Safety and efficacy of inclisiran in South African patients at high cardiovascular risk: A subanalysis of the ORION phase III clinical trials.

BACKGROUND: Inclisiran significantly reduced low-density lipoprotein cholesterol (LDL-C) in individuals with heterozygous familial hypercholesterolaemia, established atherosclerotic cardiovascular disease (ASCVD) or ASCVD risk equivalents (type 2 diabetes, familial hypercholesterolaemia or a 10-year risk of a cardiovascular event ≥20%) in the ORION phase III clinical trials. Infrequent dosing at days 1, 90, 270 and 450 resulted in a mean LDL-C reduction of ~50%. A total of 298 participants from South Africa (SA) were enrolled. Local data are needed to support the use of inclisiran in the SA population, potentially addressing an unmet need for additional LDL-C-lowering therapies. Objectives. To analyse the ORION phase III trial data to assess the efficacy and safety of inclisiran in SA participants. Methods. ORION-9, 10 and 11 were randomised, double-blind, phase III trials. Participants were receiving maximally tolerated statins with or without other lipid-lowering therapies (excluding protein convertase subtilisin/kexin type 9 (PCSK9) inhibitors). Participants were randomised 1:1 to inclisiran sodium 300 mg/284 mg (free acid) or placebo administered at days 1, 90, 270 and 450. The co-primary endpoints were the LDL-C percentage change from baseline to day 510 and the time-averaged percentage change in LDL-C from baseline after day 90 up to day 540. Key secondary endpoints included the absolute change in LDL-C from baseline to day 510, the time-averaged absolute change from baseline after day 90 up to day 540, and changes in other lipids and lipoproteins. Results. The mean age of the participants was 58.6 years (56% male). The mean LDL-C level at baseline was 3.6 mmol/L. At day 510, inclisiran reduced LDL-C levels by 54.2% compared with placebo (95% confidence interval (CI) -61.3 - -47.2; p<0.0001). The corresponding time-averaged reduction in LDL-C was 52.8% (95% CI -57.9 - -47.8; p<0.0001). Treatment-emergent adverse events at the injection site were more common with inclisiran compared with placebo (10.1% v. 0.7%); however, all were mild or moderate in nature and none were persistent. Conclusion. Inclisiran, given in addition to maximally tolerated standard lipid-lowering therapy, is effective and safe and results in robust reductions in LDL-C in SA patients at high cardiovascular risk.

Substrate specificity and inhibitory study of human airway trypsin-like protease.

Human airway trypsin-like protease (HAT), also referred to as TMPRSS11D, is an important physiological enzyme with the main activity pronounced in an airway. In this work we have described the substrate specificity and selectivity study of the protease, performed by the combinatorial approach. Fluorogenic/chromogenic tetrapeptide library was used for this purpose. The most efficiently hydrolyzed substrates' sequences that we selected were ABZ-Arg-Gln-Asp-Arg(Lys)-ANB-NH(2). The most active inhibitor with C-terminal Arg residue underwent detectable proteolysis action in the presence of 35pM of HAT. Based on the selected sequences the two peptide aldehydes were synthesized and (Abz-Arg-Gln-Asp-Arg(Lys)-H) were found to be an effective HAT inhibitor, working in nanomolar range with inhibition constant 54nM and 112nM, respectively.

New configuration in capillary isotachophoresis-capillary zone electrophoresis coupling.

The paper surveys possible configurations of a coupling capillary column operating in various electromigration modes. Special attention is given to capillary isotachophoresis-capillary zone electrophoresis (cITP-CZE) coupling and its description from the theoretical point of view. Computer simulations of separation are presented and compared with experiments. Further, we propose a new configuration of electrolyte systems in cITP-CZE coupling, which offers a possibility to perform complex analyses of micro- and macro-constituents in one run. The electrolyte system is verified by practical experiments for both anionic and cationic modes of analysis. The advantages and disadvantages of the new combination are discussed.

Optimization of background electrolytes for capillary electrophoresis I. Mathematical and computational model.

A mathematical and computational model is introduced for optimization of background electrolyte systems for capillary zone electrophoresis of anions. The model takes into account mono- or di- or trivalent ions and allows also for modeling of highly acidic or alkaline electrolytes, where a presence of hydrogen and hydroxide ions is significant. At maximum, the electrolyte can contain two co-anions and two counter-cations. The mathematical relations of the model are formulated to enable an easy algorithmization and programming in a computer language. The model assesses the composition of the background electrolyte in the analyte zone, which enables prediction of the parameters of the system that are experimentally available, like the transfer ratio, which is a measure of the sensitivity in the indirect photometric detection or the molar conductivity detection response, which expresses the sensitivity of the conductivity detection. Furthermore, the model also enables the evaluation of a tendency of the analyte to undergo electromigration dispersion and allows the optimization of the composition of the background electrolyte to reach a good sensitivity of detection while still having the dispersion properties in the acceptable range. Although the model presented is aimed towards the separation of anions, it can be straightforwardly rearranged to serve for simulation of electromigration of cationic analytes. The suitability of the model is checked by inspecting the behavior of a phosphate buffer for analysis of anions. It is shown that parameters of the phosphate buffer when used at neutral and alkaline pH values possess singularities that indicate a possible occurrence of system peaks. Moreover, if the mobility of any analyte of the sample is close to the mobilities of the system peaks, the indirect detector signals following the background electrolyte properties will be heavily amplified and distorted. When a specific detector sensitive on presence of the analyte were used, the signal would be almost lost due to the excessive dispersion of the peak.

A state trauma registry as a tool for occupational injury surveillance.

The goal of occupational surveillance is to identify and determine the magnitude of work-related disease and injury and workplace hazards for the purposes of focusing prevention programs and tracking their effectiveness. There are a number of databases that collect information on pieces of the puzzle of workplace exposure and adverse health outcomes. Other than that for the fatalities, none of these datasets specifically describes the most severe occupational injuries or their attendant disability. The goal of this study was to evaluate the usefulness of the Illinois Trauma Registry (ITR) in the surveillance of occupational injuries. The entire dataset of the ITR was obtained from the Illinois Department of Public Health for the years 1993 and 1994. The occupational injuries were extracted and frequency distributions were determined for all demographic and health variables. Background population, employment, and death-rate data were obtained for the purpose of rate calculation and for comparison of raw data. Mean costs for acute occupational injuries were calculated. There were 5844 occupational cases, comprising 6.7% of the total group. The majority of injuries had occurred in males (86%), in urban settings (81%), and were of the "blunt" injury type. External cause (coded according to the International Classification of Diseases, 9th Revision, External Injury) categories for work-related injuries were "Cut/Struck," 39%; "Falls," 36%; "Transportation," 12%; "Environmental," 6%; "Violence," 3%; and the remainder, 5%. By definition, all cases were admitted to the hospital, with 62% classified as "minor," 28% "moderate," and the remaining 11% "severe" to "life threatening." Surgery was performed in 54%, and admission to a monitored bed or the intensive care unit occurred in 15%. Although 93% were discharged home, only 54% ambulated independently. Seven percent were not independent with regard to self-feeding status. The mean hospital charge was $10,802 (standard deviation, $31,438). A pyramidal model of the place of ITR cases in the universe of occupational injuries is presented. The ITR contains a unique set of variables that broaden our understanding of serious work-related injuries. It is recommended that these variables--"occupation," "type of industry," and "nature of injury"--be added to the ITR so that it may be linked with other databases to check its validity and completeness and to enhance its value in occupational surveillance.

[Incidence of arterial hypertension during and after acute glomerulonephritis]. / Výskyt arteriální hypertenze behem a v období po akutní glomerulonefritide.

The authors investigated the incidence of arterial hypertension during acute glomerulonephritis in adults and during the period after glomerulonephritis. Hypertension was recorded in 34% of 126 patients treated on account of acute glomerulonephritis (mean age 23 +/- 6 years). Only in six patients the diastolic pressure was higher than 15.3 kPa. At the end of hospitalization hypertension persisted in four subjects. After a three-year interval following glomerulonephritis hypertension was recorded in 15% of 119 examined subjects. In 7 subjects it was isolated, in another 11 associated with a pathological finding in urine. Four to twenty years after acute glomerulonephritis (mean 11.5 years) in a group of 81 subjects hypertension was recorded in 31%. In six patients it was an isolated finding, in 19 instances it was associated with a pathological finding in urine and possibly impaired renal function. In adult age transient hypertension is associated with about one third of all cases of acute glomerulonephritis. Subsequent presence of hypertension in these patients is frequent and increases with the follow up period. Without an invasive examination it is not possible differentiate secondary hypertension from essential hypertension, in particular in subjects with isolated hypertension or hypertension associated with mild proteinuria.