Overall survival in patients with endometrial cancer treated with dostarlimab plus carboplatin-paclitaxel in the randomized ENGOT-EN6/GOG-3031/RUBY trial.

BACKGROUND: Part 1 of the RUBY trial (NCT03981796) evaluated dostarlimab plus carboplatin-paclitaxel compared with placebo plus carboplatin-paclitaxel in patients with primary advanced or recurrent endometrial cancer (EC). At the first interim analysis, the trial met one of its dual primary endpoints with statistically significant progression-free survival benefits in the mismatch repair-deficient/microsatellite instability-high (dMMR/MSI-H) and overall populations. Overall survival (OS) results are reported from the second interim analysis. PATIENTS AND METHODS: RUBY is a phase III, global, double-blind, randomized, placebo-controlled trial. Part 1 of RUBY enrolled eligible patients with primary advanced stage III or IV or first recurrent EC who were randomly assigned (1 : 1) to receive either dostarlimab (500 mg) or placebo, plus carboplatin-paclitaxel every 3 weeks for 6 cycles followed by dostarlimab (1000 mg) or placebo every 6 weeks for up to 3 years. OS was a dual primary endpoint. RESULTS: A total of 494 patients were randomized (245 in the dostarlimab arm; 249 in the placebo arm). In the overall population, with 51% maturity, RUBY met the dual primary endpoint for OS at this second interim analysis, with a statistically significant reduction in the risk of death [hazard ratio (HR) = 0.69, 95% confidence interval (CI) 0.54-0.89, P = 0.0020] in patients treated with dostarlimab plus carboplatin-paclitaxel versus carboplatin-paclitaxel alone. The risk of death was lower in the dMMR/MSI-H population (HR = 0.32, 95% CI 0.17-0.63, nominal P = 0.0002) and a trend in favor of dostarlimab was seen in the mismatch repair-proficient/microsatellite stable population (HR = 0.79, 95% CI 0.60-1.04, nominal P = 0.0493). The safety profile for dostarlimab plus carboplatin-paclitaxel was consistent with the first interim analysis. CONCLUSIONS: Dostarlimab in combination with carboplatin-paclitaxel demonstrated a statistically significant and clinically meaningful OS benefit in the overall population of patients with primary advanced or recurrent EC while demonstrating an acceptable safety profile.

Kinetics of naturally induced binding and neutralizing anti-SARS-CoV-2 antibody levels and potencies among Kenyan patients with diverse grades of COVID-19 severity

BackgroundGiven the low levels of COVID-19 vaccine coverage in Sub-Saharan Africa, despite high levels of natural SARS-CoV-2 exposures, strategies for extending the breadth and longevity of naturally acquired immunity are warranted. Designing such strategies will require a good understanding of natural immunity. MethodsWe used ELISA to measure whole-spike IgG and spike-receptor binding domain (RBD) total immunoglobulins (Igs) on 585 plasma samples collected longitudinally over five successive time points within six months of COVID-19 diagnosis in 309 COVID-19 patients. We measured antibody neutralizing potency against the wild-type (Wuhan) SARS-CoV-2 pseudo-virus in a subset of 51 patients over three successive time points. Binding and neutralizing antibody levels and potencies were then tested for correlations with COVID-19 severities, graded according to the National Institute of Health (NIH), USA criteria. ResultsRates of sero-conversion increased from Day 0 (day of PCR testing) to Day 180 (six months) (63.6% to 100 %) and (69.3 % to 97%) for anti-spike IgG and anti-spike-RBD binding Igs, respectively. Levels of these binding antibodies peaked at Day 28 (P<0.0001) and were subsequently maintained for six months without significant decay (p>0.99). Similarly, antibody neutralizing potencies peaked at Day 28 (p<0.0001) but had decreased by three-folds, six months after COVID-19 diagnosis (p<0.0001). Binding antibodies levels were highly correlated with neutralizing antibody potencies at all the time points analyzed (r>0.6, P<0.0001). Levels and potencies of binding and neutralizing antibodies increased with disease severity. ConclusionMost COVID-19 patients from Sub-Saharan Africa generate SARS-CoV-2 specific binding antibodies that remain stable during the first six months of infection. Although antibody binding levels and neutralizing potencies were directly correlated, the respective neutralizing antibodies decayed three-fold by the sixth month of COVID-19 diagnosis suggesting that they are short-lived, consistent with what has been observed elsewhere. Thus, just like for other populations, regular vaccination boosters will be required to broaden and sustain the high levels of predominantly naturally acquired anti-SARS-CoV-2 neutralizing antibodies.

Diagnostic Accuracy of High-Resolution 3D T2-SPACE in Detecting Cerebral Venous Sinus Thrombosis.

BACKGROUND AND PURPOSE: Assessment of cerebral venous sinus thrombosis on MR imaging can be challenging. The aim of this study was to evaluate the diagnostic accuracy of high-resolution 3D T2 sampling perfection with application-optimized contrasts by using different flip angle evolution (SPACE) in patients with cerebral venous sinus thrombosis and to compare its performance with contrast-enhanced 3D T1-MPRAGE. MATERIALS AND METHODS: We performed a blinded retrospective analysis of T2-SPACE and contrast-enhanced MPRAGE sequences from patients with cerebral venous sinus thrombosis and a control group. The results were compared with a reference standard, which was based on all available sequences and clinical history. Subanalyses were performed according to the venous segment involved and the clinical stage of the thrombus. RESULTS: Sixty-three MR imaging examinations from 35 patients with cerebral venous sinus thrombosis and 51 examinations from 40 control subjects were included. The accuracy, sensitivity, and specificity calculated from the initial MR imaging examination for each patient were 100% each for T2-SPACE and 95%, 91%, and 98%, respectively, for contrast-enhanced MPRAGE. The interrater reliability was high for both sequences. In the subanalysis, the accuracy for each venous segment involved and if subdivided according to the clinical stage of thrombus was ≥95% and ≥85% for T2-SPACE and contrast-enhanced MPRAGE, respectively. CONCLUSIONS: Both T2-SPACE and contrast-enhanced MPRAGE offer high accuracy for the detection and exclusion of cerebral venous sinus thrombosis; however, T2-SPACE showed a better overall performance and thus could be a useful tool if included in a multiparametric MR imaging protocol for the diagnosis of cerebral venous sinus thrombosis, especially in scenarios where gadolinium administration is contraindicated.

Stemless reverse total shoulder arthroplasty: a systematic review of contemporary literature.

PURPOSE: Reverse shoulder prostheses are increasingly used for treatment of rotator cuff tear arthropathy and other degenerative shoulder diseases. In recent years, aiming for bone stock preservation has led to the design of metaphyseal humeral components without a stem. The aims of this study were to evaluate the complication and reintervention rates, as well as the clinical and radiographic outcomes in patients who underwent reverse shoulder arthroplasty (RSA) with stemless implants. METHODS: A systematic review of the literature was completed until May 2020 using PubMed, EMBASE, CINAHL and Cochrane databases, according to PRISMA guidelines. RESULTS: The literature search revealed 2942 studies, of which 13 were included in this review, with a total of 517 patients and a mean follow-up between 6.4 and 101.6 months. The total complication rate was 6.5%, while 3.3% were humeral associated complications. Finally, the rate of shoulders that underwent a reintervention was 6.7%, with 1.4% relating to a humeral component reason. Stemless RSA led to substantial improvements in patient reported outcome measures and range of motion across all studies. Scapular notching was reported in 15.2%, and lucencies around humeral component were reported in 0.8% of shoulders. CONCLUSION: Stemless RSA resulted in low complication and reintervention rates at the mid-term follow-up. The reported clinical and radiological outcomes showed that these prostheses have at least equivalent outcomes with their stemmed counterparts. Further studies are required to investigate the long-term longevity and performance of the stemless humeral implants. LEVEL OF EVIDENCE: Level IV; Systematic Review.

Utilization of N-bromosuccinimide for the sensitive spectrophotometric determination of pipazethate HCl as antitussive drug in pure and dosage forms.

OBJECTIVES: Three simple, sensitive, precise, reproducible and validated spectrophotometric methods have been developed for the quantification of pipazethate HCl as antitussive drug in pure and dosage forms. METHODS: The methods are based on utilization of N-bromosuccinimide as an oxidant and three dyes, amaranth, methylene blue, and indigo carmine, as auxiliary reagents. The proposed methods are based on oxidation reaction of pipazethate HCl with a known excess of N-bromosuccinimide in acid medium, followed by determination of unreacted N-bromosuccinimide by the reaction with a fixed amount of dyes, amaranth, methylene blue, and indigo carmine followed by the measurement of the absorbance at 520, 663 and 610nm, respectively. The optimization of the reaction conditions was investigated. RESULTS: Under the optimum conditions, linear relationships with good correlation coefficients (0.9998-0.9999) were found over the concentration ranges of 0.3-9.0, 0.5-12 and 0.5-10µgmL-1 with a limit of detection (LOD) of 0.1, 0.15 and 0.15µgmL-1 using amaranth, methylene blue, and indigo carmine methods, respectively. Intra-day and inter-day accuracy and precision of the methods have been evaluated. No interference was observed from the common tablet excipients. CONCLUSION: The developed methods were validated in accordance with ICH guidelines and successfully applied to the analysis of pipazethate HCl in dosage forms with good accuracy and precision. The reliability of the methods was further ascertained by performing recovery studies via the standard addition method. Statistical comparison of the results obtained by applying the proposed methods with those of the reported method by applying Student's t-test and variance ratio F-test at the 95% confidence level revealed good agreement and indicates no significant difference in accuracy and precision.

A laboratory study to test the responses of human dental pulp stem cells to extracts from three dental pulp capping biomaterials.

AIM: This laboratory study aimed to investigate the effects of three endodontic biomaterials; MTA-HP, iRoot-BP-Plus and ACTIVA on the proliferation, adhesion and osteogenic differentiation of human Dental Pulp Stem Cells (hDPSCs). METHODOLOGY: The hDPSCs were isolated from the dental pulps of 21 patients scheduled for surgical extraction of their impacted third molars. The MTT assay was used for assessing cellular proliferation. Ninety-six-well plates were used and the experiment was repeated four times under the same condition and the assay was done in triplicate. Four groups were assigned in which the hDPSCs were cultured in complete media only and considered as negative control. Whilst in the 2nd , 3rd and 4th groups, the cells were treated with CM supplemented with 1.5 µl MTA-HP (CM-MTA, iRoot-BP-Plus (CM-BP), and ACTIVA(CM-AC) extracts, respectively. Attachment adhesion and growth morphology of hDPSCs were observed using SEM and the osteogenic differentiation assay was evaluated by Alizarin red stain test (ARS). The data of proliferation and osteogenic differentiation were analysed using two-way ANOVA followed by Tukey's post hoc multiple comparison test. A p-value < 0.05 was considered significant to analyse the differences amongst the means of groups. RESULTS: Both CM-MTA and CM-BP groups were associated with a significant increase in hDPSC proliferation in comparison with CM-AC and CM groups (p = 0.001). hDPSCs exhibited a greater cellular attachment to iRoot-BP-Plus surfaces followed by MTA-HP, whilst less attachment was observed in the ACTIVA group. Moreover, at day 7 there was a significant difference in formation of mineralizing nodules; CM-BP, CM-MTA and CM-AC groups respectively (p = 0.001). Whilst there was no significance of difference between CM-AC and CM groups (p > 0.05). CONCLUSIONS: In a laboratory setting, ACTIVA, MTA-HP and iRoot-BP-Plus promoted hDPSCs proliferation, mineralization and attachment, which may explain their in-situ success as endodontic biomaterials.

Efficacy of Itraconazole in the Prevention of Recurrence of Tinea Versicolor: A Three Year Follow Up.

Pityriasis versicolor (PV) also known as tinea versicolor, which is chronic and superficial fungal skin disease caused by Malassezia yeasts. A permanent cure may difficult to achieve and this may explain the long-term nature of the disease. Consequently, a preventive treatment regimen may help to prevent the recurrence of pityriasis versicolor. Whether, the recurrence of tinea versicolor could be prevented by monthly itraconazole treatment regimen after a short course of itraconazole therapy. Open treatment followed by a randomized, single blind placebo control trial. Multi-center trial was characterized by an open, active treatment phase with itraconazole followed by a randomized placebo controlled treatment for prevention of recurrence. A total 200 patients (150 male and 50 female) were included in this study and was given 200mg itraconazole daily for 7 days (treatment phase). Patients in whom tinea versicolor was mycologically cured divided into Group A and Group B. Active open treatment was followed by preventive itraconazole treatment 200mg twice daily in Group A and placebo in Group B monthly for 6 consecutive months. The patients were diagnosed clinically and confirmed by Wood's lamp examination and KOH microscopy. Clinical improvement in 90%, negative Wood's lamp examination in 86.5% and Mycological cure in 85.5% were found at the end of open treatment. The mycological cure, 171 subjects were taken into this study for preventive treatment phase and divided into two groups- Group A & Group B. Preventive treatment was given in Group A and placebo in Group B. After the preventive treatment, the end point (After 6 months), clinical improvement, negative Wood's lamp examination and mycological cure were found in 81(90%), 76(84.4%) and 75(83.3%) in Group A and 44(55%), 41(51.3%) and 42(52.5%) in Group B respectively. In preventive treatment phase, 1 patient in Group A did not complete the study. No patient experienced any serious adverse effects. Prevention of recurrence of Pityriasis versicolor with itraconazole is as effective as treatment.

Lesión del labrum superior anteroposterior (SLAP) en el entorno laboral / Superior labral anterior to posterior (SLAP) injury in the workplace

Antecedentes y objetivo: La lesión del labrum superior anteroposterior (SLAP) es una conocida causa de dolor y disfunción del hombro en pacientes activos. El objetivo fue estudiar las lesiones de SLAP en población laboral y valorar la fiabilidad de la exploración física y las técnicas de imagen en el diagnóstico de las lesiones de SLAP en el entorno laboral. Material y métodos: Revisión retrospectiva de 58 lesiones de SLAP tratadas en nuestra mutua laboral desde 2005 hasta 2015 en 815 pacientes en los que se realizó una artroscopia de hombro. Se han recogido datos del mecanismo lesional, datos clínicos, pruebas complementarias (comparando el informe radiológico inicial con el de un radiólogo especializado en musculoesquelético), hallazgos artroscópicos y tratamiento realizado. Resultados: El mecanismo lesional más frecuente ha sido la lesión aguda levantando peso, en la mayoría de casos, por encima de la cabeza. La lesión de SLAP se sospechó en el 41% con anamnesis y exploración física, en el 29% de los informes radiológicos iniciales y en el 52% en los informes del radiólogo especialista en musculoesquelético. Presentaron lesiones asociadas el 78%, la mayoría lesiones del manguito rotador. Conclusión: La lesión de SLAP en el entorno laboral es infrecuente y muchas veces se diagnostica durante una artroscopia realizada por otra lesión. La artrorresonancia magnética y la resonancia magnética tienen menos fiabilidad que la evaluación clínica para su diagnóstico. Un radiólogo especializado en musculoesquelético podría mejorar la rentabilidad de las pruebas de imagen en el diagnóstico de estas lesiones

Background and objective: Superior labral anterior to posterior (SLAP) injuries are widely recognised as a cause of pain and dysfunction in the shoulders of active patients. The aims of the present study were to analyze SLAP injuries in the workplace, and to evaluate the reliability of physical examination and imaging techniques for the diagnosis of work-related SLAP injuries. Material and methods: Retrospective chart review of 58 SLAP injuries treated in our occupational health centre from 2005 to 2015 in 815 patients undergoing shoulder arthroscopy. Data were collected on mechanism of injury, clinical proceedings, complementary tests (contrasting the initial magnetic resonance imaging report with that of a radiologist specializing in musculoskeletal pathology), arthroscopy findings and treatments performed. Results: The most common mechanism of injury was acute injury while handling weight, in the majority of cases, above the head. SLAP injury was suspected in 41% of cases through anamnesis and physical exam, in 29% through the initial magnetic resonance imaging report, and in 52% through the specialised radiologist's report. In 78%, associated injuries were present, the most common being rotator cuff injuries. Conclusions: SLAP injuries in the workplace are rare and are often a diagnostic finding during surgical intervention performed for a different associated injury. Arthro-magnetic resonance imaging and magnetic resonance imaging have lower reliability than physical exams in the diagnosis of work-related SLAP injuries. A radiologist specializing in musculoskeletal pathology could probably improve the reliability of imaging test interpretation in work-related SLAP injuries

Superior labral anterior to posterior (SLAP) injury in the workplace. / Lesión del labrum superior anteroposterior (SLAP) en el entorno laboral.

BACKGROUND AND OBJECTIVE: Superior labral anterior to posterior (SLAP) injuries are widely recognised as a cause of pain and dysfunction in the shoulders of active patients. The aims of the present study were to analyze SLAP injuries in the workplace, and to evaluate the reliability of physical examination and imaging techniques for the diagnosis of work-related SLAP injuries. MATERIAL AND METHODS: Retrospective chart review of 58 SLAP injuries treated in our occupational health centre from 2005 to 2015 in 815 patients undergoing shoulder arthroscopy. Data were collected on mechanism of injury, clinical proceedings, complementary tests (contrasting the initial magnetic resonance imaging report with that of a radiologist specializing in musculoskeletal pathology), arthroscopy findings and treatments performed. RESULTS: The most common mechanism of injury was acute injury while handling weight, in the majority of cases, above the head. SLAP injury was suspected in 41% of cases through anamnesis and physical exam, in 29% through the initial magnetic resonance imaging report, and in 52% through the specialised radiologist's report. In 78%, associated injuries were present, the most common being rotator cuff injuries. CONCLUSIONS: SLAP injuries in the workplace are rare and are often a diagnostic finding during surgical intervention performed for a different associated injury. Arthro-magnetic resonance imaging and magnetic resonance imaging have lower reliability than physical exams in the diagnosis of work-related SLAP injuries. A radiologist specializing in musculoskeletal pathology could probably improve the reliability of imaging test interpretation in work-related SLAP injuries.

Needlescopic assisted internal ring suturing; a novel application of low-cost home-made instruments for pediatric inguinal hernia repair.

BACKGROUND: Congenital inguinal hernia (CIH) is a commonly performed surgical procedure in infants and children. Single port laparoscopic hernia repair using percutaneous internal inguinal ring (IIR) suturing procedure is a widely employed technique for indirect inguinal hernia repair in children. The majority of extracorporeal techniques use extracorporeal knotting and burying the knot subcutaneously. This may result in many drawbacks. The aim of this multicenter study is to introduce a new technique for pediatric inguinal hernia repair using only needles without any laparoscopic instruments. PATIENTS AND METHODS: This is a multicenter study which was conducted at Pediatric Surgical Departments of Al-Azhar, Mansoura, Alexandria and Tanta Universities during the period from January 2015 to June 2017. 314 patients with CIH underwent Needlescopic Assisted Internal Ring Suturing (NAIRS) after cauterization of the hernia sac at its neck. The main outcome measures were: feasibility, safety of the technique, operative time, recurrence rate, hydrocele and cosmetic results. RESULTS: A total of 314 patients with CIH were corrected by NAIRS. They were 232 males and 82 females. The mean age was 28.12 ± 1.3 months (range 6-120 months). The mean operative time was 12.6 ± 1.7 min (range 8-15 min) for unilateral cases and 18.6 ± 1.7 min (range 14-20 min) for the bilateral repairs. All cases were completed laparoscopically without major intraoperative complications. No recurrence was detected in this study. No wound complications or umbilical hernias developed. Hydrocele occurred in five males (2.16%), without detection of testicular atrophy or iatrogenic ascent of the testis. CONCLUSION: This preliminary study showed that NAIRS after cauterization of the neck of the hernia sac in infants and children is safe, feasible, reproducible with excellent cosmetic results.

Molecular characteristics of methicillin-resistant Staphylococcus aureus nasal carriage from hospitalized patients and medical staff in Isfahan, Iran.

OBJECTIVES: Nasal carriage of methicillin-resistant Staphylococcus aureus (MRSA) has been accounted as one of the main risk factors for the development of complicated nosocomial infections. The present study aimed to determine nasal carriage rate, antimicrobial susceptibility pattern and molecular characteristics of MRSA isolates. METHODS: This cross-sectional study was performed within 6 months period from July 2015 at 3 hospitals of Isfahan, Iran. Totally, 326 nasal samples were collected by cotton sterile swab from the nasal cavity of participants. Standard microbiological methods were used for identification S. aurues and MRSA isolates. Antibiotic susceptibility pattern was determined by the disc diffusion method according to the CLSI recommendation. Determination of SCCmec typing, agr groups, and virulence genes were performed by PCR method. RESULTS: Overall, 23.6% of cases were S. aureus carriers including, 23.4% (25/107) of HCWs and 23.7% (52/219) of patients. The rate of MRSA nasal carriages among patients was found to be 51.9% and 16% in HCWs. The highest levels of resistance among MRSA isolates were against ampicillin (93.5%) and tetracycline (83.4%); while, the most effective antibiotics were vancomycin and co-trimoxazole with 100% and 71%, susceptibility. The presence of hla and pvl genes was detected in 80.6% and 3.2% of MRSA isolates, respectively. SCCmec types I, III, IV and V were found in 16.1%, 25.8%, 25.8%, and 16.1% of isolates, respectively. Moreover, agr group I was the predominant type with 43.3. CONCLUSION: Our results showed a high rate of MRSA colonization in hospitalized patients which remains a significant healthcare problem in our region.

Typing of staphylococcal cassette chromosome mec encoding methicillin resistance in Staphylococcus aureus isolates in Ahvaz, Iran.

Methicillin-resistant Staphylococcus aureus (MRSA) is a major nosocomial pathogen. We sought to determine the frequency of the different types of SCCmec in MRSA isolates by performing a cross-sectional study. A total of 72 S. aureus isolates were collected from Imam Khomeini and Golestan hospitals and analysed for MRSA and SCCmec typing by multiplex PCR. The pattern of antibiotic resistance among S. aureus isolates was determined by disc diffusion analysis. Of the 72 S. aureus isolates, 29 (40.27%) were recognized as MRSA. SCCmec type III was the most common type, with 55.17% (16/29), followed by type II with 27.58% (8/29); type IV with 10.34% (3/29); and type I with 6.89% (2/29). All 29 MRSA isolates were resistant to chloramphenicol and erythromycin. In addition, resistance to cephalothin, gentamicin, clindamycin, ciprofloxacin, tetracycline and rifampicin was seen in 24 (75%), 26 (63.4%), 17 (94.4%), 27 (71.05%), 10 (71.42%) and 13 (68.42%) MRSA isolates, respectively. A decreased sensitivity of MRSA to the antibiotics used was observed, with type III SCCmec being the predominant isolate.

Tuberculosis is a Mimicker of JIA: A Rare Case Report.

Cystic tuberculosis of the bone is a rare form of tuberculosis (TB). The condition presents like Juvenile idiopathic arthritis (JIA) of children. In children, the lesions symmetrically involve the peripheral skeleton, which are less sclerotic than adults. A case report is presented here where the patient presented with i) the extensive involvement of bones with cystic lesion, ii) Hand & feet involvement with multiple bony exostosis iii) Synovial swelling of multiple joints and 4) fever for 6 months. Swelling of the joints was disproportionately greater than pain. For the last 6 month patient developed low grade fever with evening rise of temperature & dry cough. There was associated anorexia & significant weight loss. Patient was moderately anaemic & there was cervical lymphadenopathy on both sides. The chest examination revealed features suggestive of consolidation in the right lung. Regarding MSK findings there was swelling of both knee & right wrist with G-II tenderness, sublaxation of both anterior and posterior cruciate ligament with mild effusion. Bony exostosis at the base of left index finger & at the base of right middle finger was found. Investigation shows low Hb, very high ESR, positive tuberculin test. X-ray Chest suggestive of consolidation, FNA of right cervical lymph node consistent with tuberculosis. X-ray Pelvis has shown expansile mixed sclerotic radiolucent areas with interval septation involving upper part of both femoral shafts. MRI findings of right knee joint were suggestive of tuberculous osteomyelitis. At this stage the patient was put on Anti-TB chemotherapy. After 2 month and 4 month of follow up with Anti-TB drug both MSK & lung condition was improved significantly. Ultimately the patient was diagnosed as cystic tuberculosis of bone & continued Anti-TB drugs.

Genetic and Nongenetic Factors Affecting Clopidogrel Response in the Egyptian Population.

Aspirin and clopidogrel are the mainstay oral antiplatelet regimens, yet a substantial number of major adverse cardiac events (MACE) still occur. Herein, we investigated genetic and nongenetic factors associated with clopidogrel response in Egyptians. In all, 190 Egyptians with acute coronary syndrome (ACS) and/or percutaneous coronary intervention (PCI), treated with clopidogrel (75 mg/day) for at least a month, were genotyped for CYP2C19 *2, *3, *6, *8, *10, and *17, CES1 G143E and ABCB1*6 and *8. These variants along with nongenetic factors were tested for association with the risk of having MACE in clopidogrel-treated patients. CYP2C19 loss-of-function (LOF) alleles carriers had increased risk of MACE vs. noncarriers (odds ratio 2.52; 95% confidence interval 1.23-5.15, P = 0.011). In a logistic regression, CYP2C19 LOF variants (P = 0.011), age (P = 0.032), and body mass index (BMI, P = 0.039) were significantly associated with the incidence of MACE in patients taking clopidogrel. CYP2C19 genetic variants, age, and BMI are potential predictors associated with variability to clopidogrel response in Egyptians.

Impact of GGCX, STX1B and FPGS Polymorphisms on Warfarin Dose Requirements in European-Americans and Egyptians.

Genotype-based algorithms that include VKORC1 and CYP2C9 genotypes are less predictive of warfarin dose variability in Africans as opposed to Europeans. Polymorphisms in GGCX, FPGS, or STX1B are associated with warfarin dose requirements in African-Americans. We sought to determine if they influenced warfarin dose in European-Americans, and another African population, specifically Egyptians. We genotyped 529 adults (n = 325 European-Americans, 204 Egyptians) on a stable warfarin dose for GGCX rs12714145 and rs10654848, FPGS rs7856096, and STX1B rs4889606. Rs12714145, rs10654848, and rs7856096 were not associated with warfarin dose, whereas STX1B rs4889606 was a significant determinant in univariate analysis (P < 0.0001) in both cohorts. However, STX1B rs4889606 was in high linkage disequilibrium with VKORC1-1639 G>A, and was no longer significant after including VKORC1-1639 G>A in the regression model. Based on these data, the polymorphisms do not appear to influence, in a clinically important way, warfarin dose requirements in European-Americans and Egyptians.

Molecular dynamics of amorphous pharmaceutical fenofibrate studied by broadband dielectric spectroscopy$ / 药物分析学报

Fenofibrate is mainly used to reduce cholesterol level in patients at risk of cardiovascular disease. Thermal transition study with the help of differential scanning calorimetry (DSC) shows that the aforesaid active pharmaceutical ingredient (API) is a good glass former. Based on our DSC study, the molecular dynamics of this API has been carried out by broadband dielectric spectroscopy (BDS) covering wide temperature and frequency ranges. Dielectric measurements of amorphous fenofibrate were per-formed after its vitrification by fast cooling from a few degrees above the melting point (Tm ? 354.11 K) to deep glassy state. The sample does not show any crystallization tendency during cooling and reaches the glassy state. The temperature dependence of the structural relaxation has been fitted by single Vogel–Fulcher–Tamman (VFT) equation. From VFT fit, glass transition temperature (Tg) was estimated as 250.56 K and fragility (m) was determined as 94.02. This drug is classified as a fragile glass former. Deviations of experimental data from Kohlrausch–Williams–Watts (KWW) fits on high-frequency flank of α-peak indicate the presence of an excess wing in fenofibrate. Based on Ngai's coupling model, we identified the excess wing as true Johari–Goldstein (JG) process. Below the glass transition temperature one can clearly see a secondary relaxation (γ) with an activation energy of 32.67 kJ/mol.

Pharmacometabolomic Assessments of Atenolol and Hydrochlorothiazide Treatment Reveal Novel Drug Response Phenotypes.

Achieving hypertension (HTN) control and mitigating the adverse health effects associated with HTN continues to be a global challenge. Some individuals respond poorly to current HTN therapies, and mechanisms for response variation remain poorly understood. We used a nontargeted metabolomics approach (gas chromatography time-of-flight/mass spectrometry gas chromatography time-of-flight/mass spectrometry) measuring 489 metabolites to characterize metabolite signatures associated with treatment response to anti-HTN drugs, atenolol (ATEN), and hydrochlorothiazide (HCTZ), in white and black participants with uncomplicated HTN enrolled in the Pharmacogenomic Evaluation of Antihypertensive Responses study. Metabolite profiles were significantly different between races, and metabolite responses associated with home diastolic blood pressure (HDBP) response were identified. Metabolite pathway analyses identified gluconeogenesis, plasmalogen synthesis, and tryptophan metabolism increases in white participants treated with HCTZ (P < 0.05). Furthermore, we developed predictive models from metabolite signatures of HDBP treatment response (P < 1 × 10(-5)). As part of a quantitative systems pharmacology approach, the metabolites identified herein may serve as biomarkers for improving treatment decisions and elucidating mechanisms driving HTN treatment responses.

Pregnancy-associated glycoprotein (PAG) profile of Holstein-Friesian cows as compared to dual-purpose and beef cows.

Pregnancy-associated glycoproteins (PAGs) are produced by mono- and binucleate trophoblast cells in the ruminant placenta. PAG appears in maternal blood and, from approximately 4 weeks after fertilization onward, may serve as a reliable means of diagnosing pregnancy. A range of factors are said to affect plasma PAG concentrations, such as number and sex of foetus, mass of calf and placenta, level of milk production and genetic constitution. In this study, PAG pregnancy profiles of a dual-purpose (Simmental) and two beef breeds (Uckermark and Aubrac) are compared with the profile of the specialized dairy breed Holstein-Friesian. Holstein-Friesian cows were sampled weekly; the levels of the other breeds were presented at 3-week intervals. The overall significant breed difference (p = 0.013) was founded on deviations during the initial 3 weeks of pregnancy and from 23 weeks onward. During the period critical for the detection of pregnancy, between four and 22 weeks, agreement between PAG levels of various breeds was close (p > 0.05). No significant effect of body mass of cow or calf (relative to mass of dam) was detected. These findings imply that the PAG pregnancy test may be executed uniformly irrespective of breed or type of cow, affirming the suitability of the test as a valuable asset for the cattle industry.

Impact of the CYP4F2 p.V433M polymorphism on coumarin dose requirement: systematic review and meta-analysis.

A systematic review and a meta-analysis were performed to quantify the accumulated information from genetic association studies investigating the impact of the CYP4F2 rs2108622 (p.V433M) polymorphism on coumarin dose requirement. An additional aim was to explore the contribution of the CYP4F2 variant in comparison with, as well as after stratification for, the VKORC1 and CYP2C9 variants. Thirty studies involving 9,470 participants met prespecified inclusion criteria. As compared with CC-homozygotes, T-allele carriers required an 8.3% (95% confidence interval (CI): 5.6-11.1%; P < 0.0001) higher mean daily coumarin dose than CC homozygotes to reach a stable international normalized ratio (INR). There was no evidence of publication bias. Heterogeneity among studies was present (I(2) = 43%). Our results show that the CYP4F2 p.V433M polymorphism is associated with interindividual variability in response to coumarin drugs, but with a low effect size that is confirmed to be lower than those contributed by VKORC1 and CYP2C9 polymorphisms.

Nicotine improves ethanol-induced impairment of memory: possible involvement of nitric oxide in the dorsal hippocampus of mice.

In the present study, the possible involvement of nitric oxide (NO) systems in the dorsal hippocampus in nicotine's effect on ethanol-induced amnesia and ethanol state-dependent memory was investigated. Adult male mice were cannulated in the CA1 regions of the dorsal hippocampus and trained on a passive avoidance learning task for memory assessment. We found that pre-training intraperitoneal (i.p.) administration of ethanol (1 g/kg) decreased inhibitory avoidance memory when tested 24 h later. The response induced by pre-training ethanol was significantly reversed by pre-test administration of the drug. Similar to ethanol, pre-test administration of nicotine (0.4 and 0.8 µg/mouse, intra-CA1) alone and nicotine (0.2, 0.4 and 0.8 µg/mouse) plus an ineffective dose of ethanol also significantly reversed the amnesia induced by ethanol. Ethanol amnesia was also prevented by pre-test administration of L-arginine (1.2 µg/mouse, intra-CA1), a NO precursor. Interestingly, an ineffective dose of nicotine (0.2 µg/mouse) in combination with a low dose of L-arginine (0.8 µg/mouse) synergistically improved memory performance impaired by ethanol given before training. In contrast, pre-test intra-CA1 microinjection of L-NAME (NG-nitro-L-arginine methyl ester), a nitric oxide synthase (NOS) inhibitor (0.4 and 0.8 µg/mouse), which reduced memory retrieval in inhibitory avoidance task by itself, in combination with an effective dose of nicotine (0.4 µg/mouse) prevented the improving effect of nicotine on memory impaired by pre-training ethanol. Moreover, intra-CA1 microinjection of L-NAME reversed the L-arginine-induced potentiation of the nicotine response. The results suggest the importance of NO system(s) in the CA1 regions of the dorsal hippocampus for improving the effect of nicotine on the ethanol-induced amnesia.