HIV-1 drug resistance mutations emerging on darunavir therapy in PI-naive and -experienced patients in the UK

\ua9 The Author 2016. Background: Darunavir is considered to have a high genetic barrier to resistance. Most darunavir-associated drug resistance mutations (DRMs) have been identified through correlation of baseline genotype with virological response in clinical trials. However, there is little information on DRMs that are directly selected by darunavir in clinical settings. Objectives: We examined darunavir DRMs emerging in clinical practice in the UK. Patients and methods: Baseline and post-exposure protease genotypes were compared for individuals in the UK Collaborative HIV Cohort Study who had received darunavir; analyses were stratified for PI history. A selection analysis was used to compare the evolution of subtype B proteases in darunavir recipients and matched PInaive controls. Results: Of 6918 people who had received darunavir, 386 had resistance tests pre- and post-exposure. Overall, 2.8% (11/386) of these participants developed emergent darunavir DRMs. The prevalence of baseline DRMs was 1.0% (2/198) among PI-naive participants and 13.8% (26/188) among PI-experienced participants. Emergent DRMs developed in 2.0% of the PI-naive group (4 mutations) and 3.7% of the PI-experienced group (12 mutations). Codon 77 was positively selected in the PI-naive darunavir cases, but not in the control group. Conclusions: Our findings suggest that although emergent darunavir resistance is rare, it may be more common among PI-experienced patients than those who are PI-naive. Further investigation is required to explore whether codon 77 is a novel site involved in darunavir susceptibility

Clinical Guidelines of the Russian Society of Surgeons, the Russian Gastroenterological Association, the Association of Surgeons-Hepatologists and the Endoscopic Society “REndO” on Diagnostics and Treatment of Chronic Pancreatitis

Aim: to present modern methods of diagnosis and treatment of chronic pancreatitis for gastroenterologists, general practitioners and physicians.Chronic pancreatitis (CP) is a long-term inflammatory disease of the pancreas, manifested by irreversible morphological changes in the parenchyma and pancreatic ducts, which cause pain and/or persistent impairment of function. Current concept on the etiology of CP is reflected by the TIGAR-O classification. The criteria for establishing the diagnosis of CP include typical attacks of abdominal pain and/or clinical and laboratory signs of exocrine, endocrine insufficiency with the mandatory detection of characteristic morphological changes (calcifications in the parenchyma and pancreatic ductal stones, dilatation of the main pancreatic duct and its branches). CT, MRCP, and pancreatobiliary endosonography are recommended as the methods of choice to verify the diagnosis of CP. Conservative treatment of patients with CP is provided for symptom relief and prevention of complications. Individual cases with severe non-interactable abdominal pain, as well as a complicated course of the disease (development of ductal hypertension due to main pancreatic duct stones or strictures, obstructive jaundice caused by compression of the common bile duct, symptomatic postnecrotic cysts, portal hypertension due to compression of the portal vein or thrombosis of the splenic vein, persistent duodenal obstruction, pseudoaneurysm of the celiac trunk basin and the superior mesenteric artery) serve as an indication for endoscopic or surgical treatment. The Guidelines set out modern approaches to the diagnosis, conservative, endoscopic and surgical treatment of CP, and the prevention of its complications.Conclusion. The implementation of clinical guidelines can contribute to the timely diagnosis and improve the quality of medical care for patients with chronic pancreatitis

Virological failure and development of new resistance mutations according to CD4 count at combination antiretroviral therapy initiation

Objectives: No randomized controlled trials have yet reported an individual patient benefit of initiating combination antiretroviral therapy (cART) at CD4 counts > 350 cells/μL. It is hypothesized that earlier initiation of cART in asymptomatic and otherwise healthy individuals may lead to poorer adherence and subsequently higher rates of resistance development. Methods: In a large cohort of HIV-positive individuals, we investigated the emergence of new resistance mutations upon virological treatment failure according to the CD4 count at the initiation of cART. Results: Of 7918 included individuals, 6514 (82.3%), 996 (12.6%) and 408 (5.2%) started cART with a CD4 count ≤ 350, 351-499 and ≥ 500 cells/μL, respectively. Virological rebound occurred while on cART in 488 (7.5%), 46 (4.6%) and 30 (7.4%) with a baseline CD4 count ≤ 350, 351-499 and ≥ 500 cells/μL, respectively. Only four (13.0%) individuals with a baseline CD4 count > 350 cells/μL in receipt of a resistance test at viral load rebound were found to have developed new resistance mutations. This compared to 107 (41.2%) of those with virological failure who had initiated cART with a CD4 count < 350 cells/μL. Conclusions: We found no evidence of increased rates of resistance development when cART was initiated at CD4 counts above 350 cells/μL. HIV Medicin

Historical and Legal Characteristics of the Judges Status and Judicial Discretion in the Countries of the Ancient East

У статті проведено аналіз статусу суддів та судового розсуду у таких країнах, як Стародавній Єгипет, Стародавня Індія, Стародавній Китай та Стародавній Вавилон. Характерними рисами системи правосуддя у стародавні часи була належність вищої судової влади главі держави (фараону, царю). На місцях судову владу здійснювали призначувані главою держави судді. На судовий розсуд впливали ряд чинників об’єктивного та суб’єктивного характеру. The article analyzes the notions of status of judges and judicial discretion in such countries, as Ancient Egypt, Ancient India, Ancient China and Ancient Babylon. The peculiar feature of the judicial system in ancient times was the fact that the highest judicial power belonged to the Head of a State (Pharaoh, Tsar). At the local level, judicial power was exercised by the judges appointed by the head of a state. A number of objective and subjective factors influenced the judicial discretion. These factors included the social position of both the justice officials and the participants in the process. The ideological (religious) factor had a significant influence on the discretion of the judge in ancient times, although there was a gradual transition from spiritual to secular courts. However, there was one common feature in all the states of the ancient world. It was the requirement regarding the volitional and emotional qualities of a judge. The judge had to be able to hear people and have a high level of the morality norms of the then society

PHASE EQUILIBRIA IN THE Al2O3–TiO2–Y(Er)2O3 SYSTEMS AT 1400 ºС

The aim of this investigation is the construction of isothermal sections for the Al2O3-TiO2-Y(Gd)2O3 phase diagrams at 1400ºС as part of systematic investigations of Al2O3-TiO2-Ln2O3 (Ln=lanthanides, Y) systems. The 1400°C was taken as the temperature, at which no liquid phases are expected in the both systems. The isothermal sections at 1400 °С for the Al2O3– TiO2–Y(Er)2O3 phase diagrams were constructed for the first time. Samples were prepared by a chemical method. Samples were annealed in air at 1400°С for 80 hours and cooled in the furnace. This temperature value was selected with a view to provide possibility of phase transformations character studies. New phases and appreciable solubility regions based on the components and binary compounds were not found, as predicted. Triangulation of the systems is determined by the phase Y(Er)2T2O7, which is in equilibria with compounds Al2TiO5, Y(Er)3Al5O12, Y(Er)AlO3, Y(Er)4Al2O9 and components TiO2 and Al2O3. The structures of isothermal sections of the both systems are similar. The systems are triangulated into six secondary triangles, in which three-phase eutectic are expected. In five quasibinary sections two-phase eutectic should expect to exist. The obtained results will make a significant contribution to the understanding of interactions between the components in the systems studied.This systems offer a number of promising opportunities such as high-temperature structural composites based on directionally solidified two-phase and three-phase eutectic materials, solid electrolytes (SOFCs, oxygen sensors, film for electronic devices, etc.), promising to accumulate water, immobilizing materials for nuclear industry, tough ceramics, catalysts carriers, wear- and corrosion-resistant ceramic coatings and super refractories

ФАЗОВІ РІВНОВАГИ В СИСТЕМАХ Al2O3–TiO2–Y(Er)2O3 ПРИ 1400 ºС

The aim of this investigation is the construction of isothermal sections for the Al2O3-TiO2-Y(Gd)2O3 phase diagrams at 1400ºС as part of systematic investigations of Al2O3-TiO2-Ln2O3 (Ln=lanthanides, Y) systems. The 1400°C was taken as the temperature, at which no liquid phases are expected in the both systems. The isothermal sections at 1400 °С for the Al2O3– TiO2–Y(Er)2O3 phase diagrams were constructed for the first time. Samples were prepared by a chemical method. Samples were annealed in air at 1400°С for 80 hours and cooled in the furnace. This temperature value was selected with a view to provide possibility of phase transformations character studies. New phases and appreciable solubility regions based on the components and binary compounds were not found, as predicted. Triangulation of the systems is determined by the phase Y(Er)2T2O7, which is in equilibria with compounds Al2TiO5, Y(Er)3Al5O12, Y(Er)AlO3, Y(Er)4Al2O9 and components TiO2 and Al2O3. The structures of isothermal sections of the both systems are similar. The systems are triangulated into six secondary triangles, in which three-phase eutectic are expected. In five quasibinary sections two-phase eutectic should expect to exist. The obtained results will make a significant contribution to the understanding of interactions between the components in the systems studied.This systems offer a number of promising opportunities such as high-temperature structural composites based on directionally solidified two-phase and three-phase eutectic materials, solid electrolytes (SOFCs, oxygen sensors, film for electronic devices, etc.), promising to accumulate water, immobilizing materials for nuclear industry, tough ceramics, catalysts carriers, wear- and corrosion-resistant ceramic coatings and super refractories.Вперше побудовано ізотермічні перерізи діаграм стану систем Al2O3–TiO2–Y(Er)2O3 при 1400 °С. Триангуляція систем визначається фазою Y(Er)2T2O7, яка знаходиться в рівновазі зі сполуками Al2TiO5, Y(Er)3Al5O12, Y(Er)AlO3, Y(Er)4Al2O9 та компонентами системи TiO2 і Al2O3. Системи триангулюються на шість вторинних трикутників, в яких очікується наявність трифазних евтектик, а на п’яти квазібінарних перерізах систем слід очікувати існування квазіподвійних евтектик

Mortality of treated HIV-1 positive individuals according to viral subtype in Europe and Canada: collaborative cohort analysis

Objectives: To estimate prognosis by viral subtype in HIV-1-infected individuals from start of antiretroviral therapy (ART) and after viral failure. Design: Collaborative analysis of data from eight European and three Canadian cohorts. Methods: Adults (N>20 000) who started triple ART between 1996 and 2012 and had data on viral subtype were followed for mortality. We estimated crude and adjusted (for age, sex, regimen, CD4þ cell count, and AIDS at baseline, period of starting ART, stratified by cohort, region of origin and risk group) mortality hazard ratios (MHR) by subtype. We estimated MHR subsequent to viral failure defined as two HIV-RNA measurements greater than 500 copies/ml after achieving viral suppression. Results: The most prevalent subtypes were B (15 419; 74%), C (2091; 10%), CRF02AG (1057; 5%), A (873; 4%), CRF01AE (506; 2.4%), G (359; 1.7%), and D (232; 1.1%). Subtypes were strongly patterned by region of origin and risk group. During 104 649 person-years of observation, 1172/20 784 patients died. Compared with subtype B, mortality was higher for subtype A, but similar for all other subtypes. MHR for A versus B were 1.13 (95% confidence interval 0.85,1.50) when stratified by cohort, increased to 1.78 (1.27,2.51) on stratification by region and risk, and attenuated to 1.59 (1.14,2.23) on adjustment for covariates. MHR for A versus B was 2.65 (1.64,4.28) and 0.95 (0.57,1.57) for patients who started ART with CD4þ cell count below, or more than, 100 cells/ml, respectively. There was no difference in mortality between subtypes A, B and C after viral failure. Conclusion: Patients with subtype A had worse prognosis, an observation which may be confounded by socio-demographic factors

Associations between baseline characteristics, CD4 cell count response and virological failure on first-line efavirenz

Objectives The aim of this study was to investigate associations between baseline characteristics and CD4 cell count response on first-line antiretroviral therapy and risk of virological failure (VF) with or without drug resistance. Methods We conducted an analysis of UK Collaborative HIV Cohort data linked to the UK HIV Drug Resistance Database. Inclusion criteria were viral sequence showing no resistance prior to initiation of first-line efavirenz + tenofovir disoproxil fumarate + emtricitabine and virological suppression within 6 months. Outcomes of VF (≥200 copies/mL) with or without drug resistance were assessed using a competing risks approach fitted jointly with a model for CD4 cell count recovery. Hazard ratios for each VF outcome were estimated for baseline CD4 cell count and viral load and characteristics of CD4 cell count response using latent variables on a standard normal scale. Results A total of 3640 people were included with 338 VF events; corresponding viral sequences were available in 134 with ≥1 resistance mutation in 36. VF with resistance was associated with lower baseline CD4 (0.30, 0.09–0.62), lower CD4 recovery (0.04, 0.00–0.17) and higher CD4 variability (4.40, 1.22–12.68). A different pattern of associations was observed for VF without resistance, but the strength of these results was less consistent across sensitivity analyses. Cumulative incidence of VF with resistance was estimated to be <2% at 3 years for baseline CD4 ≥350 cells/μL. Conclusion Lower baseline CD4 cell count and suboptimal CD4 recovery are associated with VF with drug resistance. People with low CD4 cell count before ART or with suboptimal CD4 recovery on treatment should be a priority for regimens with high genetic barrier to resistance