Rapid Lowering Research Articles

SELECTIVE TARGETING OF FCRN AND IGG CLEARANCE BY NIPOCALIMAB PRESERVES KEY IMMUNE FUNCTIONS

Autoantibody disorders are caused by immune-system-produced antibodies that can damage the body's tissues or organs. In the case of warm autoimmune hemolytic anemia (wAIHA), pathogenic autoantibodies lead to the destruction of red blood cells. There is an unmet need for innovative targeted therapies that address the underlying pathogenesis of wAIHA in a safe and efficacious way. Nipocalimab is a fully human, aglycosylated, effectorless IgG1 monoclonal antibody that blocks the IgG binding site on the neonatal Fc receptor (FcRn) which prevents IgG recycling, leading to reduced serum levels of total IgGs, including pathogenic IgG autoantibodies. Nipocalimab is in clinical development for the treatment of multiple IgG-mediated autoantibody diseases, including wAIHA (NCT04119050). Rapid, sustained lowering of IgG was observed in the phase 2 VIVACITY study in generalized myasthenia gravis (gMG) and in phase 1 healthy volunteers. In gMG patients, nipocalimab induced rapid and sustained lowering of anti-AChR autoantibodies and MG-ADL scores, but no serious adverse events including clinically significant infections. Here, we characterize the effect of nipocalimab on immune function. Nipocalimab was evaluated extensively in vitro and in nonhuman primate-based chronic toxicology studies to evaluate selectivity, tolerability, safety and immunopharmacology. Safety, tolerability and immune-focused assessments in clinical phase 1 and Phase 2 MG studies were also completed (NCT02828046, NCT03772587). Nipocalimab binds specifically in vitro to FcRn without activation of effector function or inhibition of antigen presentation. In nonhuman primates administered up to 300 mg/kg nipocalimab QW for up to 6 months, sustained lowering of IgG was observed without adverse effects. Immunotoxicology identified no effect on immune cell phenotypes; CD8 T cell, NK or innate cell functions; T-dependent neoantigen IgM responses. Neoantigen IgG production was observed, but with lowered peak IgG titers consistent with the anticipated increase in IgG clearance with nipocalimab. In clinical studies, nipocalimab demonstrated a reproducible selective decrease in total serum IgG, including all subclasses of IgG, with no effect on IgM, IgA, IgE, CH50, C3, C4, inflammatory cytokines or acute phase proteins including, C-reactive protein (CRP). These data suggest that nipocalimab can selectively lower IgG and IgG autoantibodies while preserving cellular immunity, complete IgM response and IgG production after neoantigen challenge. Overall, nipocalimab's selective effect on IgG recycling provides a mechanistic rationale for potentially decreased infection risk despite substantial IgG lowering. LEL *, FY *, CJB *, JB *, RX *, AMBP are employed by the Janssen Pharmaceutical Companies of Johnson & Johnson and may hold stock or stock options in Johnson & Johnson; ST * is an employee of Orna Therapeutics; SK * is an employee of Checkmate Pharmaceuticals; JD * is an employee of Faze Medicines; WA * is an employee of Kisbee Therapeutics. *Former employees of Momenta Pharmaceuticals which was acquired by Janssen Pharmaceutical Companies of Johnson & Johnson.

Physical Modeling for Large-Scale Landslide with Chair-Shaped Bedrock Surfaces under Precipitation and Reservoir Water Fluctuation Conditions

The deformation and failure mechanisms of historical landslides, characterized with different types of bedrock surface shapes which are known to have been induced by rainfall and reservoir water fluctuations, is an important issue currently being addressed by many researchers. The Zhaoshuling Landslide of the Three Gorges Reservoir Region, which was characterized with a chair-shaped bedrock surface under rainfall and reservoir water fluctuation conditions, was selected as an example in this study’s physical modeling process. The results of different parameters, including the displacements, pore water pressure, and total soil pressure during the landslide event, revealed that the Zhaoshuling Landslide with a chair-shaped bedrock surface had been extremely sensitive to heavy rainfall coupled with the rapid lowering of the water levels. Then, based on the data analysis results of the monitoring of the rainfall and groundwater levels, as well as the reservoir water levels, a conceptual model was put forward to explain the failure mechanisms. It was believed that the chair-shaped bedrock at the toe of the slope had been subjected to a localized zone of high transient pore water pressure, which had significantly adverse effects on the mechanisms of the slope stability.

The Effect of Smoking on Humoral Response to COVID-19 Vaccines: A Systematic Review of Epidemiological Studies.

While the role of active smoking on response to vaccines is yet to be fully understood, some real-world studies have outlined a possible link between smoking and humoral response to COVID-19 vaccines. Thus, the present rapid systematic review aimed at summarizing the current epidemiological evidence on this association. Following PRISMA and WHO guidelines on rapid systematic reviews, we systematically reviewed published literature on this topic and discussed the findings according to the aim of analysing smoking and its impact on humoral response to COVID-19 postvaccination antibody titres. The search strategy yielded a total of 23 articles. The sample size amongst the studies ranged between 74 and 3475 participants (median, 360), with the proportion of smokers being between 4.2% and 40.8% (median, 26.0%). The studies included in this review analysis investigated the dynamics of antibody response to different type of COVID-19 vaccines. In 17 out of 23 studies, current smokers showed much lower antibody titres or more rapid lowering of the vaccine-induced IgG compared with nonsmokers. This rapid systematic review indicates that active smoking negatively impacts humoral response to COVID-19 vaccines, although the pathophysiologic mechanisms for this association have not been entirely suggested. The results advocate targeted policies to promote tailored health promotion initiatives, which can increase risk perception and ensure appropriate protection measures to be taken to avoid the health consequences of COVID-19 in smokers.

Lipid Levels and Short-Term Risk of Recurrent Brain Infarcts in Symptomatic Intracranial Stenosis

ObjectivesHyperlipidemia is a strong risk factor for intracranial atherosclerotic disease (ICAD) and clinical stroke recurrence. We explored the effect of serum lipid levels on subclinical infarct recurrence in the Mechanisms of earlY Recurrence in Intracranial Atherosclerotic Disease (MYRIAD) study. Materials and MethodsWe included enrolled MYRIAD patients with lipid measurements and brain MRI at baseline and brain MRI at 6-8 weeks. Infarct recurrence was defined as new infarcts in the territory of the symptomatic artery on brain MRI at 6-8 weeks compared to baseline brain MRI. We assessed the association between baseline total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglyceride (TG) levels and recurrent infarct at 6-8 weeks using multivariable logistic regression. ResultsAmong 74 patients (mean age 64.2±12.9 years, 59.5% were white, 60.8% men), 20 (27.0%) had new or recurrent infarcts. Mean HDL-C (37.2 vs. 43.9 mg/dL, P=0.037) was lower and TG (113.5 vs. 91.3 mg/dL, P=0.008) was higher while TC (199.8 vs. 174.3 mg/dL, P=0.061) and LDL-C (124.3 vs. 101.2 mg/dL, P=0.053) were nominally higher among those with recurrent infarcts than those without. LDL-C (adj. OR 1.022, 95% CI 1.004-1.040, P=0.015) and TG (adj. OR 1.009, 95% CI 1.001-1.016, P=0.021) were predictors of recurrent infarct at 6-8 weeks adjusting for other clinical and imaging factors. ConclusionsBaseline cholesterol markers can predict early infarct recurrence in patients with symptomatic ICAD. More intensive and rapid lipid lowering drugs may be required to reduce risk of early recurrence.

Fructose-induced severe hypertriglyceridemia and diabetes mellitus: a cautionary tale.

SummaryDrinking fruit juice is an increasingly popular health trend, as it is widely perceived as a source of vitamins and nutrients. However, high fructose load in fruit beverages can have harmful metabolic effects. When consumed in high amounts, fructose is linked with hypertriglyceridemia, fatty liver and insulin resistance. We present an unusual case of a patient with severe asymptomatic hypertriglyceridemia (triglycerides of 9182 mg/dL) and newly diagnosed type 2 diabetes mellitus, who reported a daily intake of 15 L of fruit juice over several weeks before presentation. The patient was referred to our emergency department with blood glucose of 527 mg/dL and glycated hemoglobin (HbA1c) of 17.3%. Interestingly, features of diabetic ketoacidosis or hyperosmolar hyperglycemic state were absent. The patient was overweight with an otherwise unremarkable physical exam. Lipase levels, liver function tests and inflammatory markers were closely monitored and remained unremarkable. The initial therapeutic approach included i.v. volume resuscitation, insulin and heparin. Additionally, plasmapheresis was performed to prevent potentially fatal complications of hypertriglyceridemia. The patient was counseled on balanced nutrition and detrimental effects of fruit beverages. He was discharged home 6 days after admission. At a 2-week follow-up visit, his triglyceride level was 419 mg/dL, total cholesterol was 221 mg/dL and HbA1c was 12.7%. The present case highlights the role of fructose overconsumption as a contributory factor for severe hypertriglyceridemia in a patient with newly diagnosed diabetes. We discuss metabolic effects of uncontrolled fructose ingestion, as well as the interplay of primary and secondary factors, in the pathogenesis of hypertriglyceridemia accompanied by diabetes.Learning pointsExcessive dietary fructose intake can exacerbate hypertriglyceridemia in patients with underlying type 2 diabetes mellitus (T2DM) and absence of diabetic ketoacidosis or hyperosmolar hyperglycemic state.When consumed in large amounts, fructose is considered a highly lipogenic nutrient linked with postprandial hypertriglyceridemia and de novo hepatic lipogenesis (DNL).Severe lipemia (triglyceride plasma level > 9000 mg/dL) could be asymptomatic and not necessarily complicated by acute pancreatitis, although lipase levels should be closely monitored.Plasmapheresis is an effective adjunct treatment option for rapid lowering of high serum lipids, which is paramount to prevent acute complications of severe hypertriglyceridemia.

Comparison of premade clevidipine and pharmacy-prepared nicardipine in time to goal systolic blood pressure in acute cerebrovascular accident.

To compare pharmacy-prepared nicardipine and premade clevidipine with regard to time to goal systolic blood pressure (SBP) in acute cerebrovascular accident (CVA). A retrospective, observational study was conducted comparing patients with acute CVA who received nicardipine or clevidipine. The primary objective was time to goal SBP. Secondary objectives included time from order to administration, time from administration to goal SBP, percentage of SBP readings below goal, total volume administered, hospital and intensive care unit lengths of stay, inpatient mortality and adverse events. Seventy-one patients were included in the study, 37 in the nicardipine group and 34 in the clevidipine group. A significant difference was found in mean time to goal SBP (150.9 minutes in the nicardipine group vs 69.3 minutes in the clevidipine group, P < 0.01). Time from order to administration was 80.1 minutes in the nicardipine group and 35.2 minutes in the clevidipine group (P < 0.01). Mean time from administration to goal SBP was 70.9 minutes in the nicardipine group and 42.3 minutes in the clevidipine group (P = 0.02). There was no difference between groups in percentage of SBP readings below goal, total volume administered, length of stay, or inpatient mortality. Adverse events occurred in 13 (35.1%) of the nicardipine-treated patients and 17 (50%) of the clevidipine-treated patients (P = 0.42). Compared to use of pharmacy-prepared nicardipine, use of premade clevidipine was associated with a shorter time to goal SBP in patients with acute CVA. There were no significant between-group differences in safety outcomes. Premade clevidipine should be considered over pharmacy-prepared nicardipine when rapid blood pressure lowering is warranted in acute CVA.

Efficacy of peritoneal dialysis on encephalopathic patient with Citrullinemia type I

Abstract Citrullinemia type I (CTLN1) clinical spectrum includes an acute neonatal form ("classic" form) and a milder late-onset form (“non-classic" form). Infants with classic form appear normal at birth. Shortly thereafter, they experienced hyperammonemia and develops symptoms. Without prompt intervention, rapid neurological deterioration with seizures, spasticity, loss of consciousness and even death can occur. Continuous venovenous hemofiltration should be started in neonates and children with ammonia levels &amp;gt; 500 µmol/L or even at lower levels if there has been an inadequate response to medical management after 4 hours. Alternatively, but only in centers that lack ability or expertise to perform extracorporeal therapy, peritoneal dialysis can be utilized. The hallmarks of dialysis is rapid lowering of plasma ammonia concentration to avoid neurotoxicity and irreversible brain damage. Objectives To evaluate the effect of peritoneal dialysis on plasma ammonia levels and the clinical outcome in an encephalopathic Egyptian patient with CTLN1. Patient and Methods A 2.5 year old male patient with a classical form of CTLN1was recruited. The first presenting symptom of the patient was poor suckling and disturbed conscious level at the age of 5 day. He was admitted to neonatal intensive-care unit (NICU) with hyperammonemic encephalopathy and abnormal pattern of breathing. He developed apneic attack and underwent mechanical ventilation. The diagnosis of CTLN1 was established with elevated plasma ammonia concentration (350 µmol/L) and plasma citrulline concentration (2570 µmol/L). The patient was managed with peritoneal dialysis for 4 days, together with protein restriction, sodium benzoate, arginine therapy and high caloric intake. Results Plasma ammonia level was decreased with improvement of general condition and conscious level after dialysis. Upon discharge from NICU, the patient was referred to our Genetic clinic and no history of further hospital admission since then. Mild developmental delay mainly cognitive was noted during his regular clinic follow up. Conclusion CTLN1 can present with hyperammonemic encephalopathy which could be lethal if not promptly managed. Peritoneal dialysis proved to be an effective therapy of reducing plasma ammonia rapidly and improving outcome of the patient.

Intensive blood pressure lowering with nicardipine and outcomes after intracerebral hemorrhage: An individual participant data systematic review.

Nicardipine has strong, rapidly acting antihypertensive activity. The effects of acute systolic blood pressure levels achieved with intravenous nicardipine after onset of intracerebral hemorrhage on clinical outcomes were determined. A systematic review and individual participant data analysis of articles before 1 October 2020 identified on PubMed were performed (PROSPERO: CRD42020213857). Prospective studies involving hyperacute intracerebral hemorrhage adults treated with intravenous nicardipine whose outcome was assessed using the modified Rankin Scale were eligible. Outcomes included death or disability at 90 days, defined as the modified Rankin Scale score of 4-6, and hematoma expansion, defined as an increase ≥6 mL from baseline to 24-h computed tomography. Three studies met the eligibility criteria. For 1265 patients enrolled (age 62.6 ± 13.0 years, 484 women), death or disability occurred in 38.2% and hematoma expansion occurred in 17.4%. Mean hourly systolic blood pressure during the initial 24 h was positively associated with death or disability (adjusted odds ratio (aOR) 1.12, 95% confidence interval (CI) 1.00-1.26 per 10 mmHg) and hematoma expansion (1.16, 1.02-1.32). Mean hourly systolic blood pressure from 1 h to any timepoint during the initial 24 h was positively associated with death or disability. Later achievement of systolic blood pressure to ≤140 mmHg increased the risk of death or disability (aOR 1.02, 95% CI 1.00-1.05 per hour). Rapid lowering of systolic blood pressure by continuous administration of intravenous nicardipine during the initial 24 h in hyperacute intracerebral hemorrhage was associated with lower risks of hematoma expansion and 90-day death or disability without increasing serious adverse events.

Time Course of Metabolic, Neuroendocrine, and Adipose Effects During 2 Years of Follow-up After Gastric Bypass in Patients With Type 2 Diabetes

ContextRoux-en-Y gastric bypass surgery (RYGB) markedly improves glycemia in patients with type 2 diabetes (T2D), but underlying mechanisms and changes over time are incompletely understood.ObjectiveIntegrated assessment of neuroendocrine and metabolic changes over time in T2D patients undergoing RYGB.Design and SettingFollow-up of single-center randomized study.PatientsThirteen patients with obesity and T2D compared to 22 healthy subjects.InterventionsBlood chemistry, adipose biopsies, and heart rate variability were obtained before and 4, 24, and 104 weeks post-RYGB.ResultsAfter RYGB, glucose-lowering drugs were discontinued and hemoglobin A1c fell from mean 55 to 41 mmol/mol by 104 weeks (P < 0.001). At 4 weeks, morning cortisol (P < 0.05) and adrenocorticotropin (P = 0.09) were reduced by 20%. Parasympathetic nerve activity (heart rate variability derived) increased at 4 weeks (P < 0.05) and peaked at 24 weeks (P < 0.01). C-reactive protein (CRP) and white blood cells were rapidly reduced (P < 0.01). At 104 weeks, basal and insulin-stimulated adipocyte glucose uptake increased by 3-fold vs baseline and expression of genes involved in glucose transport, fatty acid oxidation, and adipogenesis was upregulated (P < 0.01). Adipocyte volume was reduced by 4 weeks and more markedly at 104 weeks, by about 40% vs baseline (P < 0.01).ConclusionsWe propose this order of events: (1) rapid glucose lowering (days); (2) attenuated cortisol axis activity and inflammation and increased parasympathetic tone (weeks); and (3) body fat and weight loss, increased adipose glucose uptake, and whole-body insulin sensitivity (months-years; similar to healthy controls). Thus, neuroendocrine pathways can partly mediate early glycemic improvement after RYGB, and adipose factors may promote long-term insulin sensitivity and normoglycemia.

Hypertriglyceridemia-induced pancreatitis in pregnancy: case review on the role of therapeutic plasma exchange.

SummaryGestational hypertriglyceridemia-induced pancreatitis is associated with significant maternal and fetal morbidity and mortality. We report a case of gestational hypertriglyceridemia-induced pancreatitis in a primigravida at 31-weeks gestation, complicated by impending preterm labor and metabolic acidosis requiring hemodialysis. This was successfully managed with therapeutic plasma exchange (TPE), followed by i.v. insulin, low-fat diet, and omega-3. Triglyceride levels stabilized after TPE and the patient underwent an uncomplicated term delivery. In pregnancy, elevated estrogen and insulin resistance exacerbate hypertriglyceridemia. Management is challenging as risks and benefits of treatment options need to be weighed against fetal wellbeing. We discuss management options including a review of previous case reports detailing TPE use, dietary optimization, and delivery timing. This case emphasizes the importance of multidisciplinary care to optimize maternal and fetal outcomes.Learning pointsGestational hypertriglyceridemia-induced pancreatitis has high morbidity.A multidisciplinary team approach is a key as maternal and fetal needs must be addressed.Rapid lowering of triglycerides is crucial and can be achieved successfully and safely with plasma exchange.A low-fat diet while ensuring adequate nutrition in pregnancy is important.Timing of delivery requires consideration of fetal maturity and risk of recurrent pancreatitis.

Impact of Intravenous Antihypertensives on Outcomes Among Hospitalized Patients.

Many hospitalized patients with acute elevations in blood pressure (BP) are treated with intravenous (IV) antihypertensive medications without evidence of benefit. This study investigated the effects of IV as-needed (PRN) antihypertensives on BP, hospital length of stay, and mortality. We included hospitalized patients with an order for an IV PRN antihypertensive medication. We excluded patients with target organ damage. We performed multivariate analysis to assess whether the medication was independently associated with outcomes. 1,784 out of 5,680 patients (31%) had an administration of the PRN medication. Patients who received the medication had a longer hospital stay compared with patients with an order for the medication who did not receive it (4.9 ± 6.1 vs. 3.1 ± 4.1 days, P < 0.001). This remained statistically significant after adjusting for covariates. In-hospital mortality was higher in the group that received the medication (3.3% vs. 1.6%, P < 0.001), but this was not statistically significant on multivariate analysis. IV hydralazine caused the most significant reduction in BP and led to a shorter length of stay when compared with enalapril and labetalol. A total of 62% of patients received the medication for a systolic BP lower than 180 mm Hg. Treating hypertension in the in-patient setting remains complex. Rapid lowering of BP can cause harm to patients, and this study showed that antihypertensive medication increased hospital length of stay. Once assuring no target organ damage, a strategic approach should be to treat modifiable factors and gradually reduce BP.

Sinkhole development in the Sivas gypsum karst, Turkey

The extensive gypsum karst of Sivas, Turkey is one of the most outstanding examples of bare gypsum karst in the world. It displays a number of remarkable geomorphic features, including: (1) two stepped planation surfaces cut-across folded gypsum developed during an initial phase of slow base level deepening punctuated by periods of stability; (2) unusual deeply entrenched gypsum canyons related to a subsequent phase of rapid fluvial incision and water table lowering; (3) a polygonal karst of superlative quality mainly developed in the upper surface; (4) relict valleys disrupted by sinkholes in the lower erosional surface; (5) a large number of bedrock collapse sinkholes mostly associated with the lower surface; and (6) numerous cover subsidence sinkholes developed in the valley floors. This work analyses the spatial distribution, characteristics and evolution of the sinkholes within the broad Plio-Quaternary geomorphological and paleohydrological evolution of the epigene karst system dominated by autogenic recharge. A cartographic sinkhole inventory has been produced in an area covering 2820 km2 with morphometric data and including 295 bedrock collapse sinkholes and 302 cover subsidence sinkholes. The different sinkhole types show a general spatial zonation controlled by the hydrogeological functioning of the different sectors: (1) solution sinkholes (polygonal karst) in the upper recharge area; (2) bedrock collapse sinkholes in the lower denudation surface and close to the base level, where well developed caves are inferred; and (3) cover subsidence sinkholes, with high densities probably associated with areas of preferred groundwater discharge. The morphology of the bedrock collapse sinkholes, varying from small cylindrical holes to large and deep tronco-conical depressions with gentle slopes reflect to geomorphic evolution of these sinkholes that reach exceptionally large hectometre-scale diameters. Their evolution, involving substantial enlargement and deepening, is attributed to the solutional removal as solute load of large volumes of gypsum by downward vadose flow. This type of morphological evolution with significant post-collapse solutional denudation differs from that observed in carbonate rocks characterised by lower solubility and erodibility. The analysis of historical imagery reveals that bedrock collapse sinkholes currently have a very low probability of occurrence and that buried cover subsidence sinkholes are used for urban development creating risk situations.

Evaluating sinkhole formation with multicriteria decision analysis: a case study in Karapınar-Konya, Turkey

Sinkholes (dolines) are considered natural hazards that threaten both human life and agricultural economic income. Due to their characteristic sudden occurrences, sinkholes are almost impossible to avoid. Geology, hydrogeology, irrigation, precipitation, climate, land use changes, and urbanization are the main factors that activate sinkhole occurrences. More than 300 sinkholes have been reported in the Karapinar region situated in Konya Province, Turkey, and this number has increased in the last 5 years. In particular, increasing agricultural activities cause rapid lowering of groundwater levels by excessive pumping for irrigation. A total of 55,267 water wells are in use in the region, which increases the risk factors for sinkholes in Karapinar. The importance of Karapinar region for solar energy, intensive agricultural activities, and a planned thermal power plant to be built soon gives estimating sinkhole probability and investigating ways of predicting and preventing sinkholes vital importance. The main purpose of this study is to predict possible sinkhole formation in the Konya region based on historical occurrences and to ensure reporting to authorities to raise awareness of this problem. Sinkhole susceptibility maps using the AHP, TOPSIS, and VIKOR methods, which are included in the multicriteria decision analysis (MCDA) concept, were prepared for the Karapinar region to achieve this purpose. The elevation, slope, geology, rock strength values, land use, water well density, and distance to settlements and roads were considered criteria to generate the sinkhole susceptibility maps. Strength test results (geological data set), which were not added to susceptibility maps in previous studies, were used in this study. The generated susceptibility maps were verified by correlation analysis and by overlaying existing sinkholes with susceptibility values. Necessary suggestions are presented for the Karapinar region based on the results of this study. The calculated ratios using the AHP, TOPSIS, and VIKOR methods are 3.53%, 2.55%, and 2.86%, respectively, which imply that the study area is highly susceptible to sinkhole occurrences. Based on the correlation analysis, an r value of 0.982 is derived using the AHP and VIKOR methods. When existing sinkhole locations are considered, the AHP method produces the most likely sinkhole locations. In addition, the AHP method can be used to prepare and update the susceptibility maps for any region that is at risk of sinkhole formation.

Commentary: Prophylactic laser barrage before laser-assisted in-situ keratomileusis.

The debate on prophylactic laser barrage, especially before refractive surgery, continues to divide retina specialists. There are surgeons who believe that every predisposing lesion must be treated, while some are sceptical about the preventive role of laser to the retinal lesions. Rhegmatogenous retinal detachment (RD) is common in myopes in eyes with lattice degeneration and posterior vitreous detachment (PVD).[1] Low myopes (−1.00 to −3.00 D) have a fourfold increased risk of RD over emmetropic patients. This risk increases significantly when the patient’s refractive error exceeds −3.00 D.[2] Lattice degeneration is present in 6–8% of the population and increases the risk of retinal detachment. Myopes, in addition to having peripheral retinal degenerations and lattice, have PVD at a younger age compared to emmetropes. The procedure of laser-assisted in-situ keratomileusis (LASIK) increases the risk of RD due to sudden fluctuation in the intraocular pressure (IOP) during the procedure. The increase in IOP that occurs during suction prior to engaging the microkeratome, and rapid lowering of IOP when the suction ring is decompressed, or the shock wave generated by the excimer laser may lead to PVD resulting in retinal tears.[3] Hence, LASIK patients should undergo an extensive retinal evaluation with prophylactic photocoagulation of lattice degeneration, atrophic holes, and/or flap tears in an attempt to reduce any risk of an RD. The prophylactic treatment of high-risk lesions is believed to prevent RD. Ruiz-Moreno et al. retrospectively studied 1554 consecutive eyes (878 patients) undergoing LASIK and reported a low incidence (0.25%) of RD in their patients after prophylactic barrage laser to lesions predisposing to RD.[4] Several other studies have reported a higher incidence of RD in patients who had undergone prior LASIK than would be predicted from myopia alone.[5] Till date, there have been no prospective studies directly comparing prophylactic treatment versus nontreatment and showing any definite RD risk reduction for asymptomatic retinal lesions in general. In a recent study by Srinivasan et al., of the 694 eyes that had undergone LASIK, 5 eyes (0.7%) developed RD over 7 years.[6] Increased risk of RD was not associated with age at LASIK surgery, gender, laterality and spherical equivalent. While RD was statistically significantly higher in eyes which had prior prophylactic laser photocoagulation, the number of eyes who developed RD was so low that it could not be clinically meaningful, with very wide confidence intervals of the hazard ratio. Only three eyes had lattice degeneration prior to LASIK which were lasered, and one eye with lattice was unlasered. Ideally, a study should compare a substantial number of eyes which had lattice degeneration prior to LASIK and assign them to prophylactic laser or no laser. Hence, it cannot be conclusively proven from this study that prophylactic laser adversely increases the risk of RD after LASIK. Proliferation of the epiretinal membrane (ERM) or macular pucker has been occasionally observed following treatment for a retinal break. However, a direct cause-and-effect relationship of treatment of a retinal break to ERM remains unclear. After laser photocoagulation of the retinal lesions, the adhesive force between the retina and choroid increases over a few days to 2 weeks. Hence, refractive surgery is recommended after at least 7 days following laser photocoagulation. Patients at high risk should also be educated about the symptoms of PVD and retinal detachment as well as about the value of periodic follow-up examinations. Patients should be counselled that the refractive surgery does not reduce the risk of RD, even though the refractive error may be cured after LASIK. In conclusion, all patients should have a thorough dilated indirect ophthalmoscopy with scleral depression prior to refractive surgery. Treatment of any retinal lesion predisposing to the development of RD is mandatory.

Intensive Blood Pressure Lowering With Nicardipine for Better Outcomes After Intracerebral Haemorrhage: A Systematic Review and Meta-Analysis of Individual Participant Data

Background: Nicardipine has strong, rapidly acting antihypertensive activity. The effects of acute systolic blood pressure (SBP) levels achieved with intravenous nicardipine immediately after onset of intracerebral haemorrhage (ICH) on clinical outcomes were determined. Methods: A systematic review and individual patient data analysis of articles before October 1, 2020 identified on PubMed were performed. Prospective studies involving hyperacute ICH adults treated with intravenous nicardipine whose outcome was assessed using the modified Rankin Scale (mRS) were eligible. Outcomes included death or disability at 90 days, defined as an mRS score of 4-6, and haematoma expansion, defined as an increase ≥6 mL from baseline to 24-h computed tomography. Findings: Three studies met the eligibility criteria. Of 1,271 patients overall, 1,265 (age 62.6±13.0 years, 484 women) with available SBP data were included. Death or disability occurred in 38.2%, and haematoma expansion occurred in 17.4%. Mean hourly SBP during the initial 24 h was positively associated with death or disability [adjusted odds ratio (aOR) 1.12, 95% CI 1.00–1.26 per 10 mmHg] and haematoma expansion (1.16, 1.02–1.32). The association of SBP with death or disability was modified by race, baseline diastolic BP, and study population (higher SBP increased the risk in Asians, aOR 1.26, 95% CI 1.10–1.43). Mean hourly SBP from 1 h to any timepoint during the initial 24 h was positively associated with death or disability. Slower lowering of SBP to ≤140 mmHg increased the risk of death or disability (aOR 1.02, 95% CI 1.00–1.05, per hour). Interpretation: Rapid lowering of SBP by continuous administration of intravenous nicardipine during the initial 24 h in hyperacute ICH decreased early haematoma expansion and 90-day death or disability without increasing serious adverse events. Funding: Japan Agency for Medical Research and Development. Conflict of Interest: All of the following conflicts are outside the submitted work.Toyoda reports personal fees from Daiichi-Sankyo, Bayer Yakuhin, Bristol-Myers-Squibb (BMS), and Nippon Boehringer-Ingelheim (NBI). Ihara reports grants from Panasonic, Shimadzu Corporation, BMS, Otsuka Pharmaceutical, and personal fees from Daiichi-Sankyo, Eisai, and Bayer Yakuhin.Itabashi reports grants from Tohoku Fukushi University and NBI. Yamagami reports research grants from BMS; lecturer’s fees from Stryker, Terumo, Medtronic, Medico’s Hirata, Johnson and Johnson, Bayer, Daiichi-Sankyo, BMS, NBI, Takeda, and Otsuka Pharmaceutical; and membership of the advisory boards for Daiichi-Sankyo. Itabashi reports honoraria from Bayer, Eisai, BMS, Daiichi Sankyo, NBI, Takeda, Otsuka Pharmaceutical, Tanabe-Mitsubishi Parma, Pfizer, GE Healthcare Japan, Stryker, Medtronic, and Johnson and Johnson, and research support from Tohoku Fukushi University and NBI. Sakai reports grants from Daiichi-Sankyo, Jimro, Medtronic, Terumo, and honoraria from Asahi-Intec, Biomedical Solutions, Daiichi-Sankyo, Medtronic, and Stryker. Inoue reports personal fees from Daiichi-Sankyo, Bayer, BMS, and Medtronic. Minematsu reports personal fees and other from Bayer Yakuhin and AstraZeneca, personal fees from Otsuka Pharmaceutical, NBI, Mitsubishi Tanabe Pharma, BMS, Pfizer, Japan Stryker, Daiichi-Sankyo, Astellas Pharma, Nippon Chemiphar, and Fuji Film RI Pharma; and other (Advisory Board) from CSL Behring, Medico’s Hirata, EPS Corporation, HEALIOS K.K., and T-PEC Corporation. Koga reports honoraria from Bayer Yakuhin, Otsuka, Daiichi-Sankyo, and NBI, scientific advisory board from Ono, and research support from Takeda, Daiichi-Sankyo, NBI, and Shionogi.None of the other authors has any conflicts of interest to declare. Ethical Approval: The study design followed PRISMA guidelines for IPD systematic reviews. Ethical approval to perform the present IPD analysis was obtained from the site of the corresponding author. The study is registered with PROSPERO (CRD42020213857).

Feasibility and safety of early initiation of a PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor in patients with acute myocardial infarction undergoing primary PCI

Abstract Background Recent ESC/EAS Guidelines for the management of dyslipidemia stated that the treatment goal of LDL cholesterol (LDL-C) in very high-risk patients is less than 55mg/dl. PCSK9 inhibitors in addition to strong statins could be a useful strategy for rapid and aggressive lowering of LDL-C. However, the feasibility and safety of early initiation of a PCSK9 inhibitor for AMI patients undergoing primary PCI remain unclear. Objectives We examined the effects of early initiation of a PCSK9 inhibitor, evolocumab, on lipid profile and inflammatory markers and its safety in AMI patients undergoing primary PCI. Methods This study is a single center, randomized, controlled trial involving 102 patients hospitalized for AMI. The patients were randomly assigned 1:1 to the evolocumab group and the control group. Evolocumab (140 mg) was subcutaneously injected within 24 hours after PCI and then every two weeks. All patients received pitavastatin (2mg/day) in addition to the allocated treatment. The primary endpoints were changes in lipid profile and inflammatory markers from baseline to 4 weeks. Results 102 patients were enrolled between October 2017 and December 2019. 89 patients were ST-segment elevation myocardial infarction (STEMI), 13 patients were non-STEMI. Primary PCI was successfully performed in all patients. 76 patients were statin-naïve. 2 patients were excluded from analyses because they died severe heart failure in acute phase. Finally, 100 patients (evolocumab; n=51 and control; n=49) were analyzed. Baseline LDL-C was 121.6±30.3 mg/dl in the evolocumab group and 124.7±33.6 mg in the control group. Change in LDL-C from the baseline to 4 weeks was −92.4±32.4 mg/dl (−75%) in the evolocumab group and −44.8±32.1 mg/dl (−33.1%) in the control group (mean difference; 47.6mg/dl, 95% CI; 34.8 to 60.4 mg/dl, p&amp;lt;0.001). LDL-C &amp;lt;70mg/dl at 4 weeks was achieved in 96.0% of the evolocumab group as compared with 26.5% of the control group. Further, in the evolocumab group. LDL &amp;lt;55mg/dl was achieved in 92.1% at 2 weeks and 92.1% at 4 weeks. Regarding inflammatory markers, there were no significant difference in change in high-sensitivity C-reactive protein (p=0.49) and tumor necrosis factor-alpha (p=0.63) between two groups even after adjustment of baseline value. No adverse event associated with evolocumab was observed during this study. Conclusion In patients with AMI undergoing primary PCI, early initiation of evolocumab rapidly reduced LDL-C without no adverse event, and achieved LDL-C&amp;lt;55mg/dl in most patients within 2 weeks. Early administration of a PCSK9 inhibitor combined with a strong statin could be a feasible and safe treatment for AMI patients undergoing PCI. Funding Acknowledgement Type of funding source: None

EFFICACY AND SAFETY OF IV INSULIN INFUSION FOR MANAGEMENT OF HYPERTRIGLYCERIDEMIC PANCREATITIS

SESSION TITLE: Critical Care Posters SESSION TYPE: Original Investigation Posters PRESENTED ON: October 18-21, 2020 PURPOSE: Hypertriglyceridemic pancreatitis (HTGP) portends significant morbidity and mortality, and management involves rapid lowering of serum triglycerides (TG). Both plasmapheresis (PL) and intravenous (IV) insulin infusions are effective for this purpose, although comparative analyses of these interventions have not been performed. Furthermore, the role of IV insulin in patients with HTGP without diabetes remains unknown. We aimed to investigate these questions in a cohort of patients hospitalized for HTGP at a tertiary care center. METHODS: A retrospective chart review of patients hospitalized for acute HTGP between January 1, 2001 and December 31, 2018 was performed. Patients were stratified according to treatment modality: IV insulin infusion, PL+/- IV insulin, or conservative management. Efficacy of TG-lowering and clinical outcomes were compared between groups. RESULTS: One hundred and four patients with HTGP were identified. Seventy-eight patients (75 %) were treated with IV insulin, 6 (5.8%) were treated with PL, and 20 (19.2%) received conservative management. Admission TG levels were significantly higher in the IV insulin and PL vs. conservative group (p = 0.009). The percent decline in TG levels from admission to hospital discharge was 80.8% ±13.2%, 90.0% ± 5.6%, 63.9% ± 30.5% among the IV insulin, PL, and conservative groups, respectively (p=0.0214), with no statistically significant differences seen between IV insulin and PL groups. Eighty (80.0%) patients had diabetes mellitus, the majority of whom received IV insulin (81.3%). Among patients without diabetes, 54.2% received IV insulin only. Hospital complications, hypoglycemic events, and LOS did not differ between patients with and without diabetes who received IV insulin. CONCLUSIONS: Intravenous insulin infusion is a safe and effective method for reducing serum triglyceride levels in both diabetic and non-diabetic patients diagnosed with acute HTGP. CLINICAL IMPLICATIONS: IV insulin infusion is effective and safe for management of acute HTPG when compared to conservative management or plasmapheresis. Given the challenges associated with use of plasmapheresis and its limited clinical utility, IV insulin infusion should be considered as a first line therapy for treatment of this entity in both diabetic and non-diabetic individuals. DISCLOSURES: No relevant relationships by Hasan Ahmad Hasan Albitar, source=Web Response No relevant relationships by Adham Alkurashi, source=Web Response No relevant relationships by Yahya Almodallal, source=Web Response no disclosure on file for Tiffany Cortes; No relevant relationships by Kristen Gonzales, source=Web Response No relevant relationships by Sumedh Hoskote, source=Web Response No relevant relationships by Maria Hurtado, source=Web Response No relevant relationships by vivek iyer, source=Web Response no disclosure on file for Prashant Jagtap; No relevant relationships by Vinaya Simha, source=Web Response

Role of Lipid-Lowering Therapy in Low-Density Lipoprotein Cholesterol Goal Attainment: Focus on Patients With Acute Coronary Syndrome.

:Dyslipidemia is a major risk factor for cardiovascular (CV) disease, which is the leading cause of death globally. Acute coronary syndrome (ACS) is a common cause of death, accounting for nearly half of the global burden of CV mortality. Epidemiologic studies have identified low-density lipoprotein cholesterol (LDL-C) as an independent CV risk factor, and this is now the primary target for initiating and adjusting lipid-lowering therapies in most current guidelines. Evidence from pivotal studies supports the use of high-intensity statin therapy and a lower level for optimal LDL-C in secondary prevention of atherosclerotic CV disease, especially in patients with ACS undergoing percutaneous coronary intervention. However, current research has identified a gap between the target LDL-C goal attainment and target LDL-C levels recommended by the guidelines. Statins have proven benefits in the management of CV disease and are the cornerstone of lipid-lowering management in patients with ACS. Recent randomized controlled trials have also demonstrated the benefits of cholesterol absorption inhibitors and proprotein convertase subtilisin/kexin type 9 inhibitors. This review summarizes the current evidence for LDL-lowering therapy in patients with ACS, with an emphasis on the importance of LDL-C goal attainment, rapid LDL-C lowering, and duration of LDL-C–lowering therapy.

Abrupt Holocene ice-sheet thinning along the southern Soya Coast, Lützow-Holm Bay, East Antarctica, revealed by glacial geomorphology and surface exposure dating

Geological reconstruction of the retreat history of the East Antarctic Ice Sheet (EAIS) since the Last Glacial Maximum (LGM) is essential for understanding the response of the ice sheet to global climatic change and the mechanisms of retreat, including a possible abrupt melting event. Such information is key for constraining climatic and ice-sheet models that are used to predict future Antarctic Ice Sheet AIS melting. However, data required to make a detailed reconstruction of the history of the EAIS involving changes in its thickness and lateral extent since the LGM remain sparse. Here, we present a new detailed ice-sheet history for the southern Soya Coast, Lützow-Holm Bay, East Antarctica, based on geomorphological observations and surface exposure ages. Our results demonstrate that the ice sheet completely covered the highest peak of Skarvsnes (400 m a.s.l.) prior to ∼9 ka and retreated eastward by at least 10 km during the Early to Mid-Holocene (ca. 9 to 5 ka). The timing of the abrupt ice-sheet thinning and retreat is consistent with the intrusion of modified Circumpolar Deep Water (mCDW) into deep submarine valleys in Lützow-Holm Bay, as inferred from fossil foraminifera records of marine sediment cores. Thus, we propose that the mechanism of the abrupt thinning and retreat of the EAIS along the southern Soya Coast was marine ice-sheet instability caused by mCDW intrusion into deep submarine valleys. Such abrupt ice-sheet thinning and retreat with similar magnitude and timing have also been reported from Enderby Land, East Antarctica. Our findings suggest that abrupt thinning and retreat as a consequence of marine ice-sheet instability and intrusion of mCDW during the Early to Mid-Holocene may have led to rapid ice-surface lowering of hundreds of meters in East Antarctica.

Rapid filamentary accretion as the origin of extended thin discs

ABSTRACT Galactic outflows driven by stellar feedback are crucial for explaining the inefficiency of star formation in galaxies. Although strong feedback can promote the formation of galactic discs by limiting star formation at early times and removing low angular momentum (AM) gas, it is not understood how the same feedback can result in diverse objects such as elliptical galaxies or razor thin spiral galaxies. We investigate this problem using cosmological zoom-in simulations of two galaxies forming within 1012 M⊙ haloes with almost identical mass accretion histories and halo spin parameters. However, the two resulting galaxies end up with very different bulge-to-disc ratios at z = 0. At z &amp;gt; 1.5, the two galaxies feature a surface density of star formation ΣSFR ≃ 10 M⊙ yr−1 kpc−2, leading to strong outflows. After the last starburst episode, both galaxies feature a dramatic gaseous disc growth from 1 to 5 kpc during 1 Gyr, a decisive event we dub ‘the Grand Twirl’. After this event, the evolutionary tracks diverge strongly, with one galaxy ending up as a bulge-dominated galaxy, whereas the other ends up as a disc-dominated galaxy. The origins of this dichotomy are the AM of the accreted gas, and whether it adds constructively to the initial disc angular momentum. The build-up of this extended disc leads to a rapid lowering of ΣSFR by over two orders of magnitude with ΣSFR ≲ 0.1 M⊙ yr−1 kpc−2, in remarkable agreement with what is derived from Milky Way stellar populations. As a consequence, supernovae explosions are spread out and cannot launch galactic outflows anymore, allowing for the persistence of a thin, gently star-forming, extended disc.