Analytical and clinical validity of wearable, multi-sensor technology for assessment of motor function in patients with Parkinson's disease in Japan.

Continuous, objective monitoring of motor signs and symptoms may help improve tracking of disease progression and treatment response in Parkinson's disease (PD). This study assessed the analytical and clinical validity of multi-sensor smartwatch measurements in hospitalized and home-based settings (96 patients with PD; mean wear time 19 h/day) using a twice-daily virtual motor examination (VME) at times representing medication OFF/ON states. Digital measurement performance was better during inpatient clinical assessments for composite V-scores than single-sensor-derived features for bradykinesia (Spearman |r|= 0.63, reliability = 0.72), tremor (|r|= 0.41, reliability = 0.65), and overall motor features (|r|= 0.70, reliability = 0.67). Composite levodopa effect sizes during hospitalization were 0.51-1.44 for clinical assessments and 0.56-1.37 for VMEs. Reliability of digital measurements during home-based VMEs was 0.62-0.80 for scores derived from weekly averages and 0.24-0.66 for daily measurements. These results show that unsupervised digital measurements of motor features with wrist-worn sensors are sensitive to medication state and are reliable in naturalistic settings.Trial Registration: Japan Pharmaceutical Information Center Clinical Trials Information (JAPIC-CTI): JapicCTI-194825; Registered June 25, 2019.

A phase 2 study of a combined diphtheria-tetanus-acellular pertussis vaccine with a Sabin-derived inactivated poliovirus vaccine in children.

Background: With the goal of global eradication of poliomyelitis due to wild-type viruses within sight, WHO now recommends that infants receive at least one dose of trivalent inactivated poliovirus vaccine (IPV) with bivalent OPV (types 1 and 3) replacing trivalent OPV. Limited manufacturing capacity and new regulations on manufacturers' use of wild-type viruses is driving the development of IPV based on attenuated Sabin type polioviruses. Takeda are developing a Sabin-based IPV (sIPV) to augment global capacity and supply. Methods: This study was performed to evaluate three dosages (low, medium and high) of the sIPV when administered as a combination vaccine with diphtheria-tetanus-acellular pertussis antigens (DTaP-sIPV) as a three dose primary series or as booster dose in Japanese infants and toddlers. Results: All formulations were immunogenic and well-tolerated with no safety concerns in either infants or toddlers. There was a dosage-dependent induction of neutralizing antibodies against Sabin polioviruses, the only statistically significant differences being between the low-dose and medium- and high-dose sIPVs. There was good correlation of neutralizing antibodies against Sabin and wild-type polioviruses. No sIPV dose had an observable effect on immune responses to DTaP components or the reactogenicity profile of the combined vaccine. Conclusion: When administered as a DTaP-sIPV combination, Takeda's sIPV vaccine was well-tolerated and highly immunogenic in infant and toddler schedules. The medium-dose formulation offers the optimal balance between immunogenicity and potential dose-sparing to provide a new source of sIPV to enhance the global supply, while mitigating the environmental risks associated with manufacturing vaccines with wild-type viruses.

Proinsulin lacking the A7-B7 disulfide bond, Ins2Akita, tends to aggregate due to the exposed hydrophobic surface.

A single mutation (C96Y) in the Ins2 gene, which disrupts the A7-B7 disulfide bond, causes the diabetic phenotype in Akita mice. We biochemically analyzed the conformation of wild-type and Akita mutant recombinant proinsulins. Gel filtration chromatography and dynamic light scattering revealed that the apparent size of the mutant proinsulin molecules was significantly larger than that of wild-type proinsulin, even in the absence of intermolecular disulfide bonds. Titration with a hydrophobic probe, 1-anilinonaphthalene-8-sulfonate, demonstrated that the mutant proinsulin was more hydrophobic than the wild type. In addition, circular dichroism studies revealed that the conformation of the mutant proinsulin was less stable than the wild type, which is consistent with the observation that hydrophobic residues are exposed on the surface of the proinsulin molecules. Studies with antiserum against the C-peptide of proinsulin indicated that the mutant proinsulin had an immunoreactivity that was at least one-tenth weaker than wild-type proinsulin, suggesting that the C-peptide of mutant proinsulin is buried inside the aggregate of the proinsulin molecule. These findings indicate that increased hydrophobicity of mutant proinsulin facilitates aggregate formation, providing a clue to the dominant negative effect in the Akita mouse.