Developments in statistical evaluation of clinical trials

This book describes various ways of approaching and interpreting the data produced by clinical trial studies, with a special emphasis on the essential role that biostatistics plays in clinical trials. Over the past few decades the role of statistics in the evaluation and interpretation of clinical data has become of paramount importance. As a result the standards of clinical study design, conduct and interpretation have undergone substantial improvement. The book includes 18 carefully reviewed chapters on recent developments in clinical trials and their statistical evaluation, with each chapter providing one or more examples involving typical data sets, enabling readers to apply the proposed procedures. The chapters employ a uniform style to enhance comparability between the approaches

A novel ICK mutation causes ciliary disruption and lethal endocrine-cerebro-osteodysplasia syndrome

BACKGROUND: Endocrine-cerebro-osteodysplasia (ECO) syndrome [MIM:612651] caused by a recessive mutation (p.R272Q) in Intestinal cell kinase (ICK) shows significant clinical overlap with ciliary disorders. Similarities are strongest between ECO syndrome, the Majewski and Mohr-Majewski short-rib thoracic dysplasia (SRTD) with polydactyly syndromes, and hydrolethalus syndrome. In this study, we present a novel homozygous ICK mutation in a fetus with ECO syndrome and compare the effect of this mutation with the previously reported ICK variant on ciliogenesis and cilium morphology. RESULTS: Through homozygosity mapping and whole-exome sequencing, we identified a second variant (c.358G \u3e T; p.G120C) in ICK in a Turkish fetus presenting with ECO syndrome. In vitro studies of wild-type and mutant mRFP-ICK (p.G120C and p.R272Q) revealed that, in contrast to the wild-type protein that localizes along the ciliary axoneme and/or is present in the ciliary base, mutant proteins rather enrich in the ciliary tip. In addition, immunocytochemistry revealed a decreased number of cilia in ICK p.R272Q-affected cells. CONCLUSIONS: Through identification of a novel ICK mutation, we confirm that disruption of ICK causes ECO syndrome, which clinically overlaps with the spectrum of ciliopathies. Expression of ICK-mutated proteins result in an abnormal ciliary localization compared to wild-type protein. Primary fibroblasts derived from an individual with ECO syndrome display ciliogenesis defects. In aggregate, our findings are consistent with recent reports that show that ICK regulates ciliary biology in vitro and in mice, confirming that ECO syndrome is a severe ciliopathy

Responsiveness of the Canadian occupational performance measure

This study evaluated the responsiveness of the Canadian Occupational Performance Measure (COPM), an individualized, client-centered outcome measure for the identification and evaluation of self-perceived occupational performance problems. We recruited 152 consecutive patients with various diagnoses, admitted to the outpatient clinic of two occupational therapy departments, to complete a COPM interview and three self-reported health status questionnaires on two occasions: prior to the start of occupational therapy treatment and 3 months later. The three questionnaires were the Sickness Impact Profile (SIP68), the Disability and Impact Profile (DIP), and the Impact on Participation and Autonomy (IPA). We assessed criterion responsiveness by calculating the area under the curve (AUC) for the receiver operating characteristic curve and the optimal cutoff values for the COPM scores. To determine construct responsiveness, we calculated correlations between the change in COPM scores and the change in the SIP68, DIP, and IPA scores. The AUC ranged from 0.79 to 0.85, and the optimal cut-off values for the performance scores and satisfaction scores ranged from 0.9 to 1.9. We found significant positive correlations between the COPM scores and the SIP68, DIP, and IPA scores. The capability of the COPM to detect changes in perceived occupational performance issues is supporte

Reproducibility and responsiveness of the Frailty Index and Frailty Phenotype in older hospitalized patients

BACKGROUND: There is growing interest for interventions aiming at preventing frailty progression or even to reverse frailty in older people, yet it is still unclear which frailty instrument is most appropriate for measuring change scores over time to determine the effectiveness of interventions. The aim of this prospective cohort study was to determine reproducibility and responsiveness properties of the Frailty Index (FI) and Frailty Phenotype (FP) in acutely hospitalized medical patients aged 70 years and older. METHODS: Reproducibility was assessed by Intra-Class Correlation Coefficients (ICC), standard error of measurement (SEM) and smallest detectable change (SDC); Responsiveness was assessed by the standardized response mean (SRM), and area under the receiver operating characteristic curve (AUC). RESULTS: At baseline, 243 patients were included with a median age of 76 years (range 70–98). The analytic samples included 192 and 187 patients in the three and twelve months follow-up analyses, respectively. ICC of the FI were 0.85 (95 % confidence interval [CI]: 0.76; 0.91) and 0.84 (95% CI: 0.77; 0.90), and 0.65 (95% CI: 0.49; 0.77) and 0.77 (95% CI: 0.65; 0.84) for the FP. SEM ranged from 5 to 13 %; SDC from 13 to 37 %. SRMs were good in patients with unchanged frailty status (< 0.50), and doubtful to good for deteriorated and improved patients (0.43–1.00). AUC’s over three months were 0.77 (95% CI: 0.69; 0.86) and 0.71 (95% CI: 0.62; 0.79) for the FI, and 0.68 (95% CI: 0.58; 0.77) and 0.65 (95% CI: 0.55; 0.74) for the FP. Over twelve months, AUCs were 0.78 (95% CI: 0.69; 0.87) and 0.82 (95% CI: 0.73; 0.90) for the FI, and 0.78 (95% CI: 0.69; 0.87) and 0.75 (95% CI: 0.67; 0.84) for the FP. CONCLUSIONS: The Frailty Index showed better reproducibility and responsiveness properties compared to the Frailty Phenotype among acutely hospitalized older patients. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12877-021-02444-y

Effectiveness of 3D-printed orthoses for traumatic and chronic hand conditions: A scoping review

Background In the field of orthotics, the use of three-dimensional (3D) technology as an alternative to the conventional production process of orthoses is growing. Purpose This scoping review aimed to systematically map and summarize studies assessing the effectiveness of 3D-printed orthoses for traumatic and chronic hand conditions, and to identify knowledge gaps. Methods The Cochrane Library, PubMed, EMBASE, CINAHL, Web of Science, IEEE, and PEDro were searched for studies of any type of 3D-printed orthoses for traumatic and chronic hand conditions. Any outcome related to the effectiveness of 3D-printed orthoses was considered. Two reviewers selected eligible studies, charted data on study characteristics by impairment type, and critically appraised the studies, except for case reports/series. Results Seventeen studies were included: Four randomized controlled trials, four uncontrolled trials, four case series and five case reports. Only three studies had a sample size >20. Impairments described were forearm fractures (n = 5), spasticity (n = 5), muscle weakness (n = 4), joint contractures (n = 2) and pain (n = 1). Four poor to fair quality studies on forearm fractures supported the effectiveness of 3D-printed orthoses on hand function, functionality, and satisfaction. One good quality study on spasticity demonstrated the effectiveness of 3D-printed orthoses on hand function. One poor quality pain study reported limited positive effects on satisfaction. Studies on muscle weakness and joint contractures showed no benefits. Conclusion Current literature addressing the effectiveness of 3D-printed orthoses for traumatic and chronic hand conditions consists primarily of small and poor methodological quality studies. There is a need for well-designed controlled trials including patient-related outcomes, production time and cost analyses

Visualization and Analysis Techniques for Three Dimensional Information Acquired by Confocal Microscopy

Confocal Scanning Laser Microscopy (CSLM) is particularly well suited for the acquisition of 3-dimensional data of microscopic objects. In the CSLM a specific volume in the object is sampled during the imaging process and the result is stored in a digital computer as a three-dimensional memory array. Optimal use of these data requires both the development of effective visual representations as well as analysis methods. In addition to the well known stereoscopic representation method a number of alternatives for various purposes are presented. When rendering in terms of solid-looking or semitransparent objects is required, an algorithm based on a simulated process of excitation and fluorescence is very suitable. Graphic techniques can be used to examine the 3-dimensional shape of surfaces. For (near-)real time applications a representation method should not require extensive previous data-processing or analysis. From the very extensive field of 3-D image analysis two examples are given

A Bodyweight-Dependent Allometric Exponent for Scaling Clearance Across the Human Life-Span

Purpose: To explore different allometric equations for scaling clearance across the human life-span using propofol as a model drug. Methods: Data from seven previously published propofol studies ((pre)term neonates, infants, toddlers, children, adolescents and adults) were analysed using NONMEM VI. To scale clearance, a bodyweight-based exponential equation with four different structures for the exponent was used: (I) 3/4 allometric scaling model; (II) mixture model; (III) bodyweight-cut-point separated model; (IV) bodyweight-dependent exponent model. Results: Model I adequately described clearance in adults and older children, but overestimated clearance of neonates and underestimated clearance of infants. Use of two different exponents in Model II and Model III showed significantly improved performance, but yielded ambiguities on the boundaries of the two subpopulations. This discontinuity was overcome in Model IV, in which the exponent changed sigmoidally from 1.35 at a hypothetical bodyweight of 0 kg to a value of 0.56 from 10 kg onwards, thereby describing clearance of all individuals best. Conclusions: A model was developed for scaling clearance over the entire human life-span with a single continuous equation, in which the exponent of the bodyweight-based exponential equation varied with bodyweight