25-hydroxyvitamin D concentration or vitamin D supplement given singly) and cause specific mortality outcomes. DATA EXTRACTION: Data were extracted by two independent investigators, and a consensus was reached with involvement of a third. Study specific relative risks from 73 cohort studies (849,412 participants) and 22 randomised controlled trials (vitamin D given alone versus placebo or no treatment; 30,716 participants) were meta-analysed using random effects models and were grouped by study and population characteristics. RESULTS: In the primary prevention observational studies, comparing bottom versus top thirds of baseline circulating 25-hydroxyvitamin D distribution, pooled relative risks were 1.35 (95% confidence interval 1.13 to 1.61) for death from cardiovascular disease, 1.14 (1.01 to 1.29) for death from cancer, 1.30 (1.07 to 1.59) for non-vascular, non-cancer death, and 1.35 (1.22 to 1.49) for all cause mortality. Subgroup analyses in the observational studies indicated that risk of mortality was significantly higher in studies with lower baseline use of vitamin D supplements. In randomised controlled trials, relative risks for all cause mortality were 0.89 (0.80 to 0.99) for vitamin D3 supplementation and 1.04 (0.97 to 1.11) for vitamin D2 supplementation. The effects observed for vitamin D3 supplementation remained unchanged when grouped by various characteristics. However, for vitamin D2 supplementation, increased risks of mortality were observed in studies with lower intervention doses and shorter average intervention periods. CONCLUSIONS: Evidence from observational studies indicates inverse associations of circulating 25-hydroxyvitamin D with risks of death due to cardiovascular disease, cancer, and other causes. Supplementation with vitamin D3 significantly reduces overall mortality among older adults; however, before any widespread supplementation, further investigations will be required to establish the optimal dose and duration and whether vitamin D3 and D2 have different effects on mortality risk.

Decreased serum concentrations of 25-hydroxycholecalciferol are associated with increased risk of progression to impaired fasting glucose and diabetes.

OBJECTIVE: To study the association between vitamin D status and the risk of incident impaired fasting glucose (IFG) and diabetes in a population-based cohort of diabetes-free subjects. RESEARCH DESIGN AND METHODS: In a historical prospective cohort study of subjects from the Clalit Health Services database, which includes information on nearly 4 million people, diabetes-free subjects aged 40-70 years with serum 25-hydroxycholecalciferol (25-OHD) measurements available were followed for 2 years to assess the development of IFG and diabetes in five 25-OHD subgroups: ≥25, 25.1-37.5, 37.6-50, 50.1-75, and >75 nmol/L. RESULTS: The baseline cohort included 117,960 adults: 83,526 normoglycemic subjects and 34,434 subjects with IFG. During follow-up, 8,629 subjects (10.3% of the normoglycemic group) developed IFG, and 2,162 subjects (1.8% of the total cohort) progressed to diabetes. A multivariable model adjusted for age, sex, population group, immigrant status, BMI, season of vitamin D measurement, LDL and HDL cholesterol, triglycerides, estimated glomerular filtration rate, history of hypertension or cardiovascular disease, Charlson comorbidity index, smoking, and socioeconomic status revealed an inverse association between 25-OHD and the risk of progression to IFG and diabetes. The odds of transitioning from normoglycemia to IFG, from normoglycemia to diabetes, and from IFG to diabetes in subjects with a 25-OHD level ≤25 nmol/L were greater than those of subjects with a 25-OHD level >75 nmol/L [odds ratio 1.13 (95% CI 1.03-1.24), 1.77 (1.11-2.83), and 1.43 (1.16-1.76), respectively]. CONCLUSIONS: Vitamin D deficiency appears to be an independent risk factor for the development of IFG and diabetes.

MicroRNAs as a potential prognostic factor in gastric cancer.

AIM: To compare the microRNA (miR) profiles in the primary tumor of patients with recurrent and non-recurrent gastric cancer. METHODS: The study group included 45 patients who underwent curative gastrectomies from 1995 to 2005 without adjuvant or neoadjuvant therapy and for whom adequate tumor content was available. Total RNA was extracted from formalin-fixed paraffin-embedded tumor samples, preserving the small RNA fraction. Initial profiling using miR microarrays was performed to identify potential biomarkers of recurrence after resection. The expression of the differential miRs was later verified by quantitative real-time polymerase chain reaction (qRT-PCR). Findings were compared between patients who had a recurrence within 36 mo of surgery (bad-prognosis group, n = 14, 31%) and those who did not (good-prognosis group, n = 31, 69%). RESULTS: Three miRs, miR-451, miR-199a-3p and miR-195 were found to be differentially expressed in tumors from patients with good prognosis vs patients with bad prognosis (P < 0.0002, 0.0027 and 0.0046 respectively). High expression of each miR was associated with poorer prognosis for both recurrence and survival. Using miR-451, the positive predictive value for non-recurrence was 100% (13/13). The expression of the differential miRs was verified by qRT-PCR, showing high correlation to the microarray data and similar separation into prognosis groups. CONCLUSION: This study identified three miRs, miR-451, miR-199a-3p and miR-195 to be predictive of recurrence of gastric cancer. Of these, miR-451 had the strongest prognostic impact.

Tumor growth rates derived from data for patients in a clinical trial correlate strongly with patient survival: a novel strategy for evaluation of clinical trial data.

PURPOSE: The slow progress in developing new cancer therapies can be attributed in part to the long time spent in clinical development. To hasten development, new paradigms especially applicable to patients with metastatic disease are needed. PATIENTS AND METHODS: We present a new method to predict survival using tumor measurement data gathered while a patient with cancer is receiving therapy in a clinical trial. We developed a two-phase equation to estimate the concomitant rates of tumor regression (regression rate constant d) and tumor growth (growth rate constant g). RESULTS: We evaluated the model against serial levels of prostate-specific antigen (PSA) in 112 patients undergoing treatment for prostate cancer. Survival was strongly correlated with the log of the growth rate constant, log(g) (Pearson r = -0.72) but not with the log of the regression rate constants, log(d) (r = -0.218). Values of log(g) exhibited a bimodal distribution. Patients with log(g) values above the median had a mortality hazard of 5.14 (95% confidence interval, 3.10-8.52) when compared with those with log(g) values below the median. Mathematically, the minimum PSA value (nadir) and the time to this minimum are determined by the kinetic parameters d and g, and can be viewed as surrogates. CONCLUSIONS: This mathematical model has applications to many tumor types and may aid in evaluating patient outcomes. Modeling tumor progression using data gathered while patients are on study, may help evaluate the ability of therapies to prolong survival and assist in drug development.

A weather-driven model of malaria transmission.

BACKGROUND: Climate is a major driving force behind malaria transmission and climate data are often used to account for the spatial, seasonal and interannual variation in malaria transmission. METHODS: This paper describes a mathematical-biological model of the parasite dynamics, comprising both the weather-dependent within-vector stages and the weather-independent within-host stages. RESULTS: Numerical evaluations of the model in both time and space show that it qualitatively reconstructs the prevalence of infection. CONCLUSION: A process-based modelling structure has been developed that may be suitable for the simulation of malaria forecasts based on seasonal weather forecasts.

Comparison of linear growth patterns in the first three years of life across two generations in Guatemala.

OBJECTIVE: The secular increase in height is assumed to result from long-term improvements in nutritional intakes and reductions in infectious disease burdens. Nutritional supplementation in early life reduces stunting in chronically undernourished populations. It is not known whether these improvements have an impact on the growth of subsequent generations. Our objective was to estimate the intergenerational effect on offspring length of improved nutrition in the mother's early childhood. METHODS: We studied 283 mother-child pairs (mothers born 1969-1977; children born 1996-1999). The mothers had received nutritional supplementation--either atole (enhanced protein-energy) or fresco (moderate energy, no protein), with both containing vitamins and minerals--prenatally and up to age 7 y as part of a community trial conducted in 4 villages in Guatemala. Length was measured on repeated occasions to 36 months of age in both mothers and children. Growth was modeled as a fractional polynomial. RESULTS: Children grew faster than their mothers. Children of mothers who received atole grew faster than children of women who received fresco. In both groups, lengths of individual children were positively correlated with lengths of their own mothers at the same ages. Correlations were generally stronger when the mothers had received atole in early life. CONCLUSION: We have confirmed a secular trend in growth of children in a developing country setting. The rate of child growth reflects, in part, the growth pattern of the mother, including improvements to that pattern resulting from nutritional supplementation.