Mendelian or Multifactorial? Current Undergraduate Genetics Assessments Focus on Genes and Rarely Include the Environment

Undergraduate genetics courses have historically focused on simple genetic models, rather than taking a more multifactorial approach where students explore how traits are influenced by a combination of genes, the environment, and gene-by-environment interactions. While a focus on simple genetic models can provide straightforward examples to promote student learning, they do not match the current scientific understanding and can result in deterministic thinking among students. In addition, undergraduates are often interested in complex human traits that are influenced by the environment, and national curriculum standards include learning objectives that focus on multifactorial concepts. This research aims to discover to what extent multifactorial genetics is currently being assessed in undergraduate genetics courses. To address this, we analyzed over 1,000 assessment questions from a commonly used undergraduate genetics textbook; published concept assessments; and open-source, peer-reviewed curriculum materials. Our findings show that current genetics assessment questions overwhelmingly emphasize the impact of genes on phenotypes and that the effect of the environment is rarely addressed. These results indicate a need for the inclusion of more multifactorial genetics concepts, and we suggest ways to introduce them into undergraduate courses

Investigating the Links between Lower Iron Status in Pregnancy and Respiratory Disease in Offspring Using Murine Models.

Maternal iron deficiency occurs in 40-50% of all pregnancies and is associated with an increased risk of respiratory disease and asthma in children. We used murine models to examine the effects of lower iron status during pregnancy on lung function, inflammation and structure, as well as its contribution to increased severity of asthma in the offspring. A low iron diet during pregnancy impairs lung function, increases airway inflammation, and alters lung structure in the absence and presence of experimental asthma. A low iron diet during pregnancy further increases these major disease features in offspring with experimental asthma. Importantly, a low iron diet increases neutrophilic inflammation, which is indicative of more severe disease, in asthma. Together, our data demonstrate that lower dietary iron and systemic deficiency during pregnancy can lead to physiological, immunological and anatomical changes in the lungs and airways of offspring that predispose to greater susceptibility to respiratory disease. These findings suggest that correcting iron deficiency in pregnancy using iron supplements may play an important role in preventing or reducing the severity of respiratory disease in offspring. They also highlight the utility of experimental models for understanding how iron status in pregnancy affects disease outcomes in offspring and provide a means for testing the efficacy of different iron supplements for preventing disease

Targeted Disruption of the Low-Affinity Leukemia Inhibitory Factor-Receptor Gene Causes Placental, Skeletal, Neural and Metabolic Defects and Results in Perinatal Death

The low-affinity receptor for leukemia inhibitory factor (LIFR)* interacts with gp130 to induce an intracellular signal cascade, The LIFR-gp130 heterodimer is implicated in the function of diverse systems, Normal placentation is disrupted in LIFR mutant animals, which leads to poor intrauterine nutrition but allows fetuses to continue to term. Fetal bone volume is reduced greater than three-fold and the number of osteoclasts is increased six-fold, resulting in severe osteopenia of perinatal bone. Astrocyte numbers are reduced in the spinal cord and brain stem. Late gestation fetal livers contain relatively high stores of glycogen, indicating a metabolic disorder. Hematologic and primordial germ cell compartments appear normal. Pleiotropic defects in the mutant animals preclude survival beyond the day of birth

Linking Land and Sea Through an Ecological-Economic Model of Coral Reef Recreation

This is the author accepted manuscript. The final version is available from Elsevier via the DOI in this recordCoastal zones are popular recreational areas that substantially contribute to social welfare. Managers can use information about specific environmental features that people value, and how these might change under different management scenarios, to spatially target actions to areas of high current or potential value. We explored how snorkelers' experience would be affected by separate and combined land and marine management actions in West Maui, Hawaiʻi, using a Bayesian belief network (BBN) and a spatially explicit ecosystem services model. The BBN simulates the attractiveness of a site for recreation by combining snorkeler preferences for coastal features with expert opinions on ecological dynamics, snorkeler behavior, and management actions. A choice experiment with snorkelers elucidated their preferences for sites with better ecological and water-quality conditions. Linking the economic elicitation to the spatially explicit BBN to evaluate land-sea management scenarios provides specific guidance on where and how to act in West Maui to maximize ecosystem service returns. Improving coastal water quality through sediment runoff and cesspool effluent reductions (land management), and enhancing coral reef ecosystem conditions (marine management) positively affected overall snorkeling attractiveness across the study area, but with differential results at specific sites. The highest improvements were attained through joint land-sea management, driven by strong efforts to increase fish abundance and reduce sediment; however, the effects of management at individual beaches varied.Pacific Islands Climate Science Center (PICSC)US Department of Agriculture National Institute of Food and Agriculture (USDA-NIFA)National Oceanic and Atmospheric Administration Coral Reef Conservation ProgramNational Socio-Environmental Synthesis Center (SESYNC

A mutation in the viral sensor 2'-5'-oligoadenylate synthetase 2 causes failure of lactation.

We identified a non-synonymous mutation in Oas2 (I405N), a sensor of viral double-stranded RNA, from an ENU-mutagenesis screen designed to discover new genes involved in mammary development. The mutation caused post-partum failure of lactation in healthy mice with otherwise normally developed mammary glands, characterized by greatly reduced milk protein synthesis coupled with epithelial cell death, inhibition of proliferation and a robust interferon response. Expression of mutant but not wild type Oas2 in cultured HC-11 or T47D mammary cells recapitulated the phenotypic and transcriptional effects observed in the mouse. The mutation activates the OAS2 pathway, demonstrated by a 34-fold increase in RNase L activity, and its effects were dependent on expression of RNase L and IRF7, proximal and distal pathway members. This is the first report of a viral recognition pathway regulating lactation

The challenges faced in the design, conduct and analysis of surgical randomised controlled trials

Randomised evaluations of surgical interventions are rare; some interventions have been widely adopted without rigorous evaluation. Unlike other medical areas, the randomised controlled trial (RCT) design has not become the default study design for the evaluation of surgical interventions. Surgical trials are difficult to successfully undertake and pose particular practical and methodological challenges. However, RCTs have played a role in the assessment of surgical innovations and there is scope and need for greater use. This article will consider the design, conduct and analysis of an RCT of a surgical intervention. The issues will be reviewed under three headings: the timing of the evaluation, defining the research question and trial design issues. Recommendations on the conduct of future surgical RCTs are made. Collaboration between research and surgical communities is needed to address the distinct issues raised by the assessmentof surgical interventions and enable the conduct of appropriate and well-designed trials.The Health Services Research Unit is funded by the Scottish Government Health DirectoratesPeer reviewedPublisher PD

The Hordaland Women's Cohort: A prospective cohort study of incontinence, other urinary tract symptoms and related health issues in middle-aged women

<p>Abstract</p> <p>Background</p> <p>Urinary incontinence (UI) is a prevalent symptom in middle-aged women, but data on incidence is limited and rarely reported. In order to analyze incidence, remission, or development patterns of severity and types of UI, we have established a 15-year prospective cohort (1997–2012).</p> <p>Methods</p> <p>The Cohort is based on the national collection of health data gathered from county studies (CONOR). Hordaland Health Study (HUSK) is one of them from Hordaland County. Each of the county studies may have local sub-studies and our Cohort is one of them. The Cohort included women aged 40–45 in order to have a broad approach to women's health including UI and other lower urinary tract symptoms (LUTS). A onefifth random sampling from HUSK was used to create the Cohort in 1997–1999. For the necessary sample size a preliminary power calculation, based on a 70% response rate at inclusion and 5% annual attrition rates was used. The Cohort is planned to collect data through questionnaires every second year for the 15-year period from 1997–2012.</p> <p>Discussion</p> <p>The Cohort represents a relatively large random sample (N = 2,230) of about 15% of the total population of women born between 1953–57 in the county of Hordaland. Our data shows that the cohort population is very similar to the source population. The baseline demographic, social and medical characteristics of the Cohort are compared with the rest of women in HUSK (N = 7,746) and there were no significant differences between them except for the level of education (P = 0.001) and yearly income (P = 0.018), which were higher in the Cohort population. Urological characteristics of participants from the Cohort (N = 1,920) were also compared with the other participants (N = 3,400). There were no significant statistical differences except for somewhat more urinary continence (P = 0.04), more stress incontinence (P = 0.048) and smaller amount of leakage (P = 0.015) in the Cohort. In conclusion, the Cohort ispopulation-based, with little selection bias, and thus is a rather unique study forinvestigating UI and LUTS in comparison with many other projects with similar purposes.</p

Pulmonary metastasectomy versus continued active monitoring in colorectal cancer (PulMiCC): a multicentre randomised clinical trial

BACKGROUND: Lung metastasectomy in the treatment of advanced colorectal cancer has been widely adopted without good evidence of survival or palliative benefit. We aimed to test its effectiveness in a randomised controlled trial (RCT). METHODS: Multidisciplinary teams in 13 hospitals recruited participants with potentially resectable lung metastases to a multicentre, two-arm RCT comparing active monitoring with or without metastasectomy. Other local or systemic treatments were decided by the local team. Randomisation was remote and stratified by site with minimisation for age, sex, primary cancer stage, interval since primary resection, prior liver involvement, the number of metastases, and carcinoembryonic antigen level. The central Trial Management Group were blind to patient allocation until completion of the analysis. Analysis was on intention to treat with a margin for non-inferiority of 10%. RESULTS: Between December 2010 and December 2016, 65 participants were randomised. Characteristics were well-matched in the two arms and similar to those in reported studies: age 35 to 86 years (interquartile range (IQR) 60 to 74); primary resection IQR 16 to 35 months previously; stage at resection T1, 2 or 3 in 3, 8 and 46; N1 or N2 in 31 and 26; unknown in 8. Lung metastases 1 to 5 (median 2); 16/65 had previous liver metastases; carcinoembryonic antigen normal in 55/65. There were no other interventions in the first 6 months, no crossovers from control to treatment, and no treatment-related deaths or major adverse events. The Hazard ratio for death within 5 years, comparing metastasectomy with control, was 0.82 (95%CI 0.43, 1.56). CONCLUSIONS: Because of poor and worsening recruitment, the study was stopped. The small number of participants in the trial (N = 65) precludes a conclusive answer to the research question given the large overlap in the confidence intervals in the proportions still alive at all time points. A widely held belief is that the 5-year absolute survival benefit with metastasectomy is about 35%: 40% after metastasectomy compared to < 5% in controls. The estimated survival in this study was 38% (23-62%) for metastasectomy patients and 29% (16-52%) in the well-matched controls. That is the new and important finding of this RCT. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT01106261. Registered on 19 April 2010

Effect of a Low-Intensity PSA-Based Screening Intervention on Prostate Cancer Mortality: The CAP Randomized Clinical Trial

IMPORTANCE Prostate cancer screening remains controversial because potential mortality or quality-of-life benefits may be outweighed by harms from overdetection and overtreatment. OBJECTIVE To evaluate the effect of a single prostate-specific antigen (PSA) screening intervention and standardized diagnostic pathway on prostate cancer-specific mortality. DESIGN, SETTING, AND PARTICIPANTS The Cluster Randomized Trial of PSA Testing for Prostate Cancer (CAP) included 419 582 men aged 50 to 69 years and was conducted at 573 primary care practices across the United Kingdom. Randomization and recruitment of the practices occurred between 2001 and 2009; patient follow-up ended on March 31, 2016. INTERVENTION An invitation to attend a PSA testing clinic and receive a single PSA test vs standard (unscreened) practice. MAIN OUTCOMES AND MEASURES Primary outcome: prostate cancer-specific mortality at a median follow-up of 10 years. Prespecified secondary outcomes: diagnostic cancer stage and Gleason grade (range, 2-10; higher scores indicate a poorer prognosis) of prostate cancers identified, all-cause mortality, and an instrumental variable analysis estimating the causal effect of attending the PSA screening clinic. RESULTS Among 415 357 randomizedmen(mean [SD] age, 59.0[5.6] years), 189 386 in the intervention group and 219 439 in the control groupwere included in the analysis (n = 408 825; 98%). In the intervention group, 75 707 (40%)attended the PSAtesting clinic and 67 313 (36%) underwent PSAtesting. Of 64 436 with a valid PSAtest result, 6857 (11%) had a PSA level between 3 ng/mLand 19.9 ng/mL, ofwhom5850 (85%) had a prostate biopsy. After a median follow-up of 10 years, 549 (0.30 per 1000 person-years) died of prostate cancer in the intervention group vs 647 (0.31 per 1000 person-years) in the control group (rate difference, -0.013 per 1000 person-years [95%CI, -0.047 to0.022]; rate ratio [RR] ,0.96 [95%CI,0.85 to 1.08]; P = .50). The number diagnosed with prostate cancerwas higher in the intervention group (n = 8054; 4.3%) than in the control group (n = 7853; 3.6%) (RR, 1.19 [95%CI, 1.14 to 1.25] ; P < .001). More prostate cancer tumors with a Gleason grade of 6 or lowerwere identified in the intervention group (n = 3263/189 386 [1.7%]) than in the control group (n = 2440/219 439 [1.1%] ) (difference per 1000 men, 6.11 [95%CI, 5.38 to 6.84]; P < .001). In the analysis of all-cause mortality, therewere 25 459 deaths in the intervention group vs 28 306 deaths in the control group (RR,0.99 [95%CI,0.94 to 1.03]; P = .49). In the instrumental variable analysis for prostate cancer mortality, the adherence-adjusted causal RRwas0.93 (95%CI,0.67 to 1.29; P = .66). CONCLUSIONS AND RELEVANCE Among practices randomized to a single PSA screening intervention vs standard practice without screening, there was no significant difference in prostate cancer mortality after a median follow-up of 10 years but the detection of low-risk prostate cancer cases increased. Although longer-term follow-up is under way, the findings do not support single PSA testing for population-based screening. TRIAL REGISTRATION ISRCTN Identifier: ISRCTN92187251

Ground-Based Measurements of the 2014–2015 Holuhraun Volcanic Cloud (Iceland)

The 2014–2015 Bárðarbunga fissure eruption at Holuhraun in central Iceland was distinguished by the high emission of gases, in total 9.6 Mt SO2, with almost no tephra. This work collates all ground-based measurements of this extraordinary eruption cloud made under particularly challenging conditions: remote location, optically dense cloud with high SO2 column amounts, low UV intensity, frequent clouds and precipitation, an extensive and hot lava field, developing ramparts, and high-latitude winter conditions. Semi-continuous measurements of SO2 flux with three scanning DOAS instruments were augmented by car traverses along the ring-road and along the lava. The ratios of other gases/SO2 were measured by OP-FTIR, MultiGAS, and filter packs. Ratios SO2/HCl = 30–110 and SO2/HF = 30–130 show a halogen-poor eruption cloud. Scientists on-site reported extremely minor tephra production during the eruption. OPC and filter packs showed low particle concentrations similar to non-eruption cloud conditions. Three weather radars detected a droplet-rich eruption cloud. Top of eruption cloud heights of 0.3–5.5 km agl were measured with ground- and aircraft-based visual observations, web camera and NicAIR II infrared images, triangulation of scanning DOAS instruments, and the location of SO2 peaks measured by DOAS traverses. Cloud height and emission rate measurements were critical for initializing gas dispersal simulations for hazard forecasting