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Using wastewater accumulating around rural waterpoints to irrigate community gardens, borehole-garden permaculture presents a method of local sustainable water management. Alongside this, borehole-garden permaculture also presents public health benefits through the removal of stagnant water around boreholes, key Malaria breeding grounds, and through providing year-round food to supplement diets. By analysing a dataset of over 100,000 cases, this research examines the awareness and adoption of borehole-garden permaculture across Malawi. Generalised linear models identified significant variables influencing borehole-garden permaculture awareness and uptake revealing that socioeconomic, biophysical, and waterpoint-specific variables influenced both the awareness and adoption of borehole-garden permaculture. While 43.0% of communities were aware of borehole-garden permaculture uptake in Malawi was low; only 2.4% of communities surveyed were practising borehole-garden permaculture. Communities in areas with unreliable rainfall and high malaria susceptibility had low borehole-garden permaculture awareness despite borehole-garden permaculture being particularly beneficial to these communities. This work suggests that future work in the promotion of borehole-garden permaculture should focus their efforts within these areas. Furthermore, this work highlights the value of community networks in knowledge sharing and suggests that such social capital could be further used by NGOs and the Government of Malawi in the promotion of borehole-garden permaculture and other sustainable practices in water management.

The purpose of this DNP project is to examine what is known from existing literature about postoperative ileus development in the adult surgical patient population after receiving intraoperative opioids versus a combination of intraoperative opioids and NSAIDs.

BackgroundThe leucine-rich repeat kinase 2 (LRRK2) gene harbors both rare highly damaging missense variants (e.g. p.G2019S) and common non-coding variants (e.g. rs76904798) with lower effect sizes that are associated with Parkinson’s disease risk.ObjectivesThis study aimed to investigate in a large meta-analysis whether the LRRK2 GWAS signal represented by rs76904798 is independently associated with Parkinson’s disease risk from LRRK2 coding variation, and whether complex linkage disequilibrium structures with p.G2019S and the 5’ non-coding haplotype account for the association of LRRK2 coding variants.MethodsWe performed a meta-analysis using imputed genotypes from 17,838 cases, 13,404 proxy-cases and 173,639 healthy controls of European ancestry. We excluded carriers of p.G2019S and/or rs76904798 to clarify the role of LRRK2 coding variation in mediating disease risk, and excluded carriers of relatively rare LRRK2 coding variants to assess the independence of rs76904798. We also investigated the co-inheritance of LRRK2 coding variants with p.G2019S, rs76904798 and p.N2081D.ResultsLRRK2 rs76904798 remained significantly associated with Parkinson’s disease after excluding carriers of relatively rare LRRK2 coding variants. LRRK2 p.R1514Q and p.N2081D were frequently co-inherited with rs76904798 and the allele distribution of p.S1647T significantly changed among cases after removing rs76904798 carriers.ConclusionsThese data suggest that the LRRK2 coding variants previously linked to Parkinson’s disease (p.N551K, p.R1398H, p.M1646T and p.N2081D) do not drive the 5’ non-coding GWAS signal. These data, however, do not preclude the independent association of the haplotype p.N551K-p.R1398H and p.M1646T with altered disease risk.

Mutations in leucine-rich repeat kinase 2 (LRRK2) are associated with inherited forms of Parkinson’s disease (PD), causing disease by a gain of kinase function. Here, we describe a series of isogenic iPSC lines with any of five pathogenic mutations (N1437H, R1441C, Y1699C, G2019S and I2020T); two hypothesis testing mutations (GTP binding null, T1348N, and kinase dead, K1906M) and two LRRK2 knockouts. This resource could be used to assess effects of mutations on the function of endogenous LRRK2 and/or to study LRRK2 interactors and substrates in iPSC-derived cellular models.

Studies of the genetic basis of Parkinson’s disease (PD) have identified many disease-associated genetic variants, but the mechanisms linking variants to pathogenicity are largely unknown. PD risk is attributed to both coding mutations in the Leucine-rich repeat kinase 2 (LRRK2) gene and to common non-coding variation upstream of the LRRK2 locus. Here we show that the influence of genotype at non-coding variant rs76904798 on LRRK2 expression is propagated specifically through microglia, in contrast to evaluations based on general rather than genotype-dependent expression. We find evidence of microglia-specific regulatory regions that may modulate LRRK2 expression using single nuclei sequencing analyses of human frontal cortex and confirm these results in a human induced pluripotent stem cell-derived microglia model. Our study demonstrates that cell type is an important consideration in interrogation of the role of non-coding variation in disease pathogenesis.

Massive genetic analysis identifies critical pathways and cell types involved in pathogenesis of amyotrophic lateral sclerosis., Despite the considerable progress in unraveling the genetic causes of amyotrophic lateral sclerosis (ALS), we do not fully understand the molecular mechanisms underlying the disease. We analyzed genome-wide data involving 78,500 individuals using a polygenic risk score approach to identify the biological pathways and cell types involved in ALS. This data-driven approach identified multiple aspects of the biology underlying the disease that resolved into broader themes, namely, neuron projection morphogenesis, membrane trafficking, and signal transduction mediated by ribonucleotides. We also found that genomic risk in ALS maps consistently to GABAergic interneurons and oligodendrocytes, as confirmed in human single-nucleus RNA-seq data. Using two-sample Mendelian randomization, we nominated six differentially expressed genes (ATG16L2, ACSL5, MAP1LC3A, MAPKAPK3, PLXNB2, and SCFD1) within the significant pathways as relevant to ALS. We conclude that the disparate genetic etiologies of this fatal neurological disease converge on a smaller number of final common pathways and cell types.

Mutations in leucine-rich repeat kinase 2 (LRRK2) cause autosomal dominant Parkinson’s disease (PD) while polymorphic LRRK2 variants are associated with sporadic PD. PD-linked mutations increase LRRK2 kinase activity and induce neurotoxicity in vitro and in vivo. The small GTPase Rab8a is a LRRK2 kinase substrate and is involved in receptor-mediated recycling and endocytic trafficking of transferrin, but the effect of PD-linked LRRK2 mutations on the function of Rab8a are poorly understood. Here, we show that gain-of-function mutations in LRRK2 induce sequestration of endogenous Rab8a into lysosomes in cells while pharmacological inhibition of LRRK2 kinase activity reverses this phenotype. Furthermore, we show that LRRK2 mutations drive accumulation of endocytosed transferrin into Rab8a-positive lysosomes leading to a dysregulation of iron transport. LRRK2 has been nominated as an integral part of cellular responses downstream of proinflammatory signals and is activated in microglia in post-mortem PD tissue. Here, we show that iPSC-derived microglia from patients carrying the most common LRRK2 mutation, G2019S, mistraffic transferrin to lysosomes proximal to the nucleus in proinflammatory conditions. Furthermore, G2019S knock-in mice show significant increase in iron deposition in microglia following intrastriatal LPS injection compared to wild type mice, accompanied by striatal accumulation of ferritin. Our data support a role of LRRK2 in modulating iron uptake and storage in response to proinflammatory stimuli in microglia.

Despite the considerable progress in unraveling the genetic causes of amyotrophic lateral sclerosis (ALS), we do not fully understand the molecular mechanisms underlying the disease. We analyzed genome-wide data involving 78,500 individuals using a polygenic risk score approach to identify the biological pathways and cell types involved in ALS. This data-driven approach identified multiple aspects of the biology underlying the disease that resolved into broader themes, namely neuron projection morphogenesis, membrane trafficking, and signal transduction mediated by ribonucleotides. We also found that genomic risk in ALS maps consistently to GABAergic cortical interneurons and oligodendrocytes, as confirmed in human single-nucleus RNA-seq data. Using two-sample Mendelian randomization, we nominated five differentially expressed genes (ATG16L2, ACSL5, MAP1LC3A, PLXNB2, and SCFD1) within the significant pathways as relevant to ALS. We conclude that the disparate genetic etiologies of this fatal neurological disease converge on a smaller number of final common pathways and cell types.

The prevalence of hidradenitis suppurativa (HS) in the pediatric population is unknown. We sought to establish standardized overall as well as gender-, age-, and race-specific prevalence estimates of HS among children and adolescents in the United States. We performed a cross-sectional analysis in a heterogeneous sample of 55 million patients across all census regions. We identified 1,240 patients with HS in whom the ratio of girls to boys was 3.8:1. Almost all (96.8%) patients with HS were ≥10 years of age. Overall, HS prevalence was 0.028%, or 28.1 (95% confidence interval [CI] 26.5-29.7) per 100,000 children and adolescents. Standardized prevalence was higher in girls (44.6 [95% CI 41.8-47.5] per 100,000), in patients aged 15-17 years (113.7 [95% CI 106.4-121.4] per 100,000), and among African Americans (78.7 [95% CI 71.0-86.9] per 100,000). Highest prevalence of HS was observed among female adolescents aged 15-17 years who were African Americans (525.1 [95% CI 459.4-597.5] per 100,000) and biracial (253.2 [95% CI 121.4-465.6] per 100,000). Patients with HS who went undiagnosed were not captured, and as such prevalence estimates may be underestimated. HS appears to be a postpubertal disease that disproportionately afflicts girls and African Americans in the pediatric population.

Ineffective erythropoiesis was diagnosed in an 8-year-old male castrated Labrador Retriever. Despite treatment with immunosuppressive therapy for suspected immune-mediated erythrocyte maturation arrest, resolution of the nonregenerative anemia was not achieved. Following documentation of Bartonella henselae bacteremia by Bartonella alpha proteobacteria growth medium (BAPGM) enrichment blood culture, immunosuppressive therapy was discontinued, and the anemia resolved following prolonged antibiotic therapy. Bartonella immunofluorescent antibody testing was negative, whereas B henselae western blot was consistently positive. The contribution of B henselae bacteremia to ineffective erythropoiesis remains unknown; however, the potential role of B henselae in the pathophysiology of bone marrow dyscrasias warrants additional investigation.

Since the discovery of protein aggregates in the brains of individuals with Parkinson's disease (PD) in the early 20th century, the scientific community has been interested in the role of dysfunctional protein metabolism in PD etiology. Recent advances in the field have implicated defective protein handling underlying PD through genetic, in vitro, and in vivo studies incorporating many disease models alongside neuropathological evidence. Here, we discuss the existing body of research focused on understanding cellular pathways of protein synthesis and degradation, and how aberrations in either system could engender PD pathology with special attention to α-synuclein-related consequences. We consider transcription, translation, and post-translational modification to constitute protein synthesis, and protein degradation to encompass proteasome-, lysosome- and endoplasmic reticulum-dependent mechanisms. Novel findings connecting each of these steps in protein metabolism to development of PD indicate that deregulation of protein production and turnover remains an exciting area in PD research.

Objective: To objectively measure color vision dysfunction in idiopathic Parkinson's disease (iPD) using an easily administered, essentially free, modified Stroop test. Methods: Sixty-one iPD patients and 26 age-matched controls (HC) were enrolled after IRB approval and performed congruent (CST) and incongruent (IST) modified Stroop tests consisting of 40 words in 10 colors arranged in a 5 x 8 grid. The scorer was blinded to participant diagnosis. Errors on IST were defined as type 1 (written word reported rather than color) or type 2 (color reported different from the written word or its color). Results: The iPD group and the control group completed testing with similar CST performance. On the IST, 75.4% of iPD patients had type 2 errors (p = 0.001, OR 4.907, 95%CI 1.838-13.097) compared to 38.5% HC, with a positive predictive value of 82%. The mean number of type 2 errors was also higher in the iPD group, even with MoCA scores as a covariate in the analysis. Type 1 errors were not significantly different between the groups. A univariate logistic regression model with age, gender, MoCA, normalized IST completion time and the presence/absence of type 2 errors also resulted in type 2 errors as the only significant factor in the equation (p = 0.026). Conclusions: The modified Stroop test incorporated into the clinical evaluation of a patient may provide a quick and inexpensive objective measure of a non-motor feature of iPD, which could help in the clinical diagnosis of iPD in conjunction with the motor assessments currently used by neurologists.

OBJECTIVEThe American Association of Neurological Surgeons (AANS) Neurosurgery Research and Education Foundation (NREF) provides ongoing competitive research fellowships for residents and young investigators. The authors sought to determine the characteristics and career tracks of award recipients.METHODSThe authors analyzed characteristics and academic productivity parameters of NREF resident and young investigator awardees in the United States and Canada from 1983 to 2017. Data were extracted from the NREF database and online resources (Web of Science, NIH reporter).RESULTSIn total, 224 research grants were awarded to 31 women (14%) and 193 men (86%) from 1983 to 2017. Neuro-oncology (36%) was the most common research category. Sixty percent of awardees were in training and most resident award winners were in postgraduate year 5 (37%). Forty-nine percent of all awardees had an additional postgraduate degree (PhD 39%, Master’s 10%) with a significantly higher number of PhD recipients being from Canada in comparison to any US region (p = 0.024). The Northeastern and Southeastern United States were the regions with the highest and lowest numbers of award recipients, respectively. More than one-third (40%) of awardees came from institutions that have a National Institute of Neurological Disorders and Stroke Research Education Grant (NINDS R25) for neurosurgical training. Awardees from NINDS R25–funded programs were significantly more likely to go on to receive funding from the National Institutes of Health (NIH) (40.4% vs 26.1%; p = 0.024). The majority of recipients (72%) who were no longer in training pursued fellowships, with a significant likelihood that fellowship subspecialty correlated with NREF research category (p < 0.001). Seventy-nine percent of winners entered academic neurosurgery practice, with 18% obtaining the position of chair. The median h-index among NREF winners was 11. NIH funding was obtained by 71 awardees (32%) with 36 (18%) being a principal investigator on an R01 grant from the NIH Research Project Grant Program.CONCLUSIONSThe majority of AANS/NREF research award recipients enter academics as fellowship-trained neurosurgeons, with approximately one-third obtaining NIH funding. Analysis of this unique cohort allows for identification of characteristics of academic success.

Mutations in the Leucine-rich repeat kinase 2 (LRRK2) gene have been implicated in the pathogenesis of Parkinson’s disease (PD). Identification of PD-associated LRRK2 mutations has led to the development of novel animal models, primarily in mice. However, the characteristics of human LRRK2 and mouse Lrrk2 protein have not previously been directly compared. Here we show that proteins from different species have different biochemical properties, with the mouse protein being more stable but having significantly lower kinase activity compared to the human orthologue. In examining the effects of PD-associated mutations and risk factors on protein function, we found that conserved substitutions such as G2019S affect human and mouse LRRK2 proteins similarly, but variation around position 2385, which is not fully conserved between humans and mice, induces divergent in vitro behavior. Overall our results indicate that structural differences between human and mouse LRRK2 are likely responsible for the different properties we have observed for these two species of LRRK2 protein. These results have implications for disease modelling of LRRK2 mutations in mice and on the testing of pharmacological therapies in animals.

A 71-year-old woman presented with five scalp nodules that were clinically suspicious for pilar cysts. Histopathologic examination showed a proliferation of mitotically active pleomorphic spindle cells arranged into intersecting fascicles in the dermis and subcutis. Tumor cells displayed deeply eosinophilic cytoplasm and expressed desmin but were negative for S100 protein by immunohistochemistry. Before 10 years, the patient was diagnosed with high-grade retroperitoneal leiomyosarcoma and underwent resection with intraoperative radiation. Metastatic disease involving the lungs, liver and soft tissue developed, requiring treatment with resections, radiation and chemotherapy. Owing to the presentation of multiple scalp nodules with microscopic features of leiomyosarcoma in conjunction with the clinical history of retroperitoneal leiomyosarcoma, a diagnosis of metastatic leiomyosarcoma was made. Scalp metastasis from retroperitoneal leiomyosarcoma is extremely rare and portends a poor prognosis. To our knowledge, only two other cases have been reported in the English literature, and a further search discovered only nine additional cases of scalp metastasis from soft tissue leiomyosarcoma of any non-gynecologic anatomic site. This case highlights the striking microscopic similarity between primary cutaneous and metastatic leiomyosarcoma and illustrates the necessity of adequate clinical information and an appropriate index of suspicion in excluding the possibility of cutaneous metastases of leiomyosarcoma from somatic soft tissue.

Objectives To compare sexual function based on the Pelvic Organ Prolapse/Urinary Incontinence Sexual Function Questionnaire (PISQ) in women who underwent vaginal versus nonvaginal surgery for prolapse. Methods This was a prospective cohort study of women who underwent vaginal versus nonvaginal (abdominal or robotic) surgery for stage II to stage IV pelvic organ prolapse. We compared 2 groups: those who received vaginal prolapse surgery (defined as any surgical procedure for prolapse requiring incisions in the vaginal wall) and those who received nonvaginal (ie, exclusively abdominal or robotic) prolapse surgery. Women completed the PISQ and additional pelvic floor symptom questionnaires at baseline and 6 months after surgery. Our primary outcome was change in PISQ score from baseline to 6 months. Results Of the 80 women in our study population, 58 participants completed 6-month follow-up. Baseline PISQ and pelvic floor symptom questionnaire scores were similar between the vaginal and nonvaginal surgery groups. There were significant overall improvements in sexual function based on the PISQ but no differences in scores between vaginal and nonvaginal surgery groups (mean PISQ change score 6.4 ± 9.2 vs 6.1 ± 14.8; P = 0.92). In a linear regression model adjusting for potential confounders, there were still no differences in 6-month PISQ scores between the groups. Conclusions In women with prolapse, sexual function is likely to improve after reconstructive surgery, regardless of the route.

In December 2009, the American Society for Veterinary Clinical Pathology (ASVCP) Quality Assurance and Laboratory Standards committee published the updated and peer-reviewed ASVCP Quality Assurance Guidelines on the Society's website. These guidelines are intended for use by veterinary diagnostic laboratories and veterinary research laboratories that are not covered by the US Food and Drug Administration Good Laboratory Practice standards (Code of Federal Regulations Title 21, Chapter 58). The guidelines have been divided into 3 reports: (1) general analytical factors for veterinary laboratory performance and comparisons; (2) hematology, hemostasis, and crossmatching; and (3) clinical chemistry, cytology, and urinalysis. This particular report is one of 3 reports and documents recommendations for control of preanalytical, analytical, and postanalytical factors related to urinalysis, cytology, and clinical chemistry in veterinary laboratories and is adapted from sections 1.1 and 2.2 (clinical chemistry), 1.3 and 2.5 (urinalysis), 1.4 and 2.6 (cytology), and 3 (postanalytical factors important in veterinary clinical pathology) of these guidelines. These guidelines are not intended to be all-inclusive; rather, they provide minimal guidelines for quality assurance and quality control for veterinary laboratory testing and a basis for laboratories to assess their current practices, determine areas for improvement, and guide continuing professional development and education efforts.

The epidemiology of primary biliary cirrhosis was described as early as the 1970s, yet decades later the true frequency of this disease and its associated risk factors are still in question. There has been a wealth of data documenting the various incidence and prevalence rates across the world, demonstrating potential risk factors inherent to geographic differences. Studies that follow primary biliary cirrhosis in a set population over time have offered the most reliable picture of disease frequency. Analysis of clustering effects through region and time has offered valuable information on the complexity of the disease development. Improved epidemiologic surveillance of primary biliary cirrhosis around the world will be necessary to provide definitive evidence on the phenomenon of clustering and its associations with proposed risk factors in the literature.

This study was conducted to assess national rates in stress urinary incontinence (SUI) surgery in the USA from 1998 to 2007.We utilized the 1998-2007 Nationwide Inpatient Sample and assessed women aged 20 years and older who underwent SUI surgery based on the International Classification of Diseases, 9th Revision (ICD-9) procedure and diagnosis codes.The total number of SUI surgeries performed during this 10-year period was 759,821. The annual number of procedures increased from 37,953 in 1998 to 94,910 in 2007. The type of SUI surgery performed also changed (p0.001). In 1998, retropubic suspensions represented 52.3%, decreasing to 13.8% in 2007. "Other repair of SUI" (ICD-9 59.79) comprised 22.4% in 1998, increasing to 75.2% in 2007, likely representing midurethral slings.The total number and incidence rates of SUI surgeries have increased from 1998 to 2007. The type of SUI surgery performed has also changed significantly, likely secondary to adoption of midurethral slings.

In the period since LRRK2 (leucine-rich repeat kinase 2) was identified as a causal gene for late-onset autosomal dominant parkinsonism, a great deal of work has been aimed at understanding whether the LRRK2 protein might be a druggable target for Parkinson's disease (PD). As part of this effort, animal models have been developed to explore both the normal and the pathophysiological roles of LRRK2. However, LRRK2 is part of a wider family of proteins whose functions in different organisms remain poorly understood. In this review, we compare the information available on biochemical properties of LRRK2 homologues and orthologues from different species from invertebrates (e.g. Caenorhabditis elegans and Drosophila melanogaster) to mammals. We particularly discuss the mammalian LRRK2 homologue, LRRK1, and those species where there is only a single LRRK homologue, discussing examples where each of the LRRK family of proteins has distinct properties as well as those cases where there appear to be functional redundancy. We conclude that uncovering the function of LRRK2 orthologues will help to elucidate the key properties of human LRRK2 as well as to improve understanding of the suitability of different animal models for investigation of LRRK2-related PD.

Our first study focuses on interpersonal violence and characteristics of resilience (evaluated by the Multidimensional Trauma Resilience and Recovery [MTRR] interview and rating scales) in a sample of incarcerated women. The second study applies qualitative data analysis to a case study of one participant in group therapy for incarcerated women with a history of childhood sexual abuse. Despite extensive history of both frequent and severe abuse, the women displayed a high degree of resilience across multiple domains, including, in particular, the ability to derive meaning from traumatic events and to place the memories into context, ability to form meaningful relationships with others, and ability to regulate affect. These findings were replicated in study two, which illustrates the process of recovery from a poly-traumatic history.

Alterations in an individual analyte rarely provide an indication of the initiating circumstances that caused the abnormality. It is obvious from the previous discussion that multiple organs or organ systems can cause abnormal results in the same analyte. This fact underscores the importance of evaluating a biochemical profile in an integrated fashion, relating abnormalities of a particular analyte with the rest of the profile as well as with the signalment, history, and physical findings in the patient. Furthermore, assessment of abnormalities should be approached with some degree of skepticism because they may not be indicative of an actual disease.

This study evaluated effectiveness of group therapy for incarcerated women with histories of childhood sexual and/or physical abuse. The intervention was based on a two-stage model of trauma treatment and included Dialectical Behavior Therapy skills and writing assignments. We randomly assigned 24 participants to group treatment (13 completed) and 25 to a no-contact comparison condition (18 completed). We evaluated treatment effects, using the Beck Depression Inventory, Inventory of Interpersonal Problems, and Trauma Symptom Inventory. The data demonstrate significant reductions in PTSD, mood, and interpersonal symptoms in the treatment group.

Incarcerated women’s perceptions of the prison environment were explored with respect to relative level of safety from interpersonal abuse in prison as compared to before incarceration. Perceived levels of safety were analyzed based on reported past experiences of interpersonal violence. Participants were 65 women incarcerated in a medium security prison for women with mental and physical health problems. Women’s perceptions of safety were evaluated using closeended quantitative and open-ended qualitative self-report questions. The results suggest that, for some women, prison may be a relatively safe environment and that perceived level of safety may vary with the extent of previous experience of interpersonal violence in childhood and adulthood. Given that the structure of correctional institutions often incorporates abusive dynamics, the directionality of the findings is theoretically and socially important. The patterns apparent in these data are also consistent with other research and theory on the experiences of incarcerated women. In the last 15 years, the number of incarcerated women in the United States has increased dramatically. According to the U.S. Department of Justice Bureau of Justice Statistics (1999), 950,000 women (i.e., approximately 1% of the U.S. female population) are currently “under the care, custody, or control of federal, state or local corrections.” Eighty-five percent of these women are supervised in the community by probation or parole, whereas approximately 150,000 women are incarcerated in U.S. jails or prisons. Moreover, women are the fastest growing group of people involved in the criminal justice system (Powell, 1999). Incarcerated women, as compared to the general population of women, are disproportionately likely to have experienced interpersonal victimization prior to incarceration (Chesney-Lind, 1997). However, the rates of abuse reported by incarcerated women are consistent with rates reported by homeless and housed poor women (Browne & Bassuk, 1997). Browne, Miller, and Maguin (1999) conducted one of the most comprehensive studies to date examining the prevalence of pre-prison interpersonal violence among incarcerated women. Their sample included 150 women incarcerated in a New York state prison. They reported a 59% rate of childhood sexual abuse, a 70% rate of child physical abuse by a caretaker, a 49% rate of rape as an adult, and a 75% rate of “severe” physical abuse by an

Matrix metalloproteinase-9 (MMP9) is a protease associated with degradation of collagen and elastin. Because increased MMP9 activity in vaginal tissue has been associated with pelvic organ prolapse (POP), we sought to comprehensively estimate MMP9 genetic variants and the risk for advanced prolapse.This is a candidate gene association study of women with stage III-IV prolapse (case group, n=239) and women with stage 0-1 prolapse (control group, n=197). We attempted to oversample "extreme" phenotypes, including younger women with severe prolapse and older women without prolapse, in an attempt to concentrate the genetic effect. We used a linkage disequilibrium tagged approach to identify single nucleotide polymorphisms in MMP9 to evaluate in our study. To minimize potential confounding by race, our analysis focused on non-Hispanic white women. We performed multivariable logistic regression to estimate the association between MMP9 single nucleotide polymorphisms and case-control status, adjusting for age and vaginal parity.Women with advanced prolapse were slightly younger (64.8 ± 10.3 compared with 69.0 ± 10.2 years, P.001) and more likely to have had one or more vaginal deliveries (96.6% compared with 82.2%, P.001) when compared with control participants. Eight single nucleotide polymorphisms were assessed, which represented 93% coverage of the MMP9 gene. Of these, two were associated with advanced prolapse: 1) rs3918253 (adjusted odds ratio [OR] 0.64, 95% confidence interval [CI] 0.41-1.0, P=.05); and 2) rs3918256 (adjusted OR 0.64, 95% CI 0.41-1.01, P=.05).MMP9 is a biologically plausible candidate gene for POP given our results.

OBJECTIVE : Symptoms of overactive bladder (OAB) can have profound effects on women's quality of life. However, quantitative data on how women value these symptoms and their treatments are limited. We sought to assess women's preferences, which are referred to as utilities, for different severities of and treatment options for OAB. METHODS : Eighty women-40 with OAB symptoms and 40 without OAB-were recruited from urogynecology and urology practices at an academic institution from April to November 2009. A single, trained interviewer administered a computerized preference elicitation tool to measure preferences for 4 OAB severity levels (urgency/frequency and mild, moderate, and severe urge incontinence), as well as 3 OAB treatments with and without adverse effects or complications, which included (1) anticholinergic medications, (2) botulinum toxin injection, and (3) sacral neuromodulation. Preferences were assessed using the time trade-off (TTO) method. RESULTS : Median TTO scores for OAB decreased as severity increased (urgency/frequency, 0.88; mild, 0.92; moderate, 0.85; severe, 0.73). Median TTO scores assigned to anticholinergic medications were higher (0.93) than those for botulinum (0.88) and sacral neuromodulation (0.85), and adverse effects or complications lowered the utilities for each treatment (anticholinergics, 0.88; botulinum, 0.75; and sacral neuromodulation, 0.78). CONCLUSIONS : Women view symptoms of OAB, particularly moderate or severe symptoms, as being quite burdensome. The degree of invasiveness and the number of adverse effect/complications are important contributors to the utilities that women assign to the various treatment options.

Objective We sought to comprehensively evaluate the association of laminin gamma-1 ( LAMC1 ) and advance pelvic organ prolapse. Study Design We conducted a candidate gene association of patients (n = 239) with stages III-IV prolapse and controls (n = 197) with stages 0-I prolapse. We used a linkage disequilibrium (LD)–tagged approach to identify single-nucleotide polymorphisms (SNPs) in LAMC1 and focused on non-Hispanic white women to minimize population stratification. Additive and dominant multivariable logistic regression models were used to test for association between individual SNPs and advanced prolapse. Results Fourteen SNPs representing 99% coverage of LAMC1 were genotyped. There was no association between SNP rs10911193 and advanced prolapse ( P = .34). However, there was a trend toward significance for SNPs rs1413390 ( P = .11), rs20563 ( P = .11), and rs20558 ( P = .12). Conclusion Although we found that the previously reported LAMC1 SNP rs10911193 was not associated with nonfamilial prolapse, our results support further investigation of this candidate gene in the pathophysiology of prolapse.

OBJECTIVE Genetic studies require a clearly defined phenotype to reach valid conclusions. Our aim was to characterize the phenotype of advanced prolapse by comparing women with stage III to IV prolapse with controls without prolapse. METHODS Based on the pelvic organ prolapse quantification examination, women with stage 0 to stage I prolapse (controls) and those with stage III to stage IV prolapse (cases) were prospectively recruited as part of a genetic epidemiologic study. Data regarding sociodemographics; medical, obstetric, and surgical history; family history; and body mass index were obtained by a questionnaire administered by a trained coordinator and abstracted from electronic medical records. RESULTS There were 275 case patients with advanced prolapse and 206 controls with stage 0 to stage I prolapse. Based on our recruitment strategy, the women were younger than the controls (64.7 ± 10.1 vs 68.6 ± 10.4 years; P

To estimate the number of women who will have symptomatic pelvic floor disorders in the United States from 2010 to 2050.We used population projections from the U.S. Census Bureau from 2010 to 2050 and published age-specific prevalence estimates for bothersome, symptomatic pelvic floor disorders (urinary incontinence [UI], fecal incontinence, and pelvic organ prolapse [POP]) from the 2005 National Health and Nutrition Examination Survey. We abstracted data regarding the number of women aged 20 years or older in 20-year age groups. We assumed that the age-specific prevalences for these disorders and the population distribution of risk factors remained unchanged thru 2050. We also conducted sensitivity analyses that varied both the prevalence estimates and the population projections.The number of American women with at least one pelvic floor disorder will increase from 28.1 million in 2010 to 43.8 million in 2050. During this time period, the number of women with UI will increase 55% from 18.3 million to 28.4 million. For fecal incontinence, the number of affected women will increase 59% from 10.6 to 16.8 million, and the number of women with POP will increase 46% from 3.3 to 4.9 million. The highest projections for 2050 estimate that 58.2 million women will have at least one pelvic floor disorder, with 41.3 million with UI, 25.3 million with fecal incontinence, and 9.2 million with POP.The prevalence of pelvic floor disorders will increase substantially given the changing demographics in the United States. This increase has important implications for public health and the field of gynecology.III.

Since initial reports in the mid-1970s provided epidemiology data on primary biliary cirrhosis (PBC), many studies have characterized the variable frequency of this disease in diverse populations worldwide and sought to identify associated risk factors. Recent research confirms earlier work suggesting that the incidence and prevalence of PBC are on the rise, although geographic variation persists. Analysis of familial and geographic clustering supports the hypothesis that development and progression of the disease hinge on a complex interplay between genetic and environmental risk factors. International clinical data systems are needed to advance PBC epidemiologic research. Given this complexity, international clinical data systems are needed to advance PBC epidemiologic research.

Mutations in theDJ-1gene cause autosomal recessive parkinsonism in humans. Several mouse models ofDJ-1deficiency have been developed, but they do not have dopaminergic neuron cell death in the substantia nigra pars compacta (SNpc). Mitochondrial DNA (mtDNA) damage occurs frequently in the aged human SNpc but not in the mouse SNpc. We hypothesized that the reasonDJ-1-deficient mice do not have dopaminergic cell death is due to an absence of mtDNA damage. We tested this hypothesis by crossingDJ-1-deficient mice with mice that have similar amounts of mtDNA damage in their SNpc as aged humans (Polgmutator mice). At 1 year of age, we counted the amount of SNpc dopaminergic neurons in the mouse brains using both colorimetric and fluorescent staining followed by unbiased stereology. No evidence of dopaminergic cell death was observed inDJ-1-deficient mice with thePolgmutator mutation. Furthermore, we did not observe any difference in dopaminergic terminal immunostaining in the striatum of these mice. Finally, we did not observe any changes in the amount of GFAP-positive astrocytes in the SNpc of these mice, indicative of a lack of astrogliosis. Altogether, our findings demonstrate theDJ-1-deficient mice,Polgmutator mice, andDJ-1-deficientPolgmutator mice have intact nigrastriatal pathways. Thus, the lack of mtDNA damage in the mouse SNpc does not underlie the absence of dopaminergic cell death inDJ-1-deficient mice.