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.

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.

Mobile battery blast injuries: An emerging ocular health hazard in children.

PURPOSE: To assess clinical features, visual outcomes, and setting of mobile battery blast-induced eye injuries in children. METHODS: Retrospective case sheets of children with mobile battery blast injuries were reviewed at a tertiary eye care center from January 2015 to March 2022. We noted the mode of injury, battery status, and clinical presentation and analyzed the treatment outcomes. RESULTS: The study included 14 eyes of 11 patients. Three patients (27%) had bilateral ocular injuries. The most common reasons for the blast were wiring a bulb to the battery or charging the battery with a universal mobile charger, seen in four cases each. Three eyes had closed-globe injuries (CGIs), whereas 11 had open-globe injuries (OGIs). Of the 11 eyes with OGI, four also had a retained intraocular foreign body (IOFB). Only four (36%) eyes having OGI could achieve vision better than 6/60. All three eyes with CGIs developed secondary glaucoma, and two underwent trabeculectomy. However, the visual prognosis was better (>6/36) in eyes with CGI. Overall, mean visual acuity at the final follow-up was improved to 1.41 ± 1.14 logMAR from 2.32 ± 0.76 logMAR at presentation. This was also found to be statistically significant with a P value of 0.02. CONCLUSION: Battery blast-induced ocular injuries, although rare, often lead to poor outcomes. Apart from charging, playing with discarded or damaged batteries was a common reason for battery blasts in our series.

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.

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.

Awareness and knowledge among paramedical staff about glaucoma surgeries and post-surgery counseling - A questionnaire based study at a tertiary eye care center in Central Rural India.

Purpose: To determine the level of awareness and knowledge about glaucoma surgery and post-surgery counseling amongst paramedical staff at a tertiary eye-care hospital. Methods: This observational cross-sectional study included a random sample of 94 hospital personnel: 37 general nurse midwives, 47 ophthalmic assistants, and 10 patient caretakers (PCTs). Participants were administered a questionnaire about glaucoma surgery and post-surgery counseling of patients. Results: The study included 41 (43.6%) females and 53 (56.4%) males. The mean age of the participants was 24.85 ± 4.54 years. All participants were aware of trabeculectomy surgery in glaucoma (100%). A total of 95.7% knew that surgery helps in controlling IOP, of whom 57 (60.6%) participants got information during their course of learning. Overall 53 (56.4%) believed that surgery is done when medication failure occurs, and 58 (61.7%) knew that surgery helps in preserving vision. A total of 63 (67.0%) participants knew to counsel patients to visit an ophthalmologist when called for and take the treatment as advised, whereas 74 (78.7%) correctly said to visit an ophthalmologist immediately if pain/diminution of vision/discharge occurs. Overall, PCTs were found to be having significantly better knowledge (P = 0.01) compared to others and they also reported ophthalmologists as the chief source of information. Conclusion: This study revealed that paramedical staff had an excellent awareness of trabeculectomy surgery. However, the knowledge and counseling parts of the questionnaire revealed less than satisfactory responses. So, there is a need to continuously educate paramedical staff members so that they can help in propagating information about the role of glaucoma surgery and the importance of proper follow-up.

A Food-Effect Study to Evaluate the Oral Bioavailability of Desidustat.

This randomized, single-treatment, 2-sequence study evaluated the food effect on oral bioavailability of desidustat. Healthy adult male and female subjects were enrolled and randomly assigned to receive desidustat 50 mg orally in a fasting state in one period and a fed state in the other period. A standardized high-fat, high-calorie breakfast was served to assess the food effect. The pharmacokinetic results showed that the time to maximum blood concentration of desidustat was delayed significantly (P < .0001) in the fed state compared to the fasting state. The ingestion of food decreased the maximum blood concentration (Cmax ) compared to the fasting state (mean Cmax , 3248 ng/mL in the fed state vs 5496 ng/mL in the fasting state). The geometric mean ratio of fed/fasting for log-normal (ln) Cmax was 57. The exposure decreased in the fed state compared to the fasting state (mean area under the concentration-time curve [AUC] over the dosing interval, 25 559 ng â€¢ h/mL in the fed state versus 33 705 ng â€¢ h/mL in the fasting state; mean AUC from time 0 to infinity [AUC0-∞ ], 25,910 ng â€¢ h/mL in the fed state vs 34 233 ng â€¢ h/mL in the fasting state). The geometric mean ratio of fed/fasting for lnAUC from time 0 to the last quantifiable concentration and ln AUC0- ∞  was 77 and 76, respectively. The 90%CI of fed/fasting ratio of the geometric mean of lnCmax , AUC over the dosing interval, and AUC0-∞ of desidustat 50 mg did not fall within 80%-125% margin. Therefore, the absence of food effect could not be established. It can be inferred that food has a significant effect on the oral absorption of desidustat. Therefore, food must not be consumed 1 hour before and 2 hours after the oral administration of desidustat.

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.

Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of the Oral NLRP3 Inflammasome Inhibitor ZYIL1: First-in-Human Phase 1 Studies (Single Ascending Dose and Multiple Ascending Dose).

ZYIL1 is a nucleotide-binding oligomerization domain, leucine rich repeat and pyrin domain-containing 3 (NLRP3) inflammasome inhibitor, which prevents NLRP3-induced apoptosis-associated speck-like protein containing a caspase activation and recruitment domain oligomerization, thus inhibiting NLRP3 inflammasome pathway. We investigated the safety, tolerability, pharmacokinetic, and pharmacodynamic profiles of ZYIL1 after single and multiple doses in healthy subjects. The subjects aged 18-55 years were enrolled in 2 different studies: single and multiple ascending dose. Blood/urine samples were collected at designated time points for pharmacokinetic and pharmacodynamic analysis. In the single-ascending-dose study, 30 subjects were enrolled (6 subjects each in 5 dose groups). One adverse event was reported during the study. ZYIL1 was well absorbed with median time to maximum plasma concentration at 1-1.5 hours. The exposures were dose proportional across the dose ranges. ZYIL1 is excreted as an unchanged form via the renal route. The mean elimination half-life was 6-7 hours. In the multiple-ascending-dose study, 18 subjects were enrolled (6 subjects each in 3 dose groups). Eleven adverse events were reported by 6 subjects during the study. The accumulation index at steady state for area under the plasma concentration-time curve indicated that ZYIL1 has a marginal accumulation upon repeated dosing. Dose-proportional exposure was observed across the dose ranges. All subjects showed >90% interleukin (IL)-1ß inhibition in all dose groups for both studies. Inhibition in IL-1ß and IL-18 was observed throughout the 14 days of treatment in the multiple-dose study. The safety profile, rapid absorption, marginal accumulation, and significant inhibition of IL-1ß and IL-18 level support its development for the management of inflammatory disorders.

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.

Central macular thickness and subfoveal choroidal thickness changes on spectral domain optical coherence tomography after cataract surgery in pediatric population.

Purpose: To evaluate the central macular thickness (CMT) and subfoveal choroidal thickness (SFCT) changes on spectral domain optical coherence tomography (SD-OCT) after cataract surgery with intraocular lens (IOL) implantation in a pediatric population. Methods: This was a longitudinal, prospective, interventional study which included 90 pediatric patients who underwent cataract extraction with IOL implantation. Serial SD-OCT scans were done at postoperative day 1, 1-month, and 3-month follow-up. CMT and SFCT were measured at each visit. Results: A statistically significant increase in CMT was noted at 1 month (from 199.3 µm to 210.04 µm) post surgery, which declined over a 3-month period (202.70 µm, P = 0.0001). In case of SFCT, a constant increase was observed for over 3 months of follow-up (baseline: 296.52 µm; 1 month: 309.04 µm; and 3 months: 319.03 µm, P = 0.0001). The traumatic cataract group showed more pronounced changes in CMT and SFCT than the non-traumatic cataract group. No significant difference was observed regarding these parameters between those who underwent primary posterior capsulotomy (PPC) versus those who did not. None of the patients in the study group developed cystoid macular edema. These posterior segment-related anatomical changes did not affect the final visual outcomes. Conclusion: Cataract surgery induces potential inflammatory changes in the macula and choroid in pediatric patients. Such changes are more pronounced in trauma-related cases; however, they are not significant enough to affect the visual outcomes. Similarly, the additional surgical step of PPC does not induce significant anatomical or functional changes.

Intestinal Pseudo-Obstruction - An Under-Recognized Presentation of Systemic Lupus Erythematosus.

Intestinal pseudo-obstruction (IPO), characterized by obstruction without an identifiable anatomic cause, is a rare and poorly understood entity that may occur as a primary condition or secondary to other autoimmune disorders such as systemic lupus erythematosus (SLE). A12-year-old female child was brought with abdominal distension, vomiting, and fever for 15 days. Examination showed height and weight less than the third centile for age, tachypnea, tachycardia, and hypertension with severe abdominal distension, copious bilious aspirate, and very sluggish bowel sounds. Abdominal X-ray showed multiple air fluid levels. Ultrasound abdomen and unenhanced computed tomography (CT) scan revealed thickened dilated bowel loops, ascites, and pleural effusion. In view of multisystem nature of the disease, Koch's abdomen or autoimmune disease was suspected and emergency laparotomy procedure was deferred. She was evaluated and diagnosed to have SLE with lupus nephritis class V as per the International Society of Nephrology/Royal Pathology Society. She was managed conservatively with nasogastric decompression, immunosuppressive therapy and supportive hemodialysis.