Electronic health records to facilitate clinical research

Electronic health records (EHRs) provide opportunities to enhance patient care, embed performance measures in clinical practice, and facilitate clinical research. Concerns have been raised about the increasing recruitment challenges in trials, burdensome and obtrusive data collection, and uncertain generalizability of the results. Leveraging electronic health records to counterbalance these trends is an area of intense interest. The initial applications of electronic health records, as the primary data source is envisioned for observational studies, embedded pragmatic or post-marketing registry-based randomized studies, or comparative effectiveness studies. Advancing this approach to randomized clinical trials, electronic health records may potentially be used to assess study feasibility, to facilitate patient recruitment, and streamline data collection at baseline and follow-up. Ensuring data security and privacy, overcoming the challenges associated with linking diverse systems and maintaining infrastructure for repeat use of high quality data, are some of the challenges associated with using electronic health records in clinical research. Collaboration between academia, industry, regulatory bodies, policy makers, patients, and electronic health record vendors is critical for the greater use of electronic health records in clinical research. This manuscript identifies the key steps required to advance the role of electronic health records in cardiovascular clinical research

Density functional theory calculations of the carbon ELNES of small diameter armchair and zigzag nanotubes: core-hole, curvature and momentum transfer orientation effects

We perform density functional theory calculations on a series of armchair and zigzag nanotubes of diameters less than 1nm using the all-electron Full-Potential(-Linearised)-Augmented-Plane-Wave (FPLAPW) method. Emphasis is laid on the effects of curvature, the electron beam orientation and the inclusion of the core-hole on the carbon electron energy loss K-edge. The electron energy loss near-edge spectra of all the studied tubes show strong curvature effects compared to that of flat graphene. The curvature induced $\pi-\sigma$ hybridisation is shown to have a more drastic effect on the electronic properties of zigzag tubes than on those of armchair tubes. We show that the core-hole effect must be accounted for in order to correctly reproduce electron energy loss measurements. We also find that, the energy loss near edge spectra of these carbon systems are dominantly dipole selected and that they can be expressed simply as a proportionality with the local momentum projected density of states, thus portraying the weak energy dependence of the transition matrix elements. Compared to graphite, the ELNES of carbon nanotubes show a reduced anisotropy.Comment: 25 pages, 15 figures, revtex4 submitted for publication to Phys. Rev.

Bi-allelic variants in IPO8 cause a connective tissue disorder associated with cardiovascular defects, skeletal abnormalities, and immune dysregulation.

Dysregulated transforming growth factor TGF-β signaling underlies the pathogenesis of genetic disorders affecting the connective tissue such as Loeys-Dietz syndrome. Here, we report 12 individuals with bi-allelic loss-of-function variants in IPO8 who presented with a syndromic association characterized by cardio-vascular anomalies, joint hyperlaxity, and various degree of dysmorphic features and developmental delay as well as immune dysregulation; the individuals were from nine unrelated families. Importin 8 belongs to the karyopherin family of nuclear transport receptors and was previously shown to mediate TGF-β-dependent SMADs trafficking to the nucleus in vitro. The important in vivo role of IPO8 in pSMAD nuclear translocation was demonstrated by CRISPR/Cas9-mediated inactivation in zebrafish. Consistent with IPO8's role in BMP/TGF-β signaling, ipo8-/- zebrafish presented mild to severe dorso-ventral patterning defects during early embryonic development. Moreover, ipo8-/- zebrafish displayed severe cardiovascular and skeletal defects that mirrored the human phenotype. Our work thus provides evidence that IPO8 plays a critical and non-redundant role in TGF-β signaling during development and reinforces the existing link between TGF-β signaling and connective tissue defects

UNC45A deficiency causes microvillus inclusion disease–like phenotype by impairing myosin VB–dependent apical trafficking

International audienceVariants in the UNC45A cochaperone have been recently associated with a syndrome combining diarrhea, cholestasis, deafness, and bone fragility. Yet the mechanism underlying intestinal failure in UNC45A deficiency remains unclear. Here, biallelic variants in UNC45A were identified by next-generation sequencing in 6 patients with congenital diarrhea. Corroborating in silico prediction, variants either abolished UNC45A expression or altered protein conformation. Myosin VB was identified by mass spectrometry as client of the UNC45A chaperone and was found misfolded in UNC45A(KO) Caco-2 cells. In keeping with impaired myosin VB function, UNC45A(KO) Caco-2 cells showed abnormal epithelial morphogenesis that was restored by full-length UNC45A, but not by mutant alleles. Patients and UNC45A(KO) 3D organoids displayed altered luminal development and microvillus inclusions, while 2D cultures revealed Rab11 and apical transporter mislocalization as well as sparse and disorganized microvilli. All those features resembled the subcellular abnormalities observed in duodenal biopsies from patients with microvillus inclusion disease. Finally, microvillus inclusions and shortened microvilli were evidenced in enterocytes from unc45a-deficient zebrafish. Taken together, our results provide evidence that UNC45A plays an essential role in epithelial morphogenesis through its cochaperone function of myosin VB and that UNC45A loss causes a variant of microvillus inclusion disease

Factors affecting body temperatures of toads

Factors influencing levels and rates of variation of body temperature ( T b ) in montane Bufo boreas boreas and in lowland Bufo boreas halophilus were investigated as an initial step toward understanding the role of natural thermal variation in the physiology and energetics of these ectothermic animals. Body temperatures of boreas can vary 25–30° C over 24-h periods. Such variation is primarily due to both nocturnal and diurnal activity and the physical characteristics of the montane environment. Bufo boreas halophilus are primarily nocturnal except during breeding and are voluntarily active at body temperatures ranging between 10 and 25° C. Despite variation in T b encountered in the field, boreas select a narrow range of T b in a thermal gradient, averaging 23.5 and 26.2° C for fasted individuals maintained under field conditions or acclimated to 20° C, respectively. In a thermal gradient the mean T b of fasted halophilus acclimated to 20° C is 23.9° C. Skin color of boreas varies in the field from very dark to light. The dark skins absorb approximately 4% more radiation than the light ones. Light colored boreas should absorb approximately 5% more radiation than similarly colored halophilus . Evaporative water losses increase directly with skin temperatures and vapor pressure deficit in both subspecies. Larger individuals heat and cool more slowly than smaller ones. Calculation of an enery budget for boreal toads suggests that they could sit in direct sunlight for long periods without fatally overheating, providing the skin was continually moist.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/47722/1/442_2004_Article_BF00344732.pd

Diagnostic yield of next-generation sequencing in very early-onset inflammatory bowel diseases: a multicenter study (vol 12, pg 1104, 2021)

Transplantation and immunomodulatio

Light-based technologies for management of COVID-19 pandemic crisis.

The global dissemination of the novel coronavirus disease (COVID-19) has accelerated the need for the implementation of effective antimicrobial strategies to target the causative agent SARS-CoV-2. Light-based technologies have a demonstrable broad range of activity over standard chemotherapeutic antimicrobials and conventional disinfectants, negligible emergence of resistance, and the capability to modulate the host immune response. This perspective article identifies the benefits, challenges, and pitfalls of repurposing light-based strategies to combat the emergence of COVID-19 pandemic