Immune response of the Almaco jack (Seriola rivoliana) against the infestation with Neobenedenia sp. in three cultivated temperatures.

The Almaco jack (Seriola rivoliana) is a marine fish maintained in mariculture systems and frequently infested by monogenean parasites like Neobenedenia sp. Severe infestations can lead to high mortalities and economic losses for farmers. This study evaluated the effects of temperature on the immune response on Almaco jack infested with Neobenedenia sp. We exposed infested fishes at temperatures of 20 °C, 24 °C, and 30 °C for 20 days and took samples of different tissues at the beginning of the experiment, and after 3 and 20 days. The tissues considered were the skin, thymus, cephalic kidney, and spleen to evaluate the relative gene expression of different genes: Hsp70, IgM, IL-1ß, IL-10, and MyD88. Our results showed an increase in IL-1ß gene expression in the skin after 20 days of infestation but no significant effect of temperature on gene expression, despite increases in infestation rates with temperature. Therefore, relative genetic expression was controlled by the number of parasites and the days post-infestation. These results show that the parasite infestation induced a local response in the skin, but that temperature has an indirect effect on the immune system of Almaco jack.

Effect of calcium soaps from garlic (Allium sativum) and willow (Salix babylonica) extracts on nematode loads, nutrient intake and digestibility, nitrogen balance and rumen fermentation kinetics in dairy goats.

The objective of this study was to determine the effect of dietary calcium soaps from garlic (Allium sativum) and willow (Salix babylonica) extracts on nematode loads, nutrient intake and digestibility, nitrogen balance and rumen fermentation kinetics in dairy goats. Nine adult non-lactating Saanen goats were grouped into a complete randomized block design with 3 treatments (n = 3) over a period of 28 d. Animals were fed a diet based on alfalfa hay and a concentrate that was supplemented (65 g/kg DM) with calcium soaps of safflower (control), garlic or willow. Intake of dry matter (DM), organic matter (OM) and neutral detergent fiber (NDF) were not affected by dietary calcium soaps. However, the highest digestibility of DM and OM were observed in willow supplemented goats. In vitro gas kinetics and fermentation profile were not affected by diets. Results from fecal egg count indicated a reduction in total count, Haemonchus spp. and Trychostrongylus spp. for both garlic and willow compared to control. Our results suggest that calcium soaps of garlic or willow extracts can be used to reduce gastrointestinal parasites in goats without compromising productive traits or rumen function.

Novel Loss-of-Function KCNA5 Variants in Pulmonary Arterial Hypertension.

Reduced expression and/or activity of Kv1.5 channels (encoded by KCNA5) is a common hallmark in human or experimental pulmonary arterial hypertension (PAH). Likewise, genetic variants in KCNA5 have been found in patients with PAH, but their functional consequences and potential impact on the disease are largely unknown. Herein, this study aimed to characterize the functional consequences of seven KCNA5 variants found in a cohort of patients with PAH. Potassium currents were recorded by patch-clamp technique in HEK293 cells transfected with wild-type or mutant Kv1.5 cDNA. Flow cytometry, Western blot, and confocal microscopy techniques were used for measuring protein expression and cell apoptosis in HEK293 and human pulmonary artery smooth muscle cells. KCNA5 variants (namely, Arg184Pro and Gly384Arg) found in patients with PAH resulted in a clear loss of potassium channel function as assessed by electrophysiological and molecular modeling analyses. The Arg184Pro variant also resulted in a pronounced reduction of Kv1.5 expression. Transfection with Arg184Pro or Gly384Arg variants decreased apoptosis of human pulmonary artery smooth muscle cells compared with the wild-type cells, demonstrating that KCNA5 dysfunction in both variants affects cell viability. Thus, in addition to affecting channel activity, both variants were associated with impaired apoptosis, a crucial process linked to the disease. The estimated prevalence of dysfunctional KCNA5 variants in the PAH population analyzed was around 1%. The data indicate that some KCNA5 variants found in patients with PAH have critical consequences for channel function, supporting the idea that KCNA5 pathogenic variants may be a causative or contributing factor for PAH.

Sigma-1 receptor modulation fine-tunes KV1.5 channels and impacts pulmonary vascular function.

KV1.5 channels are key players in the regulation of vascular tone and atrial excitability and their impairment is associated with cardiovascular diseases including pulmonary arterial hypertension (PAH) and atrial fibrillation (AF). Unfortunately, pharmacological strategies to improve KV1.5 channel function are missing. Herein, we aimed to study whether the chaperone sigma-1 receptor (S1R) is able to regulate these channels and represent a new strategy to enhance their function. By using different electrophysiological and molecular techniques in X. laevis oocytes and HEK293 cells, we demonstrate that S1R physically interacts with KV1.5 channels and regulate their expression and function. S1R induced a bimodal regulation of KV1.5 channel expression/activity, increasing it at low concentrations and decreasing it at high concentrations. Of note, S1R agonists (PRE084 and SKF10047) increased, whereas the S1R antagonist BD1047 decreased, KV1.5 expression and activity. Moreover, PRE084 markedly increased KV1.5 currents in pulmonary artery smooth muscle cells and attenuated vasoconstriction and proliferation in pulmonary arteries. We also show that both KV1.5 channels and S1R, at mRNA and protein levels, are clearly downregulated in samples from PAH and AF patients. Moreover, the expression of both genes showed a positive correlation. Finally, the ability of PRE084 to increase KV1.5 function was preserved under sustained hypoxic conditions, as an in vitro PAH model. Our study provides insight into the key role of S1R in modulating the expression and activity of KV1.5 channels and highlights the potential role of this chaperone as a novel pharmacological target for pathological conditions associated with KV1.5 channel dysfunction.

Endovascular Versus Surgical Treatment for All Comer Patients With Prosthetic Bypass Graft Occlusion: The Multicentre ENSUPRO Study.

OBJECTIVE: Bypass surgery plays a key role in complex lower limb lesions. However, there is a lack of evidence regarding the management of symptomatic prosthetic bypass graft (PBG) occlusion. This study aimed to report outcomes following open, hybrid, or endovascular management of patients presenting with symptomatic PBG occlusion. METHODS: A multicentre, retrospective cohort study was conducted, including patients presenting with PBG occlusion between January 2014 and December 2021 from 18 centres. It assessed the comparative value of treatment strategies, including (1) recanalisation of native vessels, (2) endovascular treatment of the failed PBG, (3) hybrid treatment, and (4) open surgery. The primary outcome measure was amputation free survival (AFS, time to major amputation and or death), whereas all cause mortality, major amputation, PBG re-occlusion, target lesion revascularisation (TLR), and Rutherford category (RC) improvement during follow up were considered as secondary endpoints. RESULTS: Of 260 patients with occluded PBGs, 108 (41.5%) were treated endovascularly (24 [22.2%] by recanalisation of native vessels and 84 [77.7%] by PBG re-opening), 57 (21.9%) underwent hybrid revascularisation, and 58 (22.3%) had surgery. In addition, 27 (10.4%) were treated conservatively and 10 (3.8%) received systemic thrombolysis. With a median follow up of 1.4 (0.6 - 3.0) years, AFS was 95.5%, 76.4%, 45.5%, and 37.1%, respectively in Groups 1 - 4 (p = .007). Older age and non-endovascular treatment (HR 1.05 and 1.70; p < .01 for both) were independent predictors of poor AFS. Endovascular treatment was associated with lower rates of major amputation (p = .04), PBG re-occlusion (p < .001), and TLR (p = .037), and higher RC improvements (p < .001), whereas all cause mortality was comparable between treatment groups (p = .21). CONCLUSION: Endovascular treatment is associated with higher rates of AFS and RC improvement and lower rates of PBG re-occlusion and TLR in patients with PBG occlusion.

Editor's Choice - RANDOMisation Screening for Drug coated or Drug Eluting Device Randomised Trials Among Patients Undergoing Endovascular FemorOPopliteal Procedures (RANDOM-STOP study).

OBJECTIVE: The aim was to assess the proportion of patients undergoing endovascular therapy for femoropopliteal arterial disease (FP) who would be eligible to take part in seven major randomised controlled trials (RCTs) that investigated the efficacy of some of the currently available paclitaxel based (PTX) devices used in this clinical context. Various RCTs have shown a potential clinical benefit from the use of paclitaxel in FP endovascular therapy. Nonetheless, patients enrolled were highly selected and the generalisability of these findings in pragmatic cohorts is unclear. METHODS: Between 1 January and 31 December 2021, all consecutive patients who underwent endovascular procedures for symptomatic FP disease in 16 European centres were retrospectively screened and included in this analysis. The primary outcome measure was individual patient eligibility for inclusion into at least one of the seven RCTs. The reasons for exclusion (clinical and or radiological) as well as in hospital death and morbidity were also reported. RESULTS: A total of 1 567 consecutive patients (959 male, 61%), corresponding to 1 567 lower limbs, were included. Most patients (1 009 patients, 64.39%) were treated for chronic limb threatening ischaemia (CLTI). A total 1 280 patients (81.68%) were not eligible for inclusion in any of the evaluated RCTs. Of them, 741 (47.28%) were excluded for clinical and 1 125 (71.79%) for radiological reasons. CONCLUSION: The analysed RCTs assessing the efficacy or effectiveness of PTX based endovascular therapies do not seem representative of the patient population with FP disease receiving endovascular therapy in routine clinical practice.

Prognostic heterogeneity of adult B-cell precursor acute lymphoblastic leukaemia patients with t(1;19)(q23;p13)/TCF3-PBX1 treated with measurable residual disease-oriented protocols.

The prognosis of t(1;19)(q23;p13)/transcription factor 3-pre-B-cell leukaemia homeobox 1 (TCF3-PBX1) in adolescent and adult patients with acute lymphoblastic leukaemia (ALL) treated with measurable residual disease (MRD)-oriented trials remains controversial. In the present study, we analysed the outcome of adolescent and adult patients with t(1;19)(q23;p13) enrolled in paediatric-inspired trials. The patients with TCF3-PBX1 showed similar MRD clearance and did not have different survival compared with other B-cell precursor ALL patients. However, patients with TCF3-PBX1 had a significantly higher cumulative incidence of relapse, especially among patients aged ≥35 years carrying additional cytogenetic alterations. These patients might benefit from additional/intensified therapy (e.g. immunotherapy in first complete remission with or without subsequent haematopoietic stem cell transplantation).

Safety and preliminary efficacy on cognitive performance and adaptive functionality of epigallocatechin gallate (EGCG) in children with Down syndrome. A randomized phase Ib clinical trial (PERSEUS study).

PURPOSE: Although some caregivers are using epigallocatechin gallate (EGCG) off label in hopes of improving cognition in young adults with Down syndrome (DS), nothing is known about its safety, tolerability, and efficacy in the DS pediatric population. We aimed to evaluate safety and tolerability of a dietary supplement containing EGCG and if EGCG improves cognitive and functional performance. METHODS: A total of 73 children with DS (aged 6-12 years) were randomized. Participants received 0.5% EGCG (10 mg/kg daily dose) or placebo for 6 months with 3 months follow up after treatment discontinuation. RESULTS: In total, 72 children were treated and 66 completed the study. A total of 38 participants were included in the EGCG group and 35 in the placebo group. Of 72 treated participants, 62 (86%) had 229 treatment-emergent adverse events (AEs). Of 37 participants in the EGCG group, 13 (35%) had 18 drug-related treatment-emergent AEs and 12 of 35 (34%) from the placebo group had 22 events. In the EGCG group, neither severe AEs nor increase in the incidence of AEs related to safety biomarkers were observed. Cognition and functionality were not improved compared with placebo. Secondary efficacy outcomes in girls point to a need for future work. CONCLUSION: The use of EGCG is safe and well-tolerated in children with DS, but efficacy results do not support its use in this population.

Timing of chocolate intake affects hunger, substrate oxidation, and microbiota: A randomized controlled trial.

Eating chocolate in the morning or in the evening/at night, may differentially affect energy balance and impact body weight due to changes in energy intake, substrate oxidation, microbiota (composition/function), and circadian-related variables. In a randomized controlled trial, postmenopausal females (n = 19) had 100 g of chocolate in the morning (MC), in the evening/at night (EC), or no chocolate (N) for 2 weeks and ate any other food ad libitum. Our results show that 14 days of chocolate intake did not increase body weight. Chocolate consumption decreased hunger and desire for sweets (P < .005), and reduced ad libitum energy intake by ~300 kcal/day during MC and ~150 kcal/day during EC (P = .01), but did not fully compensate for the extra energy contribution of chocolate (542 kcal/day). EC increased physical activity by +6.9%, heat dissipation after meals +1.3%, and carbohydrate oxidation by +35.3% (P < .05). MC reduced fasting glucose (4.4%) and waist circumference (-1.7%) and increased lipid oxidation (+25.6%). Principal component analyses showed that both timings of chocolate intake resulted in differential microbiota profiles and function (P < .05). Heat map of wrist temperature and sleep records showed that EC induced more regular timing of sleep episodes with lower variability of sleep onset among days than MC (60 min vs 78 min; P = .028). In conclusion, having chocolate in the morning or in the evening/night results in differential effects on hunger and appetite, substrate oxidation, fasting glucose, microbiota (composition and function), and sleep and temperature rhythms. Results highlight that the "when" we eat is a relevant factor to consider in energy balance and metabolism.

TRAF3 alterations are frequent in del-3'IGH chronic lymphocytic leukemia patients and define a specific subgroup with adverse clinical features.

Interstitial 14q32 deletions involving IGH gene are infrequent events in chronic lymphocytic leukemia (CLL), affecting less than 5% of patients. To date, little is known about their clinical impact and molecular underpinnings, and its mutational landscape is currently unknown. In this work, a total of 871 CLLs were tested for the IGH break-apart probe, and 54 (6.2%) had a 300 kb deletion of 3'IGH (del-3'IGH CLLs), which contributed to a shorter time to first treatment (TFT). The mutational analysis by next-generation sequencing of 317 untreated CLLs (54 del-3'IGH and 263 as the control group) showed high mutational frequencies of NOTCH1 (30%), ATM (20%), genes involved in the RAS signaling pathway (BRAF, KRAS, NRAS, and MAP2K1) (15%), and TRAF3 (13%) within del-3'IGH CLLs. Notably, the incidence of TRAF3 mutations was significantly higher in del-3'IGH CLLs than in the control group (p < .001). Copy number analysis also revealed that TRAF3 loss was highly enriched in CLLs with 14q deletion (p < .001), indicating a complete biallelic inactivation of this gene through deletion and mutation. Interestingly, the presence of mutations in the aforementioned genes negatively refined the prognosis of del-3'IGH CLLs in terms of overall survival (NOTCH1, ATM, and RAS signaling pathway genes) and TFT (TRAF3). Furthermore, TRAF3 biallelic inactivation constituted an independent risk factor for TFT in the entire CLL cohort. Altogether, our work demonstrates the distinct genetic landscape of del-3'IGH CLL with multiple molecular pathways affected, characterized by a TRAF3 biallelic inactivation that contributes to a marked poor outcome in this subgroup of patients.

Prevalence of post-COVID-19 in patients with fibromyalgia: a comparative study with other inflammatory and autoimmune rheumatic diseases.

OBJECTIVES: To determine the prevalence and characteristics of post-COVID-19 (PC) in fibromyalgia (FM) patients. METHODS: Retrospective, multi-centric, observational study, comparing a group of FM patients (FM group) with another group of patients with other rheumatic diseases (RD group). COVID-19 diagnosis was established by positive polymerase chain reaction or antigen during acute infection or by positive antibodies thereafter. We considered PC diagnosis when symptoms remain after COVID-19. We collected the principal characteristics of COVID-19, the severity of fatigue, waking unrefreshed and cognitive impairment, and persistent symptoms. The American College of Rheumatology (ACR) criteria and the Combined Index of Severity in Fibromyalgia (ICAF) were collected in the FM group. RESULTS: RD group (n = 56) had more pneumonia (p = 0.001) and hospital admissions (p = 0.002), but the FM group (n = 78) had a higher number of symptoms (p = 0.002). The percentage of patients with PC was similar between groups (FM group 79.5%; RD group 66.1%, p = 0.081). FM group had more PC symptoms (p = 0.001), more impairment after COVID-19 (p = 0.002) and higher severity of fatigue, waking unrefreshed and cognitive impairment (p <  0.0001). Only loss of smell was more frequent in the FM group (p = 0.005). The FM group with PC (n = 29) showed more severity of the Combined Index of Severity in Fibromyalgia (ICAF) total score and physical factor after COVID-19, while emotional, coping factors and the ACR criteria did not change. CONCLUSIONS: The prevalence of PC in FM patients is similar to RD patients. In FM patients, the presence of PC does not appear to impact the severity of FM.

Experience With Unfavorable Iliac Access When Performing Fenestrated/Branched Endovascular Aneurysm Repair.

PURPOSE: To review a single-center experience with fenestrated and branched endovascular aneurysm repair (f/bEVAR) in patients with challenging iliac anatomies. MATERIALS AND METHODS: A retrospective review of the department's database identified 398 consecutive patients who underwent complex endovascular repair f/bEVAR between January 2010 and June 2018; of these, 67 had challenging accesses. The strategies implemented to overcome access issues were reviewed, using a dedicated scoring system to evaluate the access (integrating diameter, tortuosity, calcification, and previous open or endovascular repair). RESULTS: In this subgroup of patients, the most common graft design was a 4-vessel fenestrated endograft (27, 40.3%). Hostile access was due to small diameter (<7 mm) in 25 patients (37.3%) and/or concentric calcifications in 19 patients (26.9%). Mean iliac diameter was 5.5±2.6 mm on the right side and 6.0±2.5 mm on the left side. Previous open or endovascular aortoiliac repair had been performed in 15 patients (22.4%), and 20 patients (29.9%) had a stent previously implanted in at least 1 iliac artery, resulting in the inability to perform standard fenestrated repair with access from both sides. Five patients (7.5%) had a single patent iliac access. Eight distinctive strategies were identified to overcome these access issues, including the use of preloaded renal catheters in the endograft delivery system, angioplasty, graft modification (branches instead of fenestrations or 4 preloaded fenestrations), a conduit via a retroperitoneal approach, iliac artery recanalization, and/or the multiple puncture technique. Technical success was achieved in 62 cases (92.5%). Four patients had access complications and 1 died in the early postoperative period of multiorgan failure. Median follow-up was 24.6 months (IQR 7.2, 41.3). Clinical success at the end of follow-up was achieved in 57 patients (85.1%). During follow-up, 14 patients died, including 4 from an aorta-related cause. CONCLUSION: Dedicated strategies can be implemented to overcome hostile iliac access in patients with complex aneurysms when f/bEVAR is required. Typically, these maneuvers are associated with favorable outcomes.

Sonochemical degradation of neonicotinoid pesticides in natural surface waters. Influence of operational and environmental conditions.

Neonicotinoids sonochemical oxidation at high-frequency ultrasound (MHz range) has been carried out in ultrapure and natural surface-water matrices (river, reservoir and wastewater treatment plant effluent). To evaluate the influence of the operating variables, that is initial pollutant concentration, ultrasound frequency, ultrasound power, and pulse-stop time a Box-Behnken experimental design was planned. Optimal results were obtained using a frequency of 578 kHz, a power of 40 W L-1, with a pollutant concentration of 1 µM (for each pesticide), and using a pulse-stop time of 100 ms. The experimental data adjustment using the Langmuir-Hinshelwood heterogeneous kinetic model showed that neonicotinoids oxidation was carried out in the bubble-liquid interface by the attack of hydroxyl radicals. Experiments performed in the presence of radical scavengers, that is, methanol, ethanol and tert-butyl alcohol corroborated this reaction mechanism. The influence of some environmental conditions such as pH, presence of soluble inorganic species (Cl-, SO42-, NO3-, HPO42-, HCO3-) and soluble organic species (humic acids content) were established. Finally, the aqueous matrix's influence was investigated for three natural surface water cases, and the results were rationalized according to the main water physicochemical characteristics.

2',7'-dichlorofluorescin-based analysis of Fenton chemistry reveals auto-amplification of probe fluorescence and albumin as catalyst for the detection of hydrogen peroxide.

Fluorophore 2',7'-dichlorofluorescin (DCF) is the most frequently used probe for measuring oxidative stress in cells, but many aspects of DCF remain to be revealed. Here, DCF was used to study the Fenton reaction in detail, which confirmed that in a cell-free system, the hydroxyl radical was easily measured by DCF, accompanied by the consumption of H2O2 and the conversion of ferrous iron into ferric iron. DCF fluorescence was more specific for hydroxyl radicals than the measurement of thiobarbituric acid (TBA)-reactive 2-deoxy-D-ribose degradation products, which also detected H2O2. As expected, hydroxyl radical-induced DCF fluorescence was inhibited by iron chelation, anti-oxidants, and hydroxyl radical scavengers and enhanced by low concentrations of ascorbate. Remarkably, due to DCF fluorescence auto-amplification, Fenton reaction-induced DCF fluorescence steadily increased in time even when all ferrous iron was oxidized. Surprisingly, the addition of bovine serum albumin rendered DCF sensitive to H2O2 as well. Within cells, DCF appeared not to react directly with H2O2 but indirect via the formation of hydroxyl radicals, since H2O2-induced cellular DCF fluorescence was fully abolished by iron chelation and hydroxyl radical scavenging. Iron chelation in H2O2-stimulated cells in which DCF fluorescence was already increasing did not abrogate further increases in fluorescence, suggesting DCF fluorescence auto-amplification in cells. Collectively, these data demonstrate that DCF is a very useful probe to detect hydroxyl radicals and hydrogen peroxide and to study Fenton chemistry, both in test tubes as well as in intact cells, and that fluorescence auto-amplification is an intrinsic property of DCF.

KV1.5-KVß1.3 Recycling Is PKC-Dependent.

KV1.5 channel function is modified by different regulatory subunits. KVß1.3 subunits assemble with KV1.5 channels and induce a fast and incomplete inactivation. Inhibition of PKC abolishes the KVß1.3-induced fast inactivation, decreases the amplitude of the current KV1.5-KVß1.3 and modifies their pharmacology likely due to changes in the traffic of KV1.5-KVß1.3 channels in a PKC-dependent manner. In order to analyze this hypothesis, HEK293 cells were transfected with KV1.5-KVß1.3 channels, and currents were recorded by whole-cell configuration of the patch-clamp technique. The presence of KV1.5 in the membrane was analyzed by biotinylation techniques, live cell imaging and confocal microscopy approaches. PKC inhibition resulted in a decrease of 33 ± 7% of channels in the cell surface due to reduced recycling to the plasma membrane, as was confirmed by confocal microscopy. Live cell imaging indicated that PKC inhibition almost abolished the recycling of the KV1.5-KVß1.3 channels, generating an accumulation of channels into the cytoplasm. All these results suggest that the trafficking regulation of KV1.5-KVß1.3 channels is dependent on phosphorylation by PKC and, therefore, they could represent a clinically relevant issue, mainly in those diseases that exhibit modifications in PKC activity.

BDD electrochemical oxidation of neonicotinoid pesticides in natural surface waters. Operational, kinetic and energetic aspects.

Neonicotinoids pesticides were introduced to the market in the 1990s to control various pests. Its accumulation in the environment supposes a severe problem that can affect human health. This study investigates the electrochemical degradation of four common neonicotinoid pesticides; thiamethoxam (TMX), imidacloprid (ICP), acetamiprid (ACP) and thiacloprid (TCP), in different natural surface waters by a boron-doped diamond anode (BDD). The most influencing variable was the current density (j), and to a lesser extent, the supporting electrolyte concentration (Ce). In optimal conditions (j = 34.14 mA cm-2 and Ce = 10.00 mM, using Na2SO4 as electrolyte) pesticide removals for TMX, ICP, ACP and TCP were 97.2, 96.9, 87.8 and 98.2 %, respectively. The obtained results with different support electrolytes (Na2SO4, NaCl, NaNO3 and HK2PO4) suggest that sulphate electrolyte was the optimum for TMX, ICP and ACP. However, for TCP, a total removal was achieved in less than 10 min using NaCl. It was also verified that the initial pH of the solution did not significantly influence the process in the range 3-9. All these results were rationalized in this paper. Finally, to evaluate the matrix influence, some experiments were carried out in different natural surface water matrices (river, reservoir and two different WWTP effluents). The factors influencing the process were the conductivity of the solution and the organic matter content. It was noticeable that the specific energy consumption (SEC) reduced by approximately 15 % for river water and WWTP effluent. High mineralization rates were obtained for all water matrices, with TOC removals ranging between 60 and 80 %.

Chronic lymphocytic leukemia patients with IGH translocations are characterized by a distinct genetic landscape with prognostic implications.

Chromosome 14q32 rearrangements/translocations involving the immunoglobulin heavy chain (IGH) are rarely detected in chronic lymphocytic leukemia (CLL). The prognostic significance of the IGH translocation is controversial and its mutational profile remains unknown. Here, we present for the first time a comprehensive next-generation sequencing (NGS) analysis of 46 CLL patients with IGH rearrangement (IGHR-CLLs) and we demonstrate that IGHR-CLLs have a distinct mutational profile with recurrent mutations in NOTCH1, IGLL5, POT1, BCL2, FBXW7, ZMYM3, MGA, BRAF and HIST1H1E genes. Interestingly, BCL2 and FBXW7 mutations were significantly associated with this subgroup and almost half of BCL2, IGLL5 and HISTH1E mutations reported were previously identified in non-Hodgkin lymphomas. Notably, IGH/BCL2 rearrangements were associated with a lower mutation frequency and carried BCL2 and IGLL5 mutations, while the other IGHR-CLLs had mutations in genes related to poor prognosis (NOTCH1, SF3B1 and TP53) and shorter time to first treatment (TFT). Moreover, IGHR-CLLs patients showed a shorter TFT than CLL patients carrying 13q-, normal fluorescence in situ hybridization (FISH) and +12 CLL, being this prognosis particularly poor when NOTCH1, SF3B1, TP53, BIRC3 and BRAF were also mutated. The presence of these mutations not only was an independent risk factor within IGHR-CLLs, but also refined the prognosis of low-risk cytogenetic patients (13q-/normal FISH). Hence, our study demonstrates that IGHR-CLLs have a distinct mutational profile from the majority of CLLs and highlights the relevance of incorporating NGS and the status of IGH by FISH analysis to refine the risk-stratification CLL model.

Genome-wide transcriptomics leads to the identification of deregulated genes after deferasirox therapy in low-risk MDS patients.

The iron chelator deferasirox is widely used in patients with iron overload. Patients with low-grade myelodysplastic syndromes (MDS) get transfusion dependency and need to be treated with deferasirox to avoid iron overload. Moreover, in some patients an increase in both erythroid and platelets have been observed after deferasirox therapy. However, the mechanisms involved in these clinical findings are poorly understood. The aim of this work was to analyze, in patients treated with deferasirox, the changes in the gene-expression profile after receiving the treatment. A total of 15 patients with the diagnosis of low-grade MDS were studied. Microarrays were carried out in RNA from peripheral blood before and after 14 weeks of deferasirox therapy. Changes in 1457 genes and 54 miRNAs were observed: deferasirox induced the downregulation of genes related to the Nf kB pathway leading of an overall inactivation of this pathway. In addition, the iron chelator also downregulated gamma interferon. Altogether these changes could be related to the improvement of erythroid response observed in these patients after therapy. Moreover, the inhibition of NFE2L2/NRF2, which was predicted in silico, could be playing a critical role in the reduction of reactive oxygen species (ROS). Of note, miR-125b, overexpressed after deferasirox treatment, could be involved in the reduced inflammation and increased hematopoiesis observed in the patients after treatment. In summary this study shows, for the first time, the mechanisms that could be governing deferasirox impact in vivo.

Women undergoing endovascular thoracoabdominal aortic aneurysm repair differ significantly from their male counterparts preoperatively and postoperatively.

OBJECTIVE: A rational approach to the management of aortic aneurysm disease relies on weighing the risk of aneurysm rupture against the complications and durability of operative repair. In men, seminal studies of infrarenal aortic aneurysm disease and its endovascular management can provide a reasoned argument for the timing and modality of surgery, which is then extrapolated to the management of thoracoabdominal aortic aneurysms (TAAAs). In contrast, there is less appreciation for the natural history of TAAA disease in women and its response to therapy. METHODS: We used a retrospective cohort design of women, all men, and matched men, fit for complex endovascular thoracoabdominal aneurysm repair at two large aortic centers. We controlled for preoperative anatomic and comorbidity differences, and assessed technical success, postoperative renal dysfunction, spinal ischemia, and early mortality. Women and matched men were reassessed at follow-up for long-term durability and survival. RESULTS: Assessing women and all men undergoing complex endovascular aortic reconstruction, we demonstrate that these groups are dissimilar before the intervention with respect to comorbidities, aneurysm extent, and aneurysm size; women have a higher proportion of proximal Crawford extent 1, 2, and 3 aneurysms. Matching men and women for demographic and anatomic differences, we find persistent elevated perioperative mortality in women (16%) undergoing endovascular thoracoabdominal aneurysm repair compared with matched men (6%); however, at the 3-year follow-up, both groups have the same survival. Furthermore, women demonstrate more favorable anatomic responses to aneurysm exclusion, with good durability and greater aneurysm sac regression at follow-up, compared with matched men. CONCLUSIONS: Women and unmatched men with TAAA disease differ preoperatively with respect to aneurysm extent and comorbidities. Controlling for these differences, after complex endovascular aneurysm repair, there is increased early mortality in women compared with matched men. These observations argue for a careful risk stratification of women undergoing endovascular thoracoabdominal aneurysm treatment, balanced with women's good long-term survival and durability of endovascular aneurysm repair.

Coronavirus disease 2019 (COVID-19) in autoimmune and inflammatory conditions: clinical characteristics of poor outcomes.

OBJECTIVE: To describe clinical characteristics of patients with rheumatic and musculoskeletal diseases (RMDs) and immunosuppressive therapies with Coronavirus disease 2019 (COVID-19) at an academic rheumatology center in Madrid and to identify baseline variables associated with a severe infection requiring hospitalization. METHODS: We identified SARS-CoV-2 positive cases by polymerase chain reaction performed at our center within an updated RMDs database in our clinic. Additional RMDs patients were identified when they contacted the clinic because of a positive infection. Data extraction included diagnosis, demographics, immunosuppressive treatment, comorbidities, and laboratory tests. Comparisons between patients with or without hospitalization were performed. Multivariate logistic regression was used to analyze associations between baseline variables and need for hospitalization. RESULTS: A total of 62 patients with COVID-19 and underlying RMDs were identified by April 24, 2020. Median age was 60.9 years, and 42% men. Forty-two patients required hospitalization; these were more frequently men, older and with comorbidities. There were no statistically significant between-group differences for rheumatologic diagnosis and for baseline use of immunosuppressive therapy except for glucocorticoids that were more frequent in hospitalized patients. Total deaths were 10 (16%) patients. In multivariate analysis, male sex (odds ratio [OR], 8.63; p = 0.018), previous lung disease (OR, 27.47; p = 0.042), and glucocorticoids use (> 5 mg/day) (OR, 9.95; p = 0.019) were significantly associated to hospitalization. CONCLUSION: Neither specific RMD diagnoses or exposures to DMARDs were associated with increased odds of hospitalization. Being male, previous lung disease and exposure to glucocorticoids were associated with higher odds of hospitalization in RMDs patients.