Genome-wide linkage and association analysis of primary open-angle glaucoma endophenotypes in the Norfolk Island isolate.

PURPOSE: Primary open-angle glaucoma (POAG) refers to a group of heterogeneous diseases involving optic nerve damage. Two well-established risk factors for POAG are elevated intraocular pressure (IOP) and a thinner central corneal thickness (CCT). These endophenotypes exhibit a high degree of heritability across populations. Large-scale genome-wide association studies (GWASs) of outbred populations have robustly implicated several susceptibility gene variants for both IOP and CCT. Despite this progress, a substantial amount of genetic variance remains unexplained. Population-specific variants that might be rare in outbred populations may also influence POAG endophenotypes. The Norfolk Island population is a founder-effect genetic isolate that has been well characterized for POAG endophenotypes. This population is therefore a suitable candidate for mapping new variants that influence these complex traits. METHODS: Three hundred and thirty participants from the Norfolk Island Eye Study (NIES) core pedigree provided DNA. Ocular measurements of CCT and IOP were also taken for analysis. Heritability analyses and genome-wide linkage analyses of short tandem repeats (STRs) were conducted using SOLAR. Pedigree-based GWASs of single-nucleotide polymorphisms (SNPs) were performed using the GenABEL software. RESULTS: CCT was the most heritable endophenotype in this cohort (h2 = 0.77, p = 6×10-6), while IOP showed a heritability of 0.39 (p = 0.008). A genome-wide linkage analysis of these POAG phenotypes identified a maximum logarithm of the odds (LOD) score of 1.9 for CCT on chromosome 20 (p = 0.0016) and 1.3 for IOP on chromosome 15 (p = 0.0072). The GWAS results revealed a study-wise significant association for IOP at rs790357, which is located within DLG2 on chr11q14.1 (p = 1.02×10-7). DLG2 is involved in neuronal signaling and development, and while it has not previously been associated with IOP, it has been associated with myopia. An analysis of 12 known SNPs for IOP showed that rs12419342 in RAPSN on chromosome 11 was nominally associated in Norfolk Island (NI; p = 0.0021). For CCT, an analysis of 26 known SNPs showed rs9938149 in BANP-ZNF469 on chromosome 16 was nominally associated in NI (p = 0.002). CONCLUSIONS: These study results indicate that CCT and IOP exhibit a substantial degree of heritability in the NI pedigree, indicating a genetic component. A genome-wide linkage analysis of POAG endophenotypes did not reveal any major effect loci, but the GWASs did implicate several known loci, as well as a potential new locus in DLG2, suggesting a role for neuronal signaling in development in IOP and perhaps POAG. These results also highlight the need to target rarer variants via whole genome sequencing in this genetic isolate.

Scalpel versus electrosurgery for major abdominal incisions.

BACKGROUND: Scalpels or electrosurgery can be used to make abdominal incisions. The potential benefits of electrosurgery may include reduced blood loss, dry and rapid separation of tissue, and reduced risk of cutting injury to surgeons. Postsurgery risks possibly associated with electrosurgery may include poor wound healing and complications such as surgical site infection. OBJECTIVES: To assess the effects of electrosurgery compared with scalpel for major abdominal incisions. SEARCH METHODS: The first version of this review included studies published up to February 2012. In October 2016, for this first update, we searched the Cochrane Wounds Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), Ovid MEDLINE (including In-Process & Other Non-Indexed Citations), Ovid Embase, EBSCO CINAHL Plus, and the registry for ongoing trials (www.clinicaltrials.gov). We did not apply date or language restrictions. SELECTION CRITERIA: Studies considered in this analysis were randomised controlled trials (RCTs) that compared electrosurgery to scalpel for creating abdominal incisions during major open abdominal surgery. Incisions could be any orientation (vertical, oblique, or transverse) and surgical setting (elective or emergency). Electrosurgical incisions were made through major layers of the abdominal wall, including subcutaneous tissue and the musculoaponeurosis (a sheet of connective tissue that attaches muscles), regardless of the technique used to incise the skin and peritoneum. Scalpel incisions were made through major layers of abdominal wall including skin, subcutaneous tissue, and musculoaponeurosis, regardless of the technique used to incise the abdominal peritoneum. Primary outcomes analysed were wound infection, time to wound healing, and wound dehiscence. Secondary outcomes were postoperative pain, wound incision time, wound-related blood loss, and adhesion or scar formation. DATA COLLECTION AND ANALYSIS: Two review authors independently carried out study selection, data extraction, and risk of bias assessment. When necessary, we contacted trial authors for missing data. We calculated risk ratios (RR) and 95% confidence intervals (CI) for dichotomous data, and mean differences (MD) and 95% CI for continuous data. MAIN RESULTS: The updated search found seven additional RCTs making a total of 16 included studies (2769 participants). All studies compared electrosurgery to scalpel and were considered in one comparison. Eleven studies, analysing 2178 participants, reported on wound infection. There was no clear difference in wound infections between electrosurgery and scalpel (7.7% for electrosurgery versus 7.4% for scalpel; RR 1.07, 95% CI 0.74 to 1.54; low-certainty evidence downgraded for risk of bias and serious imprecision). None of the included studies reported time to wound healing.It is uncertain whether electrosurgery decreases wound dehiscence compared to scalpel (2.7% for electrosurgery versus 2.4% for scalpel; RR 1.21, 95% CI 0.58 to 2.50; 1064 participants; 6 studies; very low-certainty evidence downgraded for risk of bias and very serious imprecision).There was no clinically important difference in incision time between electrosurgery and scalpel (MD -45.74 seconds, 95% CI -88.41 to -3.07; 325 participants; 4 studies; moderate-certainty evidence downgraded for serious imprecision). There was no clear difference in incision time per wound area between electrosurgery and scalpel (MD -0.58 seconds/cm2, 95% CI -1.26 to 0.09; 282 participants; 3 studies; low-certainty evidence downgraded for very serious imprecision).There was no clinically important difference in mean blood loss between electrosurgery and scalpel (MD -20.10 mL, 95% CI -28.16 to -12.05; 241 participants; 3 studies; moderate-certainty evidence downgraded for serious imprecision). Two studies reported on mean wound-related blood loss per wound area; however, we were unable to pool the studies due to considerable heterogeneity. It was uncertain whether electrosurgery decreased wound-related blood loss per wound area. We could not reach a conclusion on the effects of the two interventions on pain and appearance of scars for various reasons such as small number of studies, insufficient data, the presence of conflicting data, and different measurement methods. AUTHORS' CONCLUSIONS: The certainty of evidence was moderate to very low due to risk of bias and imprecise results. Low-certainty evidence shows no clear difference in wound infection between the scalpel and electrosurgery. There is a need for more research to determine the relative effectiveness of scalpel compared with electrosurgery for major abdominal incisions.

GRADE equity guidelines 4: considering health equity in GRADE guideline development: evidence to decision process.

OBJECTIVES: The aim of this paper is to provide detailed guidance on how to incorporate health equity within the GRADE (Grading Recommendations Assessment and Development Evidence) evidence to decision process. STUDY DESIGN AND SETTING: We developed this guidance based on the GRADE evidence to decision framework, iteratively reviewing and modifying draft documents, in person discussion of project group members and input from other GRADE members. RESULTS: Considering the impact on health equity may be required, both in general guidelines and guidelines that focus on disadvantaged populations. We suggest two approaches to incorporate equity considerations: (1) assessing the potential impact of interventions on equity and (2) incorporating equity considerations when judging or weighing each of the evidence to decision criteria. We provide guidance and include illustrative examples. CONCLUSION: Guideline panels should consider the impact of recommendations on health equity with attention to remote and underserviced settings and disadvantaged populations. Guideline panels may wish to incorporate equity judgments across the evidence to decision framework. This is the fourth and final paper in a series about considering equity in the GRADE guideline development process. This series is coming from the GRADE equity subgroup.

GRADE equity guidelines 2: considering health equity in GRADE guideline development: equity extension of the guideline development checklist.

OBJECTIVE: To provide guidance for guideline developers on how to consider health equity at key stages of the guideline development process. STUDY DESIGN AND SETTING: Literature review followed by group discussions and consensus building. RESULTS: The key stages at which guideline developers could consider equity include setting priorities, guideline group membership, identifying the target audience(s), generating the guideline questions, considering the importance of outcomes and interventions, deciding what evidence to include and searching for evidence, summarizing the evidence and considering additional information, wording of recommendations, and evaluation and use. We provide examples of how guidelines have actually considered equity at each of these stages. CONCLUSION: Guideline projects should consider the aforementioned suggestions for recommendations that are equity sensitive.

GRADE equity guidelines 3: considering health equity in GRADE guideline development: rating the certainty of synthesized evidence.

OBJECTIVES: The aim of this paper is to describe a conceptual framework for how to consider health equity in the Grading Recommendations Assessment and Development Evidence (GRADE) guideline development process. STUDY DESIGN AND SETTING: Consensus-based guidance developed by the GRADE working group members and other methodologists. RESULTS: We developed consensus-based guidance to help address health equity when rating the certainty of synthesized evidence (i.e., quality of evidence). When health inequity is determined to be a concern by stakeholders, we propose five methods for explicitly assessing health equity: (1) include health equity as an outcome; (2) consider patient-important outcomes relevant to health equity; (3) assess differences in the relative effect size of the treatment; (4) assess differences in baseline risk and the differing impacts on absolute effects; and (5) assess indirectness of evidence to disadvantaged populations and/or settings. CONCLUSION: The most important priority for research on health inequity and guidelines is to identify and document examples where health equity has been considered explicitly in guidelines. Although there is a weak scientific evidence base for assessing health equity, this should not discourage the explicit consideration of how guidelines and recommendations affect the most vulnerable members of society.

Early versus delayed oral fluids and food for reducing complications after major abdominal gynaecologic surgery.

BACKGROUND: This is an updated version of the original Cochrane review published in 2007. Traditionally, after major abdominal gynaecologic surgery postoperative oral intake is withheld until the return of bowel function. There has been concern that early oral intake would result in vomiting and severe paralytic ileus with subsequent aspiration pneumonia, wound dehiscence, and anastomotic leakage. However, evidence-based clinical studies suggest that there may be benefits from early postoperative oral intake. OBJECTIVES: To assess the effects of early versus delayed (traditional) initiation of oral intake of food and fluids after major abdominal gynaecologic surgery. SEARCH METHODS: We searched the Menstrual Disorders and Subfertility Group's Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), electronic databases (MEDLINE, EMBASE, CINAHL), and the citation lists of relevant publications. The most recent search was conducted 1 April 2014. We also searched a registry for ongoing trials (www.clinicaltrials.gov) on 13 May 2014. SELECTION CRITERIA: Randomised controlled trials (RCTs) were eligible that compared the effect of early versus delayed initiation of oral intake of food and fluids after major abdominal gynaecologic surgery. Early feeding was defined as oral intake of fluids or food within 24 hours post-surgery regardless of the return of bowel function. Delayed feeding was defined as oral intake after 24 hours post-surgery and only after signs of postoperative ileus resolution. DATA COLLECTION AND ANALYSIS: Two review authors selected studies, assessed study quality and extracted the data. For dichotomous data, we calculated the risk ratio (RR) with a 95% confidence interval (CI). We examined continuous data using the mean difference (MD) and a 95% CI. We tested for heterogeneity between the results of different studies using a forest plot of the meta-analysis, the statistical tests of homogeneity of 2 x 2 tables and the I² value. We assessed the quality of the evidence using GRADE methods. MAIN RESULTS: Rates of developing postoperative ileus were comparable between study groups (RR 0.47, 95% CI 0.17 to 1.29, P = 0.14, 3 RCTs, 279 women, I² = 0%, moderate-quality evidence). When we considered the rates of nausea or vomiting or both, there was no evidence of a difference between the study groups (RR 1.03, 95% CI 0.64 to 1.67, P = 0.90, 4 RCTs, 484 women, I² = 73%, moderate-quality evidence). There was no evidence of a difference between the study groups in abdominal distension (RR 1.07, 95% CI 0.77 to 1.47, 2 RCTs, 301 women, I² = 0%) or a need for postoperative nasogastric tube placement (RR 0.48, 95% CI 0.13 to 1.80, 1 RCT, 195 women).Early feeding was associated with shorter time to the presence of bowel sound (MD -0.32 days, 95% CI -0.61 to -0.03, P = 0.03, 2 RCTs, 338 women, I² = 52%, moderate-quality evidence) and faster onset of flatus (MD -0.21 days, 95% CI -0.40 to -0.01, P = 0.04, 3 RCTs, 444 women, I² = 23%, moderate-quality evidence). In addition, women in the early feeding group resumed a solid diet sooner (MD -1.47 days, 95% CI -2.26 to -0.68, P = 0.0003, 2 RCTs, 301 women, I² = 92%, moderate-quality evidence). There was no evidence of a difference in time to the first passage of stool between the two study groups (MD -0.25 days, 95% CI -0.58 to 0.09, P = 0.15, 2 RCTs, 249 women, I² = 0%, moderate-quality evidence). Hospital stay was shorter in the early feeding group (MD -0.92 days, 95% CI -1.53 to -0.31, P = 0.003, 4 RCTs, 484 women, I² = 68%, moderate-quality evidence). Infectious complications were less common in the early feeding group (RR 0.20, 95% CI 0.05 to 0.73, P = 0.02, 2 RCTs, 183 women, I² = 0%, high-quality evidence). In one study, the satisfaction score was significantly higher in the early feeding group (MD 11.10, 95% CI 6.68 to 15.52, P < 0.00001, 143 women, moderate-quality evidence). AUTHORS' CONCLUSIONS: Early postoperative feeding after major abdominal gynaecologic surgery for either benign or malignant conditions appeared to be safe without increased gastrointestinal morbidities or other postoperative complications. The benefits of this approach include faster recovery of bowel function, lower rates of infectious complications, shorter hospital stay, and higher satisfaction.

Heritability and genome-wide linkage analysis of migraine in the genetic isolate of Norfolk Island.

Migraine is a common neurovascular disorder with a complex envirogenomic aetiology. In an effort to identify migraine susceptibility genes, we conducted a study of the isolated population of Norfolk Island, Australia. A large portion of the permanent inhabitants of Norfolk Island are descended from 18th Century English sailors involved in the infamous mutiny on the Bounty and their Polynesian consorts. In total, 600 subjects were recruited including a large pedigree of 377 individuals with lineage to the founders. All individuals were phenotyped for migraine using International Classification of Headache Disorders-II criterion. All subjects were genotyped for a genome-wide panel of microsatellite markers. Genotype and phenotype data for the pedigree were analysed using heritability and linkage methods implemented in the programme SOLAR. Follow-up association analysis was performed using the CLUMP programme. A total of 154 migraine cases (25%) were identified indicating the Norfolk Island population is high-risk for migraine. Heritability estimation of the 377-member pedigree indicated a significant genetic component for migraine (h(2)=0.53, P=0.016). Linkage analysis showed peaks on chromosome 13q33.1 (P=0.003) and chromosome 9q22.32 (P=0.008). Association analysis of the key microsatellites in the remaining 223 unrelated Norfolk Island individuals showed evidence of association, which strengthen support for the linkage findings (P≤0.05). In conclusion, a genome-wide linkage analysis and follow-up association analysis of migraine in the genetic isolate of Norfolk Island provided evidence for migraine susceptibility loci on chromosomes 9q22.22 and 13q33.1.

The Norfolk Island Eye Study (NIES): rationale, methodology and distribution of ocular biometry (biometry of the bounty).

AIM: To describe the recruitment, ophthalmic examination methods and distribution of ocular biometry of participants in the Norfolk Island Eye Study, who were individuals descended from the English Bounty mutineers and their Polynesian wives. METHODS: All 1,275 permanent residents of Norfolk Island aged over 15 years were invited to participate, including 602 individuals involved in a 2001 cardiovascular disease study. Participants completed a detailed questionnaire and underwent a comprehensive eye assessment including stereo disc and retinal photography, ocular coherence topography and conjunctival autofluorescence assessment. Additionally, blood or saliva was taken for DNA testing. RESULTS: 781 participants aged over 15 years were seen (54% female), comprising 61% of the permanent Island population. 343 people (43.9%) could trace their family history to the Pitcairn Islanders (Norfolk Island Pitcairn Pedigree). Mean anterior chamber depth was 3.32mm, mean axial length (AL) was 23.5mm, and mean central corneal thickness was 546 microns. There were no statistically significant differences in these characteristics between persons with and without Pitcairn Island ancestry. Mean intra-ocular pressure was lower in people with Pitcairn Island ancestry: 15.89mmHg compared to those without Pitcairn Island ancestry 16.49mmHg (P = .007). The mean keratometry value was lower in people with Pitcairn Island ancestry (43.22 vs. 43.52, P = .007). The corneas were flatter in people of Pitcairn ancestry but there was no corresponding difference in AL or refraction. CONCLUSION: Our study population is highly representative of the permanent population of Norfolk Island. Ocular biometry was similar to that of other white populations. Heritability estimates, linkage analysis and genome-wide studies will further elucidate the genetic determinants of chronic ocular diseases in this genetic isolate.

Does Haber's law apply to human sensory irritation?

Irritation of the eyes, nose, and throat by airborne chemicals--also referred to as "sensory irritation"--is an important endpoint in both occupational and environmental toxicology. Modeling of human sensory irritation relies on knowledge of the physical chemistry of the compound(s) involved, as well as the exposure parameters (concentration and duration). A reciprocal relationship between these two exposure variables is postulated under Haber's law, implying that protracted, low-level exposures may be toxicologically equivalent to brief, high-level exposures. Although time is recognized as having an influence on sensory irritation, the quantitative predictions of Haber's Law have been addressed for only a handful of compounds in human experimental studies. We have conducted a systematic literature review that includes a semiquantitative comparison of psychophysical data extracted from controlled human exposure studies versus. the predictions of Haber's law. Studies containing relevant data involved exposures to ammonia (2), chlorine (2), formaldehyde (1), inorganic dusts such as calcium oxide (1), and the volatile organic compound 1-octene (1). With the exception of dust exposure, varying exposure concentration has a proportionally greater effect on sensory irritation than does changing exposure duration. For selected time windows, a more generalized power law model (c(n) x t = k) rather than Haber's law per se (c x t = k) yields reasonably robust predictions. Complicating this picture, however, is the frequent observation of intensity-time "plateauing," with time effects disappearing, or even reversing, after a relatively short period, depending on the test compound. The implications of these complex temporal dynamics for risk assessment and standard setting have been incompletely explored to date.