Renal impairment and its impact on clinical outcomes in patients who are critically ill with COVID-19: a multicentre observational study.

Renal impairment is common in patients who are critically ill with coronavirus disease-19 (COVID-19). We examined the association between acute and chronic kidney disease with clinical outcomes in 372 patients with coronavirus disease-19 admitted to four regional intensive care units between 10 March 2020 and 31 July 2020. A total of 216 (58%) patients presented with COVID-19 and renal impairment. Acute kidney injury and/or chronic kidney disease was associated with greater in-hospital mortality compared with patients with preserved renal function (107/216 patients (50%) (95%CI 44-57) vs. 32/156 (21%) (95%CI 15-28), respectively; p < 0.001, relative risk 2.4 (95%CI 1.7-3.4)). Mortality was greatest in patients with renal transplants (6/7 patients (86%) (95%CI 47-100)). Mortality rates increased in patients with worsening renal injury according to the Kidney Disease: Improving Global Outcomes classification: stage 0 mortality 33/157 patients (21%) (95%CI 15-28) vs. stages 1-3 mortality 91/186 patients (49%) (95%CI 42-56); p < 0.001, relative risk 2.3 (95%CI 1.7-3.3). Survivors were less likely to require renal replacement therapy compared with non-survivors (57/233 patients (24%) vs. 64/139 patients (46%), respectively; p < 0.001, relative risk 1.9 (95%CI 1.4-2.5)). One-fifth of survivors who required renal replacement therapy acutely in intensive care continued to require renal support following discharge. Our data demonstrate that renal impairment in patients admitted to intensive care with COVID-19 is common and is associated with a high mortality and requirement for on-going renal support after discharge from critical care. Our findings have important implications for future pandemic planning in this patient cohort.

Ridge regression and its applications in genetic studies.

With the advancement of technology, analysis of large-scale data of gene expression is feasible and has become very popular in the era of machine learning. This paper develops an improved ridge approach for the genome regression modeling. When multicollinearity exists in the data set with outliers, we consider a robust ridge estimator, namely the rank ridge regression estimator, for parameter estimation and prediction. On the other hand, the efficiency of the rank ridge regression estimator is highly dependent on the ridge parameter. In general, it is difficult to provide a satisfactory answer about the selection for the ridge parameter. Because of the good properties of generalized cross validation (GCV) and its simplicity, we use it to choose the optimum value of the ridge parameter. The GCV function creates a balance between the precision of the estimators and the bias caused by the ridge estimation. It behaves like an improved estimator of risk and can be used when the number of explanatory variables is larger than the sample size in high-dimensional problems. Finally, some numerical illustrations are given to support our findings.

Efeito de diferentes concentrações de ingestão de gossipol livre sobre morfometria testicular e qualidade seminal de touros da raça Nelore / Effect of free gossypol intake in different levels on the testicular morphometry and seminal quality of Nelore bulls

A cotonicultura tem forte fator de impacto na economia nacional, e o estado de Mato Grosso se destaca por ser o maior produtor de algodão herbáceo e deter o maior rebanho bovino do país, condições essas que estimulam o uso do caroço, da torta e do farelo de algodão na alimentação animal. Considerando que o gossipol está presente nos subprodutos do algodão e que seus efeitos sobre a reprodução podem reduzir a fertilidade dos animais, objetivou-se, com essa pesquisa, avaliar o efeito da ingestão de dietas com diferentes teores de gossipol livre por dia sobre a morfometria testicular e a qualidade seminal de touros da raça Nelore. Foram utilizados 28 touros, distribuídos aleatoriamente em seis tratamentos: T0, 0 grama de gossipol livre/touro/dia ; T1, 1,08 grama de gossipol livre/touro/dia; T2, 2,07 gramas de gossipol livre/touro/dia; T3, 3,24 gramas de gossipol livre/touro/dia; T4, 3,82 gramas de gossipol livre/touro/dia e T5, 5,08 gramas de gossipol livre/touro/dia. Os animais de cada tratamento foram mantidos confinados em área média de 100m2, dotada de bebedouro, cochos para mistura mineral e para volumoso/concentrado. O consumo de 3,24 gramas de gossipol livre/touro/dia alterou a qualidade espermática e a morfometria testicular de touros.(AU)

The cotton industry has a strong impact factor in the Brazilian economy and the state of Mato Grosso stands out for being the largest upland-type cotton producer and also holds the largest cattle herd in the country, conditions that stimulate the use of cottonseed pie and cottonseed meal in animal feed. Whereas gossypol is present in cotton by-products and their effects on reproduction can reduce the animal fertility, this research evaluated the effect of diets with different free gossypol contents in the testicular morphometry and semen quality of Nelore bulls. 28 bulls were randomly distributed in six treatments: T0, receiving no free gossypol; T1, receiving 1.08g / bull / day; T2, receiving 2.07g / bull / day; T3, receiving 3.24g / bull / day; T4, receiving 3.82g / bull / day and T5, receiving 5.08g / bull / day of free gossypol respectively. The animals in each treatment were kept confined in an averaged area of 100m2, having fresh water, troughs for mineral mixture and roughage / concentrate. The consumption of 3.24g of free gossypol / bull / day altered the bulls sperm quality and testicular morphometry.(AU)

Loss functions in restricted parameter spaces and their Bayesian applications.

Squared error loss remains the most commonly used loss function for constructing a Bayes estimator of the parameter of interest. However, it can lead to suboptimal solutions when a parameter is defined on a restricted space. It can also be an inappropriate choice in the context when an extreme overestimation and/or underestimation results in severe consequences and a more conservative estimator is preferred. We advocate a class of loss functions for parameters defined on restricted spaces which infinitely penalize boundary decisions like the squared error loss does on the real line. We also recall several properties of loss functions such as symmetry, convexity and invariance. We propose generalizations of the squared error loss function for parameters defined on the positive real line and on an interval. We provide explicit solutions for corresponding Bayes estimators and discuss multivariate extensions. Four well-known Bayesian estimation problems are used to demonstrate inferential benefits the novel Bayes estimators can provide in the context of restricted estimation.

A proposal for a new PhD level curriculum on quantitative methods for drug development.

This paper provides an overview of "Improving Design, Evaluation and Analysis of early drug development Studies" (IDEAS), a European Commission-funded network bringing together leading academic institutions and small- to large-sized pharmaceutical companies to train a cohort of graduate-level medical statisticians. The network is composed of a diverse mix of public and private sector partners spread across Europe, which will host 14 early-stage researchers for 36 months. IDEAS training activities are composed of a well-rounded mixture of specialist methodological components and generic transferable skills. Particular attention is paid to fostering collaborations between researchers and supervisors, which span academia and the private sector. Within this paper, we review existing medical statistics programmes (MSc and PhD) and highlight the training they provide on skills relevant to drug development. Motivated by this review and our experiences with the IDEAS project, we propose a concept for a joint, harmonised European PhD programme to train statisticians in quantitative methods for drug development.

Clinical findings and prognosis of interference injuries to the palmar aspect of the forelimbs in Standardbred racehorses: A study on 74 cases.

BACKGROUND: Information on interference injuries in racehorses is lacking. OBJECTIVE: To describe clinical findings and prognosis of palmar forelimb interference injuries in Standardbreds. STUDY DESIGN: Retrospective cohort study. METHODS: Records of 74 racehorses sustaining palmar forelimb interference injuries were studied; 7 occurred during training and 67 during racing. The number of starts before injury, hind shoeing status, gait penalties and racing speeds in cases occurring during racing were compared with negative controls (67 age, sex and speed category matched horses) from the same races. The number of starts and racing speed in 30 racing days preceding recruitment were compared with those following recruitment (negative controls) or return to racing (cases). Clinical aspects and outcome in interference-induced superficial digital flexor (SDF) tendonitis were compared with 77 horses with overstrain-induced SDF tendonitis. RESULTS: In 89% of cases, there was SDF tendonitis and this was associated with a longer time to return to racing (6 months vs. 1 months; P<0.001). The presence of gait penalties (odds ratio (OR) 11.13; 95% CI 3.74, 41.64; P<0.001) and unshod hind feet (OR = 6.26, 95% CI 2.26, 19.62; P<0.001) increased risk of interference injuries. After recruitment/return to racing, horses with interference injuries participated in a lower number of races (24 starts per racing day, interquartile range [IQR] 20-32) compared with controls (49, IQR 43-55, P<0.0001). Interference-induced tendonitis cases (n = 58) had a shorter time to return to racing (245 ± 137 days) than overstrain-induced tendonitis cases (331 ± 118 days, P<0.001). MAIN LIMITATIONS: Data were collected retrospectively; time of ultrasonographic assessment varied and health status of the racing controls is unknown. CONCLUSIONS: SDF tendonitis is common with palmar forelimb interference injuries in Standardbreds and increases time to return to racing. Interference-induced SDF tendonitis has a better prognosis than overstrain-induced tendonitis.

18F-FDG PET/CT versus bone scintigraphy in the follow-up of gastric cancer / 18F-FDG PET/TC en comparación con la gammagrafía ósea en el seguimento del cancer gástrico

A 53-year-old patient underwent a positron emission tomography/computed tomography with 2-fluoro-2-deoxy-d-glucose (18F-FDG PET/CT) in the suspicious of gastric tumor recurrence (mediastinal and abdominal lymph nodes). PET/CT identified only an area of 18F-FDGuptake in the twelfth thoracic vertebrae. Unexpectedly, a bone scintigraphy revealed many "hot" spots changing the diagnosis (single metastasis versus plurimetastatic disease) and impacting on patient's management (AU)

Un paciente de 53 años fue sometido a una tomografía por emisión de positrones-tomografía computarizada con 18F-2-fluoro-2 deoxi-d-glucosa (18F-FDG PET/TC) ante la sospecha de recidiva de cáncer de estómago (nódulos linfáticos en mediastino y abdomen). El PET/TC identificó únicamente una zona de captación de 18F-FDG en la duodécima vértebra torácica. Sorpresivamente, la gammagrafía ósea reveló muchas imágenes hipercaptantes que modificaron el diagnóstico (metástasis única en lugar de metástasis múltiples) con el consiguiente impacto en el tratamiento del paciente (AU)

(18)F-FDG PET/CT versus bone scintigraphy in the follow-up of gastric cancer.

A 53-year-old patient underwent a positron emission tomography/computed tomography with 2-fluoro-2-deoxy-d-glucose ((18)F-FDG PET/CT) in the suspicious of gastric tumor recurrence (mediastinal and abdominal lymph nodes). PET/CT identified only an area of (18)F-FDGuptake in the twelfth thoracic vertebrae. Unexpectedly, a bone scintigraphy revealed many "hot" spots changing the diagnosis (single metastasis versus plurimetastatic disease) and impacting on patient's management.

Neuropsychological predictors of rapidly progressive Alzheimer's disease.

OBJECTIVE: Alzheimer's disease (AD), the most common cause of dementia, typically shows a slow clinical progression over time. 'Rapidly progressive' AD, a variant of the disease characterized by an aggressive course, exhibits distinct clinical, biological, and neuropathological features. Here, we investigate neuropsychological predictors of rapid decline in a group of mild patients with AD. METHODS: One hundred fifty-three mild patients with AD admitted to a memory disorder clinic and followed for up to 3 years were included in this study. A comprehensive neuropsychological (NP) battery was performed at the time of enrollment. Patients were defined as 'rapidly progressive' if they exhibited a drop of 6 or more points on the Mini Mental State Examination (MMSE) between two consecutive annual visits. This event defined the main outcome in multiple analyses of variance and Cox proportional hazards models that investigated the impact of NP predictors. Categorical principal component analysis (CATPCA) was also employed in order to delineate clusters of NP tests and to test their effect on the outcome. RESULTS: Of 153 subjects, thirty-seven (24%) were classified as 'rapidly progressive'; those subjects showed younger age of symptoms onset compared to slow decliners (68 vs 71.5 years old). Baseline lower performance on a neuropsychological test of naming predicted a rapid decline over the follow-up (P = 0.001). Three clusters of NP were defined by CATPCA: (i) executive/language, (ii) visuospatial memory, and (iii) verbal memory. The executive/language component predicted a rapid decline over the follow-up (P = 0.016). CONCLUSION: Early executive/language impairment is highly predictive of a rapid progression of AD.

Binge eating and fast cognitive worsening in an early-onset bvFTD patient carrying C9ORF72 expansion.

An expanded hexanucleotide (GGGGCC) repeat in a non-coding promoter region of open reading frame 72 of chromosome 9 (C9ORF72) has been recently identified as a major cause of familial and sporadic frontotemporal lobar degeneration. We describe the clinical picture of a 64-year-old woman carrying the hexanucleotide repeat expansion, who developed a sporadic early-onset form of behavioral variant frontotemporal dementia characterized by the occurrence of uncommon behavioral manifestations such as binge eating disturbance and by a rapid worsening of cognitive abilities. Our report confirms previous studies asserting that C9ORF72 repeats may sustain heterogeneous clinical syndromes.

A Bayesian adaptive dose selection procedure with an overdispersed count endpoint.

Adaptive trial designs can considerably improve upon traditional designs, by modifying design aspects of the ongoing trial, like early stopping, adding, or dropping doses, or changing the sample size. In the present work, we propose a two-stage Bayesian adaptive design for a Phase IIb study aimed at selecting the lowest effective dose for Phase III. In this setting, efficacy has been proved for a high dose in a Phase IIa proof-of-concept study, but the existence of a lower but still effective dose is investigated before the scheduled Phase III starts. In the first stage, we randomize patients to placebo, maximal tolerated dose, and one or more additional doses within the dose range. Based on an interim analysis, we either stop the study for futility or success or continue the study to the second stage, where newly recruited patients are allocated to placebo, some fairly high dose, and one additional dose chosen based on interim data. At the interim analysis, we use the criteria based on the predictive probability of success to decide on whether to stop or to continue the trial and, in the latter case, which dose to select for the second stage. Finally, we will select a dose as lowest effective dose for Phase III either at the end of the first stage or at the end of the second stage. We evaluate the operating characteristics of the procedure via simulations and present the results for several scenarios, comparing the performance of the proposed procedure to those of the non-adaptive design.

Mid-term prognostic value of coronary artery disease in patients undergoing transcatheter aortic valve implantation: a meta-analysis of adjusted observational results.

AIMS: Coronary artery disease (CAD) negatively affects prognosis in patients undergoing surgical aortic valve replacement, being currently evaluated in the most common used risk score. Our meta-analysis aims to clarify the prognostic role of CAD on mid-term survival in patients undergoing TAVI. METHODS AND RESULTS: Studies reporting multivariate predictors of adverse outcomes in patients undergoing TAVI were systematically searched for and pooled, when appropriate, using a random-effect method. 960 citations were first screened and finally 7 studies (2472 patients) were included. Diagnosis of CAD was reported in 52%(42-65) of patients and 1169 Edwards SAPIEN and 1303 CoreValve prostheses were implanted. After a median follow up of 452 days (357-585) 24% of patients (19-33) died, and 23 (14-32) for cardiovascular death. At pooled analysis of multivariate approach, diagnosis of coronary artery disease did not increase risk of death (OR 1.0, 95% CI, confidence interval, 0.67-1.50 I(2) 0%). CONCLUSION: CAD does not affect mid-term TAVI outcome: this finding should be weighted to accurately evaluate risk and strategies for patients with severe aortic stenosis.

Restless legs syndrome in a group of patients with Alzheimer's disease.

BACKGROUND: Restless legs syndrome (RLS) is a neurological disorder characterized by the urge to move the legs associated with peculiar unpleasant sensations during periods of rest and inactivity that are relieved by movement. A few studies analyzed RLS in neurodegenerative diseases such as Alzheimer's Disease (AD). The aim of our study was to assess the prevalence and the clinical characteristics of RLS in a cohort of AD patients. METHODS: Three hundred and thirty-nine subjects with a diagnosis of AD were recruited. Cognitive, functional, and neuropsychiatric measures were collected at baseline and six-monthly for a 2-years follow-up RESULTS: Fourteen subjects met the RLS criteria. RLS subjects were more frequently male (p:0,006) and younger than AD subject without RLS (p:0,029). MMSE, ADL and IADL were not significantly different. NPI total scores did not differ significantly, however, AD patients with RLS were found to be more apathetic (p:0,001) than AD subjects without RLS. CONCLUSION: RLS prevalence in our AD cohort was estimated to be about 4%. RLS appeared to be associated with neuropsychiatric symptoms such as apathy. RLS and apathy might share a common pathophysiological basis represented by a dysfunction of the central dopaminergic system.

Increased fatigability of the gastrocnemius medialis muscle in individuals with intermittent claudication.

BACKGROUND: We attempted to identify possible differences in the contractility of the gastrocnemius medialis (GM) muscle between healthy controls and individuals with peripheral arterial disease (PAD) and intermittent lower-limb claudication. METHODS: The GM muscles of 17 PAD patients and 17 healthy controls were examined with tensiomyography. Single or multiple electrical impulses were used to trigger muscle contractions, and the time and amplitude of contractions were measured. RESULTS: After single-impulse stimulation, the GM muscles of PAD patients showed significantly shorter contraction times (P < 0.001) than the GM muscles of controls. During 1 min of repetitive electrical stimulation, the contraction velocity of the controls' GM muscles typically showed a sustained increase throughout the stimulation period, whereas in PAD patients, a significant decrease in contraction velocity was observed after 30 s. The onset of muscle fatigue was unrelated to the ankle brachial index (ABI) of the examined leg. When the legs of PAD patients with higher and lower ABIs were compared to each other, no significant differences were found regarding the time and amplitude of contraction after single-impulse stimulation. CONCLUSIONS: The GM muscles of individuals with intermittent claudication contract more quickly and fatigue earlier than the GM muscles of healthy controls. Because the contraction time, measured with tensiomyography, reflects the individual's muscle fibre composition, our findings may reflect a shift from type I fibres to type II fibres in the GM muscles of PAD patients. Our data support the idea that calf myopathy is present in claudication-prone patients and, in part, determines the clinical manifestations of PAD.

The London APP mutation (Val717Ile) associated with early shifting abilities and behavioral changes in two Italian families with early-onset Alzheimer's disease.

BACKGROUND/AIMS: Mutations in the amyloid precursor protein gene were the first to be recognized as a cause of Alzheimer's disease (AD). METHODS: We describe 2 Italian families showing the missense mutation in exon 17 of the amyloid precursor protein gene on chromosome 21 (Val717Ile), known as London mutation. RESULTS: In 1 family, this mutation was responsible for AD in 3 out of 7 siblings and it is also present in a fourth sibling who has only shown signs of executive dysfunction so far. Two subjects of the other family with AD diagnosis were carriers of the same mutation. CONCLUSION: All AD subjects showed a cognitive profile characterized by early impairment in long-term memory, shifting abilities and affective symptoms beginning in the fifth decade of life.

Ethical issues in end of life treatments for patients with dementia.

Dementia is a terminal disease, associated with great suffering and difficult decisions in the severe stage. The decision-making process is characterized by uncertainty because of lack of scientific evidence in treatments and by the need to reconcile conflicting points of view. In intercurrent diseases, aggressive interventions are used without consideration of its futility; in comparison with cancer, several consequences of physicians' attitude not to consider dementia as a terminal disease have been reported, especially concerning pain relief. Lack of evidence of artificial nutrition and hydration effectiveness makes advance care planning relevant.