Effectiveness and safety of first-generation protease inhibitors in clinical practice: Hepatitis C virus patients with advanced fibrosis

AIM: To evaluates the effectiveness and safety of the first generation, NS3/4A protease inhibitors (PIs) in clinical practice against chronic C virus, especially in patients with advanced fibrosis. METHODS: Prospective study and non-experimental analysis of a multicentre cohort of 38 Spanish hospitals that includes patients with chronic hepatitis C genotype 1, treatment-nai¨ve (TN) or treatment-experienced (TE), who underwent triple therapy with the first generation NS3/4A protease inhibitors, boceprevir (BOC) and telaprevir (TVR), in combination with pegylated interferon and ribavirin. The patients were treatment in routine practice settings. Data on the study population and on adverse clinical and virologic effects were compiled during the treatment period and during follow up. RESULTS: One thousand and fifty seven patients were included, 405 (38%) were treated with BOC and 652 (62%) with TVR. Of this total, 30% (n = 319) were TN and the remaining were TE: 28% (n = 298) relapsers, 12% (n = 123) partial responders (PR), 25% (n = 260) null-responders (NR) and for 5% (n = 57) with prior response unknown. The rate of sustained virologic response (SVR) by intention-to-treatment (ITT) was greater in those treated with TVR (65%) than in those treated with BOC (52%) (P < 0.0001), whereas by modified intention-to-treatment (mITT) no were found significant differences. By degree of fibrosis, 56% of patients were F4 and the highest SVR rates were recorded in the non-F4 patients, both TN and TE. In the analysis by groups, the TN patients treated with TVR by ITT showed a higher SVR (P = 0.005). However, by mITT there were no significant differences between BOC and TVR. In the multivariate analysis by mITT, the significant SVR factors were relapsers, IL28B CC and non-F4; the type of treatment (BOC or TVR) was not significant. The lowest SVR values were presented by the F4-NR patients, treated with BOC (46%) or with TVR (45%). 28% of the patients interrupted the treatment, mainly by non-viral response (51%): this outcome was more frequent in the TE than in the TN patients (57% vs 40%, P = 0.01). With respect to severe haematological disorders, neutropaenia was more likely to affect the patients treated with BOC (33% vs 20%, P = 0.0001), and thrombocytopaenia and anaemia, the F4 patients (P = 0.000, P = 0.025, respectively). CONCLUSION: In a real clinical practice setting with a high proportion of patients with advanced fibrosis, effectiveness of first-generation PIs was high except for NR patients, with similar SVR rates being achieved by BOC and TVR

Deep-sequencing reveals broad subtype-specific HCV resistance mutations associated with treatment failure

A percentage of hepatitis C virus (HCV)-infected patients fail direct acting antiviral (DAA)-based treatment regimens, often because of drug resistance-associated substitutions (RAS). The aim of this study was to characterize the resistance profile of a large cohort of patients failing DAA-based treatments, and investigate the relationship between HCV subtype and failure, as an aid to optimizing management of these patients. A new, standardized HCV-RAS testing protocol based on deep sequencing was designed and applied to 220 previously subtyped samples from patients failing DAA treatment, collected in 39 Spanish hospitals. The majority had received DAA-based interferon (IFN) a-free regimens; 79% had failed sofosbuvir-containing therapy. Genomic regions encoding the nonstructural protein (NS) 3, NS5A, and NS5B (DAA target regions) were analyzed using subtype-specific primers. Viral subtype distribution was as follows: genotype (G) 1, 62.7%; G3a, 21.4%; G4d, 12.3%; G2, 1.8%; and mixed infections 1.8%. Overall, 88.6% of patients carried at least 1 RAS, and 19% carried RAS at frequencies below 20% in the mutant spectrum. There were no differences in RAS selection between treatments with and without ribavirin. Regardless of the treatment received, each HCV subtype showed specific types of RAS. Of note, no RAS were detected in the target proteins of 18.6% of patients failing treatment, and 30.4% of patients had RAS in proteins that were not targets of the inhibitors they received. HCV patients failing DAA therapy showed a high diversity of RAS. Ribavirin use did not influence the type or number of RAS at failure. The subtype-specific pattern of RAS emergence underscores the importance of accurate HCV subtyping. The frequency of “extra-target” RAS suggests the need for RAS screening in all three DAA target regions

Insights into the high-energy γ-ray emission of Markarian 501 from extensive multifrequency observations in the Fermi era

We report on the γ-ray activity of the blazar Mrk 501 during the first 480 days of Fermi operation. We find that the average Large Area Telescope (LAT) γ-ray spectrum of Mrk 501 can be well described by a single power-law function with a photon index of 1.78 ± 0.03. While we observe relatively mild flux variations with the Fermi-LAT (within less than a factor of two), we detect remarkable spectral variability where the hardest observed spectral index within the LAT energy range is 1.52 ± 0.14, and the softest one is 2.51 ± 0.20. These unexpected spectral changes do not correlate with the measured flux variations above 0.3 GeV. In this paper, we also present the first results from the 4.5 month long multifrequency campaign (2009 March 15-August 1) on Mrk 501, which included the Very Long Baseline Array (VLBA), Swift, RXTE, MAGIC, and VERITAS, the F-GAMMA, GASP-WEBT, and other collaborations and instruments which provided excellent temporal and energy coverage of the source throughout the entire campaign. The extensive radio to TeV data set from this campaign provides us with the most detailed spectral energy distribution yet collected for this source during its relatively low activity. The average spectral energy distribution of Mrk 501 is well described by the standard one-zone synchrotron self-Compton (SSC) model. In the framework of this model, we find that the dominant emission region is characterized by a size ≲0.1 pc (comparable within a factor of few to the size of the partially resolved VLBA core at 15-43 GHz), and that the total jet power (≃1044 erg s-1) constitutes only a small fraction (∼10-3) of the Eddington luminosity. The energy distribution of the freshly accelerated radiating electrons required to fit the time-averaged data has a broken power-law form in the energy range 0.3 GeV-10 TeV, with spectral indices 2.2 and 2.7 below and above the break energy of 20 GeV. We argue that such a form is consistent with a scenario in which the bulk of the energy dissipation within the dominant emission zone of Mrk 501 is due to relativistic, proton-mediated shocks. We find that the ultrarelativistic electrons and mildly relativistic protons within the blazar zone, if comparable in number, are in approximate energy equipartition, with their energy dominating the jet magnetic field energy by about two orders of magnitude. © 2011. The American Astronomical Society

A global research priority agenda to advance public health responses to fatty liver disease

Background & aims An estimated 38% of adults worldwide have non-alcoholic fatty liver disease (NAFLD). From individual impacts to widespread public health and economic consequences, the implications of this disease are profound. This study aimed to develop an aligned, prioritised fatty liver disease research agenda for the global health community. Methods Nine co-chairs drafted initial research priorities, subsequently reviewed by 40 core authors and debated during a three-day in-person meeting. Following a Delphi methodology, over two rounds, a large panel (R1 n = 344, R2 n = 288) reviewed the priorities, via Qualtrics XM, indicating agreement using a four-point Likert-scale and providing written feedback. The core group revised the draft priorities between rounds. In R2, panellists also ranked the priorities within six domains: epidemiology, models of care, treatment and care, education and awareness, patient and community perspectives, and leadership and public health policy. Results The consensus-built fatty liver disease research agenda encompasses 28 priorities. The mean percentage of ‘agree’ responses increased from 78.3 in R1 to 81.1 in R2. Five priorities received unanimous combined agreement (‘agree’ + ‘somewhat agree’); the remaining 23 priorities had >90% combined agreement. While all but one of the priorities exhibited at least a super-majority of agreement (>66.7% ‘agree’), 13 priorities had 90% combined agreement. Conclusions Adopting this multidisciplinary consensus-built research priorities agenda can deliver a step-change in addressing fatty liver disease, mitigating against its individual and societal harms and proactively altering its natural history through prevention, identification, treatment, and care. This agenda should catalyse the global health community’s efforts to advance and accelerate responses to this widespread and fast-growing public health threat. Impact and implications An estimated 38% of adults and 13% of children and adolescents worldwide have fatty liver disease, making it the most prevalent liver disease in history. Despite substantial scientific progress in the past three decades, the burden continues to grow, with an urgent need to advance understanding of how to prevent, manage, and treat the disease. Through a global consensus process, a multidisciplinary group agreed on 28 research priorities covering a broad range of themes, from disease burden, treatment, and health system responses to awareness and policy. The findings have relevance for clinical and non-clinical researchers as well as funders working on fatty liver disease and non-communicable diseases more broadly, setting out a prioritised, ranked research agenda for turning the tide on this fast-growing public health threat

Tratamiento del dolor orofacial en pacientes con síndrome del ligamento estilomandibular (síndrome de Ernest)

Resumen: Introducción: El síndrome de Ernest se define como una alteración del ligamento estilomandibular, caracterizado por la presencia de dolor en la región preauricular y en el ángulo mandibular, irradiado al cuello, el hombro y el ojo del mismo lado, asociado a dolor durante la palpación del ligamento estilomandibular. El objetivo es presentar las características clínicas, el tratamiento y la evolución de una serie de pacientes con el síndrome de Ernest. Métodos: Se realizó un estudio clínico, observacional, retrospectivo, entre los años 1998 y 2008. Se recogieron todos los datos con respecto a la edad, el sexo, el tiempo de evolución y las características del dolor. A todos los pacientes se les infiltró 40 mg de acetónido de triamcinolona en la inserción mandibular del ligamento estilomandibular. Resultados: Se incluyó a 6 pacientes. La edad media fue de 40,3 años (rango 35-51). El 100% eran mujeres. Cuatro de las 6 pacientes recibieron tratamientos odontológicos prolongados el mes previo a la aparición del dolor. El tiempo de evolución medio antes de la primera visita fue de 23 meses. Tras el tratamiento realizado, se obtuvo una resolución completa de todos los pacientes, con un periodo de seguimiento mínimo de 12 meses. Conclusiones: Se han analizado las características clínicas del dolor, el tratamiento recibido y la evolución de 6 pacientes con el síndrome de Ernest. Es importante realizar un correcto diagnóstico para poder establecer el tratamiento correcto. Creemos que esta enfermedad es más prevalente de lo encontrado en la literatura, pudiéndose confundir con otros dolores orofaciales. Abstract: Introduction: Ernest syndrome involves the stylomandibular ligament. It is characterised by pain in the preauricular area and mandibular angle, radiating to the neck, shoulder, and eye on the same side, and associated with pain during palpation of that ligament. The purpose of this study is to describe the clinical characteristics, treatment, and course of the disease in a series of patients with Ernest syndrome. Methods: Retrospective observational study covering the period from 1998 to 2008. We recorded patients’ age, sex, duration of the disorder, and pain characteristics. All patients were injected with 40 mg triamcinolone acetonide at the mandibular insertion of the stylomandibular ligament. Results: The study included a total of 6 patients. Mean age was 40.3 years (range, 35-51). All of the subjects were women. Four patients had undergone lengthy dental treatments in the month prior to onset of the pain. The mean time between pain onset and first consultation was 23 months. The syndrome resolved completely in all cases after treatment, with a minimum follow-up period of 12 months. Conclusions: We analysed the clinical characteristics, treatment, and course of disease in 6 patients with Ernest syndrome. Correct diagnosis is the key to being able to provide proper treatment. This disorder is sometimes confused with other types of orofacial pain, and may therefore be more prevalent than the literature would indicate. Palabras clave: Síndrome de Ernest, Dolor miofascial, Estilomandibular, Síndrome de Eagle, Dolor orofacial, Keywords: Ernest syndrome, Myofascial pain, Stylomandibular, Eagle syndrome, Orofacial pai

Treatment of orofacial pain in patients with stylomandibular ligament syndrome (Ernest syndrome)

Introduction: Ernest syndrome involves the stylomandibular ligament. It is characterised by pain in the preauricular area and mandibular angle, radiating to the neck, shoulder, and eye on the same side, and associated with pain during palpation of that ligament. The purpose of this study is to describe the clinical characteristics, treatment, and course of the disease in a series of patients with Ernest syndrome. Methods: Retrospective observational study covering the period from 1998 to 2008. We recorded patients’ age, sex, duration of the disorder, and pain characteristics. All patients were injected with 40 mg triamcinolone acetonide at the mandibular insertion of the stylomandibular ligament. Results: The study included a total of 6 patients. Mean age was 40.3 years (range, 35–51). All the subjects were women. Four patients had undergone lengthy dental treatments in the month prior to onset of the pain. The mean time between pain onset and first consultation was 23 months. The syndrome resolved completely in all cases after treatment, with a minimum follow-up period of 12 months. Conclusions: We analysed the clinical characteristics, treatment, and course of disease in 6 patients with Ernest syndrome. Correct diagnosis is the key to being able to provide proper treatment. This disorder is sometimes confused with other types of orofacial pain, and may therefore be more prevalent than the literature would indicate. Resumen: Introducción: El síndrome de Ernest se define como una alteración del ligamento estilomandibular, caracterizado por la presencia de dolor en la región preauricular y en el ángulo mandibular, irradiado al cuello, el hombro y el ojo del mismo lado, asociado a dolor durante la palpación del ligamento estilomandibular. El objetivo es presentar las características clínicas, el tratamiento y la evolución de una serie de pacientes con el síndrome de Ernest. Métodos: Se realizó un estudio clínico, observacional, retrospectivo, entre los años 1998 y 2008. Se recogieron todos los datos con respecto a la edad, el sexo, el tiempo de evolución y las características del dolor. A todos los pacientes se les infiltró 40 mg de acetónido de triamcinolona en la inserción mandibular del ligamento estilomandibular. Resultados: Se incluyó a 6 pacientes. La edad media fue de 40,3 años (rango 35-51). El 100% eran mujeres. Cuatro de las 6 pacientes recibieron tratamientos odontológicos prolongados el mes previo a la aparición del dolor. El tiempo de evolución medio antes de la primera visita fue de 23 meses. Tras el tratamiento realizado, se obtuvo una resolución completa de todos los pacientes, con un periodo de seguimiento mínimo de 12 meses. Conclusiones: Se han analizado las características clínicas del dolor, el tratamiento recibido y la evolución de 6 pacientes con el síndrome de Ernest. Es importante realizar un correcto diagnóstico para poder establecer el tratamiento correcto. Creemos que esta enfermedad es más prevalente de lo encontrado en la literatura, pudiéndose confundir con otros dolores orofaciales. Keywords: Ernest syndrome, Myofascial pain, Stylomandibular, Eagle syndrome, Orofacial pain, Palabras clave: Síndrome de Ernest, Dolor miofascial, Estilomandibular, Síndrome de Eagle, Dolor orofacia

Validez del exceso de bases como factor pronóstico de mortalidad en pacientes traumatizados

5 páginasBackground: Base excess is used to determine the mag-nitude of metabolic abnormality secondary to hemorrhage or direct organ damage of patients with polytrauma Objective: To determine what are the values of change that BE can have over time and that allow predicting early mortality in patients with polytrauma. Methods: Retrospective cohort study in subjects older than 18 years, who were admitted to the intensive care unit for any type of trauma. The response to the change of the base excess at 6, 12 and 24 hours after the trauma was evaluated. Results: 261 subjects were included, 22.6% (59/261) died. Polytrauma occurred in 73.2% (191/261) and traf-fic accident was the most common mechanism of trauma in the study population with 75.9%. The change in BE between admission and the first 6 hours was 1.7 mEq/L (SD: 4.02) in the living population and 1.9 mEq/L (SD: 8.1) in the deceased (p<0.001). The change in mEq/L between admission and first 6 hours showed a low receiver operat-ing characteristics curve area of 0.661 (95% CI: 0.523-0.8; p=0.025). Conclusión: The change in base excess between the first 6 to 12 hours after patient admission can be used to esti-mate mortality in patients diagnosed with trauma. © 2023, Venezuelan Society of Pharmacology and Clinical and Therapeutic Pharmacology. All rights reserved