Established Diagnosis Research Articles

The Importance of the Skin Syndrome in the Primary Diagnosis of Connective Tissue Diseases in Children: Case Report

Background. Timely verification of the clinical diagnosis of connective tissue diseases in children based on the onset of the earliest symptoms, including skin manifestations, and timely initiation of treatment can prevent the development of irreversible complications, increase the life expectancy of patients and its quality. The aim of the study. To analyze the nature of skin manifestations as a marker of the onset connective tissue disorders, such as systemic lupus erythematosus (SLE), localized scleroderma (morphea), juvenile dermatomyositis (JDM), juvenile polyarteritis nodosa (PAN), systemic juvenile idiopathic arthritis (SJIA), and the timing of the main clinical diagnosis from the moment of manifestation of connective tissue disorders. To clearly demonstrate the importance of skin syndrome in the timeliness of clinical diagnosis, a clinical case is presented. Methods. Analysis of medical records and prospective observation of 47 patients aged up to 17 years 11 months with an established diagnosis of connective tissue diseases and the presence of skin syndrome at the onset of the disease. Results. Among patients with SLE, only 20.0% of children had skin syndrome only in the form of butterfly rash, and other skin manifestations were noted in 80.0% of patients. The period from the onset of skin syndrome to diagnosis was 8.0 ± 2.1 months. In 57.2% of patients with morphea, skin syndrome was detected exclusively in the form of single or multiple elements, and in 42.8% there was a combination of a pathognomonic morphological element with alopecia and scleroderma. The average time to make a clinical diagnosis of morphea from the onset of the skin syndrome was 11.0 ± 1.9 months. In all patients with JDM, skin manifestations were characterized by polymorphism (papules and Gottron’s sign, heliotrope rash, palmar capillaritis, livedo reticularis, cheilitis). The diagnosis was made 14.0 ± 3.2 months from the onset of skin syndrome. In patients with documented PAN, skin manifestations debuted in the form of erythema, areas of necrosis, palmar capillaritis, livedo reticularis, and cheilitis. The period from the onset of skin syndrome to clinical diagnosis was 6.0 ± 2.4 months. Among patients with SJIA, skin syndrome was represented by a maculopapular rash associated with fever and its regression when body temperature normalized. The period until clinical diagnosis was made from the onset of the skin syndrome was 2.0 ± 1.1 months. Conclusion. In most cases, the skin syndrome in patients at the onset of the disease was characterized by polymorphism and diversity of elements with the involvement of the vascular component. At the same time, the time from the debut of connective tissue disease in the form of the appearance of skin syndrome to the clinical diagnosis varied in the range from 2 to 14 months.

Influenza and non-influenza ARVI in children. A relationship between cytokine profile, parameters of the “lipid peroxidation – antioxidant defense system” as well as clinical and laboratory indicators

Influenza and acute respiratory viral infections (ARVI) impose a substantial damage to the population health in the Russian Federation due to their seasonal circulation and predominantly affect young children. A very few data on the cytokine profile, the nonspecific LPO — AOD system and their relationships with clinical characteristics in such diseases in preschool children are available. The aim of this study was to assess the cytokine profile, LPO — AOD system parameters and their relationship with the clinical and laboratory characteristics of diseases in preschool children with influenza and other ARVI. 86 preschool children (3–6 years old) were examined: with an established diagnosis of influenza (n = 31), non-influenza ARVI (n = 28), apparently healthy children (control group (n = 27). All pediatric samples were analyzed by enzyme-linked immunosorbent assay assessing blood serum concentrations of C-reactive protein and cytokines IL-1β, IL-4, IL-6, IL-8, TNFα, IFNα, IFNγ. Spectrophotometric, fluorometric and enzyme immunoassay methods to assess the state of the “LPO — AOD” system were used. In the group of children with influenza vs other ARVI, a higher incidence of intoxication syndrome was revealed. Cytokine profile in children from both clinical groups compared with control cohort was featured with higher indicators of both pro-inflammatory and anti-inflammatory origin. Children with non-influenza ARVI, had increased magnitude of LPO final products in the nonspecific LPO — AOD system along with lowered concentration of fat-soluble vitamins, general antioxidant activity, GSH level, and SOD activity. In the group with influenza, the level of primary and final lipid peroxidation products was increased, whereas that of for retinol,α-tocopherol, and total antioxidant activity was decreased paralleled with higher GSSG and SOD levels. Numerous correlations were noted in the group of children with ARVI: IL-1β/ketones, IL-6/ketones, IL-8/ketones, TNFα/ketones, IL-4/ketones, IFNg/shortness of breath, IFNα/cough, double bonds/fever, double bonds/AST, SO/intoxication, retinol/fever, GSSG/cough. The influenza group differed in the following relationships: IL-4/ketones, IL-4/fever, IFNα/ketones, CDs/AST. It can be concluded that in preschool children with ARVI and influenza, changes in the cytokine profile are accompanied by increased pro- and anti-inflammatory cytokine levels, increased intensity of lipid peroxidation reactions along with reduced magnitude of antioxidant factors. In the group with ARVI, there was a relationship between the final toxic products of lipid peroxidation — Schiff bases — and the intoxication index, as well as the presence of protective mechanisms in the form of connections between interferons and disease clinical manifestations. The group with influenza was distinguished by the presence of protective relations, which may have a beneficial effect in the context of developing pathological process. The data obtained will help expand the understanding of the pathogenetic mechanisms related to immune reactivity and nonspecific lipid peroxidation reactions in preschool patients and formulate appropriate measures for correction.

Novel cardiovascular magnetic resonance imaging heterogeneity biomarkers to diagnose and predict cardiovascular disease: a UK Biobank CMR strain study

Abstract Background Myocardial strain evaluation on cardiovascular magnetic resonance imaging (CMR) shows significant promise to investigate cardiac function in vivo. There is concern that derived global longitudinal strain (GLS) and global circumferential strain (GCS) are less sensitive to early pathological cardiac remodelling, especially when regional. By quantifying contractile variability across the myocardium, the absolute longitudinal and circumferential strain coefficients of variation, |CoVLS| and |CoVCS| may facilitate earlier diagnosis and improved prognostication. Purpose We compared experimental heterogeneity biomarkers, |CoVLS| and |CoVCS|, to established global strain markers, GLS and GCS, to discriminate prevalent cardiovascular disease (CVD) and predict major adverse cardiovascular events (MACE). Methods Prevalent and incident CVD were defined among 44,955 participants from the UK Biobank (UKBB), who had feature-tracking (FT-CMR) derived strain markers. Prevalent CVD was the sum of established cardiovascular diagnoses at the time of baseline CMR, including hypertension, diabetes, atrial fibrillation, coronary artery disease, stroke and heart failure (HF). Incident CVD was newly identified MACE, including death from any cause, myocardial infarction, HF and stroke. Biomarkers were separately regressed against said endpoints, using ordinal logistic and Cox proportional hazards regression respectively. Statistical adjustment was performed for important baseline co-variables, including age, sex, ethnicity, smoking status, body mass index (BMI), low-density lipoprotein (LDL), left atrial volume, left ventricular mass and ejection fraction. Results Overall, 30,289 (67.4%) participants had no prevalent CVD, 10,362 (23.0%) had 1 CVD and 29 (0.06%) had ≥5 CVD. |CoVLS|, GLS, |CoVCS| and GCS were associated with a higher odds of prevalent CVD diagnoses (Figure 1). GLS had the greatest strength of association (OR 1.25, 95% CI 1.20-1.29), followed by |CoVCS| (OR 1.14, 95% CI 1.10-1.17). Over median 2.7 years (Q1-Q3 1.9-4.1 years), 966 (2.1%) participants experienced MACE, including 379 (0.8%) deaths, 263 (0.6%) MI, 246 (0.5%) HF, 237 (0.5%) stroke. |CoVLS|, |CoVCS| and GLS were comparable risk markers for MACE (Figure 2). The largest and smallest effect sizes were in predicting HF and death from any cause respectively. Conclusion Subclinical cardiac disease is often patchy, diffuse and regional; measures of heterogeneity may be more sensitive to these early pathological signals. We demonstrated that |CoVLS| and |CoVCS| are comparable to GLS and better than GCS in discriminating prevalent cardiac disease and predicting future cardiovascular events. These findings need to be replicated in other population studies and diseased cohorts.

Contemporary characteristics, outcomes and novel risk score for Takotsubo cardiomyopathy: a national inpatient sample analysis

Abstract Background Takotsubo cardiomyopathy (TC) is an established differential diagnosis in the category of myocardial infarction with non-obstructive coronaries with significant recent interest but limited data on prognostication. We reviewed the characteristics and in-hospital outcomes and developed a novel risk score for TC. Methods Adult patients (≥18 years of age) with a diagnosis of acute coronary syndrome (ACS) and TC were identified from the National Inpatient Sample 2016-2020 in the United States. The cohort was divided into ACS with and without TC, and the related baseline data was retrieved. Multivariable regression analysis was performed to identify clinical factors associated with TC and its adverse outcomes and to create a risk-scoring system estimating mortality risk in the TC cohort. Results Amongst 7,219,004 adult patients admitted for ACS, 78,214 (1.0%) were diagnosed with TC, with a mean age of 68.2 years, 64,526 (82.5%) being female, and 5,475 (7.0%, compared with 8.4% for other ACS) in-hospital mortality events. Key factors significantly associated with TC diagnosis were female sex (OR 6.78 (95%CI 6.47-7.09), p<0.001) and chronic heart failure (OR 1.60 (95%CI 1.54-1.66), p<0.001). Based on multivariable analyses for in-hospital mortality in TC patients, a novel risk score was developed, with parameters and score assignment listed in the Figure. The score can be divided into three categories: low risk (-3 to +3), moderate risk (4 to 7), and high risk (8 to 19), and its area under curves for in-hospital mortality were 0.716 in the derivation and 0.726 in the validation cohorts. Conclusion TC remains a high-risk diagnosis in a minority of ACS hospitalizations, with comparable in-hospital mortality rates to other causes of ACS. A novel score was developed to risk stratify TC inpatients with moderate discrimination and internal validation, warranting external validation.Takotsubo Cardiomyopathy Risk Score

Invasive quantitative assessment of coronary microvascular dysfunction in patients with hypertrophic cardiomyopathy

Abstract Background Patients (P) with hypertrophic cardiomyopathy (HCM) commonly suffer from coronary microvascular dysfunction (CMD) - the affection of function/structure of the coronary microvasculature. Invasive assessment of CMD through thermodilution methods allows for the calculation of coronary flow reserve (CFR) and index of microvascular resistance (IMR). These methods, while extensively studied in the context of non-obstructive coronary artery disease and myocardial infarction, have not been thoroughly validated in HCM P. Objectives To invasively assess the presence of CMD in P with HCM and to determine clinical predictors of invasively assessed CMD. Methods In a prospective single-centre study, we opportunistically recruited consecutive adult P with an established diagnosis of HCM with or without LVOTO that had an indication to pursue elective coronarography – such as pre-procedural evaluation for alcoholic septal ablation (ASA) or exclusion of epicardial coronary artery disease. P characteristics and coronary hemodynamic invasive assessment data were extracted. CFR was calculated as the ratio between resting and hyperemia mean transit times (TmnRest;TmnHyper). IMR was calculated as the ratio between distal coronary pressure (Pd) and the inverse of TmnHyper (IMR=Pd/TmnHyper-1). A cutoff of ≤22.0 in IMR, an ≥d 2 in CFR was used. We excluded P with end-stage HCM (LV EF <50% and/or or left ventricular wall thinning), or with epicardial coronary artery disease. Continuous variables were reported as mean ± SD or median and IQR depending on data distribution pattern and categorical data as frequencies and percentages. A linear regression model was used to test predictors of IMR and CFR involvement. Results 25 HCM P with a mean age of 63±10 years were included, 14 (56%) were female. In 20 (80%) of the P the cause for coronary angiography was ASA. All P referred for ASA had LVOTO and were on beta-blocker therapy (Table 1.). Median CFR was 2.5 [1.5-3] and median IMR was 19 [14-22], both within normal range. A total of 13 (44%) P had a reduced CFR and 5 (20%) of P had an increased IMR. 14 P (56%) had an altered CFR or IMR value, with the presence of a functional CMD phenotype in 10 P (40%) (Table 2). Angina was associated with a higher IMR (5.3, 95% CI - 0.05-10, p=0.053) and for each +1 increase in CCS a larger increase in the likelihood of a higher IMR was observed (CCS 1, +7 (95%CI 0.68 – 14); CCS 2, +9 (95%CI 4 – 14); CCS 3, 10 (95%CI 2 – 18)). A similar but non significant trend was observed for higher CCS correlating with lower CFR (Table 3). Conclusion In a prospective cohort of HCM P submited to invasive angiographic evaluation 56% had at least one invasive measure compatible with CMD. Angina, and a higher degree of anginal symptoms correlated positively with the presence of higher IMR and therefore with a higher level of CMD. In the future, we intend to correlate these findings with multimodality imaging/clinical outcomes.Patient characteristics and LR results

Left atrioventricular coupling index is an independent associate of new-onset AF and stroke in hypertrophic cardiomyopathy: a CMR study

Abstract Background Left atrial (LA) dysfunction is an important marker of disease progression in hypertrophic cardiomyopathy (HCM). LA volumes and functional parameters are associated with new-onset atrial fibrillation (AF) and its complications including stroke. The association between left atrioventricular coupling (LACI), a parameter reflecting the contribution of the left ventricular and LA remodeling to LA dysfunction, with the occurrence of new-onset AF and stroke has not been evaluated. Aim To investigate the association between LACI and the occurrence of new-onset AF or stroke in patients with HCM. Methods In patients with an established diagnosis of HCM and cardiac magnetic resonance (CMR) data, LACI was calculated as the ratio between the LA and the LV end-diastolic volumes. New-onset AF or occurrence of stroke comprised the primary combined endpoint. Cumulative event-free survival rates for the occurrence of the primary endpoint were estimated with the population divided according to a LACI cut-off value of 40%. The association between clinical and CMR variables and the primary endpoint was assessed with univariable and multivariable Cox proportional hazard regression models. Results Of 114 patients with HCM, (mean age 54±16 years, 33 (29%) female, LV ejection fraction 67.0±8.4%), 71 patients (49%) had a LACI > 40% (left atrioventricular uncoupling). During a median follow-up of 4.1 (1.8-6.4) years, 19 (16.7%) patients experienced new-onset AF or stroke. Patients with preserved left atrioventricular coupling (LACI ≤ 40%) had a lower cumulative rate of events compared to those with left atrioventricular uncoupling (log-rank p=0.031, Fig. 1). LACI was independently associated with new-onset AF or stroke after adjusting by the presence of late gadolinium enhancement (LGE) sex and age (HR=23.27, p=0.016). Conclusions In patients with HCM, the presence of left atrioventricular uncoupling is independently associated with the occurrence of new-onset AF or stroke.

Real-world eligibility for GLP1-ra therapy in a cohort of heart failure patients

Abstract Background GLP1-ra have demonstrated substantial cardiovascular (CV) benefits in diabetic and, more recently, non-diabetic patients, however their use in heart failure (HF) patients is still limited. Purpose To evaluate real-word eligibility to GLP1-ra in a cohort of HF patients. Methods Demographic and clinical data from HF patients evaluated at a single center HF unit from August 1st 2021 to November 29th 2023 were automatically retrieved from the electronic health record (EHR). Patients were deemed eligible to GLP1-ra based on (1) absence of ongoing treatment with GLP1-ra and (2) either having type 2 diabetes mellitus (T2DM) or satisfying the inclusion criteria of the SELECT trial or those of the STEP-HFpEF trial, which were adapted according to the available information. A sensitivity analysis lowering the body mass-index cut-off to >= 27 kg/m2 also for the STEP-HFpEF trial was performed. Results 1754 patients with an established diagnosis of HF were included; median age was 78.3 (IQR 70.7-83.8) years and 697 patients were female (39.7%). 6 patients had type 1 diabetes mellitus. Among the remaining 1749 patients, 633 (36.2%) patients had T2DM and 14 were already treated with GLP1-ra. Among 1116 patients without diabetes, 302 (27.1%) were eligible to receive GLP1-ra according to the inclusion criteria of the SELECT or STEP-HFpEF trials. 226 (20.2%) satisfied the SELECT trial inclusion criteria and among them 100 (44.8%) had HF with reduced ejection fraction, whereas 136 patients (12.2%) were eligible to receive GLP1-ra according to the STEP-HFpEF trial. Changing the BMI cut-off to >= 27 kg/mq, as in the SELECT trial, 219 patients (19.6%) according to the STEP-HFpEF inclusion criteria and 344 (30.8%) overall were found to be eligible for GLP1-ra therapy. Conclusion Real-word eligibility to GLP1-ra may reach up to 55% of HF patients according to diabetes status or trial inclusion criteria.

Пути оптимизации антропометрических параметров у детей с фармакорезистентной эпилепсией, получающих кетогенную диетотерапию

Ketogenic diet (KD) whilst being an effective method of diet therapy for drug-resistant epilepsy (DRE) is nevertheless accompanied by a significant number of side effects that include the possibility for the delayed physical development in pediatric patients. The problem is multifactorial and is primarily associated with the non-physiological nature of the ketogenic diet itself. Foreign studies on the KD effect on the physical development in children are contradictory and there are none domestic ones. The purpose of this research was to study the dynamics of anthropometric parameters in children with DRE against the background of KD and to assess the possibilities of the alimentary factor in its improvement. Materials and methods used: single-center retrospective cohort study had been carried out on the basis of the Russian Federal Research Centre for Nutrition, Biotechnology and Food Safety (Moscow, Russia) in 2016-2024. The study included patients with an established diagnosis of DRE against the background of KD aged 1 to 18 y/o. Patients were monitored for 24 months as follows: quarterly during the first year and semiannually during the second year of observation, using anthropometric, clinical-laboratory and clinical-instrumental research methods. Results: by the 3rd month of KD, out of 174 pediatric patients, the diet was effective in 105 (60%); by 12th month, 100% control over attacks was achieved in 11 (6%). Analysis of anthropometric parameters made it possible to establish that at the initial point of observation, in accordance with the z-score of the body mass index (BMI), 108 (64%) had normal nutritional status, 22 (13%) had malnutrition and 40 (24%) were overweight/obese. When studying the dynamics of weight and height indicators of children who were on KD throughout the observation period, it was found that the median BMI z-score statistically significantly changed upward (p=0.047), which was largely due to growth retardation, with a decrease in the height/age z-score throughout the observation period (p<0.001). It was found that the protein component of the diet, as well as the level of ketonemia, have a significant impact on the dynamics of the BMI z-score in KD patients. The amount of protein in the diet at 6% to 7% of the energy value contributed to the maintenance of optimal growth parameters in children within this research. Conclusion: the significance of the BMI indicator in assessing the nutritional status over KD decreases against the background of growth retardation. Taking into account the value of the protein/energy indicator when calculating nutrition helps in maintaining of the physical development rate in such patients.

The prevalence of multiple sclerosis in Israel based on validation of a health care organization database

In Israel there is no registry of multiple sclerosis (MS), thus the prevalence of MS is unknown. Clalit Health Services (CHS) is Israel’s largest health care organization. We have developed an algorithm to identify people with MS (PwMS) using CHS database and validated it against a gold-standard diagnosis by expert neurologists. People with a possible diagnosis of MS were identified in CHS database according to ICD-9 code or dispense of MS specific disease modifying treatment (DMT). The electronic medical records (EMRs) of a random sample of 25% of this population, stratified by age and sex were examined to determine positive predictive value (PPV). Another age- and sex- stratified random sample of 15% of pwMS under our care were searched in CHS database to determine database sensitivity (Sn). Finally, a random sample of 40% of people without MS were searched in CHS database to evaluate database specificity (Sp). The best case definition to retrieve pwMS was ICD-9 code 340 as an established diagnosis or at least one dispense of a DMT (PPV = 87%, Sn = 92%, Sp = 90%). Using this definition the prevalence of MS in Israel was 68, 82 and 95 per 100,000 population by the end of 2011, 2016 and 2021, respectively. The prevalence of MS in Israel is rising, in line with the worldwide trend.

Phenotype and Genotype of Children with ALS2 gene-Related Disorder.

The Alsin Rho Guanine Nucleotide Exchange Factor (ALS2) gene encodes a protein alsin that functions as a guanine nucleotide exchange factor. The variations in ALS2 gene leads to degeneration of upper motor neurons of the corticospinal tract. The phenotypes resulting from variants in ALS2 gene are infantile-onset ascending hereditary spastic paralysis (IAHSP, OMIM # 607225), juvenile primary lateral sclerosis (JPLS, OMIM # 606353), and juvenile amyotrophic lateral sclerosis (JALS, OMIM # 205100). Our study objectives were to describe the clinical phenotype and genotype of children with an established diagnosis of ALS2 gene-related disorder. The clinical details, laboratory data, and genotype findings of children with an established diagnosis of ALS2 gene-related disorder were collected from the hospital electronic database after obtaining institutional review board approval. One family with three affected siblings, a second family with a proband and an affected fetus, and a third family with two affected siblings with ALS2 gene variants were identified. IAHSP was diagnosed in all of our patients with variants in ALS2 gene. The clinical findings observed in our patients were insidious onset progressive spastic paraparesis, contractures, and dysarthria. Nonsense variants were observed in four patients while frameshift variant was observed in one family. Novel variants in ALS2 gene were identified in two unrelated families. ALS2 mutation results in rare neurodegenerative disorders with the clinical spectrum encompassing IAHSP, JPLS, and JALS disorders. In view of allelic heterogeneity described in the literature, more research studies are needed for establishing genotype-phenotype correlation in patients with ALS2 gene-related disorder.

An alternative instrumental method for studying the morphofunctional state of eyelids in chronic blepharitis

Background: To date, the assessment of morphofunctional changes within eyelids is performed using laser scanning confocal microscopy, which has extensive diagnostic capabilities. Identification of the indicators equivalence of this method and laser Doppler flowmetry will confirm the existence of an alternative, objective and economical method of eyelid examination in chronic blepharitis. Aim: To prove the possibility of laser Doppler flowmetry application as an alternative method of eyelid morphofunctional state assessment. Materials and methods: The study included 62 patients (124 eyes) with an established diagnosis of chronic mixed demodecticosis blepharitis, including 46 women and 16 men, mean age 65.8 ± 3.2 years, randomly assigned into two groups with identical age and gender composition. Group 1 patients (31 patients, 62 eyes) were treated with cosmeceuticals containing terpenes and terpenoids 2 times a day and tear substitute 3 times a day for 1.5 months. Group 2 patients (31 patients, 62 eyes) used an eyelid care gel containing sulphur medicaments 2 times a day and a tear substitute 3 times a day for 1.5 months. In addition to standard ophthalmological examination, laser Doppler flowmetry and laser scanning confocal microscopy were performed. Dynamic follow-up was performed after 1.5 and 3 months. Results: The analysis of laser scanning confocal microscopy and laser Doppler flowmetry parameters revealed a high inverse correlation between the density of inflammatory cells of the eyelids tarsal conjunctiva and neurogenic oscillations of blood flow, as well as high direct correlation with the index of blood flow shunting. A marked direct correlation between the density index of meibomian gland acinuses and the parameters of myogenic oscillations of blood flow and neurogenic oscillations of lymph flow was established. Conclusions: Pearson’s correlation analysis performed on laser scanning confocal microscopy and laser Doppler flowmetry parameters assessing the morphofunctional state of the eyelids demonstrated the presence of equivalence in both study groups with high statistical reliability. The obtained data confirm the possibility of using laser Doppler flowmetry method for objective assessment of eyelid condition and allow the parameters of this method to serve as criteria for choosing pathogenetically oriented therapy of chronic blepharitis with evaluation of its effectiveness.

7673 Genetic Analysis and Clinical Characterization of Patients with Congenital Hypopituitarism Due to Gene Defects

Abstract Disclosure: T.M. Sasson: None. I.J. Arnhold: None. B.B. Mendonca: None. L.R. Carvalho: None. Introduction: Congenital hypopituitarism is characterized by the deficiency of one or more hormones secreted by the anterior pituitary gland. The genetics of this pathology is complex, and the molecular diagnosis is established in approximately 13% of cases. Objectives: The aim of the present study is to characterize the phenotype harboring pathogenic variants causing congenital hypopituitarism. Methods: Among 393 subjects with congenital hypopituitarism followed up at a tertiary health center, 57 subjects (14,5%) were selected due to a confirmed molecular diagnosis by exome in 9 subjects or by gene panel or Sanger sequencing in 48 subjects. This was a retrospective study where data from medical records, clinical, laboratory and radiological characteristics were analyzed. Results: The most frequent variants identified by sequencing analyzes were in the following genes: PROP1 (29.8%), GH1 (22.8%), GHRHR (15.7%), followed by GLI2, OTX2, HESX1, POU1F1, TGIF1, GHRS, CDH2, SATB1, SOX3 e LZTR1. Consanguinity was reported in 50% of cases, and there was the presence of familial cases of short stature in 60%. The average age at the start of follow-up was 11.1 years (11 SD), 40% of them were male and 52.3% had physical stigmata typical of GH deficiency. Regarding hormonal deficiencies, 27 (47%) had isolated Growth Hormone Deficiency (DGHI) and the others, multiple deficiencies. MRI study of the pituitary gland showed some alteration in 66%, 54% of whom had adenohypophysis hypoplasia and 31% had an ectopic or non-visualized neurohypophysis. From 29 patients with IGF-1 levels available, 28 were below the reference range for sex and age. The serum GH peak after the stimulus test was on average 1.28 ng/mL (1.4SD), of these, only 4 cases had GH peak between 3.3 and 5.0 ng/mL and 1 patient with low IGF-1 and an ectopic neurohypophysis had GH peak of 6.0 ng/mL in a glucagon test. Regarding growth, the initial height in z-score was -4.8 and the average growth at the end of the first year of treatment was 10.7cm, with the average height after this period of Z-3.35. The average of final delta target height (final height Z-score minus the target height Z-score) of patients who underwent hormonal treatment was -0,53 (good response = delta <-1.5). Conclusion: In subjects with congenital hypopituitarism and an established molecular diagnosis, the most frequently affected genes were PROP1 and GH1, the great majority presented a stimulated GH peak < 3.3 ng/mL (only one patient had GH > 5), low basal serum IGF-1 and good increase in growth speed at the end of the first year of treatment with recovery of final height at the end of GH therapy. Presentation: 6/3/2024

7692 Morning Cortisol Levels In Patients With Established Primary Adrenal Insufficiency

Abstract Disclosure: A. Prete: Research Investigator; Self; Diurnal. V. Theiler-Schwetz: Research Investigator; Self; Diurnal. W. Arlt: Research Investigator; Self; Diurnal. I.O. Chifu: Research Investigator; Self; Diurnal. B. Harbeck: Research Investigator; Self; Diurnal. C. Napier: Research Investigator; Self; Diurnal. J.D. Newell-Price: Research Investigator; Self; Diurnal. A. Rees: Research Investigator; Self; Diurnal. N. Reisch: Research Investigator; Self; Diurnal. G.K. Stalla: Research Investigator; Self; Diurnal. N. Aslam: Employee; Self; Diurnal. H. Coope: Employee; Self; Diurnal. K. Maltby: Employee; Self; Diurnal. J. Porter: Employee; Self; Diurnal. J. Quirke: Employee; Self; Diurnal. R.J. Ross: Consulting Fee; Self; Diurnal. Background: Primary adrenal insufficiency (PAI) is rare: prevalence ∼100-140/million and incidence 4:1 000 000/year in Western societies [1]. The diagnosis of PAI is suggested by an early-morning cortisol <140 nmol/L (5 µg/dL) [1]. The commonest cause in adults is autoimmunity (∼90% in Western countries) and it is generally considered progressive once the diagnosis is made, although it has been reported that residual cortisol secretion is present in ∼30% of patients 2. We have developed a modified-release formulation of hydrocortisone to replace the physiological cortisol circadian rhythm and are undertaking a Double-Blind, Double-Dummy, Two-Way Cross-Over, Randomised, Phase II Study of Modified-Release Hydrocortisones: Chronocort® Versus Plenadren® in PAI. During recruitment, we were surprised by the number of patients who were ineligible as they had detectable morning cortisol levels. Methods: Main inclusion criteria: Participants with known PAI on stable glucocorticoid replacement therapy and an early morning pre-dose cortisol <50 nmol/L (1.8 µg/dl). Baseline serum cortisol was taken at ∼0700h and measured in a central laboratory by ADVIA Centaur® immunoassay with the lower limit of detection <14nmol/l (<0.5 µg/dL). Results: 86 patients with PAI (autoimmune aetiology in 71), median age 52 years (range 20-73), 60 female, were screened in 8 centres in UK and Germany. 18 (21%) patients were excluded from the study based on morning cortisol >50 nmol/L (1.8 µg/dL), and of those 68 patients who qualified on the main inclusion criteria 51 (59% of screened) had a cortisol <14 nmol/L (<0.5 µg/dL). Of the 18 patients (autoimmune aetiology in 10) excluded based on their morning cortisol level, 9 (50%) were female and 11 (13% of screened), had morning cortisol ≥140 nmol/L (5.0 µ/dL). 12 patients with morning cortisol of >50nmol/L (1.8 µ/dL) were retested and only 2 then qualified; their initial morning cortisol levels were 70 and 51 nmol/L. In patients retested the median difference between retest and the initial sample was 13 nmol/L (range 1-421 nmol/L). Conclusions: In patients with an established diagnosis of PAI, the majority had undetectable morning cortisol, but cortisol was detectable in 41% of patients and above 140 nmol/L in 13% confirming previous publications 2. Retesting patients with a cortisol >50nmol/L showed very similar results suggesting that the detectable cortisol was not an artefact and likely due to background cortisol secretion. 1. Bornstein SR, et al. J Clin Endocrinol Metab 2016;101:364-89.2.Pearce SHS, et al. European Journal of Endocrinology (2021) 184, R61–R67 Presentation: 6/1/2024

Comparative analysis of the structure of the heart and blood vessels surgeries, taking into account the clinical and functional status of patients with coronary heart disease in 2015 and 2020

Relevance. In a very short period of time, surgical treatment methods have become widespread due to the expansion of indicators for performing heart surgery in patients with severe complicated forms of coronary heart disease and the use of combined surgical operations.Aim: To study changes in the clinical and functional status of patients depending on the type of surgical intervention for coronary artery disease in different time periods in the gender aspect.Material and Methods. The study was conducted retrospectively. For comparative analysis, patients with an established diagnosis of coronary heart disease who underwent surgical treatment at the Federal Center for Cardiovascular Surgery of the of the Ministry of Healthcare of the Russian Federation (Chelyabinsk) in 2015 (n = 1017) and 2020 (n = 967) were included. Of the total number of patients in 2015, there were 771 (75.8%) men and 246 (24.2%) women, in 2020 718 (74.3%) and 249(25.7%), respectively.Results. In the structure of interventions performed, there is a decrease in the number of almost all types of surgical interventions for complications of myocardial infarction, most pronounced in relation to resection of the left ventricular aneurysm, reconstruction of the left ventricle and operations in combination with mitral valve replacement. In a large percentage of cases, patients with a history of risk factors for cardiovascular diseases are referred for coronary artery bypass surgery, regardless of gender. The majority of patients had angina pectoris of the 3rd–4th functional class. However, there is a trend towards a decrease in the proportion of people with post-infarction cardiosclerosis when referred for surgery.Conclusion. Despite the significant volume and availability of practical information, the number of patients with major cardiovascular risk factors is not decreasing.

The impact of chronic obstructive pulmonary disease on risk for complications after pancreatoduodenectomy - a single centre cohort study

BackgroundThe association between chronic obstructive pulmonary disease (COPD) and risk for postoperative complications after pancreatic surgery has not been clarified. The aim of this study was to investigate if COPD is associated with increased risk for postoperative complications after pancreatoduodenectomy. MethodsAll patients aged ≥18 years undergoing pancreatoduodenectomy from 2008 to 2019 at a high-volume tertiary centre for pancreatic cancer surgery were included. COPD was defined as an established diagnosis according to the International Statistical Classification of Diseases. The primary outcome was Clavien-Dindo-score (CD) ≥ IIIa. ResultsOut of 1009 available patients, 57 (5.6 %) had a diagnosis of COPD. There was no association between COPD and CD ≥ IIIa (25.5 % vs. 29.8 % p-value 0.471). COPD was associated with an increased risk for postoperative pancreatic fistula (odds ratio [OR] 3.06, 95 % confidence interval [CI] 1.62–5.89; p < 0.001). The 12 months mortality rate was higher among patients with COPD compared to patients without COPD, although not statistically significant (28.07 per cent vs., 18.17 per cent, p-value = 0.063). ConclusionCOPD was associated with increased risk for postoperative pancreatic fistula. These results imply that among patients deemed fit enough to undergo surgery, COPD should be thoroughly evaluated in the risk stratification.

Contemporary characteristics, outcomes and novel risk score for Takotsubo cardiomyopathy: a national inpatient sample analysis

BackgroundTakotsubo cardiomyopathy (TC) is an established differential diagnosis of myocardial infarction with non-obstructive coronaries with significant interest but limited data on prognostication. We reviewed the characteristics and in-hospital outcomes and...

Idiosyncratic Hepatocellular Drug-Induced Liver Injury by Flucloxacillin with Evidence Based on Roussel Uclaf Causality Assessment Method and HLA B*57:01 Genotype: From Metabolic CYP 3A4/3A7 to Immune Mechanisms.

Idiosyncratic drug-induced liver injury (iDILI) by flucloxacillin presents as both cholestatic and hepatocellular injury. Its mechanistic steps are explored in the present analysis as limited data exist on the cascade of events leading to iDILI in patients with an established diagnosis assessed for causality by the Roussel Uclaf Causality Assessment Method (RUCAM). Studies with human liver microsomes showed that flucloxacillin is a substrate of cytochrome P450 (CYP) with ist preferred isoforms CYP 3A4/3A7 that toxified flucloxacillin toward 5'-hydroxymethylflucloxacillin, which was cytotoxic to human biliary epithelial cell cultures, simulating human cholestatic injury. This provided evidence for a restricted role of the metabolic CYP-dependent hypothesis. In contrast, 5'-hydroxymethylflucloxacillin generated metabolically via CYP 3A4/3A7 was not cytotoxic to human hepatocytes due to missing genetic host features and a lack of non-parenchymal cells, including immune cells, which commonly surround the hepatocytes in the intact liver in abundance. This indicated a mechanistic gap regarding the clinical hepatocellular iDILI, now closed by additional studies and clinical evidence based on HLA B*57:01-positive patients with iDILI by flucloxacillin and a verified diagnosis by the RUCAM. Naïve T-cells from volunteers expressing HLA B*57:01 activated by flucloxacillin when the drug antigen was presented by dendritic cells provided the immunological basis for hepatocellular iDILI caused by flucloxacillin. HLA B*57:01-restricted activation of drug-specific T-cells caused covalent binding of flucloxacillin to albumin acting as a hapten. Following drug stimulation, T-cell clones expressing CCR4 and CCR9 migrated toward CCL17 and CCL25 and secreted interferon-γ and cytokines. In conclusion, cholestatic injury can be explained metabolically, while hepatocellular injury requires both metabolic and immune activation.

Permanent magnet synchronous motor demagnetization fault diagnosis based on PCA-ISSA-PNN

Aiming at the demagnetization fault problem of the permanent magnet synchronous motor (PMSM), a demagnetization fault diagnosis method based on the combination of the principal component analysis (PCA) algorithm, the improved sparrow search algorithm (ISSA), and the probabilistic neural network (PNN) algorithm is proposed. First, the principal components of phase currents are extracted using PCA. Second, ISSA is used to optimize the smoothing coefficients of the PNN algorithm, and the optimized PNN algorithm is combined with PCA to obtain the PCA-ISSA-PNN fault diagnosis model. Finally, the established fault diagnosis model was tested using the current data collected from the experiments and compared with the fault diagnosis indexes and optimization performance of the conventional PNN, PCA-PNN, PCA-GA (genetic algorithm)-PNN, PCA-DA (dragonfly algorithm)-PNN, PCA-GTO (artificial gorilla troop optimizer)-PNN, PCA-AHA-PNN, and PCA-SSA-PNN. The test results show that the fault diagnosis accuracy of PCA-ISSA-PNN reaches 95.83%, and the fault diagnosis indexes are significantly higher than those of PNN, PCA-PNN, PCA-GA-PNN, and PCA-DA-PNN; its optimization performance is also significantly better than that of PCA-GTO-PNN, PCA-AHA-PNN, and PCA-SSA-PNN, which verifies the accuracy and efficiency of the proposed method.

Indirect bypass surgery as a line of management of pediatric moyamoya disease

Moyamoya disease (MMD) is a chronic, rare cerebrovascular disorder of unknown cause featured by extensive narrowing of the terminal internal carotid artery (ICA) and its main branches. As a compensatory mechanism, perforators dilate forming fragile collateral vessels that appear as an abnormal vascular network resembling ‘puff of smoke drifting in the air’ observed via angiography around stenotic area in the brain.Patients and methodsThe database of the current hospital was retrospectively studied. All patients with ischemic strokes owing to MMD treated with surgical revascularization between January 2015 and December 2022 were included. MMD was identified on catheter-based digital subtraction angiography (DSA) by the presence of stenosis at the terminal portions of both internal carotid arteries and the development of abnormal collateral “moyamoya vessels” around the base of the brain. Clinical, radiological and follow-up data were retrospectively analyzed.ResultsDuring the mentioned time window, nine patients were diagnosed with moyamoya disease among all pediatric patients with established diagnosis of ischemic stroke in our institute; six of them underwent surgery. Unilateral EDMS was performed in 5 cases (83.3%), while one patient (16.67%) underwent staged bilateral surgeries with no added neurological deficit.ConclusionIndirect revascularization surgery for pediatric moyamoya-related stroke patients has high rates of reperfusion and promising outcomes.

Role of right ventricular–pulmonary arterial coupling assessed by echocardiography to predict adverse outcomes in patients with acute pulmonary embolism

BackgroundPulmonary embolism (PE) is a lethal type of venous thromboembolic disease. Right ventricular (RV) failure is not an uncommon complication of PE leading to higher adverse outcomes. The tricuspid annular peak systolic excursion/pulmonary artery systolic pressure (TAPSE/PASP) ratio as a surrogate for RV–pulmonary artery coupling has proven to be among the predictor of clinical outcomes in multiple patient groups. We evaluated in this study the role of TAPSE/PASP ratio in predicting adverse clinical outcomes in patients with acute PE.ResultsAmong patients with established diagnosis of acute PE admitted to the coronary care unit, echocardiography was done within 12 h of admission and TAPSE/PASP ratio was calculated. The patients were followed during hospitalization and after discharge for 3 months for development of adverse outcomes including rehospitalization due to heart failure, recurrent PE and mortality. A total of fifty-five consecutive patients were recruited with mean age 58.3 ± 6.9 years and nearly equal male-to-female ratio. The mean ratio of TAPSE/PASP was 0.479 ± 0.206. In-hospital and 3-month follow-up showed that 10.9% needed rehospitalization with heart failure, 14.5% developed recurrent pulmonary embolism, and mortality was 9.1%. TAPSE/PASP ratio was significantly lower among the patients who developed adverse outcomes. TAPSE/PASP ratio was among the independent predictors of rehospitalization with heart failure, recurrent pulmonary embolism but not mortality at 3-month follow-up. TAPSE/PASP ratio predicted rehospitalization with heart failure at a cutoff point ≤ 0.325, with 100% sensitivity and 79.6% specificity, and predicted recurrent pulmonary embolism at a cutoff point ≤ 0.325, with 75% sensitivity and 78.7% specificity.ConclusionTAPSE/PASP ratio is a noninvasive tool that can predict the development of early adverse outcomes in patients with acute PE including rehospitalization with heart failure and recurrent pulmonary embolism.