Similarity-Based Virtual Screening to Find Antituberculosis Agents Based on Novel Scaffolds: Design, Syntheses and Pharmacological Assays.

A method to identify molecular scaffolds potentially active against the Mycobacterium tuberculosis complex (MTBC) is developed. A set of structurally heterogeneous agents against MTBC was used to obtain a mathematical model based on topological descriptors. This model was statistically validated through a Leave-n-Out test. It successfully discriminated between active or inactive compounds over 86% in database sets. It was also useful to select new potential antituberculosis compounds in external databases. The selection of new substituted pyrimidines, pyrimidones and triazolo[1,5-a]pyrimidines was particularly interesting because these structures could provide new scaffolds in this field. The seven selected candidates were synthesized and six of them showed activity in vitro.

Treatments and therapeutic protocols for the recovery of an asphyxiated new-born: A review of pre-clinical and clinical studies in human neonates and in different animal models.

The objective of this review is to ascertain the advantages and disadvantages of several treatments and therapeutic protocols that have been used for the prevention and treatment of perinatal asphyxia in human neonates and in different animal models. Perinatal asphyxia is one of the main causes of mortality worldwide and is an important factor in triggering physio-metabolic disorders that result in serious neurological consequences and learning disorders not only in human foetuses and neonates, but also in animals. In recent years, the search for new pharmacological protocols to prevent and reverse physio-metabolic disorders and brain damage derived from perinatal asphyxia has been and continues to be the subject of intense research. Currently, within these pharmacological protocols, therapeutic strategies have been evaluated that use respiratory and hormonal stimulants, as well as hypothermic therapies in combination with other putative neuroprotective agents. Similarly, energy supplements have been evaluated with the objective of preventing perinatal asphyxia and treating new-borns with this condition, and to decrease the incidence of neonatal and foetal deaths associated with it. However, despite these promising advances, this pathology has persisted, since the administration of these therapies in low doses may not exert a neuroprotective effect or, in high doses, can trigger adverse effects (such as reduced cardiac contractility, reduced cerebral blood flow, poor perfusion, sympathetic and neuroendocrine stimulation, and increased blood viscosity) in human foetuses and neonates as well as in different animal models (rats, piglets, sheep and rabbits). Therefore, it is important to determine the minimum effective dose with which these therapies exert a neuroprotective effect, as well as the mode of administration, the duration of therapy, etc. Therefore, until a powerful strategy is found to improve the consequences of suffocation, this topic will continue to be the subject of intensive research in the future.

Metastatic pancreatic and lung cancer patient in complete remission following immunotherapy: A case report and review of literature.

BACKGROUND: Metastatic pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy with dispiriting survival data. Immunotherapy is a promising approach to many cancer types, but achieves poor outcomes in advanced PDAC due to its immunosuppressive tumor microenvironment. We describe a case of metastatic PDAC effectively treated with pembrolizumab. CASE SUMMARY: We report the case of a 67-year-old woman with unresectable locally advanced PDAC, treated with gemcitabine plus nab-paclitaxel followed by radiotherapy plus capecitabine. At nine months, pancreatic tumor progression was observed at the level of the hepatic hilum with the appearance of a new pulmonary nodule suggestive of a second primary, confirmed by left lung biopsy. Systemic immunotherapy was then initiated with pembrolizumab, an immune checkpoint inhibitor targeting programmed cell death protein-1 that covers the two tumor types. The patient showed a complete metabolic response that was maintained throughout the treatment. The patient continues to be disease-free at 5.6 years since the start of immunotherapy. CONCLUSION: These results suggest that the administration of pembrolizumab after chemoradiotherapy has a beneficial effect in patients with metastatic PDAC. To our knowledge, this is the first reported case of a patient with metastatic PDAC and metastatic lung cancer showing such a long-lasting complete response after pembrolizumab treatment without curative surgery. Further studies are required to determine biomarkers that identify PDAC patients most likely to benefit from this immunotherapy.

Quasi-3D Model for Lateral Resonances on Homogeneous BAW Resonators.

Lateral modes are responsible for the in-band spurious resonances that appear on BAW resonators, degrading the in-band filter response. In this work, a fast computational method based on the transmission line matrix (TLM) method is employed to model the lateral resonances of BAW resonators. Using the precomputed dispersion curves of Lamb waves and an equivalent characteristic impedance for the TE1 mode, a network of transmission lines is used to calculate the magnitude of field distributions on the electrodes. These characteristics are specific to the stack layer configuration. The model's implementation is based on nodal Y matrices, from which particle displacement profiles are coupled to the electric domain via piezoelectric constitutive relations. Consequently, the input impedance of the resonator is obtained. The model exhibits strong agreement with FEM simulations of FBARs and SMRs, and with measurements of several SMRs. The proposed model can provide accurate predictions of resonator input impedance, which is around 200 times faster than conventional FEM.

Septic Shock From Pan-Spinal Epidural Abscess Attributed to Recent Acupuncture and Trigger Point Injections for Acute Lower Back Pain in a Previously Undiagnosed Diabetic Patient: A Case Report.

Epidural abscesses can lead to devastating neurological consequences if not diagnosed and managed in a timely manner, especially in immunocompromised patients. We report the case of a 60-year-old woman with undiagnosed diabetes mellitus who presented to the hospital with a complaint of progressive altered mental status for the past two days. Eight days prior to presentation, the patient tripped over a pillow at home and developed mildly nagging, acute lower back pain. Upon the recommendation of her friends, she underwent two sessions of acupuncture around the lumbar area on days six and five prior to being brought to the hospital. She also saw her primary care physician on day three prior to presentation, who performed a history and physical examination and, after feeling that she did not have any red flags, empirically administered lidocaine-based trigger point injections near the same lumbar areas with the patient's consent. On the day of presentation, the patient fell at home and was unable to walk, after which she was immediately brought to the hospital, where she demonstrated toxic metabolic encephalopathy due to diabetic ketoacidosis (DKA) and lower extremity paraplegia. Emergent imaging revealed a pan-spinal epidural abscess (PSEA) after an attempted lumbar puncture led to immediate pus in the syringe. Diagnosing an epidural abscess can be difficult as signs and symptoms can mimic other conditions such as meningitis, encephalitis, and stroke. High suspicion on the physician's end is needed when a patient presents with acute back pain, fevers, and neurological deterioration if the condition is otherwise unexplained, and especially in the presence of risk factors for PSEA that may be recognized only upon presentation.

Effect of thiamine pyrophosphate on the characteristics of farrowing and piglet vitality.

Asphyxia is considered the main non-infectious cause of prepartum mortality in swine, as well as an important factor that negatively affects neonatal vitality and can trigger physiological and metabolic disorders. Hence, the search for pharmacological protocols to reduce the harmful effects of asphyxia is a key area of research. Recent observations show that administering thiamine pyrophosphate (TPP) prior to a hypoxic event in certain species (rabbits, rats) has a neuroprotector effect that preserves energy metabolism under hypoxic conditions. Given this, the objective of this study was to evaluate a prophylactic protocol in high- and low-vitality neonate piglets based on TPP's effect on physiological and metabolic responses, body temperature, and weight. A total of 149 piglets born from 15 multiparous sows were used. The dams were randomly divided into two groups: control (NaCl 0.9%) and TPP (25 ml of TTP) administered 24 and 12 h before the expected farrowing date. The following reproductive variables of the sows were recorded: duration of farrowing, total number of piglets born per litter, number of liveborn piglets per litter, number of stillbirths and mummified fetuses at birth, and number of live piglets at weaning. In addition, the expulsion interval and vitality of all neonates were evaluated, body temperatures were recorded at ten intervals, and physiological profiles (blood gases, electrolytes, glucose) were registered for each neonate. Results show that the TPP-treated sows had shorter farrowing duration (P = 0.0060) and higher percentage of high-vitality neonates (60%). Moreover, their offspring exhibited greater vitality, fewer imbalances in their physiological and metabolic profiles, and greater weight gain at weaning (P < 0.0001). Findings suggest that administering TPP exerts a protective effect when hypoxic events occur, though this differs from results obtained with rat pups, where applying TPP after such events did not provide protection from asphyxia-induced damage. These differences may be due to the moment at which TPP was applied. The application time we selected was distinct from the procedure followed with rats because it was based on a dataset that describes the influence of administering TPP as a prophylactic treatment before a hypoxic event. Prophylactic administration of TPP to sows at the end of gestation exerted a neuroprotective effect on neonatal vitality and gas exchanges and energy metabolism in the offspring that were reflected in the greater weekly weight gain in those piglets.

Single Nucleotide Polymorphisms in the Vitamin D Metabolic Pathway as Survival Biomarkers in Colorectal Cancer.

Several studies have suggested that single nucleotide polymorphisms (SNPs) related to vitamin D metabolism may affect CRC carcinogenesis and survival. The aim of this study was to evaluate the influence of 13 SNPs involved in the vitamin D metabolic pathway on CRC survival. We conducted an observational retrospective cohort study, which included 127 Caucasian CRC patient from the south of Spain. SNPs in VDR, CYP27B1, CYP2R1, CYP24A1, and GC genes were analyzed by real-time polymerase chain reaction. Progression-free survival (PFS) and overall survival (OS) were assessed. Cox regression analysis adjusted for metastasis, age of diagnosis, stage (IIIB, IV or IVB), ECOG score (2-4), lymph node involvement, adjuvant chemotherapy, and no family history of CRC showed that the VDR ApaI (p = 0.036), CYP24A1 rs6068816 (p < 0.001), and GC rs7041 (p = 0.006) were associated with OS in patients diagnosed with CRC, and CYP24A1 rs6068816 (p < 0.001) was associated with PFS adjusted for metastasis, age of diagnosis, stage (IIIB, IV or IVB), ECOG score (2-4), lymph node involvement, adjuvant chemotherapy, and no primary tumor resection. The rest of the SNPs showed no association with CRC survival. Thus, the SNPs mentioned above may have a key role as prognostic biomarkers of CRC.

Distributed Nonlinear Model and Fast Analysis for In-Band IMD3 Prediction of Surface Acoustic Wave Resonators.

The motivation of this work is to analyze the in-band intermodulation distortion (IMD) occurring in surface acoustic wave (SAW) devices, using a recently developed fast method based on the input-output equivalent sources (IOES). The method calculates the equivalent current sources of a given harmonic (H) or IMD, which when applied at the boundaries of any uniform nonlinear region produce the same nonlinearities as the full distributed circuit. The accuracy of the method is validated with a very simplified SAW resonator with ten digits, which is modeled by a discretized Mason-based circuit. The IOES method provides equal results to the ones obtained through harmonic balance (HB) simulations, performed by means of commercial software, being the first 1000 times faster. Once the accuracy of the method is guaranteed, it is used to analyze the measured in-band IMD3 of several lithium tantalite 42° cut leaky SAW (LSAW) resonators with different pitches and duty factors at the B66 long term evolution (LTE) frequency band. Those resonators are comprised of 100 and 20 electrode pairs for the active region and each of the reflectors, respectively, which implies the analysis of a very large distributed nonlinear problem with thousands of nonlinear local sources. The IOES method takes 35.4 s in simulating 51 frequency points, whereas this simulation is not possible using a commercial HB simulator on a general-purpose computer.

Thalidomide with peginterferon alfa-2b and ribavirin in the treatment of non-responders genotype 1 chronic hepatitis C patients: proof of concept.

BACKGROUND: fewer than half of patients infected with hepatitis C virus (HCV) achieve sustained viral clearance after peginterferon alfa/ribavirin (Peg-IFN/RBV) therapy. AIMS: thalidomide posses anti-inflammatory and immunomodulatory properties through inhibition of tumor necrosis factor and costimulatory effect on human CD8+ T cells. METHODS: we started a prospective, open label trial of retreatment of very-difficult-to-treat genotype 1 chronic hepatitis C patients (CHC) patients, who had failed to respond to the (Peg-IFN/RBV), with a triple therapy consisting in these same antivirals plus thalidomide 200 mg/day (the TRITAL study). RESULTS: none of the eleven patients fulfilling the inclusion criteria and included in the trial reached complete early virological response or sustained virological response. Viral load decline after 12 weeks of triple therapy thalidomide-based retreatment did not differ from viral dynamics during the first course. The triple therapy was well tolerated and only one patient developed mild bilateral neuropathy. CONCLUSIONS: thalidomide addition to standard therapy is tolerated and did not increase the SVR rate in very-difficult-to-treat genotype 1 CHC patients. Different schedules are warranted to improve attempting retreatment of non responder CHC patients.

The Input-Output Equivalent Sources Method for Fast Simulations of Distributed Nonlinearities in Bulk Acoustic Wave Resonators and Filters.

This work presents a new method to analyze weak distributed nonlinear (NL) effects, with a focus on the generation of harmonics (H) and intermodulation products (IMD) in bulk acoustic wave (BAW) resonators and filters composed of them. The method consists of finding equivalent current sources [input-output equivalent sources (IOES)] at the H or IMD frequencies of interest that are applied to the boundary nodes of any layer that can contribute to the nonlinearities according to its local NL constitutive equations. The new methodology is compared with the harmonic balance (HB) analysis, by means of a commercial tool, of a discretized NL Mason model, which is the most used model for NL BAW resonators. While the computation time is drastically reduced, the results are fully identical. For the simulation of a seventh-order filter, the IOES method is around 700 times faster than the HB simulations.

Cost of Venous Thromboembolic Disease in Patients with Lung Cancer: Costecat Study.

BACKGROUND: Patients with lung cancer (LC) are at significantly higher risk of developing venous thromboembolism (VTE), which may lead to increased use of health resources and the cost of management. The main aim of the study was to determine the cost of the management of VTE events in patients with LC treated with Low Molecular Weight Heparins (LMWH) in Spain. METHODS: Costecat was an, observational, ambispective pharmacoeconomic study. Patients with LC, with a first episode of VTE (symptomatic or incidental) in treatment with LMWH, were recruited from six third-level hospitals and followed up for six months. Sociodemographic, clinical and resource use variables of VTE-related implications and its treatment were collected. Direct healthcare costs and direct non-healthcare costs were recorded. Data collection was documented in an electronic case report. Unit costs were obtained from national databases. Costs (€2018) were estimated from the healthcare perspective. Statistical analysis was performed using the statistical program R 3.4.3 version (30 November 2017). RESULTS: Forty-seven patients were included. Mean age was 65.4 years, 66.0% were male. The percentage of patients with LC who had metastatic disease was 78.7%. Twenty-three patients (48.9%) needed hospital admissions due to thromboembolic episode. Total average cost of patients with cancer associated VTE (CAT) was €109,696.6 per patient/semester. The hospitalizations represent 65.8% of total costs (7207.3 € SD 13,996.9 €), followed by LMWH therapy which represents 18.6% (2033.8 € SD:630.5 €). CONCLUSIONS: Venous thromboembolism episodes induce an economic impact on patients and healthcare systems. Direct healthcare costs are the major burden of the total cost, in which hospitalizations are the main drivers of cost.

Impact of a risk-sharing agreement in rheumatoid arthritis in Spain.

CONTEXT AND OBJECTIVE: Risk-sharing agreements(RSA) allow decision-makers to manage the uncertainty associated with effectiveness and costs of treatments. Our objective was to estimate the economic impact of RSA implementation on treatment of patients diagnosed with rheumatoid arthritis(RA) with certolizumab pegol(CZP) and assess the potential impact of alternative RSA. METHODS: Under original RSA, treatment with CZP was reimbursed when the response was optimal (DAS28 score <3.2) or satisfactory (DAS28 score ≥3.2 and reduction from baseline ≥1.2) at 12 weeks. Alternative RSA would additionally include a 50 % reimbursement for moderate responders(DAS28 score >3.2 and ≤5.1, and reduction from baseline between 0.6 and 1.2). We estimated average savings per patient for hospital's pharmacy service(HPS) at 12 weeks, taking into account the pharmacological cost of CZP. Uncertainty associated with effectiveness of CZP was assessed through 1000 Monte Carlo simulations. RESULTS: After 12 weeks of treatment, 57.8 % (n = 52) and 22.2 %(n = 20) of patients had optimal and satisfactory responses, respectively, and average disease activity improved by 1.77 points. Average savings for HPS amounted to 876.9€ and 706.4€ per patient under original and alternative RSA, respectively. Savings in simulated cohort reached 846.2€ and 681.8€ per patient, respectively, leading to estimated net savings for HPS of 846,209€ and 681,790€, respectively. CONCLUSIONS: RSA implementation on patients with RA treated with CZP has generated savings and improved efficiency within HPS.

Early metabolic reactivation versus antioxidant therapy after a traumatic spinal cord injury in adult rats.

Disability after traumatic spinal cord injury (TSCI) results from physical trauma and from "secondary mechanisms of injury" such as low metabolic energy levels, oxidative damage and lipid peroxidation. In order to prove if early metabolic reactivation is a better therapeutic option than antioxidant therapy in the acute phase of TSCI, spinal cord contusions were performed in adult rats using a well-characterized weight drop technique at thoracic 9 level. After TSCI, pyrophosphate of thiamine or non-degradable cocarboxylase (NDC) enzyme was used to maintain energy levels, antioxidants such as superoxide dismutase and catalase (ANT) were used to decrease oxidative damage and methylprednisolone (MP), which has both therapeutic properties, was used as a control. Rats were divided into one sham group and six with TSCI; one of them received no treatment, and the rest were treated with NDC, MP, NDC + MP, NDC + ANT or ANT. The ANT group decreased lactate and creatine phosphokinase levels and increased the amount of preserved tissue (morphometric analysis) as well as functional recovery (Basso, Beattie and Bresnahan or BBB motor scale). In contrast, NDC treatment increased lipid peroxidation, measured through thiobarbituric acid reactive substances (TBARS) levels, as well as spinal cord tissue destruction and functional deficit. Early metabolic reactivation after a TSCI may be deleterious, while natural early metabolic inhibition may not be a "secondary mechanism of injury" but a "secondary neuroprotective response". While increased antioxidant defence after a TSCI may currently be an ideal therapeutic strategy, the usefulness of metabolic reactivation should be tested in the sub-acute or chronic phases of TSCI and new strategies must continue to be tested for the early ones.

[Infection by Coxiella burnetii (Q fever)]. / Infección por Coxiella burnetii (fiebre Q).

In spite of being described over 60 years, Q fever is still a little known disease. The exact prevalence is also unknown, but probably the number of cases of Q fever is underestimated. There is much variation in the clinical presentation, including severe forms with a poor prognosis. Acute cases often present as an asymptomatic infection, flu-like syndrome, pneumonia or hepatitis. Presumably, host factors play an important role in the development of chronic disease, which may present as endocarditis with negative blood culture. The diagnosis of Q fever should be considered in cases of fever of unknown origin, especially if the subject has been in contact with mammals suspicious to be infected. The best methods of microbiological diagnosis are those that allow direct detection of bacteria (cell culture and PCR), although these procedures should be performed in laboratories with adequate biosafety measures, and with specialized personnel. For serologícal diagnosis, the reference method is indirect immunofluorescence (IIF), which is very sensitive and specific. In suspected cases of acute Q fever, diagnosis should be confirmed by serum titers (IgG and/or IgM), obtained by immunofluorescence above the cutoff calculated for each geographic area, or by seroconversion.

TREML4 Promotes Inflammatory Programs in Human and Murine Macrophages and Alters Atherosclerosis Lesion Composition in the Apolipoprotein E Deficient Mouse.

The Triggering Receptor Expressed on Myeloid cells-like 4 (TREML4) is a member of the TREM receptor family, known modulators of inflammatory responses. We have previously found that TREML4 expression positively correlates with human coronary arterial calcification (CAC). However, the role of TREML4 in the pathogenesis of cardiovascular disease remains incompletely defined. Since macrophages play a key role in inflammatory conditions, we investigated if activated macrophages selectively expressed TREML4 and found that carriage of either one of the eQTL SNP's previously associated with increased TREML4 expression conferred higher expression in human inflammatory macrophages (M1) compared to alternatively activated macrophages (M2). Furthermore, we found that TREML4 expression in human M1 dysregulated several inflammatory pathways related to leukocyte activation, apoptosis and extracellular matrix degradation. Similarly, murine M1 expressed substantial levels of Treml4, as did oxLDL treated macrophages. Transcriptome analysis confirmed that murine Treml4 controls the expression of genes related to inflammation and lipid regulation pathways, suggesting a possible role in atherosclerosis. Analysis of Apoe-/-/Treml4-/- mice showed reduced plaque burden and lesion complexity as indicated by decreased stage scores, macrophage content and collagen deposition. Finally, transcriptome analysis of oxLDL-loaded murine macrophages showed that Treml4 represses a specific set of genes related to carbohydrate, ion and amino acid membrane transport. Metabolomic analysis confirmed that Treml4 deficiency may promote a beneficial relationship between iron homeostasis and glucose metabolism. Together, our results suggest that Treml4 plays a role in the development of cardiovascular disease, as indicated by Treml4-dependent dysregulation of macrophage inflammatory pathways, macrophage metabolism and promotion of vulnerability features in advanced lesions.

Assessing Pharmacists' Preferences towards Efficacy Attributes of Disease-Modifying Therapies in Relapsing-Remitting Multiple Sclerosis.

Introduction: Hospital pharmacists are increasingly playing a critical role in the care of patients with multiple sclerosis (MS). However, little is known about their preferences and perspectives towards different attributes of disease-modifying therapies (DMTs). The objective of this research was to assess pharmacists´ preferences for DMT efficacy attributes. Methods: A multicenter, non-interventional, cross-sectional, web-based study was conducted. Preventing relapses, delaying disease progression, controlling radiological activity, and preserving health-related quality of life (HRQoL) and cognition were the attributes selected based on a literature review and a focus group with six hospital pharmacists. Conjoint analysis was used to determine preferences in eight hypothetical treatment scenarios, combining different levels of each attribute and ranking them from most to least preferred. Results: Sixty-five hospital pharmacists completed the study (mean age: 43.5 ± 7.8 years, 63.1% female, mean years of professional experience: 16.1 ± 7.4 years). Participants placed the greatest preference on delaying disease progression (35.7%) and preserving HRQoL (21.6%) and cognition (21.6%). Importance was consistent in all groups of pharmacists stratified according to demographic characteristics, experience, research background, and volume of patients seen per year. Conclusions: Understanding which treatment characteristics are meaningful to hospital pharmacists may help to enhance their synergistic role in the multidisciplinary management of patients with MS.

Effect of genetic polymorphisms on therapeutic response in multiple sclerosis relapsing-remitting patients treated with interferon-beta.

Treatment with interferon beta (IFNß) is one of the first-line treatments for multiple sclerosis. In clinical practice, however, many patients present suboptimal response to IFNß, with the proportion of non-responders ranging from 20 to 50%. This variable response can be affected by genetic factors, such as polymorphisms in the genes involved in the disease state, pharmacodynamics, metabolism or in the action mechanism of IFNß, which can affect the efficacy of this drug. This review assesses the impact of pharmacogenetics studies on response to IFNß treatment among patients diagnosed with relapsing-remitting multiple sclerosis (RRMS). The results suggest that the detection of polymorphisms in several genes (CD46, CD58, FHIT, IRF5, GAPVD1, GPC5, GRBRB3, MxA, PELI3 and ZNF697) could be used in the future as predictive markers of response to IFNß treatment in patients diagnosed with RRMS. However, few studies have been carried out and they have been performed on small sample sizes, which makes it difficult to generalize the role of these genes in IFNß treatment. Studies on large sample sizes with longer term follow-up are therefore required to confirm these results.

FCGR2A/FCGR3A Gene Polymorphisms and Clinical Variables as Predictors of Response to Tocilizumab and Rituximab in Patients With Rheumatoid Arthritis.

We evaluated the influence of clinical, biochemical, and genetic factors on response in 142 patients diagnosed with rheumatoid arthritis, of whom 87 patients were treated with tocilizumab (61.26%) and 55 patients were treated with rituximab (38.7%;) according to the variables European League Against Rheumatism (EULAR) response, remission, low disease activity, and improvement in Disease Activity Score, 28 joints (DAS28) at 6, 12, and 18 months. A retrospective prospective cohort study was conducted. Patients carrying the FCGR3A rs396991-TT genotype treated with tocilizumab showed higher EULAR response (OR, 5.075; 95%CI, 1.20-21.33; P = .027) at 12 months, those who were naive for biological disease-modifying antirheumatic drugs (bDMARDs) at the beginning of treatment showed satisfactory EULAR response, higher remission, and greater improvement in DAS28 at 6 months. Younger age at start of tocilizumab treatment was associated with satisfactory EULAR response at 18 months and greater remission at 6 and 18 months. Subcutaneous tocilizumab administration was associated with higher remission at 6 months and improved low disease activity rate at 12 months. In patients treated with rituximab, carriers of the FCGR2A rs1801274-TT genotype had higher EULAR response at 6 months (OR, 4.861; 95%CI, 1.11-21.12; P = .035), 12 months (OR, 4.667; p = 0.066, 95%CI, 0.90-24.12; P = .066), and 18 months (OR, 2.487; 95%CI, 0.35-17.31; P = .357), higher remission (OR: 10.625; p = 0.044, CI95% : 1.07, 105.47) at 6 months, and greater improvement in DAS28 at 12 months (B = 0.782; 95%CI, -0.15 to 1.71; P = .098) and 18 months (B = 1.414; 95%CI, 0.19-2.63; P = .025). The FCGR3A rs396991-G allele was associated with improved low disease activity rate (OR, 4.904; 95%CI, 0.84-28.48; P = .077) and greater improvement in DAS28 (B = -1.083; 95%CI, -1.98 to -0.18; P = .021) at 18 months. Patients with a lower number of previous biological therapies had higher remission at 12 months. We suggest that the FCGR3A rs396991-TT genotype, higher baseline value of DAS28, subcutaneous tocilizumab administration, younger age at the beginning of treatment, and being bDMARD naive are associated with better response to tocilizumab. In patients treated with rituximab, we found better response in those patients with the FCGR2A rs1801274-TT genotype, the FCGR3A rs396991-G allele, and lower number of previous biological therapies.

Pomalidomide in the treatment of multiple myeloma: design, development and place in therapy.

Multiple myeloma is a very heterogeneous disease with variable survival. Despite recent progress and the widespread use of new agents, patients with relapsed and refractory disease have a poor outcome. Immunomodulatory drugs play a key role in both the front-line and the relapsed/refractory setting. The combination of pomalidomide (POM) and dexamethasone is safe and effective in relapsed and refractory patients, even in those with high-risk cytogenetic features. Furthermore, it can be used in most patients without the need to adjust according to the degree of renal failure. In order to further improve the results, POM-based triplet therapies are currently used. This article highlights the most relevant issues of POM and POM-based combinations in the relapsed/refractory multiple myeloma setting, from a pharmacological and clinical point of view.

Electro-thermo-mechanical model for bulk acoustic wave resonators.

We present the electro-thermo-mechanical constitutive relations, expanded up to the third order, for a BAW resonator. The relations obtained are implemented into a circuit model, which is validated with extensive linear and nonlinear measurements. The mathematical analysis, along with the modeling, allows us to identify the dominant terms, which are the material temperature derivatives and two intrinsic nonlinear terms, and explain, for the first time, all observable effects in a BAW resonator by use of a unified physical description. Moreover, the terms that are responsible for the second-harmonic generation and the frequency shift with dc voltage are shown to be the same.