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1.
Hum Vaccin Immunother ; : 1-15, 2021 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-34757894

RESUMO

Influenza vaccination and antiviral therapeutics may attenuate disease, decreasing severity of illness in vaccinated and treated persons. Standardized assessment tools, definitions of disease severity, and clinical endpoints would support characterizing the attenuating effects of influenza vaccines and antivirals. We review potential clinical parameters and endpoints that may be useful for ordinal scales evaluating attenuating effects of influenza vaccines and antivirals in hospital-based studies. In studies of influenza and community-acquired pneumonia, common physiologic parameters that predicted outcomes such as mortality, ICU admission, complications, and duration of stay included vital signs (hypotension, tachypnea, fever, hypoxia), laboratory results (blood urea nitrogen, platelets, serum sodium), and radiographic findings of infiltrates or effusions. Ordinal scales based on these parameters may be useful endpoints for evaluating attenuating effects of influenza vaccines and therapeutics. Factors such as clinical and policy relevance, reproducibility, and specificity of measurements should be considered when creating a standardized ordinal scale for assessment.

2.
A A Pract ; 15(11): e01545, 2021 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-34752439

RESUMO

The increasing coincidence of obesity with heart failure may preclude eligibility for orthotopic heart transplantation, requiring continuous-flow left ventricular assist devices (LVADs) as destination therapy. This report describes intraoperative considerations for patients who underwent LVAD implantation with concurrent laparoscopic sleeve gastrectomy (LSG) to promote weight loss. In particular, right ventricular dysfunction associated with acute left ventricular unloading may be compounded by pneumoperitoneum for LSG due to the difficulty in ventilating patients with obesity, hypercarbia-mediated increase in pulmonary vascular resistance, and variable cardiac loading conditions. We identify specific anesthetic challenges and discuss methods of monitoring and management.


Assuntos
Coração Auxiliar , Laparoscopia , Obesidade Mórbida , Gastrectomia , Humanos , Obesidade Mórbida/cirurgia , Estudos Retrospectivos , Resultado do Tratamento
4.
ASAIO J ; 2021 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-34799527

RESUMO

After demonstrated myocardial recovery in patients with durable left ventricular assist device (LVAD) support, the device may occasionally be explanted. A 38-year-old female with nonischemic cardiomyopathy underwent implantation of an LVAD as a bridge-to-transplant therapy. After one year, the patient demonstrated sufficient myocardial recovery allowing the LVAD to be explanted. A Teflon felt strip plug was created and placed within the apical sewing ring to occlude the opening into the left ventricle. Eleven years later, the patient presented with recurrence of severe heart failure. Due to morbid obesity, the patient was not a heart transplant candidate. Therefore, a second LVAD was implanted with a concomitant gastric sleeve procedure. When the plug was surgically removed from the sewing ring, no thrombus was observed; however, the ventricular surface was completely endothelialized. The patient recovered without any complications, was discharged from the hospital, and is currently listed for a heart transplant. This case demonstrates remission from heart failure lasting for more than a decade. If a second LVAD is needed due to exacerbation of severe heart failure, it can be safely introduced through the previous sewing ring after removing the Teflon plug.

5.
Plants (Basel) ; 10(11)2021 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-34834772

RESUMO

Metabolomics is now considered a wide-ranging, sensitive and practical approach to acquire useful information on the composition of a metabolite pool present in any organism, including plants. Investigating metabolomic regulation in plants is essential to understand their adaptation, acclimation and defense responses to environmental stresses through the production of numerous metabolites. Moreover, metabolomics can be easily applied for the phenotyping of plants; and thus, it has great potential to be used in genome editing programs to develop superior next-generation crops. This review describes the recent analytical tools and techniques available to study plants metabolome, along with their significance of sample preparation using targeted and non-targeted methods. Advanced analytical tools, like gas chromatography-mass spectrometry (GC-MS), liquid chromatography mass-spectroscopy (LC-MS), capillary electrophoresis-mass spectrometry (CE-MS), fourier transform ion cyclotron resonance-mass spectrometry (FTICR-MS) matrix-assisted laser desorption/ionization (MALDI), ion mobility spectrometry (IMS) and nuclear magnetic resonance (NMR) have speed up precise metabolic profiling in plants. Further, we provide a complete overview of bioinformatics tools and plant metabolome database that can be utilized to advance our knowledge to plant biology.

6.
ANZ J Surg ; 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34724334

RESUMO

BACKGROUND: There are few studies examining retroperitoneal lymph node dissection (RPLND) for testicular cancer in Australia. This study examines the perioperative outcomes, complications and survival rates following RPLND, by a high volume, single surgeon. METHODS: A retrospective, case series of a single surgeon, multi-centre study included all patients who underwent RPLND following testicular cancer at Westmead Public Hospital, Westmead Private Hospital, and Macquarie University Hospital 2005-2020. One hundred one patients identified, with 94 having sufficient available data. RESULTS: At time of operation, median age was 29.5 years. 84.2% had T1 or T2 primary tumours at diagnosis. Most common RPLND indication was residual mass post-chemotherapy (92.6%), with bleomycin, etoposide and cisplatin (BEP)x3 and BEPx4 most common chemotherapy regimens (50% and 35% respectively). Post-chemotherapy, largest residual mass ranged from 0.9 to 20 cm (median 3.32 cm). Post-chemotherapy, 95.7% masses were found in retroperitoneum (64.4% para-aortic region). 93.6% had open approach. 42.5% had bilateral nerve sparing. Majority (97.1%) did not require blood transfusion. No complications reported in 52.1% of patients. No deaths recorded within 90 days of surgery. At time of analysis, 91.5% had recurrence free survival, and 92.6% overall survival, at a median follow-up since surgery of 47.5 months (range 11 to 200 months). CONCLUSIONS: This retrospective study, addressing peri-operative surgical outcomes for RPLND surgery in Australia, is comparable to high-volume international urological centre studies, and shows that centralisation of post-chemotherapy RPLND to an experienced surgeon, results in low perioperative morbidity and mortality.

7.
Int J Mol Sci ; 22(22)2021 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-34830124

RESUMO

Vegetable cultivation is a promising economic activity, and vegetable consumption is important for human health due to the high nutritional content of vegetables. Vegetables are rich in vitamins, minerals, dietary fiber, and several phytochemical compounds. However, the production of vegetables is insufficient to meet the demand of the ever-increasing population. Plant-growth-promoting rhizobacteria (PGPR) facilitate the growth and production of vegetable crops by acquiring nutrients, producing phytohormones, and protecting them from various detrimental effects. In this review, we highlight well-developed and cutting-edge findings focusing on the role of a PGPR-based bioinoculant formulation in enhancing vegetable crop production. We also discuss the role of PGPR in promoting vegetable crop growth and resisting the adverse effects arising from various abiotic (drought, salinity, heat, heavy metals) and biotic (fungi, bacteria, nematodes, and insect pests) stresses.

8.
MMWR Morb Mortal Wkly Rep ; 70(42): 1483-1488, 2021 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-34673751

RESUMO

Pfizer-BioNTech COVID-19 vaccine is authorized for use in children and adolescents aged 12-15 years and is licensed by the Food and Drug Administration (FDA) for persons aged ≥16 (1). A randomized placebo-controlled trial demonstrated an efficacy of 100% (95% confidence interval [CI] = 75.3%-100%) in preventing outpatient COVID-19 in persons aged 12-15 years (2); however, data among adolescents on vaccine effectiveness (VE) against COVID-19 in real-world settings are limited, especially among hospitalized patients. In early September 2021, U.S. pediatric COVID-19 hospitalizations reached the highest level during the pandemic (3,4). In a test-negative, case-control study at 19 pediatric hospitals in 16 states during June 1-September 30, 2021, the effectiveness of 2 doses of Pfizer-BioNTech vaccine against COVID-19 hospitalization was assessed among children and adolescents aged 12-18 years. Among 464 hospitalized persons aged 12-18 years (179 case-patients and 285 controls), the median age was 15 years, 72% had at least one underlying condition, including obesity, and 68% attended in-person school. Effectiveness of 2 doses of Pfizer-BioNTech vaccine against COVID-19 hospitalization was 93% (95% CI = 83%-97%), during the period when B.1.617.2 (Delta) was the predominant variant. This evaluation demonstrated that 2 doses of Pfizer-BioNTech vaccine are highly effective at preventing COVID-19 hospitalization among persons aged 12-18 years and reinforces the importance of vaccination to protect U.S. youths against severe COVID-19.


Assuntos
Vacinas contra COVID-19/administração & dosagem , COVID-19/prevenção & controle , Hospitalização/estatística & dados numéricos , Adolescente , COVID-19/epidemiologia , Criança , Feminino , Humanos , Masculino , Estados Unidos/epidemiologia , Vacinas Sintéticas
9.
Artigo em Inglês | MEDLINE | ID: mdl-34704375

RESUMO

BACKGROUND: Antiviral treatment is recommended for all hospitalized children with suspected or confirmed influenza, regardless of their risk profile. Few data exist on adherence to these recommendations, so we sought to determine factors associated with influenza testing and antiviral treatment in children. METHODS: Hospitalized children <18 years of age with acute respiratory illness (ARI) were enrolled through active surveillance at pediatric medical centers in seven cities between 11/1/2015 and 6/30/2016; clinical information was obtained from parent interview and chart review. We used generalized linear mixed-effects models to identify factors associated with influenza testing and antiviral treatment. RESULTS: Of the 2299 hospitalized children with ARI enrolled during one influenza season, 51% (n = 1183) were tested clinically for influenza. Clinicians provided antiviral treatment for 61 of 117 (52%) patients with a positive influenza test versus 66 of 1066 (6%) with a negative or unknown test result. In multivariable analyses, factors associated with testing included neuromuscular disease (aOR = 5.35, 95% CI [3.58-8.01]), immunocompromised status (aOR = 2.88, 95% CI [1.66-5.01]), age (aOR = 0.93, 95% CI [0.91-0.96]), private only versus public only insurance (aOR = 0.78, 95% CI [0.63-0.98]), and chronic lung disease (aOR = 0.64, 95% CI [0.51-0.81]). Factors associated with antiviral treatment included neuromuscular disease (aOR = 1.86, 95% CI [1.04, 3.31]), immunocompromised state (aOR = 2.63, 95% CI [1.38, 4.99]), duration of illness (aOR = 0.92, 95% CI [0.84, 0.99]), and chronic lung disease (aOR = 0.60, 95% CI [0.38, 0.95]). CONCLUSION: Approximately half of children hospitalized with influenza during the 2015-2016 influenza season were treated with antivirals. Because antiviral treatment for influenza is associated with better health outcomes, further studies of subsequent seasons would help evaluate current use of antivirals among children and better understand barriers for treatment.

10.
ASAIO J ; 2021 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-34593680

RESUMO

For the first time, we present a novel technique that enables the exchange of the Impella CP (Abiomed Inc., Danvers, Massachusetts, USA) to the Impella 5.5 (Abiomed Inc.) with no interruption of mechanical support in patients with minimal left ventricular reserve. Specifically, the aortic valve is crossed with the Impella 5.5 whereas the Impella CP is still functioning within the left ventricle. The Impella 5.5 is then initiated, and the Impella CP is weaned. Finally, the Impella CP is pulled out into the descending aorta. This exchange provides continuous support with no hemodynamic disarrangement.

11.
Ann Diagn Pathol ; 55: 151832, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34628284

RESUMO

INTRODUCTION: Granulomatous infections are common in patients with chronic lung disease. We aim to study the incidence and clinicopathological features of granulomatous infections in a cohort of patients undergoing lung transplantation for end-stage chronic lung disease. METHODS: Pathology reports of 50 explanted native lungs of patients who underwent lung transplantation since 2015 at our institution were reviewed. Four cases with granulomatous lesions were identified. Correlation was made with clinical findings in the 4 cases. RESULTS: The granulomatous infections include non-necrotizing cryptococcal pneumonitis (case 1), necrotizing pneumonia due to Scedosporium sp. and Mycobacterium avium Complex (MAC) (Cases 2 and 3), and invasive Aspergillus pneumonia (Case 4). One patient received pre-transplant fungal prophylaxis (Case 4). Post-transplant infectious complications included invasive (Cases 2 and 4) and non-invasive (Case 1) fungal infections and bacterial pneumonia (Cases 1 and 2). Two patients (Cases 3 and 4) developed acute cellular rejection (ACR) in the first 30 days. The third patient (Case 1) was identified with ACR in the 9 months post-transplant and chronic lung allograft dysfunction at 29 months. In terms of mortality, 1 patient (Case 1) died at 30 months post-transplant from pseudomonal sepsis and chronic graft failure. Two patients with invasive fungal infections (Cases 2 and 4) are on secondary prophylaxis and doing well. One patient (Case 3) remains infection-free and on MAC prophylaxis. CONCLUSIONS: In our case series, patients with chronic lung diseases with superimposed granulomatous infestations frequently experienced post-transplant complications. These include invasive infections and repeat ACRs that predispose patients to chronic graft dysfunction. Pre- and post-transplant antifungal prophylaxis reduces fungal load and complication risk post-transplant.

12.
J Immunother Cancer ; 9(10)2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34663640

RESUMO

BACKGROUND: Recurrent and/or metastatic (R/M) disease develops in approximately 65% of patients with squamous cell carcinoma of the head and neck (SCCHN) and is associated with a poor prognosis. Immune checkpoint inhibitors have proven effective in multiple tumor types, including R/M SCCHN. We report the efficacy and safety of avelumab (antiprogrammed death ligand 1 antibody) in an expansion cohort of patients with platinum-refractory/ineligible R/M SCCHN enrolled in the phase I JAVELIN Solid Tumor trial (NCT01772004). METHODS: Eligible patients with R/M SCCHN were aged ≥18 years and had received ≥1 line of platinum-based chemotherapy with disease progression or recurrence within 6 months of the last dose or were ineligible for platinum-based chemotherapy. All patients received avelumab 10 mg/kg every 2 weeks. Tumor assessments were carried out by a blinded independent review committee (IRC) and investigators according to Response Evaluation Criteria in Solid Tumors V.1.1 (RECIST 1.1). Key endpoints included best overall response, duration of response (DOR) and progression-free survival (PFS) assessed by IRC and investigator per RECIST 1.1, overall survival (OS), and safety. RESULTS: Between April 24, 2015, and November 13, 2015, 153 patients were enrolled. Patients had a median of two prior lines of therapy for metastatic or locally advanced disease (range 0-6); 12 patients (7.8%) were not eligible for platinum-based chemotherapy. At data cut-off (December 31, 2017), the confirmed objective response rate was 9.2% (95% CI 5.1% to 14.9%) assessed by IRC and 13.1% (95% CI 8.2% to 19.5%) assessed by investigator. Median DOR was not reached (95% CI 4.2 to not estimable) based on IRC assessment. Median PFS was 1.4 months (95% CI 1.4 to 2.6) assessed by IRC and 1.8 months (95% CI 1.4 to 2.7) assessed by investigator; median OS was 8.0 months (95% CI 6.5 to 10.2). Any-grade treatment-related adverse events (TRAEs) occurred in 83 patients (54.2%) and were grade ≥3 in 10 patients (6.5%). The most common TRAEs were fatigue (n=19, 12.4%), fever (n=14, 9.2%), pruritus (n=12, 7.8%), and chills (n=11, 7.2%), and there were no treatment-related deaths. CONCLUSION: Avelumab showed clinical activity and was associated with a low rate of grade ≥3 TRAEs in heavily pretreated patients with platinum-refractory/ineligible R/M SCCHN.

13.
Foods ; 10(10)2021 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-34681531

RESUMO

Brown seaweeds have shown high potential of bioactivity and provide health benefits as an important functional food ingredient. Therefore, four abundantly growing tropical brown seaweeds-Iyengaria stellata, Spatoglossum asperum, Sargassum linearifolium, and Stoechospermum polypodioides-were collected from the Saurashtra Coast of the Arabian Sea. They were analyzed for metabolite profiling, biochemical activities (including total antioxidant, reducing, scavenging, and anti-proliferative characteristics), and total phenolic and flavonoid contents. A concentration-dependent antioxidant, reducing, and scavenging activities were observed for all four brown seaweeds. The S. asperum and I. stellata extracts showed maximum total antioxidant activity. S. asperum also showed high scavenging and reducing activities compared to other studied brown seaweeds. Further, S. asperum contained high total phenolic and flavonoid content compared to other brown seaweeds collected from the same coast. A multivariate correlation study confirmed a positive correlation between total phenolic and flavonoid contents, and biochemical activities (total antioxidant, scavenging and reducing) for all brown seaweeds. About 35% anti-proliferative activity was observed with S. asperum extract on Huh7 cells; in contrast S. polypodioide showed about 44% proliferation inhibition of Huh7 cells. Similarly, 26% proliferation inhibition of HeLa cells was observed with S. asperum extract. Overall, S. asperum possesses high total flavonoid and phenolic amounts, and showed potential antioxidant, scavenging and reducing characteristics. The study confirmed the nutraceutical potential of S. asperum and that it could be a promising functional food ingredient.

14.
PLoS One ; 16(10): e0258482, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34673782

RESUMO

BACKGROUND: Experimental studies have shown that vaccination can reduce viral replication to attenuate progression of influenza-associated lower respiratory tract illness (LRTI). However, clinical studies are conflicting, possibly due to use of non-specific outcomes reflecting a mix of large and small airway LRTI lacking specificity for acute lung or organ injury. METHODS: We developed a global ordinal scale to differentiate large and small airway LRTI in hospitalized adults with influenza using physiologic features and interventions (PFIs): vital signs, laboratory and radiographic findings, and clinical interventions. We reviewed the literature to identify common PFIs across 9 existing scales of pneumonia and sepsis severity. To characterize patients using this scale, we applied the scale to an antiviral clinical trial dataset where these PFIs were measured through routine clinical care in adults hospitalized with influenza-associated LRTI during the 2010-2013 seasons. RESULTS: We evaluated 12 clinical parameters among 1020 adults; 210 (21%) had laboratory-confirmed influenza, with a median severity score of 4.5 (interquartile range, 2-8). Among influenza cases, median age was 63 years, 20% were hospitalized in the prior 90 days, 50% had chronic obstructive pulmonary disease, and 22% had congestive heart failure. Primary influencers of higher score included pulmonary infiltrates on imaging (48.1%), heart rate ≥110 beats/minute (41.4%), oxygen saturation <93% (47.6%) and respiratory rate >24 breaths/minute (21.0%). Key PFIs distinguishing patients with severity < or ≥8 (upper quartile) included infiltrates (27.1% vs 90.0%), temperature ≥ 39.1°C or <36.0°C (7.1% vs 27.1%), respiratory rate >24 breaths/minute (7.9% vs 47.1%), heart rate ≥110 beats/minute (29.3% vs 65.7%), oxygen saturation <90% (14.3% vs 31.4%), white blood cell count >15,000 (5.0% vs 27.2%), and need for invasive or non-invasive mechanical ventilation (2.1% vs 15.7%). CONCLUSION: We developed a scale in adults hospitalized with influenza-associated LRTI demonstrating a broad distribution of physiologic severity which may be useful for future studies evaluating the disease attenuating effects of influenza vaccination or other therapeutics.


Assuntos
COVID-19 , Influenza Humana , Humanos , Pessoa de Meia-Idade
15.
Blood Adv ; 2021 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-34547767

RESUMO

Phosphoinositide 3-kinase-delta (PI3Kδ) inhibitors are active in lymphoid malignancies, though associated toxicities can limit their use. Umbralisib is a dual inhibitor of PI3Kδ and casein kinase-1ε (CK1ε). This study analyzed integrated comprehensive toxicity data from 4 open-label, phase 1 and 2 studies that included 371 adult patients (median age, 67 years) with relapsed/refractory non-Hodgkin lymphoma (follicular lymphoma [n = 147]; marginal zone lymphoma [n = 82]; diffuse large B-cell lymphoma/mantle cell lymphoma [n = 74]; chronic lymphocytic leukemia [n = 43]; and other [n = 25]) who were treated with recommended phase 2 dose of umbralisib 800 mg or higher once daily. At data cutoff, median duration of umbralisib treatment was 5.9 months (range, 0.1-75.1), and 107 patients (28.8%) received umbralisib for ≥12 months. Any-grade treatment-emergent adverse events (TEAEs) occurred in 366/371 patients (98.7%), with the most frequent being diarrhea (52.3%), nausea (41.5%), and fatigue (31.8%). Grade ≥3 TEAEs occurred in 189/371 of patients (50.9%), including neutropenia (11.3%), diarrhea (7.3%), and increased aminotransferases (5.7%). Treatment-emergent serious AEs occurred in 95/371 patients (25.6%). AEs of special interest were limited and included pneumonia (29/371 [7.8%]), noninfectious colitis (9/371 [2.4%]), and pneumonitis (4/371 [1.1%]). AEs led to discontinuation of umbralisib in 51 patients (13.7%). Four patients (1.1%) died due to AEs, none of which were deemed related to umbralisib. No cumulative toxicities were reported. The favorable long-term tolerability profile and low rates of immune-mediated toxicities support the potential use of umbralisib for the benefit of a broad population of patients with lymphoid malignancies.

16.
J Infect Dis ; 2021 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-34498052

RESUMO

Evaluations of vaccine effectiveness (VE) are important to monitor as COVID-19 vaccines are introduced in the general population. Research staff enrolled symptomatic participants seeking outpatient medical care for COVID-19-like illness or SARS-CoV-2 testing from a multisite network. VE was evaluated using the test-negative design. Among 236 SARS-CoV-2 nucleic acid amplification test-positive and 576 test-negative participants aged ≥16 years, VE of mRNA vaccines against COVID-19 was 91% (95% CI: 83-95) for full vaccination and 75% (95% CI: 55-87) for partial vaccination. Vaccination was associated with prevention of most COVID-19 cases among people seeking outpatient medical care.

17.
Target Oncol ; 16(5): 569-589, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34559360

RESUMO

BACKGROUND: The checkpoint kinase 1 (CHK1) inhibitor prexasertib exhibited modest monotherapy antitumor activity in prior trials, suggesting that combination with chemotherapy or other targeted agents may be needed to maximize efficacy. OBJECTIVES: The aim of this study was to determine the recommended phase II dose and schedule of prexasertib in combination with either cisplatin, cetuximab, pemetrexed, or 5-fluorouracil in patients with advanced and/or metastatic cancer, and to summarize preliminary antitumor activity of these combinations. PATIENTS AND METHODS: This phase Ib, nonrandomized, open-label study comprised dose-escalation phase(s) with multiple sub-arms evaluating different prexasertib-drug combinations: Part A, prexasertib + cisplatin (n = 63); Part B, prexasertib + cetuximab (n = 41); Part C, prexasertib + pemetrexed (n = 3); Part D, prexasertib + 5-fluorouracil (n =8). Alternate dose schedules/regimens intended to mitigate toxicity and maximize dose exposure and efficacy were also explored in sub-parts. RESULTS: In Part A, the maximum tolerated dose (MTD) of prexasertib in combination with cisplatin (75 mg/m2) was declared at 80 mg/m2, with cisplatin administered on Day 1 and prexasertib on Day 2 of a 21-day cycle. The overall objective response rate (ORR) in Part A was 12.7%, and 28 of 55 evaluable patients (50.9%) had a decrease in target lesions from baseline. The most frequent treatment-related adverse events (AEs) in Part A were hematologic, with the most common being white blood cell count decreased/neutrophil count decreased, experienced by 73.0% (any grade) and 66.7% (grade 3 or higher) of patients. In Part B, an MTD of 70 mg/m2 was established for prexasertib administered in combination with cetuximab (500 mg /m2), both administered on Day 1 of a 14-day cycle. The overall ORR in Part B was 4.9%, and 7 of 31 evaluable patients (22.6%) had decreased target lesions compared with baseline. White blood cell count decreased/neutrophil count decreased was also the most common treatment-related AE (56.1% any grade; 53.7% grade 3 or higher). In Parts A and B, hematologic toxicities, even with the addition of prophylactic granulocyte colony-stimulating factor, resulted in frequent dose adjustments (> 60% of patients). In Part C, evaluation of prexasertib + pemetrexed was halted due to dose-limiting toxicities in two of the first three patients; MTD was not established. In Part D, the MTD of prexasertib in combination with 5-fluorouracil (label dose) was declared at 40 mg /m2, both administered on Day 1 of a 14-day cycle. In Part D, overall ORR was 12.5%. CONCLUSIONS: This study demonstrated the proof-of-concept that prexasertib can be combined with cisplatin, cetuximab, and 5-fluorouracil. Schedule was a key determinant of the tolerability and feasibility of combining prexasertib with these standard-of-care agents. Reversible hematologic toxicity was the most frequent AE and was dose-limiting. Insights gleaned from this study will inform future combination strategies for the development of prexasertib and next-generation CHK1 inhibitors. CLINICALTRIALS. GOV IDENTIFIER: NCT02124148 (date of registration 28 April 2014).

18.
EClinicalMedicine ; 40: 101112, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34485878

RESUMO

Background: Multisystem inflammatory syndrome in children (MIS-C) consensus criteria were designed for maximal sensitivity and therefore capture patients with acute COVID-19 pneumonia. Methods: We performed unsupervised clustering on data from 1,526 patients (684 labeled MIS-C by clinicians) <21 years old hospitalized with COVID-19-related illness admitted between 15 March 2020 and 31 December 2020. We compared prevalence of assigned MIS-C labels and clinical features among clusters, followed by recursive feature elimination to identify characteristics of potentially misclassified MIS-C-labeled patients. Findings: Of 94 clinical features tested, 46 were retained for clustering. Cluster 1 patients (N = 498; 92% labeled MIS-C) were mostly previously healthy (71%), with mean age 7·2 ± 0·4 years, predominant cardiovascular (77%) and/or mucocutaneous (82%) involvement, high inflammatory biomarkers, and mostly SARS-CoV-2 PCR negative (60%). Cluster 2 patients (N = 445; 27% labeled MIS-C) frequently had pre-existing conditions (79%, with 39% respiratory), were similarly 7·4 ± 2·1 years old, and commonly had chest radiograph infiltrates (79%) and positive PCR testing (90%). Cluster 3 patients (N = 583; 19% labeled MIS-C) were younger (2·8 ± 2·0 y), PCR positive (86%), with less inflammation. Radiographic findings of pulmonary infiltrates and positive SARS-CoV-2 PCR accurately distinguished cluster 2 MIS-C labeled patients from cluster 1 patients. Interpretation: Using a data driven, unsupervised approach, we identified features that cluster patients into a group with high likelihood of having MIS-C. Other features identified a cluster of patients more likely to have acute severe COVID-19 pulmonary disease, and patients in this cluster labeled by clinicians as MIS-C may be misclassified. These data driven phenotypes may help refine the diagnosis of MIS-C.

19.
Int J Mol Sci ; 22(17)2021 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-34502020

RESUMO

Metabolic regulation is the key mechanism implicated in plants maintaining cell osmotic potential under drought stress. Understanding drought stress tolerance in plants will have a significant impact on food security in the face of increasingly harsh climatic conditions. Plant primary and secondary metabolites and metabolic genes are key factors in drought tolerance through their involvement in diverse metabolic pathways. Physio-biochemical and molecular strategies involved in plant tolerance mechanisms could be exploited to increase plant survival under drought stress. This review summarizes the most updated findings on primary and secondary metabolites involved in drought stress. We also examine the application of useful metabolic genes and their molecular responses to drought tolerance in plants and discuss possible strategies to help plants to counteract unfavorable drought periods.


Assuntos
Secas , Metabolômica , Plantas/genética , Estresse Fisiológico , Regulação da Expressão Gênica de Plantas , Fenômenos Fisiológicos Vegetais , Plantas/metabolismo
20.
BJU Int ; 2021 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-34374190

RESUMO

OBJECTIVE: To externally validate and compare the performance of the European Randomized Study of Screening for Prostate Cancer risk calculator 3/4 (ERSPC-RC3/4), the Prostate Biopsy Collaborative Group risk calculator (PBCG-RC) and the van Leeuwen model to determine which prediction model would perform the best in a contemporary Australian cohort undergoing transperineal (TP) biopsy. MATERIALS AND METHODS: A retrospective review identified all patients undergoing TP biopsy across two centres. Of the 797 patients identified, 373 had the data required to test all three risk calculators. The probability of high-grade prostate cancer, defined as International Society of Urological Pathology Grade Group >1, was calculated for each patient. For each prediction model discrimination was assessed using area under the receiver-operating characteristic curve (AUC), calibration using numerical and graphical summaries, and net benefit using decision curve analysis. RESULTS: Assessment of model discrimination for detecting high-grade prostate cancer showed AUCs of 0.79 (95% confidence interval [CI] 0.74-0.84) for the ERSPC-RC3/4, 0.81 (95% CI 0.77-0.86) for the van Leeuwen model, and 0.68 (95% CI 0.63-0.74) for the PBCG-RC, compared to 0.58 (95% CI 0.52-0.65) for prostate-specific antigen alone. The ERSPC-RC3/4 was the best calibrated in the moderate-risk range of 10-40%, whilst the van Leeuwen model was the best calibrated in the low-risk range of 0-10%. The van Leeuwen model demonstrated the greatest net benefit from 10% risk onwards, followed closely by the ERSPC-RC3/4 and then the PBCG-RC. CONCLUSION: The ERPSC-RC3/4 demonstrated good performance and was comparable to the van Leeuwen model with regard to discrimination, calibration and net benefit for an Australian population undergoing TP prostate biopsy. It is one of the most accessible risk calculators with an easy-to-use online platform, therefore, we recommend that Australian urologists use the ERSPC-RC3/4 to predict risk in the clinical setting.

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