Evaluating Sex Differences in Efficacy, Safety and Pharmacokinetics in Patients Treated with Cannabis by a Metered-Dose Inhaler.

BACKGROUND: Clinical studies on medical cannabis (MC) treatment have shown sex-related differences, including higher susceptibility to adverse events among women and greater analgesia among men. Here, we used the Syqe metered-dose inhaler (MDI) and a single chemovar to analyze sex differences. METHODS: A total of 1249 Israeli chronic pain patients were assessed for pain intensity, sleep and adverse events (AEs) over 240 days. RESULTS: Following the first two weeks, no significant sex differences were found in the effectiveness or safety of MC treatment (p > 0.05). Inhaled Δ9-THC doses did not vary significantly between sexes (p > 0.05) except in the first month of treatment. Pain reduction and sleep improvement were similar for both sexes (p > 0.05). The overall rate of AEs was equal and relatively low at 10% (n = 65, 10% of women and n = 60, 10% of men; χ2 (1) = 0.05, p = 0.820). A secondary analysis of pharmacokinetic data showed no significant differences between sexes in Δ9-THC and its metabolite pharmacokinetics, cardiovascular measures, or AE severity (p > 0.05). CONCLUSIONS: Uniform MC treatment via the Syqe MDI showed no sex differences in short-term effectiveness, safety and pharmacokinetics, nor in long-term effects, under "real-life" conditions. These findings provide insights into MC treatment which may inform clinical practice and policy-making in the field.

Is There Gender Discrimination in Acute Renal Colic Pain Management? A Retrospective Analysis in an Emergency Department Setting.

BACKGROUND: Pain is a widespread problem, affecting both men and women; studies have found that women in the emergency department receive analgesic medication and opioids less often compared with men. AIMS: The aim of this study was to examine the administration and management of analgesics by the medical/paramedical staff in relation to the patients' gender, and thereby to examine the extent of gender discrimination in treating pain. DESIGN: This is a single-center retrospective cohort study that included 824 patients. SETTINGS: Emergency department of tertiary hospital in Israel. PARTICIPANTS/SUBJECTS: The patients stratified by gender to compare pain treatments and waiting times between men and women in renal colic complaint. METHODS: As an acute pain model, we used renal colic with a nephrolithiasis diagnosis confirmed by imaging. We recorded pain level by Visual Analog Scale (VAS) scores and number of VAS examinations. Time intervals were calculated between admissions to different stations in the emergency department. We recorded the number of analgesic drugs administered, type of drugs prescribed, and drug class (opioids or others). RESULTS: A total of 824 patients (414 women and 410 men) participated. There were no significant differences in age, ethnicity, and laboratory findings. VAS assessments were higher in men than in women (6.43 versus 5.90, p = .001, respectively). More men than women received analgesics (68.8% versus 62.1%, p = .04, respectively) and opioids were prescribed more often for men than for women (48.3 versus 35.7%, p = .001). The number of drugs prescribed per patient was also higher in men compared with women (1.06 versus 0.93, p = .03). A significant difference was found in waiting time length from admission to medical examination between non-Jewish women and Jewish women. CONCLUSIONS: We found differences in pain management between genders, which could be interpreted as gender discrimination. Yet these differences could also be attributed to other factors not based on gender discrimination but rather on gender differences.

Gender differences in the comprehension of care plans in an emergency department setting.

BACKGROUND: Previous studies have shown that, in a variety of health care settings, patients often do not understand what health care professionals tell them about their diagnoses and care plans; this is particularly true among male patients. Emergency department (ED) settings present unique challenges to communication with patients due to the rapid pace of activity, substantial changes in personnel over the course of the day and the week, and the need for fast decision-making processes. The aim of our study was to investigate the extent to which patients in an Israeli ED comprehended their plan of care and whether there were gender differences in this regard. METHODS: We conducted a questionnaire-based prospective study, in which patients admitted to the ED at Rabin Medical Center were evaluated during the years 2014-2016. The primary outcome was patients' comprehension of their plan of care, stratified by gender of patients. Plan of care included information related to diagnosis, treatment and discharge instructions. The secondary outcome was patients' satisfaction with the instruction process. RESULTS: One hundred seventy seven ED patients met study criteria and were asked to participate in the study; 85% of them agreed to do so. Overall, 150 ED patients aged 18-80 were recruited [75 men (50%) and 75 women (50%)]. 80% of the respondents reported a satisfactory understanding of their plan of care. Overall, no gender-related differences were found. Differences between men and women concerning satisfaction with the instructions provided by nurses were found among non-Hebrew speakers, but not among Hebrew speakers. CONCLUSION: Contrary to most earlier studies, patients at our ED demonstrated a high degree of self-reported adequate comprehension concerning their plan of care, and overall no gender-related differences were found. These finding may be due in part to improved training of the medical staff to better communicate with the patients and to answer their questions. In addition, patients may feel more comfortable than in the past about asking the medical staff questions regarding their plan of care and diagnosis. The main implication of this study is that physician education programs should continue to emphasize patient-physician communications skills and improving methods for providing patients with information.

[SCIENTIFIC PUBLICATIONS: ON HONORS AND GHOSTS].

INTRODUCTION: The ethics committee at the Sackler Faculty of Medicine, Tel Aviv University deals with complaints which are not necessarily related to teaching or to issues in the realm of the Institutional Review Board (Helsinki Commission). Virtually all complaints reaching the committee are based on disputed authorship of scientific publications. Researchers and clinicians are interested in publishing their research in order to share knowledge but also in order to comply with the dictum "Publish or Perish". They are publishing to enhance their reputation, to improve chances for funding and to increase the likelihood for clinical and academic promotion. Yet, lack of appropriate planning and agreements on authorship ahead of time may lead to frictions, misunderstandings and outright belligerence between authors. The issue of authorship is being addressed by scientific journals, academic institutions and committees of editors. All of them have published appropriate guidelines which form the basis for the work of the ethics committee. We deal with "honorary authorship", that is individuals who are listed as authors, although they have not contributed sufficiently to the research in order to merit authorship and we deal with "Ghost Authorship" that is when contributing researchers are not listed, as they should be among authors of a scientific publication. Specific case studies are presented.

Sex in basic research: concepts in the cardiovascular field.

Women and men, female and male animals and cells are biologically different, and acknowledgement of this fact is critical to advancing medicine. However, incorporating concepts of sex-specific analysis in basic research is largely neglected, introducing bias into translational findings, clinical concepts and drug development. Research funding agencies recently approached these issues but implementation of policy changes in the scientific community is still limited, probably due to deficits in concepts, knowledge and proper methodology. This expert review is based on the EUGenMed project (www.eugenmed.eu) developing a roadmap for implementing sex and gender in biomedical and health research. For sake of clarity and conciseness, examples are mainly taken from the cardiovascular field that may serve as a paradigm for others, since a significant amount of knowledge how sex and oestrogen determine the manifestation of many cardiovascular diseases (CVD) has been accumulated. As main concepts for implementation of sex in basic research, the study of primary cell and animals of both sexes, the study of the influence of genetic vs. hormonal factors and the analysis of sex chromosomes and sex specific statistics in genome wide association studies (GWAS) are discussed. The review also discusses methodological issues, and analyses strength, weaknesses, opportunities and threats in implementing sex-sensitive aspects into basic research.

[Informed consent: going through the motions?].

We review the concept of informed consent in clinical medicine and in research. Informed consent is a complex practice designed to protect the legal rights of the patient, to maintain ethics in support of the patient's autonomy to arrive at his own decisions related to medical interventions, to ensure appropriate quality of care, and to build trust between the physician and the patient regarding medical procedures, medication or clinical research. It must be borne in mind that the patient's signature on a document of informed consent does not automatically imply comprehension. Physicians need to provide the information about the patient's condition, and in the case of research, they need to provide an exhaustive explanation related to benefits and the risks of the research project for the patient and to society. Physicians need to be available to readily answer patients' questions. Signing an informed consent form should not become a mere bureaucratic procedure of "going through the motions". Without emphasis on delivering understandable and relevant information, tailored to the recipient and clarifying that explanations have been properly understood, informed consent becomes but a bureaucratic burden. There is an urgent need to complete the process of conveying information by a structured mechanism aimed to ensure adequate comprehension. Only then will the process of obtaining informed consent become meaningful.

Gender aspects suggestive of gastroparesis in patients with diabetes mellitus: a cross-sectional survey.

BACKGROUND: It is suggested that symptoms related to gastroparesis are more common in female than in male patients with type 2 diabetes mellitus (T2DM). The association between sex and prevalence of symptoms suggestive of gastroparesis among patients with T2DM in Israel has not been reported. The aim of this study was to describe the associations between sex, clinical characteristics, type, severity and prevalence of dyspeptic symptoms in a large population of patients with T2DM in Israel. METHODS: All patients completed a demographic questionnaire and the Gastroparesis Cardinal Symptom Index (GCSI). Data regarding disease duration, medications, complications, recent blood glucose and HbA1c levels were also collected. In this nested case-control study, 173 female and 209 male patients were identified from within a cross-sectional survey of 382 patients with T2DM. Logistic and general linear modeling was used to assess associations between sex, clinical data, and the presence (type and number) of symptoms. RESULTS: Compared to males, female patients with T2DM had a higher body mass index (BMI) (31.9 vs. 29.2; P = 0.001) and HbA1c levels (7.9 vs. 7.5; P = 0.04). A larger proportion of males suffered from peripheral vascular disease (P = 0.02) and ischemic heart disease (P = 0.001). Other disease characteristics did not differ between the sexes. The prevalence of nausea (P = 0.001), early satiety (P = 0.005), loss of appetite (P = 0.002), or presence of any cardinal symptom (P = 0.001) was significantly higher among females. Severity of most cardinal symptoms was also higher in females. The presence of at least one cardinal symptom was more likely among obese females with longer disease duration and poor glycemic control. CONCLUSIONS: Prevalence and severity of symptoms suggestive of gastroparesis is particularly high among obese females with long standing and poorly controlled T2DM.

Fetal sex and intrauterine growth patterns.

OBJECTIVES: To analyze the effect of fetal sex on intrauterine growth patterns during the second and third trimesters. METHODS: We conducted a cross-sectional study of women with uncomplicated singleton pregnancies who underwent sonographic fetal weight estimation during the second and third trimesters in a single tertiary center. The effect of fetal sex on intrauterine growth patterns was analyzed for each of the routine fetal biometric indices (biparietal diameter, head circumference, occipitofrontal diameter, abdominal circumference, and femur length) and their ratios. Sex-specific regression models were generated for these indices and their ratios as a function of gestational age. Sex-specific growth curves were generated from these models for each of the biometric indices and their ratios for gestational weeks 15 to 42. RESULTS: Overall, 12,132 sonographic fetal weight estimations were included in the study. Fetal sex had an independent effect on the relationship between each of the biometric indices and their ratios and gestational age. These effects were most pronounced for biparietal diameter (male/female ratio, 1.021) and the head circumference/femur length and biparietal diameter/femur length ratios (male/female ratios, 1.014 and 1.016, respectively). For the head measurements, these sex-related differences were observed as soon as the early second trimester, whereas for abdominal circumference, the differences were most notable during the late second and late third trimesters. CONCLUSIONS: Female fetuses grow considerably slower than male fetuses, and these differences are observed from early gestation. However, the female fetus is not merely a smaller version of the male fetus, but, rather, there is a sex-specific growth pattern for each of the individual fetal biometric indices. These findings provide support for the use of sex-specific sonographic models for fetal weight estimation as well as the use of sex-specific reference growth charts.

Early first-trimester crown-rump length measurements in male and female singleton fetuses in IVF pregnancies.

OBJECTIVES: The generally higher birth-weight of male newborns compared to female newborns is attributed mainly to intrauterine exposure to testosterone. We aimed to determine if crown-rump length (CRL) differs between male and female fetuses early in the first trimester. METHODS: A retrospective cohort study of 333 women with nondiabetic singleton IVF pregnancies attending a single university-affiliated tertiary medical center in 2000-2007 who underwent CRL measurement before 50 days of pregnancy (date of measurement minus oocyte retrieval date plus 14 days). Data on pregnancy outcome, including fetal sex, were collected by routine follow-up telephone interview and combined with the delivery data. RESULTS: There were 169 female and 164 male fetuses according to the reported fetal sex at delivery. Most of the CRL measurements (68.7%) were performed at an actual gestational age of 43-45 days. On linear regression analysis, male fetal sex was a significant (p = 0.011) predictor of larger CRL: CRL (mm) = -23.851 + GA (days) × 0.621 + 0.334 × Sex (F = 1, M = 2), R(2) = 0.512, p <0.001. A general linear model, adjusted for gestational age (40-50 days), revealed that mean CRL was significantly higher in male than in female fetuses (4.58 ± 0.09 mm, [95% CI: 4.3-4.7] vs 4.24 ± 0.09 mm [4.0-4.4]; p < 0.001). CONCLUSIONS: Male fetuses are larger than female fetuses in the early first trimester. Given that gonadal differentiation has not yet occurred, still unidentified nonhormonal factors are apparently responsible for this difference.

The association between stillbirth and fetal gender.

OBJECTIVE: Stillbirth accounts for approximately 50% of all perinatal deaths. We aimed to characterize the relationship between fetal gender and stillbirths. METHODS: A retrospective cohort study of all stillbirths cases in a tertiary medical center, between 1995 and 2007. Patient's medical charts were reviewed for demographic information, medical data, and assumed etiology for stillbirth. Stillbirth was defined as fetal death after 20 completed weeks of gestation or birth weight above 500 g, excluding cases of fetal death due to elective termination of pregnancy. RESULTS: Overall, during the study period there were 77,120 deliveries, of them the stillbirth rate was 0.14% (n = 105). There were 59 females, 39 males (60.2% vs. 48.5%, p = 0.04) and 7 cases of stillbirth with undetermined gender. There were no differences in the demographic and obstetrical characteristics at diagnosis between women carrying a male versus female stillbirth fetuses. The rate of intra uterine fetal death due to placental abruption was significantly higher for male fetuses (OR = 2.1, 95% CI 1.3-4.5) and the rate of stillbirth due to placental insufficiency was significantly higher for female fetuses (OR = 3.7, 95% CI 1.6-5.1). CONCLUSIONS: Female fetuses are overrepresented in cases of stillbirths compared with male fetuses.

Pregnancy course and outcome following blunt trauma.

OBJECTIVE: To investigate short- and long-term outcome following blunt trauma in pregnancy, and to identify risk factors for adverse pregnancy outcome in these cases. METHODS: A retrospective cohort study of all pregnant women who were admitted following blunt trauma (N=411). Women who experienced immediate complications (N=13) were compared with those who did not (N=398). Pregnancy outcome of women who experienced trauma during pregnancy and did not deliver during the trauma admission (N=303) were compared with a control group of women matched to by maternal age and parity in a 3:1 ratio (N=909). RESULTS: The overall rate of immediate complications was 3.2%, with the most common complications being preterm labor (2.0%) and placental abruption (1.7%). Independent risk factors for immediate complications were higher severity of trauma, multiple gestation, vaginal bleeding and uterine contractions at admission. Patients who experienced trauma were at increased risk for long-term adverse outcome including preterm labor, placental abruption, and perinatal morbidity. Increased trauma severity (ISS ≥ 5) and the need for laparotomy during the trauma hospitalization were independently associated with long-term adverse pregnancy outcome. CONCLUSION: Trauma during pregnancy is associated with both immediate and long-term adverse pregnancy outcome. Women who experience trauma should be followed more closely throughout pregnancy.

Gender and birth trauma in full-term infants.

OBJECTIVE: To investigate the association between gender and birth trauma in full-term infants. METHODS: A retrospective, cohort, case-control study was conducted. All singleton full-term neonates born in 1986-2009 and diagnosed with birth trauma (ICD9-CM codes 767.0-767.9) were identified from the hospital's computerized birth-discharge records. The study group was matched in a 2:1 ration with neonates delivered immediately after each index case of neonatal trauma. RESULTS: Of the 118, 280 singleton full-term infants delivered during the study period, 2876 (24/1000) experienced birth trauma. The most frequent birth traumas were scalp injury (63.9%) and clavicle fracture (32.1%). The overall risk of birth trauma was unrelated to fetal gender. However, fetal male gender was a significant and independent risk factor for scalp injury (OR=1.31, 95%-CI 1.15-1.49), and female fetal gender was a significant and independent risk factor for clavicle fracture (OR=1.27, 95%-CI 1.09-1.49). The significance of these associations persisted even after adjustment for potential confounders including mode of delivery, gestational age, neonatal length, timing of delivery, head circumference, parity, and birth weight. CONCLUSION: Fetal gender appears to be a predisposing risk factor for specific types of birth trauma. Further studies are needed to investigate the reasons for this observation.

[The "30 minutes rule"--always applicable?].

The "30 minute rule" is a clinical guideline of obstetrical organizations in several countries of the Western world. It dictates a lag time of no more than 30 minutes between the decision to terminate a delivery by cesarean section when fetal distress is suspected and the implementation. There is no scientific foundation for this rule and physicians may be unjustly exposed to claims when they fail to comply. In this review, we criticalLy discuss the pertinent literature, the relevant guidelines and propose a modification of the "30-minutes rule", which is aimed to differentiate between emergent and urgent operations.

[To rescue a vanishing obstetric skill--vaginal breech delivery].

In 2000, a large randomized controlled trial was published (Term Breech Trial - TBT). The authors concluded that cesarean section (CS) was safer for newborns in breech presentation than vaginal breech delivery (VBD). This conclusion was endorsed by major professional institutions, was adopted almost immediately by the medical community and led to a wholesale abandonment of planned VBD in the western world, including Israel. In past years, serious criticism has been voiced related to the methodology applied in the TBT and numerous studies have contradicted the recommendations. Subsequently, the professional institutions published revised guidelines with the recommendation that pregnant women with breech presentation should, under certain circumstances, be given the choice between CS and VBD. Yet, in most delivery wards, following a decade of abandonment of VBD, the expertise for this technique had almost vanished. An unbearable situation had materialized: CS increases maternal mortality and morbidity when compared to vaginal delivery but most obstetricians are no longer capable of offering women the choice of VBD. Recently, and with the support of the Israel Societies of Obstetrics and Gynecology and Feto-Maternal Medicine, representatives of 17 obstetrical departments convened and decided on urgent steps to revive VBD, including updating the relevant clinical guidelines and informed consent forms and, most importantly, to issue a call to train obstetricians in VBD. In March 2010, a workshop dedicated to breech delivery was conducted at the Beilinson Hospital, with the representatives of most Israeli hospitals and specialists from abroad. Subsequently, and at the same hospital, a week-long program for VBD was conducted at which approximately 30 obstetricians received hands-on training. Time will show if "turning back the tide" will help to progress into a safer future for women with breech presentation and to annually avoid between 1000 and 2000 needless cesarean sections in Israel.

[Lethal sex].

Asphyxiophilic sex is a form of autoerotic activity, in which the user creates mechanical means (such as hanging or bondage) in order to achieve cerebral hypoxia, which, in turn, enhances sexual, as well as orgasmic, stimulus. Failure of safety mechanisms, created by the user, may lead to instant death as a result of asphyxiation or strangulation. This kind of sexual practice is more prevalent among men than in women. In cases of death, it is difficult to relate it to the sexual practice itself. Suicide and homicide are the main differential diagnoses. Closely related derivatives of asphyxiophilic sex are anesthesiophilia (inhalation of variable volatile substances) and electrophilia (use of electric current during sexual activity)--both also intended to enhance the sexual stimulation. These forms of sexual practice are less prevalent than asphyxiophilia.

The effect of menstrual cycle on platelet aggregation in reproductive-age women.

Our aim was to assess the change in platelet activity along the menstrual cycle. We conducted a prospective observational study. The study group included 16 healthy women with regular menstrual cycles, which were compared to a control group of 14 healthy males. Exclusion criteria were age <18 years or >45 years, use of oral contraceptives or any other forms of hormonal therapy and medical disorders or medications that might affect platelet aggregation. Blood samples were taken from each of the women at four different phases of the menstrual cycle: day 1 +/- 1, day 7 +/- 1, day 14 +/- 1, and day 21 +/- 1. A single blood sample was taken from the males. Platelet aggregation was assessed in whole blood samples using the Multiplate analyzer with three different agonists (ADP, arachidonic acid (AA), and thrombin-receptor activating peptide (TRAP)). Platelet aggregation for each of the women at each of the phases of the menstrual cycle was expressed as the percentage change from the day 1 +/- 1 value. A total of 390 aggregation assays were performed. The mean aggregation activity was significantly higher in females compared with males, irrespective of the agonist used. For the TRAP and the ADP agonists, the relative platelet activity decreased along the menstrual cycle from day 1 towards day 21 and from day 7 towards day 21, respectively, although differences reached statistical significance only for day 21 (-12.4% +/- 3.2%, P < 0.05 for TRAP, and -9.5% +/- 3.9%, P < 0.05 for ADP). When using AA to induce platelet aggregation, the relative platelet activity was highest around the time of ovulation (11.0% +/- 4.7%) and was significantly lower on day 21 (-8.5% +/- 6.7%, P < 0.05). In conclusion, platelet aggregation activity is higher in females compared with males. The association between the phase of the menstrual cycle and platelet activity appears to vary with the type of agonist, but platelet aggregation is consistently lowest in the mid-luteal phase irrespective of the agonist used.

Fetal gender and pregnancy outcome.

OBJECTIVE: To assess the effect of fetal gender on pregnancy outcome. METHODS: Retrospective study of all singleton pregnancies at a tertiary hospital during 1995-2006. RESULTS: Of the 66,387 women studied, 34,367 (51.8%) delivered male and 32,020 (48.2%) delivered female neonates. The rate of preterm delivery (as early as 29 weeks) was higher for male fetuses and was attributed to an increased incidence of spontaneous preterm labor and preterm premature rupture of membranes. Women carrying male fetuses were at increased risk for operative vaginal delivery (OVD) for non-reassuring fetal heart rate, failed OVD and cesarean delivery. Female fetuses were more likely to experience fetal growth restriction (FGR). CONCLUSION: Fetal gender is independently associated with adverse pregnancy outcome. Although the added risk is relatively small, further investigation of the mechanisms underlying this association may contribute to our understanding of the pathophysiology of pregnancy complications such as preterm delivery and FGR.

[The feminization of obstetrics and gynecology].

Contemporary data indicate female dominance of obstetrics and gynecology. The authors sought to look for the effects of this domination on the discipline and further understand the reasons for these effects as reflected from the relevant current literature. Data clearly show a worldwide "creeping" process of female domination in the field of obstetrics and gynecology. Gender bias is present in hiring policies both for residency and afterwards. Female physicians encounter specific gender problems such as pregnancy, maternity leave and the additional burden of taking care of their family. These tasks may interfere with academic medicine. Furthermore, personal characteristics of women, which favor them for patients, may affect their productivity within the framework of community medicine. None of the alleged problems, which were linked to female obstetrician-gynecologists, is irresolvable, assuming professional establishment, as well as government acceptance and proper planning.

Vaginal fetal fibronectin evaluation before and immediately after ultrasonographic vaginal cervical length measurements in symptomatic women at risk of preterm birth: a pilot study.

OBJECTIVE: To determine if vaginal ultrasound for cervical length measurement induces the release of vaginal fetal fibronectin (fFN), leading to a false-positive fFN test. METHODS: Participants included women with singleton pregnancies at 24-34 weeks' gestation who presented with uterine contractions without bleeding or membrane rupture. Women who had had intercourse or underwent pelvic examination less than 24 h previously were excluded. The first fFN test was followed immediately by vaginal ultrasonography with a transvaginal probe (three images per patient) and, thereafter, a second fFN test. RESULTS: The first fFN test was positive in three patients, and in all, the second, post-ultrasound, fFN test was also positive. In all women with a negative baseline fFN test (n = 25), the second, post-ultrasound, fFN test was also negative. CONCLUSION: Vaginal ultrasound examination does not artificially change the fFN status. This is in contrast to common understanding and may permit the performance of ultrasound examination before fFN, which can be restricted to cases of short cervix.