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Introduction: Non-natural deaths associated with sexual activity may occur either with or without the involvement of other persons., Aim: The present study provides an overview of cases of non-natural death related to sexual activities as well as recommendations of how to handle these cases and to identify potentially dangerous pleasure-enhancing techniques., Methods: This medicolegal, postmortem, retrospective, and prospective study is based on data of autopsies performed at the Institute of Legal Medicine at University Hospital, Goethe University, Frankfurt, Germany., Main Outcome Measure: Identification of circumstances, sexual practices, and gender distribution of cases of non-natural death in this context., Results: Between 1993 and 2017 (25 years), 16,437 medicolegal autopsies were performed, of which 74 cases (43 males, 31 females) of non-natural death were found to relate to sexual activities (0.45%). One female and 21 males had died in the course of autoerotic practices (group I, n = 22). Nine males and 14 females had performed sexual practices with mutual consent (group II, n = 23), and 13 males and 16 females without mutual consent (group III, n = 29). The average age in group I was 45.4 years; in group II, 40.6 years; and in group III, 39.2 years. Most of the deceased were found in their own apartments. Forms of stimulation included vaginal, anal, and oral intercourse; insertion of foreign bodies; use of chemical substances; and tools for respiratory depression/hypoxia. Three cases of death occurred during sexual activities involving bondage and discipline, sadism, and masochism (BDSM). Death due to strangulation was the main cause in group I, whereas intoxications were predominant in group II. Sharp force (eg, knife) was mainly responsible for death in group III. Anogenital injuries were documented in all groups in approximately equal percentages., Clinical Implications: The cases presented show a high variety of circumstances in which non-natural death connected to sexual activity may occur., Strengths & Limitations: This study presents a large postmortem collection of non-natural death cases with associated sexual activity. As the main limiting factor, it must be stated that mutual consent for a sexual practice or consumption of substances was presumed based on the information provided and a lack of evidence against this assumption., Conclusion: In cases of death associated with sexual activity, medical staff should perform thorough unbiased examinations and documentations. Strangulation and the consumption of stimulants should be classified as life-threatening, pleasure-enhancing techniques. Patients and young people should be informed about these risks. Bunzel L, Koelzer SC, Zedler B, et al. Non-Natural Death Associated with Sexual Activity: Results of a 25-Year Medicolegal Postmortem Study. J Sex Med 2019;16:1547-1556., (Copyright © 2019 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.)

Purpose: A standardized definition for serious opioid overdose has not been clearly established for disease surveillance or assessing the impact of risk mitigation strategies. The purpose of this study was to use medical chart review to clinically validate a claims-based algorithm to identify serious opioid overdose events., Methods: The algorithm for serious opioid overdose required an opioid poisoning or external cause ICD-9-CM code occurring within 1 day of (a) an adverse effect code for serious central nervous system or respiratory depression or (b) a mechanical ventilation or critical care CPT code. The claims coding algorithm identified a sample of 145 individuals 18 years or older among patients that presented to the emergency department of two large hospitals in metropolitan Atlanta, Georgia from January 2014 to August 2015. Claims-defined cases were evaluated against rigorous clinical definitions for serious opioid overdose using (a) literature-based criteria for typical clinical manifestations of opioid overdose and/or (b) clinical response to the opioid-specific reversal agent naloxone. The positive predictive value (PPV) for a serious opioid overdose was calculated as the percentage of clinically confirmed cases (definite or probable)., Results: Among 140 evaluable claims-defined cases, 107 fulfilled clinical criteria for a serious opioid overdose [95 definite and 12 probable; PPV of 76.4% (95% CI 69.4%, 83.5%)]. Among 30 nonconfirmed cases, 20 were polyintoxications involving one or more nonopioid psychoactive agents., Conclusions: An administrative claims coding algorithm for serious opioid overdose had high clinical predictive performance in a medical chart review., (© 2019 John Wiley & Sons, Ltd.)

Background: Pregnancy-associated deaths are extremely rare in Germany. Most deaths are from natural causes, and a range of causes are possible., Method: The deaths of 22 women who died of pregnancy-associated causes and who were autopsied in the Institute of Forensic Medicine of Justus-Liebig University Gießen between 1992 and 2016 were analyzed., Results: The autopsy results and histological examinations for the majority of women who died of pregnancy-associated causes between 1992 and 2016 showed that they had died of natural causes, although complications of pregnancy were a leading cause of death., Conclusion: The death of a pregnant woman should not automatically raise the suspicion of malpractice, although the question does arise in cases of bleeding complications only detected at very late stages. Experts must prove that a real mistake was made during treatment and provide evidence of the causality between malpractice and patient death. Particularly when well-known complications of pregnancy were present, this is only the case if poor monitoring resulted in the complication being detected too late or if treatment was not in accordance with accepted standards of care. The majority of pregnancy-associated deaths are from natural causes and the death of a pregnant woman does not mean that medical malpractice was involved, although this accusation is often levelled in cases where rupture was not immediately diagnosed or in cases of fatal postpartum hemorrhage.

Objective: To characterize the risk factors associated with overdose or serious opioid-induced respiratory depression (OIRD) among medical users of prescription opioids in a commercially insured population (CIP) and to compare risk factor profiles between the CIP and Veterans Health Administration (VHA) population., Subjects and Methods: Analysis of data from 18,365,497 patients in the IMS PharMetrics Plus health plan claims database (CIP) who were dispensed a prescription opioid in 2009 to 2013. Baseline factors associated with an event of serious OIRD among 7,234 cases and 28,932 controls were identified using multivariable logistic regression. The CIP risk factor profile was compared with that from a corresponding logistic regression among 817 VHA cases and 8,170 controls in 2010 to 2012., Results: The strongest associations with serious OIRD in CIP were diagnosed substance use disorder (odds ratio [OR] = 10.20, 95% confidence interval [CI] = 9.06-11.40) and depression (OR = 3.12, 95% CI = 2.84-3.42). Other strongly associated factors included other mental health disorders; impaired liver, renal, vascular, and pulmonary function; prescribed fentanyl, methadone, and morphine; higher daily opioid doses; and concurrent psychoactive medications. These risk factors, except depression, vascular disease, and specific opioids, largely aligned with VHA despite CIP being substantially younger, including more females and less chronic disease, and having greater prescribing prevalence of higher daily opioid doses, specific opioids, and most selected nonopioids., Conclusions: Risk factor profiles for serious OIRD among US medical users of prescription opioids with private or public health insurance were largely concordant despite substantial differences between the populations in demographics, clinical conditions, health care delivery systems, and clinical practices., (© 2017 American Academy of Pain Medicine.)

Objective: To validate a risk index that estimates the likelihood of overdose or serious opioid-induced respiratory depression (OIRD) among medical users of prescription opioids., Subjects and Methods: A case-control analysis of 18,365,497 patients with an opioid prescription from 2009 to 2013 in the IMS PharMetrics Plus commercially insured health plan claims database (CIP). An OIRD event occurred in 7,234 cases. Four controls were selected per case. Validity of the Risk Index for Overdose or Serious Opioid-induced Respiratory Depression (RIOSORD), developed previously using Veterans Health Administration (VHA) patient data, was assessed. Multivariable logistic regression was used within the CIP study population to develop a slightly refined RIOSORD. The composition and performance of the CIP-based RIOSORD was evaluated and compared with VHA-based RIOSORD., Results: VHA-RIOSORD performed well in discriminating OIRD events in CIP (C-statistic = 0.85). Additionally, re-estimation of logistic model coefficients in CIP yielded a 0.90 C-statistic. The resulting comorbidity and pharmacotherapy variables most highly associated with OIRD and retained in the CIP-RIOSORD were largely concordant with VHA-RIOSORD. These variables included neuropsychiatric and cardiopulmonary disorders, impaired drug excretion, opioid characteristics, and concurrent psychoactive medications. The average predicted probability of OIRD ranged from 2% to 83%, with excellent agreement between predicted and observed incidence across risk classes., Conclusions: RIOSORD had excellent predictive accuracy in a large population of US medical users of prescription opioids, similar to its performance in VHA. This practical risk index is designed to support clinical decision-making for safer opioid prescribing, and its clinical utility should be evaluated prospectively., (© 2017 American Academy of Pain Medicine.)

Background: Although sexual activity can cause moderate stress, it can cause natural death in individuals with pre-existing illness. The aim of this study was to identify additional pre-existing health problems, sexual practices, and potential circumstances that may trigger fatal events., Methods: This medicolegal postmortem, retrospective, and prospective study is based on data of autopsies performed at the Institute of Legal Medicine of the University hospital, Goethe-University, Frankfurt/Main, Germany., Outcomes: Identification of pre-existing health problems, sexual practices, and potential circumstances than could trigger fatal events., Results: From 1972 to 2016 (45 years) approximately 38,000 medicolegal autopsies were performed, of which 99 cases of natural death were connected to sexual activities (0.26%). Except for eight women, men represented most cases. The women's mean age was 45 years (median = 45) and the men's mean age was 57.2 years (median = 57). Causes of death were coronary heart disease (n = 28), myocardial infarction (n = 21) and reinfarction (n = 17), cerebral hemorrhage (n = 12), rupture of aortic aneurysms (n = 8), cardiomyopathy (n = 8), acute heart failure (n = 2), sudden cardiac arrest (n = 1), myocarditis (n = 1), and a combination of post myocardial infarction and cocaine intoxication (n = 1). Most cases showed increased heart weights and body mass indices. Death occurred mainly during the summer and spring and in the home of the deceased. If sexual partners were identified, 34 men died during or after sexual contact with a female prostitute, two cases at least two female prostitutes. Nine men died during or after sexual intercourse with their wife, in seven cases the sexual partner was a mistress, and in four cases the life partner. Five men died during homosexual contacts. Based on the situation 30 men were found in, death occurred during masturbation. Of the women, five died during intercourse with the life partner, two died during intercourse with a lover or friend, and in one case no information was provided., Clinical Translation: Natural deaths connected with sexual activity appear to be associated with male sex and pre-existing cardiovascular disorders. Most cases recorded occurred with mistresses, prostitutes, or during masturbation. If death occurs, the spouse or life partner might need psychological support., Strength and Limitations: To our knowledge, the present study contains the largest collection of postmortem data on natural deaths connected with sexual activities. However, the cases presented were of forensic interest; a larger number of undetected cases especially in the marital or stable relationship sector must be assumed., Conclusion: Patients should be informed about the circumstances that could trigger the "love death." Lange L, Zedler B, Verhoff MA, Parzeller M. Love Death-A Retrospective and Prospective Follow-Up Mortality Study Over 45 Years. J Sex Med 2017;14:1226-1231., (Copyright © 2017 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.)

Aims: To assess the safety of buprenorphine compared with methadone to treat pregnant women with opioid use disorder., Methods: We searched PubMed, Embase and the Cochrane Library from inception to February 2015 for randomized controlled trials (RCT) and observational cohort studies (OBS) that compared buprenorphine with methadone for treating opioid-dependent pregnant women. Two reviewers assessed independently the titles and abstracts of all search results and full texts of potentially eligible studies reporting original data for maternal/fetal/infant death, preterm birth, fetal growth outcomes, fetal/congenital anomalies, fetal/child neurodevelopment and/or maternal adverse events. We ascertained each study's risk of bias using validated instruments and assessed the strength of evidence for each outcome using established methods. We computed effect sizes using random-effects models for each outcome with two or more studies., Results: Three RCTs (n = 223) and 15 cohort OBSs (n = 1923) met inclusion criteria. In meta-analyses using unadjusted data and methadone as comparator, buprenorphine was associated with lower risk of preterm birth [RCT risk ratio (RR) = 0.40, 95% confidence interval (CI) = 0.18, 0.91; OBS RR = 0.67, 95% CI = 0.50, 0.90], greater birth weight [RCT weighted mean difference (WMD) = 277 g, 95% CI = 104, 450; OBS WMD = 265 g, 95% CI = 196, 335] and larger head circumference [RCT WMD = 0.90 cm, 95% CI = 0.14, 1.66; OBS WMD = 0.68 cm, 95% CI = 0.41, 0.94]. No treatment differences were observed for spontaneous fetal death, fetal/congenital anomalies and other fetal growth measures, although the power to detect such differences may be inadequate due to small sample sizes., Conclusions: Moderately strong evidence indicates lower risk of preterm birth, greater birth weight and larger head circumference with buprenorphine treatment of maternal opioid use disorder during pregnancy compared with methadone treatment, and no greater harms., (© 2016 The Authors. Addiction published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction.)

Background: Untreated opioid dependence in pregnant women is associated with adverse birth outcomes. Buprenorphine and methadone are options for opioid agonist medication-assisted treatment during pregnancy., Objective: The aim of this study was to describe adverse birth outcomes observed with buprenorphine or methadone treatment compared to the general population in Sweden., Methods: Pregnant women and their corresponding births during 2005-2011 were identified in the Swedish Medical Birth Register. Data on stillbirth, neonatal/infant death, mode of delivery, gestational age at birth, Apgar score, growth outcomes, neonatal abstinence syndrome, and congenital malformations were examined. Frequencies were compared using two-sided Fisher's exact tests. Unadjusted estimates of birth outcomes for women treated with buprenorphine or methadone were compared to the registered general population., Results: A total of 746,257 pregnancies among 538,178 unique women resulted in 746,485 live births. Among the 194 women treated with buprenorphine (N = 176) or methadone (N = 52), no stillbirths or neonatal/infant deaths occurred. Neonatal abstinence syndrome developed in 23.3% and 38.5% of infants born to mothers treated with buprenorphine and methadone, respectively. The frequency of the selected adverse birth outcomes assessed in women treated with buprenorphine as compared to the general population was not significantly different. However, a significantly higher frequency of preterm birth and congenital malformations was observed in women treated with methadone as compared to the general population. Compared with the general population, methadone-treated women were significantly older than buprenorphine-treated women, and both treatment groups began prenatal care later, were more likely to smoke cigarettes, and did not cohabitate with the baby's father., Conclusions: An increased frequency of the selected adverse birth outcomes was not observed with buprenorphine treatment during pregnancy. Twofold increased frequency of preterm birth [2.21 (1.11, 4,41)] and congenital malformations [2.05 (1.08, 3.87)] was observed in the methadone group, which may be partly explained by older average maternal age and differences in other measured and unmeasured confounders.

Background: The Total Exposure Study was a stratified, multi-center, cross-sectional study designed to estimate levels of biomarkers of tobacco-specific and non-specific exposure and of potential harm in U.S. adult current cigarette smokers (≥one manufactured cigarette per day over the last year) and tobacco product non-users (no smoking or use of any nicotine containing products over the last 5 years). The study was designed and sponsored by a tobacco company and implemented by contract research organizations in 2002-2003. Multiple analyses of smoking behavior, demographics, and biomarkers were performed. Study data and banked biospecimens were transferred from the sponsor to the Virginia Tobacco and Health Research Repository in 2010, and then to SRI International in 2012, for independent analysis and dissemination., Methods: We analyzed biomarker distributions overall, and by biospecimen availability, for comparison with existing studies, and to evaluate generalizability to the entire sample. We calculated genome-wide statistical power for a priori hypotheses. We performed clinical chemistries, nucleic acid extractions and genotyping, and report correlation and quality control metrics., Results: Vital signs, clinical chemistries, and laboratory measures of tobacco specific and non-specific toxicants are available from 3585 current cigarette smokers, and 1077 non-users. Peripheral blood mononuclear cells, red blood cells, plasma and 24-h urine biospecimens are available from 3073 participants (2355 smokers and 719 non-users). In multivariate analysis, participants with banked biospecimens were significantly more likely to self-identify as White, to be older, to have increased total nicotine equivalents per cigarette, decreased serum cotinine, and increased forced vital capacity, compared to participants without. Effect sizes were small (Cohen's d-values ≤ 0.11). Power for a priori hypotheses was 57 % in non-Hispanic Black (N = 340), and 96 % in non-Hispanic White (N = 1840), smokers. All DNA samples had genotype completion rates ≥97.5 %; 68 % of RNA samples yielded RIN scores ≥6.0., Conclusions: Total Exposure Study clinical and laboratory assessments and biospecimens comprise a unique resource for cigarette smoke health effects research. The Total Exposure Study Analysis Consortium seeks to perform molecular studies in multiple domains and will share data and analytic results in public repositories and the peer-reviewed literature. Data and banked biospecimens are available for independent or collaborative research.

Objective: Develop a risk index to estimate the likelihood of life-threatening respiratory depression or overdose among medical users of prescription opioids., Subjects, Design, and Methods: A case-control analysis of administrative health care data from the Veterans' Health Administration identified 1,877,841 patients with a pharmacy record for an opioid prescription between October 1, 2010 and September 30, 2012. Overdose or serious opioid-induced respiratory depression (OSORD) occurred in 817. Ten controls were selected per case (n = 8,170). Items for an OSORD risk index (RIOSORD) were selected through logistic regression modeling, with point values assigned to each predictor. Modeling of risk index scores produced predicted probabilities of OSORD; risk classes were defined by the predicted probability distribution., Results: Fifteen variables most highly associated with OSORD were retained as items, including mental health disorders and pharmacotherapy; impaired drug metabolism or excretion; pulmonary disorders; specific opioid characteristics; and recent hospital visits. The average predicted probability of experiencing OSORD ranged from 3% in the lowest risk decile to 94% in the highest, with excellent agreement between predicted and observed incidence across risk classes. The model's C-statistic was 0.88 and Hosmer-Lemeshow goodness-of-fit statistic 10.8 (P > 0.05)., Conclusion: RIOSORD performed well in identifying medical users of prescription opioids within the Veterans' Health Administration at elevated risk of overdose or life-threatening respiratory depression, those most likely to benefit from preventive interventions. This novel, clinically practical, risk index is intended to provide clinical decision support for safer pain management. It should be assessed, and refined as necessary, in a more generalizable population, and prospectively evaluated., (© 2015 The Authors Pain Medicine published by Wiley Periodicals, Inc. on behalf of American Academy of Pain Medicine.)

Objective: Prescription opioid use and deaths related to serious toxicity, including overdose, have increased dramatically in the United States since 1999. However, factors associated with serious opioid-related respiratory or central nervous system (CNS) depression or overdose in medical users are not well characterized. The objective of this study was to examine the factors associated with serious toxicity in medical users of prescription opioids., Design: Retrospective, nested, case-control analysis of Veterans Health Administration (VHA) medical, pharmacy, and health care resource utilization administrative data., Subjects: Patients dispensed an opioid by VHA between October 1, 2010 and September 30, 2012 (N=8,987)., Methods: Cases (N=817) experienced life-threatening opioid-related respiratory/CNS depression or overdose. Ten controls were randomly assigned to each case (N=8,170). Logistic regression was used to examine associations with the outcome., Results: The strongest associations were maximum prescribed daily morphine equivalent dose (MED)≥ 100 mg (odds ratio [OR]=4.1, 95% confidence interval [CI], 2.6-6.5), history of opioid dependence (OR=3.9, 95% CI, 2.6-5.8), and hospitalization during the 6 months before the serious toxicity or overdose event (OR=2.9, 95% CI, 2.3-3.6). Liver disease, extended-release or long-acting opioids, and daily MED of 20 mg or more were also significantly associated., Conclusions: Substantial risk for serious opioid-related toxicity and overdose exists at even relatively low maximum prescribed daily MED, especially in patients already vulnerable due to underlying demographic factors, comorbid conditions, and concomitant use of CNS depressant medications or substances. Screening patients for risk, providing education, and coprescribing naloxone for those at elevated risk may be effective at reducing serious opioid-related respiratory/CNS depression and overdose in medical users of prescription opioids., (Wiley Periodicals, Inc.)

Isolated coronary anomalies are rare abnormalities that can be divided into benign and malignant forms. Malignant coronary artery abnormalities generally present already during infancy or early childhood by causing symptoms or sudden death. Benign abnormalities often remain asymptomatic because they are hemodynamically irrelevant. Among the 12,985 autopsies performed at the Institute of Legal Medicine at the University of Frankfurt (Germany) between 1995 and 2013, there were eight cases (0.062%) with isolated coronary artery abnormalities. Five of these cases (0.039%) could be included in our retrospective study. These involved one deceased female and four deceased male subjects, aged between 2 and 57 years. In three of these cases (aged 6, 9, and 11 years old), the coronary anomaly was classified as malignant and was recorded as the cause of death. Benign isolated coronary anomalies are often incidental findings during autopsies. However, in one of the cases in our study, coronary sclerosis in precisely the anomalous vessel was found to be the origin of a fatal myocardial infarction. Malignant isolated coronary artery anomalies attain medicolegal significance when they remain undetected despite advanced early detection protocols and cause sudden death in childhood.

The article deals with the new regulations in the German Civil Code (Bürgerliches Gesetzbuch - BGB), which came into effect in Germany as the Patient Rights Act (PatRG) on the 2/26/2013. In the third part, the burden of proof in liability questions (and 630h BGB) are discussed and critically analysed. In the discussion and a final resume points of criticism of the new law are pointed out.

The article deals with the new regulations in the German Civil Code (BGB) which came into effect in Germany on 26 Feb 2013 as the Patient Rights Act (PatRG). In the second part, the consent of the patient (Section 630d Civil Code), the physician's duties to inform the patient (Section 630e Civil Code), the documentation of treatment (Section 630f Civil Code), and the right of access to the patient file (Section 630g Civil Code) are discussed and critically analysed.

The article deals with the new regulations in the German Civil Code (BGB) which came into effect in Germany on 26 Feb 2013 as the Patient Rights Act (PatRG). In Part I, the legislative procedure, the treatment contract and the contracting parties (Section 630a Civil Code), the applicable regulations (Section 630b Civil Code) and the obligations to cooperate and inform (Section 630c Civil Code) are discussed and critically analysed.

Background: In international epidemiological studies, associations between suicides and body height, or body mass index (BMI) were found. Because of the recently growing number of suicides in Germany, a closer look on different anthropometric measures of suicide victims autopsied at the Institute of Forensic Medicine of the Goethe-University in Frankfurt/Main, Germany, was taken., Method: A retrospective analysis of 1,271 non-natural death cases autopsied between 2006 and 2010 was performed. A total of 566 other than suicide (control group) and 245 suicide cases (study group) with a given body height and weight aged between 18 and 96 years were examined., Results: Body mass indices of the 18-59-year-old male and 60-79-year-old female suicide victims were significantly lower. Old-aged women who committed suicide exhibited beside a significant lower body mass a significantly slender body shape measured as smaller pelvic circumference, waist circumference, and waist-to-tallness ratio. Self-poisoning was by far the leading suicide method in both genders. The victims of the suicide method hanging were the youngest on average, and this method was most common in the male underweight and female lightly normal weight BMI categories, whereas old, overweight, and obese men killed themselves predominantly with firearms., Conclusion: The analysis showed that body measures of suicide cases in comparison to other non-natural death circumstance cases differ. For criminal procedural reasons, all suicide cases should be autopsied. But high autopsy rates are also needed for scientific research and to ensure a high level of patient safety.

Background: Calendar blister packaging (CBP) that incorporates a day or date feature is a simple medication packaging technology that is designed to improve medication adherence and persistence., Objective: This study was conducted to assess the effect of a new calendar packaging technology on prescription refill adherence and persistence for daily, self-administered, long-term medication use., Methods: Anonymized pharmacy dispensing data from a large US mass merchandiser were analyzed. This retrospective cohort study included people aged 18 to 75 years who filled prescriptions for oral lisinopril or enalapril (control group) at a study pharmacy during 1 year before and after the switch of lisinopril packaging from vials to CBP. Cohorts were stratified into new and prevalent medication users. We used linear and logistic regression modeling and propensity score matching to assess the impact of CBP on refill adherence, using medication possession ratio (MPR) and proportion of days covered (PDC), and persistence using length of therapy (LOT)., Results: Our sample comprised 76,321 new users and 249,040 prevalent users. Across all user, medication, and packaging groups, the mean unadjusted LOT decreased in the follow-up year, possibly due to economic recession. The LOT decline was attenuated in the CBP cohort. After adjustment for covariates, CBP use in new and prevalent medication users was associated with significantly higher LOT and PDC but not MPR. The odds of achieving PDC ≥80% were higher by 15% in new users (odds ratio [OR] = 1.15; 95% CI, 1.09-1.21) and 12% in prevalent users (OR = 1.12; 95% CI, 1.09-1.15) who switched to CBP, compared with continued vial use., Conclusions: CBP of medication prescribed for daily, self-administered, long-term use was associated with modest improvement in prescription refill adherence and persistence. An adherence strategy of even small effect size that is broadly implemented on a population level could significantly leverage therapeutic effect and provide substantial cumulative public health benefit. Clinical benefit, or harm, associated with use of CBP should be investigated. Usability assessments of CBP in patient subgroups may provide insight about differential impact on adherence and persistence., (Copyright © 2011 Elsevier HS Journals, Inc. All rights reserved.)

In the last few years, male circumcision has become the subject of controversial discussion. On the one hand, medical and hygienic arguments, ideology, freedom of religion, cultural identity and social adequacy are claimed by those supporting male circumcision. On the other hand, the justification of this practice also has to be critically scrutinized just as the question whether the parents have the right to consent to the operation. Today, opinions range from those who claim that religion and culture alone justify the practice to those who consider circumcision of minors unable to give their consent as bodily injury subject to punishment. In contrast to female genital mutilation, most positions do not postulate that circumcision violates morality. If the person concerned is able to give his consent, freedom of religion may also justify circumcision after weighing its pros and cons as well as its risks and potential side effects.

Background: The therapeutic benefit of self-administered medications for long-term use is limited by an average 50% nonadherence rate. Patient forgetfulness is a common factor in unintentional nonadherence. Unit-of-use packaging that incorporates a simple day-and-date feature (calendar packaging) is designed to improve adherence by prompting patients to maintain the prescribed dosing schedule., Objective: To review systematically, in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement, randomized controlled trial evidence of the adherence benefits and harms of calendar blister packaging (CBP) and calendar pill organizers (CPO) for self-administered, long-term medication use., Methods: Data sources included the MEDLINE and Web of Science and Cochrane Library databases from their inception to September 2010 and communication with researchers in the field. Key search terms included blister-calendar pack, blister pack, drug packaging, medication adherence, medication compliance, medication compliance devices, medication containers, medication organizers, multicompartment compliance aid, persistence, pill-box organizers, prescription refill, randomized controlled trials, and refill compliance. Selected studies had an English-language title; a randomized controlled design; medication packaged in CBP or CPO; a requirement of solid, oral medication self-administered daily for longer than 1 month in community-dwelling adults; and at least 1 quantitative outcome measure of adherence. Two reviewers extracted data independently on study design, sample size, type of intervention and control, and outcomes., Results: Ten trials with a total of 1045 subjects met the inclusion criteria, and 9 also examined clinical outcomes (seizures, blood pressure, psychiatric symptoms) or health care resource utilization. Substantial heterogeneity among trials precluded meta-analysis. In 3 studies, calendar packaging was part of a multicomponent adherence intervention. Six of 10 trials reported higher adherence, but it was associated with clinically significant improvement in only 1 study: 50% decreased seizure frequency with a CPO-based, multicomponent intervention. No study reported sufficient information to examine conclusively potential harms related to calendar packaging., Limitations: All trials had significant methodological limitations, such as inadequate randomization or blinding, or reported insufficient information regarding enrolled subjects and attrition, which resulted in a moderate-to-high risk of bias and, in 2 studies, unevaluable outcome data. Trials were generally short and sample sizes small, with heterogeneous adherence outcome measures., Conclusions: Calendar packaging, especially in combination with education and reminder strategies, may improve medication adherence. Methodological limitations preclude definitive conclusions about the effect size of adherence and clinical benefits or harms associated with CBP and CPO. High-quality trials of adequate size and duration are needed to assess the clinical effectiveness of such interventions., (Copyright © 2011 Elsevier HS Journals, Inc. All rights reserved.)

Female genital mutilation (FGM) is considered to be against the law and against morality not only in Western countries, although a woman of age and able to consent may sometimes think differently. The procedure may have serious physical and emotional consequences for the girl or woman. Nevertheless there are attempts to justify the procedure with medical and hygienic pseudoarguments, ideology, freedom of religion, cultural identity and social adequacy. Outside the Western world, some people claim that religion and culture alone justify the practice. In Germany, parents can lose the right to determine the residence of their daughter, if she is faced with the risk of genital mutilation in order to prevent that the child or girl is taken to her home country. Genital mutilation as a gender-specific threat is recognized as a reason to grant asylum or prevent deportation. Proposals to make genital mutilation a separate punishable offence are presently discussed by the legislator.

Background: Chronic obstructive pulmonary disease (COPD) is an inflammatory lung disease with associated systemic effects., Objective: To use gene expression microarrays in peripheral blood leukocytes of current and former cigarette smokers to identify differences associated with COPD., Materials and Methods: Random forest modelling and a split-sample case-control approach were used to identify candidate predictors., Results: We identified 1013 genes and one smoking exposure variable that differentiated current and former smokers with or without COPD. This predictor set was reduced to a nine-gene classifier (IL6R, CCR2, PPP2CB, RASSF2, WTAP, DNTTIP2, GDAP1, LIPE and RPL14)., Conclusion: These gene expression profiles represent potential biomarkers for COPD and may help increase mechanistic understanding of the disease.

Purpose: The potential of dual energy computed tomography (DECT) for the analysis of gallstone compounds was investigated. The main goal was to find parameters, that can reliably define high percentage (>70%) cholesterol stones without calcium components., Materials and Methods: 35 gallstones were analyzed with DECT using a phantom model. Stone samples were put into specimen containers filled with formalin. Containers were put into a water-filled cylindrical acrylic glass phantom. DECT scans were performed using a tube voltage/current of 140 kV/83 mAs (tube A) and 80 kV/340 mAs (tube B). ROI-measurements to determine CT attenuation of each sector of the stones that had different appearance on the CT images were performed. Finally, semi-quantitative infrared spectroscopy (FTIR) of these sectors was performed for chemical analysis., Results: ROI-measurements were performed in 45 different sectors in 35 gallstones. Sectors containing >70% of cholesterol and no calcium component (n=20) on FTIR could be identified with 95% sensitivity and 100% specificity on DECT. These sectors showed typical attenuation of -8+/-4 HU at 80 kV and +22+/-3 HU at 140 kV. Even the presence of a small calcium component (<10%) hindered the reliable identification of cholesterol components as such., Conclusion: Dual energy CT allows for reliable identification of gallstones containing a high percentage of cholesterol and no calcium component in this pre-clinical phantom model. Results from in vivo or anthropomorphic phantom trials will have to confirm these results. This may enable the identification of patients eligible for non-surgical treatment options in the future., (Copyright 2009 Elsevier Ireland Ltd. All rights reserved.)

Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of morbidity and mortality in the United States and cigarette smoking is a primary determinant of the disease. COPD is characterized by chronic airflow limitation as measured by the forced expiratory volume in one second (FEV(1)). In this study, the plasma proteomes of 38 middle-aged or older adult smokers with mild to moderate COPD, with FEV(1) decline characterized as either rapid (RPD, n = 20) or slow or absent (SLW, n = 18), were interrogated using a comprehensive high-throughput proteomic approach, the accurate mass and time (AMT) tag technology. This technology is based upon a putative mass and time tag database (PMT), high-resolution LC separations and high mass accuracy measurements using FT-ICR MS with a 9.4-T magnetic field. The peptide and protein data were analyzed using three statistical approaches to address ambiguities related to the high proportion of missing data inherent to proteomic analysis. The RPD and SLW groups were differentiated by 55 peptides which mapped to 33 unique proteins. Twelve of the proteins have known roles in the complement or coagulation cascade and, despite an inability to adjust for some factors known to affect lung function decline, suggest potential mechanistic biomarkers associated with the rate of lung function decline in COPD. Whether these proteins are the cause or result of accelerated decline will require further research.

Chronic obstructive pulmonary disease (COPD), characterized by chronic airflow limitation, is a serious public health concern. In this study, we used proton nuclear magnetic resonance ((1)H NMR) spectroscopy to identify and quantify metabolites associated with lung function in COPD. Plasma and urine were collected from 197 adults with COPD and from 195 without COPD. Samples were assayed using a 600 MHz NMR spectrometer, and the resulting spectra were analyzed against quantitative spirometric measures of lung function. After correcting for false discoveries and adjusting for covariates (sex, age, smoking) several spectral regions in urine were found to be significantly associated with baseline lung function. These regions correspond to the metabolites trigonelline, hippurate and formate. Concentrations of each metabolite, standardized to urinary creatinine, were associated with baseline lung function (minimum p-value = 0.0002 for trigonelline). No significant associations were found with plasma metabolites. Urinary hippurate and formate are often related to gut microflora. This could suggest that the microbiome varies between individuals with different lung function. Alternatively, the associated metabolites may reflect lifestyle differences affecting overall health. Our results will require replication and validation, but demonstrate the utility of NMR metabolomics as a screening tool for identifying novel biomarkers of pulmonary outcomes.

Although cigarette smoking is recognized as the most important cause of chronic obstructive pulmonary disease (COPD), the pathophysiological mechanisms underlying the lung function decline are not well understood. Using off-line strong cation exchange fractionation with RP-LC-ESI-MS/MS and robust database searching, 1758 tryptic peptides were identified in plasma samples from cigarette smokers. Using two statistical approaches, 30 peptides were identified to be associated with the annualized rate of lung function decline over 5 years among smokers with COPD characterized as having rapid (n = 18) or slow (n = 18) decline and 18 smokers without COPD. The identified peptides belong to proteins that are involved in the complement or coagulation systems or have antiprotease or metabolic functions. This research demonstrates the utility of proteomic profiling to improve the understanding of molecular mechanisms involved in cigarette smoking-related COPD by identifying plasma proteins that correlate with decline in lung function.

In a previous analysis (see Part I) we proposed a heuristic for assessing the efficacy of potential reduced-risk tobacco products (PRRPs) on lung cancer (LC) rates, using smoking cessation data published in a report from the Iowa Women's Health Study (IWHS) as a basis for sample size estimates. In this study, an additional analysis was performed using cessation data from the much larger Cancer Prevention Study II (CPS-II), which also provides data on different durations of cessation. Statistical methods were used to assess whether smokers switching to a PRRP would reduce their risk of LC. Furthermore, non-inferiority tests compared the LC risk in switchers to that in smokers who had quit smoking. The present work shows that similar sample size estimates were obtained whether the analysis was based on the IWHS or the CPS-II data sets, suggesting that the heuristic may be generally applicable to prospective real-life studies to evaluate PRRPs. Non-inferiority testing of switchers compared with quitters required approximately 10-fold more subjects than did superiority testing of switchers compared with smokers. Altogether, these estimates indicate that it is feasible, in terms of study duration and sample size, to clinically assess the LC risk-reducing potential of a PRRP., ((c) 2009 Elsevier Inc. All rights reserved.)

The risk-reducing effect of a potential reduced-risk tobacco product (PRRP) can be investigated conceptually in a long-term, prospective study of disease risks among cigarette smokers who switch to a PRRP and in appropriate comparison groups. Our objective was to provide guidance for establishing the fundamental design characteristics of a study intended to (1) determine if switching to a PRRP reduces the risk of lung cancer (LC) compared with continued cigarette smoking, and (2) compare, using a non-inferiority approach, the reduction in LC risk among smokers who switched to a PRRP to the reduction in risk among smokers who quit smoking entirely. Using standard statistical methods applied to published data on LC incidence after smoking cessation, we show that the sample size and duration required for a study designed to evaluate the potential for LC risk reduction for an already marketed PRRP, compared with continued smoking, varies depending on the LC risk-reducing effectiveness of the PRRP, from a 5-year study with 8000-30,000 subjects to a 15-year study with <5000 to 10,000 subjects. To assess non-inferiority to quitting, the required sample size tends to be about 10 times greater, again depending on the effectiveness of the PRRP., ((c) 2009 Elsevier Inc. All rights reserved.)

Background: High-throughput DNA methylation arrays are likely to accelerate the pace of methylation biomarker discovery for a wide variety of diseases. A potential problem with a standard set of probes measuring the methylation status of CpG sites across the whole genome is that many sites may not show inter-individual methylation variation among the biosamples for the disease outcome being studied. Inclusion of these so-called "non-variable sites" will increase the risk of false discoveries and reduce statistical power to detect biologically relevant methylation markers., Results: We propose a method to estimate the proportion of non-variable CpG sites and eliminate those sites from further analyses. Our method is illustrated using data obtained by hybridizing DNA extracted from the peripheral blood mononuclear cells of 311 samples to an array assaying 1505 CpG sites. Results showed that a large proportion of the CpG sites did not show inter-individual variation in methylation., Conclusions: Our method resulted in a substantial improvement in association signals between methylation sites and outcome variables while controlling the false discovery rate at the same level.

This randomized, controlled, forced-switching, open-label, parallel-group, single-center study in 100 male and female adult smokers evaluated 12 biomarkers of tobacco smoke exposure. We measured exposure to the following smoke constituents: nicotine, pyrene, tobacco-specific nitrosamines, three aromatic amines, carbon monoxide, benzene, acrolein, crotonaldehyde, and 1,3-butadiene. After baseline exposure determination, adult smokers of a conventional cigarette (CC) were switched to an electrically heated cigarette smoking system (EHCSS, Series K), continued smoking the CC, or stopped smoking (No-smoking) for 8 days in a controlled, confined, clinical setting. In the EHCSS group, the mean decrease from Baseline to Day 8 in the biomarkers of exposure ranged from 16% to 77% at Day 8 compared to Baseline. After adjusting for the residual effect (carryover effects due to long elimination half-life and non-tobacco confounding sources of exposure), the mean percent decrease from Baseline for all 12 biomarkers ranged from 47% to 90%. In conclusion, switching for 8 days from a conventional cigarette to the EHCSS substantially reduced exposure of adult smokers to several constituents of both the particulate and gas phases of cigarette smoke.

This sub-study of a randomized, controlled, forced-switching, open-label, parallel-group, clinical study compared environmental tobacco smoke (ETS) produced when 60 male and female adult smokers switched to a third-generation electrically heated cigarette smoking system (EHCSS), continued to smoke a conventional cigarette (CC), or stopped smoking (No-smoking). Concentrations of air constituents including respirable suspended particulate (RSP), carbon monoxide (CO), ammonia and total volatile organic compounds (TVOCs) and ETS markers including solanesol-related particulate matter (Sol-PM), ultraviolet absorbing particulate matter (UVPM), fluorescent particulate matter (FPM), nicotine and 3-ethenyl pyridine (3-EP) were measured in a ventilated, furnished conference room over a 2-h period on separate occasions for each smoking condition. When the EHCSS was used, concentrations of CO and most ETS markers were in the same range as during no-smoking. Concentrations of ammonia were reduced by 41% and concentrations of other selected constituents of ETS were reduced by 87-99% in the air of a room in which EHCSS cigarettes were smoked as compared to concentrations in the same room when conventional cigarettes were smoked. Switching from conventional cigarette smoking to the EHCSS resulted in substantial reductions in concentrations of several markers of environmental tobacco smoke.

This randomized, controlled, forced-switching, open-label, parallel-group, single-center study in 90 male and female adult smokers evaluated six biomarkers of tobacco smoke exposure over a 12-week period of unrestricted smoking in the participants' normal life setting. Baseline biomarker levels were measured, then participants were randomly assigned to switch to an electrically heated cigarette smoking system (EHCSS, Series K) or to continue smoking a conventional cigarette (CC) of similar tar yield (Federal Trade Commission method) for 12 weeks. Compared to Baseline, adult smokers who switched to the EHCSS for 12 weeks in their normal life setting had significantly reduced nicotine equivalents (-33%), total NNAL (a biomarker for NNK, -63%), 1-OHP (a surrogate biomarker for polycyclic aromatic hydrocarbons, -38%), carboxyhemoglobin (a biomarker for carbon monoxide, -23%), 3-HPMA (a biomarker for acrolein, -25%) and S-PMA (a biomarker for benzene, -49%), whereas exposure was stable in the CC control group.

This randomized, controlled, forced-switching, open-label, parallel-group study in 97 adult male and female smokers of conventional cigarettes evaluated biomarkers of tobacco smoke exposure and cardiovascular risk factors. After baseline measurements, smokers were either switched to a second-generation electrically heated cigarette smoking system (EHCSS) or continued smoking conventional cigarettes for 12 months. Biomarkers of exposure and cardiovascular risk factors were measured at 0.5, 1, 2, 3, 4, 5, 6, 9, and 12 months. There was a rapid and sustained reduction in all biomarkers of exposure after switching to the EHCSS, with statistically significant reductions from baseline in nicotine equivalents (-18%), plasma cotinine (-16%), total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (-73%), total 1-hydroxypyrene (-53%), urine mutagenicity (-52%), 4-aminobiphenyl hemoglobin adducts (-43%), carboxyhemoglobin AUC7-23 h (-80%), and 3-hydroxypropylmercapturic acid (-35%). These reductions in exposure in the EHCSS group were associated with statistically significant and pathophysiologically favorable changes in several cardiovascular risk factors, including white blood cell count (-0.78 x 10(3)/microL), hemoglobin (-0.16 g/dL), hematocrit (-0.44%), urine 11-dehydrothromboxane B2 (-374 ng/24 h), and high-density lipoprotein cholesterol (+5 mg/dL).

This randomized, controlled, forced-switching, open-label, parallel-group study in 100 adult male and female smokers of conventional cigarettes evaluated 8 biomarkers of tobacco smoke exposure. After baseline exposure determinations, adult smokers were switched to a second-generation electrically heated cigarette smoking system (EHCSS) for 8 days in a clinical setting. After 8 days of smoking the EHCSS biomarkers of exposure decreased by 43% to 85% compared to baseline. After correction for residual effects (carryover effects due to long elimination half-life and non-tobacco-confounding sources of exposure), reductions in exposure ranged from 59% to 97%. Results from this short-term clinical exposure study indicate that switching from a conventional cigarette to a second-generation electrically heated cigarette smoking system substantially reduced the exposure to several measured potentially harmful constituents of tobacco smoke.