Recommendations for HLA-B*15:02 and HLA-A*31:01 genetic testing to reduce the risk of carbamazepine-induced hypersensitivity reactions.

OBJECTIVE To systematically review evidence on genetic risk factors for carbamazepine (CBZ)-induced hypersensitivity reactions (HSRs) and provide practice recommendations addressing the key questions: (1) Should genetic testing for HLA-B*15:02 and HLA-A*31:01 be performed in patients with an indication for CBZ therapy to reduce the occurrence of CBZ-induced HSRs? (2) Are there subgroups of patients who may benefit more from genetic testing for HLA-B*15:02 or HLA-A*31:01 compared to others? (3) How should patients with an indication for CBZ therapy be managed based on their genetic test results? METHODS A systematic literature search was performed for HLA-B*15:02 and HLA-A*31:01 and their association with CBZ-induced HSRs. Evidence was critically appraised and clinical practice recommendations were developed based on expert group consensus. RESULTS Patients carrying HLA-B*15:02 are at strongly increased risk for CBZ-induced Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) in populations where HLA-B*15:02 is common, but not CBZ-induced hypersensitivity syndrome (HSS) or maculopapular exanthema (MPE). HLA-B*15:02-positive patients with CBZ-SJS/TEN have been reported from Asian countries only, including China, Thailand, Malaysia, and India. HLA-B*15:02 is rare among Caucasians or Japanese; no HLA-B*15:02-positive patients with CBZ-SJS/TEN have been reported so far in these groups. HLA-A*31:01-positive patients are at increased risk for CBZ-induced HSS and MPE, and possibly SJS/TEN and acute generalized exanthematous pustulosis (AGEP). This association has been shown in Caucasian, Japanese, Korean, Chinese, and patients of mixed origin; however, HLA-A*31:01 is common in most ethnic groups. Not all patients carrying either risk variant develop an HSR, resulting in a relatively low positive predictive value of the genetic tests. SIGNIFICANCE This review provides the latest update on genetic markers for CBZ HSRs, clinical practice recommendations as a basis for informed decision making regarding the use of HLA-B*15:02 and HLA-A*31:01 genetic testing in patients with an indication for CBZ therapy, and identifies knowledge gaps to guide future research. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.

Human 3β-hydroxysteroid dehydrogenase deficiency seems to affect fertility but may not harbor a tumor risk: lesson from an experiment of nature.

CONTEXT 3β-hydroxysteroid dehydrogenase deficiency (3βHSD) is a rare disorder of sexual development and steroidogenesis. There are two isozymes of 3βHSD, HSD3B1 and HSD3B2. Human mutations are known for the HSD3B2 gene which is expressed in the gonads and the adrenals. Little is known about testis histology, fertility and malignancy risk. OBJECTIVE To describe the molecular genetics, the steroid biochemistry, the (immuno-)histochemistry and the clinical implications of a loss-of-function HSD3B2 mutation. METHODS Biochemical, genetic and immunohistochemical investigations on human biomaterials. RESULTS A 46,XY boy presented at birth with severe undervirilization of the external genitalia. Steroid profiling showed low steroid production for mineralocorticoids, glucocorticoids and sex steroids with typical precursor metabolites for HSD3B2 deficiency. The genetic analysis of the HSD3B2 gene revealed a homozygous c.687del27 deletion. At pubertal age, he showed some virilization of the external genitalia and some sex steroid metabolites appeared likely through conversion of precursors secreted by the testis and converted by unaffected HSD3B1 in peripheral tissues. However, he also developed enlarged breasts through production of estrogens in the periphery. Testis histology in late puberty revealed primarily a Sertoli-cell-only pattern and only few tubules with arrested spermatogenesis, presence of few Leydig cells in stroma, but no neoplastic changes. CONCLUSIONS The testis with HSD3B2 deficiency due to the c.687del27 deletion does not express the defective protein. This patient is unlikely to be fertile and his risk for gonadal malignancy is low. Further studies are needed to obtain firm knowledge on malignancy risk for gonads harboring defects of androgen biosynthesis.

Depression predicts persistence of paranoia in clinical high-risk patients to psychosis: results of the EPOS project.

BACKGROUND The link between depression and paranoia has long been discussed in psychiatric literature. Because the causality of this association is difficult to study in patients with full-blown psychosis, we aimed to investigate how clinical depression relates to the presence and occurrence of paranoid symptoms in clinical high-risk (CHR) patients. METHODS In all, 245 young help-seeking CHR patients were assessed for suspiciousness and paranoid symptoms with the structured interview for prodromal syndromes at baseline, 9- and 18-month follow-up. At baseline, clinical diagnoses were assessed by the Structured Clinical Interview for DSM-IV, childhood adversities by the Trauma and Distress Scale, trait-like suspiciousness by the Schizotypal Personality Questionnaire, and anxiety and depressiveness by the Positive and Negative Syndrome Scale. RESULTS At baseline, 54.3 % of CHR patients reported at least moderate paranoid symptoms. At 9- and 18-month follow-ups, the corresponding figures were 28.3 and 24.4 %. Depressive, obsessive-compulsive and somatoform disorders, emotional and sexual abuse, and anxiety and suspiciousness associated with paranoid symptoms. In multivariate modelling, depressive and obsessive-compulsive disorders, sexual abuse, and anxiety predicted persistence of paranoid symptoms. CONCLUSION Depressive disorder was one of the major clinical factors predicting persistence of paranoid symptoms in CHR patients. In addition, obsessive-compulsive disorder, childhood sexual abuse, and anxiety associated with paranoia. Effective pharmacological and psychotherapeutic treatment of these disorders and anxiety may reduce paranoid symptoms in CHR patients.

Incremental Value of the CRUSADE, ACUITY, and HAS-BLED Risk Scores for the Prediction of Hemorrhagic Events After Coronary Stent Implantation in Patients Undergoing Long or Short Duration of Dual Antiplatelet Therapy

BACKGROUND Multiple scores have been proposed to stratify bleeding risk, but their value to guide dual antiplatelet therapy duration has never been appraised. We compared the performance of the CRUSADE (Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes With Early Implementation of the ACC/AHA Guidelines), ACUITY (Acute Catheterization and Urgent Intervention Triage Strategy), and HAS-BLED (Hypertension, Abnormal Renal/Liver Function, Stroke, Bleeding History or Predisposition, Labile INR, Elderly, Drugs/Alcohol Concomitantly) scores in 1946 patients recruited in the Prolonging Dual Antiplatelet Treatment After Grading Stent-Induced Intimal Hyperplasia Study (PRODIGY) and assessed hemorrhagic and ischemic events in the 24- and 6-month dual antiplatelet therapy groups. METHODS AND RESULTS Bleeding score performance was assessed with a Cox regression model and C statistics. Discriminative and reclassification power was assessed with net reclassification improvement and integrated discrimination improvement. The C statistic was similar between the CRUSADE score (area under the curve 0.71) and ACUITY (area under the curve 0.68), and higher than HAS-BLED (area under the curve 0.63). CRUSADE, but not ACUITY, improved reclassification (net reclassification index 0.39, P=0.005) and discrimination (integrated discrimination improvement index 0.0083, P=0.021) of major bleeding compared with HAS-BLED. Major bleeding and transfusions were higher in the 24- versus 6-month dual antiplatelet therapy groups in patients with a CRUSADE score >40 (hazard ratio for bleeding 2.69, P=0.035; hazard ratio for transfusions 4.65, P=0.009) but not in those with CRUSADE score ≤40 (hazard ratio for bleeding 1.50, P=0.25; hazard ratio for transfusions 1.37, P=0.44), with positive interaction (Pint=0.05 and Pint=0.01, respectively). The number of patients with high CRUSADE scores needed to treat for harm for major bleeding and transfusion were 17 and 15, respectively, with 24-month rather than 6-month dual antiplatelet therapy; corresponding figures in the overall population were 67 and 71, respectively. CONCLUSIONS Our analysis suggests that the CRUSADE score predicts major bleeding similarly to ACUITY and better than HAS BLED in an all-comer population with percutaneous coronary intervention and potentially identifies patients at higher risk of hemorrhagic complications when treated with a long-term dual antiplatelet therapy regimen. CLINICAL TRIAL REGISTRATION URL: http://clinicaltrials.gov. Unique identifier: NCT00611286.

Sexual health in hematopoietic stem cell transplant recipients

Hematopoietic stem cell transplantation (HSCT) plays a central role in patients with malignant and, increasingly, nonmalignant conditions. As the number of transplants increases and the survival rate improves, long-term complications are important to recognize and treat to maintain quality of life. Sexual dysfunction is a commonly described but relatively often underestimated complication after HSCT. Conditioning regimens, generalized or genital graft-versus-host disease, medications, and cardiovascular complications as well as psychosocial problems are known to contribute significantly to physical and psychological sexual dysfunction. Moreover, it is often a difficult topic for patients, their significant others, and health care providers to discuss. Early recognition and management of sexual dysfunction after HSCT can lead to improved quality of life and outcomes for patients and their partners. This review focuses on the risk factors for and treatment of sexual dysfunction after transplantation and provides guidance concerning how to approach and manage a patient with sexual dysfunction after HSCT.

Social capital and adolescent health risk behavior in El Salvador

An emerging body of research suggests that the social capital available in one's social environment, as defined by supportive and caring interpersonal relationships, may provide a protective effect against a number of youth risk behaviors. In exploring the potential protective effect of social capital at school and at home on adolescent health and social risk behavior, a comprehensive youth risk behavior study was carried out in El Salvador during the summer of 1999 with a sample of 984 secondary school students attending 16 public rural and urban schools. The following dissertation, entitled Social Capital and Adolescent Health Risk Behavior in El Salvador, presents three papers centered on the topics of social capital and risk behavior. ^ Paper #1. Dangers in the Adolescent River of Life: A Descriptive Study of Youth Risk Behavior among Urban and Rural presents prevalence estimates of four principal youth risk behavior domains—aggression, depression, substance use, and sexual behaviors among students primarily between the ages of 13 and 17 who attend public schools in El Salvador. The prevalence and distribution of risk behaviors is examined by gender, geographic school location, age, and subjective economic status. ^ Paper #2. Social Capital and Adolescent Health Risk Behavior among Secondary School Students in El Salvador explores the relationship between social resources (social capital) within the school context and several youth risk behaviors. Results indicated that students who perceived higher social cohesion at school and higher parental social support were significantly less likely to report fighting, having been threatened or hurt with a weapon, suicidal ideation, and sexual intercourse than students with lower perceived social cohesion at school and parental social support after adjusting for several socio-demographic variables. ^ Lastly, paper #3. School Health Environment and Social Capital : Moving beyond the individual to the broader social developmental context provides a theoretical and empirical basis for moving beyond the predominant individual-focus and physical health concerns of school health promotion to the larger social context of schools and social health of students. This paper explores the concept of social capital and relevant adolescent development theories in relation to the influence of social context on adolescent health and behavior. ^

Non-sexual household transmission of HCV infection: A cohort study

Objective. This study was designed to determine the prevalence and incidence of HCV infection among non-sexual household contacts of HCV-infected women and to describe the association between HCV infection and potential household risk factors in order to examine whether non-sexual household contact is a route of transmission for HCV infection. ^ Methods. A baseline prevalence survey included 409 non-sexual household contacts of 241 HCV-infected index women in the Houston area from 1994 to 1997. A total of 470 non-sexual household contacts with no evidence of HCV infection at baseline investigation were re-assessed approximately three years after baseline enrollment. Information on potential risk factors was collected through face to face interviews and blood samples were tested for anti-HCV with ELISA-2 and Matrix/RIBA-2. The relationships between HCV infection and potential risk factors were examined by using univariate and multivariate logistic regression analyses. ^ Results. The overall prevalence of anti-HCV positivity among 409 non-sexual household contacts was 4.4%. The highest prevalence of anti-HCV was found in parents (19.5%), followed by siblings (8.1%) and other relatives (5.6%); the children had the lowest prevalence of anti-HCV (1.2%). The univariate analysis showed that IDU, blood transfusion, tattoos, sexual contact with injecting drug users, more than 3 sexual partners in a lifetime, history of a STD, incarceration, previous hepatitis, and contact with hepatitis patients were significantly associated with HCV infection, however, sharing razors, nail clippers, toothbrushes, gum, food or beds with HCV-infected women, and history of dialysis, health care job, body piercing, and homosexual activities were not. Multivariate analysis found that IDU (OR = 221.7 with 95% CI of 22.8 to 2155.7) and history of a STD (OR = 11.7 with 95% CI of 1.2 to 113.1) were the only variables significantly associated with HCV infection. No such associations remained for other risk factors. The three-year cumulative incidence of anti-HCV among 352 non-sexual household contacts of HCV-infected women was zero. ^ Conclusion. This study has provided no evidence that non-sexual household contact is a likely route of transmission for HCV infection. The risk of sharing razors, nail clippers, toothbrushes, gum, food and/or beds with HCV-infected women is not evident and has not been shown to be the likely mode for HCV spread among family members. This study does suggest that IDU is the likely route of transmission for most HCV infection. Association also has been shown independently with a history of STD. The prevalence of anti-HCV among non-sexual household contacts was low. Exposure to common parenteral risk factors and sexual transmission between sexual partners may account for HCV spread among household members of HCV-infected persons. ^

The utility of rapid participatory appraisal for community assessment, diagnosis, and policy development

The selection of a model to guide the understanding and resolution of community problems is an important issue relating to the foundation of public health practice: assessment, policy development, and assurance. Many assessment models produce a diagnosis of community weaknesses, but fail to promote planning and interventions. Rapid Participatory Appraisal (RPA) is a participatory action research model which regards assessment as the first step in the problem solving process, and claims to achieve assessment and policy development within limited resources of time and money. Literature documenting the fulfillment of these claims, and thereby supporting the utility of the model, is relatively sparse and difficult to obtain. Very few articles discuss the changes resulting from RPA assessments in urban areas, and those that do describe studies conducted outside the U.S.A. ^ This study examines the utility of the RPA model and its underlying theories: systems theory, grounded theory, and principles of participatory change, as illustrated by the case study of a community assessment conducted for the Texas Diabetes Institute (TDI), San Antonio, Texas, and subsequent outcomes. Diabetes has a high prevalence and is a major issue in San Antonio. Faculty and students conducted the assessment by informal collaboration between two nursing and public health assessment courses, providing practical student experiences. The study area was large, and the flexibility of the model tested by its use in contiguous sub-regions, reanalyzing aggregated results for the study area. Official TDI reports, and a mail survey of agency employees, described policy development resulting from community diagnoses revealed by the assessment. ^ The RPA model met the criteria for utility from the perspectives of merit, worth, efficiency, and effectiveness. The RPA model best met the agencies' criteria (merit), met the data needs of TDI in this particular situation (worth), provided valid results within budget, time, and personnel constraints (efficiency), and stimulated policy development by TDI (effectiveness). ^ The RPA model appears to have utility for community assessment, diagnosis, and policy development in circumstances similar to the TDI diabetes study. ^

Adolescent Pregnancy Prevention in San Jose, Costa Rica : Assessment of an Educational Intervention

This thesis explores adolescent pregnancy in San Jose, Costa Rica and examines a school-based pregnancy prevention intervention. The relationships between school, gender and risk of adolescent pregnancy are also analyzed, and recommendations are made for effective pregnancy prevention programming. The Purral region of Guadalupe on the outskirts of San Jose, Costa Rica, suffers a higher rate of adolescent pregnancy compared to the rest of the country. In response to this problem, the International Health Central American Institute (IHCAI) implemented a sexual health education program in two local secondary schools in 2006. Very little information about the program is available. It is known that the program was initially evaluated through assessments of the participants’ knowledge before and after the educational sessions. There was no evaluation of the youth attitudes or behaviors, adolescent pregnancies, or long-term impact. The author worked with IHCAI in San Jose, Costa Rica to perform an assessment of the longer term effects of this sexual health education program. They developed a questionnaire to evaluate the knowledge, attitudes, and behaviors surrounding sexual health of youth in the Purral community. Researchers at IHCAI later used this survey to collect data from adolescents who had participated in the educational intervention and those who had not. This thesis analyzes the data collected by IHCAI to assess the effectiveness of the - 2 - educational intervention and the influence of other factors on the knowledge, attitudes, and behaviors of adolescents in the Purral region. The thesis begins with an overview of adolescent pregnancy, Costa Rica and the Purral region, and a description of the education intervention implemented by IHCAI. The research goal, logic model, and methods are then described. The results are reported, and the thesis then concludes with discussion of the results as well as study limitations and recommendations for future research and intervention. This thesis will be used to guide IHCAI’s continuation and expansion of adolescent pregnancy prevention programming.

The association of sexual behavior with oropharyngeal cancer and correlations with HPV-16 serologic status

Objectives. This hospital-based case-case study compared the characteristics of sexual behavior in patients with cancer of the oropharynx to patients with cancers of other head and neck sites. Additionally, the prevalence of certain sexual behaviors of HPV-16 seropositive head and neck cancer patients was compared to that of seronegative patients. ^ Methods. One hundred sixty five oropharyngeal cancer patients and 86 patients with cancers of other head and neck sites completed a sexual history questionnaire. ^ Results. Oropharyngeal cancer patients were significantly more likely to have had a greater number of lifetime sex partners, to have engaged in oral-genital sex, and to have had a greater number of oral-genital sex partners than non-oropharyngeal cancer patients. Oral-genital sex was significantly more common in the HPV-16 seropositive group. ^ Conclusion. These findings add to the evidence that HPV-16 is sexually transmitted to the upper aerodigestive tract and that certain sexual behaviors increase the risk for HPV-associated oropharyngeal cancer. ^

A cross sectional examination of risky sexual behaviors among a population of drug users

This study is a secondary data analysis that assesses the relationship between risky sexual behaviors and sexually transmitted infections (STIs) among drug users. This study analyzes data collected from drug users in the Houston Metropolitan area during 2004 and through August 2005, by researchers with the DASH (Drugs, AIDS, STDs and Hepatitis) project at The University of Texas at Houston School of Public Health. Specifically, the sexually transmitted infections that will be of interest in this proposed study are Human Immunodeficiency Virus (HIV) and Hepatitis B Virus (HBV). Risky sexual behaviors that will be examined include lack of condom use, sexual orientation, trading sex for drugs, trading sex for money, and number of male and female sexual partners in the last 4 weeks. ^ Unadjusted, gender, sexual orientation, number of recent male and female sex partners, and a history of injection drug use were all found to be significant independent variables that increased the odds of STI status. When included in an overall model, these variables significantly increased the odds of STI status, including HBV infection, HIV infection, and HBV/HIV co-infection. History of injection drug use was significant for both HBV and HBV/HIV co-infection, whereas a gay sexual orientation was significant for both HIV and HBV/HIV co-infection. Additionally, having excessive female sex partners was significant for HIV infection. This significant association increases the need for implementation of stronger intervention programs tailored to suit this population's needs such as a combination of drug and sexually transmitted disease (STD) treatment. ^ The importance of these findings is that they establish the strength of associations between the previously mentioned risky sexual behaviors and STI status among drug users. This is crucial for assessing future risk of infection as well as for serving as a necessary component in intervention and treatment programs both for drug use and STIs. ^

An examination of the Gonorrhea Cases & Places study: An analysis of the Theory of Gender and Power, Situational/Environmental Variables Theory, and Sexual Script Theory as it relates to risky sexual behavior in African American adults

Objective. The purpose of the study is to provide a holistic depiction of behavioral & environmental factors contributing to risky sexual behaviors among predominantly high school educated, low-income African Americans residing in urban areas of Houston, TX utilizing the Theory of Gender and Power, Situational/Environmental Variables Theory, and Sexual Script Theory. ^ Methods. A cross-sectional study was conducted via questionnaires among 215 Houston area residents, 149 were women and 66 were male. Measures used to assess behaviors of the population included a history of homelessness, use of crack/cocaine among several other illicit drugs, the type of sexual partner, age of participant, age of most recent sex partner, whether or not participants sought health care in the last 12 months, knowledge of partner's other sexual activities, symptoms of depression, and places where partner's were met. In an effort to determine risk of sexual encounters, a risk index employing the variables used to assess condom use was created categorizing sexual encounters as unsafe or safe. ^ Results. Variables meeting the significance level of p<.15 for the bivariate analysis of each theory were entered into a binary logistic regression analysis. The block for each theory was significant, suggesting that the grouping assignments of each variable by theory were significantly associated with unsafe sexual behaviors. Within the regression analysis, variables such as sex for drugs/money, low income, and crack use demonstrated an effect size of ≥±1, indicating that these variables had a significant effect on unsafe sexual behavioral practices. ^ Conclusions. Variables assessing behavior and environment demonstrated a significant effect when categorized by relation to designated theories. ^

Youth population's health issues in Comal County, Texas

This study assesses adolescent's health issues in Comal County, TX. Adolescents are defined as youth between the ages of 12 to 17 years of age, who resided in Comal County during the time period of 2000 to 2007. The analysis focused on high risk behaviors including use of gateway drugs—tobacco and alcohol; illegal substance use; and reproductive health related indicators, including sexual activity, sexually transmitted diseases, and pregnancy. This study is based on the primary and secondary data collected as part of the 2008 Comal County Community Assessment. It compares findings from the primary data sources to extant data from four secondary data sources including: (1) The Centers for Disease Control & Prevention (national) Healthy People 2010; (2) The Centers for Disease Control & Prevention, Youth Risk Behavior Surveillance Survey, 2007; (3) The Texas Department of State Health Services, 2000 to 2007; and The Pride Survey (Local and Statewide). The methods are drawn from the literature on "rapid epidemiologic appraisal" (Annett H. & Rifkin S. B., 1988). The study focus on corroborating the perceptions, subjective concerns, opinions and beliefs of the Comal County key stakeholders and community participants with qualitative and quantitative indicators of health and well being. The value of this approach is to inform community leaders using a public health perspective and evidence in their decisions about priority setting and resources allocation activities for prevention of high risk behaviors and promotion of adolescent health and well being. ^

Prevalence and risk factors for human immunodefiency virus and hepatitis C virus co-infection among drug users in innercity neighborhoods in Houston, Texas

Background. There are 200,000 HIV/HCV co-infected people in the US and IDUs are at highest risk of exposure. Between 52-92% of HIV infected IDUs are chronically infected with HCV. African Americans and Hispanics bear the largest burden of co-infections. Furthermore HIV/HCV co-infection is associated with high morbidity and mortality if not treated. The present study investigates the demographic, sexual and drug related risk factors for HIV/HCV co-infection among predominantly African American injecting and non-injecting drug users living in two innercity neighborhoods in Houston, Texas. ^ Methods. This secondary analysis used data collected between February 2004 and June 2005 from 1,889 drug users. Three case-comparison analyses were conducted to investigate the risk factors for HIV/HCV co-infection. HIV mono-infection, HCV mono-infection and non-infection were compared to HIV/HCV co-infection to build multivariate logistic regression models. Race/ethnicity and age were forced into each model regardless of significance in the univariate analysis. ^ Results. The overall prevalence of HIV/HCV co-infection was 3.9% while 39.8% of HIV infected drug users were co-infected with HCV and 10.7% of HCV infected drug users were co-infected with HIV. Among HIV infected IDUs the prevalence of HCV was 71.7% and among HIV infected NIDUs the prevalence of HCV was 24%. In the multivariate analysis, HIV/HCV co-infection was associated with injecting drug use when compared to HIV mono-infection, with MSM when compared to HCV mono-infection and with injecting drug use as well as MSM when compared to non-infection. ^ Conclusion. HIV/HCV co-infection was associated with a combination of sexual and risky injecting practices. More data on the prevalence and risk factors for co-infection among minority populations is urgently needed to support the development of targeted interventions and treatment options. Additionally there should be a focus on promoting safer sex and injecting practices among drug users as well as the expansion of routine testing for HIV and HCV infections in this high risk population.^

Sexually transmissible diseases, sexual factors and prostate cancer: A review of literature

A review of literature was carried out regarding sexually related factors, sexually transmissible diseases (STD's) and infections with prostate cancer (PC) development risk. The review of literature, in conjunction with the tabulation of studies, suggested that ejaculation and circumcision may play a protective role in the development of PC and that multiple sex partners and an active sex life may play a causal role in the development of PC which may negate and counteract the protective effects of ejaculation and circumcision. HIV infection may plausibly play a function in deteriorating and compromising immune controls on carcinogenesis. Because of the coexistence of a highly active sexual lifestyle and sexual promiscuity with the growing occurence of STD's, their maybe a correlation with the high incidence of prostate cancer in the United States. Potential multi-institutional studies are warranted to confirm the high incidence of this neoplasm with the increasing cases of STD's and if in fact there is a proportional association to further elucidate the factors responsible for its high incidence.^