Shortening Of Interval Research Articles

Efficacy and safety of HERG channel agonists for treatment of Long QT Syndrome type 8

Abstract Background Substrate-based approach aimed at repolarization abbreviaton using mexiletine was shown to normalize the QTc interval and reduce the event rate in LQT3, and is now considered standard-of-care. Unfortunately, mexiletine is partially efficacious in other malignant forms of LQTS, such as LQT2 and LQT8. Novel compounds, such as HERG channel agonists, potentially capable of safely and efficaciously abbreviating the repolarization have not been tested in a clinically relevant model. Purpose To investigate the efficacy and safety of repolarization shortening using ICA-105574, the most potent compound belonging to the class of HERG channel agonists, in a clinically relevant, first-in-class porcine model of LQT8. Methods We used a combination of 12-lead ECG and electroanatomical mapping (EAM) to obtain data on the QTc interval, local activation time (LAT), local repolarization time (LRT) and its gradients, and reentrant vulnerability index (RVI), at baseline and after drug administration. We used LQT8 pigs of both genders weighing between 60 kg and 80 kg. All procedures were conducted following local regulations for the care and use of laboratory animals after authorization by relevant authorities. We used mixed effects linear regression model to assess the effect of ICA-105574 on the QTc interval and paired nested t-test to assess the effect of ICA-105574 on EAM-derived parameters. Results As a first step, we assessed the effects of ICA-105574 on the QTc interval. Compared to baseline, a single dose of 3 mg/kg of ICA-105574 resulted in an immediate and pronounced shortening of the QTc interval in all animals (∆QTc at 5 minutes post-injection: -28%, p<0.001). We then investigated repeated intravenous administrations of 3 mg/kg doses at 10-minute intervals for a total of 4 doses (i.e., overall drug dose of 12 mg/kg). Importantly, we did not observe excessive QTc shortening (∆QTc 6 mg/kg: -26%; ∆QTc 9 mg/kg: -26%; ∆QTc 12 mg/kg: -30%, p<0.001 for all) nor did we observe any proarrhythmic events in any of the animals studied. In a second phase of the study, we used EAM to assess the modifications in the arrhythmic substrate induced by ICA-105574. Importantly, ICA-105574 not only shortened the duration of ventricular repolarization (∆LRT: -21%, p=0.017), but also reduced the dispersion of ventricular repolarization (∆Max. LRT gradient: -69%, p=0.020). This, coupled with reduction of the activation delay as compared to baseline (∆LAT: -28%, p=0.072), had a net positive effect on the arrhythmic substrate, as evidenced by an amelioration by 30% of global RVI (∆RVIG,D: -32%, p=0.029). Conclusions In our LQT8 pig model, ICA-105574, a potent HERG channel agonist, safely and efficaciously ameliorated the arrhythmic substrate. These results suggest that HERG channel agonists, as a novel class of antiarrhythmics, could have clinical application as a novel substrate-based therapy for LQT8.Figure 1

Cardiac NAD+ depletion in mice promotes hypertrophic cardiomyopathy and arrhythmias prior to impaired bioenergetics.

Nicotinamide adenine dinucleotide (NAD+) is an essential co-factor in metabolic reactions and co-substrate for signaling enzymes. Failing human hearts display decreased expression of the major NAD+ biosynthetic enzyme nicotinamide phosphoribosyltransferase (Nampt) and lower NAD+ levels, and supplementation with NAD+ precursors is protective in preclinical models. Here we show that Nampt loss in adult cardiomyocytes caused depletion of NAD+ along with marked metabolic derangements, hypertrophic remodeling and sudden cardiac deaths, despite unchanged ejection fraction, endurance and mitochondrial respiratory capacity. These effects were directly attributable to NAD+ loss as all were ameliorated by restoring cardiac NAD+ levels with the NAD+ precursor nicotinamide riboside (NR). Electrocardiograms revealed that loss of myocardial Nampt caused a shortening of QT intervals with spontaneous lethal arrhythmias causing sudden cardiac death. Thus, changes in NAD+ concentration can have a profound influence on cardiac physiology even at levels sufficient to maintain energetics.

Treatment Targets Should Influence Choice of Infliximab Dose Intensification Strategy in Inflammatory Bowel Disease: A Pharmacokinetic Simulation Study.

The optimal infliximabdose intensification strategy to address loss of response associated with subtherapeutic infliximabtrough levels remains uncertain, as does whether post-intensification trough and treatment targets should influence this decision. This pharmacokineticsimulation study aimed to identify infliximab dose intensification strategies capable of achieving post-intensification infliximab trough thresholds associated with clinical and objective treatment targets in Crohn's disease and ulcerative colitis. A validated pharmacokinetic infliximab model, applied to 200 simulated patients, identified those with subtherapeutic (<3.00mg/L) trough levels after 30weeks of standard (5mg/kg 8-weekly) dosing, and subsequently applied 10 dose intensification strategies over a further 32weeks. The proportion of simulations achieving 32-week post-intensification infliximab trough levels associated with endoscopic remission (ulcerative colitis >7.50 mg/L, Crohn's disease >9.70 mg/L) was the primary outcome, with perianal fistula healing (Crohn's disease >10.10 mg/L) and clinical improvement (ulcerative colitis >3.70 mg/L, Crohn's disease >7.00mg/L) evaluated as secondary outcomes. All outcomes were stratified by intensity of dose intensification, with standard (≤10mg/kg 8-weekly or 5mg/kg 4-weekly; n=5) and intensive (>10mg/kg 8-weekly or 5mg/kg 4-weekly; n=5) dosing strategies defined, respectively. The median pre-intensification infliximab trough level was 0.91mg/L (interquartile range 1.37). Intensive dosing strategies were more likely to achieve infliximab trough concentrations associated with endoscopic remission (ulcerative colitis 36.48% vs. 10.80%, Crohn's disease 25.98 vs. 4.68%), perianal fistula healing (24.52% vs. 4.36%) and clinical improvement (ulcerative colitis 61.90% vs. 34.86%, Crohn's disease 40.32 vs. 12.08%) than standard intensification strategies (all p<0.01). When controlling for cumulative (mg/kg) infliximab dose over 32weeks, strategies that concurrently dose increased and interval shortened achieved the highestinfliximab trough levels (all p<0.01). This simulation-based analysis highlights the potential of using post-intensification infliximab trough thresholds associated with aspirational treatment targets in Crohn's disease and ulcerative colitis to guide choice of infliximab dose intensification strategy. Intensive dose intensification strategies, particularly those that concurrently dose increase and interval shorten, appear to achieve higher infliximab levels than standard dose intensification strategies. This may be particularly important in the pursuit of stringent endpoints, such as endoscopic remission and fistula healing, which have been consistently associated with higher infliximab trough levels. These findings require validation across real-world cohorts.

Taurine and enzymatically modified isoquercitrin protected against methotrexate-induced deteriorations in the conductivity and rhythmicity of the heart in rats: Antioxidant, anti-inflammatory, and histological architecture approach.

Cardiotoxicity is one of the most devastating complications of cancer treatment by methotrexate (MTX). The present study aimed to investigate the potential anti-cardiotoxic efficacy of taurine (Tau) and enzymatically modified isoquercitrin (EMIQ) alone or combined against MTX-induced cardiotoxicity in adult male rats. A total of 36 rats were randomly divided into six groups (six animals each): control, MTX (a single i.p. dose of 20 mg/kg), EMIQ + MTX (26 mg/kg of EMIQ, p.o. for 16 days), Tau + MTX (500 mg/kg of Tau, p.o. for 16 days), EMIQ + Tau + MTX at the same previous doses, and (EMIQ + Tau)½+ MTX. MTX reduced the percentage of body weight change, the expression of dihydrofolate reductase (DHFR) and folypolyglutamyl synthetase (FPGS), the cleaved tumor necrosis factor alpha (TNF-α) level in the cardiac tissue, and the elevated serum TNF-α level. MTX extensively deteriorated the electrocardiography (ECG), inducing tachycardia with shortening of the time intervals between successive heartbeats (R-R interval), associated with elongation of ventricular depolarization (QRS interval), and the corrected total time for ventricular de- and repolarization (QTc) duration. Treatment with MTX resulted in a significant reduction in atrial depolarization (P amplitude) and rapid repolarization (T amplitude) and a significant elevation in plateau phase (ST height). MTX treatment resulted in swelling of cardiomyocytes with extensive vacuolization of sarcoplasm with numerous variably sized vacuoles in addition to apoptotic cells. Tau and EMIQ protected against MTX-induced deteriorations in the conductivity and rhythmicity of the heart through antioxidative, anti-inflammatory, and antiapoptotic activities. Treatment with tau and EMIQ combined at high or low doses offered superior protection to the heart than using each agent alone.

Multiple-signal-joint-processing-based guard interval shortening method for a CS-NFDM system.

Aiming to further improve the spectral efficiency (SE) of a continuous spectrum modulated nonlinear frequency division multiplexing (CS-NFDM) system, we propose a novel ,to the best of our knowledge, multiple-signal-joint-processing (MSJP)-based guard interval (GI) shortening method. In this method, multiple NFDM time-domain signals are jointly processed as a whole to carry out nonlinear Fourier transform and inverse nonlinear Fourier transform (NFT-INFT) operations. These operations can fuse the multiple NFDM time-domain signals together, which is equivalent to the corresponding inverse process of a fiber transmission. Experimental results show that the normalized SE of the proposed method can reach 0.99 when approaching the limit value of 1 and obtain a 2.33 dB Q2-factor improvement compared with the pre-dispersion compensation (PDC) method under the same GI of 0.03 ns in an 80 km SSMF transmission of a 46 GHz signal bandwidth. Furthermore, in comparison with the PDC method, the proposed method can achieve 32.86% normalized SE improvement in the 1120 km SSMF transmission of 32 GHz signal bandwidth under the SD-FEC of 2.4E-2.

The Potential of Insulin Therapy in Improving Cardiovascular and Pulmonary Health for Diabetic Patients

Aims: This study aimed to investigate the effects of diabetes on cardiac contractile proteins and assess the potential reversibility of these effects through insulin therapy, with a specific focus on the interconnectedness of cardiovascular and pulmonary health. Methods: A prospective 9-month study involving 150 adults categorized into three groups, including diabetic individuals without insulin treatment, those with insulin treatment, and a control group. Comprehensive baseline assessments were conducted, and various measurements, including cardiac contractile proteins, glycemic control, heart function, and pulmonary health, were analyzed at regular intervals. Statistical analyses encompassed paired and independent t-tests, ANOVA, and regression analysis, utilizing SPSS software (version 23) with a significance threshold of p &lt; 0.05. Results: Both diabetic groups demonstrated improved glycemic control, with the Diabetic Insulin Group (DIG) experiencing a reduction in HbA1c levels from 8.3% to 7.9% and the Diabetic Group (DG) displaying a decrease in fasting blood glucose levels from 166.2 mg/dL to 158.4 mg/dL. DG showed enhanced ejection fraction, suggesting improved cardiac function, and a minor shortening of the QTc interval, indicating better electrical cardiac stability, potentially linked to enhanced pulmonary function. A noteworthy increase in actin levels was observed in DIG, signifying a potential reversal of cardiac protein changes with potential implications for pulmonary health. Conclusion: This study underscores the significance of effective glycemic control and the potential of insulin therapy in preserving or restoring heart function in individuals with diabetes, emphasizing the need for comprehensive diabetes management in addressing and preventing cardiac issues. Pulmonary function tests indicated minimal changes in pulmonary health within the study's timeframe, suggesting limited impact during this period.

Ventricular pre-excitation in an elderly cat

An 18-year-old female neutered Domestic Shorthair cat was referred for investigation of seizure-like episodes. Physical and neurological examination were unremarkable, as were systemic arterial blood pressure, cardiac troponin I, complete blood count and biochemistry profile. Diagnostic tests included transthoracic echocardiography which ruled out any structural cardiomyopathy, and electrocardiography which showed an underlying regular wide QRS-complex rhythm with pronounced shortening of the PR interval. Considering the findings, a diagnosis of suspected ventricular pre-excitation secondary to an accessory pathway was made. Further investigations were declined and, as no periods of tachycardia were seen on the five-minute electrocardiogram, no antiarrhythmic treatment was started.

Short-Term Real-World Outcomes of Intensive Aflibercept Injection for Refractory Neovascular Age-Related Macular Degeneration.

Background: The aim of this study is to report short-term outcomes after the shortening of the treatment interval to 4 weeks with a treat-and-extend (TAE) regimen (Si4w) of aflibercept in patients with refractory neovascular age-related macular degeneration (nAMD). Methods: This retrospective study included 34 patients given aflibercept with a TAE regimen of a minimum of a 4-week interval when they had a limited response to bimonthly aflibercept. The best-corrected visual acuity (BCVA) and central macular thickness (CMT) were compared before and after Si4w. The resolution of subretinal and intraretinal fluid before and after Si4w was also examined. The risk factors associated with persistent fluid were analyzed. Results: The average treatment duration until initiation of Si4w was 57.82 ± 28.59 months, with an average of 23.64 ± 12.40 injections administered. The BCVA was not significantly improved after Si4w. The CMT decreased significantly from 427.91 ± 125.74 μm to 336.38 ± 121.67 μm at the third visit (p < 0.001). Eighteen eyes (52.9%) showed complete resolution, and twenty-three eyes (67.6%) experienced complete resolution at least once during the three visits. The duration of fluid before Si4w was significantly associated with complete resolution (p = 0.011). Conclusions: Si4w of aflibercept showed satisfactory anatomical outcomes with complete resolution of fluid in patients with a limited response to bimonthly aflibercept injections, and should be considered as a useful treatment option.

Electrocontractile remodeling of isolated cardiomyocytes induced during early-stage hypercholesterolemia.

Hypercholesterolemia is one of the most important risk factors for cardiovascular diseases. However, it is mostly associated with vascular dysfunction and atherosclerotic lesions, while evidence of direct effects of hypercholesterolemia on cardiomyocytes and heart function is still incomplete and controversial. In this study, we assessed the direct effects of hypercholesterolemia on heart function and the electro-contractile properties of isolated cardiomyocytes. After 5 weeks, male Swiss mice fed with AIN-93 diet added with 1.25% cholesterol (CHO), developed an increase in total serum cholesterol levels and cardiomyocytes cholesterol content. These changes led to altered electrocardiographic records, with a shortening of the QT interval. Isolated cardiomyocytes displayed a shortening of the action potential duration with increased rate of depolarization, which was explained by increased IK, reduced ICa.L and altered INa voltage-dependent inactivation. Also, reduced diastolic [Ca2+]i was found with preserved adrenergic response and cellular contraction function. However, contraction of isolated hearts is impaired in isolated CHO hearts, before and after ischemia/reperfusion, although CHO heart was less susceptible to arrhythmic contractions. Overall, our results demonstrate that early hypercholesterolemia-driven increase in cellular cholesterol content is associated with direct modulation of the heart and cardiomyocytes' excitability, Ca2+ handling, and contraction.

Incubation Period and Serial Interval of Mpox in 2022 Global Outbreak Compared with Historical Estimates.

Understanding changes in the transmission dynamics of mpox requires comparing recent estimates of key epidemiologic parameters with historical data. We derived historical estimates for the incubation period and serial interval for mpox and contrasted them with pooled estimates from the 2022 outbreak. Our findings show the pooled mean infection-to-onset incubation period was 8.1 days for the 2022 outbreak and 8.2 days historically, indicating the incubation periods remained relatively consistent over time, despite a shift in the major mode of transmission. However, we estimated the onset-to-onset serial interval at 8.7 days using 2022 data, compared with 14.2 days using historical data. Although the reason for this shortening of the serial interval is unclear, it may be because of increased public health interventions or a shift in the mode of transmission. Recognizing such temporal shifts is essential for informed response strategies, and public health measures remain crucial for controlling mpox and similar future outbreaks.

Handgrip strength test for the diagnosis of long QT syndrome

Long QT syndrome (LQTS) assessment is based on the QT/ÖRR equation (the so-called Bazett's formula) and calculating the corrected QT (QTc). However, this formula reliably estimates the QT interval in the heart rate range (HR) of 60-90 bpm, which makes it difficult to diagnose LQTS in patients with sinus bradycardia, typical of this disease.Aim. To improve the LQTS diagnosis in patients with sinus bradycardia using the handgrip strength test.Material and methods. A total of 188 patients aged 5-53 years (16 [13;17]) were examined: group I — 40 healthy children aged 9-17 years (14 [12;16]); group II — 98 athletes with sinus bradycardia &lt;60 bpm aged 16 [16;17] years; group III — 50 patients with LQTS aged 5-53 years (12 [10;16]). The handgrip strength test consisted of regular rhythmic compression of a hand expander with a resistance of 20 kg until the heart rate increased &gt;60 bpm. The patients had an electrocardiogram recorded twice before and after the handgrip test. Heart rate, QT and QTc intervals were analyzed.Results. In all groups, after using the expander, there was a significant increase in heart rate, QT interval shortening and QTc interval prolongation. QTc interval prolongation after the handgrip test &gt;460 ms was a highly sensitive marker of LQTS (Se 96%, Sp 60%).Conclusion. Proposed handgrip test for sinus bradycardia makes it possible to increase heart rate, which ensures a more correct use of the Bazett's formula for assessing the corrected QT interval (QTc). QTc interval prolongation over 460 ms after the handgrip test is a highly sensitive additional marker for identifying patients with LQTS.

1,4-Disubstituted Piperazin-2-Ones as Selective Late Sodium Current Inhibitors with QT Interval Shortening Properties in Isolated Rabbit Hearts.

Late sodium current (INa) inhibitors are a new subclass of antiarrhythmic agents. To overcome the drawbacks, e.g., low efficacy and inhibition effect on K+ current, of the FDA-approved late INa inhibitor ranolazine, chain amide 6a-6q, 1,4-disubstituted piperazin-2-ones 7a-7s, and their derivatives 8a-8n were successively designed, synthesized, and evaluated in vitro on the NaV1.5-transfected HEK293T cells by the whole-cell patch clamp recording assay at the concentration of 40 μM. Among the new skeleton compounds, 7d showed the highest efficacy (IC50 = 2.7 μM) and good selectivity (peak/late ratio >30 folds), as well as excellent pharmacokinetics properties in mice (T1/2 of 3.5 h, F = 90%, 3 mg/kg, po). It exhibited low hERG inhibition and was able to reverse the ATX-II-induced augmentation of late INa phenotype of LQT3 model in isolated rabbit hearts. These results suggest the application potentials of 7d in the treatments of arrhythmias related to the enhancement of late INa.

Antarctic station Vostok as an analogue of a future lunar base: physiological reactions of the human cardiorespiratory system during a year-long exposure to the conditions of hypobaric hypoxia, isolation and hypokinesia

A number of physiological investigations focused on human cardiorespiratory system have been conducted at Vostok station in Central Antarctica during the wintering of 2019.During the one-year expedition at the Vostok station, the cardiorespiratory system gradually adapted to the unusual conditions of life and work in the isolated, confined and extreme (ICE) environment of Central Antarctica.We hypothesized that during a long stay in the conditions of the Central Antarctica the adaptation strategy to physical environmental conditions for representatives of two age groups will differ, which will be evident from the dynamics of indicators of the functioning of the cardiovascular system and when assessing the autonomic nervous system status.The level of blood oxygen saturation stabilized by the second month and was in the range of 86.0-91.0%, which corresponded to a reduced partial pressure of oxygen in the inhaled air. In terms of the respiratory system, central sleep apnea was noted in all subjects throughout the study. Quantitative analysis revealed that the average number of apneas per hour was 43, and their average duration was 25.2 seconds. The maximum apnea number was recorded at the beginning and middle of wintering, while before the end of the expedition the episodes became rarer. In all age groups there was a shortening of the PQ interval, with a tendency towards normalization by the end of wintering, while in the first age group the shortening of the interval was more significant than in the second, which apparently can be explained by a more pronounced active reaction of the sympathetic nervous system of polar explorers of the first age group.Adaptive Potential Index (API) level remained practically unchanged throughout the wintering period in 9 out of 11 members of the expedition. The API value was predominantly in the range from 2.11 to 3.20 points, which corresponds to the level of “adaptation stress”. The autonomous nervous system (ANS) status was assessed by Kerdo Index (KI) values. KI positive dynamic was noted in 90% of cases by the 5th month of wintering. A direct correlation was found between the degree of positive shift in the KI value and the age of the participant. The gained results do not allow us to state that ANS has fully adapted to the conditions of life and work at the station. The results of this investigation demonstrate stable and positive adaptation trend to the ICE environment of Central Antarctica throughout the study period, regardless of age and wintering experience.

Anti-VEGF Treatment for Secondary Neovascularization in Pseudoxanthoma Elasticum - Age of Onset, Treatment Frequency, and Visual Outcome

PurposeTo assess the onset, treatment frequency, and visual outcome of anti-vascular endothelial growth factor (anti-VEGF) treatment due to secondary choroidal neovascularization (CNV) in patients with pseudoxanthoma elasticum (PXE). DesignRetrospective cohort study MethodsOne-hundred six eyes of 53 patients with PXE were analyzed. The assessment of CNV activity relied on hemorrhage visible on funduscopy and intra- / subretinal fluid on optical coherence tomography (OCT), individually defining a shortening or extension of treatment interval. Best-corrected visual acuity (BCVA) at baseline, age at anti-VEGF therapy initiation, and BCVA-drop events at exudation onset (worsening of BCVA of 2 or more lines) were documented. Further, we assessed the number of injections during the first year and the total number of injections, the time to treatment initiation of the fellow eye, and BCVA over time. ResultsDuring a median observation period of 77 months (IQR 49; 126) patients received a median number of 28.0 anti VEGF-injections (IQR 9.8; 43.5). Eight patients received no injection (median age at baseline 38.1 years), 11 patients underwent anti-VEGF treatment in one eye (median age 47.2 years) and 34 patients in both eyes (median age 51.8 years). The median age at the first anti-VEGF treatment was 52.80 years (IQR 47.2 – 57.6). Applying Cox regression models, the median 'survival' time of fellow eye until treatment initiation was 16.8 months. In the group of bilateral treated patients, the median time difference was 9.6 months (IQR 2.1 – 32.4, range 0 – 122) The median number of injections was 5.5 per eye in the first year of treatment (IQR 3 – 7) and was associated with the total number of injections in the observation period (2.33, CI 1.22 – 3.44, p<0.001). A better BCVA at the last follow-up visit was associated with a better baseline BCVA (p<0.001, R2=0.318) and with the absence of a BCVA drop at the onset of exudation (p=0.035, R2=0.339). ConclusionsThe results of this study indicate that anti-VEGF treatment is required for most PXE patients at a relatively young age. Once treatment in one eye is initiated, the time to fellow eye treatment is relatively short. A BCVA drop before treatment initiation is a risk factor for worse visual outcomes, suggesting that treatment is prudent before exudation affects the central retina. Given the young age of onset and intensive treatment needs, patients with PXE might particularly benefit from longer-acting anti-VEGF therapeutics.

A257 EARLY PROACTIVE THERAPEUTIC DRUG MONITORING WITH USTEKINUMAB THERAPY IN PAEDIATRIC CROHN’S DISEASE

Abstract Background Ustekinumab (UST) is an effective therapy for adults with moderate to severe Crohn’s disease (CD), but data concerning optimal dosing in children are sparse. Aims To examine real-world post-induction PK and efficacy in a prospective multicentre cohort study of paediatric CD (Canadian Children IBD Network (CIDsCaNN)). Methods Children 2-17 years-old with CD were eligible for this analysis if they received IV UST for treatment of luminal CD and had serum UST levels measured at week 8. Median with interquartile range (IQR) UST dose and serum trough levels at weeks 8 and 16 were compared between children ampersand:003C40 kg and ≥40 kg with Mann-Whitney U test. Clinical remission was defined as weighted Pediatric CD Activity Index (wPCDAI) ampersand:003C12.5. UST durability was compared between those with a week 8 serum UST level ampersand:003C5 versus ≥5 µg/mL (log-rank p-value). Results Between 21/04/2017 and 30/04/2023, 39 children were eligible (74% M; median age 13.5 (IQR 11.9-15.6) y; median weight 44.7 (IQR 30.4-55.0) kg, 12 children ampersand:003C40 kg; 84% bio-naïve). Median disease duration at UST start was 4 (IQR 1-17) months; CD location distal ileal ± limited cecal (18%), colonic (26%), ileocolonic (54%). Median follow-up duration was 10.0 (IQR 6.7-12.7) months. All children received UST IV induction (67% 260 mg, 18% 390 mg) followed by 90 mg SC every 8 weeks. Induction doses in mg per kg were higher in those ampersand:003C40 kg (median 9.11 (IQR 8.68-10.08)) compared to those ≥40 kg (5.77 (IQR 5.24-6.45) mg/kg), pampersand:003C0.001. Induction doses in mg per body surface area (BSA) in m2 were similarly higher in those ampersand:003C40 kg (median 251.66 (IQR 244.16-258.99) versus 195.15 (IQR 172.71-224.11) mg/m2, pampersand:003C0.001). Despite higher induction doses, week 8 trough levels were numerically lower in those ampersand:003C40 kg (median 4.32 (IQR 1.33-8.36) versus 6.96 (IQR 5.38-8.90) µg/mL, p=0.29). Week 16 serum UST levels were also numerically lower in ampersand:003C40 kg versus ≥40 kg (median 4.04 (IQR 1.92-6.98) versus 5.50 (IQR 3.17-8.27) µg/mL, p=0.57). Interval shortening during maintenance to every 4 weeks occurred in 7 children prior to week 16, and in 14 children prior to 6 months. By 4 months, 19 of 33 children with available data (56%) achieved clinical remission. Overall, 8/39 (21%) ceased UST. Those who discontinued UST had significantly lower week 8 levels than those who continued UST (median 3.52 (IQR 1.19-6.12) versus 7.15 (IQR 5.09-10.15) µg/mL, p=0.027). In survival analysis, week 8 trough level ampersand:003C5 µg/mL was associated with an increased risk of UST discontinuation (log-rank p=0.032) (Figure 1). Conclusions Higher UST concentration at week 8 is associated with greater drug durability. A higher BSA-based induction for children ampersand:003C40 kg is supported by higher serum drug levels and improved drug durability. Figure 1. Ustekinumab durability by week 8 serum drug level Funding Agencies CIHR

Evaluation of axis straightness error in the machining of hole and shaft parts based on improved exponential distribution optimizer

The straightness error of hole and shaft parts is one of the important parameters to reflect machining quality. The modeling process of traditional mathematical methods is complex, and the solution precision is not high. The intelligent optimization algorithm has significant advantages in solving this kind of problem. It can depend on random operators jumping out of local optima and does not need to calculate a large gradient information. Therefore, this paper proposes an improved exponential distribution optimization (IEDO) algorithm to achieve the minimum zone evaluation of straightness error. Firstly, the mathematical model of minimum zone method for axis straightness evaluation is established as the objective function. Secondly, the principle of the basic exponential distribution optimization (EDO) algorithm is described, and the exponential distribution optimizer is improved in three aspects: in the initialization, the interval shortening strategy is introduced to solve the problem of uneven initial population distribution; the adaptive switch probability is proposed to replace the constant value (0.5) to balance the ability of global exploration and local exploitation; a guidance strategy based on weight is proposed to guide the search process to reach the global optimal quickly. Then, nine typical benchmark functions are utilized to test the performance of the improved algorithm, which reveals satisfactory results. Finally, IEDO successfully applies to evaluation of axis straightness error with good accuracy.

P512 Early proactive therapeutic drug monitoring with ustekinumab therapy in paediatric Crohn's Disease

Abstract Background In the treatment of paediatric Crohn’s disease (CD), the youngest (lightest) children have historically been underdosed by standard weight-based dosing. Paediatric data on optimal dosing and drug levels are sparse. We aimed to examine real-world post-induction pharmacokinetic and effectiveness in a prospective multicentre paediatric CD cohort. Methods Luminal CD patients 2-17 years old in the Canadian Children IBD Network were eligible if they received UST IV and had a serum UST level measured proactively at week (wk) 8. Wk8 and subsequent UST levels were compared between children &amp;lt;40 and ≥40 kg (Mann-Whitney-U), dosed in accordance with an ongoing phase 3 paediatric trial. We calculated a “dose to exposure ratio” by dividing induction dose by wk8 level. Clinical remission was defined as wPCDAI &amp;lt;12.5 while still on UST. We used ROC curves to define optimal (Youden index) wk8 levels associated with wk16 remission and subsequent UST continuation. Continuous measures are reported as median (IQR). Results 44 children were eligible from April 2017-April 2023 (70% M; age 13.1 (10.8-15.5) y; disease duration 0.3 (0.08-1.3) y; weight 44.7 (30.4-55.0) kg, 12 &amp;lt;40kg; 75% bio-naïve; L1 18%, L2 23%, L3 52%; SES-CD at diagnosis 17 (11-21)). At UST start, wPCDAI was 27.5 (10-52.5) and albumin was similar between weight groups (p=0.3). Median follow-up was 10 (7-13) months. 68% received 260 mg IV loading dose, 16% 390 mg. All received 90 mg SC q8 weekly maintenance. Induction doses in mg/kg and mg/m2 were significantly higher in children &amp;lt;40 kg (Table 1). Despite this, wk8 levels were similar between weight groups, with the same pattern at other times. The dose (mg/kg) to exposure ratio was 1.45x higher in children &amp;lt;40kg, indicating they received more drug per unit increase in serum UST level relative to heavier children. Interval shortening to q4wk occurred in 7 prior to wk16, and in 16 (36%) by 6 months. By wk16, 56% of patients with available wPCDAI were in clinical remission and 60% at 1 year. Overall, 7 (16%) ceased UST. Wk8 UST levels were numerically higher in those who achieved wk16 clinical remission (7.4 (6.2-10.2) vs. 5.5 (2.6-7.1), p=0.094), and numerically lower in those who ceased UST (4.9 (2.6-6.9) vs. 7.3 (5.4-10.7), p=0.087). Based on ROC, the optimal wk8 UST level associated with wk16 clinical remission was 5.8 (AUC 0.68, sensitivity 78%, specificity 57%). The optimal level associated with UST continuation was 7.9 (AUC 0.73, sensitivity 43%, specificity 100%, Figure 1). Conclusion Paediatric CD patients weighing &amp;lt;40kg required higher UST doses to achieve comparable drug exposure to those ≥40kg. Positive clinical outcomes were associated with higher UST levels (with optimal cut-offs 6-8). Figure 1

The Kir2.1E299V mutation increases atrial fibrillation vulnerability while protecting the ventricles against arrhythmias in a mouse model of short QT syndrome type 3.

Short QT syndrome type 3 (SQTS3) is a rare arrhythmogenic disease caused by gain-of-function mutations in KCNJ2, the gene coding the inward rectifier potassium channel Kir2.1. We used a multidisciplinary approach and investigated arrhythmogenic mechanisms in an in-vivo model of de-novo mutation Kir2.1E299V identified in a patient presenting an extremely abbreviated QT interval and paroxysmal atrial fibrillation. We used intravenous adeno-associated virus-mediated gene transfer to generate mouse models, and confirmed cardiac-specific expression of Kir2.1WT or Kir2.1E299V. On ECG, the Kir2.1E299V mouse recapitulated the QT interval shortening and the atrial-specific arrhythmia of the patient. The PR interval was also significantly shorter in Kir2.1E299V mice. Patch-clamping showed extremely abbreviated action potentials in both atrial and ventricular Kir2.1E299V cardiomyocytes due to a lack of inward-going rectification and increased IK1 at voltages positive to -80 mV. Relative to Kir2.1WT, atrial Kir2.1E299V cardiomyocytes had a significantly reduced slope conductance at voltages negative to -80 mV. After confirming a higher proportion of heterotetrameric Kir2.x channels containing Kir2.2 subunits in the atria, in-silico 3D simulations predicted an atrial-specific impairment of polyamine block and reduced pore diameter in the Kir2.1E299V-Kir2.2WT channel. In ventricular cardiomyocytes, the mutation increased excitability by shifting INa activation and inactivation in the hyperpolarizing direction, which protected the ventricle against arrhythmia. Moreover, Purkinje myocytes from Kir2.1E299V mice manifested substantially higher INa density than Kir2.1WT, explaining the abbreviation in the PR interval. The first in-vivo mouse model of cardiac-specific SQTS3 recapitulates the electrophysiological phenotype of a patient with the Kir2.1E299V mutation. Kir2.1E299V eliminates rectification in both cardiac chambers but protects against ventricular arrhythmias by increasing excitability in both Purkinje-fiber network and ventricles. Consequently, the predominant arrhythmias are supraventricular likely due to the lack of inward rectification and atrial-specific reduced pore diameter of the Kir2.1E299V-Kir2.2WT heterotetramer.

QT interval in children with orthostatic dysregulation: Changes in standing load.

The corrected QT interval (QTc) is affected by changes in autonomic sympathovagal modulation. The aim of this study was to determine whether children with orthostatic dysregulation (OD) have a longer QTc while standing than children without OD. We retrospectively assessed patients who underwent the Schellong test and electrocardiography between November 2016 and November 2019. Patients who met the criteria of OD subtypes according to the Japanese clinical guidelines for juvenile OD (version 1) were classified as OD positive (the OD-positive group), and patients who did not meet the criteria were classified as OD negative (the OD-negative group). There were 73 patients in the OD-positive group and 52 patients in the OD-negative group. Baseline heart rate, QT interval, and QTc were comparable between the OD-positive and OD-negative groups. Heart rate after standing was significantly higher in the OD-positive group than in the OD-negative group (median: 33 bpm vs. 21 bpm, p < 0.001). Further, shortening of QT interval after standing was greater in the OD-positive group than in the OD-negative group (median: 19 ms vs. 8 ms, p = 0.015). The QTc significantly increased from baseline to standing in both groups. Changes in the QT interval corrected by Bazett's formula were greater in the OD-positive group than in the OD-negative group (median: 73 ms vs. 42 ms, p < 0.001). The QTc increased significantly from baseline to standing in the OD-positive group. Thus, a high QTc while standing could be considered an auxiliary marker for OD diagnosis.

Cardiorhythm in postural changes depending on the autonomic centers reactivity

Postural changes are accompanied by the formation of an adaptive response of the cardiovascular system. This is manifested by a change in heart rate variability. The features of the reaction largely depend on the excitability (reactivity) of the vegetative centers. The aim of the study was to identify individual features of heart rate regulation in postural changes depending on the reactivity of sympathetic and parasympathetic autonomic centers in students. Material and Methods. In 50 men, temporal, frequency, geometric and calculated indicators of heart rate variability were determined in a horizontal position, with active orthostasis, passive orthostasis and passive antiorthostasis. The reactivity of the sympathetic system was assessed by the change of heart rate in active orthostasis. The reactivity of the parasympathetic system was determined by K30:15. Results and Discussion. With normal and high sympathetic reactivity, active orthostasis causes an increase in the low-frequency power of the spectrum, stress index, heart rate, a decrease in the high-frequency component and the duration of cardiac intervals. The changes are more pronounced with high sympathetic reactivity. In passive orthostasis, high sympathetic reactivity is manifested by a large increase in heart rate, shortening of cardiac intervals and a decrease in the proportion of the spectrogram high-frequency component. Passive antiorthostasis with normal sympathetic reactivity causes a decrease in the adequacy of the regulation processes and an expansion of the scatterogram. In subjects with high parasympathetic reactivity with active orthostasis, the increase in the stress index is less than with normal and low reactivity. With low parasympathetic reactivity, the indicator of the adequacy of the regulation processes is greater than with normal and high reactivity, and the increase in heart rate and shortening of the minimum cardiac interval is greater than with normal. In passive orthostasis, the proportion of the high-frequency component decreases, the proportion of the ultra-low-frequency component increases, the modal cardiointerval shortens, which is more pronounced with low parasympathetic reactivity than with normal. In passive antiorthostasis, the ultra-low frequency component decreases in individuals with normal reactivity. With high reactivity, the maximum value of the high-frequency component increases and the adequacy of the regulation processes decreases. Conclusion. Active and passive orthostasis is accompanied by activation of sympathetic centers. It is more pronounced with high reactivity of the sympathetic department and low reactivity of the parasympathetic. Passive antiorthostasis stimulates the activity of parasympathetic cardiac centers in subjects with normal, high parasympathetic reactivity and normal sympathetic reactivity.