Real-world patient characteristics, treatment patterns, and treatment outcomes of patients with diffuse large B-cell lymphoma by line of therapy.

BACKGROUND: Although initial treatment of diffuse large B-cell lymphoma (DLBCL) with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) can be effective, up to 50% of patients will develop refractory or relapsed (R/R) disease. This study aimed to provide contemporary data on characteristics, treatment patterns, and outcomes for R/R-DLBCL. METHODS: Patients with incident (January 2016 to March 2021) DLBCL age ≥18 years who initiated first-line (1L) therapy were identified from the COTA real-world database. Baseline characteristics, treatment patterns, and real-world outcomes, including time to next treatment (rwTTNT) and overall survival (rwOS), were assessed for the study population and by line of therapy (LOT). RESULTS: A total of 1347 eligible DLBCL patients were identified. Of these, 340 (25.2%) proceeded to receive 2L, of whom 141 (41.5%) proceeded to receive 3L, of whom 51 (36.2%) proceeded to receive 4L+. Most common treatments were R-CHOP in 1L (63.6%), stem cell transplant (SCT) in 2L (17.9%), polatuzumab vedotin, bendamustine, and rituximab (Pola-BR) in 3L (9.9%), and chimeric antigen receptor T-cell therapy (CAR-T) in 4L (11.8%). Treatment patterns were more variable in later LOTs. One- and 3-year rwOS from 1L initiation were 88.5% and 78.4%, respectively. Patients who received later LOTs experienced numerically lower 1- and 3-year rwOS (from 2L initiation: 62.4% and 46.4%, respectively). CONCLUSIONS: In this real-world analysis, 25.2% of patients experienced R/R-DLBCL after 1L with poor outcomes. Given the findings of this study, there is a high unmet need for novel, safe, and effective treatment options for patients with R/R DLBCL.

Carbapenemase-producing Enterobacterales strains causing infections in companion animals-Portugal.

An increase in Klebsiella pneumoniae carbapenem-resistant human nosocomial strains is occurring in Europe, namely with the blaOXA-48-like and blaKPC-like genes. We determined the prevalence of carbapenemase-producing Enterobacterales clinical strains in companion animals in Portugal and characterized their mobile genetic elements. Susceptibility data of a consecutive collection of 977 Enterobacterales clinical strains from a Portuguese private veterinary diagnostic laboratory were evaluated (January-December 2020). Additional phenotypical and genotypical assays were performed in a subset of 261 strains with a resistant phenotype. Whole-genome sequencing was performed for carbapenemase-producing strains. The frequency of carbapenemase-producing Enterobacterales clinical strains in companion animals in Portugal was 0.51% (n = 5/977). Thus, five strains were characterized: (i) one OXA-181-producing K. pneumoniae ST273, (ii) two KPC-3-producing K. pneumoniae ST147; (iii) one KPC-3-producing K. pneumoniae ST392; and (iv) one OXA-48-producing E. coli ST127. The blaKPC-3 gene was located on transposon Tn4401d on IncFIA type plasmid for the K. pneumoniae ST147 strains and on a IncN-type plasmid for the K. pneumoniae ST392 strain, while blaOXA-181 gene was located on an IncX3 plasmid. All de novo assembled plasmids and plasmid-encoded transposons harboring carbapenemase genes were homologous to those previously described in the human healthcare. No plasmid replicons were detected on the OXA-48-producing E. coli ST127. The dissemination of carbapenem resistance is occurring horizontally via plasmid spreading from the human high burden carbapenem resistance setting to the companion animal sector. Furthermore, companion animals may act as reservoirs of carbapenem resistance. Implementation of carbapenemase detection methods in routine clinical veterinary microbiology is urgently needed. IMPORTANCE: This is the first study on the prevalence of carbapenemase-producing Enterobacterales (CPE) clinical strains from companion animals in Portugal. Despite the generally low prevalence of CPE in companion animals, it is imperative for veterinary diagnostic laboratories to employ diagnostic methods for carbapenemase detection. The resemblance found in the mobile genetic elements transporting carbapenemase genes between veterinary medicine and human medicine implies a potential circulation within a One Health framework.

A Pooled Analysis of Treatment-Free Survival in Advanced Renal Cell Carcinoma.

PURPOSE: A clinically meaningful attribute of some immune-oncology (IO) regimens is potential durable clinical benefit during a treatment-free interval. We characterize treatment-free survival (TFS) with and without ongoing toxicity in trials of frontline IO-VEGF tyrosine kinase inhibitor (TKI) combinations in patients with advanced renal cell carcinoma (aRCC). PATIENTS AND METHODS: Individual patient data were pooled by treatment arm from randomized trials submitted to the FDA evaluating IO-TKI combination in treatment-naïve aRCC with at least 30 months of median follow-up. OS, TFS, TFS with and without toxicity, and time to all protocol therapy cessation were assessed. TFS was estimated by 30-month restricted mean times defined as area between Kaplan-Meier curves for two time-to-event endpoints originating at randomization: time to all protocol therapy cessation and time to subsequent systemic therapy initiation or death. RESULTS: Three trials met criteria for analysis; 1183 pts received IO-TKI versus 1184 on control arms received TKI alone (sunitinib [SUN]). IO-TKI and SUN groups spent 9% (2.7 months [95% confidence interval (CI): 1.8, 3.5]) and 10% (2.9 months [95% CI: 2.1, 3.8]) of the 30-mo period alive and treatment-free, respectively. Mean TFS without grade ≥3 toxicity was 1.7 and 2.3 months in IO-TKI and SUN groups, respectively. CONCLUSIONS AND RELEVANCE: In this post hoc partitioned survival analysis, TFS and TFS without toxicity appeared similar in the IO-TKI group compared to the SUN group. These findings may reflect continuation of TKI until progression per protocol design in all trials and discontinuation of IO after 2 years in 2 trials.

Real-World Clinical Characterisation of Polycythaemia Vera Patients from a Prospective Registry in Portugal: Is Resistance to Hydroxyurea a Reality?

Patients with polycythaemia vera (PV) are at increased risk of thrombosis and haemorrhages. Although hydroxyurea (HU) has been the frontline therapy for patients at high risk of vascular complications, about 25% of patients develop resistance/intolerance to this therapy. The aim of this non-interventional, multicentre cohort study was to understand the clinical characteristics and HU treatment response of Portuguese PV patients. HU resistance/intolerance was defined according to adjusted European LeukemiaNet (ELN) criteria. In total, 134 PV patients with a mean (SD) disease duration of 4.8 (5.0) years were included and followed up for 2 years. At baseline, most patients were ≥60 years old (83.2%), at high risk for thrombotic events (87.2%), and receiving HU therapy (79.1%). A total of 10 thrombotic events and 8 haemorrhagic events were reported, resulting in a 5-year probability of thrombo-haemorrhagic events of 17.2%. Haematocrit (p = 0.007), haemoglobin (p = 0.012) and MPN10 symptom score (12.0 (11.6) vs. 10.3 (9.1); p = 0.041) decreased significantly at the 24-month visit compared to baseline. Overall, 75.9% of patients met at least one of the adjusted ELN criteria for HU resistance, and 14.4% of patients remained on HU throughout the study. The results from this real-world study may help identify the subset of patients at higher risk for disease sequelae who may benefit from earlier second-line treatment.

The Influence of the Omicron Variant on RNA Extraction and RT-qPCR Detection of SARS-CoV-2 in a Laboratory in Brazil.

The emergence of SARS-CoV-2 variants can affect their detection via RT-qPCR. The Omicron variant has a greater affinity for the upper respiratory system and causes clinical conditions similar to bronchitis, as opposed to the pneumonitis-like conditions caused by other SARS-CoV-2 variants. This characteristic increases the viscosity of clinical samples collected for diagnosis. Coinciding with the arrival of the Omicron variant, we observed a failure in control gene expression in our laboratory. In this report, we have optimized a rapid nucleic acid extraction step to restore gene expression and detect the presence of the SARS-CoV-2 virus. We reevaluated 3000 samples, compared variant types occurring in different time periods, and confirmed that the presence of the Omicron variant was responsible for changes observed in the characteristics of these clinical samples. For samples with large amounts of mucus, such as those containing the Omicron variant, a modification to the nucleic acid extraction step was sufficient to restore the quality of RT-qPCR results.

Real-world study of disease-free survival & patient characteristics associated with disease-free survival in early-stage non-small cell lung cancer: A retrospective observational study.

INTRODUCTION/ BACKGROUND: Surgical resection remains standard of care for patients with early-stage non-small cell lung cancer (NSCLC), but research shows that adjuvant therapy can reduce the risk of disease recurrence. Our objective was to characterize disease-free survival (DFS) using real-world data. MATERIALS AND METHODS: This was a retrospective study using the COTA real-world database derived from electronic health records in the United States (US). Adults diagnosed with stage IB-IIIA NSCLC from 2013 to 2018 who underwent complete surgical resection (index date) for NSCLC were included. DFS was analyzed using the Kaplan-Meier method. A multivariable Cox-Proportional Hazard (PH) model stratified by year of diagnosis was developed to evaluate covariates associated with DFS. RESULTS: 703 patients met the study criteria (mean age 66.2 years, female (56%), White (82%), and median follow-up time was 37.4 months from index date. Approximately 48% of patients experienced recurrence or death with a median DFS of 42.9 months (95% CI: 37.4-52.2). Patients who received adjuvant therapy, neoadjuvant and adjuvant therapy, neoadjuvant therapy, and surgery only experienced a median DFS of 43.7, 32.3, 33.7, and 49.4 months, respectively. After adjustment, stage at diagnosis and adjuvant therapy status were significantly associated with DFS events. CONCLUSIONS: Higher stage at diagnosis and lack of adjuvant therapy were associated with greater risk of recurrence. Future research should focus on the adoption and effect of adjuvant/ neoadjuvant therapies on disease recurrence, including in patients with oncogenic driver mutations.

Eligibility criteria and enrollment of a diverse racial and ethnic population in multiple myeloma clinical trials.

The narrow eligibility criteria may contribute to the underrepresentation of racial and ethnic subgroups in cancer clinical trials. We conducted a retrospective pooled analysis of multicenter global clinical trials submitted to the US Food and Drug Administration between 2006 and 2019 to support the approval of the use of multiple myeloma (MM) therapies that analyze the rates and reasons for trial ineligibility based on race and ethnicity in MM clinical trials. Race and ethnicity were coded per Office of Management and Budget standards. Patients flagged as having screen failures were identified as ineligible. Ineligibility rates were calculated as the percentage of patients who were ineligible compared with the screened population within the respective racial and ethnic subgroups. Trial eligibility criteria were grouped into specific categories to analyze the reasons for trial ineligibility. Black patients (24%) and other (23%) race subgroups had higher ineligibility rates than White patients (17%). The Asian race had the lowest ineligibility rate (12%) among all racial subgroups. Failure to meet the hematologic laboratory criteria (19%) and treatment-related criteria (17%) were the most common reasons for ineligibility among Black patients and were more common in Black patients than in other races. Failure to meet disease-related criteria was the most common reason for ineligibility among White (28%) and Asian (29%) participants. Our analysis indicates that specific eligibility criteria may contribute to enrollment disparities for racial and ethnic subgroups in MM clinical trials. However, the small number of screened patients in the underrepresented racial and ethnic subgroups limits definitive conclusions.

FDA Analysis of Ineligibility for Acute Myeloid Leukemia Clinical Trials by Race and Ethnicity.

BACKGROUND: Patients of certain racial and ethnic groups have been underrepresented in clinical trials for treatment of malignancy. One potential barrier to participation is entry requirements that lead to patients in various racial and ethnic groups not meeting eligibility criteria for studies (ie, "screen failure"). The objective of this study was to analyze the rates and reasons for trial ineligibility by race and ethnicity in trials of acute myeloid leukemia (AML) submitted to the U.S. Food and Drug Administration (FDA) between 2016 and 2019. MATERIALS AND METHODS: Multicenter, global clinical trials submitted to the FDA to support AML drugs and biologics. We examined the rate of ineligibility among participants screened for studies of AML therapies submitted to the FDA from 2016 to 2019. Data were extracted from 13 trials used in approval evaluations, including race, screen status, and reason for ineligibility. RESULTS: Overall, patients in historically underrepresented racial and ethnic groups were less likely to meet entry criteria for studies compared to White patients, with 26.7% of White patients, 29.4% of Black patients, and 35.9% of Asian patients not meeting entry criteria. Lack of relevant disease mutation was the reason for ineligibility more frequently among Black and Asian patients. The findings were limited by the small number of underrepresented patients screened for participation. CONCLUSION: Our results suggest that entry requirements for studies may put underrepresented patients at a disadvantage, leading to less eligible patients and thus lower participation in clinical trials.

Phenolics Profiling by HPLC-DAD-ESI/MSn of the Scientific Unknown Polygonum hydropiperoides Michx. and Its Antioxidant and Anti-Methicillin-Resistant Staphylococcus aureus Activities.

Polygonum hydropiperoides Michx. is an Asian native plant species that is also widely distributed in the Americas. Despite its traditional uses, P. hydropiperoides is scarcely scientifically exploited. This study aimed to chemically characterize and investigate the antioxidant and antibacterial activities of hexane (HE-Ph), ethyl acetate (EAE-Ph), and ethanolic (EE-Ph) extracts from aerial parts of P. hydropiperoides. The chemical characterization was performed through HPLC-DAD-ESI/MSn. The antioxidant activity was assessed by the phosphomolybdenum reducing power, nitric oxide inhibition, and the ß-carotene bleaching assays. The antibacterial activity was determined by the minimal inhibitory concentration (MIC) and the minimal bactericidal concentration followed by the classification of the antibacterial effect. Chemical characterization revealed the expressive presence of phenolic acids and flavonoids in EAE-Ph. An increased antioxidant capacity was revealed in EAE-Ph. Regarding antibacterial activity, EAE-Ph showed weak to moderate property against 13 strains tested with MIC values ranging from 625 to 5000 µg/mL, with bactericidal or bacteriostatic effects. Glucogallin and gallic acid stand out as the most relevant bioactive compounds. These results suggest that P. hydropiperoides is a natural source of active substances, supporting this species' traditional use.

Longitudinal Study Detects the Co-Carriage of ESBL and mcr-1 and -4 Genes in Escherichia coli Strains in a Portuguese Farrow-to-Finish Swine Herd.

Cephalosporins and polymyxins are employed in antimicrobial protocols to control and treat neonatal infections and post-weaning diarrhoea in swine operations. We conducted a longitudinal study to evaluate the colonization and transmission of antibiotic-resistant Escherichia coli in sows and their piglets in a farrow-to-finish operation, focusing on characterization of Extended Spectrum Beta-Lactamase (ESBL) and mcr genes, virulence traits and genetic relatedness. A total of 293 E. coli isolates were obtained from faecal samples collected in five time points. At birth blaCTX-M-1group cluster was detected in E. coli isolates from 9 sows and 49 piglets (73.41%), while in the following four' piglets sampling moments it was detected in 91.8%, 57.6%, 71.4% and 97.4%. The gene mcr-1 was detected in E. coli from one sow and from three piglets from different litters at birth and increased in the first weeks of piglet life (68.85%, 100%, 90% and 8.1%). A new mcr-4 allele, mcr-4.7, was identified in 3.28%, 28.57%, 7.5% of E. coli isolates. Most mcr-positive E. coli isolates (96,7%) carried blaCTX-M-1Group genes and 93,33% carried both mcr-4 and mcr-1. CTX-M-1 and CTX-M-32 were the most predominant ESBLs. Plasmids belonged to IncI1, IncF and IncN groups. Most isolates belong to phylogenetic group B1; PAI IV536 marker was detected in nine isolates. The strains were kept in the different stages of the piglets' life. The use of ceftiofur and colistin may explain the high prevalence and co-selection of blaCTX-M-1Group and mcr-1 and/or -4 genes, contributing to the maintenance of resistant and virulent isolates throughout the pig life cycle that may reach the food chain.

Rabies in a Captive Lowland Tapir (Tapirus terrestris).

Rabies is a severe viral zoonosis of mammals and causes irreversible neurological damage. We describe the clinical presentation and anatomopathological lesions of rabies in a captive lowland tapir (Tapirus terrestris) in Bauru, São Paulo State, Brazil. The clinical course of the disease lasted 6 days and was characterized by progressive neurological deterioration and death. The main anatomopathological findings were non-suppurative encephalitis and presence of Negri bodies within neurons. Direct immunofluorescence and mouse inoculation tests were positive for rabies virus. This is the first report of rabies in a lowland tapir and highlights the importance of disease prevention under managed care and continuous control measures in urbanized environments.

Exploring racial disparities in treatment patterns and outcomes for patients with multiple myeloma using real world data.

This retrospective observational study evaluated racial disparities among Black and White patients with multiple myeloma (MM). We included patients from a longitudinal de-identified EHR-derived database who had ≥2 visits recorded on or after 1/1/2011, documented treatment, and race listed as White or Black. Black patients (n = 1172) were more likely female (54.8%/42.9%) and younger (<65 years, 40.8%/30.8%) than White patients (n = 4637). Unadjusted median real-world overall survival (rwOS) indexed to first-line of therapy (LOT) was 64.6 months (95% CI: 57.8-74.0) for Blacks and 54.5 months (95% CI: 50.9-56.2) for Whites. Adjusted rwOS estimates (for sex, age at index date, and practice type) to either first- (aHR = 0.94; 95% CI: 0.84-1.06) or second-LOT (aHR = 0.90; 95% CI: 0.77-1.05) were similar. Unadjusted derived response rate (dRR) during first-LOT was 84.8% (95% CI: 80.7-88.1) for Blacks and 86.9% (95% CI: 85.0-88.5) for Whites (odds ratio [OR] = 0.78 [95% CI: 0.57-1.10]); in second-LOT, 67.2% (95% CI: 58.4-75.0) for Blacks and 72.4% (95% CI: 68.1-76.3) for Whites (OR = 0.72 [95% CI: 0.46-1.13]). High representation of Black patients enabled this robust analysis, albeit with limitations inherent to the observational data source, the retrospective design, and the analytic use of newly derived endpoints requiring further validation.

Analysis of racial and ethnic disparities in multiple myeloma US FDA drug approval trials.

African Americans (AAs) have a higher incidence of multiple myeloma (MM) than White patients. Mortality is also higher in AAs compared with White patients. AAs more commonly have immunoglobulin H translocations t(11;14) and t(14;16) compared with White patients. We sought to characterize the demographic representation in MM clinical trials and evaluate outcomes based on race and ethnicity. We conducted a pooled analysis of all trials submitted to the US Food and Drug Administration (FDA) to support approval of a MM therapeutic between 2006 and 2019. Demographic characteristics were analyzed descriptively. An age-adjusted stratified Cox regression model was used to evaluate the relationship between time-to-event outcomes and race and ethnicity. Nineteen global trials comprising 10 157 patients were pooled. White, Asian, and Black patients comprised 84%, 7%, and 4% of the dataset, respectively; Hispanic patients comprised 4%. The age-adjusted overall survival hazard ratio (HR) for Black compared with White patients was 0.89 (95% confidence interval [CI], 0.75-1.05). The age-adjusted HR for US Black vs US White patients was 0.82 (95% CI, 0.66-1.02). For rest-of-world (RoW) Black vs RoW White patients, the HR was 1.31 (95% CI, 0.97-1.77). Black and Hispanic patients were underrepresented in the trials supporting FDA approval of MM drugs. Black patients were primarily enrolled in the United States. Outcomes in US patients were more favorable compared with those in patients in the RoW. Given the higher incidence of MM in AAs and the different disease characteristics, efforts should be made to improve representation of AAs in MM clinical trials.

Review of patient-reported outcomes in multiple myeloma registrational trials: highlighting areas for improvement.

Over the past 13 years, there have been advances in characterizing the patient experience in oncology trials, primarily using patient-reported outcomes (PROs). This review aims to provide details on the PRO measures and analyses used in multiple myeloma (MM) registrational trials. We identified registrational trials supporting MM indications from 2007 to 2020 from FDA databases. Trial protocols, statistical analysis plans, and clinical study reports were reviewed for PRO measures used, collection methods, statistical analyses, baseline and instrument completion definitions, and thresholds for clinical meaningfulness. Twenty-five trials supporting 20 MM indications were identified; 17 (68%) contained submitted PRO data. Of the 17 trials, 14 were randomized controlled trials and the remainder were single-arm trials. All but one trial were open label trials. Seven trials collected data electronically and five in paper format. The majority of trials evaluated at least two PRO measures (82%) with two trials (12%) utilizing four measures. Nine unique PRO measures were used, most commonly the EORTC QLQ-30 (87%), EQ-5D (65%), and QLQ-MY20 (47%). All 17 (100%) trials provided descriptive summaries, 10 (59%) carried out longitudinal mixed model analysis, 9 (53%) conducted responder analysis, and 2 (12%) did a basic inferential test. We noted substantial heterogeneity in terms of PRO collection methods, measures, definitions, and analyses, which may hinder the ability to effectively capture and interpret patient experience in future MM clinical trials. Further research is needed to determine the most appropriate approaches for statistical and analytical methodologies for PRO data in MM trials.

Clinical Impact of a Comprehensive Medication Management Service in Primary Health Care.

OBJECTIVE: To evaluate the clinical impact of a comprehensive medication management (CMM) service in a Brazilian primary health-care setting. METHODS: A quasi-experimental study has been carried out between July 2014 and November 2016 with patients who received the service in the primary care setting of a Brazilian city (n = 1057). Factors associated with drug therapy problems (DTP) detection in the initial assessment were evaluated by performing univariate and multivariate analyzes. To evaluate the impact of the CMM service, a linear regression model was constructed from the difference between the initial and final values of the clinical and laboratory parameters adjusted by multiple variables. RESULTS: A total of 1642 DTPs was identified, the most prevalent one being "nonadherence" (31.9%) and the "need for additional drug therapy" (22.9%). The use of 5 or more medications and the presence of 3 or more diseases were positively associated with the identification of 3 or more DTPs during the initial assessment. Even after multiple adjustments, a statistically significant reduction has been observed in the values of glycated hemoglobin, systolic blood pressure, low-density cholesterol, and total cholesterol. CONCLUSION: The CMM service contributed to the resolution of DTP and showed positive clinical impact in primary health care in the studied setting.

FDA Approval Summary: Alpelisib Plus Fulvestrant for Patients with HR-positive, HER2-negative, PIK3CA-mutated, Advanced or Metastatic Breast Cancer.

On May 24, 2019, the FDA granted regular approval to alpelisib in combination with fulvestrant for postmenopausal women, and men, with hormone receptor (HR)-positive, HER2-negative, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA)-mutated, advanced or metastatic breast cancer as detected by an FDA-approved test following progression on or after an endocrine-based regimen. Approval was based on the SOLAR-1 study, a randomized, double-blind, placebo-controlled trial of alpelisib plus fulvestrant versus placebo plus fulvestrant. The primary endpoint was investigator-assessed progression-free survival (PFS) per RECIST v1.1 in the cohort of trial participants whose tumors had a PIK3CA mutation. The estimated median PFS by investigator assessment in the alpelisib plus fulvestrant arm was 11 months [95% confidence interval (CI), 7.5-14.5] compared with 5.7 months (95% CI, 3.7-7.4) in the placebo plus fulvestrant arm (HR, 0.65; 95% CI, 0.50-0.85; two-sided P = 0.001). The median overall survival was not yet reached for the alpelisib plus fulvestrant arm (95% CI, 28.1-NE) and was 26.9 months (95% CI, 21.9-NE) for the fulvestrant control arm. No PFS benefit was observed in trial participants whose tumors did not have a PIK3CA mutation (HR, 0.85; 95% CI, 0.58-1.25). The most common adverse reactions, including laboratory abnormalities, on the alpelisib plus fulvestrant arm were increased glucose, increased creatinine, diarrhea, rash, decreased lymphocyte count, increased gamma glutamyl transferase, nausea, increased alanine aminotransferase, fatigue, decreased hemoglobin, increased lipase, decreased appetite, stomatitis, vomiting, decreased weight, decreased calcium, decreased glucose, prolonged activated partial thromboplastin time, and alopecia.

Mass spectrometry imaging as a potential technique for diagnostic of Huanglongbing disease using fast and simple sample preparation.

Huanglongbing (HLB) is a disease of worldwide incidence that affects orange trees, among other commercial varieties, implicating in great losses to the citrus industry. The disease is transmitted through Diaphorina citri vector, which inoculates Candidatus Liberibacter spp. in the plant sap. HLB disease lead to blotchy mottle and fruit deformation, among other characteristic symptoms, which induce fruit drop and affect negatively the juice quality. Nowadays, the disease is controlled by eradication of sick, symptomatic plants, coupled with psyllid control. Polymerase chain reaction (PCR) is the technique most used to diagnose the disease; however, this methodology involves high cost and extensive sample preparation. Mass spectrometry imaging (MSI) technique is a fast and easily handled sample analysis that, in the case of Huanglongbing allows the detection of increased concentration of metabolites associated to the disease, including quinic acid, phenylalanine, nobiletin and sucrose. The metabolites abieta-8,11,13-trien-18-oic acid, suggested by global natural product social molecular networking (GNPS) analysis, and 4-acetyl-1-methylcyclohexene showed a higher distribution in symptomatic leaves and have been directly associated to HLB disease. Desorption electrospray ionization coupled to mass spectrometry imaging (DESI-MSI) allows the rapid and efficient detection of biomarkers in sweet oranges infected with Candidatus Liberibacter asiaticus and can be developed into a real-time, fast-diagnostic technique.

Regulatory Considerations for Contribution of Effect of Drugs Used in Combination Regimens: Renal Cell Cancer Case Studies.

The development and review of combination drug regimens in oncology may present unique challenges to investigators and regulators. For regulatory approval of combination regimens, it is necessary to demonstrate the contribution of effect of each monotherapy to the overall combination. Alternative approaches to traditional designs may be needed to accelerate oncology drug development, for example, when combinations are substantially superior to available therapy, to reduce exposure to less effective therapies, and for drugs that are inactive as single agents and that in combination potentiate activity of another drug. These approaches include demonstration of activity in smaller randomized trials and/or monotherapy trials conducted in a similar disease setting. This article will discuss alternative approaches used in the development of approved drugs in combination, based on examples of recent approvals of combination regimens in renal cell carcinoma.

Exploring the interaction between citrus flavonoids and phytopathogenic fungi through enzymatic activities.

Flavonoids are involved in citrus defense against phytopathogens. In this study, we applied in vitro biocatalysis assays using the flavanones glycosides hesperidin and naringin to explore the enzymatic activities involved in such interaction. The main enzymatic activity observed was the hydrolysis catalyzed by fungi naringinases and hesperidinases. Withing 7 days, the two citrus phytopathogenic fungi, Penicillium digitatum and Penicillium italicum, exhibited the highest hydrolyzing rate on the flavanones, reaching conversion values higher than 90%. In addition, Geothrichum citri-aurantii exhibited no enzymatic activity and Penicillium expansum only hydrolyzed hesperidin. In order to evaluate flavonoid biotransformation by the fungi in vivo, citrus fruits infected with P. digitatum were analyzed through molecular networking and Imaging Mass Spectrometry (IMS). In vivo assays revealed that citrus fruit in response to the infection is able to hydroxylate flavonoids, and novel flavonoid structures were associated to the citrus' defense. The data reported here present a new point of view in the relation between citrus flavonoids and phytopathogenic fungi and can be useful to understand the infection processes and host-pathogen interaction.

Educação física escolar, tecnologias digitais e saúde: incursões exploratórias pela literatura / Physical education, digital technologies and health: exploratory for aysinto the literature / Educación física escolar, tecnologías digitales y salud: incursiones exploratorias a través de la literatura

Considerando a onipresença das tecnologias digitais atualmente e o massivo consumo destas por escolares, este estudo objetiva descrever e discutir os achados de uma revisão exploratória do conhecimento sobre a abordagem do tema saúde na Educação Física escolar que consideram os dispositivos/aplicativos tecnológicos. Trata-se de uma revisão não sistemática e investiga a literatura acadêmica da Educação Física considerando periódicos reconhecidamente relevantes que dialoguem diretamente com a educação. A busca centrou-se nos termos "escola", "tecnologia" e "saúde", sendo o diálogo na esfera escolar o principal critério de inclusão. Os achados apontam para 20 publicações que foram organizadas em categorias temáticas: a) tecnologia e suas implicações pedagógicas; b) monitoramento e uso de dados, um debate ético e; c) jogos digitais e tecnologias móveis. Destacam-se debates centrados em implicações pedagógicas de usos tecnológicos pelos professores, além de aspectos vinculados à exibição de si, quantificação de si e gamificação da vida pelos alunos.

Considering the ubiquity of digital technologies today and the massive consumption of these by schoolchildren, this study aims to describe and discuss the findings of an exploratory review of knowledge on the approach to health in school Physical Education that consider technological devices / applications. It is a non-systematic review and investigates the academic literature of Physical Education considering periodically relevant journals that dialogue directly with education. The search focused on the terms "school", "technology" and "health", with dialogue in the school sphere being the main inclusion criterion. The findings point to 20 publications that were organized into thematic categories: a) technology and its pedagogical implications; b) monitoring and use of data, an ethical debate and; c) digital games and mobile technologies. There are debates centered on the pedagogical implications of technological uses by teachers, in addition to aspects linked to self-display, self-quantification and gamification of life by students.

Considerando la ubicuidad de las tecnologías digitales actualmente y el consumo masivo por parte de jóvenes escolares, este estudio objetivo describe y discute los resultados de una revisión exploratoria del conocimiento sobre lo tema salud en la educación física escolar que considera los dispositivos/aplicaciones tecnológicas. Es una revisión no sistemática e investiga la literatura académica de Educación Física considerando publicaciones relevantes que dialogan directamente con la educación. La búsqueda se centró en los términos "escuela", "tecnología" y "salud", siendo el diálogo escolar el principal criterio inclusivo. Los hallazgos apuntan a 20 publicaciones que se organizaron en categorías: a) tecnología y sus implicaciones pedagógicas; b)monitoreo y uso de datos, un debate ético y; c)juegos digitales y tecnologías móviles. Hay debates centrados en las implicaciones pedagógicas de los usos tecnológicos de los docentes, además de los aspectos vinculados a la autoexposición, la auto cuantificación y la gamificación de la vida de los estudiantes.