A phase II study of potentiation of pembrolizumab with binimetinib and bevacizumab in refractory microsatellite stable colorectal cancer.

PURPOSE: In this single-institution phase II investigator-initiated study we assessed the ability of MAPK and VEGF pathway blockade to overcome resistance to immunotherapy in microsatellite stable metastatic colorectal cancer (MSS mCRC). PATIENTS AND METHODS: Patients with MSS, BRAF wild-type mCRC who progressed on ≥2 prior lines of therapy received pembrolizumab, binimetinib, and bevacizumab until disease progression or unacceptable toxicity. After a safety run-in, patients were randomized to a 7-day run-in of binimetinib or simultaneous initiation of all study drugs, to explore whether MEK inhibition may increase tumor immunogenicity. The primary endpoint was objective response rate in all patients combined (ORR, by RECIST v1.1). RESULTS: Fifty patients received study drug treatment; 54% were male with median age 55 years (range 31-79). The primary endpoint, ORR, was 12.0% (95% confidence interval [CI] 4.5-24.3%), which was not statistically different than the historical control data of 5% (p=0.038, exceeding pre-specified threshold of 0.025). The disease control rate was 70.0% (95% CI 55.4-82.1%), median progression-free survival 5.9 months (95% CI 4.2-8.7 months), and median overall survival 9.3 months (95% CI 6.7-12.2 months). No difference in efficacy was observed between the randomized cohorts. Grade 3 and 4 adverse events were observed in 56% and 8% of patients, respectively; the most common were rash (12%) and increased aspartate aminotransferase (12%). CONCLUSION: Pembrolizumab, binimetinib, and bevacizumab failed to meet its primary endpoint of higher ORR compared to historical control data, demonstrated a high disease control rate, and demonstrated acceptable tolerability in refractory MSS mCRC.

Association of microbiological factors with mortality in Escherichia coli bacteraemia presenting with sepsis/septic shock: a prospective cohort study.

OBJECTIVES: This study aimed to determine the association of Escherichia coli microbiological factors with 30-day mortality in patients with bloodstream infection (BSI) presenting with a dysregulated response to infection (i.e. sepsis or septic shock). METHODS: Whole-genome sequencing was performed on 224 E coli isolates of patients with sepsis/septic shock, from 22 Spanish hospitals. Phylogroup, sequence type, virulence, antibiotic resistance, and pathogenicity islands were assessed. A multivariable model for 30-day mortality including clinical and epidemiological variables was built, to which microbiological variables were hierarchically added. The predictive capacity of the models was estimated by the area under the receiver operating characteristic curve (AUROC) with 95% confidence intervals (CI). RESULTS: Mortality at day 30 was 31% (69 patients). The clinical model for mortality included (adjusted OR; 95% CI) age (1.04; 1.02-1.07), Charlson index ≥3 (1.78; 0.95-3.32), urinary BSI source (0.30; 0.16-0.57), and active empirical treatment (0.36; 0.11-1.14) with an AUROC of 0.73 (95% CI, 0.67-0.80). Addition of microbiological factors selected clone ST95 (3.64; 0.94-14.04), eilA gene (2.62; 1.14-6.02), and astA gene (2.39; 0.87-6.59) as associated with mortality, with an AUROC of 0.76 (0.69-0.82). DISCUSSION: Despite having a modest overall contribution, some microbiological factors were associated with increased odds of death and deserve to be studied as potential therapeutic or preventive targets.

Whole-genome characterisation of Escherichia coli isolates from patients with bacteraemia presenting with sepsis or septic shock in Spain: a multicentre cross-sectional study.

BACKGROUND: Escherichia coli is the most frequent cause of bloodstream infections (BSIs). About one-third of patients with BSIs due to E coli develop sepsis or shock. The objective of this study is to characterise the microbiological features of E coli blood isolates causing sepsis or septic shock to provide exploratory information for future diagnostic, preventive, or therapeutic interventions. METHODS: E coli blood isolates from a multicentre cross-sectional study of patients older than 14 years presenting with sepsis or septic shock (according to the Third International Consensus Definitions for Sepsis and Septic Shock criteria) from hospitals in Spain between Oct 4, 2016, and Oct 15, 2017, were studied by whole-genome sequencing. Phylogroups, sequence types (STs), serotype, FimH types, antimicrobial resistance (AMR) genes, pathogenicity islands, and virulence factors were identified. Susceptibility testing was performed by broth microdilution. The main outcome of this study was the characterisation of the E coli blood isolates in terms of population structure by phylogroups, groups (group 1: phylogroups B2, F, and G; group 2: A, B1, and C; group 3: D), and STs and distribution by geographical location and bloodstream infection source. Other outcomes were virulence score and prevalence of virulence-associated genes, pathogenicity islands, AMR, and AMR-associated genes. Frequencies were compared using χ² or Fisher's exact tests, and continuous variables using the Mann-Whitney test, with Bonferroni correction for multiple comparisons. FINDINGS: We analysed 224 isolates: 140 isolates (63%) were included in phylogenetic group 1, 52 (23%) in group 2, and 32 (14%) in group 3. 85 STs were identified, with four comprising 44% (n=98) of the isolates: ST131 (38 [17%]), ST73 (25 [11%]), ST69 (23 [10%]), and ST95 (12 [5%]). No significant differences in phylogroup or ST distribution were found according to geographical areas or source of bloodstream infection, except for ST95, which was more frequent in urinary tract infections than in other sources (11 [9%] of 116 vs 1 [1%] of 108, p=0·0045). Median virulence score was higher in group 1 (median 25·0 [IQR 20·5-29·0) than in group 2 (median 14·5 [9·0-20·0]; p<0·0001) and group 3 (median 21 [16·5-23·0]; p<0·0001); prevalence of several pathogenicity islands was higher in group 1. No significant differences were found between phylogenetic groups in proportions of resistance to antibiotics. ST73 had higher median virulence score (32 [IQR 29-35]) than the other predominant clones (median range 21-28). Some virulence genes and pathogenicity islands were significantly associated with each ST. ST131 isolates had higher prevalence of AMR and a higher proportion of AMR genes, notably blaCTX-M-15 and blaOXA-1. INTERPRETATION: In this exploratory study, the population structure of E coli causing sepsis or shock was similar to previous studies that included all bacteraemic isolates. Virulence genes, pathogenicity islands, and AMR genes were not randomly distributed among phylogroups or STs. These results provide a comprehensive characterisation of invasive E coli isolates causing severe response syndrome. Future studies are required to determine the contribution of these microbiological factors to severe clinical presentation and worse outcomes in patients with E coli bloodstream infection. FUNDING: Instituto de Salud Carlos III.

Overcoming doxorubicin resistance in triple-negative breast cancer using the class I-targeting HDAC inhibitor bocodepsin/OKI-179 to promote apoptosis.

BACKGROUND: Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype with a poor prognosis. Doxorubicin is part of standard curative therapy for TNBC, but chemotherapy resistance remains an important clinical challenge. Bocodepsin (OKI-179) is a small molecule class I histone deacetylase (HDAC) inhibitor that promotes apoptosis in TNBC preclinical models. The purpose of this study was to investigate the combination of bocodepsin and doxorubicin in preclinical TNBC models and evaluate the impact on terminal cell fate, including apoptosis and senescence. METHODS: TNBC cell lines were treated with doxorubicin and CellTiter-Glo was used to assess proliferation and determine doxorubicin sensitivity. Select cell lines were treated with OKI-005 (in vitro version of bocodepsin) and doxorubicin and assessed for proliferation, apoptosis as measured by Annexin V/PI, and cell cycle by flow cytometry. Immunoblotting was used to assess changes in mediators of apoptosis, cell cycle arrest, and senescence. Senescence was measured by the senescence-associated ß-galactosidase assay. An MDA-MB-231 xenograft in vivo model was treated with bocodepsin, doxorubicin, or the combination and assessed for inhibition of tumor growth. shRNA knockdown of p53 was performed in the CAL-51 cell line and proliferation, apoptosis and senescence were assessed in response to combination treatment. RESULTS: OKI-005 and doxorubicin resulted in synergistic antiproliferative activity in TNBC cells lines regardless of p53 mutation status. The combination led to increased apoptosis and decreased senescence. In vivo, the combination resulted in increased tumor growth inhibition compared to either single agent. shRNA knock-down of p53 led to increased doxorubicin-induced senescence that was decreased with the addition of OKI-005 in vitro. CONCLUSION: The addition of bocodepsin to doxorubicin resulted in synergistic antiproliferative activity in vitro, improved tumor growth inhibition in vivo, and promotion of apoptosis which makes this a promising combination to overcome doxorubicin resistance in TNBC. Bocodepsin is currently in clinical development and has a favorable toxicity profile compared to other HDAC inhibitors supporting the feasibility of evaluating this combination in patients with TNBC.

Pancreatic Ductal Adenocarcinoma Cells Regulate NLRP3 Activation to Generate a Tolerogenic Microenvironment.

Defining feature of pancreatic ductal adenocarcinoma (PDAC) that participates in the high mortality rate and drug resistance is the immune-tolerant microenvironment which enables tumors to progress unabated by adaptive immunity. In this study, we report that PDAC cells release CSF-1 to induce nucleotide-binding domain, leucine-rich containing family, pyrin domain-containing-3 (NLRP3) activation in myeloid cells. Increased NLRP3 expression was found in the pancreas of patients with PDAC when compared with normal pancreas which correlated with the formation of the NLRP3 inflammasome. Using human primary cells and an orthotopic PDAC mouse model, we show that NLRP3 activation is responsible for the maturation and release of the inflammatory cytokine IL1ß which selectively drives Th2-type inflammation via COX2/PGE2 induction. As a result of this inflammation, primary tumors were characterized by reduced cytotoxic CD8+ T-cell activation and increased tumor expansion. Genetic deletion and pharmacologic inhibition of NLRP3 enabled the development of Th1 immunity, increased intratumoral levels of IL2, CD8+ T cell­mediated tumor suppression, and ultimately limited tumor growth. In addition, we observed that NLRP3 inhibition in combination with gemcitabine significantly increased the efficacy of the chemotherapy. In conclusion, this study provides a mechanism by which tumor-mediated NLRP3 activation exploits a distinct adaptive immunity response that facilitates tumor escape and progression. Considering the ability to block NLRP3 activity with safe and small orally active molecules, this protein represents a new promising target to improve the limited therapeutic options in PDAC. SIGNIFICANT: This study provides novel molecular insights on how PDAC cells exploit NLRP3 activation to suppress CD8 T-cell activation. From a translational perspective, we demonstrate that the combination of gemcitabine with the orally active NLRP3 inhibitor OLT1177 increases the efficacy of monotherapy.

Beam Steering 3D Printed Dielectric Lens Antennas for Millimeter-Wave and 5G Applications.

Two types of cost-efficient antennas based on dielectric gradient index dielectric lens have been designed for 5G applications at 28 GHz. The first is a linearly polarized flat lens antenna (LP-FLA) for terrestrial 5G communications. The second is a novel circularly polarized stepped lens antenna (CP-SLA) for 5G satellite services. An efficient design method is presented to optimize and conform the lens topology to the radiation pattern coming from the antenna feeder. The LP-FLA is fed by a traditional linearly polarized pyramidal horn antenna (PHA). The CP-SLA is fed by an open-ended bow-tie waveguide cavity (BCA) antenna. This cavity feeder (BCA), using cross-sections with bow-tie shapes, allows having circular polarization at the desired frequency bandwidth. The two types of presented antennas have been manufactured in order to verify their performance by an easy, low-cost, three-dimensional (3D) printing technique based on stereolithography. The peak realized gain value for the flat (LP-FLA) and stepped (CP-SLA) lens antennas have been increased at 28 GHz to 25.2 and 24.8 dBi, respectively, by disposing the lens structures at the appropriated distance from the feeders. Likewise, using an array of horns (PHA) or open-ended bow-tie waveguide cavity (BCA) antenna feeders, it is possible to obtain a maximum steering angle range of 20° and 35°, for a directivity over 15 dBi and 10 dBi, in the planar and stepped lens antennas, respectively.

Completeness of Race and Ethnicity Reporting in Person-Level COVID-19 Surveillance Data, 50 States, April 2020-December 2021.

OBJECTIVES: Black, Indigenous, and People of Color have borne a disproportionate incidence of COVID-19 cases in the United States. However, few studies have documented the completeness of race and ethnicity reporting in national COVID-19 surveillance data. The objective of this study was to describe the completeness of race and ethnicity ascertainment in person-level data received by the Centers for Disease Control and Prevention (CDC) through national COVID-19 case surveillance. METHODS: We compared COVID-19 cases with "complete" (ie, per Office of Management and Budget 1997 revised criteria) data on race and ethnicity from CDC person-level surveillance data with CDC-reported aggregate counts of COVID-19 from April 5, 2020, through December 1, 2021, in aggregate and by state. RESULTS: National person-level COVID-19 case surveillance data received by CDC during the study period included 18 881 379 COVID-19 cases with complete ascertainment of race and ethnicity, representing 39.4% of all cases reported to CDC in aggregate (N = 47 898 497). Five states (Georgia, Hawaii, Nebraska, New Jersey, and West Virginia) did not report any COVID-19 person-level cases with multiple racial identities to CDC. CONCLUSION: Our findings highlight a high degree of missing data on race and ethnicity in national COVID-19 case surveillance, enhancing our understanding of current challenges in using these data to understand the impact of COVID-19 on Black, Indigenous, and People of Color. Streamlining surveillance processes to decrease reporting incidence and align reporting requirements with an Office of Management and Budget-compliant collection of data on race and ethnicity would improve the completeness of data on race and ethnicity for national COVID-19 case surveillance.

Pleiotrophin drives a prometastatic immune niche in breast cancer.

Metastatic cancer cells adapt to thrive in secondary organs. To investigate metastatic adaptation, we performed transcriptomic analysis of metastatic and non-metastatic murine breast cancer cells. We found that pleiotrophin (PTN), a neurotrophic cytokine, is a metastasis-associated factor that is expressed highly by aggressive breast cancers. Moreover, elevated PTN in plasma correlated significantly with metastasis and reduced survival of breast cancer patients. Mechanistically, we find that PTN activates NF-κB in cancer cells leading to altered cytokine production, subsequent neutrophil recruitment, and an immune suppressive microenvironment. Consequently, inhibition of PTN, pharmacologically or genetically, reduces the accumulation of tumor-associated neutrophils and reverts local immune suppression, resulting in increased T cell activation and attenuated metastasis. Furthermore, inhibition of PTN significantly enhanced the efficacy of immune checkpoint blockade and chemotherapy in reducing metastatic burden in mice. These findings establish PTN as a previously unrecognized driver of a prometastatic immune niche and thus represents a promising therapeutic target for the treatment of metastatic breast cancer.

COVID-19 Among Non-Hispanic American Indian and Alaska Native People Residing in Urban Areas Before and After Vaccine Rollout-Selected States and Counties, United States, January 2020-October 2021.

Objectives. To evaluate COVID-19 disparities among non-Hispanic American Indian/Alaska Native (AI/AN) and non-Hispanic White persons in urban areas. Methods. Using COVID-19 case surveillance data, we calculated cumulative incidence rates and risk ratios (RRs) among non-Hispanic AI/AN and non-Hispanic White persons living in select urban counties in the United States by age and sex during January 22, 2020, to October 19, 2021. We separated cases into prevaccine (January 22, 2020-April 4, 2021) and postvaccine (April 5, 2021-October 19, 2021) periods. Results. Overall in urban areas, the COVID-19 age-adjusted rate among non-Hispanic AI/AN persons (n = 47 431) was 1.66 (95% confidence interval [CI] = 1.36, 2.01) times that of non-Hispanic White persons (n = 2 301 911). The COVID-19 prevaccine age-adjusted rate was higher (8227 per 100 000; 95% CI = 6283, 10 770) than was the postvaccine rate (3703 per 100 000; 95% CI = 3235, 4240) among non-Hispanic AI/AN compared with among non-Hispanic White persons (2819 per 100 000; 95% CI = 2527, 3144; RR = 1.31; 95% CI = 1.17, 1.48). Conclusions. This study highlights disparities in COVID-19 between non-Hispanic AI/AN and non-Hispanic White persons in urban areas. These findings suggest that COVID-19 vaccination and other public health efforts among urban AI/AN communities can reduce COVID-19 disparities in urban AI/AN populations. (Am J Public Health. 2022;112(10):1489-1497. https://doi.org/10.2105/AJPH.2022.306966).

Digital Pregnancy Test Powered by an Air-Breathing Paper-Based Microfluidic Fuel Cell Stack Using Human Urine as Fuel.

The direct integration of paper-based microfluidic fuel cells (µFC's) toward creating autonomous lateral flow assays has attracted attention. Here, we show that an air-breathing paper-based µFC could be used as a power supply in pregnancy tests by oxidizing the human urine used for the diagnosis. We present an air-breathing paper-based µFC connected to a pregnancy test, and for the first time, as far as we know, it is powered by human urine without needing any external electrolyte. It uses TiO2-Ni as anode and Pt/C as cathode; the performance shows a maximum value of voltage and current and power densities of ∼0.96 V, 1.00 mA cm-2, and 0.23 mW cm-2, respectively. Furthermore, we present a simple design of a paper-based µFC's stack powered with urine that shows a maximum voltage and maximum current and power densities of ∼1.89 V, 2.77 mA cm-2 and 1.38 mW cm-2, respectively, which powers the display of a pregnancy test allowing to see the analysis results.

Risk Factors and Predictive Score for Bacteremic Biliary Tract Infections Due to Enterococcus faecalis and Enterococcus faecium: a Multicenter Cohort Study from the PROBAC Project.

Biliary-tract bloodstream infections (BT-BSI) caused by Enterococcus faecalis and E. faecium are associated with inappropriate empirical treatment and worse outcomes compared to other etiologies. The objective of this study was to investigate the risk factors for enterococcal BT-BSI. Patients with BT-BSI from the PROBAC cohort, including consecutive patients with BSI in 26 Spanish hospitals between October 2016 and March 2017, were selected; episodes caused by E. faecalis or E. faecium and other causes were compared. Independent predictors for enterococci were identified by logistic regression, and a predictive score was developed. Eight hundred fifty episodes of BT-BSI were included; 73 (8.5%) were due to target Enterococcus spp. (48 [66%] were E. faecium and 25 [34%] E. faecalis). By multivariate analysis, the variables independently associated with Enterococcus spp. were (OR; 95% confidence interval): cholangiocarcinoma (4.48;1.32 to 15.25), hospital acquisition (3.58;2.11 to 6.07), use of carbapenems in the previous month (3.35;1.45 to 7.78), biliary prosthesis (2.19;1.24 to 3.90), and moderate or severe chronic kidney disease (1.55;1.07 to 2.26). The AUC of the model was 0.74 [95% CI0.67 to 0.80]. A score was developed, with 7, 6, 5, 4, and 2 points for these variables, respectively, with a negative predictive value of 95% for a score ≤ 6. A model, including cholangiocarcinoma, biliary prosthesis, hospital acquisition, previous carbapenems, and chronic kidney disease showed moderate prediction ability for enterococcal BT-BSI. Although the score will need to be validated, this information may be useful for deciding empirical therapy in biliary tract infections when bacteremia is suspected. IMPORTANCE Biliary tract infections are frequent, and a significant cause of morbidity and mortality. Bacteremia is common in these infections, particularly in the elderly and patients with cancer. Inappropriate empirical treatment has been associated with increased risk of mortality in bacteremic cholangitis, and the probability of receiving inactive empirical treatment is higher in episodes caused by enterococci. This is because many of the antimicrobial agents recommended in guidelines for biliary tract infections lack activity against these organisms. To the best of our knowledge, this is the first study analyzing the predictive factors for enterococcal BT-BSI and deriving a predictive score.

Efficacy and Safety of Lithium Treatment in SARS-CoV-2 Infected Patients.

At the beginning of the pandemic, we observed that lithium carbonate had a positive effect on the recovery of severely ill patients with COVID-19. Lithium is able to inhibit the replication of several types of viruses, some of which are similar to the SARS-CoV-2 virus, increase the immune response and reduce inflammation by preventing or reducing the cytokine storm. Previously, we published an article with data from six patients with severe COVID-19 infection, where we proposed that lithium carbonate could be used as a potential treatment for COVID-19. Now, we set out to conduct a randomized clinical trial number EudraCT 2020-002008-37 to evaluate the efficacy and safety of lithium treatment in patients infected with severe SARS-CoV-2. We showed that lithium was able to reduce the number of days of hospital and intensive care unit admission as well as the risk of death, reduces inflammatory cytokine levels by preventing cytokine storms, and also reduced the long COVID syndromes. We propose that lithium carbonate can be used to reduce the severity of COVID-19.

Caracterización fisicoquímica y evaluación in vitro de sistemas autoemulsionables de liberación de indometacina

Objetivo: incorporar la indometacina en sistemas autoemulsionables de liberación con la finalidad de aumentar su solubilidad en medio acuoso, la velocidad de disolución y permeación in vitro. Metodología: se llevaron a cabo ensayos de solubilidad al equilibrio para preparar formulaciones con los excipientes, en los cuales la indome-tacina presentó mayor incremento de solubilidad; los sistemas fueron caracterizados por medio del tiempo de autoemulsificación, estabilidad física, tamaño de partícula, potencial zeta, perfiles de disolución y permeación a través de membrana sintética. Resultados: el diseño experimental de los sistemas autoemulsionables de liberación permitió crear formulaciones que aumentaron la solubilidad de la indometacina en un orden de 105 veces con respecto a la solubilidad acuosa. Las formulaciones que resultaron viables presentaron tiempos de autoemulsificación menores que 60 segundos, además, las distribuciones de tamaño de partícula de las dispersiones fueron inferiores a los 300 nm, presentó índices de polidispersión inferiores a 0,3 y valores de potencial zeta menores de -25 mV. Los perfiles de disolución mostraron que las formulaciones cumplen con un valor de factor de similitud mayor que 50, además, la permeabilidad a través de membrana sintética es mayor para las formulaciones autoemulsionables que el producto de referencia. Conclusiones: la formulación de indometacina en sistemas autoemulsionables de liberación incrementa la solubilidad en medio acuoso, aumenta la disolución y liberación. Estos resultados sugieren que la administración oral de indometacina incorporada en sistemas autoe-mulsionables puede acelerar el inicio del efecto farmacológico.

SUMMARY Aim: To load indomethacin into self-emulsifying delivery systems in order to increase, water-solubility, rate dissolution and in vitro permeation. Methodology: Equilibrium solubility tests were carried out to prepare formulations with the excipients, in which indomethacin presented a greater increase in solubility; the systems were characterized by self-emulsification time, physical stability, particle size, zeta potential, dissolution profiles and permeation through synthetic membrane. Results: The experimental design of self-emulsifying delivery systems allowed to create formulations that increase the solubility of indomethacin in an order of 105 times with respect to the aqueous solubility. The feasible formulations presented autoemulsification times less than 60 seconds, in addition, the particle size distributions of the dispersions were less than 300 nm, with polydispersity index smaller than 0.3, and zeta potential values lower than -25 mV. The dissolution profiles showed that the formulations comply with a similarity factor value greater than 50, in addition, the permeability through a synthetic membrane is higher for the self-emulsifying formulations than the reference product. Conclusion: The formulation of indomethacin into self-emulsifying delivery systems enhances the solubility in aqueous medium, increases dissolution and accelerate release. These results suggest that the oral administration of indomethacin incorporated into self-emulsifying delivery systems can accelerate the onset of the pharmacological effect.

Objetivo: incorporar a indometacina em sistemas de liberação autoemulsificantes a fim de aumentar sua solubilidade em meio aquoso, a taxa de dissolução e permeação in vitro. Metodologia: foram realizados testes de solubilidade de equilíbrio para preparar formulações com os excipientes, nas quais a indometacina apresentou maior aumento na solubilidade; os sistemas foram caracterizados quanto ao tempo de autoemulsificação, estabilidade física, tamanho de partícula, potencial zeta, perfis de dissolução e permeação através de membrana sintética. Resultados: o desenho experimental dos sistemas de liberação autoemulsificantes permitiu a criação de formulações que aumentaram a solubilidade da indometacina na ordem de 105 vezes em relação à solubilidade aquosa. As formulações que se mostraram viáveis apresentaram tempos de autoemulsificação inferiores a 60 segundos, além disso, as distribuições granulométricas das dispersões foram inferiores a 300 nm, apresentaram índices de polidispersidade inferiores a 0,3 e valores de potencial zeta inferiores a -25 mV. Os perfis de dissolução mostraram que as formulações atendem a um valor de fator de similaridade maior que 50, além disso, a permeabilidade através da membrana sintética é maior para as formulações autoemulsionantes do que para o produto de referência. Conclusões: a formulação de indometacina em sistemas de liberação autoemulsificantes aumenta a solubilidade em meio aquoso, aumenta a dissolução e a liberação. Esses resultados sugerem que a administração oral de indometacina incorporada em sistemas autoemulsificantes pode acelerar o início do efeito farmacológico.

Reestenosis de stents liberadores de paclitaxel frente a stents convencionales

RESUMEN Introducción: La reestenosis de los stents liberadores de paclitaxel utilizados en Cuba no ha sido estudiada. Objetivo: Evaluar la reestenosis de los stents liberadores de paclitaxel y los convencionales. Métodos: Se incluyeron 64 pacientes con reestenosis de stent, de un estudio prospectivo previo; en 318 pacientes seguidos por 3 años luego de intervención coronaria percutánea; 25 con stent liberador de paclitaxel y 39 stent metálico convencional. Se consideró reestenosis como nueva lesión ≥ 50 % de la luz del vaso con isquemia demostrada. Se describió el tiempo de aparición, patrón angiográfico y alternativa de revascularización. Resultados: La reestenosis en el grupo de stents liberadores de paclitaxel fue 15,7 % con tiempo medio de supervivencia sin reestenosis de 32,4 meses vs. 24,5 % en stents convencionales, con supervivencia sin reestenosis de 29,8 meses, (p= 0,047). En el grupo de stents liberadores de paclitaxel predominó el patrón IB, (30,3 %) y stent convencional el III (28,3 %). En el 28,0 % del grupo de stents liberadores de paclitaxel, se recurrió a la cirugía de revascularización vs. 5,1 % en el grupo de stent convencional. Conclusiones: El stent liberador de paclitaxel logra una supervivencia libre de reestenosis superior y más perdurable que el stent convencional. La reestenosis en los de stents liberadores de paclitaxel es focal, con mayor frecuencia de nueva revascularización por cirugía y en los stents convencionales es mayormente difusa.

ABSTRACT Introduction: The restenosis of the paclitaxel-eluting stents used in Cuba has not been studied. Objective: To evaluate the restenosis of paclitaxel-eluting stents and conventional stents. Methods: 64 patients with stent restenosis were included, from a previous prospective study; in 318 patients followed up for 3 years after percutaneous coronary intervention; 25 with a paclitaxel-eluting stent and 39 conventional metal stent. Restenosis was considered as a new lesion ≥ 50 % of the vessel lumen with proven ischemia. The time to onset, angiographic pattern and alternative revascularization were described. Results: Restenosis in the group with paclitaxel-eluting stents was 15.7 % with a mean survival time without restenosis of 32.4 months vs. 24.5 % in conventional stents, with restenosis-free survival of 29.8 months, (p = 0.047). In the group with paclitaxel-eluting stents, the IB pattern predominated (30.3 %) and the conventional stent III (28.3 %). In 28.0 % of the paclitaxel-eluting stent group, revascularization surgery was used vs. 5.1 % in the conventional stent group. Conclusions: The paclitaxel-eluting stent achieves a superior and more durable restenosis-free survival than the conventional stent. Restenosis in paclitaxel-eluting stents is focal, with a higher frequency of revascularization by surgery, and in conventional stents it is mostly diffuse.

Cancer disparities among non-Hispanic urban American Indian and Alaska Native populations in the United States, 1999-2017.

BACKGROUND: Disparities in cancer incidence have not been described for urban American Indian/Alaska Native (AI/AN) populations. The purpose of the present study was to examine incidence rates (2008-2017) and trends (1999-2017) for leading cancers in urban non-Hispanic AI/AN (NH AI/AN) compared to non-Hispanic White (NHW) populations living in the same urban areas. METHODS: Incident cases from population-based cancer registries were linked with the Indian Health Service patient registration database for improved racial classification of NH AI/AN populations. This study was limited to counties in Urban Indian Health Organization service areas. Analyses were conducted by geographic region. Age-adjusted rates (per 100,000) and trends (joinpoint regression) were calculated for leading cancers. RESULTS: Rates of colorectal, liver, and kidney cancers were higher overall for urban NH AI/AN compared to urban NHW populations. By region, rates of these cancers were 10% to nearly 4 times higher in NH AI/AN compared to NHW populations. Rates for breast, prostate, and lung cancer were lower in urban NH AI/AN compared to urban NHW populations. Incidence rates for kidney, liver, pancreatic, and breast cancers increased from 2% to nearly 7% annually between 1999 to 2017 in urban NH AI/AN populations. CONCLUSIONS: This study presents cancer incidence rates and trends for the leading cancers among urban NH AI/AN compared to urban NHW populations for the first time, by region, in the United States. Elevated risk of certain cancers among urban NH AI/AN populations and widening cancer disparities highlight important health inequities and missed opportunities for cancer prevention in this population.

Mechanically Reconfigurable Waveguide Filter Based on Glide Symmetry at Millimetre-Wave Bands.

This paper presents the design and fabrication of a mechanically reconfigurable filter at W band based on the concept of glide symmetry. The tunability is achieved by breaking and regenerating the glide symmetry. The filters are made of two glide-symmetric pieces that can be displaced in a certain direction, and therefore, break the symmetry. The high filtering capacity of these designs is demonstrated by simulation and measurement and can also be adjusted mechanically. The transmission level in the manufactured filter varies from a value between -1 and -2 dB when the filter is in the glide symmetry position to values close to -40 dB in the stop-band when it is in the broken symmetry position. The transmission band obtained in the symmetrical mode is around 20%, but, after breaking the symmetry, it is split into two passbands of 6.5% and 11% separated by a stop-band of 6%. The position, bandwidth, filtering level and filter roll-off can be adjusted for both modes of operation by appropriately selecting the unit cell design parameters and the number of unit cells.

Percutaneous Coronary Intervention VersusMyocardial Revascularization Surgery inMultivessel Coronary Artery Disease: Four-Year Followup.

INTRODUCTION: In Cuba, 29,939 deaths from ischemic heart disease were recorded in 2020. Myocardial revascularization surgery and percutaneous coronary intervention are well-established methods of treating patients with multivessel coronary artery disease. These methods can reduce overall deaths, but choosing the optimal strategy for treating left main coronary ischemia is a source of debate among specialists. OBJECTIVE: Estimate survival and major cardiac and cerebrovascular events in patients treated with percutaneous coronary intervention versus myocardial revascularization surgery and their relationships with pre-existing patients' clinical and angiographic characteristics. METHODS: We conducted a retrospective cohort study in 41 patients; 35 men and 6 women aged 40-85 years who had been diagnosed with multivessel coronary artery disease and treated with percutaneous coronary intervention (n = 17) or myocardial revascularization surgery (n = 24) at the Medical-Surgical Research Center in Havana, Cuba, in 2016. The main variable under consideration was the occurrence of major adverse cardiovascular events over a four-year period following these interventions. We collected clinical and angiographic characteristics, and used the Kaplan-Meier test to calculate survival curves. Survival probabilities were compared using the log-rank test. A value of p ⟨ 0.05 was considered statistically significant. The Cox proportional hazards model was used to estimate the hazard ratio, with 95% confidence intervals used for both procedures. RESULTS: There were a total of 20 major adverse cardiovascular events, 75% (15/20) of which occurred in patients who underwent percutaneous coronary intervention and 5% in patients who had myocardial revascularization surgery. The probability of survival was 70.6% in surgery and 37.5% in interventionism; p = 0.043; hazard ratio 1.58 (95% confidence interval 0.987-2.530), p = 0.047. The need to repeat a revascularization procedure was the only major cardiovascular event that showed significant differences between methods (log-rank p = 0.015), and was more frequent in percutaneous intervention. CONCLUSIONS: Myocardial revascularization surgery offers a better chance of survival than percutaneous coronary intervention. Major adverse cardiovascular events are more frequent in patients with coronary interventionism, due to the need to repeat revascularization.

3D Inductive Frequency Selective Structures Using Additive Manufacturing and Low-Cost Metallization.

The use of additive manufacturing and different metallization techniques for prototyping radio frequency components such as antennas and waveguides are rising owing to their high precision and low costs. Over time, additive manufacturing has improved so that its utilization is accepted in satellite payloads and military applications. However, there is no record of the frequency response in the millimeter-wave band for inductive 3D frequency selective structures implemented by different metallization techniques. For this reason, three different prototypes of dielectric 3D frequency selective structures working in the millimeter-wave band are designed, simulated, and manufactured using VAT photopolymerization. These prototypes are subsequently metallized using metallic paint atomization and electroplating. The manufactured prototypes have been carefully selected, considering their design complexity, starting with the simplest, the square aperture, the medium complexity, the woodpile structure, and the most complex, the torus structure. Then, each structure is measured before and after the metallization process using a measurement bench. The metallization used for the measurement is nickel spray flowed by the copper electroplating. For the electroplating, a detailed table showing the total area to be metallized and the current applied is also provided. Finally, the effectiveness of both metallization techniques is compared with the simulations performed using CST Microwave Studio. Results indicate that a shifted and reduced band-pass is obtained in some structures. On the other hand, for very complex structures, as in the torus case, band-pass with lower loss is obtained using copper electroplating, thus allowing the manufacturing of inductive 3D frequency selective structures in the millimeter-wave band at a low cost.

Testing Cancer Immunotherapeutics in a Humanized Mouse Model Bearing Human Tumors.

Reversing the immunosuppressive nature of the tumor microenvironment is critical for the successful treatment of cancers with immunotherapy drugs. Murine cancer models are extremely limited in their diversity and suffer from poor translation to the clinic. To serve as a more physiological preclinical model for immunotherapy studies, this protocol has been developed to evaluate the treatment of human tumors in a mouse reconstituted with a human immune system. This unique protocol demonstrates the development of human immune system (HIS, "humanized") mice, followed by implantation of a human tumor, either a cell-line derived xenograft (CDX) or a patient derived xenograft (PDX). HIS mice are generated by injecting CD34+ human hematopoietic stem cells isolated from umbilical cord blood into neonatal BRGS (BALB/c Rag2-/- IL2RγC-/- NODSIRPα) highly immunodeficient mice that are also capable of accepting a xenogeneic tumor. The importance of the kinetics and characteristics of the human immune system development and tumor implantation is emphasized. Finally, an in-depth evaluation of the tumor microenvironment using flow cytometry is described. In numerous studies using this protocol, it was found that the tumor microenvironment of individual tumors is recapitulated in HIS-PDX mice; "hot" tumors exhibit large immune infiltration while "cold" tumors do not. This model serves as a testing ground for combination immunotherapies for a wide range of human tumors and represents an important tool in the quest for personalized medicine.

Association between the Level of Physical Activity and Health-Related Quality of Life in Type 1 Diabetes Mellitus. A Preliminary Study.

Type 1 Diabetes Mellitus (T1D) is a chronic autoimmune disease characterized by the selective destruction of the beta cells of the pancreas causing an absolute deficiency of insulin for life. This pathology carries associated risks so that it is essential to measure Health-Related Quality of Life (HRQoL) in this population. The aim was to analyse associations between the level of physical activity and HRQoL in people with T1D. The sample consisted of 172 participants with T1D diagnoses, between 18 and 49 years (31.29 ± 8.17). The participants answered different questionnaires related to physical activity (IPAQ) and HRQoL (EsDQOL, ViDa1, 15D, and EQ-5D-5L). The results showed significant correlations between the level of physical activity and HRQoL. Vigorous physical activity had an impact on the HRQoL questionnaires, such as the well-being dimension (rho = 0.349; p < 0.001) of the ViDa1 questionnaire. A significant correlation between total physical activity and levels of anxiety and depression was observed: anxiety (15D) (rho = 0.328; p < 0.001) and anxiety/depression (EQ-5D-5L) (rho = 0.324; p < 0.001). The present study showed associations between higher levels of physical activity and higher HRQoL parameters in the population with T1D, which can be erected as a reason for exercise prescription in these patients.