Prevalence of Electrographic Seizures in Hospitalized Patients With Altered Mental Status With No Significant Seizure Risk Factors Who Underwent Continuous EEG Monitoring: A Retrospective Study.

OBJECTIVES: The objective of this study is to evaluate the prevalence of electrographic seizures in hospitalized patients with altered mental status and no significant risk factors for seizures. METHODS: We retrospectively reviewed over a six-year period (2013-2019) the medical records of all adults admitted at Ohio State University Wexner Medical Center (OSUWMC), who underwent continuous electroencephalography (cEEG) monitoring for > 48 hours. Our primary objective was to identify the prevalence of electrographic seizures in patients with altered mental status and no significant acute or remote risk factors for seizures. RESULTS: A total of 1966 patients were screened for the study, 1892 were excluded (96.2%) and 74 patients met inclusion criteria. Electrographic seizures were identified in seven of 74 patients (9.45%). We found a significant correlation between electrographic seizures and a history of hepatic cirrhosis, n= 4 (57%), (p=0.035), acute chronic hepatic failure during admission, 71% (n=5), (p=0.027), and hyperammonemia (p =0.009). CONCLUSION: In this retrospective study of patients with altered mental status and no significant acute or remote risk factors for seizures who underwent cEEG monitoring for > 48 hours, electrographic seizures were identified in 9.45%. Electrographic seizures were associated with hepatic dysfunction and hyperammonemia. Based on our results, cEEG monitoring should be considered in patients with altered mental status and hepatic dysfunction even in the absence of other seizure risk factors.

Diagnosis and management in Rubinstein-Taybi syndrome: first international consensus statement.

Rubinstein-Taybi syndrome (RTS) is an archetypical genetic syndrome that is characterised by intellectual disability, well-defined facial features, distal limb anomalies and atypical growth, among numerous other signs and symptoms. It is caused by variants in either of two genes (CREBBP, EP300) which encode for the proteins CBP and p300, which both have a function in transcription regulation and histone acetylation. As a group of international experts and national support groups dedicated to the syndrome, we realised that marked heterogeneity currently exists in clinical and molecular diagnostic approaches and care practices in various parts of the world. Here, we outline a series of recommendations that document the consensus of a group of international experts on clinical diagnostic criteria for types of RTS (RTS1: CREBBP; RTS2: EP300), molecular investigations, long-term management of various particular physical and behavioural issues and care planning. The recommendations as presented here will need to be evaluated for improvements to allow for continued optimisation of diagnostics and care.

Diagnostic utility and reporting recommendations for clinical DNA methylation episignature testing in genetically undiagnosed rare diseases.

PURPOSE: This study aims to assess the diagnostic utility and provide reporting recommendations for clinical DNA methylation episignature testing based on the cohort of patients tested through the EpiSign Clinical Testing Network. METHODS: The EpiSign assay utilized unsupervised clustering techniques and a support vector machine-based classification algorithm to compare each patient's genome-wide DNA methylation profile with the EpiSign Knowledge Database, yielding the result that was reported. An international working group, representing distinct EpiSign Clinical Testing Network health jurisdictions, collaborated to establish recommendations for interpretation and reporting of episignature testing. RESULTS: Among 2399 cases analyzed, 1667 cases underwent a comprehensive screen of validated episignatures, imprinting, and promoter regions, resulting in 18.7% (312/1667) positive reports. The remaining 732 referrals underwent targeted episignature analysis for assessment of sequence or copy-number variants (CNVs) of uncertain significance or for assessment of clinical diagnoses without confirmed molecular findings, and 32.4% (237/732) were positive. Cases with detailed clinical information were highlighted to describe various utility scenarios for episignature testing. CONCLUSION: Clinical DNA methylation testing including episignatures, imprinting, and promoter analysis provided by an integrated network of clinical laboratories enables test standardization and demonstrates significant diagnostic yield and clinical utility beyond DNA sequence analysis in rare diseases.

Estimation of liver fibrosis using elastography in cholestatic diseases: systematic review and meta-analysis.

INTRODUCTION: staging fibrosis extent in liver disease is highly relevant for appropriate management. Liver biopsy remains the reference standard for assessment, but noninvasive methods such as elastography are becoming increasingly accurate and relevant. However, evidence regarding elastography in cholestatic diseases is lower than in other etiologies. METHODS: we searched MEDLINE, EMBASE and Web of Science for publications on the diagnostic accuracy of transient elastography and sonoelastography in cholestatic diseases (PBC and PSC) using biopsy as the reference standard. A systematic review and meta-analysis of the results was then carried out. RESULTS: a total of 13 studies were included. Using transient elastography in PBC sensitivity and specificity were estimated to be 0.76 and 0.93; 0.88 and 0.9; and 0.91 and 0.95 for ≥ F2, ≥ F3 and = F4, respectively. For sonoelastography in PBC sensitivity and specificity estimates were 0.79 and 0.82; 0.95 and 0.86; and 0.94 and 0.85 for ≥ F2, ≥ F3 y = F4, respectively. In PSC, transient elastography had a sensivity and specificity of 0.76 and 0.88; 0.91 and 0.86; and 0.71 and 0.93 for ≥ F2, ≥ F3 and = F4, respectively. CONCLUSION: elastography has adequate diagnostic accuracy in the assessment of fibrosis stages in cholestatic liver diseases.

Genotype-first approach to identify associations between CDH1 germline variants and cancer phenotypes: a multicentre study by the European Reference Network on Genetic Tumour Risk Syndromes.

BACKGROUND: Truncating pathogenic or likely pathogenic variants of CDH1 cause hereditary diffuse gastric cancer (HDGC), a tumour risk syndrome that predisposes carrier individuals to diffuse gastric and lobular breast cancer. Rare CDH1 missense variants are often classified as variants of unknown significance. We conducted a genotype-phenotype analysis in families carrying rare CDH1 variants, comparing cancer spectrum in carriers of pathogenic or likely pathogenic variants (PV/LPV; analysed jointly) or missense variants of unknown significance, assessing the frequency of families with lobular breast cancer among PV/LPV carrier families, and testing the performance of lobular breast cancer-expanded criteria for CDH1 testing. METHODS: This genotype-first study used retrospective diagnostic and clinical data from 854 carriers of 398 rare CDH1 variants and 1021 relatives, irrespective of HDGC clinical criteria, from 29 institutions in ten member-countries of the European Reference Network on Tumour Risk Syndromes (ERN GENTURIS). Data were collected from Oct 1, 2018, to Sept 20, 2022. Variants were classified by molecular type and clinical actionability with the American College of Medical Genetics and Association for Molecular Pathology CDH1 guidelines (version 2). Families were categorised by whether they fulfilled the 2015 and 2020 HDGC clinical criteria. Genotype-phenotype associations were analysed by Student's t test, Kruskal-Wallis, χ2, and multivariable logistic regression models. Performance of HDGC clinical criteria sets were assessed with an equivalence test and Youden index, and the areas under the receiver operating characteristic curves were compared by Z test. FINDINGS: From 1971 phenotypes (contributed by 854 probands and 1021 relatives aged 1-93 years), 460 had gastric and breast cancer histology available. CDH1 truncating PV/LPVs occurred in 176 (21%) of 854 families and missense variants of unknown significance in 169 (20%) families. Multivariable logistic regression comparing phenotypes occurring in families carrying PV/LPVs or missense variants of unknown significance showed that lobular breast cancer had the greatest positive association with the presence of PV/LPVs (odds ratio 12·39 [95% CI 2·66-57·74], p=0·0014), followed by diffuse gastric cancer (8·00 [2·18-29·39], p=0·0017) and gastric cancer (7·81 [2·03-29·96], p=0·0027). 136 (77%) of 176 families carrying PV/LPVs fulfilled the 2015 HDGC criteria. Of the remaining 40 (23%) families, who did not fulfil the 2015 criteria, 11 fulfilled the 2020 HDGC criteria, and 18 had lobular breast cancer only or lobular breast cancer and gastric cancer, but did not meet the 2020 criteria. No specific CDH1 variant was found to predispose individuals specifically to lobular breast cancer, although 12 (7%) of 176 PV/LPV carrier families had lobular breast cancer only. Addition of three new lobular breast cancer-centred criteria improved testing sensitivity while retaining high specificity. The probability of finding CDH1 PV/LPVs in patients fulfilling the lobular breast cancer-expanded criteria, compared with the 2020 criteria, increased significantly (AUC 0·92 vs 0·88; Z score 3·54; p=0·0004). INTERPRETATION: CDH1 PV/LPVs were positively associated with HDGC-related phenotypes (lobular breast cancer, diffuse gastric cancer, and gastric cancer), and no evidence for a positive association with these phenotypes was found for CDH1 missense variants of unknown significance. CDH1 PV/LPVs occurred often in families with lobular breast cancer who did not fulfil the 2020 HDGC criteria, supporting the expansion of lobular breast cancer-centred criteria. FUNDING: European Reference Network on Genetic Tumour Risk Syndromes, European Regional Development Fund, Fundação para a Ciência e a Tecnologia (Portugal), Cancer Research UK, and European Union's Horizon 2020 research and innovation programme.

Novel genes and sex differences in COVID-19 severity.

Here, we describe the results of a genome-wide study conducted in 11 939 coronavirus disease 2019 (COVID-19) positive cases with an extensive clinical information that were recruited from 34 hospitals across Spain (SCOURGE consortium). In sex-disaggregated genome-wide association studies for COVID-19 hospitalization, genome-wide significance (P < 5 × 10-8) was crossed for variants in 3p21.31 and 21q22.11 loci only among males (P = 1.3 × 10-22 and P = 8.1 × 10-12, respectively), and for variants in 9q21.32 near TLE1 only among females (P = 4.4 × 10-8). In a second phase, results were combined with an independent Spanish cohort (1598 COVID-19 cases and 1068 population controls), revealing in the overall analysis two novel risk loci in 9p13.3 and 19q13.12, with fine-mapping prioritized variants functionally associated with AQP3 (P = 2.7 × 10-8) and ARHGAP33 (P = 1.3 × 10-8), respectively. The meta-analysis of both phases with four European studies stratified by sex from the Host Genetics Initiative (HGI) confirmed the association of the 3p21.31 and 21q22.11 loci predominantly in males and replicated a recently reported variant in 11p13 (ELF5, P = 4.1 × 10-8). Six of the COVID-19 HGI discovered loci were replicated and an HGI-based genetic risk score predicted the severity strata in SCOURGE. We also found more SNP-heritability and larger heritability differences by age (<60 or ≥60 years) among males than among females. Parallel genome-wide screening of inbreeding depression in SCOURGE also showed an effect of homozygosity in COVID-19 hospitalization and severity and this effect was stronger among older males. In summary, new candidate genes for COVID-19 severity and evidence supporting genetic disparities among sexes are provided.

Phenotypic comparison of patients affected with DeSanto-Shinawi syndrome: Point mutations in WAC gene versus a 10p12.1 microdeletion including WAC.

INTRODUCTION: DeSanto-Shinawi syndrome is a rare neurodevelopmental disorder caused by loss-of-function variants of WAC, located on chromosome 10p12.1. This syndrome is characterized by dysmorphic facial features, intellectual disability, and behavioral problems. CASE REPORT: In this case report, we present a new deletion case and summarize the clinical data of previously reported individuals, comparing the similarities and differences between cases caused by point mutations versus those which are caused by deletions in the 10p region. CONCLUSION: Some differential features could facilitate the diagnostic suspicion guiding the optimal diagnostic tests that should be requested in each case scenario.

Copper and Chromium toxicity is mediated by oxidative stress in Caenorhabditis elegans: The use of nanoparticles as an immobilization strategy.

Environmental contamination by heavy metals (HMs) has impelled searching for stabilization strategies, where the use of zero-valent iron nanoparticles (nZVI) is considered a promising option. We have evaluated the combined effect of Cu(II)-Cr(VI) on two Caenorhabditis elegans strains (N2 and RB1072 sod-2 mutant) in aqueous solutions and in a standard soil, prior and after treatment with nZVI (5% w/w). The results showed that HMs aqueous solutions had an intense toxic effect on both strains. Production of reactive oxygen species and enhanced expression of the heat shock protein Hsp-16.2 was observed, indicating increased HM-mediated oxidative stress. Toxic effects of HM-polluted soil on worms were higher for sod-2 mutant than for N2 strain. However, nZVI treatment significantly diminished all these effects. Our findings highlighted C. elegans as a sensitive indicator for HMs pollution and its usefulness to assess the efficiency of the nanoremediation strategy to decrease the toxicity of Cu(II)-Cr(VI) polluted environments.

Variant-genetic and transcript-expression analysis showed a role for the chemokine-receptor CCR5 in COVID-19 severity.

The chemokine receptor CCR5 has been implicated in COVID-19. CCR5 and its ligands are overexpressed in patients. The pharmacological targeting of CCR5 would improve the COVID-19 severity. We sought to investigate the role of the CCR5-Δ32 variant (rs333) in COVID-19. The CCR5-Δ32 was genotyped in 801 patients (353 in the intensive care unit, ICU) and 660 healthy controls, and the deletion was significantly less frequent in hospitalysed COVID-19 than in healthy controls (p = 0.01, OR = 0.66, 95%CI = 0.49-0.88). Of note, we did not find homozygotes among the patients, compared to 1% of the controls. The CCR5 transcript was measured in leukocytes from 85 patients and 40 controls. We found a significantly higher expression of the CCR5 transcript among the patients, with significant difference when comparing the non-deletion carriers (controls = 35; patients = 81; p = 0.01). ICU-patients showed non-significantly higher expression than no-ICU cases. Our study points to CCR5 as a genetic marker for COVID-19. The pharmacological targeting of CCR5 should be a promising treatment for COVID-19.

Impact of Goal Directed Therapy in Head and Neck Oncological Surgery with Microsurgical Reconstruction: Free Flap Viability and Complications.

(1) Background: Surgical outcomes in free flap reconstruction of head and neck defects in cancer patients have improved steadily in recent years; however, correct anaesthesia management is also important. The aim of this study has been to show whether goal directed therapy can improve flap viability and morbidity and mortality in surgical patients. (2) Methods: we performed an observational case control study to analyse the impact of introducing a semi invasive device (Flo Trac®) during anaesthesia management to optimize fluid management. Patients were divided into two groups: one received goal directed therapy (GDT group) and the other conventional fluid management (CFM group). Our objective was to compare surgical outcomes, complications, fluid management, and length of stay between groups. (3) Results: We recruited 140 patients. There were no differences between groups in terms of demographic data. Statistically significant differences were observed in colloid infusion (GDT 53.1% vs. CFM 74.1%, p = 0.023) and also in intraoperative and postoperative infusion of crystalloids (CFM 5.72 (4.2, 6.98) vs. GDT 3.04 (2.29, 4.11), p < 0.001), which reached statistical significance. Vasopressor infusion in the operating room (CFM 25.5% vs. GDT 74.5%, p < 0.001) and during the first postoperative 24h (CFM 40.6% vs. GDT 75%, p > 0.001) also differed. Differences were also found in length of stay in the intensive care unit (hours: CFM 58.5 (40, 110) vs. GDT 40.5 (36, 64.5), p = 0.005) and in the hospital (days: CFM 15.5 (12, 26) vs. GDT 12 (10, 19), p = 0.009). We found differences in free flap necrosis rate (CMF 37.1% vs. GDT 13.6%, p = 0.003). One-year survival did not differ between groups (CFM 95.6% vs. GDT 86.8%, p = 0.08). (4) Conclusions: Goal directed therapy in oncological head and neck surgery improves outcomes in free flap reconstruction and also reduces length of stay in the hospital and intensive care unit, with their corresponding costs. It also appears to reduce morbidity, although these differences were not significant. Our results have shown that optimizing intraoperative fluid therapy improves postoperative morbidity and mortality.

Shorter androgen receptor polyQ alleles protect against life-threatening COVID-19 disease in European males.

BACKGROUND: While SARS-CoV-2 similarly infects men and women, COVID-19 outcome is less favorable in men. Variability in COVID-19 severity may be explained by differences in the host genome. METHODS: We compared poly-amino acids variability from WES data in severely affected COVID-19 patients versus SARS-CoV-2 PCR-positive oligo-asymptomatic subjects. FINDINGS: Shorter polyQ alleles (≤22) in the androgen receptor (AR) conferred protection against severe outcome in COVID-19 in the first tested cohort (both males and females) of 638 Italian subjects. The association between long polyQ alleles (≥23) and severe clinical outcome (p = 0.024) was also validated in an independent cohort of Spanish men <60 years of age (p = 0.014). Testosterone was higher in subjects with AR long-polyQ, possibly indicating receptor resistance (p = 0.042 Mann-Whitney U test). Inappropriately low serum testosterone level among carriers of the long-polyQ alleles (p = 0.0004 Mann-Whitney U test) predicted the need for intensive care in COVID-19 infected men. In agreement with the known anti-inflammatory action of testosterone, patients with long-polyQ and age ≥60 years had increased levels of CRP (p = 0.018, not accounting for multiple testing). INTERPRETATION: We identify the first genetic polymorphism that appears to predispose some men to develop more severe disease. Failure of the endocrine feedback to overcome AR signaling defects by increasing testosterone levels during the infection leads to the polyQ tract becoming dominant to serum testosterone levels for the clinical outcome. These results may contribute to designing reliable clinical and public health measures and provide a rationale to test testosterone as adjuvant therapy in men with COVID-19 expressing long AR polyQ repeats. FUNDING: MIUR project "Dipartimenti di Eccellenza 2018-2020" to Department of Medical Biotechnologies University of Siena, Italy (Italian D.L. n.18 March 17, 2020) and "Bando Ricerca COVID-19 Toscana" project to Azienda Ospedaliero-Universitaria Senese. Private donors for COVID-19 research and charity funds from Intesa San Paolo.

Mitochondrial genetic effect on atrial fibrillation: A case-control study.

Atrial fibrillation (AF) is a common arrhythmia in the general population and following cardiac surgery. The influence of mitochondrial genomics on AF pathogenesis is not fully understood. We analyzed mitochondrial variables from 78 human atrial samples collected from cardiac surgeries in the following groups: 1) permanent preoperative AF; 2) preoperative sinus rhythm (SR) with postoperative AF; and 3) pre-/postoperative SR. Haplogroup H appeared offer protection against, and haplogroup U predispose to permanent AF. mtDNA content was higher in group 2 than in 3. These findings contribute to a better understanding of the influence of mitochondria on AF pathogenesis.

A 22.5 kb deletion in CUL4B causing Cabezas syndrome identified using CNV approach from WES data.

Detecting clinical grade CNV based on WES is being improved in the NGS era.

Identifying extended psychosis phenotypes at school: Associations with socio-emotional adjustment, academic, and neurocognitive outcomes.

The main goal of the present study was to explore the latent structure of extended psychosis phenotypes in a representative sample of adolescents. Moreover, associations with socio-emotional adjustment, academic achievement, and neurocognition performance across the latent profiles were compared. Participants were 1506 students, 667 males (44.3%), derived from random cluster sampling. Various tools were used to measure psychosis risk, subjective well-being, academic performance, and neurocognition. Based on three psychometric indicators of psychosis risk (schizotypal traits, psychotic-like experiences, and bipolar-like experiences), four latent classes were found: non-risk, low-risk, high reality distortion experiences, and high psychosis liability. The high-risk latent groups scored significantly higher on mental health difficulties, and negative affect, and lower on positive affect and well-being, compared to the two non-risk groups. Moreover, these high-risk groups had a significantly higher number of failed academic subjects compared to the non-risk groups. In addition, no statistically significant differences in efficiency performance were found in the neurocognitive domains across the four latent profiles. This study allows us to improve the early identification of adolescents at risk of serious mental disorder in school settings in order to prevent the incidence and burden associated with these kinds of mental health problems.

New techniques and recommendations in the management of free flap surgery for head and neck defects in cancer patients.

Free flap surgery is the gold standard surgical treatment for head and neck defects in cancer patients. Outcomes have improved considerably, probably due to recent advances in surgical techniques. In this article, we review improvements in the parameters traditionally used to optimize hematocrit levels and body temperature and to prevent vasoconstriction, and describe the use of cardiac output-guided fluid management, a technique that has proved useful in other procedures. Finally, we review other parameters used in free flap surgery, such as clotting/platelet management and nutritional optimization.

Prevalence of Immunological Defects in a Cohort of 97 Rubinstein-Taybi Syndrome Patients.

Although recurrent infections in Rubinstein-Taybi syndrome (RSTS) are common, and probably multifactorial, immunological abnormalities have not been extensively described with only isolated cases or small case series of immune deficiency and dysregulation having been reported. The objective of this study was to investigate primary immunodeficiency (PID) and immune dysregulation in an international cohort of patients with RSTS. All published cases of RSTS were identified. The corresponding authors and researchers involved in the diagnosis of inborn errors of immunity or genetic syndromes were contacted to obtain up-to-date clinical and immunological information. Ninety-seven RSTS patients were identified. For 45 patients, we retrieved data from the published reports while for 52 patients, a clinical update was provided. Recurrent or severe infections, autoimmune/autoinflammatory complications, and lymphoproliferation were observed in 72.1%, 12.3%, and 8.2% of patients. Syndromic immunodeficiency was diagnosed in 46.4% of individuals. Despite the broad heterogeneity of immunodeficiency disorders, antibody defects were observed in 11.3% of subjects. In particular, these patients presented hypogammaglobulinemia associated with low B cell counts and reduction of switched memory B cell numbers. Immunoglobulin replacement therapy, antibiotic prophylaxis, and immunosuppressive treatment were employed in 16.4%, 8.2%, and 9.8% of patients, respectively. Manifestations of immune dysfunctions, affecting mostly B cells, are more common than previously recognized in patients with RSTS. Full immunological assessment is warranted in these patients, who may require detailed investigation and specific supportive treatment. Graphical Abstract.

Education and information needs for physicians about rare diseases in Spain.

BACKGROUND: Rare diseases are a priority objective for public health systems. Given its complexity, late and misdiagnoses occur very often which causes mental and physical burden for patients and family. This would be caused, in part, for unprepared clinicians in this field. The aim of this study was to report the training needs and the perceived shortcomings of Spanish physicians of the public health system in the diagnosis, treatment and monitoring of patients with rare diseases. METHODS: We used a descriptive cross-sectional study through an "ad hoc" survey of 26 questions was completed by 132 primary care physicians and 37 specialists during April and May 2018. RESULTS: Less than a third of the physicians had received training in rare disease during their undergraduate or postgraduate years, and for hospital professionals, they received more training in the postgraduate period. CONCLUSION: Primary care physicians and specialists showed low training level in rare diseases. An academical and continuous program on rare disease, as well as, multidisciplinary units and high quality practice guidelines are necessary to help to prevention and support clinical decisions and improve quality of care of patients and families.

Prevalence, features and predictive factors of liver nodules in Fontan surgery patients: The VALDIG Fonliver prospective cohort.

BACKGROUND & AIMS: Fontan surgery is used to treat a variety of congenital heart malformations, and may lead to advanced chronic liver disease in the long-term. This study examines the prevalence, characteristics and predictors of liver nodules in patients following Fontan surgery. METHODS: This was a prospective, cross-sectional, observational study conducted at 8 European centres. Consecutive patients who had undergone Fontan surgery underwent blood tests, abdominal ultrasonography (US), transient elastography (Fibroscan®), echocardiography, haemodynamic assessments, and abdominal MRI/CT scan. The primary outcome measure was liver nodules detected in the MRI/CT scan. Predictors of liver nodules were identified by multivariate logistic regression. RESULTS: One hundred and fifty-two patients were enrolled (mean age 27.3 years). The mean time elapsed from surgery to inclusion was 18.3 years. Liver nodule prevalences were 29.6% (95% CI 23-37%) on US and 47.7% (95% CI 39-56%) on MRI/CT. Nodules were usually hyperechoic (76.5%), round-shaped (>80%), hyperenhancing in the arterial phase (92%) and located in the liver periphery (75%). The sensitivity and specificity of US were 50% (95% CI 38-62%) and 85.3% (95% CI 75-92%), respectively. Inter-imaging test agreement was low (adjusted kappa: 0.34). In the multivariate analysis, time since surgery >10 years was the single independent predictor of liver nodules (odds ratio 4.18; p = 0.040). Hepatocellular carcinoma was histologically diagnosed in 2 of the 8 patients with hypervascular liver nodules displaying washout. CONCLUSION: While liver nodules are frequent in Fontan patients, they may go unnoticed in US. Liver nodules are usually hyperechoic, hypervascular and predominantly peripheral. This population is at risk of hepatocellular carcinoma, the diagnosis of which requires confirmatory biopsy. LAY SUMMARY: Fontan surgery is the standard of care for many patients with univentricular congenital cardiopathies. Recent advances have improved the survival of Fontan patients, and nowadays most of them reach adulthood. In this setting, Fontan-associated liver disease (FALD) is increasingly recognised, and has become a significant prognostic factor. Liver nodules are considered a component of FALD yet their prevalence, imaging features and predictors have hardly been evaluated. In this study, we observed that liver nodules are frequent, typically hyperechoic, hypervascular and predominantly peripheral in patients with FALD. This population is at risk of hepatocellular carcinoma, the diagnosis of which must be confirmed by biopsy.

Battle of Thermopylae: 300 Spartans (natural killer cells plus obinutuzumab) versus the immortal warriors (chronic lymphocytic leukemia cells) of Xerxes' army.

AIM: To analyze the effects of subcutaneous or intravenous rituximab + lymphokine-activated killer cells, obinutuzumab or ibrutinib on natural killer (NK) cell levels in chronic lymphocytic leukemia and follicular lymphoma patients. PATIENTS & METHODS: The distribution of peripheral blood NK cells of 31 patients was analyzed by flow cytometry. RESULTS: We detected a decrease of NK cells in peripheral blood below normal range after obinutuzumab treatment. During maintenance treatment with subcutaneous rituximab, an NK cell reduction was less pronounced than after intravenous rituximab treatment, despite lymphokine-activated killer cell infusions. CONCLUSION: After one dose of obinutuzumab, each NK cell in peripheral blood destroys 25 leukemic cells.