Models for the Assessment of Treatment Improvement: The Ideal and the Feasible

Comparisons of different treatments or production processes are the goals of a significant fraction of applied research. Unsurprisingly, two sample problems play a main role in statistics through natural questions such as. Is the the new treatment significantly better than the old. However, this is only partially answered by some of the usual statistical tools for this task. More importantly, often practitioners are not aware of the real meaning behind these statistical procedures. We analyze these troubles from the point of view of the order between distributions, the stochastic order, showing evidence of the limitations of the usual approaches, paying special attention to the classical comparison of means under the normal model. We discuss the unfeasibility of statistically proving stochastic dominance, but show that it is possible, instead, to gather statistical evidence to conclude that slightly relaxed versions of stochastic dominance hold.Research partially supported by the Spanish Ministerio de Economía y Competitividad y fondos FEDER, grants MTM2014-56235-C2-1-P and MTM2014-56235-C2-2, and by Consejería de Educación de la Junta de Castilla y León, grant VA212U13

Specific patterns of brain alterations underlie distinct clinical profiles in Huntington's disease

Huntington's disease (HD) is a genetic neurodegenerative disease which involves a triad of motor, cognitive and psychiatric disturbances. However, there is great variability in the prominence of each type of symptom across individuals. The neurobiological basis of such variability remains poorly understood but would be crucial for better tailored treatments. Multivariate multimodal neuroimaging approaches have been successful in disentangling these profiles in other disorders. Thus we applied for the first time such approach to HD. We studied the relationship between HD symptom domains and multimodal measures sensitive to grey and white matter structural alterations. Forty-three HD gene carriers (23 manifest and 20 premanifest individuals) were scanned and underwent behavioural assessments evaluating motor, cognitive and psychiatric domains. We conducted a multimodal analysis integrating different structural neuroimaging modalities measuring grey matter volume, cortical thickness and white matter diffusion indices - fractional anisotropy and radial diffusivity. All neuroimaging measures were entered into a linked independent component analysis in order to obtain multimodal components reflecting common inter-subject variation across imaging modalities. The relationship between multimodal neuroimaging independent components and behavioural measures was analysed using multiple linear regression. We found that cognitive and motor symptoms shared a common neurobiological basis, whereas the psychiatric domain presented a differentiated neural signature. Behavioural measures of different symptom domains correlated with different neuroimaging components, both the brain regions involved and the neuroimaging modalities most prominently associated with each type of symptom showing differences. More severe cognitive and motor signs together were associated with a multimodal component consisting in a pattern of reduced grey matter, cortical thickness and white matter integrity in cognitive and motor related networks. In contrast, depressive symptoms were associated with a component mainly characterised by reduced cortical thickness pattern in limbic and paralimbic regions. In conclusion, using a multivariate multimodal approach we were able to disentangle the neurobiological substrates of two distinct symptom profiles in HD: one characterised by cognitive and motor features dissociated from a psychiatric profile. These results open a new view on a disease classically considered as a uniform entity and initiates a new avenue for further research considering these qualitative individual differences

White matter cortico-striatal tracts predict apathy subtypes in Huntington's disease

BACKGROUND: Apathy is the neuropsychiatric syndrome that correlates most highly with Huntington's disease progression, and, like early patterns of neurodegeneration, is associated with lesions to cortico-striatal connections. However, due to its multidimensional nature and elusive etiology, treatment options are limited. OBJECTIVES: To disentangle underlying white matter microstructural correlates across the apathy spectrum in Huntington's disease. METHODS: Forty-six Huntington's disease individuals (premanifest (N = 22) and manifest (N = 24)) and 35 healthy controls were scanned at 3-tesla and underwent apathy evaluation using the short-Problem Behavior Assessment and short-Lille Apathy Rating Scale, with the latter being characterized into three apathy domains, namely emotional, cognitive, and auto-activation deficit. Diffusion tensor imaging was used to study whether individual differences in specific cortico-striatal tracts predicted global apathy and its subdomains. RESULTS: We elucidate that apathy profiles may develop along differential timelines, with the auto-activation deficit domain manifesting prior to motor onset. Furthermore, diffusion tensor imaging revealed that inter-individual variability in the disruption of discrete cortico-striatal tracts might explain the heterogeneous severity of apathy profiles. Specifically, higher levels of auto-activation deficit symptoms significantly correlated with increased mean diffusivity in the right uncinate fasciculus. Conversely, those with severe cognitive apathy demonstrated increased mean diffusivity in the right frontostriatal tract and left dorsolateral prefrontal cortex to caudate nucleus tract. CONCLUSIONS: The current study provides evidence that white matter correlates associated with emotional, cognitive, and auto-activation subtypes may elucidate the heterogeneous nature of apathy in Huntington's disease, as such opening a door for individualized pharmacological management of apathy as a multidimensional syndrome in other neurodegenerative disorders

Linezolid for infective endocarditis. A structured approach based on a national database experience

Current data on the frequency and efficacy of linezolid (LNZ) in infective endocarditis (IE) are based on small retrospective series. We used a national database to evaluate the effectiveness of LNZ in IE. This is a retrospective study of IE patients in the Spanish GAMES database who received LNZ. We defined 3 levels of therapeutic impact: LNZ 50% of the total treatment, and > 50% of the LNZ doses prescribed in the first weeks of treatment), and LNZ ? 7 days not fulfilling the high-impact criteria (LNZ-NHI). Effectiveness of LNZ was assessed using propensity score matching and multivariate analysis of high-impact cases in comparison to patients not treated with LNZ from the GAMES database matched for age-adjusted comorbidity Charlson index, heart failure, renal failure, prosthetic and intracardiac IE device, left-sided IE, and Staphylococcus aureus. Primary outcomes were in-hospital mortality and one-year mortality. Secondary outcomes included IE complications and relapses

The Rise and Fall of "Respectable" Spanish Liberalism, 1808-1923: An Explanatory Framework

The article focuses on the reasons behind both the consolidation of what I have termed “respectable” liberalism between the 1830s and the 1840s and its subsequent decline and fall between 1900 and 1923. In understanding both processes I study the links established between “respectable” liberals and propertied elites, the monarchy, and the Church. In the first phase these links served to consolidate the liberal polity. However, they also meant that many tenets of liberal ideology were compromised. Free elections were undermined by the operation of caciquismo, monarchs established a powerful position, and despite the Church hierarchy working with liberalism, the doctrine espoused by much of the Church was still shaped by the Counter-Reformation. Hence, “respectable” liberalism failed to achieve a popular social base. And the liberal order was increasingly denigrated as part of the corrupt “oligarchy” that ruled Spain. Worse still, between 1916 and 1923 the Church, monarch, and the propertied elite increasingly abandoned the liberal Monarchist Restoration. Hence when General Primo de Rivera launched his coup the rug was pulled from under the liberals’ feet and there was no one to cushion the fall

Mastectomía contralateral profiláctica con reconstrucción inmediata en pacientes con cáncer de mama unilateral sin mutación germinal en BRCA1/2

Introducción No existe un consenso sobre las indicaciones de mastectomía contralateral en pacientes diagnosticadas de cáncer de mama unilateral sin mutación germinal en BRCA1/2. Estudios previos han identificado algunos factores que pueden influir en la toma de la decisión dependientes del tumor, como el tamaño o histología, de la paciente, como la edad, y de la cirugía como la posibilidad de realizar una reconstrucción inmediata o la experiencia del cirujano. Métodos Estudio retrospectivo de una cohorte de 176 pacientes diagnosticadas de CM entre 2010 y 2016 a las que se les realizó cirugía mamaria. Se ha analizado la asociación de características del tumor y de la paciente con la toma de decisión de realizar mastectomía contralateral (MC) o no-MC. Asimismo, se han analizado los datos relacionados con la cirugía y la recurrencia por grupos mediante la curva de incidencia acumulada y el test de Gray. Resultados El número de MC se ha incrementado en nuestro centro. No hemos encontrado diferencias significativas en el desarrollo de complicaciones posquirúrgicas entre los 2 grupos de pacientes, pero sí en la estancia hospitalaria, siendo superior para MC. También hemos observado diferencias entre ambas cohortes en edad y tipo de tumor, siendo la MC más frecuente en aquellas pacientes más jóvenes y subtipo luminal A. Hemos hallado diferencias en la incidencia acumulada de recidiva entre ambos subgrupos (p = 0, 034). Conclusiones En nuestra cohorte la MC se realiza más frecuentemente en pacientes más jóvenes y con cáncer de mama luminal A. Introduction: There is no consensus on the indications for contralateral mastectomy (CM) in patients diagnosed with unilateral breast cancer without germline BRCA1/2 mutations. Prior studies have identified some factors that could influence decision-making. These factors include tumoural size and histological type; patient-related factors, such as age; and surgical factors such as the possibility of immediate reconstruction and the surgeon''s experience. Methods: Retrospective study of a cohort of 176 patients diagnosed with breast cancer between 2010 and 2016 who underwent breast surgery. We analysed the association between tumoural and patient-related characteristics with the decision to perform CM or not. We also analysed data related to surgery and recurrence by groups by using the cumulative incidence curve and the Gray test. Results: The number of CM has increased in our centre. We found no significant differences in the occurrence of post-surgical complications between the two patient groups but length of hospital stay was higher in CM. We also found differences between the two cohorts in age and tumoural type, with CM being more frequent in younger patients and those with luminal A subtype. Differences were found in the cumulative incidence of recurrence between subgroups (p = 0.034). Conclusions: In our cohort, CM was more frequent in younger patients and in those with luminal A breast cancer

High Hepatitis B Prevalence and Vaccination Needs Among Transgender Women and Men Sex Workers in Barcelona, Spain

Background. Transgender women sex workers (TWSWs) and men sex workers (MSWs) are especially vulnerable to acquiring hepatitis B virus (HBV) infection. We aimed to describe HBV prevalence (hepatitis B surface antigen [HBsAg] and core antibody [HBcAb]) and associated risk factors for HBV exposure (HBcAb), to assess vaccination status and risk factors for no prior vaccination, and to compare HBV prevalence and vaccination status between TWSWs and MSWs. Methods. The SexCohort study was advertised to TWSWs and MSWs through several communication channels. At cohort entry through 2 community-based organizations in Barcelona, the study population was screened for HBV and other sexually transmitted infections, and an epidemiological questionnaire was administered (n = 271). Results. Overall, 93.0% of participants were migrants, mostly from South and Central American countries. HBsAg prevalence was 1.9% (TWSWs, 2.4%; vs MSWs, 0.9%; P = .42), and previous exposure to HBV was 31.8% (TWSWs, 38.5%; vs MSWs, 20.8%; P = .002). Over 5 years of sex work (adjusted odds ratio [aOR], 9.35), prior exposure to Treponema pallidum (aOR, 3.49), and treatment with anxiolytic drugs (aOR, 3.23) were associated with HBV exposure. Overall, 33.7% of participants exhibited immunity from vaccination (TWSWs, 30.8%; vs MSWs, 38.61%; P < .001), while 34.4% were candidates to HBV vaccination (TWSWs, 30.8%; vs MSWs, 40.6%; P < .001). Never having been on pre-exposure prophylaxis for HIV (odds ratio [OR], 4.23) and non-Spanish origin (OR, 5.00) were associated with no prior HBV vaccination. Conclusions. There is a need to reinforce screening and vaccination programs aimed at TWSWs and MSWs as integrated services offered at the community centers commonly accessed by these populations

Role of age and comorbidities in mortality of patients with infective endocarditis

Purpose: The aim of this study was to analyse the characteristics of patients with IE in three groups of age and to assess the ability of age and the Charlson Comorbidity Index (CCI) to predict mortality. Methods: Prospective cohort study of all patients with IE included in the GAMES Spanish database between 2008 and 2015. Patients were stratified into three age groups:<65 years, 65 to 80 years, and = 80 years.The area under the receiver-operating characteristic (AUROC) curve was calculated to quantify the diagnostic accuracy of the CCI to predict mortality risk. Results: A total of 3120 patients with IE (1327 < 65 years;1291 65-80 years;502 = 80 years) were enrolled.Fever and heart failure were the most common presentations of IE, with no differences among age groups.Patients =80 years who underwent surgery were significantly lower compared with other age groups (14.3%, 65 years; 20.5%, 65-79 years; 31.3%, =80 years). In-hospital mortality was lower in the <65-year group (20.3%, <65 years;30.1%, 65-79 years;34.7%, =80 years;p < 0.001) as well as 1-year mortality (3.2%, <65 years; 5.5%, 65-80 years;7.6%, =80 years; p = 0.003).Independent predictors of mortality were age = 80 years (hazard ratio [HR]:2.78;95% confidence interval [CI]:2.32–3.34), CCI = 3 (HR:1.62; 95% CI:1.39–1.88), and non-performed surgery (HR:1.64;95% CI:11.16–1.58).When the three age groups were compared, the AUROC curve for CCI was significantly larger for patients aged <65 years(p < 0.001) for both in-hospital and 1-year mortality. Conclusion: There were no differences in the clinical presentation of IE between the groups. Age = 80 years, high comorbidity (measured by CCI), and non-performance of surgery were independent predictors of mortality in patients with IE.CCI could help to identify those patients with IE and surgical indication who present a lower risk of in-hospital and 1-year mortality after surgery, especially in the <65-year group