PET-CT as a predictor of outcome in resectable colorectal liver metastases

Introduction
PET-computed tomography (PET-CT) is a useful staging imaging modality in colorectal liver metastases (CRLM). This study aimed to determine whether PET-CT parameters, standardized uptake value (SUV) and reconstructed tumour volume (RTV), are predictors of prognosis and survival.

Methods
A study of all resectable CRLM patients in the regional HPB unit from 2007–2009 was performed. Preoperative PET-CT scans were retrospectively reviewed; SUV, diameter and RTV for each lesion was recorded. Correlation analysis was performed with other pathological and biochemical parameters, by Pearson’s correlation analysis. Survival analysis was performed using Cox regression hazard model. A P value of less than 0.05 was considered statistically significant.

Results
A total of 79 patients were included. SUV moderately correlated with tumour diameter, both PET-CT (r=0.4927; P<0.0001) and histology (r=0.4513; P=0.0003); RTV (r=0.4489; P<0.001), preoperative carcinoembryonic antigen (CEA) (r=0.4977; P=0.0001), and postoperative CEA (r=0.3727; P=0.004). Multivariate analysis found that an independent predictor of SUVmax was preoperative CEA (P=0.03). RTV strongly correlated with preoperative CEA (r=0.9389; P<0.0001). SUV and RTV had a negative effect on survival.

Conclusion
PET-CT, in the setting of CRLM, may have a prognostic role in assessing survival. Although no definite conclusions can be drawn regarding the prognostic role of SUV and RTV, it acts to reinforce the need for further prospective studies to validate these findings.

Suggestive association with ocular phoria at chromosome 6p22

PURPOSE. We conducted a genome-wide association study to identify genetic factors that contribute to the etiology of heterophoria.

METHODS. We measured near and far vertical and horizontal phorias in 988 healthy adults aged 16 to 40 using the Keystone telebinocular with plates 5218 and 5219. We regressed degree of phoria against genotype at 642758 genetic loci. To control for false positives, we applied the conservative genome-wide permutation test to our data.

RESULTS. A locus at 6p22.2 was found to be associated with the degree of near horizontal phoria (P = 2.3 × 10 ). The P value resulting from a genome-wide permutation test was 0.014.

CONCLUSIONS. The strongest association signal arose from an intronic region of the gene ALDH5A1, which encodes the mitochondrial enzyme succinic semialdehyde dehydrogenase (SSADH), an enzyme involved in γ-aminobutyric acid metabolism. Succinic semialdehyde dehydrogenase deficiency, resulting from mutations of ALDH5A1, causes a variety of neural and behavioral abnormalities, including strabismus. Variation in ALDH5A1 is likely to contribute to degree of horizontal phoria.

Rare and common variants in extracellular matrix gene Fibrillin 2 (FBN2) are associated with macular degeneration

Neurodegenerative diseases affecting the macula constitute a major cause of incurable vision loss and exhibit considerable clinical and genetic heterogeneity, from early-onset monogenic disease to multifactorial late-onset age-related macular degeneration (AMD). As part of our continued efforts to define genetic causes of macular degeneration, we performed whole exome sequencing in four individuals of a two-generation family with autosomal dominant maculopathy and identified a rare variant p.Glu1144Lys in Fibrillin 2 (FBN2), a glycoprotein of the elastin-rich extracellular matrix (ECM). Sanger sequencing validated the segregation of this variant in the complete pedigree, including two additional affected and one unaffected individual. Sequencing of 192 maculopathy patients revealed additional rare variants, predicted to disrupt FBN2 function. We then undertook additional studies to explore the relationship of FBN2 to macular disease. We show that FBN2 localizes to Bruch's membrane and its expression appears to be reduced in aging and AMD eyes, prompting us to examine its relationship with AMD. We detect suggestive association of a common FBN2 non-synonymous variant, rs154001 (p.Val965Ile) with AMD in 10,337 cases and 11,174 controls (OR=1.10; p-value=3.79×10(-5)). Thus, it appears that rare and common variants in a single gene - FBN2 - can contribute to Mendelian and complex forms of macular degeneration. Our studies provide genetic evidence for a key role of elastin microfibers and Bruch's membrane in maintaining blood-retina homeostasis and establish the importance of studying orphan diseases for understanding more common clinical phenotypes.

The statistical significance of randomized controlled trial results is frequently fragile: A case for a Fragility Index

Objectives

A P-value <0.05 is one metric used to evaluate the results of a randomized controlled trial (RCT). We wondered how often statistically significant results in RCTs may be lost with small changes in the numbers of outcomes.

Study Design and Setting

A review of RCTs in high-impact medical journals that reported a statistically significant result for at least one dichotomous or time-to-event outcome in the abstract. In the group with the smallest number of events, we changed the status of patients without an event to an event until the P-value exceeded 0.05. We labeled this number the Fragility Index; smaller numbers indicated a more fragile result.

Results

The 399 eligible trials had a median sample size of 682 patients (range: 15-112,604) and a median of 112 events (range: 8-5,142); 53% reported a P-value <0.01. The median Fragility Index was 8 (range: 0-109); 25% had a Fragility Index of 3 or less. In 53% of trials, the Fragility Index was less than the number of patients lost to follow-up.

Conclusion

The statistically significant results of many RCTs hinge on small numbers of events. The Fragility Index complements the P-value and helps identify less robust results. 

Desire for fertility and associated factors among people living with HIV/AIDS (PLWHA) in selected antiretroviral therapy (ART) clinics of Horro Guduru Wollega Zone, North West Oromia, Ethiopia- A cross sectional study

Background: Most recently fertility issues in HIV positive men and women are becoming increasingly important. Because of ART access and its good life effect, it is expected that the need and desire to get married, to have children and to have sexual partners for PLWHA would change with the regard to reproductive health. In Ethiopia HIV positive individuals may or may not have desire to have children. And the extent of this desire and how it varies by individual, health and demographic characteristics is not well known.

Objective: the aim of the study was to assess desire for fertility and associated factors among PLWHA in selected ART clinics of Horro Guduru Wollega Zone, Oromia National Regional State, Ethiopia.

Methods: A cross-sectional, institutional-based study that employed quantitative and qualitative in-depth interviews was conducted. Three hundred twenty one study subjects were selected using systematic random sampling technique and the data was collected using interviewer administered structured questionnaire. Data entry and analysis were performed using EPI Info version 3.5.1 and SPSS version 16. P-value <0.05 was taken as statistically significant and logistic regression was used to control potential confounding factors.

Results: Seventy three (57.9%) of the males and seventy six (39%) of the females desired to have children, giving a total of 149(46.4%) of all study participants. PLWHA who desired children were younger (AOR:3.3, 95%CI: 1.3-8.9), married (AOR: 5.8, 95%CI: 2.7-12.8), had no children (AOR: 75, 95%CI: 20.1-273.3) and males (AOR; 1.9, 95%CI: 1.02-3.62) compared with their counter parts. The major reason for those people who did not desire children were having desired number of children 80 (46.5%) followed by fear of HIV transmission to child reported by 42 (24.4%) of them.

Conclusion: A considerable number of PLWHA wants to have a child currently or in the near future. Many variables like socio demography, partner related, number of alive children and HIV related disease condition were significantly associated with fertility desire.

Exercise rehabilitation following intensive care unit discharge for recovery from critical illness

Background: Skeletal muscle wasting and weakness are significant complications of critical illness, associated with the degree of illness severity and periods of reduced mobility during mechanical ventilation. They contribute to the profound physical and functional deficits observed in survivors. These impairments may persist for many years following discharge from the intensive care unit (ICU) and may markedly influence health-related quality of life. Rehabilitation is a key strategy in the recovery of patients following critical illness. Exercise based interventions are aimed at targeting this muscle wasting and weakness. Physical rehabilitation delivered during ICU admission has been systematically evaluated and shown to be beneficial. However its effectiveness when initiated after ICU discharge has yet to be established. Objectives: To assess the effectiveness of exercise rehabilitation programmes, initiated after ICU discharge, on functional exercise capacity and health-related quality of life in adult ICU survivors who have been mechanically ventilated for more than 24 hours. Search methods:We searched the following databases: the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library), OvidSP MEDLINE, Ovid SP EMBASE, and CINAHL via EBSCO host to 15th May 2014. We used a specific search strategy for each database. This included synonyms for ICU and critical illness, exercise training and rehabilitation. We searched the reference lists of included studies and contacted primary authors to obtain further information regarding potentially eligible studies. We also searched major clinical trials registries (Clinical Trials and Current Controlled Trials) and the personal libraries of the review authors. We applied no language or publication restriction. We reran the search in February 2015. We will deal with any studies of interest when we update the review.  Selection criteria:We included randomized controlled trials (RCTs), quasi-RCTs, and controlled clinical trials (CCTs) that compared an exercise interventioninitiated after ICU discharge to any other intervention or a control or ‘usual care’ programme in adult (≥18years) survivors ofcritical illness. Data collection and analysis:We used standard methodological procedures expected by The Cochrane Collaboration. Main results:We included six trials (483 adult ICU participants). Exercise-based interventions were delivered on the ward in two studies; both onthe ward and in the community in one study; and in the community in three studies. The duration of the intervention varied according to the length of stay in hospital following ICU discharge (up to a fixed duration of 12 weeks).Risk of bias was variable for all domains across all trials. High risk of bias was evident in all studies for performance bias, although blinding of participants and personnel in therapeutic rehabilitation trials can be pragmatically challenging. Low risk of bias was at least 50% for all other domains across all trials, although high risk of bias was present in one study for random sequence generation (selection bias), incomplete outcome data (attrition bias) and other sources. Risk of bias was unclear for remaining studies across the domains.All six studies measured effect on the primary outcome of functional exercise capacity, although there was wide variability in natureof intervention, outcome measures and associated metrics, and data reporting. Overall quality of the evidence was very low. Only two studies using the same outcome measure for functional exercise capacity, had the potential for pooling of data and assessment of heterogeneity. On statistical advice, this was considered inappropriate to perform this analysis and study findings were therefore qualitatively described. Individually, three studies reported positive results in favour of the intervention. A small benefit (versus. control)was evident in anaerobic threshold in one study (mean difference, MD (95% confidence interval, CI), 1.8 mlO2/kg/min (0.4 to 3.2),P value = 0.02), although this effect was short-term, and in a second study, both incremental (MD 4.7 (95% CI 1.69 to 7.75) Watts, P value = 0.003) and endurance (MD 4.12 (95% CI 0.68 to 7.56) minutes, P value = 0.021) exercise testing demonstrated improvement.Finally self-reported physical function increased significantly following a rehabilitation manual (P value = 0.006). Remaining studies found no effect of the intervention.Similar variability in with regard findings for the primary outcome of health-related quality of life were also evident. Only two studies evaluated this outcome. Following statistical advice, these data again were considered inappropriate for pooling to determine overall effect and assessment of heterogeneity. Qualitative description of findings was therefore undertaken. Individually, neither study reported differences between intervention and control groups for health-related quality of life as a result of the intervention. Overall quality of the evidence was very low.Mortality was reported by all studies, ranging from 0% to 18.8%. Only one non-mortality adverse event was reported across all patients in all studies (a minor musculoskeletal injury). Withdrawals, reported in four studies, ranged from 0% to 26.5% in control groups,and 8.2% to 27.6% in intervention groups. Loss to follow-up, reported in all studies, ranged from 0% to 14% in control groups, and 0% to 12.5% in intervention groups. Authors’ conclusions:We are unable, at this time, to determine an overall effect on functional exercise capacity, or health-related quality of life, of an exercise based intervention initiated after ICU discharge in survivors of critical illness. Meta-analysis of findings was not appropriate. This was due to insufficient study number and data. Individual study findings were inconsistent. Some studies reported a beneficial effect of the intervention on functional exercise capacity, and others not. No effect was reported on health-related quality of life. Methodological rigour was lacking across a number of domains influencing quality of the evidence. There was also wide variability in the characteristics of interventions, outcome measures and associated metrics, and data reporting.If further trials are identified, we may be able to determine the effect of exercise-based interventions following ICU discharge, on functional exercise capacity and health-related quality of life in survivors of critical illness.

BUCKLED LAYER STRUCTURE FOR ATOMIC ADSORPTION ON W(100) - THE (ROOT-2X-ROOT-2)R45-DEGREES NITROGEN STRUCTURE FROM ATLEED

Adsorption of 0.5 monolayer of N adatoms on W{100} results in a sharp (root 2 X root 2)R45 degrees LEED pattern. The only previous quantitative LEED study of this system gave a simple overlayer model with a Pendry R-factor of 0.55. An exhaustive search has been made of possible structures, including a novel vacancy reconstruction, displacive reconstructions and underlayer adsorption. From this work a new overlayer structure is derived with an R(p) value of 0.22, displaying a considerable buckling of 0.27 +/- 0.05 Angstrom within the second W layer and consequently involving large changes in the interlayer spacings of the surface. The N adatom is pseudo-five-fold coordinated to the W surface, bonding to a second-layer W atom with a nearest-neighbour bond length of 2.13 Angstrom and with the four next-nearest-neighbour W atoms in the surface plane at 2.27 Angstrom. The structure does not resolve the work function anomaly observed on this surface.

Physical activity and sport participation for people with long-term illness

Purpose:Physical activity is recommended for optimal prevention of cardiovascular disease(CVD) and participation in sport is associated with improved well-being. However, people with long-standing illness/disability are less likely to participate in sport than others. Evidence of factors associated with their participation is limited and the best approach to encourage participation is unknown. This study aimed to identify sport participation levels and their correlates, among adults with long standing illness/disability in Northern Ireland, where CVD prevalence is high. Method:Using routinely collected data in annual surveys of population samples from 2007 to 2011, descriptive statistics were derived. Chi-squared tests were used to compare characteristics of those with a long-term illness/disability and those without long-term health problems. Uni-variate binary regression analysis for the whole sample and those with a long-standing illness/disability, using sport participation as the dependent variable, was performed and variables with a p-value of 0.1 or less were taken into a multi-variate analysis. Results:The sample included 13,683 adults; 3550(26%) reported having long-term illness/disability. Fewer of those with, than without, long-term illness/disability reported sport participation in the previous year (868/3550(24.5%) v 5615/10133(55.6%)). Multi-variate analysis showed that, for those with long-standing illness/disability, being single and less socio-economically deprived correlated positively with sport participation. For both those with long-standing illness/disability and the full sample, sport participation correlated positively with being male, aged <56 years, access to a household car/van, sports club membership, health ‘fairly good’ or ‘good’ in the previous year, doing paid/unpaid work, and living in an urban location. For the full sample but not those with long-standing illness/disability, sport participation correlated positively with being a non-smoker, higher educational status and personal internet access. Of note, personal internet access was less for those with, than without, long-term illness/disability (41% v 70%). Conclusions:Efforts to promote physical activity in sport for those with long-standing illness/disability should target older people, married females, those who live rurally, and those who are socio-economically deprived and report their health as ‘not good’. Implementation of initiatives should not rely on the internet, to which these people may not have ready access, to help support their sport participation and physical activity in optimal CVD prevention.

A systematic review and meta-analysis of the survival of feldspathic porcelain veneers over 5 and 10 years

PURPOSE: This systematic review reports on the survival of feldspathic porcelain veneers.

MATERIALS AND METHODS: The Cochrane Library, MEDLINE (OVID), Embase, Web of Knowledge, selected journals, clinical trials registers, and conference proceedings were searched independently by two reviewers. Academic colleagues were also contacted to identify relevant research. Inclusion criteria were human cohort studies (prospective and retrospective) and controlled trials assessing outcomes of feldspathic porcelain veneers in more than 15 patients and with at least some of the veneers in situ for 5 years. Of 4,294 articles identified, 116 studies underwent full-text screenings and 69 were further reviewed for eligibility. Of these, 11 were included in the qualitative analysis and 6 (5 cohorts) were included in meta-analyses. Estimated cumulative survival and standard error for each study were assessed and used for meta-, sensitivity, and post hoc analyses. The I2 statistic and the Cochran Q test and its associated P value were used to evaluate statistical heterogeneity, with a random-effects meta-analysis used when the P value for heterogeneity was less than .1. Galbraith, forest, and funnel plots explored heterogeneity, publication patterns, and small study biases.

RESULTS: The estimated cumulative survival for feldspathic porcelain veneers was 95.7% (95% confidence interval [CI]: 92.9% to 98.4%) at 5 years and ranged from 64% to 95% at 10 years across three studies. A post hoc meta-analysis indicated that the 10-year best estimate may approach 95.6% (95% CI: 93.8% to 97.5%). High levels of statistical heterogeneity were found.

CONCLUSIONS: When bonded to enamel substrate, feldspathic porcelain veneers have a very high 10-year survival rate that may approach 95%. Clinical heterogeneity is associated with differences in reported survival rates. Use of clinically relevant survival definitions and careful reporting of tooth characteristics, censorship, clustering, and precise results in future research would improve metaanalytic estimates and aid treatment decisions.

Modeling Linkage Disequilibrium Increases Accuracy of Polygenic Risk Scores

Polygenic risk scores have shown great promise in predicting complex disease risk and will become more accurate as training sample sizes increase. The standard approach for calculating risk scores involves linkage disequilibrium (LD)-based marker pruning and applying a p value threshold to association statistics, but this discards information and can reduce predictive accuracy. We introduce LDpred, a method that infers the posterior mean effect size of each marker by using a prior on effect sizes and LD information from an external reference panel. Theory and simulations show that LDpred outperforms the approach of pruning followed by thresholding, particularly at large sample sizes. Accordingly, predicted R(2) increased from 20.1% to 25.3% in a large schizophrenia dataset and from 9.8% to 12.0% in a large multiple sclerosis dataset. A similar relative improvement in accuracy was observed for three additional large disease datasets and for non-European schizophrenia samples. The advantage of LDpred over existing methods will grow as sample sizes increase.

Single nucleotide polymorphisms in the APCS gene influence geographic atrophy secondary to VEGF inhibition therapy in neovascular macular degeneration.

Introduction: Age-related macular degeneration (AMD) is a leading cause of vision loss in the elderly mostly due to the development of neovascular AMD (nAMD) or geographic atrophy (GA). Intravitreal injections of anti-vascular endothelial growth factor (VEGF) agents are an effective therapeutic option for nAMD. Following anti-VEGF treatments, increased atrophy of the retinal pigment epithelium (RPE) and choriocapillaries that resembles GA has been reported. We sought to evaluate the underlying genetic influences that may contribute to this process. Methods: We selected 68 single nucleotide polymorphisms (SNPs) from genes previously identified as susceptibility factors in AMD, along with 43 SNPs from genes encoding the VEGF protein and its cognate receptors as this pathway is targeted by treatment. We enrolled 467 consecutive patients (Feb 2009 to October 2011) with nAMD who received anti-VEGF therapy. The acutely presenting eye was designated as the study eye and retinal tomograms graded for macular atrophy at study exit. Statistical analysis was performed using PLINK to identify SNPs with a P value < 0.01. Logistic regression models with macular atrophy as dependent variable were fitted with age, gender, smoking status, common genetic risk factors and the identified SNPs as explanatory variables. Results: Grading for macular atrophy was available in 304 study eyes and 70% (214) were classified as showing macular atrophy. In the unadjusted analysis we observed significant associations between macular atrophy and two independent SNPs in the APCS gene: rs6695377: odds ratio (OR) = 1.98; 95% confidence intervals (CI): 1.23, 3.19; P = 0.004; rs1446965: OR = 2.49, CI: 1.29, 4.82; P = 0.006 and these associations remained significant after adjustment for covariates. Conclusions: VEGF is a mitogen and growth factor for choroidal blood vessels and the RPE and its inhibition could lead to atrophy of these key tissues. Anti-VEGF treatment can interfere with ocular vascular maintenance and may be associated with RPE and choroidal atrophy. As such, these medications, which block the effects of VEGF, may influence the development of GA. The top associated SNPs are found in the APCS gene, a highly conserved glycoprotein that encodes Serum amyloid P (SAP) which opsonizes apoptotic cells. SAP can bind to and activate complement components via binding to C1q, a mechanism by which SAP may remove cellular debris, affecting regulation of the three complement pathways.

The common vaginal commensal bacterium Ureaplasma parvum is associated with chorioamnionitis in extreme preterm labour

OBJECTIVE: To assess the association of vaginal commensal and low grade pathogenic bacteria including Ureaplasma parvum, Ureaplasma urealyticum, Mycoplasma hominis, Mycoplasma genitalium, Group B Streptococcus (GBS), and Gardnerella vaginalis, in women who delivered preterm at less than 37 weeks gestation in the presence or absence of inflammation of the chorioamnionitic membranes.

METHODS: A case control study involving women who delivered before 37 weeks gestation with and without inflammation of chorioamnionitic membranes. A total of 57 placental samples were histologically examined for polymorphonuclear leukocyte infiltration of placental tissue for evidence of chorioamnionitis, and by type-specific nucleic acid amplification for evidence of infection with one or more of the target bacteria. Demographic data was collected for each mother.

RESULTS: Amongst the 57 placental samples, 42.1% had chorioamnionitis and 24.6% delivered in the second trimester of pregnancy; U. parvum, U. urealyticum, G. vaginalis and GBS were all detected in the study with respective prevalence of 19.3%, 3.5%, 17.5% and 15.8%; M.genitalium and M. hominis were not detected. U. parvum was significantly associated with chorioamnionitis (p value = 0.02; OR 5.0; (95% CI 1.2-21.5) and was more common in women who delivered in the second (35.7%) compared to the third trimester of pregnancy (13.9%). None of the other bacteria were associated with chorioamnionitis or earlier delivery and all G.vaginalis positive women delivered in the third trimester of pregnancy (p value 0.04).

CONCLUSIONS: The detection of U. parvum in placental tissue was significantly associated with acute chorioamnionitis in women presenting in extreme preterm labour.

Urinary thrombomodulin levels were significantly higher following occupational exposure to chemicals, in the presence of dipstick protein, but not in the presence of dipstick blood

Currently, there are no biomarkers which can identify patients with an increased risk of developing urothelial cancer as a result of occupational chemical exposure. The aim of this study was to evaluate the relationships between final diagnosis and 22 biomarkers measured in urine, serum and plasma collected from 156 hematuric patients. Fourteen of the 80 patients (17.5%) with urothelial cancer and 13/76 (17.1%) of the controls were deemed to have a history of chemical exposure. We applied Fisher's exact tests to explore associations between chemical exposure and final diagnosis, and tumor stage and grade, where applicable; ANOVA and t-test to compare age across patients with and without chemical exposure; and Zelen's exact test to evaluate relationships across final diagnosis, chemical exposure and smoking. Following pre-selection of biomarkers using Lasso, we identified biomarkers with differential levels across patients with and without chemical exposure using Welch's t-test. Using a one-sided t-test and considering multiple testing using FDR, we observed that TM levels in urine were significantly higher in samples from patients with a history of chemical exposure regardless of their diagnosis as control or urothelial cancer (one-sided t-test, p_UC = 0.014 and p_CTL = 0.043); in the presence of dipstick protein and when urinary pH levels ≤ 6 (p = 0.003), but not in the presence of dipstick blood (p = 0.115). Urothelial cancer patients with a history of chemical exposure were significantly younger (64.1 years) than those without chemical exposure (70.2 years) (one-sided t-test p-value = 0.012); and their tumors were higher grade (Fisher's exact test; p = 0.008). There was a strong association between a history of chemical exposure and smoking in urothelial cancer patients (Zelen's exact test; p = 0.025). Elevated urinary thrombomodulin levels could have the potential to identify chemical exposure in hematuric patients at high risk of developing urothelial cancer.

Genome-wide association study reveals greater polygenic loading for schizophrenia in cases with a family history of illness

Genome-wide association studies (GWAS) of schizophrenia have yielded more than 100 common susceptibility variants, and strongly support a substantial polygenic contribution of a large number of small allelic effects. It has been hypothesized that familial schizophrenia is largely a consequence of inherited rather than environmental factors. We investigated the extent to which familiality of schizophrenia is associated with enrichment for common risk variants detectable in a large GWAS. We analyzed single nucleotide polymorphism (SNP) data for cases reporting a family history of psychotic illness (N = 978), cases reporting no such family history (N = 4,503), and unscreened controls (N = 8,285) from the Psychiatric Genomics Consortium (PGC1) study of schizophrenia. We used a multinomial logistic regression approach with model-fitting to detect allelic effects specific to either family history subgroup. We also considered a polygenic model, in which we tested whether family history positive subjects carried more schizophrenia risk alleles than family history negative subjects, on average. Several individual SNPs attained suggestive but not genome-wide significant association with either family history subgroup. Comparison of genome-wide polygenic risk scores based on GWAS summary statistics indicated a significant enrichment for SNP effects among family history positive compared to family history negative cases (Nagelkerke's R(2 ) = 0.0021; P = 0.00331; P-value threshold <0.4). Estimates of variability in disease liability attributable to the aggregate effect of genome-wide SNPs were significantly greater for family history positive compared to family history negative cases (0.32 and 0.22, respectively; P = 0.031). We found suggestive evidence of allelic effects detectable in large GWAS of schizophrenia that might be specific to particular family history subgroups. However, consideration of a polygenic risk score indicated a significant enrichment among family history positive cases for common allelic effects. Familial illness might, therefore, represent a more heritable form of schizophrenia, as suggested by previous epidemiological studies.

The adaptive value of polyembryony.

From an evolutionary standpoint, the production of offspring is the single most important aspect of an animal's life. Offspring carry an individual's genes into the next generation and it is the differential representation of genes in a population that drives evolutionary change. There are a variety of ways in which animals create offspring, ranging from cases where parents make identical copies of themselves by budding or parthenogenesis, to the standard case in vertebrates where gametes from a male and female fuse in sexual reproduction to produce the next generation. In this article we describe an usual variant of sexual reproduction, polyembryony.