MUKtwelve protocol: a phase II randomised, controlled, open, parallel group, multicentre trial of selinexor, cyclophosphamide and prednisolone (SCP) versus cyclophosphamide and prednisolone (CP) in patients with relapsed or refractory multiple myeloma.

INTRODUCTION: Multiple myeloma is a malignancy of plasma cells with around 6000 new cases per year in the UK. Cyclophosphamide plus prednisolone is considered a standard of care for disease and symptom control in the advanced relapsed or refractory myeloma setting within the UK NHS. The selective nuclear export inhibitor, selinexor, has been relatively well tolerated in previous clinical trials and offers promise when used in combination with a wide range of other anti-cancer treatments. Here, we investigate if the addition of selinexor can improve responses to cyclophosphamide plus prednisolone without adding prohibitive toxicity. METHODS AND ANALYSIS: MUKtwelve is a UK-based, randomised, controlled, open, parallel group, multicentre phase II trial designed to evaluate clinical efficacy of selinexor in combination with cyclophosphamide and prednisolone (SCP) in patients with relapsed or refractory multiple myeloma. A calibration arm will receive cyclophosphamide and prednisolone alone (CP). Participants who experience disease progression on the CP arm may, if eligible, receive SCP.The MUKtwelve trial results will be the first to assess clinical efficacy of selinexor with low-dose CP in relapsed/refractory multiple myeloma. It is widely accepted that the relapsing-remitting nature of the disease is accompanied by cellular changes that often result in the requirement for novel agents and drug combinations to regain disease control. Patients also often experience cumulative toxicities throughout their treatments, limiting the treatment intensity that can be given at relapse. Thus, there is a need for novel effective combination therapies with acceptable toxicity profiles. ETHICS AND DISSEMINATION: Ethics approval is obtained. Results will be submitted for publication in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: ISRCTN15028850

Exenatide once weekly treatment maintained improvements in glycemic control and weight loss over 2 years

<p>Abstract</p> <p>Background</p> <p>The once-weekly (QW) formulation of the glucagon-like peptide-1 receptor agonist exenatide has been demonstrated to improve A1C, fasting plasma glucose (FPG), body weight, serum lipid profiles, and blood pressure in patients with type 2 diabetes through 52 weeks of treatment. In this report, we describe the 2-year results of the open-label, open-ended extension to the DURATION-1 trial of exenatide QW for type 2 diabetes.</p> <p>Methods</p> <p>A 2-stage protocol was used: patients received either exenatide QW (2 mg) or exenatide twice daily for 30 weeks (5 μg for the first 4 weeks and 10 μg thereafter), followed by 1.5 years of treatment with exenatide QW (2 mg), for a total of 2 years (104 weeks) of exenatide treatment. Of the 295 (intent-to-treat [ITT]) patients who entered the trial, 73% (n = 216) completed 2 years of treatment (completer population). Baseline characteristics (mean ± SE) for these patients were: A1C, 8.2 ± 0.1%; FPG, 168.4 ± 43.0 mg/dL; body weight, 101.1 ± 18.7 kg; and diabetes duration, 7 ± 5 years.</p> <p>Results</p> <p>In the completer population, significant improvements (LS mean ± SE [95% CI]) were maintained after 2 years of treatment in A1C (-1.71 ± 0.08% [-1.86 to -1.55%]), FPG (-40.1 ± 2.9 mg/dL [-45.7 to -34.5 mg/dL]), and body weight (-2.61 ± 0.52 kg [-3.64 to -1.58 kg]) compared with baseline. The percentages of patients who achieved an A1C of <7.0% and ≤6.5% at 2 years were 60% and 39%, respectively. A significant reduction in systolic blood pressure (SBP; -3.0 ± 1.0 mmHg [-4.9 to -1.1 mmHg]) was maintained through 2 years of treatment. Serum lipid profiles were also significantly improved, including triglycerides (geometric LS mean change from baseline, -15 ± 2.7% [-21% to -10%]), total cholesterol (-8.6 ± 2.8 mg/dL [-14.0 to -3.1 mg/dL]), and low-density lipoproteins (-4.5 ± 2.2 mg/dL [-8.9 to -0.01 mg/dL]). Changes in A1C, body weight, FPG, SBP, and lipids in the ITT population were similar to those seen in the completer population. Nausea (predominantly mild in intensity) was the most common adverse event, although the frequency and intensity of nausea decreased over time. No severe hypoglycemia was observed.</p> <p>Conclusions</p> <p>Exenatide QW was well tolerated during the 2-year treatment period. This study demonstrated sustained glucose control and weight loss throughout 2 years of treatment with exenatide QW.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov <a href="http://www.clinicaltrials.gov/ct2/show/NCT00308139">NCT00308139</a></p

Immune Boosting Explains Regime-Shifts in Prevaccine-Era Pertussis Dynamics

Understanding the biological mechanisms underlying episodic outbreaks of infectious diseases is one of mathematical epidemiology’s major goals. Historic records are an invaluable source of information in this enterprise. Pertussis (whooping cough) is a re-emerging infection whose intermittent bouts of large multiannual epidemics interspersed between periods of smaller-amplitude cycles remain an enigma. It has been suggested that recent increases in pertussis incidence and shifts in the age-distribution of cases may be due to diminished natural immune boosting. Here we show that a model that incorporates this mechanism can account for a unique set of pre-vaccine-era data from Copenhagen. Under this model, immune boosting induces transient bursts of large amplitude outbreaks. In the face of mass vaccination, the boosting model predicts larger and more frequent outbreaks than do models with permanent or passively-waning immunity. Our results emphasize the importance of understanding the mechanisms responsible for maintaining immune memory fo

Effect of a Fatty Acid Additive on the Kinetic Friction and Stiction of Confined Liquid Lubricants

Apresentamos neste texto parte das produções de pesquisa que acompanhou a construção de corpos inseridos num Centro de Atenção Psicossocial para Álcool e outras Drogas, em cidade do nordeste brasileiro, focando de modo mais acentuado em arranjos de masculinidades. Especial atenção é dada à tensão entre normalização de corpos e tentativas de (re)existências. A argumentação se desenvolve no campo da saúde pública, em particular o da saúde mental, e alicerçada nos estudos de gênero e sexualidade. A produção de dados se valeu de observações registradas em diário de campo, acompanhamento itinerante, composição de um coletivo de pesquisa, entrevistas, grupos focais em que, dentre outras coisas, se discutia trechos de diários de campo, rodas de conversa e oficinas com profissionais e usuári*s. A aposta metodológica foi a de forjar um modo de narrar coletivo que agenciasse experimentação e desaprendizagens corporais, junto a modos de produzir cuidado em saúde e de fazer pesquisa.Apresentamos neste texto parte das produções de pesquisa que acompanhou a construção de corpos inseridos num Centro de Atenção Psicossocial para Álcool e outras Drogas, em cidade do nordeste brasileiro, focando de modo mais acentuado em arranjos de masculinidades. Especial atenção é dada à tensão entre normalização de corpos e tentativas de (re)existências. A argumentação se desenvolve no campo da saúde pública, em particular o da saúde mental, e alicerçada nos estudos de gênero e sexualidade. A produção de dados se valeu de observações registradas em diário de campo, acompanhamento itinerante, composição de um coletivo de pesquisa, entrevistas, grupos focais em que, dentre outras coisas, se discutia trechos de diários de campo, rodas de conversa e oficinas com profissionais e usuári*s. A aposta metodológica foi a de forjar um modo de narrar coletivo que agenciasse experimentação e desaprendizagens corporais, junto a modos de produzir cuidado em saúde e de fazer pesquisa.Apresentamos neste texto parte das produções de pesquisa que acompanhou a construção de corpos inseridos num Centro de Atenção Psicossocial para Álcool e outras Drogas, em cidade do nordeste brasileiro, focando de modo mais acentuado em arranjos de masculinidades. Especial atenção é dada à tensão entre normalização de corpos e tentativas de (re)existências. A argumentação se desenvolve no campo da saúde pública, em particular o da saúde mental, e alicerçada nos estudos de gênero e sexualidade. A produção de dados se valeu de observações registradas em diário de campo, acompanhamento itinerante, composição de um coletivo de pesquisa, entrevistas, grupos focais em que, dentre outras coisas, se discutia trechos de diários de campo, rodas de conversa e oficinas com profissionais e usuári*s. A aposta metodológica foi a de forjar um modo de narrar coletivo que agenciasse experimentação e desaprendizagens corporais, junto a modos de produzir cuidado em saúde e de fazer pesquisa.Apresentamos neste texto parte das produções de pesquisa que acompanhou a construção de corpos inseridos num Centro de Atenção Psicossocial para Álcool e outras Drogas, em cidade do nordeste brasileiro, focando de modo mais acentuado em arranjos de masculinidades. Especial atenção é dada à tensão entre normalização de corpos e tentativas de (re)existências. A argumentação se desenvolve no campo da saúde pública, em particular o da saúde mental, e alicerçada nos estudos de gênero e sexualidade. A produção de dados se valeu de observações registradas em diário de campo, acompanhamento itinerante, composição de um coletivo de pesquisa, entrevistas, grupos focais em que, dentre outras coisas, se discutia trechos de diários de campo, rodas de conversa e oficinas com profissionais e usuári*s. A aposta metodológica foi a de forjar um modo de narrar coletivo que agenciasse experimentação e desaprendizagens corporais, junto a modos de produzir cuidado em saúde e de fazer pesquisa.Apresentamos neste texto parte das produções de pesquisa que acompanhou a construção de corpos inseridos num Centro de Atenção Psicossocial para Álcool e outras Drogas, em cidade do nordeste brasileiro, focando de modo mais acentuado em arranjos de masculinidades. Especial atenção é dada à tensão entre normalização de corpos e tentativas de (re)existências. A argumentação se desenvolve no campo da saúde pública, em particular o da saúde mental, e alicerçada nos estudos de gênero e sexualidade. A produção de dados se valeu de observações registradas em diário de campo, acompanhamento itinerante, composição de um coletivo de pesquisa, entrevistas, grupos focais em que, dentre outras coisas, se discutia trechos de diários de campo, rodas de conversa e oficinas com profissionais e usuári*s. A aposta metodológica foi a de forjar um modo de narrar coletivo que agenciasse experimentação e desaprendizagens corporais, junto a modos de produzir cuidado em saúde e de fazer pesquisa.Apresentamos neste texto parte das produções de pesquisa que acompanhou a construção de corpos inseridos num Centro de Atenção Psicossocial para Álcool e outras Drogas, em cidade do nordeste brasileiro, focando de modo mais acentuado em arranjos de masculinidades. Especial atenção é dada à tensão entre normalização de corpos e tentativas de (re)existências. A argumentação se desenvolve no campo da saúde pública, em particular o da saúde mental, e alicerçada nos estudos de gênero e sexualidade. A produção de dados se valeu de observações registradas em diário de campo, acompanhamento itinerante, composição de um coletivo de pesquisa, entrevistas, grupos focais em que, dentre outras coisas, se discutia trechos de diários de campo, rodas de conversa e oficinas com profissionais e usuári*s. A aposta metodológica foi a de forjar um modo de narrar coletivo que agenciasse experimentação e desaprendizagens corporais, junto a modos de produzir cuidado em saúde e de fazer pesquisa.The paper presents part of the research productions that accompanied the construction of bodies inserted in a Psychosocial Care Center for Alcohol and Other Drugs (CAPS-AD) of a city in the northern region of Brasil, focusing more sharply on masculinities arrangements. Special attention is given to the tension between normalized bodies and attempts at resistance and (re) exist. The argument is in the field of public health, particularly mental health, and rooted in gender and sexuality studies. The data production methodology made use of observations recorded in a diary, itinerant follow-up of a collective of research, interviews, focus groups where, among other things, was discussed diary topics, conversation circles and workshops. The attempt was to produce a way of collective narrating strategy, combining up experience and body (un)learn well as ways of producing health care and doing research

Self-reported drunkenness among adolescents in four sub-Saharan African countries: associations with adverse childhood experiences

<p>Abstract</p> <p>Background</p> <p>Consumption of alcohol is associated with acute and chronic adverse health outcomes. There is a paucity of studies that explore the determinants of alcohol use among adolescents in sub-Saharan Africa and, in particular, that examine the effects of adverse childhood experiences on alcohol use.</p> <p>Methods</p> <p>The paper draws on nationally-representative data from 9,819 adolescents aged 12-19 years from Burkina Faso, Ghana, Malawi, and Uganda. Logistic regression models were employed to identify correlates of self-reported past-year drunkenness. Exposure to four adverse childhood experiences comprised the primary independent variables: living in a food-insecure household, living with a problem drinker, having been physically abused, and having been coerced into having sex. We controlled for age, religiosity, current schooling status, the household head's sex, living arrangements, place of residence, marital status, and country of survey. All analyses were conducted separately for males and females.</p> <p>Results</p> <p>At the bivariate level, all independent variables (except for coerced sex among males) were associated with the outcome variable. Overall, 9% of adolescents reported that they had been drunk in the 12 months preceding the survey. In general, respondents who had experienced an adverse event during childhood were more likely to report drunkenness. In the multivariate analysis, only two adverse childhood events emerged as significant predictors of self-reported past-year drunkenness among males: living in a household with a problem drinker before age 10, and being physically abused before age 10. For females, exposure to family-alcoholism, experience of physical abuse, and coerced sex increased the likelihood of reporting drunkenness in the last 12 months. The association between adverse events and reported drunkenness was more pronounced for females. For both males and females there was a graded relationship between the number of adverse events experienced and the proportion reporting drunkenness.</p> <p>Conclusions</p> <p>We find an association between experience of adverse childhood events and drunkenness among adolescents in four sub-Saharan African countries. The complex impacts of adverse childhood experiences on young people's development and behavior may have an important bearing on the effectiveness of interventions geared at reducing alcohol dependence among the youth.</p

Vertebrate Vitellogenin Gene Duplication in Relation to the “3R Hypothesis”: Correlation to the Pelagic Egg and the Oceanic Radiation of Teleosts

The spiny ray-finned teleost fishes (Acanthomorpha) are the most successful group of vertebrates in terms of species diversity. Their meteoric radiation and speciation in the oceans during the late Cretaceous and Eocene epoch is unprecedented in vertebrate history, occurring in one third of the time for similar diversity to appear in the birds and mammals. The success of marine teleosts is even more remarkable considering their long freshwater ancestry, since it implies solving major physiological challenges when freely broadcasting their eggs in the hyper-osmotic conditions of seawater. Most extant marine teleosts spawn highly hydrated pelagic eggs, due to differential proteolysis of vitellogenin (Vtg)-derived yolk proteins. The maturational degradation of Vtg involves depolymerization of mainly the lipovitellin heavy chain (LvH) of one form of Vtg to generate a large pool of free amino acids (FAA 150–200 mM). This organic osmolyte pool drives hydration of the ooctye while still protected within the maternal ovary. In the present contribution, we have used Bayesian analysis to examine the evolution of vertebrate Vtg genes in relation to the “3R hypothesis” of whole genome duplication (WGD) and the functional end points of LvH degradation during oocyte maturation. We find that teleost Vtgs have experienced a post-R3 lineage-specific gene duplication to form paralogous clusters that correlate to the pelagic and benthic character of the eggs. Neo-functionalization allowed one paralogue to be proteolyzed to FAA driving hydration of the maturing oocytes, which pre-adapts them to the marine environment and causes them to float. The timing of these events matches the appearance of the Acanthomorpha in the fossil record. We discuss the significance of these adaptations in relation to ancestral physiological features, and propose that the neo-functionalization of duplicated Vtg genes was a key event in the evolution and success of the teleosts in the oceanic environment