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Pedro L Valenzuela,1 Nicola A Maffiuletti,2 Hugo Saner,3,4 Narayan Schütz,4 Beatrice Rudin,5 Tobias Nef,6 Prabitha Urwyler4,6,7 1Department of Systems Biology, University of Alcalá, Madrid, Spain; 2Human Performance Lab, Schulthess Clinic, Zurich, Switzerland; 3Institute for Social and Preventive Medicine, University of Bern, Bern, Switzerland; 4Gerontechnology & Rehabilitation Group, University of Bern, Bern, Switzerland; 5Höhere Fachschule Pflege, Berufsbildungszentrum Olten, Olten, Switzerland; 6ARTORG Center for Biomedical Engineering Research, University of Bern, Bern, Switzerland; 7Department of Neurology, University Neurorehabilitation Unit, University Hospital Inselspital, Bern, SwitzerlandCorrespondence: Prabitha UrwylerUniversity of Bern, ARTORG Center for Biomedical Engineering Research, Murtenstrasse 50, Bern 3008, SwitzerlandTel +41 31 632 76 07Email prabitha.urwyler@artorg.unibe.chBackground: Isometric strength measures and timed up and go (TUG) tests are both recognized as valuable tools for fall prediction in older adults. However, results from direct comparison of these two tests are lacking. We aimed to assess the potential of isometric strength measures and the different modalities of the TUG test to detect individuals at risk of falling.Methods: This is a prospective cohort study including 24 community-dwelling older adults (≥ 65 years, 19 females, 88± 7 years). Participants performed three variations of the TUG test (standard, counting and holding a full cup) and three isometric strength tests (handgrip, knee extension and hip flexion) at several time points (at baseline and every ∼ 6 weeks) during a one-year follow-up. The association between these tests and the incidence of falls during the follow-up was assessed.Results: Twelve participants out of 24 participants experienced falls during the follow-up. Fallers showed a significantly lower handgrip strength (− 5.7 kg, 95% confidence interval: − 10.4 to − 1.1, p=0.019) and knee extension strength (− 4.9 kg, − 9.6 to − 0.2, p=0.042) at follow-up, while no significant differences were found for any TUG variation.Conclusions: Handgrip and knee extension strength measures – particularly when assessed regularly over time – have the potential to serve as a simple and easy tool for detecting individuals at risk of falling as compared to functional mobility measures (ie, TUG test).Keywords: functional assessment, geriatrics, elderly, physical performance, muscle strength, sarcopenia

Nikola Schütz, Dominik Roth, Michael Schwameis, Martin Röggla, Hans Domanovits Department of Emergency Medicine, Medical University of Vienna, Vienna A-1090, AustriaCorrespondence: Nikola SchützDepartment of Emergency Medicine, Medical University of Vienna, Währinger Gürtel 18-20, Vienna A-1090, AustriaTel +4314040019640Fax +4314040019650Email nikola.schuetz@meduniwien.ac.atObjective: Blood gas analysis plays an important role in both diagnosis and subsequent treatment of critically ill patients in the emergency department and the ICU. Historically, arterial blood is predominantly used for blood gas analysis. The puncture is painful and complications may occur. The purpose of the present study was to evaluate the agreement between arterial and venous blood gas analysis and whether the sole use of venous blood gas analysis would have changed therapy.Methods: Adult patients who were intubated in the field and received an arterial and venous blood gas analysis within 15 mins after admission to the ED were eligible for inclusion. The values for pH, pCO2, HCO3-, base excess and lactate levels were collected retrospectively. Mean differences were calculated by subtracting venous from arterial values. The agreement between venous and arterial measurements was assessed using the method of Bland and Altman. Blood gases were assessed by two independent physicians using a standardized questionnaire to determine whether the use of venous blood gases would have led to a different interpretation of the situation (other diagnostic path) or a change of therapy (eg. respirator adjustment). Acceptable limits were defined before the collection of data started.Results: Fifty patients (62% male, median age 63years) who were treated at the Emergency Department between June 1, 2014 and December 31, 2014 were included in the study. Following average differences and limits of agreement (LOA) were documented: pH 0.02312 with LOA from −0.048 to 0.094; pCO2 −3.612 mmHg with LOA from −15 to 8.1 mmHg; BE −0.154 mmol/l with LOA from −3.7 to 3.4 mmol/l; HCO3−0.338 mmol/l with LOA from −2.27 to 2.9 mmol/l; Lactate −0.124 mg/dl with LOA from −2.28 to 2.03 mg/dl. Using venous blood gas results 100% of the patients with metabolic alkalosis were correctly diagnosed. Metabolic acidosis was detected with a high sensitivity (80.64%), specificity (89.47%) and positive predictive value (92.59%). The answers to lactate and acidosis due to AKI showed a specificity and positive predictive value of 100%. The respiratory adjustment showed a high sensitivity (91.89%) but a low specificity (38.46%).Conclusion: For pH, bicarbonate, BE and lactate venous blood gases can be used as surrogates for arterial measurements. Venous pCO2 can be used for screening of hypercapnia and trending. Respirator adjustments may be done too often if the venous blood gas is used.Keywords: blood gas analysis, intubation, venous and arterial blood sampling, questionnaire

Introduction: The treatment of elderly multiple myeloma (MM) patients with autologous stem cell transplantation (ASCT) is a controversial procedure. Most clinical trials evaluating the safety and efficacy of ASCT have primarily included patients younger than 65 years., Design and Methods: This was a retrospective analysis of patients with MM who underwent ASCT between 2008 and 2018. Patients at or over 65 years were compared with patients under 65 years. We analyzed treatment-related mortality (TRM), response rate, progression-free survival (PFS) and overall survival (OS)., Results: Two hundred and twenty-one patients were included: 50 patients at or over 65 years, (median age 68 years), including 7 patients over 70 years and 151 patients under 65 years, (median age 57 years). No differences were found in the neutrophil and platelet engraftment, median days of hospitalization and life support requirement during the hospitalization period for the ASCT. No statistically significant differences were found in the incidence of TRM between both groups at 100 days post-transplant (2% vs. 2.9%, p = 0.322). The ASCT improved complete response and stringent complete response rates (44% vs. 37%, p < 0.001). Survival was not modified by age: after a median follow-up of 53 months, the estimated PFS rates at three years were 63% and 60% (p = 0.88) and the OS rates at five years were 75% and 74% (p = 0.72), respectively., Conclusions: Our data suggest that the ASCT is feasible in selected elderly patients with MM over 65 years of age, achieving response and survival rates similar to those of younger patients., Competing Interests: Conflicts of interest The authors declare no potential conflicts of interest, either financial or other., (Copyright © 2023 Associação Brasileira de Hematologia, Hemoterapia e Terapia Celular. Published by Elsevier España, S.L.U. All rights reserved.)

Primary plasma cell leukemia (pPCL) is an infrequent and aggressive plasma cell disorder. The prognosis is still very poor, and the optimal treatment remains to be established. A retrospective, multicentric, international observational study was performed. Patients from 9 countries of Latin America (LATAM) with a diagnosis of pPCL between 2012 and 2020 were included. 72 patients were included. Treatment was based on thalidomide in 15%, proteasome inhibitors (PI)-based triplets in 38% and chemotherapy plus IMIDs and/or PI in 29%. The mortality rate at 3 months was 30%. The median overall survival (OS) was 18 months. In the multivariate analysis, frontline PI-based triplets, chemotherapy plus IMIDs and/or PI therapy, and maintenance were independent factors of better OS. In conclusion, the OS of pPCL is still poor in LATAM, with high early mortality. PI triplets, chemotherapy plus IMIDs, and/or PI and maintenance therapy were associated with improved survival.

Monoclonal gammopathy of renal significance (MGRS) is a recognized clinical entity. Literature regarding treatment and its outcomes in MGRS is sparse due to the rarity and misdiagnosis of MGRS. We retrospectively analyzed 280 adults with an MGRS diagnosis from 2003 to 2020 across 19 clinical centers from 12 countries. All cases required renal biopsy for the pathological diagnosis of MGRS. Amyloidosis-related to MGRS (MGRS-A) was present in 180 patients; nonamyloidosis MGRS (MGRS-NA), including a broad spectrum of renal pathologies, was diagnosed in 100 patients. The median overall survival in the studied cohort was 121.0 months (95% CI: 105.0-121.0). Patients with MGRS-A had a shorter overall survival than patients with MGRS-NA (HR = 0.41, 95%CI: 0.25-0.69; p = 0.0007). Both hematologic and renal responses were associated with longer survival. Achievement of ≥VGPR was generally predictive of a renal response (OR = 8.03 95%CI: 4.04-115.96; p < 0.0001), one-fourth of patients with ≥VGPR were renal nonresponders. In MGRS-A, factors associated with poor prognosis included elevated levels of creatinine, beta-2-microglobulin, and hemodialysis at diagnosis. In MGRS-NA, only age >65 years was associated with increased risk of death. Treatments provided similar hematologic response rates in both types of MGRS. Autologous stem cell transplantation led to better response than other treatments. This multicenter and international effort is currently the largest report on MGRS., (© 2022 The Authors. American Journal of Hematology published by Wiley Periodicals LLC.)

Modern sensor technology is increasingly used in older adults to not only provide additional safety but also to monitor health status, often by means of sensor derived digital measures or biomarkers. Social isolation is a known risk factor for late-life depression, and a potential component of social-isolation is the lack of home visits. Therefore, home visits may serve as a digital measure for social isolation and late-life depression. Late-life depression is a common mental and emotional disorder in the growing population of older adults. The disorder, if untreated, can significantly decrease quality of life and, amongst other effects, leads to increased mortality. Late-life depression often goes undiagnosed due to associated stigma and the incorrect assumption that it is a normal part of ageing. In this work, we propose a visit detection system that generalizes well to previously unseen apartments - which may differ largely in layout, sensor placement, and size from apartments found in the semi-annotated training dataset. We find that by using a self-training-based domain adaptation strategy, a robust system to extract home visit information can be built (ROC AUC = 0.773). We further show that the resulting visit information correlates well with the common geriatric depression scale screening tool ( ρ = -0.87, p = 0.001), providing further support for the idea of utilizing the extracted information as a potential digital measure or even as a digital biomarker to monitor the risk of late-life depression.

Objective: We aim to evaluate factors associated with the recurrence of thromboembolic episodes among patients with a first episode of venous thromboembolic disease during anticoagulation treatment and at least one year after treatment suspension., Methods: A prospective cohort of patients with a first episode of deep vein thrombosis confirmed by Doppler ultrasound and initiated anticoagulation treatment. Participants were registered in the Institutional Registry of Thromboembolic Disease between June 2015 and March 2019. Patients with cancer, with permanent inferior vena cava filter implant, and those who refused to participate or did not provide informed consent were excluded. All patients were evaluated within treatment at 30 days and at least one year after the suspension of anticoagulation with a D-dimer study and an ultrasound. All patients were evaluated for recurrence, bleeding (major and minor), and death., Results: A total of 304 patients were recruited during the study period. Seventy-three percent were female, and the median age was 80 years. The rate of recurrence rate during anticoagulation treatment was 5% (N = 16/303; 95% confidence interval: 3 to 8), and 5% during post-suspension follow-up (N = 11/202; 95%CI: 3 to 9). The overall bleeding rate was 13% (N = 39; 95%CI: 9 to 17), and 5% for major bleeding. Patients who recurred had higher basal D-dimer mean, higher neutrophils and monocytes, and a higher prevalence of age-adjusted D-dimer ratio greater than 0.5 before discontinuation. In addition, they more frequently had complete leg involvement by ultrasound and received a shorter treatment., Conclusions: Although some baseline and pre-suspension parameters had a higher recurrence incidence, statistical significance was not reached, probably due to small statistical power and a short-term follow-up.

BceF is a bacterial tyrosine kinase (BY-kinase) from Burkholderia cepacia , a Gram-negative bacterium accountable for respiratory infections in immunocompromised and cystic fibrosis patients. BceF is involved in the production of exopolysaccharides secreted to the biofilm matrix and promotes resistant and aggressive infections. BY-kinases share no homology with mammalian kinases, and thereby offer a means to develop novel and specific antivirulence drugs. Here, we report the crystal structure of the BceF kinase domain at 1.85 Å resolution. The isolated BceF kinase domain is assembled as a dimer in solution and crystallized as a dimer in the asymmetric unit with endogenous adenosine-diphosphate bound at the active sites. The low enzymatic efficiency measured in solution may be explained by the partial obstruction of the active sites at the crystallographic dimer interface. This study provides insights into self-assembly and the specific activity of isolated catalytic domains. Several unique variations around the active site compared to other BY-kinases may allow for structure-based design of specific inhibitors to target Burkholderia cepacia virulence.

The challenge in classical Hodgkin Lymphoma (cHL) management is the 30-40% of refractory/relapsed cases., Aims: The aim of this work was to determine whether NIK and BCL-2 could be useful as prognosis biomarkers in cHL. In addition, we evaluated BCL-2 as a directed-therapy in cHL cell lines using venetoclax., Main Methods: We evaluated NIK and BCL-2 expression in 112 untreated cHL patients' lymph-node biopsies by immunohistochemistry. cHL cell lines were treated with venetoclax alone or combined with vincristine or doxorubicin. Cell viability, metabolic activity and cell death were analyzed by trypan-blue exclusion method, MTS assay and FDA/IP staining respectively., Key Findings: No correlation between NIK or BCL-2 expression and the majority of the clinical parameters was found. Patients with ≥60% BCL-2+ HRS-cells had a shorter disease-free survival (DFS) and overall survival (OS) (p = 0.002, p = 0.02 respectively). A decision tree analysis, in a 30 patients subgroup, showed that patients with <60% NIK+ HRS-cells but with ≥60% BCL-2+ HRS-cells had a worse outcome in terms of DFS and OS. These parameters performed better as prognosis indicators as compared to the diagnosis bone marrow status. Human cHL cell lines U-H01, KM-H2, L1236, SUPHD1, L540 showed sensitivity to venetoclax. The co-treatment effect of venetoclax and vincristine or doxorubicin on cell viability was diverse depending on the cell line evaluated., Significance: BCL-2 should be considered as a prognosis biomarker as well as a potential new therapeutic target in cHL. We report for the first time the cytotoxic effect of venetoclax in human cHL cell lines., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Introduction: Factor XIII (FXIII) deficiency may cause bleeding under certain clinical circumstances. Therapeutic plasma exchange (TPE) may lead to a transient deficiency., Objectives: To describe the clinical evolution of patients with acquired FXIII deficiency secondary to TPE., Methods: We respectively studied a cohort of consecutive patients from 2014 to 2019 who were treated with TPE with FXIII levels <50%. The FXIII was measured after the start of the TPE course, on days between the TPE sessions, due to suspected acquired deficiency. All TPE were performed using continuous flow cell separator. In all cases, the initial replacement fluid applied was albumin. Apheresis procedures were held at 24to 48 hours intervals., Results: Eighteen patients were included, 13 of them were recipients of kidney transplants. The main TPE prescription was humoral rejection. Median FXIII at diagnosis (measured on days between sessions of the TPE course) was 19%(IQR17-25). The median of apheresis procedures before measurement of FXIII was 3(IQR2-4). Among the total cohort, 10 patients suffered hemorrhages. None of the patients without history of kidney transplants had bleeding (n = 5), however, 10/13 with kidney transplants did. Five kidney transplant patients received therapy with FXIII concentrate because of life-threatening bleeding. In all cases, the bleeding stopped within the first 24 hours. All patients had their FXIII levels measured again after finishing the TPE course, with normal results., Conclusions: TPE is an under-diagnosed cause of acquired FXIII deficiency since routine coagulation tests remain unaltered. It might cause major bleeding, particularly in patients with a recent history of surgery like kidney transplants., (© 2020 Wiley Periodicals LLC.)

The aim of this study was to describe clinical and survival characteristics of transplant-eligible multiple myeloma (MM) patients in Latin America (LA), with a special focus on differences between public and private healthcare facilities. We included 1293 patients diagnosed between 2010 and 2018. A great disparity in outcomes and survival between both groups was observed. Late diagnosis and low access to adequate frontline therapy and ASCT in public institutions probably explain these differences. Patients treated with novel drug induction protocols, followed by autologous stem cell transplantation (ASCT) and maintenance, have similar overall survival compared to that published internationally.

This study determined whether 85 patients with multiple myeloma (MM) double-refractory to primary induction therapy with triplet regimens had a homogenous prognosis. The overall response rate (ORR) after the second-line therapy was 51%. Patients who proceeded to immediate autologous stem cell transplantation (ASCT) had better ORR than those who received conventional therapies (62% vs. 31%). The ORR for patients who had ASCT directly after the frontline therapy was higher than for those treated with other regimens as the second line therapy (91% vs. 45%) and offered ASCT as the third-line therapy (91% vs. 55%). The median progression-free survival (PFS) after the second-line therapy and median overall survival were 21.6 months and 35.6 months, respectively. ASCT after the second line treatment (HR = 0.24) was an independent predictor of PFS. Eligible patients with primary refractory MM achieve the most benefit from ASCT, also performed immediately after first line induction therapy.

Purpose: To provide pharmacists and other clinicians with a basic understanding of the underlying principles and practical applications of artificial intelligence (AI) in the medication-use process., Summary: "Artificial intelligence" is a general term used to describe the theory and development of computer systems to perform tasks that normally would require human cognition, such as perception, language understanding, reasoning, learning, planning, and problem solving. Following the fundamental theorem of informatics, a better term for AI would be "augmented intelligence," or leveraging the strengths of computers and the strengths of clinicians together to obtain improved outcomes for patients. Understanding the vocabulary of and methods used in AI will help clinicians productively communicate with data scientists to collaborate on developing models that augment patient care. This primer includes discussion of approaches to identifying problems in practice that could benefit from application of AI and those that would not, as well as methods of training, validating, implementing, evaluating, and maintaining AI models. Some key limitations of AI related to the medication-use process are also discussed., Conclusion: As medication-use domain experts, pharmacists play a key role in developing and evaluating AI in healthcare. An understanding of the core concepts of AI is necessary to engage in collaboration with data scientists and critically evaluating its place in patient care, especially as clinical practice continues to evolve and develop., (© American Society of Health-System Pharmacists 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Pervasive computing based home-monitoring has attracted increasing interest over the past years, especially regarding applications in the growing population of older adults. Applications include safety, monitoring chronic conditions like dementia, or providing preventive information about changes in health and behavior. Commonly used components of such systems are inexpensive and low-power passive infrared motion sensing units, usually placed in distinct locations of an older adult's apartment. To efficiently analyse the resulting data the majority of procedures expect the resulting sensor data to be encoded in a vector space. However, most common vector space encodings are based on orthogonal representations of the sensor locations and thus lead to loss of information as the sensors are placed in a 3D-space. In this work we introduce an embedding of sensor-locations in a 2D-space based on multidimensional scaling, without knowledge of the physical position of the sensors. We evaluate this embedding, using two different algorithms and compare it to commonly used baselines in different tasks. All evaluations are carried out on a real-world home-monitoring data-set.

In recent years, consumer-grade sensors that measure health relevant physiological signals have become widely available and are increasingly used by consumers and researchers alike. While this allows for multiple novel, potentially highly beneficial, large-scale health monitoring applications, quality of these data streams is oftentimes suboptimal. This makes alignment of different high-frequency data streams from multiple, non-connected sensors, a difficult task. In this work we describe a noise-robust framework to align high-frequency signals from different sensors, that share some underlying characteristic, obtained in a free-living, non-clinical, home environment. We demonstrate the approach on the basis of a single-lead, medical-grade, mobile electrocardiography device and a consumer-grade sleep sensor that allows for ballistocardiography. Both commercially available sensors measure the physiological process of a heartbeat. We show, on the basis of real-world data with multiple people and sensors, that the two highly noisy and sometimes dissimilar signals could in most cases be aligned with considerable precision. As a result, we could reduce mean heartbeat peak-to-peak difference by 58.1% on average and increase signal correlation by 0.40 on average.

The multicenter retrospective study conducted in 38 centers from 20 countries including 172 adult patients with CNS MM aimed to describe the clinical and pathological characteristics and outcomes of patients with multiple myeloma (MM) involving the central nervous system (CNS). Univariate and multivariate analyses were performed to identify prognostic factors for survival. The median time from MM diagnosis to CNS MM diagnosis was 3 years. Thirty-eight patients (22%) were diagnosed with CNS involvement at the time of initial MM diagnosis and 134 (78%) at relapse/progression. Upon diagnosis of CNS MM, 97% patients received initial therapy for CNS disease, of which 76% received systemic therapy, 36% radiotherapy and 32% intrathecal therapy. After a median follow-up of 3.5 years, the median overall survival (OS) from the onset of CNS involvement for the entire group was 7 months. Untreated and treated patients had median OS of 2 and 8 months, respectively (P < 0.001). At least one previous line of therapy for MM before the diagnosis of CNS disease and >1 cytogenetic abnormality detected by FISH were independently associated with worse OS. The median OS for patients with 0, 1 and 2 of these risk factors were 25 months, 5.5 months and 2 months, respectively (P < 0.001). Neurological manifestations, not considered chemotherapy-related, observed at any time after initial diagnosis of MM should raise a suspicion of CNS involvement. Although prognosis is generally poor, the survival of previously untreated patients and patients with favorable cytogenetic profile might be prolonged due to systemic treatment and/or radiotherapy. Am. J. Hematol. 91:575-580, 2016. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Patients over 60 years old with acute myeloid leukemia (AML) have a worse prognosis due to several factors that determine the therapeutic outcome. The main predictors of mortality in patients with AML reported in the literature were analyzed in our population. The primary objective was to analyze overall survival. The secondary objective was to determine treatment-related mortality, defined as death within eight weeks of starting treatment. It was designed as a retrospective study. A total of 133 treatment naive patients were included, from January 1991 to August 2014. The adjusted analysis showed that the most important variables to determine overall survival were the WBC count = 30 000 at diagnosis [adjusted HR 2.19 (1.06-4.53), p = 0.03)] and the Performance Status (ECOG) 3 or 4 [aHR 4.63 (1.69-12.68), p < 0.001)]. Performance Status 3-4 was the only variable that conditioned treatment related mortality, showing in the univariate analysis an OR 5.44 (CI 1.93-15.28, p < 0.001). It was also the only variable that kept its statistical power in the multivariate analysis adjusted OR (aOR) 12.40 (IC 1.12-137.17, p = 0.04). The inherent poor outcome in elderly patients diagnosed with AML is not fully understood. The best way of assessing these elderly patients should probably include not only age but the best way of assessing these elderly patients should probably include not only age but laboratory, genetic and molecular studies. Especially designed comorbidity and fragility indices should be included, along with functional status. Leukocytosis and poor quality of life were identified as the most powerfull factors for predicting mortality in our study.

Telomerase, shelterin proteins and various interacting factors, named non-shelterin proteins, are involved in the regulation of telomere length (TL). Altered expression of any of these telomere-associated genes can lead to telomere dysfunction, causing genomic instability and disease development. In this study, we investigated the expression profile of a set of non-shelterin genes involved in essential processes such as replication (RPA1), DNA damage repair pathways (MRE11-RAD50-NBS1) and stabilization of telomerase complex (DKC1), in 35 patients with monoclonal gammopathy of undetermined significance (MGUS) and 40 cases with multiple myeloma (MM). Results were correlated with hTERT expression, TL and clinical parameters. Overall, a significant increase in DKC1, RAD50, MRE11, NBS1 and RPA1 expression along with an upregulation of hTERT in MM compared with MGUS was observed (p≤0.032). Interestingly, in both entities high mRNA levels of non-shelterin genes were associated with short TLs and increased hTERT expression. Significant differences were observed for DKC1 in MM (p ≤0.026), suggesting an important role for this gene in the maintenance of short telomeres by telomerase in myeloma plasma cells. With regard to clinical associations, we observed a significant increase in DKC1, RAD50, MRE11 and RPA1 expression in MM cases with high bone marrow infiltration (p≤0.03) and a tendency towards cases with advanced ISS stage, providing the first evidence of non-shelterin genes associated to risk factors in MM. Taken together, our findings bring new insights into the intricate mechanisms by which telomere-associated proteins collaborate in the maintenance of plasma cells immortalization and suggest a role for the upregulation of these genes in the progression of the disease.

In this study, we have examined CKS1B gene expression and copy number in a total of 114- patients at diagnosis: 83 with multiple myeloma (MM) and 31 with monoclonal gammopathy of undetermined significance (MGUS). Results were correlated with cytogenetics, FISH and clinical characteristic. Significant CKS1B mRNA levels in MM compared to MGUS cases (p<0.048) were detected. In MM, the frequency of 1q21 (CKS1B) copy gain was significantly higher in cases with abnormal karyotype compared to patients with normal karyotype (p=0.021). Global analysis showed a positive correlation between CKS1B expression and 1q21 copy number (p<0.0001). No association between CKS1B mRNA expression and clinical parameters was found. However, a significantly higher level of β2 microglobulin in cases with 1q21 gains than those without (p=0.0094) was observed. Overall survival was shorter in cases with 1q21 gain compared to those with normal 1q21 region (p=0.0082). Our results suggest a role for CKS1B in the multiple step process of progression of MGUS to MM and show that CKS1B copy gain has a more significant prognostic value than its overexpression. This adverse impact on survival probably reflects the genetic instability associated to chromosome 1q alterations resulting in a more aggressive behavior of the disease., (Copyright © 2014. Published by Elsevier Inc.)

Background: Glutathione S-transferase P1 (GSTP1) is an important phase II enzyme involved in detoxification of carcinogens. GSTP1 gene overexpression has been observed in a variety of human cancers but there are no studies in plasma cell disorders. The aim of this study was to examine GSTP1 mRNA expression level in multiple myeloma (MM) and monoclonal gammopathy of undetermined significance (MGUS). In addition, we have determined GSTP1 polymorphic variants in order to estimate MM risk and their relationship with the expression level. Results were also correlated with laboratory parameters and clinical outcome., Methods: Bone marrow mononuclear cells from 125 patients with plasma cell disorders were studied. Peripheral blood samples of 110 age and sex matched healthy controls were also evaluated. Real-Time Quantitative RT-PCR and PCR-RFLP assays were used., Results: Upregulation of GSTP1 was observed in 37.7% MM and in 22.6% MGUS patients. A significant increase of GSTP1 expression in MM with respect to MGUS was detected (p=0.0427). Most MM patients that achieved complete remission had low transcription levels (77.8%) compared to those who did not reach this condition (44.4%) (p=0.0347). GSTP1 heterozygous carriers showed reduced expression compared to those with homozygous wild type genotype (p=0.0135)., Conclusion: Our findings suggest, for the first time, a role for GSTP1 expression in development and/or progression of plasma cell disorders, and a probable influence of functional capacity of the enzyme on clinical outcome. These results and those of the literature support GSTP1 as an interesting tumor marker and a potential therapeutic target., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

The venous thromboembolic disease (VTD) in adults has a high morbidity and mortality. It can be also associated to disabling chronic conditions. In spite of this, prophylaxis in healthcare assistance is still underused. In this article, the available evidence in thromboprophylaxis was analyzed to offer recommendations (1) or suggestions (2) classified according to different levels of evidence (A, B or C). Different medical scenarios and types of thromboprophylaxis were analyzed. In major orthopedic surgeries low molecular weight heparins, LMWH, inhibitors of the Xa and IIa factors are recommended (1B) to be started during hospitalization and continued for 35 days in hip replacement surgery and for 10 days in total knee replacement surgery. Knee arthroscopy and spine surgery do not require pharmacologic treatment (2B) unless the patient has other risks factors for thrombosis. In such cases, LMWH are recommended. Non-surgical patients who have at least one risk factor should receive LMWH, NFH or fondaparinux (1B) if they are to be bedridden or unable to walk for three or more days. Patients undergoing neurosurgery or with intracranial hemorrhage should receive mechanic prophylaxis (2C), and accordingly they should start LMWH or NFH 24 to 72 hours afterwards (2C). The latter two drugs are recommended for critically ill patients. Patients with low risk for VTD undergoing other type of surgeries should be prescribed with mechanical prophylaxis (2C) and encouraged to walk promptly (2C), while those with high risk should be prescribed with LMWH or NFH (1B or 2C according to bleeding risk factors).

Cancer cells preferentially use glycolysis rather than oxidative phosphorylation for their rapid growth. They consume large amount of glucose to produce lactate even when oxygen is abundant, a phenomenon known as the Warburg effect. This metabolic change originates from a shift in the expression of alternative spliced isoforms of the glycolytic enzyme pyruvate kinase (PK), from PKM1 to PKM2. While PKM1 is constitutively active, PKM2 is switched from an inactive dimer form to an active tetramer form by small molecule activators. The prevalence of PKM2 in cancer cells relative to the prevalence of PKM1 in many normal cells, suggests a therapeutic strategy whereby activation of PKM2 may counter the abnormal cellular metabolism in cancer cells, and consequently decreased cellular proliferation. Herein we describe the discovery and optimization of a series of PKM2 activators derived from the 2-((2,3-dihydrobenzo[b][1,4] dioxin-6-yl)thio)-1-(2-methyl-1-(methylsulfonyl)indolin-5-yl) ethanone scaffold. The synthesis, SAR analysis, enzyme active site docking, enzymatic reaction kinetics, selectivity and pharmaceutical properties are discussed., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Folding correctors of F508del-CFTR were discovered by in silico structure-based screening utilizing homology models of CFTR. The intracellular segment of CFTR was modeled and three cavities were identified at inter-domain interfaces: (1) Interface between the two Nucleotide Binding Domains (NBDs); (2) Interface between NBD1 and Intracellular Loop (ICL) 4, in the region of the F508 deletion; (3) multi-domain interface between NBD1:2:ICL1:2:4. We hypothesized that compounds binding at these interfaces may improve the stability of the protein, potentially affecting the folding yield or surface stability. In silico structure-based screening was performed at the putative binding-sites and a total of 496 candidate compounds from all three sites were tested in functional assays. A total of 15 compounds, representing diverse chemotypes, were identified as F508del folding correctors. This corresponds to a 3% hit rate, ~tenfold higher than hit rates obtained in corresponding high-throughput screening campaigns. The same binding sites also yielded potentiators and, most notably, compounds with a dual corrector-potentiator activity (dual-acting). Compounds harboring both activity types may prove to be better leads for the development of CF therapeutics than either pure correctors or pure potentiators. To the best of our knowledge this is the first report of structure-based discovery of CFTR modulators.

We have discovered novel benzofuran-based S1P1 agonists with excellent in vitro potency and selectivity. 1-((4-(5-Benzylbenzofuran-2-yl)-3-fluorophenyl)methyl) azetidine-3-carboxylic acid (18) is a potent S1P1 agonist with >1000× selectivity over S1P3. It demonstrated a good in vitro ADME profile and excellent oral bioavailability across species. Dosed orally at 0.3 mg/kg, 18 significantly reduced blood lymphocyte counts 24 h postdose and demonstrated efficacy in a mouse EAE model of relapsing MS.

Optimization of a benzofuranyl S1P1 agonist lead compound (3) led to the discovery of 1-(3-fluoro-4-(5-(2-fluorobenzyl)benzo[d]thiazol-2-yl)benzyl)azetidine-3-carboxylic acid (14), a potent S1P1 agonist with minimal activity at S1P3. Dosed orally at 0.3 mg/kg, 14 significantly reduced blood lymphocyte counts 24 h postdose and attenuated a delayed type hypersensitivity (DTH) response to antigen challenge.

Multiple myeloma is characterized by the neoplastic proliferation of a single clone of plasma cells producing a monoclonal immunoglobulin. Myelomatous nodular lesions of the liver are infrequent. We describe 3 cases with histological confirmation and we review the bibliography.

Introduction: Raised intracranial pressure (ICP) has been consistently associated with poor neurological outcome. Our purpose was to systematically review the literature to estimate the association between ICP values and patterns and short- and long-term vital and neurological outcome., Methods: Systematic review of studies identified from MEDLINE, EMBASE, and COCHRANE Registry search from 1966 to 2005, and reference lists of identified articles, with independent assessment of methodological quality, population, ICP values and patterns, management of raised ICP and neurological outcomes. Summary odds ratios (OR) were calculated for the main outcomes using proportional odds models and logistic regression., Results: Four prospective studies (409 patients) reported the effect of ICP values, and five studies (677 patients) reported the effect of ICP patterns on neurological outcome. No study reported neurological outcomes beyond 1 year. Relative to normal ICP (<20 mmHg), raised ICP was associated with elevated OR of death: 3.5 [95%CI: 1.7, 7.3] for ICP 20-40, and 6.9 [95%CI: 3.9, 12.4] for ICP>40. Raised but reducible ICP was associated with a 3-4-fold increase in the OR of death or poor neurological outcome. Refractory ICP pattern was associated with a dramatic increase in the relative risk of death (OR 114.3 [95%CI: 40.5, 322.3])., Conclusions: Refractory ICP and response to treatment of raised ICP could be better predictors of neurological outcome than absolute ICP values. Limitations in the design of the studies analyzed precluded identification of the role of ICP monitoring in predicting short- and long-term outcomes.

Objective: To determine the accuracy of continuous (in vivo) measurement of mixed venous oxygen saturation (SvO(2)), using a fibreoptic catheter, in patients having had cardiopulmonary bypass (CPB)., Methods: Using a pulmonary arterial catheter, we prospectively studied 14 patients (age 64 +/- 8) having had cardiopulmonary bypass. Mean hematocrit was 30 +/- 4%. The catheter was calibrated in vitro and in vivo, according to the manufacturer's instructions. Fifty-six simultaneous measurements of continuous SvO(2) (CSvO(2)) and measured SvO(2) (MSvO(2)) were taken with a co-oxymeter and the paired values were analyzed by the linear regression method. To make the two sets of measurements interchangeable, we established, a priori, a maximum limit of 3% (approximately 5% of the measurement), as being an acceptable difference between the two types of measurements., Results: All the measurements were obtained within four hours of the placement of the catheter. CSvO(2) was weakly correlated with MSvO(2), with a correlation coefficient of r(2) = 0.49 (P < 0.001). The Bland-Altman analysis demonstrates an objective mean bias of 0.8 +/- 3%, with 36% of the values measured falling outside clinically acceptable limits. For values of CSvO(2)

Recurrent aseptic meningitis (RAM) infrequent in elderly patients and generally secondary to drugs. Its association with rheumatologic diseases is also seldom reported in the elderly. Sjögren Syndrome (SS) sometimes affects the central nervous system, but the association between recurrent meningitis and SS is rare, specially in this age-group. We present an 88 year-old auto-valid patient, with a history of xerostomia, xerophthalmia, Raynaud, dysphagia, and recurrent parotid enlargement. In 2001 she developed a lymphocytic meningitis with a complete remission. A year later, she developed again an aseptic lymphocytic meningitis. We ruled out infectious causes. We found a FAN titer 1/160 with a nucleolar-mottled pattern, positive anti Ro and anti RNP antibodies and a positive lupus anticoagulant. We confirmed the ocular dryness and the lip biopsy was compatible with the diagnosis of SS. She had a good outcome with a complete remission without treatment in 10 days. We believe that this is a case of mixed connective tissue disease (MCTD) with predominant symptoms of SS, that developed a recurrent meningitis in its pure form. MCTD and SS should be considered in the differential diagnoses of RAM, also in the elderly.