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Summary: Idiopathic hypertrophy of the masseter muscle is a rare disorder of unknown cause. Some authors associate it with the habit of chewing gum, temporo-mandibular joint disorder, congenital and functional hypertrophies, and emotional disorders (stress and nervousness). Most patients complain of the cosmetic change caused by facial asymmetry, also called square face, however, symptoms such as trismus, protrusion and bruxism may also occur. The goals of the present investigation were: to report a case of idiopathic masseter hypertrophy, describe its symptoms and treatment. The patient reported bilateral bulging in the region of the mandible angle, of slow and progressive evolution. He did not complain of pain or discomfort, however there was bilateral otalgia, nighttime trismus and stress. In his physical exam we noticed bilateral masseter hypertrophy without local inflammatory alterations. We indicated surgical treatment with an extraoral approach. Complementary tests are indicated when there is diagnostic doubts. Treatment varies from conservative to surgical, and the later depends on surgeon skill and experience. Keywords: anxiety, hypertrophy, muscle

Conduction system pacing (CSP) has emerged as a promising alternative to biventricular pacing (BVP) in patients with heart failure with reduced ejection fraction (HFrEF) and ventricular dyssynchrony, but its benefits are uncertain. In this study, we aimed to evaluate clinical outcomes of CSP vs BVP for cardiac resynchronization in patients with HFrEF. PubMed, Scopus, and Cochrane databases were searched for randomized controlled trials comparing CSP to BVP for resynchronization therapy in patients with HFrEF. Heterogeneity was examined with I 2 statistics. A random-effects model was used for all outcomes. We included 7 randomized controlled trials with 408 patients, of whom 200 (49%) underwent CSP. Compared to BVP, CSP resulted in a significantly greater reduction in QRS duration (MD -13.34 ms; 95% confidence interval [CI] -24.32 to -2.36, P = .02; I 2 = 91%) and New York Heart Association functional class (standardized mean difference [SMD] -0.37; 95% CI -0.69 to -0.05; P = .02; I 2 = 41%), and a significant increase in left ventricular ejection fraction (mean difference [MD] 2.06%; 95% CI 0.16 to 3.97; P = .03; I 2 = 0%). No statistical difference was noted for left ventricular end-systolic volume (SMD -0.51 mL; 95% CI -1.26 to 0.24; P = .18; I 2 = 83%), lead capture threshold (MD -0.08 V; 95% CI -0.42 to 0.27; P = .66; I 2 = 66%), and procedure time (MD 5.99 minutes; 95% CI -15.91 to 27.89; P = .59; I 2 = 79%). These findings suggest that CSP may have electrocardiographic, echocardiographic, and symptomatic benefits over BVP for patients with HFrEF requiring cardiac resynchronization., Competing Interests: Disclosures The authors have no conflicts to disclose., (Copyright © 2024 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Most patients with solitary bone plasmacytomas (SBP) progress to multiple myeloma (MM) after definitive radiation therapy as their primary treatment. Whether the presence of high-risk (HR) cytogenetic abnormalities by fluorescence in situ hybridization (FISH) in the clonal plasma cells, obtained either directly from the diagnostic SBP tissue or the corresponding bone marrow examination at the time of diagnosis, is associated with a shorter time to progression (TTP) to MM is unknown. This study evaluated all patients diagnosed with SBP at the Mayo Clinic from January 2012 to July 2022. The presence of del(17p), t(14;16), t(4;14), or +1q (gain or amplification) by FISH in clonal plasma cells was defined as HR. A total of 114 patients were included in this cohort, and baseline FISH was available for 55 patients (48%), of which 22 were classified as HR (40%). The median TTP to MM for patients with SBP and HR FISH was 8 months (95% confidence interval [CI], 6.3-26) compared with 42 months (95% CI, 25-not reached [NR]) in patients with SBP without HR FISH (P < .001). In a multivariate analysis, only HR FISH was a significant predictor for shorter TTP to MM, independent of minimal marrow involvement and an abnormal serum free light chain ratio at diagnosis. Deletion (17p) and gain 1q abnormalities were the most common FISH abnormalities responsible for the short TTP to MM. Thus, assessing for HR FISH abnormalities in clonal plasma cells derived from either the diagnostic SBP tissue or the staging bone marrow examination of patients with newly diagnosed SBP is feasible and prognostic for a shorter TTP to MM., (© 2023 by The American Society of Hematology.)

Iontophoresis, a non-invasive application of a constant low-intensity electric current, is a promising strategy to accelerate wound healing. Although its mechanisms are not yet fully elucidated, part of its action seems related to inhibiting bacteria growth. This work aimed to investigate the antimicrobial effect of iontophoresis using Staphylococcus epidermidis and Escherichia coli strains, Gram-positive and Gram-negative bacteria, respectively. Anodic iontophoresis was applied to each bacterial suspension using Ag/AgCl electrodes, and bacteria viability was evaluated after 24 h incubation by counting colony-forming units. A Quality-by-Design approach was performed to assess the influence of the iontophoresis' intensity and application time on bacterial viability. Cell morphology was evaluated by scanning electron microscopy. Iontophoresis showed antimicrobial effects on the Gram-positive bacteria only at 5 mA and 60 min application. However, a linear relationship was observed between intensity and application time for the Gram-negative one, causing drastic morphological changes and up to 98 % death. The cell wall of Gram-negative bacteria seems more susceptible to disorganization triggered by iontophoresis-induced ion transport than Gram-positive ones. Therefore, anodic iontophoresis can be a powerful ally in controlling Gram-negative bacteria proliferation in wounds., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

COVID-19 adversely affects individuals with cancer. Several studies have found that seroconversion rates among patients with hematologic malignancies are suboptimal when compared to patients without cancer. Patients with non-Hodgkin lymphoma (NHL) and multiple myeloma (MM) are immunocompromised due to impaired humoral and cellular immunity in addition to prescribed immunosuppressive therapy. Chimeric antigen receptor T-cell (CAR T) therapy is now widely used for NHL and MM, but little is known about seroconversion rates after COVID-19 vaccination among these populations. We evaluated SARS-CoV-2 spike-binding IgG antibody levels following COVID-19 vaccination among NHL and MM CAR T therapy recipients. Out of 104 CAR T infusions, 19 patients developed known COVID-19 infection post-CAR T. We tested 17 patients that received CAR T for antibody spike titers post COVID-19 vaccination, only 29 % (n = 5) were able to mount a clinically relevant antibody response (>250 IU/mL)., Competing Interests: Disclosure JM receives consulting fees from Pharmacyclics/Abbvie, Bayer, Gilead/Kite Pharma, Pfizer, Janssen, Juno/Celgene, BMS, Kyowa, Alexion, Fosunkite, Innovent, Seattle Genetics, Debiopharm, Karyopharm, Genmab, ADC Therapeutics, Epizyme, Beigene, Servier, Novartis, Morphosys/Incyte, Secura Bio, TG Therapeutics, MEI, Lilly/Loxo; research funding from Bayer, Gilead/Kite Pharma, Celgene, Merck, Portola, Incyte, Genentech, Pharmacyclics, Seattle Genetics, Janssen, Millennium; Honoraria from Targeted Oncology, OncView, Curio, Kyowa, Physicians' Education Resource, and Seattle Genetics. Speaker's bureau from Gilead/Kite Pharma, Kyowa, Bayer, Pharmacyclics/Janssen, Seattle Genetics, Acrotech/Aurobindo, Beigene, Verastem, AstraZeneca, Celgene/BMS, Genentech/Roche. PV receives funds from DSMB from AbbVie, Vanda, Algernon; research from Cidara, Scynexis and fees paid to Mayo Clinic. PLB receives consulting and honoraria funding from Pfizer, Novartis, Janssen, Clgene, GSK, Genetech, and Oncopeptides. YW has financial research funding from InnoCare, Novartis, Genentech, MorphoSys and Membership on an entity's Board of Directors or advisory committees and research Funding with Incyte, LOXO Oncology, Eli Lilly, and TG Therapeutics. RF is a consultant for Amgen, BMS, Celgene, Takeda, Bayer, Janssen, Novartis, Pharcyclics, Sanofi, Merck, Juno, Kite, Aduro, OncoTracker, GSK, AbbVie, Patents and Royalties from Patent: Prognostication of myeloma via FISH and Membership on an entity's Board of Directors or advisory committees from OncoTracker, Adaptive Biotechnologies, and Caris Life Sciences. JMP receives research funding from PharmaEssentia, Incyte and consultancy and research funding from Protagonist, CTI BioPharma, and Sierra Oncology. DD receives consultancy fees from Alexion, Apellis, GSK, Sanofi, Janssen and research funding from Novartis. SK receives consultancy and research funding from BMS, Abbvie, Amgen, Takeda, Janssen, KITE, Astra-Zeneca, Roche-Genentech; consultancy fees from Beigene, Oncopeptides, and Bluebird Bio, and research funding from Tenebio, Carsgen, Merck, and Novartis. JP receives research funding from Karyopharm. SMA receives research funding from Bristol Myers Squibb, ADC Therapeutics, Seattle Genetics, Regeneron, Affimed, AI Therapeutics, Pfizer, Trillium, and Takeda. YL receives consultancy fees from Novartis, Juno, Legend, Sorrento, Gamida Cell; research funding from Merck and Takeda and consultancy and research funding from Kite, Janssen, Celgene, and Bluebird Bio. HSM receives research funding from CRISPR therapeutics., (Copyright © 2023 Elsevier Inc. All rights reserved.)

This systematic literature review (SLR) was conducted to better understand the impact of disease progression, line of therapy, and clinical response on health-related quality of life (HRQoL) in patients with multiple myeloma (MM). Multiple databases were searched to identify records relating to HRQoL in adult patients with MM. Titles and abstracts were independently screened by 2 reviewers for inclusion based on pre-defined criteria. Records flagged for inclusion had full texts subsequently screened using the same method. A third round of screening was then conducted to identify studies that assessed the relationship of HRQoL to disease progression, line of therapy, or clinical response. Quality assessment was conducted on utility studies using the National Institute for Health and Care Excellence Quality Assessment Checklist for Health State Utility Values. After all rounds of screening were complete, 44 records (representing 41 studies) were included in the SLR. Thirty records reported data relating HRQoL to disease progression, 5 reported data relating HRQoL to line of therapy, and 19 reported data relating HRQoL to response. Despite a lack of homogeneity and small number of studies, the data show overall that progressive disease and increasing lines of therapy were associated with worsened patient HRQoL and increasing depth of response was associated with improved patient HRQoL. The findings from this SLR support that desirable treatment outcomes such as delayed progression, fewer lines of therapy, and achieving the deepest possible clinical response result in improved HRQoL in patients with MM., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

While anthropogenic pollutants have decreased during the lockdown imposed as an effort to contain the spread of the Coronavirus disease 2019 (COVID-19), changes in particulate matter (PM) do not necessarily exhibit the same tendency. This is the case for the eastern Arabian Peninsula, where in March-June 2020, and with respect to the same period in 2016-2019, a 30 % increase in PM concentration is observed. A stronger than normal nocturnal low-level jet and subtropical jet over parts of Saudi Arabia, in response to anomalous convection over the tropical Indian Ocean, promoted enhanced and more frequent episodes of Shamal winds over the Arabian Peninsula. Increased surface winds associated with the downward mixing of momentum to the surface fostered, in turn, dust lifting and increased PM concentrations. The stronger low-level winds also favoured long-range transport of aerosols, changing the PM values downstream. The competing effects of reduced anthropogenic and increased dust concentrations leave a small positive signal (<5 W m -2 ) in the net surface radiation flux (R net ), with the former dominating during daytime and the latter at night. However, in parts of the Arabian Gulf, Sea of Oman and Iran R net increased by >20 W m -2 with respect to the baseline period, owing to a clearer environment and weaker winds. It is concluded that a reduction in anthropogenic emissions due to the lockdown does not necessarily go hand in hand with lower particulate matter concentrations. Therefore, emissions reduction strategies need to account for feedback effects in order to reach the planned long-term outcomes., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors.)

Objectives: Identify risk factors associated with increased hospital admission and mortality due to dengue fever (DF), and estimate the risk magnitude associated with each individual variable., Methods: Records of patients diagnosed with dengue were obtained from the Mexican National Epidemiological Surveillance System. Descriptive statistics were performed in all variables. Demographic characteristics and comorbidities were compared between patients based on type of care and mortality. Multivariable analysis was done with a logistic regression model, using two different outcomes: hospitalization and mortality., Results: A total of 24,495 patients were included in the analysis, with a DF case fatality rate of 0.58%. Patients younger than 10 and older than 60, were found to have a greater risk of both hospitalization and mortality due to DF. Comorbidities associated with a higher risk for hospital admission include cirrhosis, CKD, immunosuppression, diabetes, and hypertension. For mortality, CKD, diabetes, and hypertension were identified as risk factors, along with pregnancy., Conclusion: Identification of risk factors associated with increased hospitalization and mortality due to DF can help categorize patients that require close monitoring and inpatient care. Early identification of warning signs and patients at increased risk is key to avoiding delay of supportive care., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: Neoadjuvant chemoradiotherapy (nCRT) followed by surgery in patients with resectable esophageal or esophagogastric junctional (GEJ) (Siewert I) cancer is associated with long term overall survival benefits. Up to one third of all patients submitted to nCRT present pathological complete response (pCR). 18 F-fluorodeoxyglucose positron emission tomography with CT ( 18 F-FDG PET-CT) is an important tool for assessing treatment response. Purpose was to assess retrospectively the power of 18 F-FDG PET-CT in predicting pCR to evaluate the feasibility of a "watch and wait" approach., Patients and Methods: Retrospective analysis of a prospective database with esophageal or GEJ submitted to pre-operative chemoradiation. Pre and pos treatment 18 F-FDG PET-CT were reviewed and classified using visual assessment and PERCIST criteria and the values of maximum standard uptake value were also recorded. Patients were classified as pCR or non-PCR. 18 F-FDG PET-CT and pathological findings were compared against each other., Results: Forty-three patients were included. The median age was 67 years and 90.7% were male. All patients underwent preoperative CRT and were evaluated with 18 F-FDG PET-CT pre and post treatment. Transthoracic surgery was performed in all patients. Histological type was adenocarcinoma in 37% and squamous cell carcinoma in 58%. pCR was achieved in 56% of cases. Visual assessment of 18 F-FDG PET-CT showed overall sensitivity 57.9%, specificity 62.5% and PERCIST criteria had 100% sensibility and 16.7% specificity., Conclusions: 18 F-FDG PET-CT is not an ideal predictor of pCR but if we use the PERCIST criteria we will have a high sensitivity and negative predictive value, avoiding false negative scans., (Copyright © 2020 Société française de radiothérapie oncologique (SFRO). Published by Elsevier Masson SAS. All rights reserved.)

Osteochondral lesions of the glenoid are not so uncommon after traumatic cases of shoulder dislocation and can be a challenge to the shoulder surgeon because of the technical difficulty and the potential to progression to shoulder arthritis. An all-arthroscopic technique of fixation of a large osteochondral fragment is used to allow optimal visualization and reduction, minimize the morbidity of the open approach, and provide good functional results., (© 2020 by the Arthroscopy Association of North America. Published by Elsevier.)

Objectives: In the field of relapsed or refractory multiple myeloma (RRMM), between-trial or indirect comparisons are required to estimate relative treatment effects between competing interventions based on the available evidence. Two approaches are frequently used in RRMM: network meta-analysis (NMA) and unanchored matching-adjusted indirect comparison (MAIC). The objective of the current study was to evaluate the relevance and credibility of published NMA and unanchored MAIC studies aiming to estimate the comparative efficacy of treatment options for RRMM., Methods: Twelve relevant studies were identified in the published literature (n = 7) and from health technology assessment agencies (n = 5). Data from trials were extracted to identify between-trial differences that may have biased results. Credibility of the performed analyses and relevance of the research questions were critically appraised using the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) checklist and feedback based on consultations with clinical experts., Results: The identified studies concerned NMAs of randomized controlled trials (RCTs; n = 7), unanchored MAICs (n = 4), or both types of analyses (n = 1). According to clinical expert consultation, the majority of the identified NMAs did not consider differences in prior therapies or treatment duration across the RCTs included in the analyses, thereby compromising the relevance., Conclusion: Based on the results and feedback from clinicians, the majority of NMAs did not consider prior treatment history or treatment duration, which resulted in nonrelevant comparisons. Furthermore, it may have compromised the credibility of the estimates owing to differences in effect-modifiers between the different trials. Pairwise comparisons by means of unanchored MAICs require clear justification given the reliance on non-randomized comparisons., (Copyright © 2020 ISPOR–The Professional Society for Health Economics and Outcomes Research. Published by Elsevier Inc. All rights reserved.)

Bioabsorbable polymeric fixation devices have been used as an alternative to metallic implants in orthopedics, preventing the stress shielding effect and avoiding a second surgery for implant removal. However, several problems are still associated with current bioabsorbable implants, including the limited mechanical stiffness and strength, and the adverse tissue reactions generated. To minimize or even eliminate the problems associated with these implants, strategies have been developed to synthesize new implant materials based on chitosan. To overcome the brittle behavior of most 3D chitosan-based structures, glycerol and sorbitol were blended to chitosan and the effect of these plasticizers in the produced specimens was analyzed by flexural tests, Berkovich tests, scanning electron microscopy (SEM) and micro-CT analyzes. The improvement of the mechanical properties was also tested by adding ceramics, namely hydroxyapatite powder and biphasic mixtures of hydroxyapatite (HA) and beta-tricalcium phosphate (β-TCP). In the plasticizers group, the best combination of the measured properties was obtained for chitosan with 10% glycerol (flexural strength of 53.8 MPa and indentation hardness of 19.4 kgf/mm 2 ), while in the ceramics group the best mechanical behavior was obtained for chitosan with 10% HA+β-TCP powder (flexural strength of 67.5 MPa and indentation hardness 28.2 kgf/mm 2 ). All the tested material compositions were dense and homogeneous, fundamental condition for a good implant performance. These are encouraging results, which support the continued development of chitosan-based materials for orthopedic fixation applications., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Objectives: To identify factors limiting and facilitating patient-centered communication (PCC) in the United States hematology-oncology setting, with a focus on multiple myeloma (MM), given the limited attention to PCC and rapid pace of change that has taken place in this setting., Methods: A literature search was performed from 2007 to 2017 to identify published articles and congress abstracts related to clinician-patient communication and treatment decision-making in oncology. Search results were evaluated by year of publication and disease area. A thematic assessment was performed to identify factors limiting and promoting PCC for patients with MM and other hematologic malignancies., Results: Of the 6673 publications initially retrieved, 18 exclusively reported findings in patients with hematologic malignancies and were included in this review. We identified three critical, but modifiable, barriers to PCC in the hematologic malignancy setting, including insufficient information exchange, treatment goal misalignment, and discordant role preferences in treatment decision-making. Factors that enhanced interaction quality included educational programs for clinicians and patients., Conclusions: Patients with MM and other hematologic malignancies experience a distinct set of challenges that may affect PCC., Practice Implications: Clinicians have the opportunity to improve patient care by proactively addressing the identified barriers and implementing strategies demonstrated to improve PCC., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Skeletal-related events (SREs) are common bone complications in multiple myeloma (MM). However, there are few real-world reports of their incidence. In this study, a database of oncology electronic health records was linked to administrative claims data. Patients identified were aged ≥18 years and newly diagnosed with MM, had ≥1 clinic visit within 1 month of diagnosis, and ≥1 year of follow-up after diagnosis. The study period was January 1, 2011 to December 31, 2016. 343 patients were included, 35% of whom had a baseline history of any SRE. During a median follow-up of 25.7 months, 34% of patients experienced SREs after diagnosis. Median time to SRE was 167 days. Among patients experiencing an SRE, 68% had an SRE within the first year. The incidence rate of SREs at 1 year following MM diagnosis for patients with baseline history was 103/100 person-years (PY) versus 16/100PY for patients without baseline history. SRE incidence rates within 3 months of initiating a line of therapy increased with subsequent lines (line 1: 81/100PY, line 2: 118/100PY, line 3: 150/100PY). Risk of SREs was similar across different anti-MM regimens, including proteasome inhibitor-based regimens. These results highlight the importance of continued surveillance and management of MM-associated bone disease.

Carbohydrate binding modules (CBMs) are non-catalytic domains within larger multidomain polypeptides. The CelH from Ruminoclostridium (Clostridium) thermocellum contains a family 11 CBM (RtCBM11) with high binding affinity for the linear polysaccharide β-glucan, and low affinity for the branched xyloglucan. Screening a random RtCBM11 mutant phage library created by error prone PCR for xyloglucan binding identified RtCBM11 mutants with enhanced xyloglucan affinity. Subsequent recombination of the selected variants by site-directed mutagenesis generated the H102L/Y152F and Y46N/G52D/H102L/Y152F mutants. Fusion of the quadruple RtCBM11 mutant with the xyloglucanase from Aspergillus niveus increased the catalytic efficiency of the enzyme by 38%. Isothermal titration calorimetry demonstrated increased xyloglucan affinity for both mutants and reduced affinity for β-glucan in the H102L/Y152F mutant. Molecular dynamics simulations indicated that the increased xyloglucan specificity results both from formation of a xylosyl binding pocket in the carbohydrate binding cleft, and via modulation of a hydrogen bond network between the oligosaccharide ligand and the protein. These results explain the improved xyloglucan binding in the RtCBM11 H102L/Y152F mutant and advance the understanding of the structural determinants of CBMs binding that discriminate between branched and unbranched polysaccharides., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Objectives: This study sought to identify whether atrial strain could be used as an imaging biomarker to predict atrial fibrillation (AF)., Background: AF is found in up to 30% of cryptogenic cerebrovascular accidents (CVAs), which themselves account for 30% to 40% of ischemic CVA., Methods: This observational study evaluated all patients who had an echocardiogram (transthoracic echocardiogram [TTE]) following presentation with cryptogenic CVA from 2010 to 2014. The TTEs were evaluated for reservoir strain (ƐR), contractile strain (ƐCt), and conduit atrial strain (ƐCd) using speckle tracking. Baseline clinical and TTE characteristics of patients who developed AF over 5 years of follow-up and those who did not were compared. The independent and incremental predictive value of atrial strain over established clinical models was assessed. Discriminatory cutpoints were defined using a Classification and Regression Tree (CART) analysis to identify patients at risk of developing AF., Results: Of 538 patients, 61 (11%) developed AF, and this occurred within 2 years in 85% of patients. Patients who developed AF were older, had higher clinical risk scores, had higher LA volume, and had lower atrial strain than did those who did not develop AF. The area under the receiver-operating characteristic curve was 0.85 for ƐR, 0.83 for ƐCt, and 0.76 for ƐCd (all p < 0.001). The nested Cox regression model showed that ƐR (p = 0.03) and ƐCt (p < 0.001) demonstrated independent and incremental predictive value over the clinical risk. CART analysis identified ƐR ≤21.4%, ƐCd >10.4%, and CHARGE-AF (Cohorts for Heart and Aging Research in Genomic Epidemiology Atrial Fibrillation) score >7.8% as discriminatory for AF, with a 13-fold greater hazard of AF (p < 0.001) in patients with increased clinical risk and reduced ƐR. However, validation is needed for these strain cutoffs for detection of AF., Conclusions: Left atrial strain adds independent and incremental predictive value to current risk-prediction models for AF following cryptogenic CVA. Further studies should examine the implications of these findings for AF monitoring or empiric anticoagulation., (Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: The hematologic response is critical in patients with light chain amyloidosis because a good response is known to improve organ response and overall survival. We present a retrospective analysis to compare the hematologic and organ response in patients who received bortezomib-based therapy before autologous stem cell transplantation (ASCT) versus those who received non-bortezomib-based therapy before ASCT and those who underwent ASCT at diagnosis., Patients and Methods: Of a total of 63 patients who underwent ASCT for light chain amyloidosis, 34 received bortezomib-based therapy before ASCT (Bor-ASCT) and 29 did not receive bortezomib therapy (non-Bor-ASCT). A greater number of patients had involvement of ≥ 3 organs and cardiac involvement in the Bor-ASCT group, suggesting a greater risk at baseline in the Bor-ASCT group., Results: At 3, 6, and 12 months after ASCT, the hematologic response was better in the Bor-ASCT group, with a statistically significance difference at 6 months (partial response or better in 82% vs. 20%; P = .002) and 12 months (partial response or better in 76% vs. 33%; P = .02). Organ responses (66% vs. 21%; P < .001) and median overall survival (not reached vs. 53 months; P = .001) were also greater in the Bor-ASCT group., Conclusion: Our study has shown that bortezomib-based therapy before ASCT improves the hematologic response, organ response and overall survival, potentially by decreasing the light chain load before ASCT., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Fabry disease (FD) is a lysosomal storage disorder (LSD) that involves the cochleovestibular system. Tinnitus and progressive sensorineural hearing loss are frequent complains. A stabilization of hearing function has been reported with enzyme replacement therapy (ERT). This study aims to characterize the inner ear involvement, identify factors associated to hearing loss and evaluate the effect of ERT on the hearing function of FD patients., Methods: We reviewed the clinical records of patients with confirmed diagnosis of FD followed in a Reference Centre on LSD in the North of Portugal., Results: We included a total of 122 patients with a mean age of 47.1 ± 17.6 years and 48.3% males. Hearing loss was reported by 26.2% of the patients and 23.0% mentioned tinnitus. Pure tone audiometry revealed sensorineural hearing loss in 36.9% of the cases. FD patients presented worse age-adjusted hearing thresholds in all analysed frequencies compared to the normal population (p = .001). Patients with hearing loss presented a significantly higher value of microalbuminuria (p = .001) and a higher frequency of acroparesthesias (p = .032). Patients presented a comparable hearing level one year after starting ERT (p = .384)., Conclusions: In FD, hearing loss is common and age-matched hearing thresholds by frequency are worse than in the general population. Hearing loss was associated to the presence of acroparesthesias and higher values of microalbuminuria. Hearing loss stabilized in patients under ERT. A careful cochleo-vestibular evaluation should be part of the clinical assessment of FD., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Background: Golgi Reassembly and Stacking Proteins (GRASPs) are widely spread among eukaryotic cells (except plants) and are considered as key components in both the stacking of the Golgi cisternae and its lateral connection. Furthermore, GRASPs were also proved essential in the unconventional secretion pathway of several proteins, even though the mechanism remains obscure. It was previously observed that the GRASP homologue in Cryptococcus neoformans has a molten globule-like behavior in solution., Methods: We used circular dichroism, synchrotron radiation circular dichroism and steady-state as well as time-resolved fluorescence., Results: We report the disorder-to-order transition propensities for a native molten globule-like protein in the presence of different mimetics of cell conditions. Changes in the dielectric constant (such as those experienced close to the membrane surface) seem to be the major factor in inducing multiple disorder-to-order transitions in GRASP, which shows very distinct behavior when in conditions that mimic the vicinity of the membrane surface as compared to those found when free in solution. Other folding factors such as molecular crowding, counter ions, pH and phosphorylation exhibit lower or no effect on GRASP secondary structure and/or stability., General Significance: To the best of our knowledge, this is the first study focusing on understanding the disorder-to-order transitions of a molten globule structure without the need of any mild denaturing condition. A model is also introduced aiming at describing how the cell could manipulate the GRASP sensitivity to changes in the dielectric constant during different cell-cycle periods., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Recently, large sequencing studies have provided insights into the mutational landscape of multiple myeloma (MM), identifying actionable mutations and giving a precious opportunity for exploring new targeted therapies. The main goal of precision medicine, matching patients with the right drug, seems to be closer than ever. However, no targeted therapies in MM are approved yet. Several clinical trials testing targeted drugs and enrolling patients with MM are currently ongoing and will provide predictive biomarkers that might support clinical decision making. In this review, we evaluate the evidence supporting the implementation of precision medicine in MM and we discuss the challenges that should be dealt with in this imminent and promising new era., (Copyright © 2017 Elsevier Inc. All rights reserved.)

This phase 1/2 trial evaluated the maximum tolerated doses, safety, and efficacy of pomalidomide, bortezomib, and dexamethasone (PVD) combination in patients with relapsed lenalidomide-refractory multiple myeloma (MM). In phase 1, dose level 1 consisted of pomalidomide (4 mg by mouth on days 1 to 21), IV or subcutaneous bortezomib (1.0 mg/m 2 on days 1, 8, 15, and 22), and dexamethasone (40 mg by mouth on days 1, 8, 15, and 22) given every 28 days. Bortezomib was increased to 1.3 mg/m 2 for dose level 2 and adopted in the phase 2 expansion cohort. We describe the results of 50 patients. Objective response rate was 86% (95% confidence interval [CI], 73-94) among all evaluable patients (stringent complete response, 12%; complete response, 10%; very good partial response, 28%; and partial response, 36%) and 100% among high-risk patients. Within a median follow-up of 42 months, 20% remain progression free, 66% are alive, and 4% remain on treatment. Median progression-free survival was 13.7 months (95% CI, 9.6-17.7). The most common toxicities were neutropenia (96%), leukopenia (84%), thrombocytopenia (82%), anemia (74%), and fatigue (72%); however, the majority of these were grade 1 or 2. The most common grade ≥3 toxicities included neutropenia (70%), leukopenia (36%), and lymphopenia (20%). Deep vein thrombosis occurred in 5 patients. In conclusion, PVD is a highly effective combination in lenalidomide-refractory MM patients. Weekly administration of bortezomib enhanced tolerability and convenience. Toxicities are manageable, mostly consisting of mild cytopenias with no significant neuropathy. This trial was registered at www.clinicaltrials.gov as #NCT01212952., (© 2017 by The American Society of Hematology.)

Background: High risk and low risk multiple myeloma patients follow a very different clinical course as reflected in their PFS and OS. To be clinically useful, methodologies used to identify high and low risk disease must be validated in representative independent clinical data and available so that patients can be managed appropriately. A recent analysis has indicated that SKY92 combined with the International Staging System (ISS) identifies patients with different risk disease with high sensitivity., Patients and Methods: Here we computed the performance of eight gene expression based classifiers SKY92, UAMS70, UAMS80, IFM15, Proliferation Index, Centrosome Index, Cancer Testis Antigen and HM19 as well as the combination of SKY92/ISS in an independent cohort of 91 newly diagnosed MM patients., Results: The classifiers identified between 9%-21% of patients as high risk, with hazard ratios (HRs) between 1.9 and 8.2., Conclusion: Among the eight signatures, SKY92 identified the largest proportion of patients (21%) also with the highest HR (8.2). Our analysis also validated the combination SKY92/ISS for identification of three classes; low risk (42%), intermediate risk (37%) and high risk (21%). Between low risk and high risk classes the HR is >10., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: The appropriateness of repeat transthoracic echocardiography (TTE) for stable heart failure (HF) is based on timing of the follow-up examination, but this lacks scientific support. We sought the association of routine follow-up TTE on survival and readmission in stable HF., Methods: Patients with HF were selected from consecutive HF admissions from 2008 to 2012. Groups were divided into: no follow-up TTE; routine <1year with no change in status ("rarely appropriate"), ≥1year follow-up with no change in status ("maybe appropriate") and TTE due to change in clinical status ("appropriate"). Survival analysis was performed for the combined endpoint of HF readmission and death, and a separate analysis was performed for HF readmission, with death as a competing risk., Results: Of 550 HF patients, 141 had a follow-up TTE, including 41 (29%) within 1year. The event-free time in years was similar between no TTE (1.10years [95%CI: 0.69, 1.49], routine TTE <1year (2.61years [95% CI: 1.08, 3.04], routine >1year (2.45years [95% CI: 1.37, 5.78]); all were greater than symptomatic patients (0.09years [95% CI: 0.02, 1.80]). HF readmission was independently associated with statins, renal disease, coronary angiography and NYHA class, but not follow-up TTE timing. There were no differences in the cumulative incidence for death between groups. There were no differences in change in management in routine TTE <1year and ≥1year., Conclusion: The distinction of appropriateness of routine repeat TTE in stable HF patients, based on testing <1 or ≥1year after index admission appears unjustified., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Lenalidomide is an immunomodulatory drug (IMiDs) with clinical efficacy in multiple myeloma (MM) and other late B-cell neoplasms. Although cereblon ( CRBN ) is an essential requirement for IMiD action, the complete molecular and biochemical mechanisms responsible for lenalidomide-mediated sensitivity or resistance remain unknown. Here, we report that IMiDs work primarily via inhibition of peroxidase-mediated intracellular H 2 O 2 decomposition in MM cells. MM cells with lower H 2 O 2 -decomposition capacity were more vulnerable to lenalidomide-induced H 2 O 2 accumulation and associated cytotoxicity. CRBN-dependent degradation of IKZF1 and IKZF3 was a consequence of H 2 O 2 -mediated oxidative stress. Lenalidomide increased intracellular H 2 O 2 levels by inhibiting thioredoxin reductase (TrxR) in cells expressing CRBN, causing accumulation of immunoglobulin light-chain dimers, significantly increasing endoplasmic reticulum stress and inducing cytotoxicity by activation of BH3-only protein Bim in MM. Other direct inhibitors of TrxR and thioredoxin (Trx) caused similar cytotoxicity, but in a CRBN-independent fashion. Our findings could help identify patients most likely to benefit from IMiDs and suggest direct TrxR or Trx inhibitors for MM therapy., (© 2017 by The American Society of Hematology.)

Trichinella spiralis is an ubiquitous parasitic nematode that lives in muscle tissue of many hosts and causes trichinellosis in humans. Numerous efforts have been directed at specific detection of this infection and strategies for its control. TSL-1 and other antigens, mainly from muscle larvae (ML), have been used to induce partial protection in rodents. An improvement in protective immunity may be achieved by using antigens from other parasite stages. Further, identification of other parasite antigens may provide insights into their role in the host-parasite interaction. In this study, T. spiralis antigens from early developmental parasite stages, namely ML and pre-adult (PA) obtained at 6h, 18h and 30h post-infection, were identified by proteomic and mass spectrometry analyses. Our findings showed a differential expression of several proteins with molecular weights in the range of 13-224kDa and pI range of 4.54-9.89. Bioinformatic analyses revealed a wide diversity of functions in the identified proteins, which include structural, antioxidant, actin binding, peptidyl prolyl cis-trans isomerase, motor, hydrolase, ATP binding, magnesium and calcium binding, isomerase and translation elongation factor. This, together with the differential recognition of antigens from these parasite stages by antibodies present in intestinal fluid, in supernatants from intestinal explants, and in serum samples from mice infected with T. spiralis or re-infected with this parasite, provides information that may lead to alternatives in the design of vaccines against this parasite or for modulation of immune responses., (Copyright © 2016 Elsevier B.V. All rights reserved.)

The presence of certain high-risk cytogenetic abnormalities, such as translocations (4;14) and (14;16) and deletion (17p), are known to have a negative impact on survival in multiple myeloma (MM). The phase 3 study ASPIRE (N = 792) demonstrated that progression-free survival (PFS) was significantly improved with carfilzomib, lenalidomide, and dexamethasone (KRd), compared with lenalidomide and dexamethasone (Rd) in relapsed MM. This preplanned subgroup analysis of ASPIRE was conducted to evaluate KRd vs Rd by baseline cytogenetics according to fluorescence in situ hybridization. Of 417 patients with known cytogenetic risk status, 100 patients (24%) were categorized with high-risk cytogenetics (KRd, n = 48; Rd, n = 52) and 317 (76%) were categorized with standard-risk cytogenetics (KRd, n = 147; Rd, n = 170). For patients with high-risk cytogenetics, treatment with KRd resulted in a median PFS of 23.1 months, a 9-month improvement relative to treatment with Rd. For patients with standard-risk cytogenetics, treatment with KRd led to a 10-month improvement in median PFS vs Rd. The overall response rates for KRd vs Rd were 79.2% vs 59.6% (high-risk cytogenetics) and 91.2% vs 73.5% (standard-risk cytogenetics); approximately fivefold as many patients with high- or standard-risk cytogenetics achieved a complete response or better with KRd vs Rd (29.2% vs 5.8% and 38.1% vs 6.5%, respectively). KRd improved but did not abrogate the poor prognosis associated with high-risk cytogenetics. This regimen had a favorable benefit-risk profile in patients with relapsed MM, irrespective of cytogenetic risk status, and should be considered a standard of care in these patients. This trial was registered at www.clinicaltrials.gov as #NCT01080391., (© 2016 by The American Society of Hematology.)

Aiming to improve thermostability of the mesophilic xylanase A from Bacillus subtilis (XynA), five single mutants (S22E, S27E, N32D, N54E and N181R) were used to construct a random combinatorial library, and screening of this library for thermostable XynA variants identified a double mutant (S22E/N32D). All 6 mutants were expressed in Escherichia coli (BL21) and purified. Xylanase activity showed all mutants have an optimum catalytic temperature (Topt) of 55°C, and with the exception of the S27E mutant, a higher specific activity than the wild-type XynA. The time for loss of 50% activity at 55°C (t50) decreased in the order S22E/N32D>N181R>S22E>Wild-type>S27E=N32D≈N54E. The values of the van't Hoff denaturation enthalpy change (ΔHND), melting temperature (Tm) and heat capacity at constant pressure (ΔCp) between the native and denatured states were estimated from thermal denaturation curves monitored by circular dichroism ellipticity changes. The decreasing order of Gibbs free energy change at 328K (ΔG328) S22E/N32D>N181R>S22E>Wild-type>S27E≈N54E>N32D correlates well with the thermotolerance results, and is dominated by changes in ΔHND which is consistent with increased in hydrogen bonding in the thermostable mutants., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Multiple myeloma (MM) is characterized by a clonal proliferation of plasma cells. Although the bone marrow is the usual site of involvement, extramedullary plasmacytomas (EMPs) also occur, affecting any tissue. Cardiac and pericardial involvement, although described, have been rare occurrences. We present the case of a 61-year-old female patient 47 days after autologous stem cell transplant for MM who developed cardiac tamponade owing to extramedullary recurrence of myeloma, pulmonary embolism, and takotsubo cardiomyopathy. We performed a review of the published studies of all cases of MM presenting at diagnosis or relapse with cardiac or pericardial involvement in the past 25 years. Including our patient, 34 patients with plasmacytoma involving cardiac or pericardial structures were identified from the literature search. Approximately equal numbers of patients were male and female (42% and 57%, respectively). The mean age was 62 years. Primary plasmacytomas accounted for 12% of the cases. A history of MM, EMP, or monoclonal gammopathy of uncertain significance was noted in two thirds of the cases (66.6%). Treatment included chemotherapy and/or high-dose corticosteroids in 81.1% of cases and 27% underwent radiation therapy. The reporting of all cases to date has focused on unusual findings, rather than treatment approaches or new therapeutic strategies that might benefit patients. We suggest the formation of a database of all cases of cardiac and pericardial EMPs, with a focus on predictive disease variables, standardized staging, outcomes, and survival, to ensure that patients are optimally treated in the modern era., (Copyright © 2016 Elsevier Inc. All rights reserved.)

This phase 3 trial (Eastern Cooperative Oncology Group [ECOG] E1A06) compared melphalan, prednisone, and thalidomide (MPT-T) with melphalan, prednisone, and lenalidomide (mPR-R) in patients with untreated multiple myeloma (MM). A noninferiority design was used, and inferiority was defined as a progression-free survival (PFS) hazard ratio (HR) of MPT-T/mPR-R ≤0.82. A total of 306 patients enrolled, with a median age of 75.7 years. Median follow-up was 40.7 months. Median time on therapy was 12.1 months and 23.1 months for the 46.6% of treated patients who received maintenance, with no differences by arm. Median PFS was 21 months on MPT-T and 18.7 months on mPR-R (HR, 0.84; 95% confidence interval, 0.64-1.09). Overall survival was 52.6 months (MPT-T) vs 47.7 months (mPR-R) (P = .476). Per-protocol response rates were 63.6% (MPT-T) and 59.9% (mPR-R) (P = .557). Grade ≥3 nonhematologic toxicity was 59.5% for MPT-T vs 40.0% for mPR-R (P = .001). Second malignancies were observed in 18 MPT-T patients vs 14 mPR-R patients. Quality-of-life analysis favored mPR-R by induction end (P = .007). Use of MPT-T or mPR-R in elderly patients with untreated MM demonstrates no statistical or clinically relevant differences in response rates, PFS, and OS; however, quality of life at end of induction was improved and lower toxicity reported with mPR-R. This trial was registered at www.clinicaltrials.gov as #NCT00602641., (© 2015 by The American Society of Hematology.)

The aim of this study was to estimate genetic parameters for BW in meat quail at different ages. A total of 24,382 weight records from 3,652 quail, born between 2009 and 2011, were evaluated. Weekly BW was measured from hatch until 42 d of age. The genetic parameters were estimated by the restricted maximum likelihood method using a multivariate animal model. Heritability of BW ranged from 0.03 to 0.23. Genetic correlations were mainly high and positive. Selection for BW at 28 d of age yielded good indirect genetic progress in BW at 42 d of age., (© The Author 2015. Published by Oxford University Press on behalf of Poultry Science Association.)

Recent high-throughput sequencing and microarray studies have characterized the genetic landscape and clonal complexity of chronic lymphocytic leukemia (CLL). Here, we performed a longitudinal study in a homogeneously treated cohort of 12 patients, with sequential samples obtained at comparable stages of disease. We identified clonal competition between 2 or more genetic subclones in 70% of the patients with relapse, and stable clonal dynamics in the remaining 30%. By deep sequencing, we identified a high reservoir of genetic heterogeneity in the form of several driver genes mutated in small subclones underlying the disease course. Furthermore, in 2 patients, we identified convergent evolution, characterized by the combination of genetic lesions affecting the same genes or copy number abnormality in different subclones. The phenomenon affects multiple CLL putative driver abnormalities, including mutations in NOTCH1, SF3B1, DDX3X, and del(11q23). This is the first report documenting convergent evolution as a recurrent event in the CLL genome. Furthermore, this finding suggests the selective advantage of specific combinations of genetic lesions for CLL pathogenesis in a subset of patients., (© 2015 by The American Society of Hematology.)