The TFAP2A-IRF6-GRHL3 genetic pathway is conserved in neurulation.

Mutations in IRF6, TFAP2A and GRHL3 cause orofacial clefting syndromes in humans. However, Tfap2a and Grhl3 are also required for neurulation in mice. Here, we found that homeostasis of Irf6 is also required for development of the neural tube and associated structures. Over-expression of Irf6 caused exencephaly, a rostral neural tube defect, through suppression of Tfap2a and Grhl3 expression. Conversely, loss of Irf6 function caused a curly tail and coincided with a reduction of Tfap2a and Grhl3 expression in tail tissues. To test whether Irf6 function in neurulation was conserved, we sequenced samples obtained from human cases of spina bifida and anencephaly. We found two likely disease-causing variants in two samples from patients with spina bifida. Overall, these data suggest that the Tfap2a-Irf6-Grhl3 genetic pathway is shared by two embryologically distinct morphogenetic events that previously were considered independent during mammalian development. In addition, these data suggest new candidates to delineate the genetic architecture of neural tube defects and new therapeutic targets to prevent this common birth defect.

Changing the Criminal Justice System Response to Sexual Assault: An Empirical Study of a Participatory Action Research Project.

In jurisdictions throughout the United States, thousands of sexual assault kits (SAKs; also known as a "rape kits") have not been submitted by the police for forensic DNA testing. DNA evidence may be helpful to sexual assault investigations and prosecutions by identifying perpetrators, revealing serial offenders through DNA matches across cases, and exonerating those who have been wrongly accused. This paper describes a longitudinal action research project conducted in Detroit, Michigan after that city discovered approximately 11,000 untested sexual assault kits in a police department storage facility. We conducted a root cause analysis to examine individual, organizational, community, and societal factors that contributed to the development of the rape kit backlog in Detroit. Based on those findings, we implemented and evaluated structural changes to increase staffing, promote kit testing, and retrain police and prosecutors so that cases could be reopened for investigation and prosecution. As we conducted this work, we also studied how this action research project impacted the Detroit criminal justice system. Participating in this project changed stakeholders' attitudes about the utility of research to address community problems, the usefulness of DNA evidence in sexual assault cases, and the impact of trauma on survivors. The results led to new protocols for SAK testing and police investigations, and new state legislation mandating SAK forensic DNA testing.

Intervention Effects of "Girls on the Move" on Increasing Physical Activity: A Group Randomized Trial.

BACKGROUND: Limited intervention success in increasing and sustaining girls' moderate-to-vigorous physical activity (MVPA) underscores a need for continued research. PURPOSE: The aim of this study was to evaluate the effect of a 17-week Girls on the Move (GOTM) intervention on increasing MVPA among fifth- to eighth-grade girls. METHODS: This study is a group (cluster) randomized trial, including 24 schools, pair matched and assigned to intervention (n = 12) or control (n = 12) conditions. Participants included 1,519 girls in racially diverse public schools in urban, underserved areas of the Midwestern USA. The intervention included three components: (i) 90-min after-school physical activity (PA) club offered 3 days/week; (ii) two motivational, individually tailored counseling sessions; and (iii) an interactive Internet-based session at the midpoint of the intervention. Main outcome measures were weighted mean minutes of MVPA per week post-intervention and at 9-month follow-up measured via accelerometer. RESULTS: No between-group differences occurred for weighted mean minutes of MVPA per week at post-intervention (B = -0.08, p = .207) or 9-month follow-up (B = -0.09, p = .118) while controlling for baseline MVPA. CONCLUSIONS: Research is needed to identify interventions that assist girls in attaining and maintaining adequate PA. CLINICALTRIALS.GOV IDENTIFIER: NCT01503333.

How to Right a Wrong: Empirically Evaluating Whether Victim, Offender, and Assault Characteristics can Inform Rape Kit Testing Policies.

Hundreds of thousands of previously untested sexual assault kits (SAKs) have been uncovered in police property storage facilities across the United States, representing a national failure in institutional response to sexual assault. Faced with this discovery, jurisdictions must now decide if and how they should test these kits. Some stakeholders have suggested prioritizing kits for testing by victim, offender, or assault characteristics, based on the belief that these characteristics can predict the likely utility of DNA testing. However, little research has examined the empirical merits of such prioritization. To address this gap in the literature and inform SAK testing policies, we randomly sampled 900 previously untested SAKs from Detroit, MI. The sampled SAKs were submitted for DNA testing, and eligible DNA profiles were entered into Combined DNA Index System (CODIS), the federal DNA database. Police records associated with each SAK were coded for victim, offender, and assault characteristics, and logistic regression analyses were conducted to test whether these characteristics predict which SAKs yield DNA profiles that match ("hit") to other criminal offenses in CODIS. Testing this sample of previously-untested SAKs produced a substantial number of CODIS hits, but few of the tested variables were significant predictors of CODIS hit rate. These findings suggest that testing all previously-unsubmitted kits may generate information that is useful to the criminal justice system, while also potentially addressing the institutional betrayal victims experienced when their kits were ignored.

Sources and Types of Social Support for Physical Activity Perceived by Fifth to Eighth Grade Girls.

BACKGROUND: Information is lacking on forms and sources of social support for physical activity (PA) received by adolescent girls during various pubertal stages. Two study purposes were to (a) identify the sources and forms of social support for PA perceived by adolescent girls, and (b) examine associations of pubertal stage and social support with PA. METHODS: A secondary analysis of data from a randomized trial was conducted. Fifth through eighth grade girls (N = 1,519) completed surveys on social support for PA and pubertal stage and wore an accelerometer. RESULTS: Girls in early-middle and late-post puberty most frequently received social support from their mothers. A higher proportion of girls in late-post puberty, compared to early-middle puberty, received social support from nonfamily adults (4.2% vs. 3.0%, p = .019). Girls identifying three sources participated in more moderate-to-vigorous PA than those having fewer sources (t1,512 = -3.57, p < .001). Various forms of social support, except for encouragement, were positively related to moderate-to-vigorous PA. Girls in early-middle puberty reported greater social support than those in late-post puberty (t1,512 = 3.99, p < .001). Social support was positively associated with moderate-to-vigorous PA, while girls in late-post puberty had lower moderate-to-vigorous PA than those in early-middle puberty. CONCLUSIONS: Mothers are important sources of social support for PA. Having more than two sources may result in greater PA. Encouraging girls to increase their PA may not be sufficient. CLINICAL RELEVANCE: Efforts are needed from health professionals to prevent any decline in social support for PA as girls advance across adolescence.

Comparative effectiveness of three platinum-doublet chemotherapy regimens in elderly patients with advanced non-small cell lung cancer.

BACKGROUND: Randomized trials report equivalent efficacy among various combinations of platinum-based regimens in advanced non-small cell lung cancer (NSCLC). Their relative effectiveness and comparability based on squamous versus nonsquamous histology is uncertain. METHODS: The authors used the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked data to identify first-line chemotherapy agents administered to Medicare beneficiaries with stage IIIB or IV NSCLC diagnosed from 2000 to 2007. Overall survival was compared between patients who received the 3 most common regimens: carboplatin-paclitaxel, carboplatin-gemcitabine, and carboplatin-docetaxel. Stratified analyses distinguished between the outcomes of patients with squamous versus nonsquamous cell histology. Multivariable Cox proportional hazards models and propensity score analyses facilitated adjustment for imbalance in measurable patient characteristics. RESULTS: Of the 15,318 patients who received first-line chemotherapy, 43.1% received carboplatin-paclitaxel, 14.3% received carboplatin-gemcitabine, 8.5% received carboplatin-docetaxel, and 34.1% received other regimens. The median survival was 8.0 months (interquartile range [IQR], 3.5-17.4 months) for carboplatin-paclitaxel, 7.3 months (IQR, 3.4-15.2 months) for carboplatin-gemcitabine, and 7.5 months (IQR, 3.2-16.0 months) for carboplatin-docetaxel. Both multivariable and propensity score-adjusted Cox models demonstrated a slight inferiority associated with carboplatin-gemcitabine or carboplatin-docetaxel versus carboplatin-paclitaxel, with a hazard ratio of 1.10 (95% confidence interval, 1.04-1.15) and 1.09 (95% confidence interval, 1.02-1.16), respectively, in propensity score-stratified models. Among the subgroup of 2063 patients with squamous carcinoma, propensity score-stratified analyses had a higher risk of death (hazard ratio, 1.20; 95% confidence interval, 1.07-1.35) associated with carboplatin-gemcitabine versus carboplatin-paclitaxel. CONCLUSIONS: Carboplatin-paclitaxel was associated with slightly better survival compared with carboplatin-gemcitabine or carboplatin-docetaxel within the Medicare population with advanced NSCLC, and this was most pronounced for patients who had squamous cell histology.

Carboplatin and paclitaxel with vs without bevacizumab in older patients with advanced non-small cell lung cancer.

CONTEXT: A previous randomized trial demonstrated that adding bevacizumab to carboplatin and paclitaxel improved survival in advanced non-small cell lung cancer (NSCLC). However, longer survival was not observed in the subgroup of patients aged 65 years or older. OBJECTIVE: To examine whether adding bevacizumab to carboplatin and paclitaxel chemotherapy is associated with improved survival in older patients with NSCLC. DESIGN, SETTING, AND PARTICIPANTS: Retrospective cohort study of 4168 Medicare beneficiaries aged 65 years or older with stage IIIB or stage IV non-squamous cell NSCLC diagnosed in 2002-2007 in a Surveillance, Epidemiology, and End Results (SEER) region. Patients were categorized into 3 cohorts based on diagnosis year and type of initial chemotherapy administered within 4 months of diagnosis: (1) diagnosis in 2006-2007 and bevacizumab-carboplatin-paclitaxel therapy; (2) diagnosis in 2006-2007 and carboplatin-paclitaxel therapy; or (3) diagnosis in 2002-2005 and carboplatin-paclitaxel therapy. The associations between carboplatin-paclitaxel with vs without bevacizumab and overall survival were compared using Cox proportional hazards models and propensity score analyses including information about patient characteristics recorded in SEER-Medicare. MAIN OUTCOME MEASURE: Overall survival measured from the first date of chemotherapy treatment until death or the censoring date of December 31, 2009. RESULTS: The median survival estimates were 9.7 (interquartile range [IQR], 4.4-18.6) months for bevacizumab-carboplatin-paclitaxel, 8.9 (IQR, 3.5-19.3) months for carboplatin-paclitaxel in 2006-2007, and 8.0 (IQR, 3.7-17.2) months for carboplatin-paclitaxel in 2002-2005. One-year survival probabilities were 39.6% (95% CI, 34.6%-45.4%) for bevacizumab-carboplatin-paclitaxel vs 40.1% (95% CI, 37.4%-43.0%) for carboplatin-paclitaxel in 2006-2007 and 35.6% (95% CI, 33.8%-37.5%) for carboplatin-paclitaxel in 2002-2005. Neither multivariable nor propensity score-adjusted Cox models demonstrated a survival advantage for bevacizumab-carboplatin-paclitaxel compared with carboplatin-paclitaxel cohorts. In propensity score-stratified models, the hazard ratio for overall survival for bevacizumab-carboplatin-paclitaxel compared with carboplatin-paclitaxel in 2006-2007 was 1.01 (95% CI, 0.89-1.16; P = .85) and compared with carboplatin-paclitaxel in 2002-2005 was 0.93 (95% CI, 0.83-1.06; P = .28). The propensity score-weighted model and propensity score-matching model similarly failed to demonstrate a statistically significant superiority for bevacizumab-carboplatin-paclitaxel. Subgroup and sensitivity analyses for key variables did not change these findings. CONCLUSION: Adding bevacizumab to carboplatin and paclitaxel chemotherapy was not associated with better survival among Medicare patients with advanced NSCLC.

Improving corrected QT; Why individual correction is not enough.

The use of QT-prolongation as a biomarker for arrhythmia risk requires that researchers correct the QT-interval (QT) to control for the influence of heart rate (HR). QT correction methods can vary but most used are the universal correction methods, such as Bazett's or Van de Water's, which use a single correction formula to correct QT-intervals in all the subjects of a study. Such methods fail to account for differences in the QT/HR relationship between subjects or over time, instead relying on the assumption that this relationship is consistent. To address these changes in rate relationships, we test the effectiveness of linear and non-linear individual correction methods. We hypothesize that individual correction methods that account for additional influences on the rate relationship will result in more effective and consistent correction. To increase the scope of this study we use bootstrap sampling on ECG recordings from non-human primates and beagle canines dosed with vehicle control. We then compare linear and non-linear individual correction methods through their ability to reduce HR correlation and standard deviation of corrected QT values. From these results, we conclude that individual correction methods based on post-treatment data are most effective with the linear methods being the best option for most cases in both primates and canines. We also conclude that the non-linear methods are more effective in canines than primates and that accounting for light status can improve correction while examining the data from the light periods separately. Individual correction requires careful consideration of inter-subject and intra-subject variabilities.

A State Census of Unsubmitted Sexual Assault Kits: Comparing Forensic DNA Testing Outcomes by Geographic and Population Density Characteristics.

A growing number of U.S. cities and states have large numbers of unsubmitted sexual assault kits (SAKs) in police property facilities. Prior research conducted in large urban cities has found that testing these kits yields a sizable number of DNA profiles that meet FBI eligibility for upload to the national criminal DNA database CODIS (Combined DNA Index System) and uploaded profiles return a substantial number of matches to existing criminal profiles in CODIS. It is unknown whether these findings are unique to large urban cities with high crime rates. The purpose of current study was to document forensic testing outcomes from a state census of previously unsubmitted SAKs, which included large urban-suburban centers, as well as smaller cities and rural counties. We inventoried all previously unsubmitted SAKs in Michigan (N = 3422 SAKs) and submitted all kits for forensic DNA testing. A total of n = 1239 SAKs had a DNA profile that met eligibility for upload into CODIS (36.2% unconditional, 56.5% conditional CODIS eligible rate) and n = 585 SAKs yielded a CODIS Hit (17.1% unconditional, 47.2% conditional CODIS hit rate). These rates are consistent with studies from urban areas suggesting approximately half of SAKs tested yield a CODIS profile and approximately half of those uploaded profiles yield a hit. We compared SAK forensic testing outcomes by geographic and population density characteristics, and although rates were often higher in larger metropolitan areas, the obtained rates in micropolitan and rural areas suggest testing is warranted in smaller jurisdictions as well.

Effects of the Girls on the Move randomized trial on adiposity and aerobic performance (secondary outcomes) in low-income adolescent girls.

BACKGROUND: Limited, mixed evidence exists regarding the effectiveness of physical activity interventions on adiposity and aerobic performance in adolescent underrepresented populations. OBJECTIVE: To examine effects of Girls on the Move on body mass index z-scores (BMI-z), percent (%) body fat, and aerobic performance in fifth- to eighth-grade underrepresented girls. METHODS: A group randomized trial, involving 12 intervention and 12 control schools in low-income areas, was conducted. Participants (n = 1519) were low-active girls. The 17-week intervention included (a) a physical activity club, (b) two motivational interviewing sessions, and (c) one Internet-based session. BMI-z was determined from measured height and weight; % body fat was assessed using bioelectric impedance. Aerobic performance was assessed using a shuttle run. Demographics, physical activity (accelerometer), and pubertal development were assessed. Linear mixed models, adjusting for baseline, were used to examine group differences in postintervention. RESULTS: No significant between-group differences in BMI-z existed at postintervention, but % body fat increased less among intervention than control group girls (Mchange = 0.43% vs 0.73%). Aerobic performance decreased less in intervention vs control (Mchange = -0.39 vs -0.57). CONCLUSIONS: Although the intervention positively impacted % body fat and aerobic performance in underrepresented girls, more research is necessary to determine optimal implementation for yielding greater effects.

Tested at Last: How DNA Evidence in Untested Rape Kits Can Identify Offenders and Serial Sexual Assaults.

An increasing number of U.S. law enforcement agencies have disclosed that they have large numbers of untested sexual assault kits (SAKs; also called "rape kits") in police property storage. Whether previously untested SAKs should be tested for DNA evidence has been the subject of considerable public debate. To inform policy and practice regarding rape kit testing, the current study tested a sample of 900 previously unsubmitted SAKs from Detroit, Michigan, and documented the DNA forensic testing outcomes associated with those kits. We assessed how many SAKs yielded DNA profiles eligible for upload into CODIS (Combined DNA Index System), the federal DNA criminal database; how many resulted in a DNA match (termed a "CODIS hit"); and how many of those hits were associated to other sexual assault crimes (i.e., serial sexual assault hits). Overall, there were 259 CODIS hits, 69 of which had DNA matches to another sexual assault case. The potential utility of a DNA profile and CODIS hit may vary depending on whether offender was known or unknown to the victim, so we examined these outcomes separately for SAKs associated with stranger- and non-stranger-perpetrated sexual assaults. We also present six case study examples of how DNA testing and CODIS hits helped identify serial sexual assaults in both stranger and non-stranger sexual assault cases. Implications for rape kit testing policies are discussed.

Forward Head Posture and Activation of Rectus Capitis Posterior Muscles.

CONTEXT: Rectus capitis posterior (RCP) muscles have physical attachments to the pain-sensitive spinal dura. Atrophy of these muscles is associated with chronic headache in some patients. The authors suspect that the significance of atrophy in the RCP muscles has been undervalued because the functional role of these muscles is not well defined. OBJECTIVE: To determine whether a statistically significant change in normalized levels of electromyographic activity in RCP muscles occurs when the head is voluntarily moved from a self-selected neutral head position to a protruded head position. METHODS: Fine wire, intramuscular electrodes were used to collect electromyographic data as asymptomatic participants moved their head from a neutral head position into a forward head position and back into the neutral head position. This sequence was repeated 4 times. Normalized levels of electromyographic activity were quantified using a 2-head position × 2 sides of the body repeated measures design that incorporated mixed-effects ß regression models. RESULTS: Twenty participants were studied. Electromyographic activity collected from RCP muscles was found to increase as the head was voluntarily moved from a self-selected neutral head position (11% of maximum voluntary isometric contraction [MVIC] in RCP minor, 14% of MVIC in RCP major) into a protruded head position (35% of MVIC in RCP minor, 39% of MVIC in RCP major) (P<.001). CONCLUSION: Rectus capitis posterior muscles may contribute to segmental stabilization of the occipitoatlantal and atlantoaxial joints by helping to maintain joint congruency during movement of the head.

Comparing Standard and Selective Degradation DNA Extraction Methods: Results from a Field Experiment with Sexual Assault Kits.

A growing number of U.S. cities have large numbers of untested sexual assault kits (SAKs) in police property facilities. Testing older kits and maintaining current case work will be challenging for forensic laboratories, creating a need for more efficient testing methods. METHODS: We evaluated selective degradation methods for DNA extraction using actual case work from a sample of previously unsubmitted SAKs in Detroit, Michigan. We randomly assigned 350 kits to either standard or selective degradation testing methods and then compared DNA testing rates and CODIS entry rates between the two groups. RESULTS AND CONCLUSIONS: Continuation-ratio modeling showed no significant differences, indicating that the selective degradation method had no decrement in performance relative to customary methods. Follow-up equivalence tests indicated that CODIS entry rates for the two methods could differ by more than ±5%. Selective degradation methods required less personnel time for testing and scientific review than standard testing.

Drone and Worker Brood Microclimates Are Regulated Differentially in Honey Bees, Apis mellifera.

BACKGROUND: Honey bee (Apis mellifera) drones and workers show differences in morphology, physiology, and behavior. Because the functions of drones are more related to colony reproduction, and those of workers relate to both survival and reproduction, we hypothesize that the microclimate for worker brood is more precisely regulated than that of drone brood. METHODOLOGY/PRINCIPAL FINDINGS: We assessed temperature and relative humidity (RH) inside honey bee colonies for both drone and worker brood throughout the three-stage development period, using digital HOBO® Data Loggers. The major findings of this study are that 1) both drone and worker castes show the highest temperature for eggs, followed by larvae and then pupae; 2) temperature in drones are maintained at higher precision (smaller variance) in drone eggs and larvae, but at a lower precision in pupae than the corresponding stages of workers; 3) RH regulation showed higher variance in drone than workers across all brood stages; and 4) RH regulation seems largely due to regulation by workers, as the contribution from empty honey combs are much smaller compared to that from adult workers. CONCLUSIONS/SIGNIFICANCE: We conclude that honey bee colonies maintain both temperature and humidity actively; that the microclimate for sealed drone brood is less precisely regulated than worker brood; and that combs with honey contribute very little to the increase of RH in honey bee colonies. These findings increase our understanding of microclimate regulation in honey bees and may have implications for beekeeping practices.

Consistent Group Identification and Variable Selection in Regression with Correlated Predictors.

Statistical procedures for variable selection have become integral elements in any analysis. Successful procedures are characterized by high predictive accuracy, yielding interpretable models while retaining computational efficiency. Penalized methods that perform coefficient shrinkage have been shown to be successful in many cases. Models with correlated predictors are particularly challenging to tackle. We propose a penalization procedure that performs variable selection while clustering groups of predictors automatically. The oracle properties of this procedure including consistency in group identification are also studied. The proposed method compares favorably with existing selection approaches in both prediction accuracy and model discovery, while retaining its computational efficiency. Supplemental material are available online.

Regional variation in spending and survival for older adults with advanced cancer.

BACKGROUND: Medicare spending varies substantially across the United States. We evaluated the association between mean regional spending and survival in advanced cancer. METHODS: We identified 116 523 subjects with advanced cancer from 2002 to 2007, using Surveillance, Epidemiology and End Results (SEER)-Medicare linked data. Subjects were aged 65 years and older with non-small cell lung, colon, breast, prostate, or pancreas cancer. Of these subjects, 61 083 had incident advanced-stage cancer (incident cohort) and 98 935 had death from cancer (decedent cohort); 37% of subjects were included in both cohorts. Subjects were linked to one of 80 hospital referral regions within SEER areas. We estimated mean regional spending in both cohorts. We assessed the primary outcome, survival, in the incident cohort; the exposure measure was the quintile of regional spending in the decedent cohort. Survival in quintiles 2 through 5 was compared with that in quintile 1 (lowest spending quintile) using Cox regression models. RESULTS: From quintile 1 to 5, mean regional spending increased by 32% and 41% in the incident and decedent cohorts (incident cohort: $28 854 to $37 971; decedent cohort: $27 446 to $38 630). The association between spending and survival varied by cancer site and quintile; hazard ratios ranged from 0.92 (95% confidence interval [CI] = 0.82 to 1.04, pancreas cancer quintile 5) to 1.24 (95% CI = 1.11 to 1.39, breast cancer quintile 3). In most cases, differences in survival between quintile 1 and quintiles 2 through 5 were not statistically significant. CONCLUSION: There is substantial regional variation in Medicare spending for advanced cancer, yet no consistent association between mean regional spending and survival.