with Rare Kidney Disease.

Chronic kidney disease (CKD) affects more than 35 million people in the United States, many of whom are undiagnosed. Included in this number are individuals with many types of rare kidney diseases, affecting 20,000 to 200,000 individuals nationwide. There is a major need to educate these individuals on the disease and its progression, especially since many individuals are not aware they have the disease. Descriptive correlational research was conducted in a nationwide sample of adult individuals living with rare glomerular kidney disease. Patient activation and quality of life were the concepts studied across the five CKD stages. New findings included statistically significant differences between participants' self-reported mental health quality of life and CKD Stage 1, with CKD Stages 4 and 5 in the rare kidney disease population. Nurses are essential for educating and supporting patients with rare kidney disease to preserve kidney function and slow disease progression.

Gastrointestinal capacity, gut hormones and appetite change during rat pregnancy and lactation.

Pregnancy and lactation increase maternal appetite and adiposity, which in humans can lead to long-term body mass retention. Previous rat reproduction studies suggest that appetite-inhibiting gut hormone, peptide-YY (PYY), is elevated, despite hyperphagia also that gastrointestinal size increases. The present study characterised changes in orexigenic (appetite-stimulating) ghrelin and anorexigenic (appetite-inhibiting) PYY and glucagon-like peptide-1 (GLP-1), and gastrointestinal architecture during pregnancy and lactation, in matched fed and fasted plasma and gut tissue samples taken during the dark phase. Enteroendocrine cells were immunolabelled, and gut masses and lengths were measured. Fasted plasma ghrelin reduced during pregnancy: it was lowest by day 18, recovered to control values at parturition, then increased by the end of lactation. Ghrelin-immunoreactive stomach cells and stomach ghrelin concentrations were highest at birth, prior to the onset of lactation-associated hyperphagia. Plasma fed GLP-1 concentrations were elevated during pregnancy, and together with higher colon concentrations of PYY and GLP-1 during early lactation, they were associated with gastrointestinal tissue expansion, not satiety. Body mass increased during lactation, whereas white adipose tissue depots depleted. Extensive gut remodelling coincided with elevated colon concentrations of PYY and GLP-1. Modifications included stomach and caecum expansion, and duodenal, ascending and descending colon circumference increases, all peaking by day 10 of lactation; increased intestinal masses and lengths peaking at lactation day 10 for small intestine and lactation day 25 for large intestine. If these physical tissue increases persist post-partum, they could accelerate future nutrient assimilation and storage in dams, and may contribute to increased obesity risk.

Monitoring Effect of Human Papillomavirus Vaccines in US Population, Emerging Infections Program, 2008-2012.

In 2007, five Emerging Infections Program (EIP) sites were funded to determine the feasibility of establishing a population-based surveillance system for monitoring the effect of human papillomavirus (HPV) vaccine on pre-invasive cervical lesions. The project involved active population-based surveillance of cervical intraepithelial neoplasia grades 2 and 3 and adenocarcinoma in situ as well as associated HPV types in women >18 years of age residing in defined catchment areas; collecting relevant clinical information and detailed HPV vaccination histories for women 18-39 years of age; and estimating the annual rate of cervical cancer screening among the catchment area population. The first few years of the project provided key information, including data on HPV type distribution, before expected effect of vaccine introduction. The project's success exemplifies the flexibility of EIP's network to expand core activities to include emerging surveillance needs beyond acute infectious diseases. Project results contribute key information regarding the impact of HPV vaccination in the United States.

Population-based trends in high-grade cervical lesions in the early human papillomavirus vaccine era in the United States.

BACKGROUND: Cervical intraepithelial neoplasia grade 2, 3, and adenocarcinoma in situ (CIN2+) lesions can be monitored as early indicators of human papillomavirus (HPV) vaccine impact. Changes to screening utilization will affect observed reductions in CIN2+ rates and complicate the interpretation of vaccine impact. METHODS: From 2008 to 2012, 9119 cases of CIN2+ among 18- to 39-year-old residents of catchment areas in California, Connecticut, New York, and Oregon were reported to the HPV-IMPACT Project, a sentinel system for monitoring the population impact of HPV vaccine. Age-stratified CIN2+ incidence rates were calculated for each catchment. Annual cervical screening was estimated for California, New York, and Oregon catchments with administrative and survey data. The Cochran-Armitage test was used to examine trends. RESULTS: From 2008 to 2012, the incidence of CIN2+ significantly decreased among 18- to 20-year-olds (California, from 94 to 5 per 100,000 women; Connecticut, from 450 to 57 per 100,000 women; New York, from 299 to 43 per 100,000 women; and Oregon, from 202 to 37 per 100,000 women; Ptrend < .0001) and among 21- to 29-year-olds in Connecticut (from 762 to 589 per 100,000 women) and New York (from 770 to 465 per 100,000 women; Ptrend < .001); rates did not differ among 30- to 39-year-olds. During the same period, screening rates also declined, with the largest decreases among 18- to 20-year-olds (from 67% in Oregon to 88% in California) and with smaller declines among 21- to 29-year-olds (13%-27%) and 30- to 39-year-olds (3%-21%). CONCLUSIONS: The declines in CIN2+ detection in young women were likely due to reduced screening but could also reflect the impact of vaccination. These data illustrate challenges in interpreting CIN2+ ecologic trends in the new era of cervical cancer prevention and emphasize the importance of information such as HPV types detected in lesions to assess the impact of HPV vaccine on cervical precancers.

Cleave and Rescue gamete killers create conditions for gene drive in plants.

Gene drive elements promote the spread of linked traits, even when their presence confers a fitness cost to carriers, and can be used to change the composition or fate of wild populations. Cleave and Rescue (ClvR) drive elements sit at a fixed chromosomal position and include a DNA sequence-modifying enzyme such as Cas9/gRNAs (the Cleaver/Toxin) that disrupts endogenous versions of an essential gene, and a recoded version of the essential gene resistant to cleavage (the Rescue/Antidote). ClvR spreads by creating conditions in which those lacking ClvR die because they lack functional versions of the essential gene. We demonstrate the essential features of ClvR gene drive in the plant Arabidopsis thaliana through killing of gametes that fail to inherit a ClvR that targets the essential gene YKT61, whose expression is required in male and female gametes for their survival. Resistant (uncleavable but functional) alleles, which can slow or prevent drive, were not observed. Modeling shows plant ClvRs are likely to be robust to certain failure modes and can be used to rapidly drive population modification or suppression. Possible applications in plant breeding, weed control, and conservation are discussed.

Cleave and Rescue gamete killers create conditions for gene drive in plants.

Gene drive elements promote the spread of linked traits and can be used to change the composition or fate of wild populations. Cleave and Rescue (ClvR) drive elements sit at a fixed chromosomal position and include a DNA sequence-modifying enzyme such as Cas9/gRNAs that disrupts endogenous versions of an essential gene and a recoded version of the essential gene resistant to cleavage. ClvR spreads by creating conditions in which those lacking ClvR die because they lack functional versions of the essential gene. Here we demonstrate the essential features of the ClvR gene drive in the plant Arabidopsis thaliana through killing of gametes that fail to inherit a ClvR that targets the essential gene YKT61. Resistant alleles, which can slow or prevent drive, were not observed. Modelling shows plant ClvRs are robust to certain failure modes and can be used to rapidly drive population modification or suppression. Possible applications are discussed.

Association Between Primary Care Use Prior to Cancer Diagnosis and Subsequent Cancer Mortality in the Veterans Affairs Health System.

Importance: Primary care physicians (PCPs) are significant contributors of early cancer detection, yet few studies have investigated whether consistent primary care translates to improved downstream outcomes. Objective: To evaluate the association of prediagnostic primary care use with metastatic disease at diagnosis and cancer-specific mortality (CSM). Design, Setting, and Participants: This cohort study used databases with primary care and referral linkage from multiple Veterans' Affairs centers from 2004 to 2017 and had a 68-month median follow-up. Analysis was completed between July 2021 and September 2022. Participants included veterans older than 39 years who had been diagnosed with 1 of 12 cancers. Inclusion criteria included known clinical staging, survival follow-up, cause of death, and receiving care at the Veterans Affairs health system (VA). Exposures: Prediagnostic PCP use, measured in the 5 years prior to diagnosis. PCP visits were binned into none (0 visits), some (1-4 visits), and annual (5 visits). Main Outcomes and Measures: Metastatic disease at diagnosis, cancer-specific mortality (CSM) for entire cohort and stratified by tumor subtype. Results: Among 245 425 patients representing 12 tumor subtypes, mean age was 65.8 (9.3) years, and the cohort skewed male (97.6%), and White (76.1%), with higher levels of comorbidity (58.6% with Charlson Comorbidity Index scores ≥2). Compared with no prior visit, some PCP use was associated with 26% decreased odds of metastatic disease at diagnosis (odds ratio [OR], 0.74; 95% CI, 0.71-0.76; P < .001) and 12% reduced risk of CSM (subdistribution hazard ratio [SHR], 0.88; 95% CI, 0.86-0.89; P < .001). Annual PCP use was associated with 39% decreased odds of metastatic disease (OR, 0.61; 95% CI, 0.59-0.63; P < .001) and 21% reduced risk of CSM (SHR, 0.79; 95% CI, 0.77-0.81; P < .001). Among tumor subtypes, prostate cancer had the largest effect size for prior PCP use on metastatic disease at diagnosis (OR for annual use, 0.32; 95% CI, 0.30-0.35; P < .001) and CSM (SHRfor annual use, 0.51; 95% CI, 0.48-0.55; P < .001). Conclusions and Relevance: In this cohort study, increased primary care use before cancer diagnosis was associated with significant decreases in metastatic disease at diagnosis and cancer-related death, with potentially the greatest difference from annual use. PCPs play a vital role in cancer prevention, and additional resources should be allocated to assist these physicians.

Nurse-Led Intervention Promoting Healthy Lifestyle Behaviors in a Yazidi Community.

Introduction: Immigrating to a new country poses many challenges, including managing daily health care in a new environment. Yazidis experiencing long-standing ethnoreligious persecution in Northern Iraq, fled their homeland seeking safety and refuge in the United States, where approximately 10,000 Yazidi immigrants reside. Method: The researchers collaborated with Yazidi community members to design the healthy lifestyle intervention and ensure cultural sensitivity. Six weekly classes addressed healthy lifestyle behaviors. Data were collected on health promoting activities, biomarkers, and participants' experiences with the intervention. Results: Participants reported doing slightly more health promoting activities postintervention. Age-related health promoting activities were significantly different at baseline, χ2(2) = 6.093, p = .048, but not postintervention, χ2(2) = 0.212, p = .899. Median loss in biomarkers trended toward clinically significant findings. Participants recommended more strategies to manage stress. Discussion: The pilot study provided an empowering example of nurses collaborating with community members to design a culturally sensitive intervention.

Sleep Quality and Daytime Sleepiness in Prelicensure Baccalaureate Nursing Students.

BACKGROUND: Nursing students need to learn about sleep health to provide safe patient care. The purpose of this study was to investigate sleep in nursing students and describe factors that affect their sleep. METHOD: This study used a cross-sectional descriptive design with a convenience sample from baccalaureate nursing programs in a midwestern region of the United States. Data were collected using a demographic questionnaire, Pittsburgh Sleep Quality Index, Epworth Sleepiness Scale, and Sleep Hygiene Index. RESULTS: Two hundred fifty-four nursing students reported poor sleep quality, excessive daytime sleepiness, and maladaptive sleep hygiene, regardless of their year of study or enrollment status. Behavior of technology use into the night was the most frequent reason why students lost sleep. CONCLUSION: Learning the importance of sleep hygiene, good sleep quality, and the associated health benefits may assist nursing students with achieving optimal daytime functioning. Consideration should be given to sleep health content as a thread through nursing curriculum. [J Nurs Educ. 2021;60(4):196-202.].

Improved timed-mating, non-invasive method using fewer unproven female rats with pregnancy validation via early body mass increases.

For studies requiring accurate conception-timing, reliable, efficient methods of detecting oestrus reduce time and costs, whilst improving welfare. Standard methods use vaginal cytology to stage cycle, and breeders are paired-up using approximately five proven females with proven males to achieve at least one conception on a specific day. We describe an alternative, fast, consistent, non-invasive method of timed-mating using detection of lordosis behaviour in Wistar and Lister-Hooded rats that used unproven females with high success rates. Rats under reverse lighting had body masses recorded pre-mating, day (d) 3-4, d8, d10 and d18 of pregnancy. Using only the presence of the oestrus dance to time-mate females for 24 hours, 89% of Wistar and 88% of Lister-Hooded rats successfully conceived. We did not observe behavioural oestrus in Sprague-Dawleys without males being present. Significant body mass increases following mating distinguished pregnant from non-pregnant rats, as early as d4 of pregnancy (10% ± 1.0 increase cf. 3% ± 1.2). The pattern of increases throughout gestation was similar for all pregnant rats until late pregnancy, when there were smaller increases for primi- and multiparous rats (32% ± 2.5; 25% ± 2.4), whereas nulliparous rats had highest gains (38% ± 1.5). This method demonstrated a distinct refinement of the previous timed-mating common practice used, as disturbance of females was minimised. Only the number required of nulli-, primi- or multiparous rats were mated, and body mass increases validated pregnancy status. This new breeding management method is now established practice for two strains of rat and has resulted in a reduction in animal use.

Mutational survey of the PHEX gene in patients with X-linked hypophosphatemic rickets.

X-linked hypophosphatemic rickets (XLH) is a dominantly inherited disorder characterized by renal phosphate wasting, aberrant vitamin D metabolism, and abnormal bone mineralization. XLH is caused by inactivating mutations in PHEX (phosphate-regulating gene with homologies to endopeptidases on the X chromosome). In this study, we sequenced the PHEX gene in subjects from 26 kindreds who were clinically diagnosed with XLH. Sequencing revealed 18 different mutations, of which thirteen have not been reported previously. In addition to deletions, splice site mutations, and missense and nonsense mutations, a rare point mutation in the 3'-untranslated region (3'-UTR) was identified as a novel cause of XLH. In summary, we identified a wide spectrum of mutations in the PHEX gene. Our data, in accord with those of others, indicate that there is no single predominant PHEX mutation responsible for XLH.

Ammonia removal from facultative pond effluents in a constructed wetland and an aerated rock filter: performance comparison in winter and summer.

The effluent from a facultative pond loaded at 80 kg BOD ha(-1) day(-1) was treated in a subsurface horizontal-flow aerated rock filter (RF) and a subsurface horizontal-flow constructed wetland (CW) planted with Typha latifolia. Over a 12-month monitoring period BOD and TSS removals were higher, and effluent ammonia concentrations lower, in the RF than in the CW (> 75% vs. 25-75%, and 3.6 mg N L(-1) vs. 6 mg N L(-1), respectively). However, the ammonia concentration was lower in the CW effluent than in the aerated RF effluent during mid-July to mid-September (1.1 mg N L(-1) vs. 2.2 mg N L(-1)), but in winter it was higher than the influent concentration. Overall the performance of the aerated RF was better and more consistent than that of the CW.

Glucagon-like peptide-1 (GLP-1) increases in plasma and colon tissue prior to estrus and circulating levels change with increasing age in reproductively competent Wistar rats.

There is a well-documented association between cyclic changes to food intake and the changing ovarian hormone levels of the reproductive cycle in female mammals. Limited research on appetite-controlling gastrointestinal peptides has taken place in females, simply because regular reproductive changes in steroid hormones present additional experimental factors to account for. This study focussed directly on the roles that gastrointestinal-secreted peptides may have in these reported, naturally occurring, changes to food intake during the rodent estrous cycle and aimed to determine whether peripheral changes occurred in the anorexigenic (appetite-reducing) hormones peptide-YY (PYY) and glucagon-like peptide-1 (GLP-1) in female Wistar rats (32-44 weeks of age). Total forms of each peptide were measured in matched fed and fasted plasma and descending colon tissue samples for each animal during the dark (feeding) phase. PYY concentrations did not significantly change between defined cycle stages, in either plasma or tissue samples. GLP-1 concentrations in fed plasma and descending colon tissue were significantly increased during proestrus, just prior to a significant reduction in fasted stomach contents at estrus, suggesting increased satiety and reduced food intake at this stage of the cycle. Increased proestrus GLP-1 concentrations could contribute to the reported reduction in food intake during estrus and may also have biological importance in providing the optimal nutritional and metabolic environment for gametes at the potential point of conception. Additional analysis of the findings demonstrated significant interactions of ovarian cycle stage and fed/fasted status with age on GLP-1, but not PYY plasma concentrations. Slightly older females had reduced fed plasma GLP-1 suggesting that a relaxation of regulatory control of this incretin hormone may also take place with increasing age in reproductively competent females.

A Bayesian view of murine seminal cytokine networks.

It has long been established that active agents in seminal fluid are key to initiating and coordinating mating-induced immunomodulation. This is in part governed by the actions of a network of cytokine interactions which, to date, remain largely undefined, and whose interspecific evolutionary conservation is unknown. This study applied Bayesian methods to illustrate the interrelationships between seminal profiles of interleukin (IL)-1alpha, IL-1beta, IL-2, IL-4, IL-5, IL-6, IL-9, IL-10, IL-12 (p70), IL-13, IL-17, eotaxin, granulocyte-colony stimulating factor (G-CSF), granulocyte macrophage-colony stimulating factor (GM-CSF), interferon (IFN)-gamma, keratinocyte-derived chemokine (KC), monocyte chemoattractant protein (MCP-1), macrophage inflammatory protein (MIP-1) alpha, MIP-1beta, regulated on activation normal T cell expressed and secreted (RANTES), tumour necrosis factor (TNF)-alpha, leptin, inducible protein (IP)-10 and vascular endothelial growth factor (VEGF) in a rat model. IL-2, IL-9, IL-12 (p70), IL-13, IL-18, eotaxin, IFN-gamma, IP-10, KC, leptin, MCP-1, MIP-1alpha and TNF-alpha were significantly higher in serum, whilst IL-1beta, IL-5, IL-6, IL-10, IL-17, G-CSF and GM-CSF were significantly higher in seminal fluid. When compared to mouse profiles, only G-CSF was present at significantly higher levels in the seminal fluid in both species. Bayesian modelling highlighted key shared features across mouse and rat networks, namely TNF-alpha as the terminal node in both serum and seminal plasma, and MCP-1 as a central coordinator of seminal cytokine networks through the intermediary of KC and RANTES. These findings reveal a marked interspecific conservation of seminal cytokine networks.

Human ALOX12, but not ALOX15, is associated with BMD in white men and women.

UNLABELLED: The Alox15 gene was recently identified as a negative regulator of peak BMD in mice. Polymorphisms in human ALOX12, but not ALOX15, were significantly associated with spine BMD in white men and women, suggesting that ALOX12 may contribute to normal variation in BMD. INTRODUCTION: Osteoporosis is a complex disease with both genetic and environmental risk factors. A major determinant of osteoporosis is peak BMD, which is a highly heritable trait. Recently, the arachidonate 15-lipoxygenase (Alox15) gene was identified as a negative regulator of peak BMD in mice. MATERIALS AND METHODS: To assess the contribution of lipoxygenase genes to normal BMD variation in healthy white men and women, we performed population- and family-based association studies of two arachidonate lipoxygenase genes: ALOX15, which is the human homolog of mouse Alox15, and ALOX12, which is functionally similar to Alox15. Single nucleotide polymorphisms (SNPs) distributed across the two genes were genotyped. BMD was measured at the femoral neck and lumbar spine in 411 men 18-61 years of age and 1291 premenopausal women 20-50 years of age. RESULTS: Moderate evidence of association was found between spine BMD and six SNPs in the ALOX12 gene in both men and women (p = 0.0052-0.050). Furthermore, the most common SNP haplotype in ALOX12 showed evidence of significant association with high spine BMD in men (p = 0.0083), whereas the second most common haplotype was associated with high spine BMD in women (p = 0.0081). CONCLUSIONS: Polymorphisms in the ALOX12 gene may contribute to normal variation in spine BMD.

Plasma Ghrelin Concentrations Were Altered with Oestrous Cycle Stage and Increasing Age in Reproductively Competent Wistar Females.

Changes in appetite occur during the ovarian cycle in female mammals. Research on appetite-regulatory gastrointestinal peptides in females is limited, because reproductive changes in steroid hormones present additional experimental factors to control for. This study aimed to explore possible changes in the orexigenic (appetite-stimulating) gastrointestinal peptide hormone ghrelin during the rodent oestrous cycle. Fed and fasted plasma and stomach tissue samples were taken from female Wistar rats (32-44 weeks of age) at each stage of the oestrous cycle for total ghrelin quantification using radioimmunoassay. Sampling occurred during the dark phase when most eating takes place in rats. Statistical analysis was by paired-samples t-test, one-way ANOVA on normally distributed data, with Tukey post-hoc tests, or Kruskal-Wallis if not. GLM univariate analysis was used to assess main effects and interactions in ghrelin concentrations in the fed or fasted state and during different stages of the ovarian cycle, with age as a covariate. No consistent fed to fasted ghrelin increases were measured in matched plasma samples from the same animals, contrary to expectations. Total ghrelin concentrations did not significantly change between cycle stages with ANOVA, in either fed or fasted plasma or in stomach tissue. This was despite significantly decreased fasted stomach contents at oestrus (P = 0.028), suggesting decreased food intake. There was however a significant interaction in ghrelin plasma concentrations between fed and fasted proestrus rats and a direct effect of age with rats over 37 weeks old having lower circulating concentrations of ghrelin in both fed and fasted states. The biological implications of altered ghrelin plasma concentrations from 37 weeks of age are as yet unknown, but warrant further investigation. Exploring peripheral ghrelin regulatory factor changes with increasing age in reproductively competent females may bring to light potential effects on offspring development and nutritional metabolic programming.

Patient activation with knowledge, self-management and confidence in chronic kidney disease.

BACKGROUND: Chronic kidney disease is a growing health problem on a global scale. The increasing prevalence of chronic kidney disease presents an urgent need to better understand the knowledge, confidence and engagement in self-managing the disease. OBJECTIVES: This study examined group differences in patient activation and health-related quality of life, knowledge, self-management and confidence with managing chronic disease across all five stages of chronic kidney disease. DESIGN: The study employed a descriptive correlational design. SETTINGS: Participants were recruited from five primary care, three nephrology clinics and one dialysis centre in two Midwestern cities in the United States. PARTICIPANTS: The convenience sample included 85 adults with hypertension, diabetes mellitus and chronic kidney disease, including kidney failure, who spoke English. MEASUREMENTS: Seven measurements were used to collect data via telephone interviews with participants not receiving haemodialysis, and face-to-face interviews with those receiving haemodialysis at the beginning of their treatment session. RESULTS: Analyses indicated that half the participants were female (50.58%), the mean age was 63.21 years (SD = 13.11), and participants with chronic kidney disease stage 3 were the most activated. Post hoc differences were significant in patient activation and blood pressure self-management and anxiety across chronic kidney disease stages, excluding stage 5. CONCLUSION: Engaging patients in the self-management of their health care and enhancing patients' ability to self-manage their blood pressure may work to preserve kidney health. Healthcare providers should collaborate with patients to develop strategies that will maintain patients' health-related quality of life, like reducing anxiety as kidney disease progress.

Contribution of the LRP5 gene to normal variation in peak BMD in women.

UNLABELLED: The role of the LRP5 gene in rare BMD-related traits has recently been shown. We tested whether variation in this gene might play a role in normal variation in peak BMD. Association between SNPs in LRP5 and hip and spine BMD was measured in 1301 premenopausal women. Only a small proportion of the BMD variation was attributable to LRP5 in our sample. INTRODUCTION: Mutations in the low-density lipoprotein receptor-related protein 5 (LRP5) gene have been implicated as the cause of multiple distinct BMD-related rare Mendelian phenotypes. We sought to examine whether the LRP5 gene contributes to the observed variation in peak BMD in the normal population. MATERIALS AND METHODS: We genotyped 12 single nucleotide polymorphisms (SNPs) in LRP5 using allele-specific PCR and mass spectrometry methods. Linkage disequilibrium between the genotyped LRP5 SNPs was measured. We tested for association between these SNPs and both hip and spine BMD (adjusted for age and body weight) in 1301 healthy premenopausal women who took part in a sibling pair study aimed at identifying the genes underlying peak bone mass. Our study used both population-based (ANOVA) and family-based (quantitative transmission disequilibrium test) association methodology. RESULTS AND CONCLUSIONS: The linkage disequilibrium pattern and haplotype block structure within the LRP5 gene were consistent with that observed in other studies. Although significant evidence of association was found between LRP5 SNPs and both hip and spine BMD, only a small proportion of the total variation in these phenotypes was accounted for. The genotyped SNPs accounted for approximately 0.8% of the variation in femoral neck BMD and 1.1% of the variation in spine BMD. Results from our sample suggest that natural variation in and around LRP5 is not a major contributor to the observed variability in peak BMD at either the femoral neck or lumbar spine in white women.

Polymorphisms in the estrogen receptor beta (ESR2) gene are associated with bone mineral density in Caucasian men and women.

CONTEXT: A major determinant of osteoporotic fractures is peak bone mineral density (BMD), which is a highly heritable trait. Recently, we identified significant linkage for hip BMD in premenopausal sister pairs at chromosome 14q (LOD score = 3.5), where the estrogen receptor beta gene (ESR2) is located. OBJECTIVE: The objective of the study was to determine whether ESR2 polymorphisms are associated with normal BMD variation. DESIGN: This was a population-based genetic association study, using 11 single nucleotide polymorphisms (SNPs) distributed across the ESR2 gene. SETTING: The study was conducted at an academic research laboratory and medical center. PATIENTS AND OTHER PARTICIPANTS: A total of 411 healthy men (aged 18-61 yr) and 1291 healthy premenopausal women (aged 20-50 yr) living in Indiana participated in the study. INTERVENTION(S): There were no interventions. MAIN OUTCOME MEASURE(S): The main outcome measures were SNP genotype distributions and their association with BMD at the femoral neck and lumbar spine. RESULTS: Significant association of spine BMD was found with three SNPs in men and one SNP in women (P < or = 0.05). The conditional linkage analysis using the ESR2 haplotypes showed that the ESR2 gene accounts for, at most, 18% of the original linkage. CONCLUSIONS: ESR2 polymorphisms are significantly associated with bone mass in both men and women. However, the ESR2 gene is not entirely responsible for our original linkage, and an additional gene(s) in chromosome 14q contributes to the determination of BMD.

HPV type attribution in high-grade cervical lesions: assessing the potential benefits of vaccines in a population-based evaluation in the United States.

BACKGROUND: Two currently available vaccines targeting human papillomavirus (HPV) types 16 and 18 could prevent 70% of cervical cancers and 50% of high-grade cervical lesions. Next-generation vaccines against additional types, such as a candidate 9-valent vaccine against HPV6/11/16/18/31/33/45/52/58, could further reduce HPV-associated disease burden. METHODS: HPV was typed in archived tissues from women ages 21 to 39 years residing in five catchment areas in the United States with cervical intraepithelial neoplasia 2/3 and adenocarcinoma in situ (CIN2+) using L1 consensus PCR and type-specific hybridization. Type attribution was estimated using weights to account for lesions with multiple types detected. RESULTS: From 2008 to 2011, 5,498 of 6,306 (87.2%) specimens obtained from 8,469 women with CIN2+ had valid typing results; HPV DNA was detected in 97.3%. Overall, 50.1% of lesions were attributable to HPV16/18, ranging from 50.3% to 52.4% among those ages 21 to 34 years, and significantly declined in 35 to 39 year-olds (43.5%). HPV16/18 attribution was higher in non-Hispanic whites (56.4%) versus racial/ethnic minorities (range, 41.8%-45.9%; P < 0.001). HPV31/33/45/52/58 attribution was 25.0% overall and increased with age (P < 0.001). A higher proportion of CIN2+ was attributable to HPV31/33/45/52/58 in non-Hispanic black (29.9%), Hispanic (29.2%), and Asian (33.1%) women compared with non-Hispanic whites (22.8%; P < 0.001). CONCLUSIONS: Overall, 75% of lesions were attributable to 7 oncogenic HPV types: 50% to HPV16/18 and 25% to HPV31/33/45/52/58. HPV16/18 had the largest attributable fraction in CIN2+ across all subpopulations, although to a lesser extent in older women and racial/ethnic minorities. IMPACT: Vaccines targeting additional oncogenic HPV types could prevent more high-grade cervical lesions, especially among racial/ethnic minorities.