Modeling of Bounded Outcome Scores with Data on the Boundaries: Application to Disability Assessment for Dementia Scores in Alzheimer’s Disease

Mixed-effects beta regression (BR), boundary-inflated beta regression (ZOI), and coarsening model (CO) were investigated for analyzing bounded outcome scores with data at the boundaries in the context of Alzheimer’s disease. Monte Carlo simulations were conducted to simulate disability assessment for dementia (DAD) scores using these three models, and each set of simulated data were analyzed by the original simulation model. One thousand trials were simulated, and each trial contained 250 subjects. For each subject, DAD scores were simulated at baseline, 13, 26, 39, 52, 65, and 78 weeks. The simulation-reestimation exercise showed that all the three models could reasonably recover their true parameter values. The bias of the parameter estimates of the ZOI model was generally less than 1%, while the bias of the CO model was mainly within 5%. The bias of the BR model was slightly higher, i.e., less than or in the order of 20%. In the application to real-world DAD data from clinical studies, examination of prediction error and visual predictive check (VPC) plots suggested that both BR and ZOI models had similar predictive performance and described the longitudinal progression of DAD slightly better than the CO model. In conclusion, the investigated three modeling approaches may be sensible choices for bounded outcome scores with data on the edges. Prediction error and VPC plots can be used to identify the model with best predictive performance.     

Biomechanical analysis of the upper thoracic spine after decompressive procedures

Background contextDecompressive procedures such as laminectomy, facetectomy, and costotransversectomy are routinely performed for various pathologies in the thoracic spine. The thoracic spine is unique, in part, because of the sternocostovertebral articulations that provide additional strength to the region relative to the cervical and lumbar spines. During decompressive surgeries, stability is compromised at a presently unknown point.PurposeTo evaluate thoracic spinal stability after common surgical decompressive procedures in thoracic spines with intact sternocostovertebral articulations.Study designBiomechanical cadaveric study.MethodsFresh-frozen human cadaveric spine specimens with intact rib cages, C7–L1 (n=9), were used. An industrial robot tested all spines in axial rotation (AR), lateral bending (LB), and flexion-extension (FE) by applying pure moments (±5 Nm). The specimens were first tested in their intact state and then tested after each of the following sequential surgical decompressive procedures at T4–T5 consisting of laminectomy; unilateral facetectomy; unilateral costotransversectomy, and subsequently instrumented fusion from T3–T7.ResultsWe found that in all three planes of motion, the sequential decompressive procedures caused no statistically significant change in motion between T3–T7 or T1–T12 when compared with intact. In comparing between intact and instrumented specimens, our study found that instrumentation reduced global range of motion (ROM) between T1–T12 by 16.3% (p=.001), 12% (p=.002), and 18.4% (p=.0004) for AR, FE, and LB, respectively. Age showed a negative correlation with motion in FE (r=?0.78, p=.01) and AR (r=?0.7, p=.04).ConclusionsThoracic spine stability was not significantly affected by sequential decompressive procedures in thoracic segments at the level of the true ribs in all three planes of motion in intact thoracic specimens. Age appeared to negatively correlate with ROM of the specimen. Our study suggests that thoracic spinal stability is maintained immediately after unilateral decompression at the level of the true ribs. These preliminary observations, however, do not depict the long-term sequelae of such procedures and warrant further investigation.     

Hybrid closed-loop therapy: Where are we in 2021?

Hybrid closed-loop systems are characterized by the coexistence of algorithm-driven automated insulin delivery combined with manual mealtime boluses. Used correctly, these insulin delivery systems offer better glucose control and reduced risk of hypoglycaemia and represent the most advanced form of insulin delivery available for people with type 1 diabetes. The aim of this paper was to compare the currently available commercial hybrid closed-loop systems in the UK: the Medtronic 670G/780G, Tandem t:slim X2 Control IQ and CamAPS FX systems. The Medtronic 670G/780G systems use Guardian 3 sensor (7-day use, two to four calibrations per day), while Tandem and CamAPS systems use the calibration-free Dexcom G6 sensor (10 days). The CamAPS system is available as an android app, whereas the other two systems have the algorithm embedded in the insulin pump. During pivotal studies, depending on the study population and baseline glycated haemoglobin level, these systems achieve a time spent in the target range 3.9 to 10 mmol/L (70 to 180 mg/dL) of 65% to 76% with low burden of hypoglycaemia. All three systems allow a higher glucose target for announced exercise, while the Tandem system offers an additional night-time tighter target. The CamAPS system offers fully customizable glucose targets and is the only system licensed for use during pregnancy. Additional education is required for both users and healthcare professionals to harness the best performance from these systems as well as to troubleshoot when “automode exits” occur. We provide consensus recommendations to develop pragmatic pathways to guide patients, clinicians and commissioners in making informed decisions on the appropriate use of the diabetes technology.     

A novel peroxisome proliferator-activated gamma (PPAR gamma) agonist,CLX-0921, has potent antihyperglycemic activity with low adipogenic potential

Agonists of the nuclear receptor peroxisome proliferator-activated receptor gamma (PPAR gamma) are pharmacologically active antihyperglycemic agents that act by increasing peripheral tissue sensitivity to insulin. Many of these agonists have antihyperglycemic activity that is directly proportional to their ability to bind and activate PPAR gamma; however, recent data bring this relationship into question. In this report we describe a new PPAR gamma agonist, CLX-0921, that is derived from a natural product. This thiazolidinedione (TZD) has a spectrum of activity that differs from commercially available TZDs. It is a weak activator of PPAR gamma (EC(50) of 0.284 micromol/L) compared to rosiglitazone (EC(50) 0.009 micromol/L). Despite this difference, the drug maintains potent glucose uptake activity in vitro and glucose-lowering activity in vivo that is equipotent to that of rosiglitazone. Moreover, CLX-0921 showed a 10-fold reduction in in vitro adipogenic potential compared to rosiglitazone. CLX-0921 also increases glycogen synthesis, an activity not typically associated with rosiglitazone or pioglitazone. Thus CLX-0921 appears to have a distinct spectrum of activity relative to other TZDs.     

Selective identification of new therapeutic targets of Mycobacterium tuberculosis by IVIAT approach

The in vivo induced antigen technology (IVIAT)(1) has been used for the identification of open reading frames (ORFs) which could be possible therapeutic targets. A recombinant lambdagt11:: Mycobacterium tuberculosis H37Rv expression library was screened with pooled TB patient sera preabsorbed with in vitro grown M. tuberculosis H37Rv. Preabsorption of pooled TB patient sera allowed identification of antigens specifically expressed or upregulated during infection and growth in vivo. Six ORFs were identified, of which four (rv0287, rv2402, rv3878 and rv1045) were of hypothetical functions. Rv0287 is a probable regulatory protein. Rv3878 is present uniquely in M. tuberculosis H37Rv and is a part of RDI deletion region of M. bovis BCG, which includes esat 6 region. This could be exploited as a tool for diagnosis. Two ORFs were assigned function solely on the basis of homology, dnaQ (rv3711c) and lpdA (rv3303c). dnaQ codes for the epsilon subunit of DNA polymerase III, which is responsible for the proofreading activity of the complex. lpdA codes for dihydrolipoamide dehydrogenase, which is a part of many multienzyme complexes such as pyruvate dehydrogenase, keto-acid dehydrogenase and alpha-ketoglutarate dehydrogenase. These two enzymes appear to be potential targets for drug development.     

A tagging-via-substrate technology for detection and proteomics of farnesylated proteins

A recently developed proteomics strategy, designated tagging-via-substrate (TAS) approach, is described for the detection and proteomic analysis of farnesylated proteins. TAS technology involves metabolic incorporation of a synthetic azido-farnesyl analog and chemoselective derivatization of azido-farnesyl-modified proteins by an elegant version of Staudinger reaction, pioneered by the Bertozzi group, using a biotinylated phosphine capture reagent. The resulting protein conjugates can be specifically detected and/or affinity-purified by streptavidin-linked horseradish peroxidase or agarose beads, respectively. Thus, the technology enables global profiling of farnesylated proteins by enriching farnesylated proteins and reducing the complexity of farnesylation subproteome. Azido-farnesylated proteins maintain the properties of protein farnesylation, including promoting membrane association, Ras-dependent mitogen-activated protein kinase kinase activation, and inhibition of lovastatin-induced apoptosis. A proteomic analysis of farnesylated proteins by TAS technology revealed 18 farnesylated proteins, including those with potentially novel farnesylation motifs, suggesting that future use of this method is likely to yield novel insight into protein farnesylation. TAS technology can be extended to other posttranslational modifications, such as geranylgeranylation and myristoylation, thus providing powerful tools for detection, quantification, and proteomic analysis of posttranslationally modified proteins.     

Arts-based social skills interventions for adolescents with acquired brain injuries: Five case reports

Objective: Previous research has demonstrated the value of arts-based programs for adolescents with childhood brain disorder to facilitate social skills and participation. The current study extends this work by examining the feasibility and effectiveness of an arts-based intervention for youth with acquired brain injuries (ABI).

Methods: A case study approach was used with four adolescent participants and one case control. A battery of quantitative measures were administered four and one week pre-intervention, one week post-intervention, as well six to eight month post-intervention.

Results: Improvements in pragmatic communication skills and social and participation goals were observed across intervention participants. Similar improvements were not seen with the case control participant.

Conclusion: Results support the use of an arts-based intervention for youth with ABI to facilitate social skills and participation. Findings also highlight the need for more sensitive measures of these skills for these youth. Suggested guidelines for program implementation are provided.