The Evolving Regulatory Paradigm of AI in MedTech: A Review of Perspectives and Where We Are Today.

Artificial intelligence (AI)-enabled technologies in the MedTech sector hold the promise to transform healthcare delivery by improving access, quality, and outcomes. As the regulatory contours of these technologies are being defined, there is a notable lack of literature on the key stakeholders such as the organizations and interest groups that have a significant input in shaping the regulatory framework. This article explores the perspectives and contributions of these stakeholders in shaping the regulatory paradigm of AI-enabled medical technologies. The formation of an AI regulatory framework requires the convergence of ethical, regulatory, technical, societal, and practical considerations. These multiple perspectives contribute to the various dimensions of an evolving regulatory paradigm. From the global governance guidelines set by the World Health Organization (WHO) to national regulations, the article sheds light not just on these multiple perspectives but also on their interconnectedness in shaping the regulatory landscape of AI.

Rad regulation of CaV1.2 channels controls cardiac fight-or-flight response.

Fight-or-flight responses involve ß-adrenergic-induced increases in heart rate and contractile force. In the present study, we uncover the primary mechanism underlying the heart's innate contractile reserve. We show that four protein kinase A (PKA)-phosphorylated residues in Rad, a calcium channel inhibitor, are crucial for controlling basal calcium current and essential for ß-adrenergic augmentation of calcium influx in cardiomyocytes. Even with intact PKA signaling to other proteins modulating calcium handling, preventing adrenergic activation of calcium channels in Rad-phosphosite-mutant mice (4SA-Rad) has profound physiological effects: reduced heart rate with increased pauses, reduced basal contractility, near-complete attenuation of ß-adrenergic contractile response and diminished exercise capacity. Conversely, expression of mutant calcium-channel ß-subunits that cannot bind 4SA-Rad is sufficient to enhance basal calcium influx and contractility to adrenergically augmented levels of wild-type mice, rescuing the failing heart phenotype of 4SA-Rad mice. Hence, disruption of interactions between Rad and calcium channels constitutes the foundation toward next-generation therapeutics specifically enhancing cardiac contractility.

Computerized segmentation of liver in hepatic CT and MRI by means of level-set geodesic active contouring.

Computerized liver volumetry has been studied, because the current "gold-standard" manual volumetry is subjective and very time-consuming. Liver volumetry is done in either CT or MRI. A number of researchers have developed computerized liver segmentation in CT, but there are fewer studies on ones for MRI. Our purpose in this study was to develop a general framework for liver segmentation in both CT and MRI. Our scheme consisted of 1) an anisotropic diffusion filter to reduce noise while preserving liver structures, 2) a scale-specific gradient magnitude filter to enhance liver boundaries, 3) a fast-marching algorithm to roughly determine liver boundaries, and 4) a geodesic-active-contour model coupled with a level-set algorithm to refine the initial boundaries. Our CT database contained hepatic CT scans of 18 liver donors obtained under a liver transplant protocol. Our MRI database contains 23 patients with 1.5T MRI scanners. To establish "gold-standard" liver volumes, radiologists manually traced the contour of the liver on each CT or MR slice. We compared our computer volumetry with "gold-standard" manual volumetry. Computer volumetry in CT and MRI reached excellent agreement with manual volumetry (intra-class correlation coefficient = 0.94 and 0.98, respectively). Average user time for computer volumetry in CT and MRI was 0.57 ± 0.06 and 1.0 ± 0.13 min. per case, respectively, whereas those for manual volumetry were 39.4 ± 5.5 and 24.0 ± 4.4 min. per case, respectively, with statistically significant difference (p < .05). Our computerized liver segmentation framework provides an efficient and accurate way of measuring liver volumes in both CT and MRI.

Control of transcriptional elongation and cotranscriptional histone modification by the yeast BUR kinase substrate Spt5.

Elongation by RNA polymerase II (RNAPII) is a finely regulated process in which many elongation factors contribute to gene regulation. Among these factors are the polymerase-associated factor (PAF) complex, which associates with RNAPII, and several cyclin-dependent kinases, including positive transcription elongation factor b (P-TEFb) in humans and BUR kinase (Bur1-Bur2) and C-terminal domain (CTD) kinase 1 (CTDK1) in Saccharomyces cerevisiae. An important target of P-TEFb and CTDK1, but not BUR kinase, is the CTD of the Rpb1 subunit of RNAPII. Although the essential BUR kinase phosphorylates Rad6, which is required for histone H2B ubiquitination on K123, Rad6 is not essential, leaving a critical substrate(s) of BUR kinase unidentified. Here we show that BUR kinase is important for the phosphorylation in vivo of Spt5, a subunit of the essential yeast RNAPII elongation factor Spt4/Spt5, whose human orthologue is DRB sensitivity-inducing factor. BUR kinase can also phosphorylate the C-terminal region (CTR) of Spt5 in vitro. Like BUR kinase, the Spt5 CTR is important for promoting elongation by RNAPII and recruiting the PAF complex to transcribed regions. Also like BUR kinase and the PAF complex, the Spt5 CTR is important for histone H2B K123 monoubiquitination and histone H3 K4 and K36 trimethylation during transcription elongation. Our results suggest that the Spt5 CTR, which contains 15 repeats of a hexapeptide whose consensus sequence is S[T/A]WGG[A/Q], is a substrate of BUR kinase and a platform for the association of proteins that promote both transcription elongation and histone modification in transcribed regions.