A drug mix and dose decision algorithm for individualized type 2 diabetes management.

Pharmacotherapy guidelines for type 2 diabetes (T2D) emphasize patient-centered care, but applying this approach effectively in outpatient practice remains challenging. Data-driven treatment optimization approaches could enhance individualized T2D management, but current approaches cannot account for drug-specific and dose-dependent variations in safety and efficacy. We developed and evaluated an AI Drug mix and dose Advisor (AIDA) for glycemic management, using electronic medical records from 107,854 T2D patients in the SingHealth Diabetes Registry. Given a patient's medical profile, AIDA leverages a predict-then-optimize approach to identify the minimal drug mix and dose changes required to optimize glycemic control, subject to clinical knowledge-based guidelines. On unseen data from large internal, external, and temporal validation sets, AIDA recommendations were estimated to improve post-visit glycated hemoglobin (HbA1c) by an average of 0.40-0.68% over standard of care (P < 0.0001). In qualitative evaluations on 60 diverse cases by a panel of three endocrinologists, AIDA recommendations were mostly rated as reasonable and precise. Finally, AIDA's ability to account for drug-dose specifics offered several advantages over competing methods, including greater consistency with practice preferences and clinical guidelines for practical but effective options, indication-based treatments, and renal dosing. As AIDA provides drug-dose recommendations to improve outcomes for individual T2D patients, it could be used for clinical decision support at point-of-care, especially in resource-limited settings.

Cryptic asymptomatic parasellar high signal on time-of-flight MR angiography: how to resolve the clinical conundrum.

PURPOSE: Hyperintense parasellar signal on time-of-flight MR angiography (TOF-MRA) in asymptomatic patients may be due to a variety of nonpathological causes and mimic parasellar high flow signal in pathological arteriovenous shunts at the cavernous sinus (CSAVS). This creates a clinical conundrum between diagnosing an aggressive yet asymptomatic CSAVS subtype against exposing patients without CSAVS to potential complications of an invasive angiographic evaluation. We reviewed common nonpathological causes of hyperintense parasellar signal and contrast their imaging features against those of pathological CSAVS and proposed a systemic approach to resolve such conundrum. METHODS: The anatomy of the cavernous sinus (CS) and causes of nonpathological parasellar hyperintense TOF-MRA signal are described and explained with case reviews, illustrations, and reference to published literature where appropriate. Imaging features of proven CSAVS are juxtaposed to aid in radiological differentiation. An algorithm is proposed to manage patients with such incidental TOF-MRA findings. RESULTS: The margins, contour, extent, intensity, and stippling appearance aid in evaluation of pathological versus incidental TOF-MRA parasellar signal, and differentiation of CSAVS from nonpathological causes. Pertinent radiological features are summarized in a table. For unresolved cases suspected for CSAVS, further evaluation with dynamic time-resolved contrast-enhanced MRA is proposed and depicted in a decision tree flow chart. CONCLUSION: Familiarity with the differentiating radiological features and a systematic management workflow could aid in resolving the clinical conundrum of findings of cryptic asymptomatic parasellar TOF-MRA high signal, while facilitating timely detection of the asymptomatic CSAVS.

Individual differences in physiologic measures are stable across repeated exposures to total sleep deprivation.

Some individuals show severe cognitive impairment when sleep deprived, whereas others are able to maintain a high level of performance. Such differences are stable and trait-like, but it is not clear whether these findings generalize to physiologic responses to sleep loss. Here, we analyzed individual differences in behavioral and physiologic measures in healthy ethnic-Chinese male volunteers (n = 12; aged 22-30 years) who were kept awake for at least 26 h in a controlled laboratory environment on two separate occasions. Every 2 h, sustained attention performance was assessed using a 10-min psychomotor vigilance task (PVT), and sleepiness was estimated objectively by determining percentage eyelid closure over the pupil over time (PERCLOS) and blink rate. Between-subject differences in heart rate and its variability, and electroencephalogram (EEG) spectral power were also analyzed during each PVT. To assess stability of individual differences, intraclass correlation coefficients (ICC) were determined using variance components analysis. Consistent with previous work, individual differences in PVT performance were reproducible across study visits, as were baseline sleep measures prior to sleep deprivation. In addition, stable individual differences were observed during sleep deprivation for PERCLOS, blink rate, heart rate and its variability, and EEG spectral power in the alpha frequency band, even after adjusting for baseline differences in these measures (range, ICC = 0.67-0.91). These findings establish that changes in ocular, ECG, and EEG signals are highly reproducible across a night of sleep deprivation, hence raising the possibility that, similar to behavioral measures, physiologic responses to sleep loss are trait-like.

Effects of exposure to intermittent versus continuous red light on human circadian rhythms, melatonin suppression, and pupillary constriction.

Exposure to light is a major determinant of sleep timing and hormonal rhythms. The role of retinal cones in regulating circadian physiology remains unclear, however, as most studies have used light exposures that also activate the photopigment melanopsin. Here, we tested the hypothesis that exposure to alternating red light and darkness can enhance circadian resetting responses in humans by repeatedly activating cone photoreceptors. In a between-subjects study, healthy volunteers (n = 24, 21-28 yr) lived individually in a laboratory for 6 consecutive days. Circadian rhythms of melatonin, cortisol, body temperature, and heart rate were assessed before and after exposure to 6 h of continuous red light (631 nm, 13 log photons cm(-2) s(-1)), intermittent red light (1 min on/off), or bright white light (2,500 lux) near the onset of nocturnal melatonin secretion (n = 8 in each group). Melatonin suppression and pupillary constriction were also assessed during light exposure. We found that circadian resetting responses were similar for exposure to continuous versus intermittent red light (P = 0.69), with an average phase delay shift of almost an hour. Surprisingly, 2 subjects who were exposed to red light exhibited circadian responses similar in magnitude to those who were exposed to bright white light. Red light also elicited prolonged pupillary constriction, but did not suppress melatonin levels. These findings suggest that, for red light stimuli outside the range of sensitivity for melanopsin, cone photoreceptors can mediate circadian phase resetting of physiologic rhythms in some individuals. Our results also show that sensitivity thresholds differ across non-visual light responses, suggesting that cones may contribute differentially to circadian resetting, melatonin suppression, and the pupillary light reflex during exposure to continuous light.

Melanopsin and rod-cone photoreceptors play different roles in mediating pupillary light responses during exposure to continuous light in humans.

In mammals, the pupillary light reflex is mediated by intrinsically photosensitive melanopsin-containing retinal ganglion cells that also receive input from rod-cone photoreceptors. To assess the relative contribution of melanopsin and rod-cone photoreceptors to the pupillary light reflex in humans, we compared pupillary light responses in normally sighted individuals (n = 24) with a blind individual lacking rod-cone function. Here, we show that visual photoreceptors are required for normal pupillary responses to continuous light exposure at low irradiance levels, and for sustained pupillary constriction during exposure to light in the long-wavelength portion of the visual spectrum. In the absence of rod-cone function, pupillomotor responses are slow and sustained, and cannot track intermittent light stimuli, suggesting that rods/cones are required for encoding fast modulations in light intensity. In sighted individuals, pupillary constriction decreased monotonically for at least 30 min during exposure to continuous low-irradiance light, indicating that steady-state pupillary responses are an order of magnitude slower than previously reported. Exposure to low-irradiance intermittent green light (543 nm; 0.1-4 Hz) for 30 min, which was given to activate cone photoreceptors repeatedly, elicited sustained pupillary constriction responses that were more than twice as great compared with exposure to continuous green light. Our findings demonstrate nonredundant roles for rod-cone photoreceptors and melanopsin in mediating pupillary responses to continuous light. Moreover, our results suggest that it might be possible to enhance nonvisual light responses to low-irradiance exposures by using intermittent light to activate cone photoreceptors repeatedly in humans.