Predictive factors for decompensating events in patients with cirrhosis with primary biliary cholangitis under different lines of therapy.

BACKGROUND AND AIMS: The landscape in primary biliary cholangitis (PBC) has changed with the advent of second-line treatments. However, the use of obeticholic acid (OCA) and fibrates in PBC-related cirrhosis is challenging. We assessed the impact of receiving a second-line therapy as a risk factor for decompensated cirrhosis in a real-world population with cirrhosis and PBC, and identify the predictive factors for decompensated cirrhosis in these patients. APPROACH AND RESULTS: Multicenter study enrolling 388 patients with PBC-cirrhosis from the Spanish ColHai registry. Biopsy (20%), ultrasound (59%), or transient elastography (21%) defined cirrhosis, and the presence of varices and splenomegaly defined clinically significant portal hypertension (CSPH). Paris-II and PBC OCA international study of efficacy criteria determined the response to ursodeoxycholic acid (UDCA), fibrates (n=93), and OCA (n=104). The incidence of decompensated cirrhosis decreased for UDCA versus OCA or fibrates in the real-world population, but they were similar considering the propensity score-matched cohort (UDCA 3.77 vs. second-line therapy 4.5 100 persons-year, respectively), as patients on second-line therapy exhibited advanced liver disease. Consequently, GGT, albumin, platelets, clinically significant portal hypertension, and UDCA response were associated with a decompensating event. OCA response (achieved in 52% of patients) was associated with bilirubin (OR 0.21 [95% CI: 0.06-0.73]) and AST (OR 0.97 [95% CI: 0.95-0.99]), while fibrate response (achieved in 55% of patients) with AST [OR 0.96 (95% CI: 0.95-0.98]). In patients treated with OCA, drug response (sHR 0.23 [95% CI: 0.08-0.64]), diabetes (sHR 5.62 [95% CI: 2.02-15.68]), albumin (sHR 0.34 [95% CI: 0.13-0.89]), and platelets (sHR 0.99 [95% CI: 0.98-1.00]) were related to decompensation. In patients treated with fibrate, drug response (sHR 0.36 (95% CI: 0.14-0.95]), albumin (sHR 0.36 (95% CI: 0.16-0.81]), and clinically significant portal hypertension (sHR 3.70 (95% CI: 1.17-11.70]) were associated with decompensated cirrhosis. CONCLUSIONS: Advanced PBC, rather than OCA and fibrates, was found to be associated with decompensating events. Therefore, biochemical and clinical variables should be considered when making decisions about the management of these drugs. Moreover, a positive response to OCA and fibrates reduced the risk of decompensation.

Tenofovir Disoproxil Fumarate Reduces the Severity of COVID-19 in Patients with Chronic Hepatitis B.

BACKGROUND AND AIMS: HIV-positive patients on tenofovir hydroxyl fumarate (TDF)/emtricitabine have a lower risk of COVID-19 and hospitalization than those given other treatments. Our aim was to analyze the severity of COVID-19 in patients with chronic hepatitis B (CHB) on TDF or entecavir (ETV). METHODS: Spanish hospital databases (n = 28) including information regarding adult CHB patients on TDF or ETV for the period February 1st to November 30th 2020 were searched for COVID-19, defined as a positive SARS-CoV-2 polymerase chain reaction, and for severe COVID-19. RESULTS: Of 4736 patients, 117 had COVID-19 (2.5%), 67 on TDF and 50 on ETV. Compared to patients on TDF, those on ETV showed (p < 0.05) greater rates of obesity, diabetes, ischemic cardiopathy, and hypertension. COVID-19 incidence was similar in both groups (2.3 vs. 2.6%). Compared to TDF, patients on ETV more often (p < 0.01) had severe COVID-19 (36 vs. 6%), required intensive care unit (ICU) (10% vs. 0) or ventilatory support (20 vs. 3%), were hospitalized for longer (10.8 ± 19 vs. 3.1 ± 7 days) or died (10 vs. 1.5%, p = 0.08). In an IPTW propensity score analysis adjusted for age, sex, obesity, comorbidities, and fibrosis stage, TDF was associated with a sixfold reduction in severe COVID-19 risk (adjusted-IPTW-OR 0.17, 95%CI 0.04-0.67, p = 0.01). CONCLUSION: Compared to ETV, TDF seems to play a protective role in CHB patients with SARS-CoV-2 whereby the risk of severe COVID-19 is lowered.

Ultrafast all-optical phase switching enabled by epsilon-near-zero materials in silicon.

Transparent conducting oxides (TCOs) have emerged as both particularly appealing epsilon-near-zero (ENZ) materials and remarkable candidates for the design and fabrication of active silicon nanophotonic devices. However, the leverage of TCO's ultrafast nonlinearities requires precise control of the intricate physical mechanisms that take place upon excitation. Here we investigate such behavior for ultrafast all-optical phase switching in hybrid TCO-silicon waveguides through numerical simulation. The model is driven from the framework of intraband-transition-induced optical nonlinearity. Transient evolution is studied with a phenomenological two-temperature model. Our results reveal the best compromise between energy consumption, insertion losses and phase change per unit length for enabling ultrafast switching times below 100 fs and compact active lengths in the order of several micrometers.

Effect of physical therapy on bone remodelling in preterm infants: a multicenter randomized controlled clinical trial.

BACKGROUND: Preterm infants have a low level of bone mineralization compared to those born at term, since 80% of calcium incorporation occurs at the end of pregnancy. The purpose of the present study was to investigate the effect of reflex locomotion therapy on bone modeling and growth in preterm infants and to compare its effect with those of other Physiotherapy modalities. METHODS: A multicentre randomized controlled clinical trial was conducted (02/2016 - 07/2020). 106 preterm infants born at the Virgen de la Arrixaca University Clinical Hospital, the General University Hospital of Elche and the Torrecárdenas University Hospital of Almería, between 26 and 34 weeks with hemodynamic stability, complete enteral nutrition and without any metabolic, congenital, genetic, neurological or respiratory disorders were evaluated for inclusion. Infants were randomly assigned to three groups: one group received reflex locomotion therapy (EGrlt); another group received passive mobilizations with gentle joint compression (EGpmc); and the control group received massage (CG). All treatments were carried out in the neonatal units lasting one month. The main outcome measure was bone formation and resorption measured with bone biomarkers. A mixed ANOVA was used to compare the results of bone biomarkers, and anthropometric measurements. RESULTS: Infants were randomized to EGrlt (n = 38), EGpmc (n = 32), and CG (n = 36). All groups were similar in terms of gender (p = 0.891 female 47.2%), gestational age (M = 30.753, SD = 1.878, p = 0.39) and birth weight (M = 1413.45, SD = 347.36, p = 0.157). At the end of the study, significant differences were found between the groups in their interaction in bone formation, measured with osteocalcin [F (2,35) = 4.92, p = 0.013, ηp2 = 0.043], in benefit of the EGrlt. CONCLUSIONS: Reflex locomotion therapy has been effective in improving bone formation, more so than other Physiotherapy modalities. Therefore, reflex locomotion therapy could be considered one of the most effective physiotherapeutic modalities for the prevention and treatment of osteopenia of prematurity. TRIAL REGISTRSTION: Trial retrospectively registered at ClinicalTrials.gov. First posted on 22/04/2020. REGISTRATION NUMBER: NCT04356807 .

Coping with arid environments: A critical threshold for human expansion in Europe at the Marine Isotope Stage 12/11 transition? The case of the Iberian Peninsula.

Archaeological remains have highlighted the fact that the interglacial Marine Isotope Stage (MIS) 11 was a threshold from the perspective of hominin evolution in Europe. After the MIS 12 glaciation, considered one of the major climate-driven crises experienced by hominins, the archaeological records show an increasing number of occupations, evidence of new subsistence behaviors, and significant technical innovations. Here, we used statistical and geographic techniques to analyze the amphibian- and reptile-based paleoclimate and habitat reconstructions generated from a large data set of the Iberian Peninsula to (1) investigate if temperature, precipitation, and/or forest cover may have impacted the hominin occupation of the territory during the Early and Middle Pleistocene, (2) propose an 'Iberian' ecological model before and after the MIS 12/11 transition, and (3) evaluate, based on this model, the potential hominin occupation at a European scale. The results indicate the existence of climatic constraints on human settlement related to rainfall and environmental humidity. The Early Pleistocene and the first half of the Middle Pleistocene are dominated by the occupation of relatively humid wooded areas, whereas during the second part of the Middle Pleistocene, a broadening of the earlier ecological niche is clearly observed toward the occupation of more open arid areas. Based on the estimated occupational niche for hominins, a maximum potential distribution for early hominins is proposed in Europe before and after 426 ka. Results also indicate that parts of the Iberian Peninsula may not have been suitable for early hominin occupation. Our ecological model is consistent with the pattern of hominin occupation observed in northern and central Europe, where the earliest evidence reflects only pioneering populations merely extending their ranges in response to the expansion of their preferred habitats, as compared with a more sustained occupation by 400 ka.

Protocol for Successful Transmission of 'Candidatus Liberibacter asiaticus' from Citrus to Citrus Using Diaphorina citri.

A protocol to successfully transmit the huanglongbing (HLB) pathogen, 'Candidatus Liberibacter asiaticus', between citrus plants by using the Asian citrus psyllid (ACP) and an alternative way to help growers control ACP are proposed. Best results were obtained when pathogen acquisition by adults reared on fully symptomatic 'Ca. Liberibacter asiaticus'-positive plants, latency, and inoculation occurred at ambient air temperatures ranging from 24 to 28°C and when a single infective adult ACP was confined for 7 days on soft, newly developing vegetative shoots (stages v2 to v4). No infection resulted from confinement of infective ACP adults on mature leaves (stage v6). Under the described conditions, single ACP adults could successfully transmit 'Ca. Liberibacter asiaticus' to an average of 56.5% (35 to 83%) of plantlets with v2 to v4 shoots growing in 0.3-liter tubes and to 80.5% (76 to 86%) of plants with v2 to v4 shoots growing in 4.7-liter pots. The use of single insects and plantlets reduces labor, space, and other resources necessary to undertake transmission tests. It also reduces time needed for transmission studies and should help accelerate research on HLB. The results were used to develop an index for favorability to infection (IFI) to determine orchard vulnerabilities to 'Ca. Liberibacter asiaticus'. The IFI is based on the heterogeneous population of new shoots that occurs on tree canopies and may offer alternative or complementary alternatives to the laborious and costly insect surveys currently used in most instances to determine threshold levels for insecticide applications.

Modeling 'Candidatus Liberibacter asiaticus' Movement Within Citrus Plants.

The phloem-limited 'Candidatus Liberibacter asiaticus' (Las) causes huanglongbing, a destructive citrus disease. Graft-inoculated potted plants were used to assess Las speed of movement in phloem in the greenhouse, and the impacts of temperature on plant colonization in growth-chamber experiments. For assessment of Las speed, plants were inoculated at the main stem and assessed over time by quantitative PCR (qPCR) or symptoms at various distances from the inoculum. For colonization, the plants were inoculated in one of two opposite top branches, maintained at from 8 to 20°C, from 18 to 30°C, or from 24 to 38°C daily range, and assessed by qPCR of samples taken from noninoculated shoots. For all experiments, frequencies of Las-positive sites were submitted to analysis of variance and binomial generalized linear model and logistic regression analyses. Probabilities of detecting Las in greenhouse plants were functions of time and distance from the inoculation site, which resulted in 2.9 and 3.8 cm day-1 average speed of movement. In growth chambers, the temperature impacted plant colonization by Las, new shoot emission, and symptom expression. After a 7-month exposure time, Las was absent in all new shoots in the cooler environment (average three per plant), and present in 70% at the milder environment (six shoots, severe symptoms) and 25% in the warmer environment (eight shoots, no visible symptoms). Temperature of 25.7°C was the optimum condition for plant colonization. This explains the higher impact and incidence of huanglongbing disease during the winter months or regions of milder climates in Brazil.

Evidence That 'Candidatus Liberibacter asiaticus' Moves Predominantly Toward New Tissue Growth in Citrus Plants.

'Candidatus Liberibacter asiaticus' (Las) is an unculturable, phloem-limited, insect-transmitted bacterium associated with the Asiatic form of huanglongbing (HLB), the most destructive citrus disease. In Asia and the Americas, it is transmitted by the Asian citrus psyllid (Diaphorina citri Kuwavama). Despite considerable research, little is known about the processes involved in plant infection and colonization by Las. This study was conducted to determine whether the basal portion (below girdling) of the plant is an important route for Las to move laterally from a point of inoculation on a branch to pathogen-free branches elsewhere in the canopy, and to quantify the influence of actively growing tissues on vertical upward (acropetally) or downward (basipetally) movement of Las. Nongirdled and fully or partially girdled stems of potted plants of 'Pera' sweet orange, graft-inoculated above or below girdling, were sampled in distinct regions and assessed by qPCR, 6 months postinoculation. Las invaded all regions of partially and nongirdled plants but remained restricted to the inoculated regions of fully girdled plants, evidence that in planta bacterium movement is limited to the phloem. In fully girdled plants, starch accumulated above the girdling site, probably because of changes in flow of phloem sap. To study the influence of actively growing tissues, inoculated 'Valencia' sweet orange plants were kept intact or were top- or root-pruned to force production of new tissues, and sampled at 15-day intervals. Las migrated rapidly and most predominantly toward newly developing root and leaf tissues. The rapid and predominant movement of Las to newly developed shoots and roots would explain failures of canopy heat treatments and pruning to cure HLB-affected trees, and reinforces the need to protect rapidly growing new shoots from feeding by D. citri in order to minimize transmission and spread of the pathogen by the vector within and between orchards.

International and multicenter real-world study of sorafenib-treated patients with hepatocellular carcinoma under dialysis.

BACKGROUND & AIMS: Information on safety and efficacy of systemic treatment in patients with hepatocellular carcinoma (HCC) under dialysis are limited due to patient exclusion from clinical trials. Thus, we aimed to evaluate the rate, prevalence, tolerability, and outcome of sorafenib in this population. METHODS: We report a multicenter study comprising patients from Latin America and Europe. Patients treated with sorafenib were enrolled; demographics, dose modifications, adverse events (AEs), treatment duration, and outcome of patients undergoing dialysis were recorded. RESULTS: As of March 2018, 6156 HCC patients were treated in 44 centres and 22 patients were concomitantly under dialysis (0.36%). The median age was 65.5 years, 40.9% had hepatitis C, 75% had Child-Pugh A, and 85% were Barcelona Clinic Liver Cancer-C. The median time to first dose modification, treatment duration and overall survival rate were 2.4 months (interquartile ranges [IQR], 0.8-3.8), 10.8 months (IQR, 4.5-16.9), and 17.5 months (95% CI, 7.2-24.5), respectively. Seventeen patients required at least 1 dose modification. The main causes of first dose modification were asthenia/worsening of Eastern Cooperative Oncology Group-Performance Status and diarrhoea. At the time of death or last follow-up, four patients were still on treatment and 18 had discontinued sorafenib: 14 were due to tumour progression, 2 were sorafenib-related, and 2 were non-sorafenib-related AE. CONCLUSIONS: The outcomes observed in this cohort seem comparable to those in the non-dialysis population. Thus, to the best of our knowledge, this is the largest and most informative dataset regarding systemic treatment outcomes in HCC patients undergoing dialysis.

[Social inequality in the use of screening tests in Mexico: an analysis of the national health surveys 2006 and 2012]. / Desigualdad social en México enel uso de servicios de tamizaje en adultos: un análisis de las encuestas nacionales de salud 2006 y 2012.

OBJECTIVE: To measure health inequality in the use of screen-ing services in adults from 20 to 59 years of age from the 2006 and 2012 national health and nutrition surveys. MATERIALS AND METHODS: dults (detection of diabetes, hypertension, breast cancer, cervical cancer and prostate cancer), the Kuznets index, the slope inequality index and the health concentration index were estimated. Considering as social indicators schooling, ethnicity, unemployment, socioeconomic level and type of health protection. RESULTS: The coverage of the five tests increased, but the inequality observed only decreased in the interventions in women; and in the case of the detection of prostate cancer it was increased. CONCLUSIONS: While it is important to monitor the performance of curative services, the challenge remains to ensure effective and equitable access to early diagnosis services.

OBJETIVO: Medir la desigualdad en el uso de servicios de tamizaje en adultos de 20 a 59 años, a partir de las encuestas nacionales de salud y nutrición 2006 y 2012. MATERIAL Y MÉTODOS: A partir de la selección de cinco indicadores de tamizaje en adultos (detección de diabetes, hipertensión y cánceres de mama, cérvicouterino y de próstata) se estimaron el índice de Kuznets, el índice de desigualdad de la pendiente y el índice de concentración de salud, considerando como indicadores sociales la escolaridad, etnicidad, desempleo, nivel socioeconómico y tipo de protección en salud. RESULTADOS: Las coberturas de las cinco pruebas se incrementaron, sin embargo, la desigualdad observada disminuyó únicamente en las intervenciones en mujeres; en el caso de la detección de cáncer de próstata se incrementó. CONCLUSIONES: Si bien es importante monitorear el desempeño de los servicios curativos, persiste el reto de asegurar el acceso efectivo y equitativo a servicios de diagnóstico temprano.

Effectiveness and safety of sofosbuvir/velpatasvir/voxilaprevir in patients with chronic hepatitis C previously treated with DAAs.

BACKGROUND & AIMS: Around 5% of patients with chronic hepatitis C virus (HCV) infection treated with direct-acting antiviral (DAA) agents do not achieve sustained virological response (SVR). The currently approved retreatment regimen for prior DAA failure is a combination of sofosbuvir, velpatasvir, and voxilaprevir (SOF/VEL/VOX), although there is little data on its use in clinical practice. The aim of this study was to analyse the effectiveness and safety of SOF/VEL/VOX in the real-world setting. METHODS: This was a prospective multicentre study assessing the efficacy of retreatment with SOF/VEL/VOX in patients who had experienced a prior DAA treatment failure. The primary endpoint was SVR 12 weeks after the completion of treatment (SVR12). Data on safety and tolerability were also recorded. RESULTS: A total of 137 patients were included: 75% men, 35% with liver cirrhosis. Most were infected with HCV genotype (GT) 1 or 3. The most common prior DAA combinations were sofosbuvir plus an NS5A inhibitor or ombitasvir/paritaprevir/r+dasabuvir. A total of 136 (99%) patients achieved undetectable HCV RNA at the end of treatment. Overall SVR12 was 95% in the 135 patients reaching this point. SVR12 was lower in patients with cirrhosis (89%, p = 0.05) and those with GT3 infection (80%, p <0.001). Patients with GT3 infection and cirrhosis had the lowest SVR12 rate (69%). Of the patients who did not achieve SVR12, 1 was reinfected and 7 experienced treatment failure (6 GT3, 1 GT1a). The presence of resistance-associated substitutions did not impact SVR12. Adverse effects were mild and non-specific. CONCLUSION: Real-world data show that SOF/VEL/VOX is an effective, safe rescue therapy for patients with prior DAA treatment failure despite the presence of resistance-associated substitutions. However, patients with liver cirrhosis infected by GT3 remain the most-difficult-to-treat group. LAY SUMMARY: Treatment with sofosbuvir/velpatasvir/voxilaprevir (SOF/VEL/VOX) for 12 weeks is the current recommendation for the 5% of patients infected with HCV who do not achieve eradication of the virus under treatment with direct-acting antivirals. In a Spanish cohort of 137 patients who failed a previous combination of direct-acting antivirals, a cure rate of 95% was achieved with SOF/VEL/VOX. Genotypic characteristics of the virus (genotype 3) and the presence of cirrhosis were factors that decreased the rate of cure. Treatment with SOF/VEL/VOX is an effective and safe rescue therapy due to its high efficacy and very good safety profile.

Murraya paniculata and Swinglea glutinosa as Short-Term Transient Hosts of 'Candidatus Liberibacter asiaticus' and Implications for the Spread of Huanglongbing.

Murraya paniculata and Swinglea glutinosa are aurantioid hosts of the Asian citrus psyllid (ACP) Diaphorina citri, the principal vector of 'Candidatus Liberibacter asiaticus' (Las). Las is the pathogen associated with huanglongbing (HLB), the Asian form of which is the most devastating disease of Citrus species and cultivars (Rutaceae: Aurantioideae). M. paniculata is a common ornamental and S. glutinosa is grown as an ornamental, a citrus rootstock, and a hedgerow fence plant. Because of the uncertain status of these plants as reservoirs of Las, a series of cross-inoculation bioassays were carried out in different environments, using infected Valencia sweet orange (Citrus × aurantium) infected shoot tops as a source of inoculum and D. citri nymphs and adults reared on M. paniculata and S. glutinosa to inoculate pathogen-free Valencia orange plantlets. In contrast to sweet orange, Las was more unevenly distributed and reached much lower titers in M. paniculata and S. glutinosa. Infections in M. paniculata and S. glutinosa were also transient. Very few insects that successfully acquired Las from M. paniculata and S. glutinosa were able to transmit the pathogen to healthy citrus. Transmission rates were low from M. paniculata (1.0%) and S. glutinosa (2.0%) and occurred only in a controlled environment highly favorable to Las and ACP using 10-day-old adults that completed their life cycle on Las-positive plants. Our study showed that in HLB-endemic areas, M. paniculata and S. glutinosa can be deemed as epidemiologically dead-end hosts for Las and are not important alternative hosts of the pathogen for transmission to citrus. However, under a combination of conditions highly favorable to Las infection and transmission and in the absence of effective quarantine procedures, these plants could eventually serve as carriers of Las to regions currently free from HLB.

Increasing importance of European lineages in seeding the hepatitis C virus subtype 1a epidemic in Spain.

BackgroundReducing the burden of the hepatitis C virus (HCV) requires large-scale deployment of intervention programmes, which can be informed by the dynamic pattern of HCV spread. In Spain, ongoing transmission of HCV is mostly fuelled by people who inject drugs (PWID) infected with subtype 1a (HCV1a).AimOur aim was to map how infections spread within and between populations, which could help formulate more effective intervention programmes to halt the HCV1a epidemic in Spain.MethodsEpidemiological links between HCV1a viruses from a convenience sample of 283 patients in Spain, mostly PWID, collected between 2014 and 2016, and 1,317, 1,291 and 1,009 samples collected abroad between 1989 and 2016 were reconstructed using sequences covering the NS3, NS5A and NS5B genes. To efficiently do so, fast maximum likelihood-based tree estimation was coupled to a flexible Bayesian discrete phylogeographic inference method.ResultsThe transmission network structure of the Spanish HCV1a epidemic was shaped by continuous seeding of HCV1a into Spain, almost exclusively from North America and European countries. The latter became increasingly relevant and have dominated in recent times. Export from Spain to other countries in Europe was also strongly supported, although Spain was a net sink for European HCV1a lineages. Spatial reconstructions showed that the epidemic in Spain is diffuse, without large, dominant within-country networks.ConclusionTo boost the effectiveness of local intervention efforts, concerted supra-national strategies to control HCV1a transmission are needed, with a strong focus on the most important drivers of ongoing transmission, i.e. PWID and other high-risk populations.

Treatment of hepatitis C virus infection in patients with cirrhosis and predictive value of model for end-stage liver disease: Analysis of data from the Hepa-C registry.

Direct-acting antiviral agents (DAAs) are highly effective and well tolerated in patients with chronic hepatitis C virus infection, including those with compensated cirrhosis. However, fewer data are available in patients with more advanced liver disease. Our retrospective, noninterventional, national, multicenter study in patients from the Spanish Hepa-C registry investigated the effectiveness and safety of interferon-free DAA regimens in patients with advanced liver disease, including those with decompensated cirrhosis, in routine practice (all currently approved regimens were registered). Patients transplanted during treatment or within 12 weeks of completing treatment were excluded. Among 843 patients with cirrhosis (Child-Turcotte-Pugh [CTP] class A, n = 564; CTP class B/C, n = 175), 90% achieved sustained virologic response 12 weeks after treatment (SVR12). Significant differences in SVR12 and relapse rates were observed between CTP class A and CTP class B/C patients (94% versus 78%, and 4% versus 14%, respectively; both P < 0.001). Serious adverse events (SAEs) were more common in CTP class B/C versus CTP class A patients (50% versus 12%, respectively; P < 0.001). Incident decompensation was the most common serious adverse event (7% overall). Death rate during the study period was 16/843 (2%), significantly higher among CTP class B/C versus CTP class A patients (6.4% versus 0.9%; P < 0.001). Baseline Model for End-Stage Liver Disease (MELD) score alone (cut-off 18) was the best predictor of survival. CONCLUSION: Patients with decompensated cirrhosis receiving DAAs present lower response rates and experience more SAEs. In this setting, a MELD score ≥18 may help clinicians to identify those patients with a higher risk of complications and to individualize treatment decisions. (Hepatology 2017;65:1810-1822).

An MS-CASPT2 study of the photodecomposition of 4-methoxyphenyl azide: role of internal conversion and intersystem crossing.

The photochemical decomposition of 4-methoxyphenyl azide (CH3O-Ph-N3) is investigated using multiconfigurational second-order perturbation theory (MS-CASPT2). In addition, the multi-state resonance Raman spectra of the reactant, intermediates, and product are computed with a multi-state version of the vibronic theory of Albrecht. The results support that the key step of the photolysis of the parent azide is a 21A'/23A'' intersystem crossing which in a second step decays through a 23A''/13A'' conical intersection to give directly the formation of triplet 4-methoxyphenyl nitrene (CH3O-Ph-N) in its lowest electronic state, 13A''. It is found that the efficiency of the cited intersystem crossing is enhanced by the close presence of a 21A'/21A'' conical intersection. On the other hand, the calculated spectra suggest that the only two species which would be observed in the gas phase experiments are the triplet nitrene plus 4,4'-dimethoxyazobenzene.

Effectiveness, safety and clinical outcomes of direct-acting antiviral therapy in HCV genotype 1 infection: Results from a Spanish real-world cohort.

BACKGROUND & AIMS: Clinical trials evaluating second-generation direct-acting antiviral agents (DAAs) have shown excellent rates of sustained virologic response (SVR) and good safety profiles in patients with chronic hepatitis C virus (HCV) genotype 1 infection. We aimed to investigate the effectiveness and safety of two oral DAA combination regimens, ombitasvir/paritaprevir/ritonavir plus dasabuvir (OMV/PTV/r+DSV) and ledipasvir/sofosbuvir (LDV/SOF), in a real-world clinical practice. METHODS: Data from HCV genotype 1 patients treated with either OMV/PTV/r+DSV±ribavirin (RBV) (n=1567) or LDV/SOF±RBV (n=1758) in 35 centers across Spain between April 1, 2015 and February 28, 2016 were recorded in a large national database. Demographic, clinical and virological data were analyzed. Details of serious adverse events (SAEs) were recorded. RESULTS: The two cohorts were not matched with respect to baseline characteristics and could not be compared directly. The SVR12 rate was 96.8% with OMV/PTVr/DSV±RBV and 95.8% with LDV/SOF±RBV. No significant differences were observed in SVR according to HCV subgenotype (p=0.321 [OMV/PTV/r+DSV±RBV] and p=0.174 [LDV/SOF]) or degree of fibrosis (c0.548 [OMV/PTV/r/DSV±RBV] and p=0.085 [LDV/SOF]). Only baseline albumin level was significantly associated with failure to achieve SVR (p<0.05) on multivariate analysis. Rates of SAEs and SAE-associated treatment discontinuation were 5.4% and 1.7%, in the OMV/PTV/r+DSV subcohort and 5.5% and 1.5% in the LDV/SOF subcohort, respectively. Hepatocellular carcinoma (HCC) recurred in 30% of patients with a complete response to therapy for previous HCC. Incident HCC was reported in 0.93%. CONCLUSIONS: In this large cohort of patients managed in the real-world setting in Spain, OMV/PTV/r+DSV and LDV/SOF achieved high rates of SVR12, comparable to those observed in randomized controlled trials, with similarly good safety profiles. LAY SUMMARY: In clinical trials, second-generation direct-acting antiviral agents (DAAs) have been shown to cure over 90% of patients chronically infected with the genotype 1 hepatitis C virus and have been better tolerated than previous treatment regimens. However, patients enrolled in clinical trials do not reflect the real patient population encountered in routine practice. The current study, which includes almost 4,000 patients, demonstrates comparable rates of cure with two increasingly used DAA combinations as those observed in the clinical trial environment, confirming that clinical trial findings with DAAs translate into the real-world setting, where patient populations are more diverse and complex.

Real-World Effectiveness and Safety of Oral Combination Antiviral Therapy for Hepatitis C Virus Genotype 4 Infection.

Patients with hepatitis C virus (HCV) genotype 4 infection are poorly represented in clinical trials of second-generation direct-acting antiviral agents (DAAs). More data are needed to help guide treatment decisions. We investigated the effectiveness and safety of DAAs in patients with genotype 4 infection in routine practice. In this cohort study, HCV genotype 4-infected patients treated with ombitasvir/paritaprevir/ritonavir (OMV/PTVr) + ribavirin (RBV) (n=122) or ledipasvir/sofosbuvir (LDV/SOF) ± RBV (n=130) included in a national database were identified and prospectively followed up. Demographic, clinical and virologic data and serious adverse events (SAEs) were analyzed. Differences between treatment groups mean that data cannot be compared directly. Overall sustained virologic response at Week 12 post treatment (SVR12) was 96.2% with OMV/PTVr+RBV and 95.4% with LDV/SOF±RBV. In cirrhotic patients, SVR12 was 91.2% with OMV/PTVr+RBV and 93.2% with LDV/SOF±RBV. There was no significant difference in SVR12 according to degree of fibrosis in either treatment group (P = .243 and P = .244, respectively). On multivariate analysis, baseline albumin <3.5 g/dL (OMV/PTVr) and bilirubin >2 mg/dL (both cohorts) were significantly associated with failure to achieve SVR (P < .05). Rates of SAEs and SAE-associated discontinuation were 5.7% and 2.5%, respectively, in the OMV/PTVr subcohort and 4.6% and 0.8%, respectively, in the LDV/SOF subcohort. DAA-based regimens returned high rates of SVR12, comparable to limited data from clinical trials, in cirrhotic and non-cirrhotic HCV genotype 4 patients managed in a realworld setting. Safety profiles of both regimens were good and comparable to those reported for other HCV genotypes.

Seasonal Variation of 'Candidatus Liberibacter asiaticus' Titers in New Shoots of Citrus in Distinct Environments.

The major citrus area of Brazil occupies near 450,000 ha between the Triângulo Mineiro (TM) region of Minas Gerais State and the south of São Paulo State (SPS). Significant climatic variation occurs between regions which could affect huanglongbing (HLB) progress, which is lower in TM. To investigate this possibility, young sweet orange shoots were sampled periodically over 2 years to determine 'Candidatus Liberibacter asiaticus' titers in naturally infected trees in orchards in Analândia, central SPS, and Frutal and Comendador Gomes, within TM. Data-loggers recorded local temperature and relative humidity hourly. In the laboratory, five 'Ca. L. asiaticus'-free Diaphorina citri adults were placed on each sampled shoot for 48 h to feed and acquire the pathogen. Shoots and insects were individually analyzed by quantitative polymerase chain reaction to determine 'Ca. L. asiaticus' titers. The incidence of 'Ca. L. asiaticus'-positive shoots, 'Ca. L. asiaticus' titers, and acquisition rates were lower for shoots from Comendador Gomes than those from Frutal or Analândia. Stronger association was observed between 'Ca. L. asiaticus' titers and the number of hours below 15°C (h < 15°C) or above 30°C (h > 30°C), and cumulative rainfall registered during the 15 days prior to sampling of shoots on each occasion. 'Ca. L. asiaticus' titers associated positively with h < 15°C and rainfall and negatively with h > 30°C. The slower spread and lower incidence of HLB in TM may be related to lower incidences of 'Ca. L. asiaticus'-positive young shoots and lower titers of 'Ca. L. asiaticus' in the same shoots as a consequence of the warmer and drier conditions.

The ART-SCORE is not an effective tool for optimizing patient selection for DEB-TACE retreatment. A multicentre Spanish study.

INTRODUCTION: The appropriate selection of hepatocellular carcinoma (HCC) patients who are eligible for transarterial chemoembolization (TACE) remains a challenge. The ART score has recently been proposed as a method of identifying patients who are eligible or not for a second TACE procedure. OBJECTIVE: To assess the validity of the Assessment for Retreatment with TACE (ART) score in a cohort of patients treated with drug-eluting bead TACE (DEB-TACE). SECONDARY OBJECTIVE: to identify clinical determinants associated with overall survival (OS). METHOD: A retrospective, multicentre study conducted in Spain in patients with HCC having undergone two or more DEB-TACE procedures between January 2009 and December 2014. The clinical characteristics and OS from the day before the second DEB-TACE of patients with a high ART score (ART≥2.5) and a low ART score (ART 0-1) were compared. Risk factors for mortality were identified using Cox's proportional hazards model. RESULTS: Of the 102 patients included, 51 scored 0-1.5 and 51 scored ≥2.5. Hepatitis C was more frequent in patients scoring ≥2.5. Median OS from the day before the second DEB-TACE was 21 months (95% CI, 15-28) in the group scoring 0-1.5, and 17 months (95% CI, 10-25) in the group scoring ≥2.5 (P=0.3562). Platelet count and tumour size, but not the ART score, were independent baseline predictors of OS. CONCLUSIONS: The ART score is not suitable for guiding DEB-TACE retreatment according to Spanish clinical practice standards.