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.

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.

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.

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.

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.

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.

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.

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 descriptive study on constructional impairment in frontotemporal dementia and Alzheimer's disease.

BACKGROUND AND PURPOSE: Frontotemporal dementia (FTD) is a degenerative disorder characterized, in its frontal variant, by psychiatric onset, deficits in executive functions and sparing of memory and visuo-spatial abilities. Studies on visuo-spatial abilities in FTD and Alzheimer's disease (AD) have mainly focused on constructional abilities (CA) and have yielded contrasting data, often depending either on the task used or biases in the clinical selection of patients. The aim of our study was to evaluate the frequency of the CA impairment in FTD-fv and AD patients at the early stage of the disease, and to verify if some distinctive features of this impairment can characterize each pathology. METHODS: The copy-drawing task (Rey Complex Figure, RCF) of 41 patients with probable mild AD and 15 patients with probable mild FTD-fv were analysed by means of quantitative and qualitative indices. RESULTS: Data showed that both AD and FTD patients displayed similar RCF scores, as well as execution strategies, type of errors and global analysis. The FTD group only had a significant deficit in the analysis of inner details.

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.

Causes of cross-over in unilateral neglect: between-group comparisons, within-patient dissociations and eye movements.

Patients with left unilateral neglect bisect long horizontal lines to the right of the true centre. However, when given short lines, many of the same patients mark the midpoint to the left of the true centre, towards the otherwise neglected space. This paradoxical phenomenon has been termed 'cross-over' and is difficult to explain based on current accounts of the neglect syndrome. To explore the causes of cross-over, in a first study we evaluated bisection of 20, 100 and 200 mm horizontal lines in groups of unilateral brain-damaged patients with neglect and hemianopia, with neglect and no hemianopia, with hemianopia and no neglect and without neglect or hemianopia. Cross-over of 20 mm lines was found only in neglect patients with hemianopia. To ascertain further the influence of visual field defects on cross-over, in a second study we compared the performance of two right-brain-damaged patients with contralesional neglect and inferior quadrantanopia with that of a patient with inferior quadrantanopia and no neglect. Patients bisected lines oriented so as to cross or uncross the blind quadrant of the visual field. When short 20 mm lines crossed the blind quadrant, neglect patients showed cross-over; when the same lines crossed the seeing quadrants cross-over was absent. These findings were confirmed by the examination of a neglect patient with sparing of the central 5 degrees of the contralesional left visual hemifield in the right eye and no sparing in the left eye. In monocular viewing, cross-over was present when 20 mm lines were bisected with the left eye and absent when bisected with the right eye. Recording of eye movements showed that at the moment of bisection left eye fixations shifted towards the contralesional line endpoint whereas right eye fixations remained anchored to the centre of the line. With long lines, both eyes deviated ipsilesionally. These results show that in neglect patients ipsilesional deviation in the bisection of long lines turns into apparently paradoxical contralesional bisection of short ones only when these cross a retinotopically blind sector of the neglected space. Cross-over seems to depend on the small spatial effects produced by reflexive contralesional gaze shifts allowing eccentric fixations with the seeing hemifield. During the bisection of long lines, these effects are cancelled out by the strong attentional deviation induced by the marked extension of the ipsilesional line segment. This explanation establishes coherence between cross-over and current accounts of the neglect syndrome.

Improved staging of B-cell non-Hodgkin's lymphoma patients with 99mTc-labeled LL2 monoclonal antibody fragment.

Radioimmunodetection (RAID) with the 99mTc-labeled Fab' fragment of monoclonal antibody (MoAb) LL2 has been reported to have a high lesion detection rate for malignant lymph nodes as well as for visceral and skeletal tumor masses (20). Our purpose in this study was to evaluate the safety and staging efficacy of the 99mTc-labeled Fab' fragment of MoAb LL2 in patients with various grades and stages of B-cell non-Hodgkin's lymphoma (NHL). Thirty adult patients, 13 male and 17 female, ranging in age from 20 to 80 years, with at least one biopsy-proved malignant node (> or = 0.5 cm) and a Karnofsky performance score of > or = 60% were enrolled in this study. Patients underwent selected planar and single photon emission computed tomographic imaging at 6 and 18 h after receiving an i.v. infusion of 0.25-1 mg of LL2 Fab' fragment labeled with 25-30 mCi of 99mTc. RAID findings were compared with physical examination, chest radiography, computed tomography, magnetic resonance imaging, and bone and 67Ga scan findings. The RAID scan was positive in all but three patients. The sensitivity for known lesions was 90% and for suspected lesions, 89%, with an overall positive predictive value of 96%. Twenty-nine of the 30 patients had either low- or intermediate-grade NHL. Fifteen of 16 (94%) low-grade patients were correctly staged by RAID; three of these patients were correctly upstaged. Twelve of the 13 (92%) intermediate-grade patients were correctly staged by RAID; two of these patients were correctly upstaged. The high-grade NHL patient was staged correctly by RAID. Infused doses of 99mTc-labeled LL2 Fab' of 0.5 and 1.0 mg did not affect lesion sensitivity. The RAID sensitivity decreased as the total tumor burden increased > or = 100 g. On the basis of these initial results, the 99mTc-labeled Fab' fragment of MoAb LL2 (LymphoScan) seems to yield useful clinical information, especially for the staging of B-cell NHL patients who do not have bulky disease (i.e., tumor burdens of < or = 100 g).

(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.

Clinical and genetic heterogeneity of right bundle branch block and ST-segment elevation syndrome: A prospective evaluation of 52 families.

BACKGROUND: The ECG pattern of right bundle branch block and ST-segment elevation in leads V(1) to V(3) (Brugada syndrome) is associated with high risk of sudden death in patients with a normal heart. Current management and prognosis are based on a single study suggesting a high mortality risk within 3 years for symptomatic and asymptomatic patients alike. As a consequence, aggressive management (implantable cardioverter defibrillator) is recommended for both groups. METHODS AND RESULTS: Sixty patients (45 males aged 40+/-15 years) with the typical ECG pattern were clinically evaluated. Events at follow-up were analyzed for patients with at least one episode of aborted sudden death or syncope of unknown origin before recognition of the syndrome (30 symptomatic patients) and for patients without previous history of events (30 asymptomatic patients). Prevalence of mutations of the cardiac sodium channel was 15%, demonstrating genetic heterogeneity. During a mean follow-up of 33+/-38 months, ventricular fibrillation occurred in 5 (16%) of 30 symptomatic patients and in none of the 30 asymptomatic patients. Programmed electrical stimulation was of limited value in identifying patients at risk (positive predictive value 50%, negative predictive value 46%). Pharmacological challenge with sodium channel blockers was unable to unmask most silent gene carriers (positive predictive value 35%). CONCLUSIONS: At variance with current views, asymptomatic patients are at lower risk for sudden death. Programmed electrical stimulation identifies only a fraction of individuals at risk, and sodium channel blockade fails to unmask most silent gene carriers. This novel evidence mandates a reappraisal of therapeutic management.

Combined radiotherapy and chemotherapy in stage T3 and T4 nasopharyngeal carcinoma in children.

Twelve children younger than 16 years affected by undifferentiated nasopharyngeal carcinoma (NPC) with advanced primary tumor (T3, T4) were treated with chemotherapy consisting of Adriamycin (ADM [doxorubicin; Adria Laboratories, Columbus, OH]), vincristine (VCR), and cyclophosphamide (CYC), and radiotherapy. Preradiation chemotherapy produced partial responses in eight of ten evaluable patients. Eleven of 12 patients achieved a complete response following radiotherapy. The actuarial 3-year continuous relapse-free survival (CRFS) was 75%. This represents a significant improvement when compared with the 8% rate obtained in a previous series of patients treated with radiotherapy either with or without adjuvant CYC.

Questionable role of CNS radioprophylaxis in the therapeutic management of childhood rhabdomyosarcoma with meningeal extension.

A series of 15 consecutive children with head and neck nonorbital rhabdomyosarcoma (RMSA) with meningeal extension were prospectively treated with chemotherapy consisting of Adriamycin (doxorubicin; Adria Laboratory, Columbus, OH) (ADM), vincristine (VCR), cyclophosphamide (CPM), and dactinomycin (DACT) followed by radiotherapy (60 Gy) to the primary tumor volume, along with intrathecal methotrexate (IT MTX). Thirteen of 15 responded to preradiation chemotherapy. Four of 13 relapsed. Relapse occurred at the level of the primary tumor in three of four. The 3-year progression-free survival (PFS) was 59%, similar to that achieved in a previous series treated with a comparable therapeutic approach that also included whole-brain radiotherapy as a prophylaxis of possible occult meningeal seeding. It is concluded that CNS prophylaxis with radiotherapy is questionable in the management of childhood RMSA with meningeal extension.