Sodium/Glucose Cotransporter 2 Inhibitors and Magnesium Homeostasis: A Review.

Magnesium (Mg2+), also known as "the forgotten ion," is the second most abundant intracellular cation and is essential in a broad range of intracellular physiological and biochemical reactions. Its deficiency, hypomagnesemia (Mg2+<1.8mg/dL), is a prevalent condition and routinely poses challenges in its management in clinical practice. Sodium/glucose cotransporter 2 (SGLT2) inhibitors have emerged as a new class of drugs with treating hypomagnesemia as their unique extraglycemic benefit. The beneficial effect of SGLT2 inhibitors on magnesium balance in patients with diabetes with or without hypomagnesemia has been noted as a class effect in recent meta-analysis data from randomized clinical trials. Some reports have demonstrated their role in treating refractory hypomagnesemia in patients with or without diabetes. Moreover, studies on animal models have attempted to illustrate the effect of SGLT2 inhibitors on Mg2+homeostasis. In this review, we discuss the current evidence and possible pathophysiological mechanisms, and we provide directions for further research. We conclude by suggesting the effect of SGLT2 inhibitors on Mg2+homeostasis is a class effect, with certain patients gaining significant benefits. Further studies are needed to examine whether SGLT2 inhibitors can become a desperately needed novel class of medicines in treating hypomagnesemia.

New insights from the genetic work-up in early onset nephrotic syndrome: report from a registry in western India.

BACKGROUND: Eighty-five percent of infants with congenital nephrotic syndrome (CNS) and 66% with infantile NS (INS) are likely to have a monogenic etiology. There exists a significant genetic variability between different regions and ethnic groups. This study aimed to determine the genetic defects in children with CNS and INS by establishing a registry in western India. METHODS: In this cross-sectional study, pediatric nephrologists from 13 private and government institutions shared relevant clinical data and details of the genetic evaluation of children presenting with NS within the first year of life. RESULTS: The median age at presentation was 9 months (range 1-23, IQR 3-13 months), history of consanguinity between parents existed in 14 patients (34%), family history of similar illness in 6 (15%), and extra-renal manifestations in 17 (41%). Twenty-five (61%) were confirmed to have a monogenic etiology. NPHS1 gene was the most implicated (9/25) followed by PLCE1 (5/25). There were 12 variants of uncertain significance (VUS) involving 10 genes (10/25, 40%), and no definite genetic abnormality was found in 4 (25%). A re-analysis of these VUS attempted 2-3 years later facilitated reclassification of 7/12 (58%); increasing the diagnostic yield from 61 to 68.2%. CONCLUSIONS: Consistent with worldwide data, variants in NPHS1 gene were the most common cause of NS in infancy; however, PLCE1 was implicated more frequently in our cohort. NUP93 and COL4A3 were reported in early onset NS for the first time. Reclassification of VUS should be attempted, if feasible, since it may lead to a useful revision of diagnosis.

Artificial Intelligence-Powered Clinical Decision Support and Simulation Platform for Radiology Trainee Education.

Technological tools can redesign traditional approaches to radiology education, for example, with simulation cases and via computer-generated feedback. In this study, we investigated the use of an AI-powered, Bayesian inference-based clinical decision support (CDS) software to provide automated "real-time" feedback to trainees during interpretation of clinical and simulation brain MRI examinations. Radiology trainees participated in sessions in which they interpreted 3 brain MRIs: two cases from a routine clinical worklist (one without and one with CDS) and a teaching file-based simulation case with CDS. The CDS software required trainees to input imaging features and differential diagnoses, after which inferred diagnoses were displayed, and the case was reviewed with an attending neuroradiologist. An observer timed each case, including time spent on education, and trainees completed a survey rating their confidence in their findings and the educational value of the case. Ten trainees reviewed 75 brain MRI examinations during 25 reading sessions. Trainees had slightly lower confidence in their findings and diagnosis and rated the educational value slightly higher for simulation cases with CDS compared to clinical cases without CDS (p < 0.05). There were no significant differences in ratings of clinical cases with or without CDS. No differences in overall timing were found among the reading scenarios. Simulation cases with "CDS-provided feedback" may improve the educational value of interpreting imaging studies at a workstation without adding additional time. Further investigation will help drive innovation in trainee education, which may be particularly relevant in this era of increasing remote work and asynchronous attending review.

New Measurement Resolves Key Astrophysical Fe XVII Oscillator Strength Problem.

One of the most enduring and intensively studied problems of x-ray astronomy is the disagreement of state-of-the art theory and observations for the intensity ratio of two Fe XVII transitions of crucial value for plasma diagnostics, dubbed 3C and 3D. We unravel this conundrum at the PETRA III synchrotron facility by increasing the resolving power 2.5 times and the signal-to-noise ratio thousandfold compared with our previous work. The Lorentzian wings had hitherto been indistinguishable from the background and were thus not modeled, resulting in a biased line-strength estimation. The present experimental oscillator-strength ratio R_{exp}=f_{3C}/f_{3D}=3.51(2)_{stat}(7)_{sys} agrees with our state-of-the-art calculation of R_{th}=3.55(2), as well as with some previous theoretical predictions. To further rule out any uncertainties associated with the measured ratio, we also determined the individual natural linewidths and oscillator strengths of 3C and 3D transitions, which also agree well with the theory. This finally resolves the decades-old mystery of Fe XVII oscillator strengths.

Uncertainties in Atomic Data for Modeling Astrophysical Charge Exchange Plasmas.

Relevant uncertainties of theoretical atomic data are vital to determining the accuracy of plasma diagnostics in a number of areas, including, in particular, the astrophysical study. We present a new calculation of the uncertainties on the present theoretical ion-impact charge exchange atomic data and X-ray spectra, based on a set of comparisons with the existing laboratory data obtained in historical merged-beam, cold-target recoil-ion momentum spectroscopy, and electron beam ion traps experiments. The average systematic uncertainties are found to be 35-88% on the total cross sections, and 57-75% on the characteristic line ratios. The model deviation increases as the collision energy decreases. The errors on total cross sections further induce a significant uncertainty to the calculation of ionization balance for low-temperature collisional plasmas. Substantial improvements of the atomic database and dedicated laboratory measurements are needed to obtain the current models, ready for the X-ray spectra from the next X-ray spectroscopic mission.

Effect of Hypochlorites on the Compressive Strength and Surface Hardness of Type V Dental Stone: An In Vitro Study.

AIM: The study aimed to evaluate the compressive strength and surface hardness of a type V dental stone after hypochlorite disinfection. MATERIALS AND METHODS: Two types of specimens were made according to the American Dental Association (ADA) specification no. 25 for each wet compressive strength, dry compressive strength, and surface hardness. The specimens were split into three groups with 30 samples each according to the type of disinfection. All specimens were immersed in their respective disinfecting solutions for 30 minutes at room temperature and after removal, they were left to dry for 24 hours at room temperature. Total five cycles of immersion and drying were followed. A compressive strength test was done using a universal testing machine. Wet compressive strength was tested one hour after the last cycle and dry compressive strength was tested 7 days after the last cycle. Surface hardness was measured after 48 hours using Vickers hardness test. The results were statistically analyzed. RESULTS: There was a statistical difference between the calcium hypochlorite and sodium hypochlorite groups for both dry and wet compressive strength. The mean wet compressive strength of calcium hypochlorite was higher when compared to the sodium hypochlorite group and it was statistically significant (p = 0.042). The results were similar and statistically significant (p = 0.003) for dry compressive strength. When the mean surface hardness of the sodium hypochlorite (As) group was compared to calcium hypochlorite the results were highly significant (p = 0.0001) with the mean surface hardness of the calcium hypochlorite group more than the sodium hypochlorite group. CONCLUSION: Calcium hypochlorite used as a disinfectant showed better compressive strength and surface hardness when compared to sodium hypochlorite as a disinfectant. CLINICAL SIGNIFICANCE: Dental casts poured in the contaminated impressions which might not be disinfected at all or properly. They also come in contact with the prosthesis that might be tried inside the patient's mouth and sent to a lab for corrections without disinfecting the cast causing cross-contamination between patients, dentists, and laboratory personnel. However, immersion disinfection with sodium or calcium hypochlorite might affect important properties of the cast. Any negative effect on the mechanical or physical properties of the cast will affect the final outcome of the prosthesis.

Changes in brain functional connectivity and cognition related to white matter lesion burden in hypertensive patients from SPRINT.

PURPOSE: Hypertension is a risk factor for cognitive impairment; however, the mechanisms leading to cognitive changes remain unclear. In this cross-sectional study, we evaluate the impact of white matter lesion (WML) burden on brain functional connectivity (FC) and cognition in a large cohort of hypertensive patients from the Systolic Blood Pressure Intervention Trial (SPRINT) at baseline. METHODS: Functional networks were identified from baseline resting state functional MRI scans of 660 SPRINT participants using independent component analysis. WML volumes were calculated from structural MRI. Correlation analyses were carried out between mean FC of each functional network and global WML as well as WML within atlas-defined white matter regions. For networks of interest, voxel-wise-adjusted correlation analyses between FC and regional WML volume were performed. Multiple variable linear regression models were built for cognitive test performance as a function of network FC, followed by mediation analysis. RESULTS: Mean FC of the default mode network (DMN) was negatively correlated with global WML volume, and regional WML volume within the precuneus. Voxel-wise correlation analyses revealed that regional WML was negatively correlated with FC of the DMN's left lateral temporal region. FC in this region of the DMN was positively correlated to performance on the Montreal Cognitive Assessment and demonstrated significant mediation effects. Additional networks also demonstrated global and regional WML correlations; however, they did not demonstrate an association with cognition. CONCLUSION: In hypertensive patients, greater WML volume is associated with lower FC of the DMN, which in turn is related to poorer cognitive test performance. TRIAL REGISTRATION: NCT01206062.

Effect of saroglitazar 2 mg and 4 mg on glycemic control, lipid profile and cardiovascular disease risk in patients with type 2 diabetes mellitus: a 56-week, randomized, double blind, phase 3 study (PRESS XII study).

BACKGROUND: The potential for PPAR agonists to positively affect risk of cardiovascular disease in patients with type 2 diabetes (T2DM) is of persistent attention. The PRESS XII study primarily aimed to evaluate the efficacy and safety of saroglitazar (2 mg and 4 mg) as compared to pioglitazone 30 mg on glycemic control in patients with type 2 diabetes mellitus. METHODS: In this randomized double-blind study, patients with T2DM [glycosylated hemoglobin (HbA1c) ≥ 7.5%] were enrolled from 39 sites in India. Patients received once-daily doses of either saroglitazar or pioglitazone (1:1:1 allocation ratio) for a total of 24 weeks. Patients were continued in a double blind extension period for an additional 32 weeks. Efficacy evaluations of glycemic parameters [HbA1c (Primary endpoint at week 24), FPG and PPG] and other lipid parameters (TG, LDL-C, VLDL-C, HDL-C, TC, Non HDL-C, Apo A1 and Apo B) were conducted at week 12, 24 and 56 and compared to the baseline levels. The efficacy analyses were performed by using paired t-test and ANCOVA model. RESULTS: A total of 1155 patients were enrolled in this study. The baseline characteristics were similar between the three treatment groups. The within group mean (± SD) change in HbA1c (%) from baseline of the saroglitazar (2 mg and 4 mg) and pioglitazone treatment groups at week 24 were: - 1.38 ± 1.99 for saroglitazar 2 mg; - 1.47 ± 1.92 for saroglitazar 4 mg and - 1.41 ± 1.86 for pioglitazone, respectively. Statistically significant reduction from baseline in HbA1c was observed in each treatment group at week 24 with p-value < 0.016. There was a significant reduction in TG, LDL-C, VLDL-C, TC and Non HDL-C with a significant increase in HDL-C from baseline levels (< 0.016). Most of the AE's were 'mild' to 'moderate' in severity and were resolved by the completion of the study. CONCLUSIONS: Saroglitazar effectively improved glycemic control and lipid parameters over 56 weeks in patients of T2DM receiving background metformin therapy and has a promising potential to reduce the cardiovascular risk in T2DM patients. Trial registration CTRI/2015/09/006203, dated 22/09/2015.

High Resolution Photoexcitation Measurements Exacerbate the Long-Standing Fe XVII Oscillator Strength Problem.

For more than 40 years, most astrophysical observations and laboratory studies of two key soft x-ray diagnostic 2p-3d transitions, 3C and 3D, in Fe XVII ions found oscillator strength ratios f(3C)/f(3D) disagreeing with theory, but uncertainties had precluded definitive statements on this much studied conundrum. Here, we resonantly excite these lines using synchrotron radiation at PETRA III, and reach, at a millionfold lower photon intensities, a 10 times higher spectral resolution, and 3 times smaller uncertainty than earlier work. Our final result of f(3C)/f(3D)=3.09(8)(6) supports many of the earlier clean astrophysical and laboratory observations, while departing by five sigmas from our own newest large-scale ab initio calculations, and excluding all proposed explanations, including those invoking nonlinear effects and population transfers.

Genetics of psychosis of Alzheimer disease.

Psychotic symptoms, comprised of delusions and hallucinations, occur in about half of individuals with Alzheimer disease (AD with psychosis, AD+P). These individuals have greater agitation, aggression, depression, functional impairment, and mortality than individuals without psychosis (AD-P). Although the exact etiopathogenesis of AD+P is unclear, the rapidly developing field of genomics continues to expand our understanding of this disease. Several independent studies have demonstrated familial aggregation and heritability of AD+P. Linkage studies have been suggestive of loci on several chromosomes associated with AD+P. Association studies examining apolipoprotein E gene, the best established genetic risk factor for late-onset AD, did not find any significant association of this gene with AD+P. Other candidate gene studies focusing on monoamine neurotransmitter systems have yielded equivocal results. A genome-wide association study and studies examining copy number variations recently have detected suggestive associations, but have been underpowered. Approaches to increase sizes of AD+P samples for genome wide association studies are discussed. © 2016 Wiley Periodicals, Inc.

Intraventricular silicone oil mimicking a colloid cyst.

We report a case where intraventricular migration of silicone oil occurred into the third ventricle, mimicking the presence of a colloid cyst. To the best of our knowledge, this is the first case reported where intraventricular silicone oil (SiO) presented at the foramen of Monro, resembling the radiological appearance of a colloid cyst. The systemic dissemination of silicone oil is a very rare complication of intravitreal SiO administration that is used for providing a mechanical tamponade that maintains the retinal attachment following repair of a retinal detachment. The imaging findings that are characteristic of the presence of intraventricular silicone oil are its usual dissemination in a nondependent location and the accompaniment of changes in its location based on changes in the patient's position.

Controversies in the use of second generation antipsychotics as sleep agent.

A growing number of patients present in clinics with complaints of insomnia. Over the past century, great advances have been made in our knowledge of mechanisms of sleep and wakefulness. Understanding sleep neurochemistry has led to better management of different types of insomnias with a variety of non-pharmacological and pharmacological treatments. Unfortunately, the increasing development and availability of second generation antipsychotics (SGA) have prompted their frequent use exclusively for insomnia. However, to date, no large randomized-controlled or placebo-controlled studies have shown the utility of SGAs in the realm of treating insomnia. Many clinicians use SGAs as "off-label" for sleep induction and maintenance, but this practice needs to be readdressed given their potential risks and the current lack of evidence base. This review will highlight the neurochemistry related to sleep, the mechanisms of action by which SGA may have some benefit in treating insomnia, and the risks associated with their utilization.

Safety, tolerability, pharmacokinetics, and pharmacodynamics of a novel kappa opioid receptor agonist ZYKR1: a randomized double-blind placebo-control phase 1 study in healthy adult human participants.

To perform first-in-human single-dose escalation trial of ZYKR1, which is a potent, selective, and peripherally-restricted kappa opioid receptor agonist, is the purpose of this study. This randomized, double-blind, placebo-controlled single ascending dose study conducted at Zydus Research Centre, Ahmedabad, India included healthy male participants aged 18-55 years and weighing > 50 kg. The primary objective was to evaluate the safety and tolerability of ZYKR1. The secondary objective was to evaluate the pharmacokinetics and pharmacodynamics (PD) of ZYKR1. Participants received ZYKR1 (0.5 - 6 mcg/kg) or placebo infused intravenously in 15 ± 1 min. Of total five dose groups (0.5 - 6 mcg/kg), each group included eight participants with six and two randomized to ZYKR1 and placebo, respectively. Three participants experienced six treatment-emergent adverse events (TEAEs); two were gastrointestinal disorders (nausea and vomiting at 2 mcg/kg); and four were related to the nervous system (headache (at 2 mcg/kg) and facial tingling, facial numbness and paresthesia (at 6 mcg/kg)); all TEAEs were mild and resolved without sequelae. The Cmax of ZYKR1 was achieved after 15 - 20 min of start of infusion. The mean exposures (Cmax and AUC0 - t) increased in a dose-proportional manner. The mean t1/2 ranged from 2.20 to 2.98 h across the dose range. Increase in the mean prolactin level was significantly higher in treatment groups compared with that in the placebo group. Intravenous ZYKR1 at doses up to 6 mcg/kg showed acceptable safety and tolerability and demonstrated a short half-life with principal route of excretion as renal. ZYKR1 displayed a potent PD effect reflected by increased prolactin levels, supporting further study in patients. Trial registration Clinical Trial Registry of India: CTRI/2018/07/014927. Date of registration: 18/07/2018.

Keeping Patient Data Secure in the Age of Radiology Artificial Intelligence: Cybersecurity Considerations and Future Directions.

Artificial intelligence (AI)-based solutions are increasingly being incorporated into radiology workflows. Implementation of AI comes along with cybersecurity risks and challenges that practices should be aware of and mitigate for a successful and secure deployment. In this article, these cybersecurity issues are examined through the lens of the "CIA" triad framework-confidentiality, integrity, and availability. We discuss the implications of implementation configurations and development approaches on data security and confidentiality and the potential impact that the insertion of AI can have on the truthfulness of data, access to data, and the cybersecurity attack surface. Finally, we provide a checklist to address important security considerations before deployment of an AI application, and discuss future advances in AI addressing some of these security concerns.

Clinical features of early-onset pediatric traumatic glaucoma and predictive factors for the need of early glaucoma surgery.

Purpose: To assess the clinical presentation of pediatric patients having early traumatic glaucoma and to analyze early predictors for the need of filtration surgery. Methods: Patients with early traumatic glaucoma after close globe injury (CGI) from January 2014 to December 2020 were retrospectively reviewed. Clinical features, treatment provided (medical and surgical), and visual outcomes were documented. Patients were divided into two groups based on the management required: group A- trabeculectomy and group B- medication + minor surgery. Results: A total of 85 patients were studied after applying the necessary inclusion and exclusion criteria. Out of these, 46 underwent trabeculectomy for the control of intraocular pressure (IOP) and the remaining 39 were managed with antiglaucoma medications. Significant male predominance of 9.6:1 was observed. Patients presented to the hospital after a mean duration of 8.5 days posttrauma. Wooden objects were most commonly responsible for trauma. Mean best corrected visual acuity at presentation was 1.91 log of minimum angle of resolution (logMAR). Mean IOP at presentation was 40 mmHg. The common anterior segment finding were severe anterior chamber (AC) reaction (63.5%), followed by angle recession (56.4%). Severe AC reaction (P = 0.0001) and corneal microcystic edema (P = 0.04) were significant predictive factors for early need of trabeculectomy. Conclusion: Need of trabeculectomy was higher in patients with severe AC reaction and corneal microcystic edema. The threshold to perform trabeculectomy should be lower, as glaucoma is often relentless, severe, and may result in irreversible vision loss.

SGLT2 Inhibitors in Management of Severe Hypomagnesemia in Patients Without Diabetes: A Report of 4 Cases.

Sodium/glucose cotransporter 2 (SGLT2) inhibitors have demonstrated a class effect in improving serum magnesium levels in patients with diabetes. Additionally, recent reports have shown their promising beneficial effects in the treatment of refractory hypomagnesemia in patients with diabetes. However, their role in treating hypomagnesemia in patients without diabetes remains unexplored. Here, we report 4 cases of severe and refractory hypomagnesemia that showed dramatic improvement after initiating SGLT2 inhibitors in patients without diabetes. Case 1 had calcineurin inhibitor-associated severe hypomagnesemia. Cases 2, 3, and 4 had refractory hypomagnesemia associated with platinum-based chemotherapy with or without gastrointestinal losses. Case 1 was able to withdraw from high-dose oral magnesium supplementation. Cases 2 and 3 achieved independence from intravenous magnesium supplementation, whereas case 4 had decreased intravenous magnesium requirements. All the cases demonstrated sustainably improved serum magnesium levels. Withdrawal of SGLT2 inhibitors in case 4 resulted in worsening serum magnesium levels and intravenous magnesium requirements. The extraglycemic benefit of this group of medications not only suggests the need for further studies to better understand the effect of SGLT2 inhibitors on magnesium homeostasis but also supports expanded use in a larger patient population.