Is Sustained Virological Response a Marker of Treatment Efficacy in Patients with Chronic Hepatitis C Viral Infection with No Response or Relapse to Previous Antiviral Intervention?

Background: Randomised clinical trials (RCTs) of antiviral interventions in patients with chronic hepatitis C virus (HCV) infection use sustained virological response (SVR) as the main outcome. There is sparse information on long-term mortality from RCTs.  Methods: We created a decision tree model based on a Cochrane systematic review on interferon retreatment for patients who did not respond to initial therapy or who relapsed following SVR. Extrapolating data to 20 years, we modelled the outcome from three scenarios: (1) observed medium-term (5 year) annual mortality rates continue to the long term (20 years); (2) long-term annual mortality in retreatment responders falls to that of the general population while retreatment non-responders continue at the medium-term mortality; (3) long-term annual mortality in retreatment non-responders is the same as control group non-responders (i.e., the increased treatment-related medium mortality “wears off”).  Results: The mean differences in life expectancy over 20 years with interferon versus control in the first, second, and third scenarios were -0.34 years (95% confidence interval (CI) -0.71 to 0.03), -0.23 years (95% CI -0.69 to 0.24), and -0.01 (95% CI -0.3 to 0.27), respectively. The life expectancy was always lower in the interferon group than in the control group in scenario 1. In scenario 3, the interferon group had a longer life expectancy than the control group only when more than 7% in the interferon group achieved SVR.  Conclusions: SVR may be a good prognostic marker but does not seem to be a valid surrogate marker for assessing HCV treatment efficacy of interferon retreatment. The SVR threshold at which retreatment increases life expectancy may be different for different drugs depending upon the adverse event profile and treatment efficacy. This has to be determined for each drug by RCTs and appropriate modelling before SVR can be accepted as a surrogate marker

REFLEXÕES SOBRE TRANSTORNOS MENTAIS A PARTIR DOS PERSONAGENS DO DESENHO ANIMADO URSINHO POOH: REFLECTIONS ON MENTAL DISORDERS FROM THE CHARACTERS OF THE CARTOON POOH BEAR

RESUMO: Ainda há bastante preconceito acerca dos transtornos mentais, por isso é preciso estudar as suas representações sociais, inclusive nas mídias. Objetiva-se, neste estudo, analisar os transtornos mentais dos personagens: Pooh, Tigrão, Leitão e o Bisonho Ió do desenho animado O ursinho Pooh. Trata-se de pesquisa qualitativa, do tipo observação direta intensiva que utiliza os sentidos para captar aspectos da realidade fílmica, do tipo animação. Foram assistidos quatro episódios do Ursinho Pooh. Os dados são analisados à luz de referencial teórico, organizando-os em três categorias: Descrição dos episódios; Descrição do personagem em foco, e Análise do perfil e comportamento do personagem. Como resultados, descrevem-se as características de cada personagem e, ao analisar seu perfil e comportamento, são identificadas similaridades com transtornos mentais. Constata-se a necessidade de superar o reducionismo ao restringir o sujeito a um conjunto de sinais e sintomas, e sim percebê-lo na sua amplitude enquanto ser bio-sociocultural-psíquico. Palavras-chave: Filmes cinematográficos; Humanização da Assistência; Integralidade em Saúde; Saúde mental; Transtornos mentais.   ABSTRACT: There is still a lot of prejudice about mental disorders, so it is necessary to study their social representations, including in the media. The objective of this study is to analyze the mental disorders of the characters: Pooh, Tigger, Piglet and Eeyore Ió from the cartoon Winnie the Pooh. This is qualitative research, of the intensive direct observation type that uses the senses to capture aspects of filmic reality, of the animation type. Four episodes of Winnie the Pooh were watched. Data are analyzed in the light of a theoretical framework, organizing them into three categories. As a result, the characteristics of each character are described and, when analyzing their profile and behavior, similarities with mental disorders are identified. There is a need to overcome reductionism by restricting the subject to a set of signs and symptoms, and rather perceiving it in its breadth as a bio-socio-cultural-psychic being. Keywords: Humanization of Assistance; Integrality in Health; Motion Pictures; Mental health; Mental disorders

Redox-active and DNA-binding coordination complexes of clotrimazole

DNA interactions of anticancer mononuclear Cu2+, Co2+, Zn2+, and Ni2+ complexes with the biologically active ligand clotrimazole (clotri) are reported. To fully characterize DNA binding modes for these complexes of the formulae [M(clotri)2Cl2]·nH2O (1–4), [M(clotri)2Br2]·nH2O (5,6), [M(clotri)3NO3]NO3·nH2O (9), and [M(clotri)3(NO3)2] (10), circular dichroism (CD) and linear dichroism (LD) spectroscopy, UV melting experiments, atomic force microscopy (AFM) and ethidium bromide (EtBr) displacement methods were used. Results indicate mixed electrostatic interactions, possibly through groove binding, that result in accretion and coiling of DNA. Electrochemical studies indicate that the Cu2+ complex 9 readily reduces to the reactive-oxygen-species-generating Cu+, which oxidatively damages DNA. There is a subtle correlation between log P values, calculated electrostatic potentials, and cytotoxicity of the complexes. The extent of cell-nucleus DNA-metal adduct formation in the HeLa cervix-uterine carcinoma cell line does not necessarily correlate with cytotoxicity, indicating that the nature of DNA lesions may be crucial to activity

Reconstruction of primary vertices at the ATLAS experiment in Run 1 proton–proton collisions at the LHC

This paper presents the method and performance of primary vertex reconstruction in proton–proton collision data recorded by the ATLAS experiment during Run 1 of the LHC. The studies presented focus on data taken during 2012 at a centre-of-mass energy of √s=8 TeV. The performance has been measured as a function of the number of interactions per bunch crossing over a wide range, from one to seventy. The measurement of the position and size of the luminous region and its use as a constraint to improve the primary vertex resolution are discussed. A longitudinal vertex position resolution of about 30μm is achieved for events with high multiplicity of reconstructed tracks. The transverse position resolution is better than 20μm and is dominated by the precision on the size of the luminous region. An analytical model is proposed to describe the primary vertex reconstruction efficiency as a function of the number of interactions per bunch crossing and of the longitudinal size of the luminous region. Agreement between the data and the predictions of this model is better than 3% up to seventy interactions per bunch crossing

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements

Does Circulating Antibody Play a Role in the Protection of Piglets against Porcine Epidemic Diarrhea Virus?

The contribution of circulating antibody to the protection of naïve piglets against porcine epidemic diarrhea virus (PEDV) was evaluated using a passive antibody transfer model. Piglets (n = 62) derived from 6 sows were assigned to one of 6 different treatments using a randomized block design which provided for allocation of all treatments to all sows\u27 litters. Each treatment was designed to achieve a different level of circulating anti-PEDV antibody via intraperitoneally administration of concentrated serum antibody. Piglets were orally inoculated with PEDV (USA/IN/2013/19338E, 1 x 103 TCID50 per piglet) 24 hours later and then monitored for 14 days. Piglets remained with their dam throughout the experiment. Sow milk samples, piglet fecal samples, and data on piglet clinical signs, body weight, and body temperature were collected daily. Fecal samples were tested by PEDV real-time reverse transcriptase PCR. Serum, colostrum, and milk were tested for PEDV IgG, IgA, and virus-neutralizing antibody. The data were evaluated for the effects of systemic PEDV antibody levels on growth, body temperature, fecal shedding, survival, and antibody response. The analysis showed that circulating antibody partially ameliorated the effect of PEDV infection. Specifically, antibody-positive groups returned to normal body temperature faster and demonstrated a higher rate of survivability than piglets without PEDV antibody. When combined with previous literature on PEDV, it can be concluded that both systemic antibodies and maternal secretory IgA in milk contribute to the protection of the neonatal pig against PEDV infections. Overall, the results of this experiment suggested that passively administered circulating antibodies contributed to the protection of neonatal piglets against PEDV infection

Factors associated with delayed diagnosis of tuberculosis in hospitalized patients in a high TB and HIV burden setting: a cross-sectional study

<p>Abstract</p> <p>Background</p> <p>The most essential components of TB control are early diagnosis and adequate treatment. Delay in the diagnosis and treatment of tuberculosis may result in more extensive disease and more complications, increase severity of the disease and is associated with higher risk of mortality. The purpose of this study was to identify factors associated with delayed diagnosis of TB in hospitalized patients.</p> <p>Methods</p> <p>We conducted a cross-sectional study in a general, tertiary care, university-affiliated hospital. Adult patients with TB that were hospitalized were identified retrospectively, and risk factors for delayed diagnosis were collected.</p> <p>Results</p> <p>The median delay until diagnosis was 6 days (IQR: 2-12 days). One hundred and sixty six (54.4%) patients were diagnosed ≤ 6 days, and 139 (45.6%) > 6 days after admission. The main factors associated with diagnostic delay (> 6 days) were extra-pulmonary TB and negative sputum smear.</p> <p>Conclusions</p> <p>Although hospitalization permits a rapid management of the patient and favors a faster diagnosis, we found an unacceptable time delay before the diagnosis of pulmonary TB was made. Future studies should focus on attempt to explain the reasons of diagnostic retard in the patients with the characteristics related to delay in this study.</p

No influence of oxygen levels on pathogenesis and virus shedding in Salmonid alphavirus (SAV)-challenged Atlantic salmon (Salmo salar L.)

<p>Abstract</p> <p>Background</p> <p>For more than three decades, diseases caused by salmonid alphaviruses (SAV) have become a major problem of increasing economic importance in the European fish-farming industry. However, experimental infection trials with SAV result in low or no mortality i.e very different from most field outbreaks of pancreas disease (PD). This probably reflects the difficulties in reproducing complex biotic and abiotic field conditions in the laboratory. In this study we looked at the relationship between SAV-infection in salmon and sub-lethal environmental hypoxia as a result of reduced flow-through in tank systems.</p> <p>Results</p> <p>The experiment demonstrated that constant reduced oxygen levels (60-65% oxygen saturation: 6.5-7.0 mg/L) did not significantly increase the severity or the progress of pancreas disease (PD). These conclusions are based upon assessments of a semi-quantitative histopathological lesion score system, morbidities/mortalities, and levels of SAV RNA in tissues and water (measured by 1 MDS electropositive virus filters and downstream real-time RT-PCR). Furthermore, we demonstrate that the fish population shed detectable levels of the virus into the surrounding water during viraemia; 4-13 days after i.p. infection, and prior to appearance of severe lesions in heart (21-35 dpi). After this period, viral RNA from SAV could not be detected in water samples although still present in tissues (gills and hearts) at lasting low levels. Lesions could be seen in exocrine pancreas at 7-21 days post infection, but no muscle lesions were seen.</p> <p>Conclusions</p> <p>In our study, experimentally induced hypoxia failed to explain the discrepancy between the severities reported from field outbreaks of SAV-disease and experimental infections. Reduction of oxygen levels to constant suboptimal levels had no effect on the severity of lesions caused by SAV-infection or the progress of the disease. Furthermore, we present a modified VIRADEL method which can be used to detect virus in water and to supplement experimental infection trials with information related to viral shedding. By using this method, we were able to demonstrate for the first time that shedding of SAV from the fish population into the surrounding water coincides with viraemia.</p

Progesterone after previous preterm birth for prevention of neonatal respiratory distress syndrome (PROGRESS): a randomised controlled trial

Background: Neonatal respiratory distress syndrome, as a consequence of preterm birth, is a major cause of early mortality and morbidity during infancy and childhood. Survivors of preterm birth continue to remain at considerable risk of both chronic lung disease and long-term neurological handicap. Progesterone is involved in the maintenance of uterine quiescence through modulation of the calcium-calmodulin-myosin-light-chain-kinase system in smooth muscle cells. The withdrawal of progesterone, either actual or functional is thought to be an antecedent to the onset of labour. While there have been recent reports of progesterone supplementation for women at risk of preterm birth which show promise in this intervention, there is currently insufficient data on clinically important outcomes for both women and infants to enable informed clinical decision-making. The aims of this randomised, double blind, placebo controlled trial are to assess whether the use of vaginal progesterone pessaries in women with a history of previous spontaneous preterm birth will reduce the risk and severity of respiratory distress syndrome, so improving their infant's health, without increasing maternal risks. Methods Design: Multicentred randomised, double blind, placebo-controlled trial. Inclusion Criteria: pregnant women with a live fetus, and a history of prior preterm birth at less than 37 weeks gestation and greater than 20 weeks gestation in the immediately preceding pregnancy, where onset of labour occurred spontaneously, or in association with cervical incompetence, or following preterm prelabour ruptured membranes. Trial Entry & Randomisation: After obtaining written informed consent, eligible women will be randomised between 18 and 23+6 weeks gestation using a central telephone randomisation service. The randomisation schedule prepared by non clinical research staff will use balanced variable blocks, with stratification according to plurality of the pregnancy and centre where planned to give birth. Eligible women will be randomised to either vaginal progesterone or vaginal placebo. Study Medication & Treatment Schedules: Treatment packs will appear identical. Woman, caregivers and research staff will be blinded to treatment allocation. Primary Study Outcome: Neonatal Respiratory Distress Syndrome (defined by incidence and severity). Sample Size: of 984 women to show a 40% reduction in respiratory distress syndrome from 15% to 9% (p = 0.05, 80% power). Discussion: This is a protocol for a randomised trial.Jodie M. Dodd, Caroline A. Crowther, Andrew J. McPhee, Vicki Flenady, and Jeffrey S. Robinso

Understanding the Potential Impact of Different Drug Properties On SARS-CoV-2 Transmission and Disease Burden: A Modelling Analysis

Background The public health impact of the COVID-19 pandemic has motivated a rapid search for potential therapeutics, with some key successes. However, the potential impact of different treatments, and consequently research and procurement priorities, have not been clear. Methods Using a mathematical model of SARS-CoV-2 transmission, COVID-19 disease and clinical care, we explore the public-health impact of different potential therapeutics, under a range of scenarios varying healthcare capacity, epidemic trajectories; and drug efficacy in the absence of supportive care. Results The impact of drugs like dexamethasone (delivered to the most critically-ill in hospital and whose therapeutic benefit is expected to depend on the availability of supportive care such as oxygen and mechanical ventilation) is likely to be limited in settings where healthcare capacity is lowest or where uncontrolled epidemics result in hospitals being overwhelmed. As such, it may avert 22% of deaths in high-income countries but only 8% in low-income countries (assuming R=1.35). Therapeutics for different patient populations (those not in hospital, early in the course of infection) and types of benefit (reducing disease severity or infectiousness, preventing hospitalisation) could have much greater benefits, particularly in resource-poor settings facing large epidemics. Conclusions Advances in the treatment of COVID-19 to date have been focussed on hospitalised-patients and predicated on an assumption of adequate access to supportive care. Therapeutics delivered earlier in the course of infection that reduce the need for healthcare or reduce infectiousness could have significant impact, and research into their efficacy and means of delivery should be a priority