From cultivation to cancer: formation of N-nitrosamines and other carcinogens in smokeless tobacco and their mutagenic implications.

Tobacco use is a major cause of preventable morbidity and mortality globally. Tobacco products, including smokeless tobacco (ST), generally contain tobacco-specific N-nitrosamines (TSNAs), such as N'-nitrosonornicotine (NNN) and 4-(methylnitrosamino)-1-(3-pyridyl)-butanone (NNK), which are potent carcinogens that cause mutations in critical genes in human DNA. This review covers the series of biochemical and chemical transformations, related to TSNAs, leading from tobacco cultivation to cancer initiation. A key aim of this review is to provide a greater understanding of TSNAs: their precursors, the microbial and chemical mechanisms that contribute to their formation in ST, their mutagenicity leading to cancer due to ST use, and potential means of lowering TSNA levels in tobacco products. TSNAs are not present in harvested tobacco but can form due to nitrosating agents reacting with tobacco alkaloids present in tobacco during certain types of curing. TSNAs can also form during or following ST production when certain microorganisms perform nitrate metabolism, with dissimilatory nitrate reductases converting nitrate to nitrite that is then released into tobacco and reacts chemically with tobacco alkaloids. When ST usage occurs, TSNAs are absorbed and metabolized to reactive compounds that form DNA adducts leading to mutations in critical target genes, including the RAS oncogenes and the p53 tumor suppressor gene. DNA repair mechanisms remove most adducts induced by carcinogens, thus preventing many but not all mutations. Lastly, because TSNAs and other agents cause cancer, previously documented strategies for lowering their levels in ST products are discussed, including using tobacco with lower nornicotine levels, pasteurization and other means of eliminating microorganisms, omitting fermentation and fire-curing, refrigerating ST products, and including nitrite scavenging chemicals as ST ingredients.

Impact of the WHO FCTC on non-cigarette tobacco products.

INTRODUCTION: This paper investigates to what extent Framework Convention on Tobacco Control (FCTC) parties have successfully implemented regulatory measures against non-cigarette tobacco product (NCTP) use, considers the challenges and peculiarities in applying such regulations and proposes effective means. DATA AND METHODS: This review was based on many sources mainly: International Legal Consortium, International Tobacco Control, Campaign for Tobacco-Free Kids, FCTC, expert group visits and published literature. FINDINGS AND CONCLUSION: The FCTC provided a framework that applies to all forms of tobacco and this encouraged some parties to adopt control measures against NCTP and to incorporate them into their national tobacco control plans. Although a number of countries have adopted measures specifically targeted towards smokeless and waterpipe tobacco, greater global progress is needed. The strongest achievements have been in protection from exposure to tobacco smoke; controlling advertising, promotion and sponsorship; controlling sales to and by minors; education, communication and public awareness; and packaging and labelling of NCTP. Countries which adopted broad definitions of tobacco products have demonstrated encouraging trends in curbing their use. Future work should address the deep-rooted social acceptance of NCTP, the laxity in their control, their exclusion from regulations in some countries and the failure to subject them to increased taxation. Control measures should also specifically target the initiation risk to youth and adolescents and all factors that contribute to that such as banning flavourings and promotions through social media. Stronger global surveillance of NCTP use, tracking of policy implementation and evaluation of policy impact will provide important evidence to assist parties in fully implementing the FCTC to control their use.

Validation study of using the free volume approximation to confined thermotropic and lyotropic liquid-crystalline fluids.

We examined the accuracy of the free volume approximation (FVA) to calculate the isotropic-nematic (IN) transition properties of thermotropic and lyotropic rods between two parallel hard walls. This approximation has been proposed to ease the calculation of the confined systems. It approximates the free energy of the confined particles with a bulk free energy. It predicts a special point for these two types of liquid crystals where the first-order IN transition changes to the second one by decreasing either the temperature, the density or the pore width. This prediction is in contradiction (in spite of some qualitative agreement) with those of the other publications where the authors note that the discontinuous transition terminates at the critical point when the walls are completely impenetrable.

Role of Extended Thromboprophylaxis After Abdominal and Pelvic Surgery in Cancer Patients: A Systematic Review and Meta-Analysis.

BACKGROUND: Abdominopelvic cancer surgery increases the risk of postoperative venous thromboembolism (VTE). Low-molecular-weight heparin (LMWH) thromboprophylaxis is recommended, and the role of extended thromboprophylaxis (ETP) is controversial. We performed a systematic review to determine the effect of ETP on deep vein thrombosis (DVT), pulmonary embolism (PE), major bleeding, and all-cause mortality after abdominal or pelvic cancer surgery. METHODS: A search of the MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials was undertaken, and studies were included if they compared extended duration (2-6 weeks) with conventional duration of thromboprophylaxis (2 weeks or less) after cancer surgery. Pooled relative risk (RR) was estimated using a random effects model. RESULTS: Seven randomized and prospective studies were included, comprising 4807 adult patients. ETP was associated with a significantly reduced incidence of all VTEs [2.6 vs. 5.6 %; RR 0.44, 95 % confidence interval (CI) 0.28-0.70, number needed to treat (NNT) = 39] and proximal DVT (1.4 vs. 2.8 %; RR 0.46, 95 % CI 0.23-0.91, NNT = 71). There was no statistically significant difference in the incidence of symptomatic PE (0.8 vs. 1.3 %; RR 0.56, 95 % CI 0.23-1.40), major bleeding (1.8 vs. 1.0 %; RR 1.19, 95 % CI 0.47-2.97), and all-cause mortality (4.2 vs. 3.6 %; RR 0.79, 95 % CI 0.47-1.33). None of the outcomes differed if randomized trials were analyzed independently. CONCLUSIONS: ETP after abdominal or pelvic surgery for cancer significantly decreased the incidence of all VTEs and proximal DVTs, but had no impact on symptomatic PE, major bleeding, or 3-month mortality. ETP should be routinely considered in the setting of abdominal and pelvic surgery for cancer patients.

Effect of Different Doses of Oral Cholecalciferol on Serum 1,25(OH)2D in Vitamin D Deficient Schoolchildren.

Data regarding 1,25-dihydroxycholecalciferol in adolescents are limited. We aimed to determine serum levels of this active metabolite of vitamin D and the effects of different doses of vitamin D on its concentration in schoolchildren with high prevalence of vitamin D deficiency. In a previously published randomized double-blind, placebo-controlled trial, 210 subjects, aged 14-20 years, were assigned to 3 regimens of vitamin D treatment: group A (n=70) received 50 000 U oral cholecalciferol monthly, group B (n=70), 50 000 U bimonthly, and group C (n=70), placebo. Serum 25(OH)D, calcium, parathyroid hormone, and bone markers were measured at baseline and after 2 and 5 months of treatment. In the present study, serum levels of 1,25(OH)2D were measured in 97 boys and 95 girls. At baseline, girls had significantly higher concentrations of 1,25(OH)2D than boys (36, IQR: 24, 63 vs. 30, IQR: 15, 57.5 pmol/l; p<0.01). There was no significant correlation between serum levels of 25(OH)D and 1,25(OH)2D in the total population (Spearman rho=- 0.111; p=0.126), boys (Spearman rho=0.008; p=0.941), and girls (Spearman rho=0.036; p=0.729). Also, 1,25(OH)2D values did not change over time in different study groups. Moreover, total and sex-stratified analysis did not show any significant difference between different groups at different times of the study period. In an adolescent population with high prevalence of hypovitaminosis D especially in girls, 1,25(OH)2D values were higher in girls than boys. There was no significant change in 1,25(OH)2D concentrations with different doses of vitamin D.

ST1926, an orally active synthetic retinoid, induces apoptosis in chronic myeloid leukemia cells and prolongs survival in a murine model.

The tyrosine kinase inhibitor, imatinib, is the first line of treatment for chronic myeloid leukemia (CML) patients. Unfortunately, patients develop resistance and relapse due to bcr-abl point mutations and the persistence of leukemia initiating cells (LIC). Retinoids regulate vital biological processes such as cellular proliferation, apoptosis, and differentiation, in particular of hematopoietic progenitor cells. The clinical usage of natural retinoids is hindered by acquired resistance and undesirable side effects. However, bioavailable and less toxic synthetic retinoids, such as the atypical adamantyl retinoid ST1926, have been developed and tested in cancer clinical trials. We investigated the preclinical efficacy of the synthetic retinoid ST1926 using human CML cell lines and the murine bone marrow transduction/transplantation CML model. In vitro, ST1926 induced irreversible growth inhibition, cell cycle arrest and apoptosis through the dissipation of the mitochondrial membrane potential and caspase activation. Furthermore, ST1926 induced DNA damage and downregulated BCR-ABL. Most importantly, oral treatment with ST1926 significantly prolonged the longevity of primary CML mice, and reduced tumor burden. However, ST1926 did not eradicate LIC, evident by the ability of splenocytes isolated from treated primary mice to develop CML in untreated secondary recipients. These results support a potential therapeutic use of ST1926 in CML targeted therapy.

The validity of ICD codes coupled with imaging procedure codes for identifying acute venous thromboembolism using administrative data.

The purpose of this study was to evaluate the accuracy of using a combination of International Classification of Diseases (ICD) diagnostic codes and imaging procedure codes for identifying deep vein thrombosis (DVT) and pulmonary embolism (PE) within administrative databases. Information from the Alberta Health (AH) inpatients and ambulatory care administrative databases in Alberta, Canada was obtained for subjects with a documented imaging study result performed at a large teaching hospital in Alberta to exclude venous thromboembolism (VTE) between 2000 and 2010. In 1361 randomly-selected patients, the proportion of patients correctly classified by AH administrative data, using both ICD diagnostic codes and procedure codes, was determined for DVT and PE using diagnoses documented in patient charts as the gold standard. Of the 1361 patients, 712 had suspected PE and 649 had suspected DVT. The sensitivities for identifying patients with PE or DVT using administrative data were 74.83% (95% confidence interval [CI]: 67.01-81.62) and 75.24% (95% CI: 65.86-83.14), respectively. The specificities for PE or DVT were 91.86% (95% CI: 89.29-93.98) and 95.77% (95% CI: 93.72-97.30), respectively. In conclusion, when coupled with relevant imaging codes, VTE diagnostic codes obtained from administrative data provide a relatively sensitive and very specific method to ascertain acute VTE.

Health effects associated with waterpipe smoking.

OBJECTIVE: It is widely held that waterpipe smoking (WPS) is not associated with health hazards. However, several studies have documented the uptake of several toxicants and carcinogens during WPS that is strongly associated with harmful health effects. This paper reviews the literature on the health effects of WPS. DATA SOURCES: Three databases-PubMed, MEDLINE and EMBASE-were searched until August 2014 for the acute and long-term health effects of WPS using the terms 'waterpipe' and its synonyms (hookah, shisha, goza, narghileh, arghileh and hubble-bubble) in various spellings. STUDY SELECTION: We included original clinical studies, case reports and systematic reviews and focused on clinical human studies. ∼10% of the identified studies met the selection criteria. DATA EXTRACTION: Data were abstracted by all three authors and summarised into tables. Abstracted data included study type, results and methodological limitations and were analysed jointly by all three authors. DATA SYNTHESIS: WPS acutely leads to increased heart rate, blood pressure, impaired pulmonary function and carbon monoxide intoxication. Chronic bronchitis, emphysema and coronary artery disease are serious complications of long-term use. Lung, gastric and oesophageal cancer are associated with WPS as well as periodontal disease, obstetrical complications, osteoporosis and mental health problems. CONCLUSIONS: Contrary to the widely held misconception, WPS is associated with a variety of adverse short-term and long-term health effects that should reinforce the need for stronger regulation. In addition, this review highlights the limitations of the published work, which is mostly cross-sectional or retrospective. Prospective studies should be undertaken to assess the full spectrum of health effects of WPS, particularly in view of its growing popularity and attractiveness to youth.

A comparative study of systemic carcinogen exposure in waterpipe smokers, cigarette smokers and non-smokers.

BACKGROUND: In the past decade, waterpipe smoking-also known as hookah, shisha, narghileh-has increased among youth. The scarcity of rigorous studies linking waterpipe smoking to smoking-related diseases has hindered policy and regulatory efforts to confront the waterpipe epidemic. This study compares systemic carcinogen exposure between independent groups of exclusive waterpipe smokers, cigarette smokers and non-smokers. METHODS: This study was conducted at the Syrian Center for Tobacco Studies (SCTS) in Aleppo, Syria, between 2010 and 2011. First morning urinary samples were collected from three groups of subjects; exclusive daily waterpipe smokers (n=24), exclusive daily cigarette smokers (n=23), and non-smokers (n=28). These samples were analysed for carcinogenic tobacco-specific nitrosamines 4-(methylnitrosamino)-1-(3-pyridyl)-1- butanol (NNAL) using liquid chromatography-tandem mass spectrometry (LC-MS/MS). RESULTS: Our results show that waterpipe smokers are exposed to about 5-10 times greater NNAL than non-smokers. Mean (95% CI) free and total NNAL was 0.7 (0.3 to 1. 4) and 3.9 (1.6 to 9.5) pg/mL urine for non-smokers, 8.4 (4.8 to 14.8) and 33.0 (21.6 to 50.6) pg/mL urine for waterpipe smokers, and 10.7 (5.0 to 22.6) and 46.8 (27.6 to 79.3) pg/mL urine for cigarette smokers (p<0.001 for all comparisons). Daily waterpipe smokers were less exposed to NNAL than daily cigarette smokers, although the difference did not reach statistical significance for all measurements. CONCLUSIONS: These results provide the clearest indication to date about systemic exposure to harmful carcinogens associated with long-term waterpipe smoking. Such evidence can support policy and regulatory efforts designed to confront the emerging global waterpipe epidemic, as well as drive interventions aimed at increasing the public awareness about the cancer risk associated with waterpipe smoking.

The effects of exposure duration to optimal concentration of 2-phenoxyethanol on primary and secondary stress responses in kutum (Rutilus frisii kutum).

The goal of this study was to assess the anaesthetic induction and recovery time in kutum (Rutilus frisii kutum) after exposure to various concentrations (0.1, 0.3, 0.5, 0.7 and 0.9 ml/l) of 2-PE as an anaesthetic, as well as the effects of optimal concentration (0.7 ml/l) of 2-PE in relation to different exposure time (3, 10, 15 min) on some haematological and serum biochemical indices in this species. Moreover, the effects of 0.7 ml/l on blood parameters were assessed 24 h after the longest exposure. Significant increase was determined in Hb, MCH and MCHC after 10-min exposure to 2-PE (p < 0.05). Moreover, Hct, Hb and RBC levels increased significantly after 15 min-exposure to 2-PE (p < 0.05). There were no prominent changes in WBC and MCV. The plasma concentrations of glucose, cholesterol and cortisol increased significantly after 10- and 15-min exposure to 2-PE (p < 0.05) compared with the control group and all other exposure times. The activity of ALT and AST were significantly increased after 10- and 15-min exposure respectively (p < 0.05). In this study, it appears that anaesthetizing kutum with 2-PE at 0.7 ml/l for 3 min had no effect on the stress markers.

Effective targeting of chronic myeloid leukemia initiating activity with the combination of arsenic trioxide and interferon alpha.

Imatinib is the standard of care in chronic meloid leukemia (CML) therapy. However, imatinib is not curative since most patients who discontinue therapy relapse indicating that leukemia initiating cells (LIC) are resistant. Interferon alpha (IFN) induces hematologic and cytogenetic remissions and interestingly, improved outcome was reported with the combination of interferon and imatinib. Arsenic trioxide was suggested to decrease CML LIC. We investigated the effects of arsenic and IFN on human CML cell lines or primary cells and the bone marrow retroviral transduction/transplantation murine CML model. In vitro, the combination of arsenic and IFN inhibited proliferation and activated apoptosis. Importantly, arsenic and IFN synergistically reduced the clonogenic activity of primary bone marrow cells derived from CML patients. Finally, in vivo, combined interferon and arsenic treatment, but not single agents, prolonged the survival of primary CML mice. Importantly, the combination severely impaired engraftment into untreated secondary recipients, with some recipients never developing the disease, demonstrating a dramatic decrease in CML LIC activity. Arsenic/IFN effect on CML LIC activity was significantly superior to that of imatinib. These results support further exploration of this combination, alone or with imatinib aiming at achieving CML eradication rather than long-term disease control.

ASPL-TFE3 translocation in vulvovaginal alveolar soft part sarcoma.

Alveolar soft part sarcoma of the vulvovaginal region is limited to only 8 reported vaginal cases and 1 vulvar case in the English literature. The histogenesis of the tumor remains intriguing with postulates favoring a myogenic versus nonmyogenic origin. A reciprocal translocation for ASPL-TFE3 gene fusion, frequently detected in ~90% of cases, combined with TFE3 protein immunoexpression are highly sensitive and specific methods for diagnostic confirmation. The current report describes a unique case of vulvovaginal alveolar soft part sarcoma showing the classic morphologic features with documentation of TFE3 protein expression and the ASPL-TFE3 gene rearrangement. Furthermore, a brief review of the literature of vulvar and vaginal alveolar soft part sarcoma cases with the various treatment modalities is outlined.

Multiple Myeloma: A Personal Account of My Journey With the Disease and Response to Teclistamab.

Multiple myeloma (MM) remains an incurable hematologic cancer leading to damage to the bone marrow that causes destructive bone lesions in addition to many other effects. I am a patient with MM who has undergone treatment to date since the diagnosis of this disease in December 2019. This paper reviews the treatments and observations made throughout this period. The salient results of such treatments are discussed in chronological order. During this period, my MM relapsed and then I was introduced to teclistamab treatment. The outcome of teclistamab treatment is quite promising, and I anticipate a longer life at a maintenance dose of this drug with a better quality of life. When writing this article, I am still receiving the teclistamab treatment cycles that maintain a constant normal level of my kappa-free light chain (FLC) and kappa/lambda ratio, with no significant side effects.

The use of preoperative erythropoiesis-stimulating agents (ESAs) in patients who underwent knee or hip arthroplasty: a meta-analysis of randomized clinical trials.

Erythropoiesis-stimulating agents (ESAs) have been used in orthopedic patients to reduce allogeneic blood transfusion (ABT). The purpose of this systematic review of randomized clinical trials is to evaluate the efficacy of preoperative administration of ESAs on hemoglobin level at discharge and frequency of ABT in patients undergoing hip or knee surgery. Pooled results of 26 trials with 3560 participants showed that the use of preoperative ESAs reduced ABT in patients undergoing hip or knee surgery [RR: 0.48, 95% CI: 0.38 to 0.60, P<0.00001]. Hemoglobin mean difference between ESA and control groups was 7.16 (g/L) [95% CI of 4.73 to 9.59, P=0.00001]. There was no difference in the risk of developing thromboembolism between ESA and control groups [RD: 0, 95 % CI: -1%-2%, P=0.95]. ESAs offer an alternative blood conservation method to avoid ABT in patients undergoing hip or knee surgery.

Homozygous missense variant F12 (Gly506Asp) associated with severe factor XII deficiency: a case report.

BACKGROUND: Factor XII deficiency can be related to either homozygous or compound heterozygous pathogenic variants in the F12 gene. The disease is commonly known as Hageman trait and is inherited in both autosomal recessive or dominant patterns. Clinically, factor XII deficiency is not associated with bleeding but conversely has been linked to thrombotic events, recurrent pregnancy loss, and hereditary angioedema. Molecular data of F12 deficiency are scarce and have revealed varying results between cases. However, most of the reported variants are missense mutations, gross deletions, or small insertion. Factor XII deficiency has been reported in the Saudi population in several studies, either as isolated case reports or included within the studies of rare bleeding factors deficiency. However, molecular data are lacking as no case report of genetic studies related to factor XII deficiency has been published in our local population, to the best of our knowledge. CASE REPORT: Herein we describe a homozygous missense variant involving exon 12 within F12 gene (5:176,830,269 G>A; p.Gly506Asp) in a 36-year-old Saudi multiparous female referred from the surgical clinic with significantly high activated partial thromboplastin time during preoperative assessment for sleeve gastrectomy. The patient had no history of bleeding episodes during the previous deliveries nor any tooth extractions. She had single event of spontaneous abortion during the 15th week of gestation without any bleeding complication. There was no history of thrombosis or skin manifestations, and she was not taking any medicines. There was no family history of bleeding or thrombosis. Family history revealed consanguinity as the parents are first-degree cousins. Physical examination was unremarkable. Upon investigation, the prolonged activated partial thromboplastin time was fully corrected by a 1:1 mixing study with normal pool plasma while lupus anticoagulant tests were negative. Factor assays and von Willebrand factor tests are all within normal ranges except for factor XII, which was severely deficient. A homozygous missense variant involving exon 12 within F12 gene (5:176,830,269 G>A; p.Gly506Asp) was identified. CONCLUSION: F12 (5:176,830,269 G>A; p.Gly506Asp) variant is likely to be a pathogenic variant among homozygous factor XII-deficient patients. Genetic counseling and management of the patients and families should be based on clinical evaluation.

Response to Lisinopril in Patients with Sickle Cell Anemia and Proteinuria.

Proteinuria is a manifestation of sickle cell anemia (SCA)-related renal disease and is a risk factor of renal impairment. Angiotensin-converting enzyme (ACE) inhibitors have benefits, but their role in SCA remains undefined. This study aimed to assess the role of lisinopril, an ACE inhibitor, in reducing proteinuria in SCA patients. Thirty-five patients older than 15 years with known SCA (HbSS or HbS-ß0) and a 24-h urinary protein level of 150 mg or more participated in this study. Urine was collected over 24 h to quantify proteinuria. The patients had a mean age of 28.5 ± 6.98 years. The median 24-h urinary protein before treatment was 0.3006 g and that after treatment was 0.150 g (P = 0.01). After a median follow-up of 38 months, 24-h urinary protein decreased in 27 (77%) patients and normalized in 18 (52%) patients. Urinary protein increased in 2 (6%) patients and remained stable (no change) in 6 (17%) patients. There was no significant difference in blood pressure (BP) before and after treatment. The average dose of lisinopril was 5 mg. Twenty patients were still on lisinopril at last follow-up. The reasons for stopping lisinopril included normalization of protein, noncompliance, adverse effects, and pregnancy. Lisinopril effectively reduced proteinuria in SCA patients, without significantly reducing BP. Only a few patients developed adverse effects, including coughing, dizziness, and diarrhea. It is unclear how long lisinopril should be continued and whether it can be stopped in patients with normalized urinary protein.

Interest of external photoprotection by means of clothing and sunscreen products in young children.

BACKGROUND: Protecting young children is a major public health issue. OBJECTIVE: We tested children's clothing and sunscreen products that are specially designed for children. METHODS: The effectiveness of the different types of clothing and sunscreen products was determined using spectrophotometer equipped with an integrating sphere A measure of transmittance carried out, respectively, between 290 and 400 nm and between 320 and 400 nm, allowed us to assess the photoprotective properties in the UVB and UVA range respectively. RESULTS: Although the photoprotective effect varies according to the type of clothing (UV-protection factor [UPF] of approximately 10 for a cotton T-shirt and 500 for a pair of jeans), the effect is constant for any one type of clothing. Placing fabrics in layers is essential and this enables the protective effect to be greatly increased. Moreover, the authors wished to answer the question, 'what makes a good sun cream?' by analysing the formula of each product tested. It turns out that only creams containing both organic filters and inorganic filters have an sun protection factor (SPF) that is the same as the one stated on the product. CONCLUSION: Concerning townwear, the jeans, tracksuits, sweatshirts, pullovers and tights turned out to be very photoprotective. They enable, in effect, to reach a UPF higher than 500. The mere presence of titanium dioxide and/or zinc dioxide does not mean that the product will have a high SPF. Products containing alcohol can be eliminated from the possible choices by carefully reading the label.

Serum testosterone levels in diabetic men with and without erectile dysfunction.

Diabetes mellitus is a common chronic disease, affecting 0.5-2% worldwide. The Massachusetts Male Aging Study reported that up to 75% of men with diabetes have a lifetime risk of developing ED. Type 2 diabetes is associated with low total serum testosterone (TT) identified in several cross-sectional studies and systemic analyses. There is a lack of consensus regarding what constitutes the lowest level of testosterone within the boundaries of normality. In this retrospective study, we sought to evaluate the effect of associated co-morbidities on serum total testosterone (TT) level in men with type 2 diabetes DM, either with or without erectile dysfunction (ED). Three hundred and ninety-one patients were evaluated for erectile function using an abridged, five-item version of the International Index of Erectile Function-5. Measurements of TT, fasting lipid profile, blood sugar and glycated haemoglobin (HbA1c) were conducted. Penile hemodynamics was assessed using intracavernosal injection and penile duplex study. Hypogonadism was found in 126 cases (33.2%), and normal TT was observed in 254 (66.8%). ED was detected in 119 cases in the hypogonadal group (94.4%) as compared to 155/254 (61.0%) in eugonadal group, P = 0.0001. TT was lower in diabetic men with ED as compared to those with normal erectile function (EF), 392.4 ± 314.9 versus 524.3 ± 140.2 ng dl(-1) , respectively, P < 0.0001. After exclusion of patients with hypertension and dyslipidaemia, 185 men were evaluated, and there was no difference in the mean TT level among men with ED 490.6 ± 498.2 ng dl(-1) versus normal EF 540.6 ± 133.4 ng dl(-1) although, HbA1c remained lower in men with normal erectile function. Receiver operating characteristic (ROC) curve of TT in men without associated co-morbidities showed that EF was compromised at TT = 403.5 ng dl(-1) or less. Sensitivity of 63.3% and a specificity of 94.0% were detected. At this level, ED was found in 33/38 (86.8%) men with TT 403.5 ng dl(-1) , whereas ED was observed in 57/147 (38.8%) men with TT ≥ 403.5 ng dl(-1) (P < 0.0001). We propose a cut-off value of 403.5 ng dl(-1) of TT blood levels as an indicator for initiation of testosterone replacement therapy in diabetic men with ED. Further prospective controlled trials are recommended.

Elastoplastic Indentation Response of Sigmoid/Power Functionally Graded Ceramics Structures.

Due to the applicability of new advanced functionally graded materials (FGMs) in numerous tribological systems, this manuscript aims to present computational and empirical indentation models to investigate the elastoplastic response of FG substrate under an indention process with spherical rigid punch. The spatial variation of the ceramic volume fraction through the specimen thickness is portrayed using the power law and sigmoid functions. The effective properties of two-constituent FGM are evaluated by employing a modified Tamura-Tomota-Ozawa (TTO) model. Bilinear hardening behavior is considered in the analysis. The finite element procedure is developed to predict the contact pressure, horizontal displacement, vertical deformation, and permanent deformation of FG structure under the rigid cylindrical indentation. The empirical forms for permanent deformation were evaluated and assigned. Model validation with experimental works was considered. The convergence of the mesh and solution procedure was checked. Numerical studies were performed to illustrate the influence of gradation function, gradation index, and indentation parameters on the contact pressure, von Mises stresses, horizontal/vertical displacements, and permanent plastic deformation. The present model can help engineers and designers in the selection of an optimum gradation function and gradation index based on their applications.

The Safety and Efficacy of Low-Molecular-Weight Heparin in Pregnant Women With Rheumatic Heart Disease and Valves Replacement.

BACKGROUND: In patients with rheumatic heart disease (RHD) and prosthetic valve replacement, the risk of thromboembolic complications is the highest during and immediately after pregnancy. Therapeutic anticoagulation during this period is crucial to minimize the risk of thromboembolic complications. The use of low-molecular-weight heparin (LMWH) remains an off-label indication. The type of anticoagulants used, dosing regimens, target anti-Xa levels, and frequency of anti-Xa monitoring are highly variable in the pregnant population and have been derived from pilots, observational studies, and empirical evidence. Herein, in a real-world setting, we sought to examine the efficacy and safety of variable anticoagulation options with a focus on LMWH in the management of RHD-related valvular disease in pregnant women. METHODS: This study is a retrospective study conducted at a large university-affiliated tertiary care center (King Saud University Medical City) between January 2011 and February 2020. All pregnant women with RHD who had heart valve replacements were reviewed. Patient data were extracted for demographic information, baseline characteristics, anticoagulation type, and primary outcomes. Primary endpoints were thromboembolic events, hemorrhagic complications, and fetal outcomes. RESULTS: A total of 744 pregnancies in 149 women were identified. The mean age ± SD of the women was 43.8 ± 12 years. A total of 86 women (58%) were on the LMWH regimen, 35 women (23%) were on LMWH and warfarin regimen, and 28 women (19%) were on unfractionated heparin (UFH) and warfarin regimen. Overall, thromboembolic events developed in five (0.7%) pregnancies. Of those, two were in the LMWH group, two were in the LMWH and warfarin group, and one was in the UFH and warfarin group. In addition, significant hemorrhagic complications occurred in five pregnancies. Of these, two occurred in the LMWH group, two in the LMWH and warfarin group, and one in the UFH and warfarin group. No adverse maternal and fetal outcomes were noted. CONCLUSION: This study presents the largest retrospective study of variable anticoagulation options in pregnant women with RHD and prosthetic valve replacement. LMWH is both safe and effective in preventing major thromboembolic complications compared to other forms of anticoagulation used during pregnancy.