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Nikoletta Rahel Czobor,1,2 Jean-Jacques Lehot,3,4 Eniko Holndonner-Kirst,1 Phillip J Tully,5 Janos Gal,6 Andrea Szekely6,7 1Medical Centre of Hungarian Defense Forces, Department of Anesthesiology and Intensive Care, Budapest, Hungary; 2Semmelweis University, School of Doctoral Studies, Budapest, Hungary; 3Claude-Bernard University, Health Services and Performance Research Lab (EA 7425 HESPER), Lyon, France; 4Hôpital Neurologique Pierre Wertheimer, Department of Neuroanesthesia and Intensive Care, Hospices Civils de Lyon, Lyon, France; 5University of Adelaide, Freemasons Foundation Centre for Men’s Health, Adelaide, Australia; 6Semmelweis University, Department of Anesthesiology and Intensive Care, Budapest, Hungary; 7Semmelweis University, Heart and Vascular Center of Városmajor, Budapest, HungaryCorrespondence: Andrea SzekelyDepartment of Anaesthesiology and Intensive Therapy, Semmelweis University, Üllői út 78, Budapest 1082, HungaryTel +36206632243Email andi_szekely@yahoo.comAbstract: Frailty is presumably associated with an elevated risk of postoperative mortality and adverse outcome in vascular surgery patients. The aim of our review was to identify possible methods for risk assessment and prehabilitation in order to improve recovery and postoperative outcome. The literature search was performed via PubMed, Embase, OvidSP, and the Cochrane Library. We collected papers published in peer-reviewed journals between 2001 and 2018. The selection criterion was the relationship between vascular surgery, frailty and postoperative outcome or mortality. A total number of 52 publications were included. Frailty increases the risk of non-home discharge independently of presence or absence of postoperative complications and it is related to a higher 30-day mortality and major morbidity. The modified Frailty Index showed significant association with elevated risk for post-interventional stroke, myocardial infarction, prolonged in-hospital stays and higher readmission rates. When adjusted for comorbidity and surgery type, frailty seems to impact medium-term survival (within 2 years). Preoperative physical exercising, avoidance of hypalbuminemia, psychological and cognitive training, maintenance of muscle strength, adequate perioperative nutrition, and management of smoking behaviours are leading to a reduced length of stay and a decreased incidence of readmission rate, thus improving the effectiveness of early rehabilitation. Pre-frailty is a dynamically changing state of the patient, capable of deteriorating or improving over time. With goal-directed preoperative interventions, the decline can be prevented.Keywords: preoperative risk assessment, postoperative outcome, patient management, prehabilitation

Purpose: Current clinical challenges in Hodgkin lymphoma (HL) include difficult-to-treat relapsed/refractory disease and considerable long-term toxicities of treatment. Since clinical risk factors lack discriminatory power, intensity of therapy is mainly based on tumor burden. Exploring HL genetics and tumor microenvironment (TME) might provide valuable insights for improved risk stratification., Materials and Methods: In this study, we applied circulating tumor DNA sequencing to 243 patients obtained from pivotal German Hodgkin Study Group trials to identify subtypes of HL. Independent validation of the subtypes was performed in 96 patients treated in the EuroNet-PHL-C2 study. Outcome differences of subtypes were assessed in an event-enriched clinical validation cohort comprising 72 patients from the HD21 trial, using a refined, validated, and clinically feasible assay., Results: We propose a biologic classification of HL consisting of three distinct subtypes: inflammatory immune escape HL is characterized by frequent copy-number variations including immune escape variants such as high-level amplifications of the PD-L1 locus and an inflammatory TME. Virally-driven HL is associated with Epstein-Barr virus and/or human herpesvirus 6 and an inflammatory TME with neutrophils and macrophages, while the tumor mutational burden (TMB) is low. Oncogene-driven HL is defined by a high TMB, recurrent mutations in oncogenic drivers such as TNFAIP3 , ITPKB , and SOCS1 , and a cold TME. A refined and validated assay version aiming at clinically feasible risk stratification showed significant progression-free survival differences between subtypes. In addition, assessment of minimal residual disease (MRD) allowed for the detection of patients at very high risk of relapse within the subtypes., Conclusion: We propose a clinically feasible, noninvasive method for individualized risk stratification and MRD monitoring in patients with HL on the basis of circulating tumor DNA sequencing.

The recent developments in intensive care have resulted in improved survival rates of patients treated with acute organ deficiency. As a consequence, the rate of those who survive the acute phase and subsequently require protracted organ support due to persisting organ dysfunction has been growing. Several survivors display chronic health status deterioration leading to prolonged rehabilitation or nursing, and repeated hospitalizations. The condition developed following the survival of the acute phase and requiring long-lasting intensive care is frequently termed as chronic critical illness (CCI). Several definitions exist, most of these are based on the number of ventilator days, or days of stay at the intensive care unit. Nevertheless, in spite of the initially heterogenous etiology of the acute illness, the complications associated with CCI, as well as the pathophysiological processes underlying these, are relatively uniform. This causes CCI to be a unique clinical syndrome characterized by the development of secondary infections, myopathy, central and peripheral neuropathy, and typical alterations of the hormonal and immune system functions. The outcome is heavily influenced by the frailty and comorbidities of the patient, in addition to the severity of the acute illness. The treatment of CCI patients presents a complicated task requiring multidisciplinary view and individualized therapeutic measures. Since the aging of the population and the continuously improving success rates in overcoming acute conditions also facilitate the development of CCI, the systematic overview of the underlying pathophysiological processes is pivotal for the optimization of the medical, nursing, social and economical burden presented by this syndrome. Orv Hetil. 2023; 164(18): 702-712.

Background: Pituitary dysfunction after brainstem death can cause various hormone deficiencies in potential heart donors. The aim of this study was to evaluate the relationship between hormone replacement therapy (HRT; including antidiuretic hormone analog, thyroid hormone, and methylprednisolone) in heart donors and the recipients' outcomes after heart transplantation (HTx)., Methods: We retrospectively analyzed HTxs performed between January 2012 and October 2018. Donor and recipient characteristics were retrieved with a focus on endocrine parameters and HRT. The primary outcome was primary graft dysfunction (PGD). Secondary outcomes were the 30-day and 2-year mortality of the recipients. Univariate and multivariate Cox regression analyses were applied., Results: The study included 297 HTxs. PGD occurred in 56 recipients (18.9%). In the multivariable Cox analysis, methylprednisolone and thyroxine treatment in donors were associated with a lower odds for PGD (odds ratio [OR], 0.43; 95% CI, 0.19-1.01; P = .052; and OR,: 0.34; 95% CI, 0.15-0.76; P = .009, respectively). In multivariate analysis, thyroxine treatment in donors was associated with a lower odds of PGD (OR, 0.38; 95% CI, 0.17-0.86; P = .020). Donor thyroxine supplementation also had a beneficial effect on recipients' 2-year survival (OR, 0.53; 95% CI, 0.29-0.96; P = .036)., Conclusions: Combined thyroxine and methylprednisolone treatment could be a protective factor against PGD. Thyroxine administration was associated with better 2-year survival in recipients., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: The frailty score has been developed to determine physiological functioning capacity. The aim of our research was to explore the relationship between frailty factors and mortality in cardiac surgery patients., Methods: Our research is an observational, single-center, prospective cohort study (registered on ClinicalTrials.gov: NCT02224222), and we studied 69 patients who underwent elective cardiac surgery between 2014 and 2017. Thirty days before the surgery, they completed a questionnaire that contained questions related to social support, self-reported life quality-happiness, cognitive functions, anxiety and depression. Demographic, anthropometric and medical data were widely collected. The Geriatric Nutritional Risk Index (GNRI) and the Comprehensive Geriatric Assessment (CGA)-based frailty index were calculated as a sum and the domains, respectively. Cox regression and the Kaplan-Meier tests were applied to analyze survival and relative risk. The primary outcome was mid-term mortality., Results: The patients' mean age was 65.43 years [standard deviation (SD): 9.81 years]. The median follow-up was 1,656 days of survival [interquartile range (IQR), 1,336-2,081 years], during this period 14 patients died. The median of EuroSCORE II was 1.56 (1.00-2.58) points. The median preoperative albumin level was 32.80 g/L (IQR, 29.9-35.8 g/L). Major adverse cardiovascular and cerebral events (MACCEs) occurred 7 times during follow-up. The nutrition score of the CGA was significantly associated with worse long-term survival [score; hazard ratio (HR): 5.35; 95% CI: 1.10-25.91, P=0.037]. After adjustment for EuroSCORE II and postoperative complications the noncardiovascular CGA score was associated with overall mortality [adjusted hazard ratio (AHR): 1.44, 95% CI: 1.02-2.04, P=0.036]. In the multivariable Cox regression, GNRI <91 showed an increased risk for mortality (AHR: 4.76, 95% CI: 1.52-14.92, P=0.007)., Conclusions: The CGA-based noncardiovascular score and nutritional status should be assessed before cardiac surgery prehabilitation and may help decrease long-term mortality.

Introduction: Veno-arterial extracorporeal membrane oxygenation is a valuable therapeutic approach in patients with severe heart failure due to different etiologies. Current prognosis with veno-arterial extracorporeal membrane oxygenation is unsatisfactory, and the risk stratification is still challenging. Therefore, we aimed to evaluate the predictive value of different baseline model for end-stage liver disease scores for survival in patients with veno-arterial extracorporeal membrane oxygenation., Methods: We conducted an observational, retrospective study of consecutive veno-arterial extracorporeal membrane oxygenation-treated patients between January 2012 and August 2018. The four types of model for end-stage liver disease scores-model for end-stage liver disease, international normalized ratio-excluded model for end-stage liver disease, modified model for end-stage liver disease, and model for end-stage liver disease with sodium-were calculated preoperatively. Veno-arterial extracorporeal membrane oxygenation was used based on the four clinical indications: primer graft failure after heart transplantation, weaning failure from cardiopulmonary bypass, acute myocardial infarction with refractory cardiogenic shock, and bridge to transplantation or bridge to candidacy. The primary endpoint of the study was overall mortality. The secondary endpoint was in-hospital mortality. We performed univariable and multivariable Cox regression analyses., Results: Data from 135 patients were analyzed. The median follow-up was 952 days (interquartile range = 417-1555 days). In-hospital mortality was 62.2%, and overall mortality was 71.1%. The multivariable Cox regression analysis is adjusted for indication, and the survival after veno-arterial extracorporeal membrane oxygenation score showed that the following scores were associated with overall mortality: model for end-stage liver disease (hazard ratio = 1.04; 95% confidence interval = 1.01-1.07; p  = 0.016), modified model for end-stage liver disease (hazard ratio = 1.04; 95% confidence interval = 1.01-1.06; p  = 0.006), and model for end-stage liver disease with sodium (hazard ratio = 1.05; 95% confidence interval = 1.02-1.08; p  = 0.001)., Conclusion: Model for end-stage liver disease, modified model for end-stage liver disease, and model for end-stage liver disease with sodium scores could be useful in the risk stratification of veno-arterial extracorporeal membrane oxygenation treatment in varying clinical indications.

Objectives: Thyroid dysfunction has been shown to be associated with increased all-cause mortality and severity of chronic heart failure in critical illness and severe cardiac diseases. The present study was conducted to ascertain the relationship between perioperative free triiodothyronine and free tetraiodothyronine (fT4) levels and postoperative adverse outcomes after heart transplantation (HTX)., Design: Retrospective, observational study., Setting: Single-center study in a quaternary care university clinical center., Participants: The study comprised adult patients who underwent HTX between 2015 and 2019 and had at least 1 perioperative thyroid hormone laboratory test on the day of surgery or in the 24 hours before/after the procedure (free triiodothyronine, fT4, and thyroid-stimulating hormone)., Interventions: No interventions were applied., Measurements and Main Results: The primary outcome was primary graft dysfunction (PGD), defined by the consensus conference of the International Society for Heart and Lung Transplantation. A total of 151 patients were included in the final analyses. Twenty-nine (19.2%) patients had PGD. Fourteen (9.3%) patients had low fT4 levels. An independent association was found between fT4 and PGD (odds ratio 6.49; 95% confidence interval 2.26-18.61; p = 0.001), with adjusted multivariate Cox regression models., Conclusion: The perioperative fT4 level could be a prognostic marker of adverse outcomes in HTX. The authors suggest appropriate perioperative monitoring of fT4 levels. Additional research is warranted to examine the optimal timing, dosage, and method of replacement., Competing Interests: Declaration of Competing Interest On behalf of all authors, the corresponding author states that there is no conflict of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: The effect of thyroid dysfunction on adverse outcomes has been studied in many different patient populations. The objective of this study was to investigate the effect of thyroid hormone supplementation of donors and recipients on postoperative outcomes after orthotopic heart transplantation., Design: Retrospective., Setting: Single center, university hospital., Participants: Two-hundred and sixty-six consecutive patients undergoing heart transplantation., Interventions: No interventions., Measurements and Main Results: Demographic, hemodynamic, and clinical characteristics; donor and recipient United Network for Organ Sharing scores; and information on thyroid hormone support of donors and recipients were recorded. During the median follow-up of 4.59 years (interquartile range 4.26-4.92 y), 70 patients (26.3%) died. After adjustments were made for the United Network for Organ Sharing score, recipients who were treated preoperatively with l-thyroxine had a lower risk for all-cause mortality (adjusted hazard ratio [HR] 0.24, 95% confidence interval [CI] 0.06-0.98; p = 0.047) compared with recipients who were not treated with l-thyroxine. In addition, l-thyroxine treatment of donors was associated with a better recipient survival (HR 0.31, 95% CI 0.11-0.87; p = 0.025)., Conclusions: Pretransplantation thyroid hormone supplementation of donors and recipients was associated with improved long-term survival after heart transplantation., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objective: Preoperative liver function in heart failure patients is associated with extensive functional, structural, and hemodynamic abnormalities. The authors hypothesized that perioperative liver dysfunction is associated with worse 2-year survival after orthotopic heart transplantation., Design: Retrospective study., Setting: Single-center, university hospital., Participants: The study comprised 209 consecutive patients undergoing heart transplantation., Interventions: No interventions., Measurements and Main Results: Hepatobiliary markers, hemodynamic parameters, echocardiographic parameters, the need for mechanical cardiac support, demographic parameters, and United Network for Organ Sharing and Model for End-Stage Liver Disease (MELD) scores were investigated. Fifty-five patients (26.3%) died, and the mean survival time was 3.61 years after transplantation. In multivariate Cox regression analysis, in addition to the preoperative modified MELD score, the 4th quartiles of the maximum aspartate transaminase (AST) and alanine transaminase levels on the 4th through 7th postoperative days were independently associated with mortality (odds ratio [OR] 2.46, 95% confidence interval [CI] 1.09-5.55; p = 0.031 and OR 2.41, 95% CI 1.13-5.18; p = 0.024, respectively). By expressing the transaminase values as the multiplier of the sex-specific top normal value, the maximum AST and alanine transaminase levels (OR 1.02, 95% CI 1.01-1.02; p < 0.001 and OR 1.02, 95% CI 1.01-1.03; p = 0.001, respectively) were linked to worse survival. Among the postdischarge parameters, the modified MELD score (OR 1.17, 95% CI 1.09-1.27; p < 0.001) and the AST level were associated with postdischarge mortality (OR 1.002, 95% CI 1.001-1.003; p < 0.001 as a continuous variable; OR 1.07, 95% CI 1.05-1.10; p < 0.001, expressed as the multiplier of the sex-specific normal value, respectively)., Conclusions: The severity of postoperative liver dysfunction negatively influences survival after heart transplantation, and liver function should be closely assessed in these patients., (Copyright © 2018. Published by Elsevier Inc.)

Autosomal recessive primary microcephaly (MCPH) is characterized by reduced head circumference (50% of all reported families. In spite of the high frequency of MCPH in Pakistan only one case of compound heterozygosity for mutations in ASPM has been reported yet. In this large MCPH study we ascertained 37 families including 319 persons (140 patients). Haplotype analysis of eight STS markers suggested linkage by homozygosity in 20 families, and re-analysis of single sib ships in the remaining families demonstrated possible compound heterozygosity in two families. Direct sequencing indeed confirmed compound heterozygosity in two and homozygous mutations in 20 families, respectively, showing that up to 10% of families with MCPH caused by ASPM are compound heterozygous. In total we identified 16 different nonsense or frameshift mutations of which 12 were novel thereby increasing the number of mutations in ASPM significantly from 35 to 47. We found no correlation between the severity of the condition and the site of truncation. We suggest that the high frequency of compound heterozygosity observed in this study is taken into consideration as part of future genetic testing and counseling in Pakistani MCPH families.

Noncompaction of the ventricular myocardium (NVM) is the morphological hallmark of a rare familial or sporadic unclassified heart disease of heterogeneous origin. NVM results presumably from a congenital developmental error and has been traced back to single point mutations in various genes. The objective of this study was to determine the underlying genetic defect in a large German family suffering from NVM. Twenty four family members were clinically assessed using advanced imaging techniques. For molecular characterization, a genome-wide linkage analysis was undertaken and the disease locus was mapped to chromosome 14ptel-14q12. Subsequently, two genes of the disease interval, MYH6 and MYH7 (encoding the alpha- and beta-myosin heavy chain, respectively) were sequenced, leading to the identification of a previously unknown de novo missense mutation, c.842G>C, in the gene MYH7. The mutation affects a highly conserved amino acid in the myosin subfragment-1 (R281T). In silico simulations suggest that the mutation R281T prevents the formation of a salt bridge between residues R281 and D325, thereby destabilizing the myosin head. The mutation was exclusively present in morphologically affected family members. A few members of the family displayed NVM in combination with other heart defects, such as dislocation of the tricuspid valve (Ebstein's anomaly, EA) and atrial septal defect (ASD). A high degree of clinical variability was observed, ranging from the absence of symptoms in childhood to cardiac death in the third decade of life. The data presented in this report provide first evidence that a mutation in a sarcomeric protein can cause noncompaction of the ventricular myocardium.

400 human milk, 280 cowmilk, 56 milkpowder and 305 butter samples were examined concerning there content of chloroorganic compounds. In human milk the highest concentration had DDE, followed by PCB, DDT and HCB, the lowest values were measured for HCH. Only total DDT in human milk but no compound in the milk product samples was above the maximal tolerated limit. There is a strong reduction in comparison to the values measured in 1979 (ten times for total HCH, one half for total DDT and to one sixth for HCB) but the PCB concentration didn't change.

Proper assessment of the risk to animal health in early lactation has proved to depend decisively on knowledge of intensity of mobilisation processes as well as of the onset and general pronunciation of subsequent regeneration of endogenic energy reserves. Mere calculation of the difference between estimated energy uptake via feed ration and energy output to sustain milk production would not provide a realistic picture of energy mobilisation and deposition in the organism of a dairy cow. Milk fat levels and quantities but also high milk protein levels and quantities were the milk substances which more clearly than others indicated mobilisation of endogenic fat and protein reserves during the first three weeks of lactation. No information could be derived from milk yield and milk substances as to the onset or level of positive energy balance, following redepositing of energy.

Reported in this paper are studies which had been conducted in to excretion through the milk of butonate, trichlorophone, DDVP, and vinylbutonate, following Pedix PE 50 treatment of lactating cattle. Pedix PE 50 with butonate as its active principle, is going to be used on lactating cattle for the control of parasites, after it had been applied with good success to other animal species. The amounts of organophosphorus insecticide detectable in the above experiments and related to one kilogram of milk were 0.079 mg in the first milked portion, 0.03 mg in the second, and 0.02 mg in the third. Hence, control of the first two milked portions appears to meet all demands emanating in terms of food hygiene, toxicology, and economy, provided that in applying Pedix PE 50 to lactating cattle due consideration is given to the concentration specified in the manufacturers' instructions for use as well as to the necessary time interval between treatment and first milking.

The organophosphorus insecticide naled (O,O-dimethyl-O,O-(1,2-dibromo-2,2-dichloroethyl)-phosphate, labeled by 32P] is degraded in milk in vitro at 5 degrees C with a half-life of 35 h with dichlorvos as a metabolite, that is also formed at short time heating and UV-irradiation. The recovery in milk powder is 25% (naled + dichlorvos) of the initial concentration. Following spray application of 0,05 mg naled/kg body mass to 2 lactating cows, 5-8 ppb of naled and 7-9 ppb of dichlorvos were found in the milk 5 h p.a., not exceeding the given tolerance level of 0,02 mg/kg in the German Democratic Republic.

The passage of iodine to milk after drug redisinfection with iodophores developed in the GDR and the Polish People's Republic has been studied by labelling these preparations with iodine-131. The iodine contents found in the milk lay below the internationally indicated limits of tolerance. Therefore, from the hygienic-toxicological point of view, the use of these iodophore variants might be considered safe, provided that they were employed properly.