Pd-Mediated γ-C(sp3)-H Bond Activation in Ammonia-Ugi 4-CR Adducts by Using Picolinamide as Directing Group.

The development of a novel protocol for the fast introduction of the picolinamide directing group in aliphatic ketones by using the ammonia-Ugi 4-CR reaction and the subsequent evaluation of the Pd-mediated γ-C(sp3)-H bond activation is described. The methodology allows the efficient construction of a series of γ-arylated α-aminoamides bearing a congested carbon in two steps.

Motivational Profiles in Physical Education: Differences at the Psychosocial, Gender, Age and Extracurricular Sports Practice Levels.

The objective of this study was to analyze the motivational profiles of Physical Education (PE) students and assess differences based on the perception of the support of autonomy, the intention to be physically active, satisfaction with classes, gender, age, and extracurricular sports activities. A cross-sectional descriptive study was carried out with a sample of 2621 students, aged 8 to 18 years (M = 14.16, SD = 2.28). An analysis of profiles was implemented, taking into account the motivation and the index of psychological mediators. The result of the cluster analysis gave a solution to four motivational profiles: high quality (n = 1094), low quantity (n = 292), low quality (n = 555), and high quantity (n = 680). Students grouped in the high quantity and quality profile presented higher levels of autonomy support, physical activity intention, enjoyment, and lower levels of boredom. Male participants, younger students, and those who participated in extracurricular activity were associated with self-determined profiles. In conclusion, the importance of promoting the satisfaction of basic psychological needs and autonomous motivation in PE classes is highlighted, in order to achieve higher values in terms of autonomy support, the intention to be physically active, enjoyment, and to reduce boredom levels in students.

Prediction of the adherence to sports practice of young Ecuadorians based on the perception of the coach's interpersonal style.

Based on the framework of the self-determination theory, the present study aimed to test a predictive model in the Ecuadorian sports context by using autonomy support as a trigger, which was mediated by basic psychological needs and later by autonomous motivation. This procedure was used to predict the intention to be physically active and was carried out on 280 athletes from the province of Azuay (Ecuador) aged between 12 and 20 years (M = 15.28; SD = 1.71). Different scales were used to measure the perception of the interpersonal style of autonomy supported by the coach. The scales employed included the degree of satisfaction of basic psychological needs, motivation to practice sports, and intention to be physically active. A structural equation analysis revealed that perceived autonomy support positively predicted basic psychological needs, which in turn positively predicted autonomous motivation and, as a result, the athletes' intentions to be physically active. It was concluded that coaches' support for the interpersonal style of autonomy can benefit the development of basic psychological needs as well as autonomous motivation, which in turn can increase young athletes' intentions to be physically active. Future research is also recommended to verify this predictive model and to encourage further experimental studies in which coaches promote autonomy support for athletes intending to increase their adherence to practising sports.

Quantum-resistance in blockchain networks.

The advent of quantum computing threatens blockchain protocols and networks because they utilize non-quantum resistant cryptographic algorithms. When quantum computers become robust enough to run Shor's algorithm on a large scale, the most used asymmetric algorithms, utilized for digital signatures and message encryption, such as RSA, (EC)DSA, and (EC)DH, will be no longer secure. Quantum computers will be able to break them within a short period of time. Similarly, Grover's algorithm concedes a quadratic advantage for mining blocks in certain consensus protocols such as proof of work. Today, there are hundreds of billions of dollars denominated in cryptocurrencies and other digital assets that rely on blockchain ledgers as well as thousands of blockchain-based applications storing value in blockchain networks. Cryptocurrencies and blockchain-based applications require solutions that guarantee quantum resistance in order to preserve the integrity of data and assets in these public and immutable ledgers. The quantum threat and some potential solutions are well understood and presented in the literature. However, most proposals are theoretical, require large QKD networks, or propose new quantum-resistant blockchain networks to be built from scratch. Our work, which is presented in this paper, is pioneer in proposing an end-to-end framework for post-quantum blockchain networks that can be applied to existing blockchain to achieve quantum-resistance. We have developed an open-source implementation in an Ethereum-based (i.e., EVM compatible) network that can be extended to other existing blockchains. For the implementation we have (i) used quantum entropy to generate post-quantum key pairs, (ii) established post-quantum TLS connections and X.509 certificates to secure the exchange of information between blockchain nodes over the internet without needing a large QKD network, (iii) introduced a post-quantum second signature in transactions using Falcon-512 post-quantum keys, and (iv) developed the first on-chain verification of post-quantum signatures using three different mechanisms that are compared and analyzed: Solidity smart-contracts run by the validators for each transaction, modified EVM Opcode, and precompiled smart contracts.

[Gastric non-Hodgkin lymphoma associated with heavy metal exposures]. / Linfoma no Hodgkin gástrico asociado a intoxicación por metales pesados.

Primary extranodal Non-Hodgkin lymphoma (NHL) is a non epithelial tumours that accounts for 40% of cases of NHL. Spread of nodal lymphomas to the gastrointestinal tract (GIT) is the most common location. Within the GIT is the stomach the most affected organ (60%). We report the case of 52-year- old man , mining company worker for over 10 years, which is derived to the Service of Gastroenterology with history of epigastric pain, nausea, vomiting and weight loss. Upper gastrointestinal endoscopic examination revealed an ulcerated lesion on greater curve of stomach and histopathological examination and subsequent immunohistochemical analysis showed diffuse large B cell gastric NHL. Also, the patient had multiple organ involvement in relation to chronic exposure to heavy metals, which was found in the mineralograma, with the highest concentration of uranium, thallium, arsenic, lead and mercury. The literature has described the association of chronic occupational exposure to uranium and arsenic with NHL presenting gastrointestinal involvement. Therefore, gastric commitment can not be considered as an isolated injury, but rather part of systemic involvement associated with elevated concentrations of metals. Mining is a key driver of income for Peru; however, there are no reports to date of the association of gastrointestinal NHL commitment regarding occupational exposure to heavy metals.

Contributing to SDG 3 through Support for Trainer Autonomy: Relationship with Motivation, Basic Psychological Needs and the Intention to Be Physically Active.

The objective of the study was to identify the profiles of support for autonomy perceived by athletes and compare them with motivation, basic psychological needs, and the intention to be physically active. A cross-sectional descriptive study was carried out with 280 athletes (M = 15.28; SD = 1.71). The results reveal the existence of two profiles using the perception of support for autonomy as a grouping variable. A profile of "High perception of support for autonomy" (group 1, n = 190, M = 4.38, SD = 0.32) and a profile of "Low support for autonomy" (group 2, n = 90, M = 3.40, SD = 0.86). The data show statistically significant differences in favour of group 1 with higher values in the Self-Determination Index (p = 0.009) and three basic psychological needs measured with the Index of Psychological Mediators (p = 0.000), but no significant differences in intention to be physically active were found. In conclusion, the importance of the support of autonomy granted by coaches is demonstrated, thus favouring more adaptive motivational climates and the greater satisfaction of basic psychological needs. The intention to be physically active was not found in federated athletes. New studies are required to clarify this fact and improve the contribution of sustainable development to the social dimension.

Granzyme B Attenuates Bacterial Virulence by Targeting Secreted Factors.

Pathogenic bacteria secrete virulence factors that interact with the human host to establish infections. The human immune system evolved multiple mechanisms to fight bacterial invaders, including immune proteases that were demonstrated to contribute crucially to antibacterial defense. Here we show that granzyme B degrades multiple secreted virulence mediators from Listeria monocytogenes, Salmonella typhimurium, and Mycobacteria tuberculosis. Pathogenic bacteria, when infected in the presence of granzyme B or granzyme-secreting killer cells, fail to grow in human macrophages and epithelial cells owing to their crippled virulence. A granzyme B-uncleavable mutant form of the major Listeria virulence factor, listeriolysin O, rescued the virulence defect in response to granzyme treatment. Hence, we link the degradation of a single factor with the observed decrease in virulent bacteria growth. Overall, we reveal here an innate immune barrier function of granzyme B by disrupting bacterial virulence to facilitate bacteria clearance by bystander immune and non-immune cells.

Custom-made macroporous bioceramic implants based on triply-periodic minimal surfaces for bone defects in load-bearing sites.

The architectural features of synthetic bone grafts are key parameters for regulating cell functions and tissue formation for the successful repair of bone defects. In this regard, macroporous structures based on triply-periodic minimal surfaces (TPMS) are considered to have untapped potential. In the present study, custom-made implants based on a gyroid structure, with (GPRC) and without (GP) a cortical-like reinforcement, were specifically designed to fit an intended bone defect in rat femurs. Sintered hydroxyapatite implants were produced using a dedicated additive manufacturing technology and their morphological, physico-chemical and mechanical features were characterized. The implants' integrity and ability to support bone ingrowth were assessed after 4, 6 and 8 weeks of implantation in a 3-mm-long, femoral defect in Lewis rats. GP and GPRC implants were manufactured with comparable macro- to nano-architectures. Cortical-like reinforcement significantly improved implant effective stiffness and resistance to fracture after implantation. This cortical-like reinforcement also concentrated new bone formation in the core of the GPRC implants, without affecting newly formed bone quantity or maturity. This study showed, for the first time, that custom-made TPMS-based bioceramic implants could be produced and successfully implanted in load-bearing sites. Adding a cortical-like reinforcement (GPRC implants) was a relevant solution to improve implant mechanical resistance, and changed osteogenic mechanism compared to the GP implants. STATEMENT OF SIGNIFICANCE: Architectural features are known to be key parameters for successful bone repair using synthetic bioceramic bone graft. So far, conventional manufacturing techniques, lacking reproducibility and complete control of the implant macro-architecture, impeded the exploration of complex architectures, such as triply periodic minimal surfaces (TPMS), which are foreseen to have an unrivaled potential for bone repair. Using a new additive manufacturing process, macroporous TPMS-based bioceramics implants were produced in calcium phosphate, characterized and implanted in a femoral defect in rats. The results showed, for the first time, that such macroporous implants can be successfully implanted in anatomical load-bearing sites when a cortical-like outer shell is added. This outer shell also concentrated new bone formation in the implant center, without affecting new bone quantity or maturity.

Killing Bacteria with Cytotoxic Effector Proteins of Human Killer Immune Cells: Granzymes, Granulysin, and Perforin.

Bacterial pathogens represent a constant threat to human health that was exacerbated in recent years by a dramatic increase of strains resistant to last resort antibiotics. The immune system of higher vertebrates generally evolved several efficient innate and adaptive mechanisms to fight ubiquitous bacterial pathogens. Among those mechanisms, immune proteases were recognized to contribute essentially to antibacterial immune defense. The effector serine proteases of the adaptive immune system, the granzymes, exert potent antimicrobial activity when they are delivered into the bacterial cytosol by prokaryotic membrane disrupting proteins, such as granulysin.In this chapter, we are detailing experimental protocols to study the synergistic cytotoxic effects of human granzymes and granulysin on extracellular as well as on intracellular bacterial pathogens in vitro. In addition, we provide a simple and fast-forward method to biochemically purify native cytotoxic effector molecules necessary to perform this kind of investigations.

Determination of NLRP3 (rs4612666) and IL-1B (rs1143634) genetic polymorphisms in periodontally diseased and healthy subjects.

OBJECTIVE: The focus of the current study was to identify if a possible association between NLRP3 (rs4612666) and IL-1B (rs1143634) single-nucleotide polymorphisms (SNPs) may be implicated in the etiopathogenesis of chronic periodontitis (CP) in a Colombian population. DESIGN: One hundred and twenty-four CP subjects and 81 periodontally healthy controls (HC) were recruited. Periodontal status was assessed by criteria based on probing depth, clinical attachment level, extent, and severity of periodontal breakdown. Human genomic DNA was obtained from saliva samples of the study subjects. The polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method was used to identify the NLRP3 (rs4612666) and IL-1B (rs1143634) SNPs. The association of polymorphisms with CP was assessed individually and adjusted for confounding using a multivariate binary logistic regression model. RESULTS: Bivariate analysis showed a weak association between CT genotype of NLRP3 (rs4612666) SNP and CP, however after logistic regression analysis, neither NLRP3 (rs4612666) nor IL-1B (rs1143634) polymorphisms were strongly/independently associated with disease status. Even so, an interaction effect was significantly detected not only among CT/CC genotypes of NLRP3 gene regarding to the age stratum ≥ 48 years, but also between CC genotype of the same gene and smoking habit. CONCLUSION: Although the present results do not support that IL-1B (rs1143634) SNP could be identified as a risk predictor for CP in the present population, the synergistic interaction of the CT/CC genotypes of NLRP3 (rs4612666) SNP with ageing and/or smoking habit potentially might play a significant role in the pathogenic pathways of periodontal disease.

Infective endocarditis and caseous calcification of the mitral annulus: the odd couple.

Caseous calcification of the mitral annulus is an infrequent echocardiographic finding. The differential diagnosis includes other entities like tumors, abscess or thrombus. Both cardiac CT and cardiac MRI may be useful for its definitive diagnosis.

Mutations in filamin C cause a new form of familial hypertrophic cardiomyopathy.

Mutations in different genes encoding sarcomeric proteins are responsible for 50-60% of familial cases of hypertrophic cardiomyopathy (HCM); however, the genetic alterations causing the disease in one-third of patients are currently unknown. Here we describe a case with familial HCM of unknown cause. Whole-exome sequencing reveals a variant in the gene encoding the sarcomeric protein filamin C (p.A1539T) that segregates with the disease in this family. Sequencing of 92 HCM cases identifies seven additional variants segregating with the disease in eight families. Patients with FLNC mutations show marked sarcomeric abnormalities in cardiac muscle, and functional analysis reveals that expression of these FLNC variants resulted in the formation of large filamin C aggregates. Clinical studies indicate that FLNC-mutated patients have higher incidence of sudden cardiac death. On the basis of these findings, we conclude that mutations in the gene encoding the sarcomeric protein filamin C cause a new form of familial HMC.

The economic burden of pleural effusions in patients with chronic myeloid leukemia treated with tyrosine kinase inhibitors.

OBJECTIVE: Tyrosine kinase inhibitors (TKI), the standard of care for patients with chronic myeloid leukemia (CML) patients, may in some cases lead to the development of pleural effusion (PE). The purpose of this study is to compare healthcare resource utilization and costs associated with PE among CML patients treated with a TKI therapy. METHODS: Two large retrospective claims databases (1999-2009) were combined to identify adult CML patients who received ≥1 TKI prescription before the index date, which was defined as 30 days before the first PE diagnosis for patients with PE and a randomly selected date for PE-free patients. Patients were followed for 6 months after the index date. PE and PE-free patients were matched on a 1:1 ratio. PE-related resource utilization and costs (measured in 2009 US dollars) were estimated for PE patients. All-cause and CML-related resource utilization and costs were compared between PE and PE-free patients. Multivariate regression models were used to control for confounding factors. RESULTS: The study included 186 matched pairs. PE-free and PE patients were on average 65.4 and 63.6 years old and 39.8% and 48.9% were female, respectively. PE patients had a significantly higher number of inpatient (IP) days, IP admissions, outpatient (OP) visits and emergency room (ER) visits than PE-free patients (all p < 0.01). All-cause medical services costs were $88,526 and $30,434 for PE and PE-free patients, respectively. After adjusting for confounding factors, the PE-related total medical costs were $47,288 (p < 0.01), which was mostly accounted for by higher IP (difference: $34,123, p < 0.01) and OP (difference: $9563, p < 0.05) costs. PE patients also incurred higher CML-related medical costs compared to PE-free patients (difference: $39,599; p < 0.01). CONCLUSION: PE presents a substantial economic burden for CML patients treated with TKI.

Left ventricle non-compaction cardiomyopathy: different clinical scenarios and magnetic resonance imaging findings.

Left ventricle non-compaction cardiomyopathy is currently considered as a well-defined individual entity. However, it includes a broad spectrum of clinical, radiological and pathophysiological findings. In this review we describe 3 different scenarios of this entity: an isolated case with severe left ventricle dysfunction, an "associated" case in a patient with previous atrial septum defect and pulmonary stenosis and finally, as a finding in a patient with a transient cerebrovascular ischemic attack. In the 2 last cases, both asymptomatic, morphological criteria of left ventricle non-compaction were found but, ventricular function was normal and cardiac-MRI showed no late gadolinium hyperenhancement. Periodical follow-up and familial screening were recommended. Natural history and prognosis factors of this disease are still not well known. Further and longer series of patients with this diagnosis are needed to completely define radiological criteria, clinical presentation and evolution.

A retrospective analysis of therapy adherence in imatinib resistant or intolerant patients with chronic myeloid leukemia receiving nilotinib or dasatinib in a real-world setting.

OBJECTIVES: To compare adherence to second-generation tyrosine kinase inhibitors (TKIs) dasatinib and nilotinib in patients with imatinib resistant or intolerant chronic myeloid leukemia (CML) receiving second-line therapies. METHODS: Two U.S. administrative claims databases were reviewed (January 1997 to March 2011) for CML patients previously treated with imatinib, who received ≥1 prescription of dasatinib or nilotinib and had continuous enrollment ≥1 month before and after the index date (first dasatinib or nilotinib prescription date). Medication possession ratios (MPRs) and proportion of days covered (PDCs) were evaluated between the treatment initiation date until the end of continuous eligibility, for a maximum of 12 months. Sensitivity analyses were conducted to compare patients initiated on nilotinib to patients who initiated dasatinib 100 mg/day and 140 mg/day separately. This study provides updated results of a previously published study. RESULTS: In total, 878 CML patients who received second-line treatment with either dasatinib (n = 550) or nilotinib (n = 328) were studied. Dasatinib users were less adherent compared to nilotinib users; mean MPR was 0.739 (standard deviation [SD] 0.246) for dasatinib and 0.800 (SD 0.246) for nilotinib (adjusted difference = 0.061; P = 0.002). Subgroup analyses of patients who initiated dasatinib 100 mg/day and 140 mg/day separately presented similar trends; after multivariate adjustment, adherence was 0.039 points lower in the 100 mg/day group (P = 0.034) and 0.120 points lower in the 140 mg/day group (P < 0.001). CONCLUSIONS: Among patients treated in the second-line CML setting, those treated with nilotinib had significantly higher adherence compared to patients treated with dasatinib, regardless of dasatinib dose (100 mg/day and 140 mg/day). LIMITATIONS: The study was subject to common limitations of claims data, which lack clinical information, may contain inaccuracies in diagnosis and procedure coding, and may not truly reflect actual drug consumption. Moreover, daily doses calculated based on refill records may not reflect accurate dosing regimens.

Therapy persistence and adherence in patients with chronic obstructive pulmonary disease: multiple versus single long-acting maintenance inhalers.

OBJECTIVE: To compare persistence and adherence among patients with chronic obstructive pulmonary disease (COPD) treated with either multiple- or single- long-acting maintenance inhalers. METHODS: Patients with ≥2 COPD medical claims and ≥2 prescriptions for a long-acting inhaler within 1 year were classified as single- or multiple-inhaler users based on their treatment regimen (MarketScan database; 2004-2008) and matched on demographics and statistically significant baseline characteristics. Persistence, analyzed via time to treatment discontinuation, and treatment adherence, measured by proportion of days covered (PDC), were compared between the two groups over a 12-month period. Sensitivity analyses were conducted in patients with poorly and well-controlled disease. RESULTS: A total of 23,494 patients were grouped into 11,747 matched pairs. After adjusting for confounding factors, multiple-inhaler users had a significantly higher discontinuation rate [Hazard ratio = 1.40, p < 0.0001] compared with single-inhaler users. Multiple-inhaler users were less likely to be adherent than single-inhaler users with an average PDC of 0.51 (SD = 0.272) vs. 0.55 (SD = 0.279), respectively (p < 0.0001). These results were consistent for the poorly- and well-controlled disease groups. CONCLUSIONS: Multiple long-acting inhaler users demonstrated lower treatment persistence and adherence rates than single long-acting inhaler users. Limitations of the study are related to the retrospective, observational design and use of claims data.

Clinical and economic outcomes of multiple versus single long-acting inhalers in COPD.

OBJECTIVE: To compare healthcare resource utilization and healthcare costs between COPD patients who used multiple long-acting inhalers versus those who used a single long-acting inhaler. METHODS: COPD patients meeting study inclusion criteria were identified in the Market Scan database (2004-2008) and were classified as being a multiple- or single-inhaler user. 11,747 multiple- and single-inhaler users were matched on baseline characteristics to balance disease severity. Patients were followed for 12 months. Incremental differences between the two groups were estimated for: number of exacerbations; time to first exacerbation; all-cause and COPD-related inpatient admissions, inpatient days, emergency room visits, urgent care visits, outpatient visits, and other medical services visits; all-cause and COPD-related healthcare costs. Multivariate regression analyses were also used to control for a number of potentially confounding factors. RESULTS: After controlling for a number of potentially confounding factors, multiple-inhaler users experienced significantly more exacerbations (0.52; p < .0001) and had a higher risk of exacerbation (HR = 1.40; p < .0001) than single-inhaler users. Multiple-inhaler users also incurred significantly more inpatient admissions (IRR = 1.15; p < .0001), inpatient days (IRR = 1.20; p < .0001), urgent care visits (IRR = 1.10; p = 0.0026), outpatient visits (IRR = 1.06; p < .0001), and other medical services visits (IRR = 1.12; p = <.001) than single-inhaler users, resulting in significantly higher all-cause health care costs ($3,319; p < .0001). Results of COPD-related resource use and costs were comparable. CONCLUSIONS: After controlling for a number of potentially confounding factors, multiple-inhaler users had more exacerbations, a higher risk of exacerbation, and higher healthcare resource utilization and costs compared to single-inhaler users.

[Single coronary artery originated in the right Valsalva sinus. Usefulness of multislice coronary angiotomography]. / Arteria coronaria única con origen en seno de Valsalva derecho. Utilidad de la angiotomografía coronaria con tomografía multicorte.

Single coronary artery arising from the right sinus of Valsalva is a rare congenital coronary anomaly. We report the case of a 77- year- old man who was referred for invasive coronary angiography with a diagnosis of a non-ST-segment elevation acute coronary syndrome of inferior-lateral location. Significant lesion was detected in the proximal segment of the right coronary artery (RCA). During the procedure, it was impossible to catheterize the left coronary ostium, being the left anterior descending filled from the RCA. Given the suspicion of agenesis of the left main, 64-multidetector computed tomography was performed which confirmed the existence of a solitary coronary ostium with a single artery arising from the right sinus of Valsalva.