Efficacy, tolerability and pharmacokinetics of survodutide, a glucagon/glucagon-like peptide-1 receptor dual agonist, in cirrhosis.

BACKGROUND & AIMS: Survodutide is a glucagon/glucagon-like peptide-1 receptor dual agonist in development for treatment of metabolic dysfunction-associated steatohepatitis (MASH). We investigated survodutide in people with cirrhosis. METHODS: This multinational, non-randomized, open-label, phase 1 clinical trial initially evaluated a single subcutaneous (s.c.) dose of survodutide 0.3 mg in people with Child-Pugh class A, B or C cirrhosis and healthy individuals with or without overweight/obesity matched for age, sex, and weight; the primary endpoints were the area under the plasma concentration-time curve from 0 to infinity (AUC0-∞) and maximal plasma concentration (Cmax). Subsequently, people with overweight/obesity with or without cirrhosis and Child-Pugh class A or B received once-weekly s.c. doses escalated from 0.3 mg to 6.0 mg over 24 weeks then maintained for 4 weeks; the primary endpoint was drug-related treatment-emergent adverse events, with MASH/cirrhosis-related endpoints explored. RESULTS: In the single-dose cohorts (n = 41), mean AUC0-∞ and Cmax were similar in those with cirrhosis compared with healthy individuals (90% confidence intervals for adjusted geometric mean ratios spanned 1). Drug-related adverse events occurred in 25.0% of healthy individuals and ≤25.0% of those with cirrhosis after single doses, and 82.4% and 87.5%, respectively, of the multiple-dose cohorts (n = 41) over 28 weeks. Liver fat content, liver stiffness, liver volume, body weight, and other hepatic and metabolic disease markers were generally reduced after 28 weeks of survodutide treatment. CONCLUSIONS: Survodutide is generally tolerable in people with compensated or decompensated cirrhosis, does not require pharmacokinetic-related dose adjustment, and may improve liver-related non-invasive tests, supporting its investigation for MASH-related cirrhosis. Clinical trial number; ClinicalTrials.gov identifier: NCT05296733. IMPACT AND IMPLICATIONS: Survodutide is a glucagon receptor/glucagon-like peptide-1 receptor dual agonist in development for treatment of metabolic dysfunction-associated steatohepatitis (MASH), which causes cirrhosis in ∼20% of cases. This trial delineates the pharmacokinetic and safety profile of survodutide in people with compensated or decompensated cirrhosis, and revealed associated reductions in liver fat content, markers of liver fibrosis and body weight. These findings have potential relevance for people with MASH-including those with decompensated cirrhosis, who are usually excluded from clinical trials of investigational drugs. Based on this study, further investigation of survodutide for MASH-related cirrhosis is warranted.

Can long-read sequencing tackle the barriers, which the next-generation could not? A review.

The large-scale heterogeneity of genetic diseases necessitated the deeper examination of nucleotide sequence alterations enhancing the discovery of new targeted drug attack points. The appearance of new sequencing techniques was essential to get more interpretable genomic data. In contrast to the previous short-reads, longer lengths can provide a better insight into the potential health threatening genetic abnormalities. Long-reads offer more accurate variant identification and genome assembly methods, indicating advances in nucleotide deflect-related studies. In this review, we introduce the historical background of sequencing technologies and show their benefits and limits, as well. Furthermore, we highlight the differences between short- and long-read approaches, including their unique advances and difficulties in methodologies and evaluation. Additionally, we provide a detailed description of the corresponding bioinformatics and the current applications.

Open-label extension of a randomized trial investigating safety and efficacy of rhPTH(1-84) in hypoparathyroidism.

Hypoparathyroidism (HypoPT) is a rare disease, often inadequately controlled by conventional treatment. PARALLAX was a mandatory post-marketing trial assessing pharmacokinetics and pharmacodynamics of different dosing regimens of recombinant human parathyroid hormone 1-84 (rhPTH[1-84]) for treating HypoPT. The present study (NCT03364738) was a phase 4, 1-yr open-label extension of PARALLAX. Patients received only 2 doses of rhPTH(1-84) in PARALLAX and were considered treatment-naive at the start of the current study. rhPTH(1-84) was initiated at 50 µg once daily, with doses adjusted based on albumin-corrected serum calcium levels. Albumin-corrected serum calcium (primary outcome measure), health-related quality of life (HRQoL), adverse events, and healthcare resource utilization (HCRU) were assessed. The mean age of the 22 patients included was 50.0 yr; 81.8% were women, and 90.9% were White. By the end of treatment (EOT), 95.5% of patients had albumin-corrected serum calcium values in the protocol-defined range of 1.88 mmol/L to the upper limit of normal. Serum phosphorus was within the healthy range, and albumin-corrected serum calcium-phosphorus product was below the upper healthy limit throughout, while mean 24-h urine calcium excretion decreased from baseline to EOT. Mean supplemental doses of calcium and active vitamin D were reduced from baseline to EOT (2402-855 mg/d and 0.8-0.2 µg/d, respectively). Mean serum bone turnover markers, bone-specific alkaline phosphatase, osteocalcin, procollagen type I N-terminal propeptide, and type I collagen C-telopeptide increased 2-5 fold from baseline to EOT. The HCRU, disease-related symptoms and impact on HRQoL improved numerically between baseline and EOT. Nine patients (40.9%) experienced treatment-related adverse events; no deaths were reported. Treatment with rhPTH(1-84) once daily for 1 yr improved HRQoL, maintained eucalcemia in 95% of patients, normalized serum phosphorus, and decreased urine calcium excretion. The effects observed on urine calcium and the safety profile are consistent with previous findings. Clinical trial identifier: NCT03364738.

Extracellular vesicles promote migration despite BRAF inhibitor treatment in malignant melanoma cells.

Extracellular vesicles (EVs) constitute a vital component of intercellular communication, exerting significant influence on metastasis formation and drug resistance mechanisms. Malignant melanoma (MM) is one of the deadliest forms of skin cancers, because of its high metastatic potential and often acquired resistance to oncotherapies. The prevalence of BRAF mutations in MM underscores the importance of BRAF-targeted therapies, such as vemurafenib and dabrafenib, alone or in combination with the MEK inhibitor, trametinib. This study aimed to elucidate the involvement of EVs in MM progression and ascertain whether EV-mediated metastasis promotion persists during single agent BRAF (vemurafenib, dabrafenib), or MEK (trametinib) and combined BRAF/MEK (dabrafenib/trametinib) inhibition.Using five pairs of syngeneic melanoma cell lines, we assessed the impact of EVs - isolated from their respective supernatants - on melanoma cell proliferation and migration. Cell viability and spheroid growth assays were employed to evaluate proliferation, while migration was analyzed through mean squared displacement (MSD) and total traveled distance (TTD) measurements derived from video microscopy and single-cell tracking.Our results indicate that while EV treatments had remarkable promoting effect on cell migration, they exerted only a modest effect on cell proliferation and spheroid growth. Notably, EVs demonstrated the ability to mitigate the inhibitory effects of BRAF inhibitors, albeit they were ineffective against a MEK inhibitor and the combination of BRAF/MEK inhibitors. In summary, our findings contribute to the understanding of the intricate role played by EVs in tumor progression, metastasis, and drug resistance in MM.

Analysis of SIRT1 Gene SNPs and Clinical Characteristics in Medication-Related Osteonecrosis of the Jaw.

Certain genetic factors, including single-nucleotide polymorphisms (SNPs) in the SIRT1 gene, have been linked to medication-related osteonecrosis of the jaw (MRONJ). This study examined four SNPs in the SIRT1 gene and implemented multivariate statistical analysis to analyze genetic and clinical factors in MRONJ patients. Genomic DNA was isolated from peripheral blood samples of 63 patients of European origin treated for MRONJ, and four SNP genotypes in the gene encoding the SIRT-1 protein were determined by Sanger sequencing. The allele frequencies measured in the MRONJ population were compared with allele frequencies measured in the European population in the National Center for Biotechnology Information Allele Frequency Aggregator (NCBI ALFA) database. Genetic and clinical factors were examined with multivariate statistical analysis. A C:A allele distribution ratio of 77.8:22.2 was measured in the rs932658 SNP. In the ALFA project, a C:A allele distribution ratio of 59.9:40.1 was detected in the European population, which was found to be a significant difference (p = 4.5 × 10-5). Multivariate statistical analysis revealed a positive correlation (0.275) between the genotype of SNP rs932658 and the number of stages improved during appropriate MRONJ therapy. It is concluded that allele A in SNP rs932658 in the SIRT1 gene acts as a protective factor in MRONJ.

Extracellular Vesicles of Patients on Peritoneal Dialysis Inhibit the TGF-ß- and PDGF-B-Mediated Fibrotic Processes.

Among patients on peritoneal dialysis (PD), 50-80% will develop peritoneal fibrosis, and 0.5-4.4% will develop life-threatening encapsulating peritoneal sclerosis (EPS). Here, we investigated the role of extracellular vesicles (EVs) on the TGF-ß- and PDGF-B-driven processes of peritoneal fibrosis. EVs were isolated from the peritoneal dialysis effluent (PDE) of children receiving continuous ambulatory PD. The impact of PDE-EVs on the epithelial-mesenchymal transition (EMT) and collagen production of the peritoneal mesothelial cells and fibroblasts were investigated in vitro and in vivo in the chlorhexidine digluconate (CG)-induced mice model of peritoneal fibrosis. PDE-EVs showed spherical morphology in the 100 nm size range, and their spectral features, CD63, and annexin positivity were characteristic of EVs. PDE-EVs penetrated into the peritoneal mesothelial cells and fibroblasts and reduced their PDE- or PDGF-B-induced proliferation. Furthermore, PDE-EVs inhibited the PDE- or TGF-ß-induced EMT and collagen production of the investigated cell types. PDE-EVs contributed to the mesothelial layer integrity and decreased the submesothelial thickening of CG-treated mice. We demonstrated that PDE-EVs significantly inhibit the PDGF-B- or TGF-ß-induced fibrotic processes in vitro and in vivo, suggesting that EVs may contribute to new therapeutic strategies to treat peritoneal fibrosis and other fibroproliferative diseases.

An Open-Label Phase 2 Study of Eneboparatide, a Novel PTH Receptor 1 Agonist, in Hypoparathyroidism.

CONTEXT: Hypoparathyroidism is a rare disorder characterized by a deficiency in parathyroid hormone (PTH) resulting in hypocalcemia, hyperphosphatemia, and hypercalciuria. Eneboparatide is an investigational peptide agonist of the PTH1 receptor for the treatment of chronic hypoparathyroidism (HP). OBJECTIVE: To evaluate the efficacy, safety, and tolerability of eneboparatide in HP patients. DESIGN: Open-label, phase 2 study. PARTICIPANTS: Twenty-eight patients (21 women, 7 men), mean age (range): 58 years (28-72), with HP were enrolled into 2 consecutive cohorts (C1, n = 12, and C2, n = 16). INTERVENTION: Following an optimization period, daily subcutaneous injections of eneboparatide were administered for 3 months at 20 µg/day (C1) or 10 µg/day (C2) starting dose. Conventional therapy was progressively removed and eneboparatide could be titrated up to 60 µg (C1) or 80 µg (C2). MAIN OUTCOMES: Proportion of patients achieving independence from conventional therapy, albumin-adjusted serum calcium (ADsCa), 24-h urine calcium (uCa), serum bone turnover markers (s-CTX and P1NP), bone mineral density (BMD), and adverse events (AEs). RESULTS: After 3 months, ≥ 88% patients achieved independence from conventional therapy while mean ADsCa was maintained within target range (7.8-9 mg/dL). Eneboparatide induced a rapid and sustained reduction of mean 24-hour uCa, even among patients with hypercalciuria. Bone turnover markers slightly increased and BMD remained unchanged, consistent with progressive resumption of physiologic bone turnover. Eneboparatide was well tolerated with no serious AEs. CONCLUSION: Eneboparatide allowed independence from conventional therapy and maintenance of serum calcium within a target range, while normalizing uCa excretion and producing a balanced resumption of bone turnover.

Qudit-Based Spectroscopy for Measurement and Control of Nuclear-Spin Qubits in Silicon Carbide.

Nuclear spins with hyperfine coupling to single electron spins are highly valuable quantum bits. Here we probe and characterize the particularly rich nuclear-spin environment around single silicon vacancy color centers (V2) in 4H-SiC. By using the electron spin-3/2 qudit as a four level sensor, we identify several sets of ^{29}Si and ^{13}C nuclear spins through their hyperfine interaction. We extract the major components of their hyperfine coupling via optical detected nuclear magnetic resonance, and assign them to shells in the crystal via the density function theory simulations. We utilize the ground-state level anticrossing of the electron spin for dynamic nuclear polarization and achieve a nuclear-spin polarization of up to 98±6%. We show that this scheme can be used to detect the nuclear magnetic resonance signal of individual spins and demonstrate their coherent control. Our work provides a detailed set of parameters and first steps for future use of SiC as a multiqubit memory and quantum computing platform.

Low-dose radiotherapy for greater trochanteric pain syndrome-a single-centre analysis.

PURPOSE: To determine predictive factors associated with a good response (GR) to and efficacy of low-dose radiotherapy (LDRT) in patients with greater trochanteric pain syndrome (GTPS). METHODS: Patients with GTPS were irradiated on a linear accelerator with 0.5-1.0 Gy per fraction to a total dose of 3.0-4.0 Gy per series. The endpoint was subjective good response (GR) to treatment 2 months after completion of the last LDRT series, defined as complete pain relief or marked improvement assessed using the von Pannewitz score. A positive response to steroid injection (SI) was defined as pain relief of at least 7 days. Patient and treatment-related characteristics were evaluated with respect to LDRT outcomes. RESULTS: Outcomes were assessed for 71 peritrochanteric spaces (PTSs; 65 patients, 48 females, with mean age of 63 [44-91] years). Prior SI had been given to 55 (77%) PTSs and 40 PTSs received two series of LDRT. Two months after completion of LDRT, GR was reported in 42 PTSs (59%). Two series of LDRT provided a significantly higher rate of GR than one series (72.5 vs. 42% PTSs, p = 0.015). Temporary pain relief after prior SI predicted GR to LDRT compared with PTSs which had not responded to SI (73 vs. 28% PTSs, p = 0.001). A regional structural abnormality, present in 34 PTSs (48%), was associated with a reduction of GR to LDRT (44 vs. 73% PTSs, p = 0.017). CONCLUSION: LDRT is an effective treatment for GTPS. Administration of two LDRT series, prior response to SI, and absence of structural abnormalities may predict significantly better treatment outcomes.

The Semmelweis Study: a longitudinal occupational cohort study within the framework of the Semmelweis Caring University Model Program for supporting healthy aging.

The Semmelweis Study is a prospective occupational cohort study that seeks to enroll all employees of Semmelweis University (Budapest, Hungary) aged 25 years and older, with a population of 8866 people, 70.5% of whom are women. The study builds on the successful experiences of the Whitehall II study and aims to investigate the complex relationships between lifestyle, environmental, and occupational risk factors, and the development and progression of chronic age-associated diseases. An important goal of the Semmelweis Study is to identify groups of people who are aging unsuccessfully and therefore have an increased risk of developing age-associated diseases. To achieve this, the study takes a multidisciplinary approach, collecting economic, social, psychological, cognitive, health, and biological data. The Semmelweis Study comprises a baseline data collection with open healthcare data linkage, followed by repeated data collection waves every 5 years. Data are collected through computer-assisted self-completed questionnaires, followed by a physical health examination, physiological measurements, and the assessment of biomarkers. This article provides a comprehensive overview of the Semmelweis Study, including its origin, context, objectives, design, relevance, and expected contributions.

The effect of COVID-19 vaccination status on all-cause mortality in patients hospitalised with COVID-19 in Hungary during the delta wave of the pandemic.

The high mortality of patients with coronavirus disease 2019 (COVID-19) is effectively reduced by vaccination. However, the effect of vaccination on mortality among hospitalised patients is under-researched. Thus, we investigated the effect of a full primary or an additional booster vaccination on in-hospital mortality among patients hospitalised with COVID-19 during the delta wave of the pandemic. This retrospective cohort included all patients (n = 430) admitted with COVID-19 at Semmelweis University Department of Medicine and Oncology in 01/OCT/2021-15/DEC/2021. Logistic regression models were built with COVID-19-associated in-hospital/30 day-mortality as outcome with hierarchical entry of predictors of vaccination, vaccination status, measures of disease severity, and chronic comorbidities. Deceased COVID-19 patients were older and presented more frequently with cardiac complications, chronic kidney disease, and active malignancy, as well as higher levels of inflammatory markers, serum creatinine, and lower albumin compared to surviving patients (all p < 0.05). However, the rates of vaccination were similar (52-55%) in both groups. Based on the fully adjusted model, there was a linear decrease of mortality from no/incomplete vaccination (ref) through full primary (OR 0.69, 95% CI: 0.39-1.23) to booster vaccination (OR 0.31, 95% CI 0.13-0.72, p = 0.006). Although unadjusted mortality was similar among vaccinated and unvaccinated patients, this was explained by differences in comorbidities and disease severity. In adjusted models, a full primary and especially a booster vaccination improved survival of patients hospitalised with COVID-19 during the delta wave of the pandemic. Our findings may improve the quality of patient provider discussions at the time of admission.

Deep brain stimulation for essential tremor versus essential tremor plus: should we target the same spot in the thalamus?

Background: Although ET is a phenomenologically heterogeneous condition, thalamic DBS appears to be equally effective across subtypes. We hypothesized stimulation sites optimized for individuals with essential tremor (ET) would differ from individuals with essential tremor plus syndrome (ET-plus). We examined group differences in optimal stimulation sites within the ventral thalamus and their overlap of with relevant white matter tracts. By capturing these differences, we sought to determine whether ET subtypes are associated with anatomically distinct neural pathways. Methods: A retrospective chart review was conducted on ET patients undergoing VIM DBS at MUSC between 01/2012 and 02/2022. Clinical, demographic, neuroimaging, and DBS stimulation parameter data were collected. Clinical characteristics and pre-DBS videos were reviewed to classify ET and ET-plus cohorts. Patients in ET-plus cohorts were further divided into ET with dystonia, ET with ataxia, and ET with others. DBS leads were reconstructed using Lead-DBS and the volume of tissue activated (VTA) overlap was performed using normative connectomes. Tremor improvement was measured by reduction in a subscore of tremor rating scale (TRS) post-DBS lateralized to the more affected limb. Results: Sixty-eight ET patients were enrolled after initial screening, of these 10 ET and 24 ET-plus patients were included in the final analyses. ET group had an earlier age at onset (p = 0.185) and underwent surgery at a younger age (p = 0.096). Both groups achieved effective tremor control. No significant differences were found in lead placement or VTA overlap within ventral thalamus. The VTA center of gravity (COG) in the ET-plus cohort was located dorsal to that of the ET cohort. No significant differences were found in VTA overlap with the dentato-rubral-thalamic (DRTT) tracts or the ansa lenticularis. Dystonia was more prevalent than ataxia in the ET-plus subgroups (n = 18 and n = 5, respectively). ET-plus with dystonia subgroup had a more medial COG compared to ET-plus with ataxia. Conclusion: VIM DBS therapy is efficacious in patients with ET and ET-plus. There were no significant differences in optimal stimulation site or VTA overlap with white-matter tracts between ET, ET-plus and ET-plus subgroups.

The impact of COVID-19 infection before the vaccination era on the hospitalized patients requiring hemodialysis: a single-center retrospective cohort.

Due to effective vaccinations, the COVID-19 (coronavirus disease 2019) infection that caused the pandemic has a milder clinical course. We aimed to assess the mortality of hospitalized COVID-19 patients before the vaccination era. We investigated the mortality in those patients between 1 October 2020 and 31 May 2021 who received hemodialysis treatment [patients with previously normal renal function (nCKD), patients with chronic kidney disease previously not requiring hemodialysis (CKDnonHD), chronic kidney disease (CKD), and patients on regular hemodialysis (pHD)]. In addition, participants were followed up for all-cause mortality in the National Health Service database until 1 December 2021. In our center, 83 of 108 (76.9%) were included in the analysis due to missing covariates. Over a median of 26 (interquartile range 11-266) days of follow-up, 20 of 22 (90.9%) of nCKD, 23 of 24 (95.8%) of CKDnonHD, and 17 of 37 (45.9%) pHD patients died (p < 0.001). In general, patients with nCKD had fewer comorbidities but more severe presentations. In contrast, the patients with pHD had the least severe symptoms (p < 0.001). In a model adjusted for independent predictors of all-cause mortality (C-reactive protein and serum albumin), CKDnonHD patients had increased mortality [hazard ratio (HR) 1.91, 95% confidence interval (CI), 1.02-3.60], while pHD patients had decreased mortality (HR 0.41, 95% CI 0.20-0.81) compared to nCKD patients. After further adjustment for the need for intensive care, the difference in mortality between the nCKD and pHD groups became non-significant. Despite the limitations of our study, it seems that the survival of previously hemodialysis patients was significantly better.

A Phase I Randomized Trial of Once-Daily Versus Twice-Daily Recombinant Human Parathyroid Hormone (1-84) for Hypoparathyroidism.

Recombinant human parathyroid hormone (1-84), rhPTH(1-84), is an approved adjunctive treatment to oral calcium and active vitamin D for adult patients with hypoparathyroidism; however, there is limited information on the effect of twice daily (BID) dosing of rhPTH(1-84). This was a phase I, open-label, randomized, crossover, multicenter study conducted in adult patients with chronic hypoparathyroidism. The primary objective was to assess the pharmacokinetic profile and pharmacodynamic effects of 1 day of treatment with rhPTH(1-84) administered subcutaneously at 25 µg BID, 50 µg BID, and 100 µg once daily (QD) with or without supplemental oral calcium. Safety and tolerability were evaluated as secondary objectives. In total, 33 patients with chronic hypoparathyroidism completed the study. Treatment with rhPTH(1-84), both BID and QD, over the short-term maintained serum calcium, lowered serum phosphorus, decreased urinary calcium excretion, and increased urinary phosphorus excretion. The decrease in urinary calcium excretion was numerically greater for BID than QD. Generally, baseline-adjusted pharmacokinetic parameters including area under the curve and maximum observed concentration increased with increasing rhPTH(1-84) dose, although this effect was not dose proportional. No new safety findings were observed. Our study revealed no differences thought to be clinically meaningful in pharmacokinetic or pharmacodynamic parameters with BID versus QD rhPTH(1-84) dosing. Future long-term studies are warranted to further elucidate the effects of alternative dosing strategies. © 2023 Takeda Development Center Americas, Inc and The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

[Beta-thalassemia and vitamin B12 deficiency and associated complement-mediated hemolysis]. / Béta-thalassaemia, B12-vitamin-hiány és társuló komplementmediált hemolízis.

We present the case of a 67-year-old male patient admitted to our clinic due to weakness and repeated dizziness. Due to his severe microcytic anemia in his laboratory tests, he needed a transfusion of 6 units of selected blood in the days following admission. Our patient was diagnosed with beta-thalassemia minor, which was accompanied by a severe deficiency of vitamin B12. Surprisingly, parallel to vitamin B12 deficiency, we detected laboratory abnormalities indicating complement-mediated autoimmune hemolysis. After correcting the vitamin B12 deficiency, the patient's blood count improved, and the observed immunological abnormalities disappeared. Genetic testing of the hemoglobin gene confirmed the c.118C>T (p.Gln40STOP) variant in heterozygous form. Beta-thalassemia is a relatively common hematological disease, although rarely encountered in Hungary. Genetic testing of patients is possible at the Laboratory Medicine Institute of the Clinical Center in Debrecen. Unfortunately, we do not have accurate information about published domestic epidemiological data. Furthermore, establishing a diagnosis can be difficult if the disease is combined with other hematological disorders, such as the lack of vitamin B12, which can clinically mimic hemolytic anemia in certain features. Our case is considered a rarity in the literature, so in the case of a positive family history, it is recommended to screen immediate family members, which may facilitate the accurate establishment of a later diagnosis. Orv Hetil. 2023; 164(24): 954-960.

Hypocalcemia on Admission Is a Predictor of Disease Progression in COVID-19 Patients with Cirrhosis: A Multicenter Study in Hungary.

Hypocalcemia is a common condition in liver cirrhosis and is associated with the severity of SARS-CoV-2 infection. However, there is a lack of data demonstrating the prognostic value of hypocalcemia in COVID-19 patients with cirrhosis. This study aimed to evaluate the prognostic value of hypocalcemia for COVID-19 severity, mortality and its associations with abnormal liver function parameters. We selected 451 COVID-19 patients in this retrospective study and compared the laboratory findings of 52 COVID-19 patients with cirrhosis to those of 399 COVID-19 patients without cirrhosis. Laboratory tests measuring albumin-corrected total serum calcium were performed on admission, and the levels were monitored during hospitalization. The total serum calcium levels were significantly lower in cirrhosis cases (2.16 mmol/L) compared to those without cirrhosis (2.32 mmol/L). Multivariate analysis showed that hypocalcemia in COVID-19 patients with cirrhosis was a significant predictor of in-hospital mortality, with an OR of 4.871 (p < 0.05; 95% CI 1.566-15.146). ROC analysis showed the AUC value of total serum calcium was 0.818 (95% CI 0.683-0.953, p < 0.05), with a sensitivity of 88.3% and a specificity of 75%. The total serum calcium levels showed a significant negative correlation with the Child-Turcette-Pugh score (r = -0.400, p < 0.05). Hypocalcemia on admission was a significant prognostic factor of disease progression in COVID-19 patients with cirrhosis.

Controlled randomized open label clinical study comparing the safety and efficacy of loading schedules in vitamin D deficient patients.

Rapidly restoring vitamin D levels to normal might be desirable in certain clinical situations. Larger doses of supplementation, have been shown to increase bone loss and the risk of falls. The optimal way to perform vitamin D loading safely and effectively is still not well elucidated. Our study was aimed to assess the safety and efficacy of two oral vitamin D loading protocols. Sixty-nine subjects with vitamin D deficiency (25OH-vitamin D (25(OH)D) < 20 ng/ml) were included. Thirty-five participants received 30 000 IU of vitamin D3 per week for 10 weeks (group Slower Loading Dose (SLD)) and thirty-four received 30 000 IU twice weekly for 5 weeks (group Moderate Loading Dose (MLD)) resulting in a loading dose of 300 000 IU for all subjects. Following this initial loading phase, both groups received 30 000 IU biweekly for 4 weeks to test whether the recommended daily vitamin D supplementation in range of 2000 IU dose-equivalent could maintain the achieved levels. Seventy-nine percent of those subjects treated in group SLD and everyone in group MLD achieved a 25(OH)D level of 30 ng/ml, which is the lower limit of the recommended normal range in Hungary. The mean increase in 25(OH)D was significantly higher in group MLD than in group SLD (38.6 ± 1.80 ng/ml vs 46,6 ± 1.80 ng/ml). No significant decrease was observed with the administration of the maintenance dose. There were no clinically significant changes in serum or urine calcium, and bone biomarkers in either group. Both protocols were found to be safe and effective, but the five-week dosing caused a significantly greater increase in 25(OH)D. A maintenance dose applied for four weeks after the loading protocol did not raise 25(OH)D levels further but maintained the achieved increase. The administration of 30 000 IU of vitamin D3 twice weekly for five weeks is a rapid, effective and safe way to treat vitamin D deficiency in vitamin D deficient patients.

Interplay of Vitamin D and SIRT1 in Tissue-Specific Metabolism-Potential Roles in Prevention and Treatment of Non-Communicable Diseases Including Cancer.

The importance of the prevention and control of non-communicable diseases, including obesity, metabolic syndrome, type 2 diabetes, cardiovascular diseases, and cancer, is increasing as a requirement of the aging population in developed countries and the sustainability of healthcare. Similarly, the 2013-2030 action plan of the WHO for the prevention and control of non-communicable diseases seeks these achievements. Adequate lifestyle changes, alone or with the necessary treatments, could reduce the risk of mortality or the deterioration of quality of life. In our recent work, we summarized the role of two central factors, i.e., appropriate levels of vitamin D and SIRT1, which are connected to adequate lifestyles with beneficial effects on the prevention and control of non-communicable diseases. Both of these factors have received increased attention in relation to the COVID-19 pandemic as they both take part in regulation of the main metabolic processes, i.e., lipid/glucose/energy homeostasis, oxidative stress, redox balance, and cell fate, as well as in the healthy regulation of the immune system. Vitamin D and SIRT1 have direct and indirect influence of the regulation of transcription and epigenetic changes and are related to cytoplasmic signaling pathways such as PLC/DAG/IP3/PKC/MAPK, MEK/Erk, insulin/mTOR/cell growth, proliferation; leptin/PI3K-Akt-mTORC1, Akt/NFĸB/COX-2, NFĸB/TNFα, IL-6, IL-8, IL-1ß, and AMPK/PGC-1α/GLUT4, among others. Through their proper regulation, they maintain normal body weight, lipid profile, insulin secretion and sensitivity, balance between the pro- and anti-inflammatory processes under normal conditions and infections, maintain endothelial health; balance cell differentiation, proliferation, and fate; and balance the circadian rhythm of the cellular metabolism. The role of these two molecules is interconnected in the molecular network, and they regulate each other in several layers of the homeostasis of energy and the cellular metabolism. Both have a central role in the maintenance of healthy and balanced immune regulation and redox reactions; therefore, they could constitute promising targets either for prevention or as complementary therapies to achieve a better quality of life, at any age, for healthy people and patients under chronic conditions.

Patterns of Somatic Variants in Colorectal Adenoma and Carcinoma Tissue and Matched Plasma Samples from the Hungarian Oncogenome Program.

Analysis of circulating cell-free DNA (cfDNA) of colorectal adenoma (AD) and cancer (CRC) patients provides a minimally invasive approach that is able to explore genetic alterations. It is unknown whether there are specific genetic variants that could explain the high prevalence of CRC in Hungary. Whole-exome sequencing (WES) was performed on colon tissues (27 AD, 51 CRC) and matched cfDNAs (17 AD, 33 CRC); furthermore, targeted panel sequencing was performed on a subset of cfDNA samples. The most frequently mutated genes were APC, KRAS, and FBN3 in AD, while APC, TP53, TTN, and KRAS were the most frequently mutated in CRC tissue. Variants in KRAS codons 12 (AD: 8/27, CRC: 11/51 (0.216)) and 13 (CRC: 3/51 (0.06)) were the most frequent in our sample set, with G12V (5/27) dominance in ADs and G12D (5/51 (0.098)) in CRCs. In terms of the cfDNA WES results, tumor somatic variants were found in 6/33 of CRC cases. Panel sequencing revealed somatic variants in 8 out of the 12 enrolled patients, identifying 12/20 tumor somatic variants falling on its targeted regions, while WES recovered only 20% in the respective regions in cfDNA of the same patients. In liquid biopsy analyses, WES is less efficient compared to the targeted panel sequencing with a higher coverage depth that can hold a relevant clinical potential to be applied in everyday practice in the future.