Effectiveness of therapeutic heparin versus prophylactic heparin on death, mechanical ventilation, or intensive care unit admission in moderately ill patients with covid-19 admitted to hospital: RAPID randomised clinical trial.

OBJECTIVE: To evaluate the effects of therapeutic heparin compared with prophylactic heparin among moderately ill patients with covid-19 admitted to hospital wards. DESIGN: Randomised controlled, adaptive, open label clinical trial. SETTING: 28 hospitals in Brazil, Canada, Ireland, Saudi Arabia, United Arab Emirates, and US. PARTICIPANTS: 465 adults admitted to hospital wards with covid-19 and increased D-dimer levels were recruited between 29 May 2020 and 12 April 2021 and were randomly assigned to therapeutic dose heparin (n=228) or prophylactic dose heparin (n=237). INTERVENTIONS: Therapeutic dose or prophylactic dose heparin (low molecular weight or unfractionated heparin), to be continued until hospital discharge, day 28, or death. MAIN OUTCOME MEASURES: The primary outcome was a composite of death, invasive mechanical ventilation, non-invasive mechanical ventilation, or admission to an intensive care unit, assessed up to 28 days. The secondary outcomes included all cause death, the composite of all cause death or any mechanical ventilation, and venous thromboembolism. Safety outcomes included major bleeding. Outcomes were blindly adjudicated. RESULTS: The mean age of participants was 60 years; 264 (56.8%) were men and the mean body mass index was 30.3 kg/m2. At 28 days, the primary composite outcome had occurred in 37/228 patients (16.2%) assigned to therapeutic heparin and 52/237 (21.9%) assigned to prophylactic heparin (odds ratio 0.69, 95% confidence interval 0.43 to 1.10; P=0.12). Deaths occurred in four patients (1.8%) assigned to therapeutic heparin and 18 patients (7.6%) assigned to prophylactic heparin (0.22, 0.07 to 0.65; P=0.006). The composite of all cause death or any mechanical ventilation occurred in 23 patients (10.1%) assigned to therapeutic heparin and 38 (16.0%) assigned to prophylactic heparin (0.59, 0.34 to 1.02; P=0.06). Venous thromboembolism occurred in two patients (0.9%) assigned to therapeutic heparin and six (2.5%) assigned to prophylactic heparin (0.34, 0.07 to 1.71; P=0.19). Major bleeding occurred in two patients (0.9%) assigned to therapeutic heparin and four (1.7%) assigned to prophylactic heparin (0.52, 0.09 to 2.85; P=0.69). CONCLUSIONS: In moderately ill patients with covid-19 and increased D-dimer levels admitted to hospital wards, therapeutic heparin was not significantly associated with a reduction in the primary outcome but the odds of death at 28 days was decreased. The risk of major bleeding appeared low in this trial. TRIAL REGISTRATION: ClinicalTrials.gov NCT04362085.

Heparin for Moderately Ill Patients with Covid-19.

BACKGROUND: Heparin, in addition to its anticoagulant properties, has anti-inflammatory and potential anti-viral effects, and may improve endothelial function in patients with Covid-19. Early initiation of therapeutic heparin could decrease the thrombo-inflammatory process, and reduce the risk of critical illness or death. METHODS: We randomly assigned moderately ill hospitalized ward patients admitted for Covid-19 with elevated D-dimer level to therapeutic or prophylactic heparin. The primary outcome was a composite of death, invasive mechanical ventilation, non-invasive mechanical ventilation or ICU admission. Safety outcomes included major bleeding. Analysis was by intention-to-treat. RESULTS: At 28 days, the primary composite outcome occurred in 37 of 228 patients (16.2%) assigned to therapeutic heparin, and 52 of 237 patients (21.9%) assigned to prophylactic heparin (odds ratio, 0.69; 95% confidence interval [CI], 0.43 to 1.10; p=0.12). Four patients (1.8%) assigned to therapeutic heparin died compared with 18 patients (7.6%) assigned to prophylactic heparin (odds ratio, 0.22; 95%-CI, 0.07 to 0.65). The composite of all-cause mortality or any mechanical ventilation occurred in 23 (10.1%) in the therapeutic heparin group and 38 (16.0%) in the prophylactic heparin group (odds ratio, 0.59; 95%-CI, 0.34 to 1.02). Major bleeding occurred in 2 patients (0.9%) with therapeutic heparin and 4 patients (1.7%) with prophylactic heparin (odds ratio, 0.52; 95%-CI, 0.09 to 2.85). CONCLUSIONS: In moderately ill ward patients with Covid-19 and elevated D-dimer level, therapeutic heparin did not significantly reduce the primary outcome but decreased the odds of death at 28 days. Trial registration numbers: NCT04362085 ; NCT04444700.

Multiple endocrine neoplasia 2 in Cyprus: evidence for a founder effect.

PURPOSE: Multiple endocrine neoplasia type 2 (MEN2) affects patients with RET proto-oncogene mutations. This cohort study refers to patients who were diagnosed with familial medullary thyroid carcinoma (MTC) and underwent RET genetic testing in Cyprus between years 2002 and 2017. METHODS AND PATIENTS: Forty patients underwent RET testing by Sanger sequencing of exons 10-11 and 13-16. Genotyping with STR genetic markers flanking the RET gene along with Y-chromosome genotyping and haplogroup assignment was also performed. RESULTS: RET mutations were identified in 40 patients from 11 apparently unrelated Cypriot families and two non-familial sporadic cases. Nine probands (69.2%) were heterozygous for p.Cys618Arg, one (7.7%) for p.Cys634Phe, one (7.7%) for the somatic delE632-L633 and two (15.4%) for p.Met918Thr mutations. The mean age at MTC diagnosis of patients carrying p.Cys618Arg was 36.8 ± 14.2 years. The age of pheo diagnosis ranged from 26 to 43 years and appeared simultaneously with MTC in 5/36 (13.9%) cases. The high frequency of the p.Cys618Arg mutation suggested a possible ancestral mutational event. Haplotype analysis was performed in families with and without p.Cys618Arg. Six microsatellite markers covering the RET gene and neighboring regions identified one core haplotype associated with all patients carrying p.Cys618Arg mutation. CONCLUSIONS: The mutation p.Cys618Arg is by far the most prevalent mutation in Cyprus followed by other reported mutations of variable clinical significance. The provided molecular evidence speculates p.Cys618Arg mutation as an ancestral mutation that has spread in Cyprus due to a possible founder effect.

To which countries do European psychiatric trainees want to move to and why?

BACKGROUND: There is a shortage of psychiatrists worldwide. Within Europe, psychiatric trainees can move between countries, which increases the problem in some countries and alleviates it in others. However, little is known about the reasons psychiatric trainees move to another country. METHODS: Survey of psychiatric trainees in 33 European countries, exploring how frequently psychiatric trainees have migrated or want to migrate, their reasons to stay and leave the country, and the countries where they come from and where they move to. A 61-item self-report questionnaire was developed, covering questions about their demographics, experiences of short-term mobility (from 3 months up to 1 year), experiences of long-term migration (of more than 1 year) and their attitudes towards migration. RESULTS: A total of 2281 psychiatric trainees in Europe participated in the survey, of which 72.0% have 'ever' considered to move to a different country in their future, 53.5% were considering it 'now', at the time of the survey, and 13.3% had already moved country. For these immigrant trainees, academic was the main reason they gave to move from their country of origin. For all trainees, the overall main reason for which they would leave was financial (34.4%), especially in those with lower (<500€) incomes (58.1%), whereas in those with higher (>2500€) incomes, personal reasons were paramount (44.5%). CONCLUSIONS: A high number of psychiatric trainees considered moving to another country, and their motivation largely reflects the substantial salary differences. These findings suggest tackling financial conditions and academic opportunities.

Effects of food allergy on the dietary habits and intake of primary schools' Cypriot children.

SUMMARY: Aim. To determine whether food allergy affects overall dietary intake and food choices in Cypriot primary school children. Methods. As part of the first epidemiological study in Cyprus on food allergy in primary school children, two 24-hour recalls (one from a week and one from a weekend day) of twenty-eight food allergic children (21 girls) and thirty healthy children (20 girls) aged 6-11 years old, were analysed and compared regarding their macro- and micronutrient content, food choices and meal distribution. Results. Significant differences between the two subgroups of children were estimated regarding the total energy intake and macronutrients, where food allergic children were found to consume in lower quantities, as well as for calcium, niacin, fiber and vitamin E. Food allergic children were also found to avoid combining foods from the various food groups in their meals, and to prefer specific food products from each category, whereas they consumed higher amounts of sugar and fructose. Conclusion. Food allergy in Cypriot food allergic children impacts on both the quality and quantity of food choices, probably due to lack of nutritional education regarding proper elimination diet and alternative nutrient sources.

Is beverage intake related to overweight and obesity in school children?

BACKGROUND AND AIM: Recently, considerable attention has been given to beverage intake as a source of calories which may be linked to pediatric obesity. The purpose of our study was to evaluate the beverage intake in school children and adolescents aged 7 to 15 years old. METHODS: Six hundred and seven (607) out of 655 children participated in the study. One hundred percent fruit juice were classified those beverages that contain 100% fruit juice, without sweetener. Sweetened sugar beverages (SSBs) were included (fruit drinks sweetened fruit juice, fruit-flavored drink or drink that contained fruit juice in part, sweeten soft drinks, coffee, and tea). RESULTS: Around 84% of subjects consumed water while 81% of children who were included in the analysis consumed milk, 49.5% consumed 100% fruit juice, and 79.4 % SSBs. Whole milk was consumed by 40.9% of school children. Skim milk and 1% milk were consumed by 3.6% and 4.7% of the children, respectively. Children and adolescents consuming SSBs were 2.57 (95% CI: 1.06, 3.38) times more likely to become obese compared to normal peers. CONCLUSION: Sugar beverage drinks but not 100% fruit juices and milk are associated with obesity. Further studies investigating the relationship among beverage consumption, total energy intake, and development of overweight are needed.

Effects of diet and exercise in 337 overweight/obese adults.

BACKGROUND AND AIMS: The purpose of the study was to determine for the first time the effects of a weight loss diet with or without exercise on body fat levels and other anthropometrical characteristics in overweight and obese Cypriot adults. METHODS: Three hundred and thirty seven overweight and obese subjects were assigned randomly to either a diet only (DO) or diet and exercise group (DE) for an 18-week period. Both groups received an energy reduced diet of 1500 ± 200 Kcal. Furthermore, the DE group received specific dietary and activity guidelines involving a moderate intensity activity level included any of the following 3 criteria of ACSM guidelines and behavior modification consultation. All data analyses were performed by using the SPSS(v. 16.5) and the level of statistical significance was set at p < 0.05. RESULTS: No significant differences were observed in both DO and DE groups during baseline period. During the intervention period weight, BMI and WC decreased significantly in DO group (p<0.001). In addition, body fat levels were found to be significantly reduced (p<0.001) in the DE group compared with the DO group. In multiple regression analysis Body fat levels were independently associated with weight (Beta: 0.569, 95%CI: 0.157-1.296, P<0.001) BMI (Beta: 0.295, 95%CI:0.088-1.214, P<0.01) and WC (Beta:0.206, 95%CI:0.095-0.954, P<0.001) after adjustment of age and gender. CONCLUSIONS: Despite the reduced effects of diet alone on body weight, BMI and WC, combining a reduced diet with exercise improves also BF levels which may have important benefits on several diseases later in life.

Risk factors of obesity in a cohort of 1001 Cypriot adults: An epidemiological study.

BACKGROUND AND AIMS: To measure the prevalence of overweight and obesity in adults in the Republic of Cyprus, and to evaluate and relate possible obesity risk factors of the adult Cypriot population. METHODS: This is an epidemiological cross-sectional study on a stratified random sample of 1001 (48.5% males-51.5% females) subjects, aged 18-80 years old. Anthropometric, biochemical, and dietary/lifestyle characteristics included in the study. RESULTS: The prevalence of overweight (Ow) and obesity (Ob) was 46.9% and 28.8% for males and 26% and 27% for females, respectively. Overweight and obese subjects were found to have statistically significant higher levels of Body Mass Index (p<0.001), Waist circumference (p<0.001), Total serum cholesterol (p<0.001), Low density lipoprotein (p<0.005), Glucose (p<0.007) and Triglycerides (p<0.001) compared to normal peers. In addition, Ow and Ob participants consumed significantly lower levels of fruits and vegetables (p<0.001), exercised less time/d (p<0.001) and smoke more cigarettes/d (p<0.001), compared to normal subjects, respectively. In multiple regression analysis of factors associated with overweight and obesity, Waist Circumference (beta: 1.132, p<0.001), Glucose (beta: 0.892, p<0.045), alcohol consumption (beta: 0.563, p<0.001), and exercise levels (beta: -0.444, p<0.001), were the most significant ones. CONCLUSION: The prevalence of overweight and obesity is very high in Cypriot adults. The current study also revealed a significant positive relation of Ow and Ob with waist circumference, high blood glucose levels and increased consumption of alcohol and a negative one with decreased levels of exercise.

Differences in clinical presentation of deep vein thrombosis in men and women.

BACKGROUND: As assessment of clinical pretest probability is the first step in the diagnostic evaluation of deep vein thrombosis (DVT), it is important to know if the clinical features of DVT are the same in men and women. OBJECTIVES: To compare the prevalence and clinical characteristics of DVT, and the accuracy of clinical pretest probability assessment, between men and women with suspected DVT. METHODS: A retrospective analysis of individual patient data from three prospective studies by our group that evaluated diagnostic tests for a suspected first episode of DVT. Clinical characteristics, clinical pretest probability for DVT, and prevalence and extent of DVT was assessed in a total of 1838 outpatients. RESULTS: The overall prevalence of DVT was higher in men than in women (14.4% vs. 9.4%) (P = 0.001). The prevalence of DVT was higher in men than in women who were categorized as having a clinical pretest probability that was low (6.9% vs. 3.5%; P = 0.025) or moderate (16.9% vs. 8.7%; P = 0.04), but similar in patients in the high category (40.2% vs. 44.0%; P = 0.6). In patients diagnosed with DVT, swelling of the entire leg occurred more often (41.5% vs. 15.7%; P < 0.001), and thrombosis was more extensive (involvement of both popliteal and common femoral veins in 47.9% vs. 21.6%), in women than in men. CONCLUSIONS: In outpatients with suspected DVT, the overall prevalence of thrombosis and the prevalence of thrombosis in those with a low or a moderate clinical pretest probability were higher in men than in women.

Affecting factors in second language learning.

The present study investigated the influence of sex, handedness, level in second language (L2) and Faculty choice on the performance of phonological, syntactical and semantic tasks in L2. Level in L2 and sex were the most affecting factors. Subjects who achieved higher scores on L2 tasks had strong second language aptitude skills since they were those who had obtained a professional degree in the second language. Females performed better than males in syntax and semantics which is explained by the general female superiority on verbal tasks based on differences in hemispheric specialization for language functions between the sexes. Handedness and Faculty choice on the part of the participants had an impact on our results but only when combined with other factors.

Potential drug interaction between simvastatin and danazol causing rhabdomyolysis.

Rhabdomyolysis is a life-threatening clinical and biochemical syndrome that results from injury to skeletal muscle. Hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) have been associated with myopathy and rhabdomyolysis. Although rhabdomyolysis is a rare adverse event associated with this class of drugs, their prevalent use in the management of dyslipidemia makes it increasingly important for clinicians to understand the nature of this condition. Rhabdomyolysis can occur with all statins when used alone and particularly when combined with other drugs that are themselves myotoxic or that elevate the concentration of the statin. Statins are particularly susceptible to the latter effect because of their metabolism by the CYP450 system and their low oral bioavailability. In this report, we describe a case of rhabdomyolysis and acute renal failure secondary to the interaction between danazol and simvastatin.

Analysis of human CYP7A1 mRNA decay in HepG2 cells by reverse transcription-polymerase chain reaction.

The conversion of cholesterol to bile acids is the major pathway through which cholesterol is removed from the body. The initial and rate-limiting step in this catabolic pathway is catalyzed by the liver-specific enzyme cholesterol 7alpha-hydroxylase (CYP7A1). The HepG2 cell line has been used as a model to study human CYP7A1. The levels of CYP7A1 mRNA, however, are quite low in this cell line and require the use of poly(A)+ mRNA for detection using standard Northern analysis. As an alternative, we established a reverse transcription-polymerase chain reaction (RT-PCR) assay that can be used to study CYP7A1 mRNA in HepG2 cells. Using RT-PCR, we analyzed the influence of cell culture conditions on CYP7A1 mRNA levels. We observed an increase in CYP7A1 mRNA levels as the density of the cell culture increased. This rise in CYP7A1 was accompanied by a reciprocal drop in the levels of the proto-oncogene c-myc. Since c-myc expression is strongly associated with cell growth status, this inverse relationship suggests that conditions that favor reduced cell proliferation result in higher levels of CYP7A1 expression. We also established the validity of using RT-PCR for the measurement of mRNA decay rates using c-myc and glyceraldehyde-3-phosphate dehydrogenase mRNAs as a model: The same half-life value was obtained for the c-myc mRNA using either Northern analysis or RT-PCR. Using our RT-PCR method we determined that human CYP7A1 mRNA decays with a half-life of 4.6 +/- 0.9 h (n = 8) in HepG2 cells. We show that the protein synthesis inhibitor cycloheximide prolonged the CYP7A1 mRNA half-life, suggesting that translation is required for mRNA decay. Dexamethasone treatment, however, did not alter CYP7A1 mRNA decay rate but it increased CYP7A1 steady-state mRNA levels, suggesting that the effect of this glucocorticoid in HepG2 cells may be transcriptional.

The combination of testosterone undecanoate with tamoxifen citrate enhances the effects of each agent given independently on seminal parameters in men with idiopathic oligozoospermia.

OBJECTIVE: To evaluate the effects of combined tamoxifen citrate and T undecanoate treatment on seminal parameters in men with idiopathic oligozoospermia. DESIGN: Prospective randomized clinical study. SETTING: A state hospital tertiary clinic. PATIENT(S): Eighty oligozoospermic men were included in the protocol. INTERVENTION(S): Patients were randomized to receive placebo, T undecanoate (40 mg three times per day), tamoxifen citrate (10 mg two times per day), or T undecanoate plus tamoxifen citrate. RESULT(S): Tamoxifen citrate plus T undecanoate treatment produced a satisfactory improvement of total sperm number, motility, and functional sperm fraction after 3 and 6 months. Comparisons with other active treatment groups showed significantly higher increment values for motility and functional fraction, whereas aniline, acrosine, and free L-carnitine also were markedly better in the combination treatment group. CONCLUSION(S): These results indicate that the combination of tamoxifen citrate with T undecanoate not only improves significantly important seminal parameters but also compares favorably with the single treatments used. Therefore, this combination deserves a place as a first line of treatment in idiopathic oligozoospermia.

Seminal volume and total sperm number trends in men attending subfertility clinics in the greater Athens area during the period 1977-1993.

The trends for such important parameters of male fertility as seminal volume and total sperm number were assessed in men living permanently in the Greater Athens area over a prolonged period of time. To this end, the records of three andrological laboratories employing the same method for semen evaluation were analysed retrospectively. Out of 23,850 men examined from 1977 to 1993 (17 years) for couple subfertility, a total of 2385 (10%) were selected for evaluation by a randomization procedure. Analysis of the data included (i) estimation of mean seminal volume and total sperm number per year, (ii) assessment of percentage frequency distribution of each seminal parameter and (iii) evaluation of seminal volume and total sperm number changes in relation to the year of observation and age of the subjects. A significant decrease (P < 0.01) of total sperm number was observed over the years with a mean (+/-SEM) of 154.3 +/- 19.2 x 10(6) at the beginning (1977), dropping to 130.1 +/- 13.3 x 10(6) in the final year (1993). Mean seminal volume was lower in the final year of observation, but its difference from the initial year value was not significant. Frequency distribution analysis showed a marked decline in the 240-400 x 10(6) sub-set of the range of sperm number values from 16.9 +/- 4.5% (1977) to 10.6 +/- 1.6% in the final year (P < 0.01). Multiple regression analysis of seminal volume, total sperm number, age and year of assessment revealed a significant decline of the two seminal parameters along the years of observation (P < 0.05 and P < 0.0001 respectively). Over the same period, a marked deterioration of some air pollution indices was observed in that area. It is concluded that in this racially and ethnically homogeneous sample of men, living under the same environmental conditions, a significant decline in seminal volume and total sperm number occurred over the 17 years of observation.

Comparison of different methods for the investigation of antisperm antibodies on spermatozoa, in seminal plasma and in serum.

Since there is no gold standard for the diagnosis of immunological infertility, comparison between different methods and of their results with biological tests for the detection of antisperm antibodies must be used in defining the most reliable and clinically relevant method. We have evaluated the results of direct (n = 100) and indirect tests in serum (n = 140) and seminal plasma (n = 100) using the SpermMAR and Immunobead (IB) techniques for the detection of sperm antibodies of the immunoglobulin (Ig) classes G, A and M, and we have compared the results with those of the tray agglutination test and the adenosine triphosphate release cytotoxicity test. Results indicate the higher specificity and sensitivity of the SpermMAR results for IgG and IgA, as compared to the outcome of the IB test. It appears that the IB test for IgA may detect non-specific antibodies in serum. Little information is obtained from the tray agglutination test in seminal plasma, and the indirect SpermMar test for IgG in seminal plasma was the only independent variable associated with the outcome of the former test. Since the SpermMAR tests for IgG and IgA are more accurate and biologically relevant, as well as easier to perform than the respective IB tests, the former must be considered the method of first choice.