This statement is designed primarily as an educational resource for clinicians to help them provide quality medical services. Adherence to this statement is completely voluntary and does not ...necessarily assure a successful medical outcome. This statement should not be considered inclusive of all proper procedures and tests or exclusive of other procedures and tests that are reasonably directed toward obtaining the same results. In determining the propriety of any specific procedure or test, the clinician should apply his or her own professional judgment to the specific clinical circumstances presented by the individual patient or specimen. Clinicians are encouraged to document the reasons for the use of a particular procedure or test, whether or not it is in conformance with this statement. Clinicians also are advised to take notice of the date this statement was adopted and to consider other medical and scientific information that becomes available after that date. It also would be prudent to consider whether intellectual property interests may restrict the performance of certain tests and other procedures.Noninvasive prenatal screening using cell-free DNA (NIPS) has been rapidly integrated into prenatal care since the initial American College of Medical Genetics and Genomics (ACMG) statement in 2013. New evidence strongly suggests that NIPS can replace conventional screening for Patau, Edwards, and Down syndromes across the maternal age spectrum, for a continuum of gestational age beginning at 9-10 weeks, and for patients who are not significantly obese. This statement sets forth a new framework for NIPS that is supported by information from validation and clinical utility studies. Pretest counseling for NIPS remains crucial; however, it needs to go beyond discussions of Patau, Edwards, and Down syndromes. The use of NIPS to include sex chromosome aneuploidy screening and screening for selected copy-number variants (CNVs) is becoming commonplace because there are no other screening options to identify these conditions. Providers should have a more thorough understanding of patient preferences and be able to educate about the current drawbacks of NIPS across the prenatal screening spectrum. Laboratories are encouraged to meet the needs of providers and their patients by delivering meaningful screening reports and to engage in education. With health-care-provider guidance, the patient should be able to make an educated decision about the current use of NIPS and the ramifications of a positive, negative, or no-call result.Genet Med 18 10, 1056-1065.
Rising concentrations of atmospheric carbon dioxide are causing acidification of the oceans. This results in changes to the concentrations of key chemical species such as hydroxide, carbonate and ...bicarbonate ions. These changes will affect the distribution of different forms of trace metals. Using IPCC data for pCO2 and pH under four future emissions scenarios (to the year 2100) we use a chemical speciation model to predict changes in the distribution of organic and inorganic forms of trace metals. Under a scenario where emissions peak after the year 2100, predicted free ion Al, Fe, Cu, and Pb concentrations increase by factors of up to approximately 21, 2.4, 1.5, and 2.0 respectively. Concentrations of organically complexed metal typically have a lower sensitivity to ocean acidification induced changes. Concentrations of organically complexed Mn, Cu, Zn, and Cd fall by up to 10%, while those of organically complexed Fe, Co, and Ni rise by up to 14%. Although modest, these changes may have significance for the biological availability of metals given the close adaptation of marine microorganisms to their environment.
Purpose This AUA Guideline focuses on evaluation/counseling and management of adult patients with clinically localized renal masses suspicious for cancer, including solid-enhancing tumors and Bosniak ...3/4 complex-cystic lesions. Materials and Methods Systematic review utilized research from the Agency for Healthcare Research and Quality and additional supplementation by the authors and consultant methodologists. Evidence-based statements were based on body of evidence strength Grade A/B/C (Strong/Moderate/Conditional Recommendations, respectively) with additional statements presented as Clinical Principles or Expert Opinions. Results Great progress has been made since the previous guidelines on management of localized renal masses was released (2009). The current guidelines provide updated, evidence-based recommendations regarding evaluation/counseling of patients with clinically localized renal masses, including the evolving role of renal mass biopsy. Given great variability of clinical, oncologic and functional characteristics, index patients are not utilized and the panel advocates individualized counseling/management. Management options (partial nephrectomy/radical nephrectomy/thermal ablation/active surveillance) are reviewed including recent data about comparative effectiveness and potential morbidities. Oncologic issues are prioritized while recognizing that functional outcomes are of great importance for survivorship for most patients with localized kidney cancer. A more restricted role for radical nephrectomy is recommended following well-defined selection criteria. Priority for partial nephrectomy is recommended for clinical T1a lesions, along with selective use of thermal ablation, particularly for tumors ≤3.0 cm. Important considerations for shared decision-making about active surveillance are explicitly defined. Conclusions Several factors should be considered during counseling/management of patients with clinically localized renal masses, including general health/comorbidities, oncologic potential of the mass, pertinent functional issues and relative efficacy/potential morbidities of various management strategies.
Molecules that exhibit emission in the solid state, especially those known as aggregation-induced emission (AIE) chromophores, have found applications in areas as varied as light-emitting diodes and ...biological sensors. Despite numerous studies, the mechanism of fluorescence quenching in AIE chromophores is still not completely understood. To this end, much interest has focused on understanding the low-frequency vibrational dynamics of prototypical systems, such as tetraphenylethylene (TPE), in the hope that such studies would provide more general principles toward the design of new sensors and electronic materials. We hereby show that a perdeuterated TPE-based metal–organic framework (MOF) serves as an excellent platform for studying the low-energy vibrational modes of AIE-type chromophores. In particular, we use solid-state 2H and 13C NMR experiments to investigate the phenyl ring dynamics of TPE cores that are coordinatively trapped inside a MOF and find a phenyl ring flipping energy barrier of 43(6) kJ/mol. DFT calculations are then used to deconvolute the electronic and steric contributions to this flipping barrier. Finally, we couple the NMR and DFT studies with variable-temperature X-ray diffraction experiments to propose that both the ethylenic CC bond twist and the torsion of the phenyl rings are important for quenching emission in TPE, but that the former may gate the latter. To conclude, we use these findings to propose a set of design criteria for the development of tunable turn-on porous sensors constructed from AIE-type molecules, particularly as applied to the design of new multifunctional MOFs.
Background Studies suggest that oral immunotherapy (OIT) and sublingual immunotherapy (SLIT) for food allergy hold promise; however, the immunologic mechanisms underlying these therapies are not well ...understood. Objective We sought to generate insights into the mechanisms and duration of suppression of immune responses to peanut during immunotherapy. Methods Blood was obtained from subjects at baseline and at multiple time points during a placebo-controlled trial of peanut OIT and SLIT. Immunologic outcomes included measurement of spontaneous and stimulated basophil activity by using automated fluorometry (histamine) and flow cytometry (activation markers and IL-4), measurement of allergen-induced cytokine expression in dendritic cell (DC)–T-cell cocultures by using multiplexing technology, and measurement of MHC II and costimulatory molecule expression on DCs by using flow cytometry. Results Spontaneous and allergen-induced basophil reactivity (histamine release, CD63 expression, and IL-4 production) were suppressed during dose escalation and after 6 months of maintenance dosing. Peanut- and dust mite–induced expression of TH 2 cytokines was reduced in DC–T-cell cocultures during immunotherapy. This was associated with decreased levels of CD40, HLA-DR, and CD86 expression on DCs and increased expression of CD80. These effects were most striking in myeloid DC–T-cell cocultures from subjects receiving OIT. Many markers of immunologic suppression reversed after withdrawal from immunotherapy and in some cases during ongoing maintenance therapy. Conclusion OIT and SLIT for peanut allergy induce rapid suppression of basophil effector functions, DC activation, and TH 2 cytokine responses during the initial phases of immunotherapy in an antigen-nonspecific manner. Although there was some interindividual variation, in many patients suppression appeared to be temporary.
The cross-β amyloid form of peptides and proteins represents an archetypal and widely accessible structure consisting of ordered arrays of β-sheet filaments. These complex aggregates have remarkable ...chemical and physical properties, and the conversion of normally soluble functional forms of proteins into amyloid structures is linked to many debilitating human diseases, including several common forms of age-related dementia. Despite their importance, however, cross-β amyloid fibrils have proved to be recalcitrant to detailed structural analysis. By combining structural constraints from a series of experimental techniques spanning five orders of magnitude in length scale—including magic angle spinning nuclear magnetic resonance spectroscopy, X-ray fiber diffraction, cryoelectron microscopy, scanning transmission electron microscopy, and atomic force microscopy—we report the atomic-resolution (0.5 Å) structures of three amyloid polymorphs formed by an 11-residue peptide. These structures reveal the details of the packing interactions by which the constituent β-strands are assembled hierarchically into protofilaments, filaments, and mature fibrils.
This multicenter study, to our knowledge, is the first phase III trial to compare trabectedin versus dacarbazine in patients with advanced liposarcoma or leiomyosarcoma after prior therapy with an ...anthracycline and at least one additional systemic regimen.
Patients were randomly assigned in a 2:1 ratio to receive trabectedin or dacarbazine intravenously every 3 weeks. The primary end point was overall survival (OS), secondary end points were disease control-progression-free survival (PFS), time to progression, objective response rate, and duration of response-as well as safety and patient-reported symptom scoring.
A total of 518 patients were enrolled and randomly assigned to either trabectedin (n = 345) or dacarbazine (n = 173). In the final analysis of PFS, trabectedin administration resulted in a 45% reduction in the risk of disease progression or death compared with dacarbazine (median PFS for trabectedin v dacarbazine, 4.2 v 1.5 months; hazard ratio, 0.55; P < .001); benefits were observed across all preplanned subgroup analyses. The interim analysis of OS (64% censored) demonstrated a 13% reduction in risk of death in the trabectedin arm compared with dacarbazine (median OS for trabectedin v dacarbazine, 12.4 v 12.9 months; hazard ratio, 0.87; P = .37). The safety profiles were consistent with the well-characterized toxicities of both agents, and the most common grade 3 to 4 adverse effects were myelosuppression and transient elevation of transaminases in the trabectedin arm.
Trabectedin demonstrates superior disease control versus conventional dacarbazine in patients who have advanced liposarcoma and leiomyosarcoma after they experience failure of prior chemotherapy. Because disease control in advanced sarcomas is a clinically relevant end point, this study supports the activity of trabectedin for patients with these malignancies.
Introduction/Aims
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative illness with great unmet patient need. We aimed to evaluate whether mesenchymal stem cells induced to secrete high ...levels of neurotrophic factors (MSC‐NTF), a novel autologous cell‐therapy capable of targeting multiple pathways, could safely slow ALS disease progression.
Methods
This randomized, double‐blind, placebo‐controlled study enrolled ALS participants meeting revised El Escorial criteria, revised ALS Functional Rating Scale (ALSFRS‐R) ≥25 (screening) and ≥3 ALSFRS‐R points decline prior to randomization. Participants received three treatments of MSC‐NTF or placebo intrathecally. The primary endpoint evaluated efficacy of MSC‐NTF through a responder analysis and safety. A change in disease progression post‐treatment of ≥1.25 points/mo defines a clinical response. A pre‐specified analysis leveraged baseline ALSFRS‐R of 35 as a subgroup threshold.
Results
Overall, MSC‐NTF treatment was well tolerated; there were no safety concerns. Thirty‐three percent of MSC‐NTF and 28% of placebo participants met clinical response criteria at 28 wk (odds ratio OR = 1.33, P = .45); thus, the primary endpoint was not met. A pre‐specified analysis of participants with baseline ALSFRS‐R ≥ 35 (n = 58) showed a clinical response rate at 28 wk of 35% MSC‐NTF and 16% placebo (OR = 2.6, P = .29). Significant improvements in cerebrospinal biomarkers of neuroinflammation, neurodegeneration, and neurotrophic factor support were observed with MSC‐NTF, with placebo unchanged.
Discussion
The study did not reach statistical significance on the primary endpoint. However, a pre‐specified subgroup suggests that MSC‐NTF participants with less severe disease may have retained more function compared to placebo. Given the unmet patient need, the results of this trial warrant further investigation.
Evidence-based guidelines for managing patients with intra-abdominal infection were prepared by an Expert Panel of the Surgical Infection Society and the Infectious Diseases Society of America. These ...updated guidelines replace those previously published in 2002 and 2003. The guidelines are intended for treating patients who either have these infections or may be at risk for them. New information, based on publications from the period 2003–2008, is incorporated into this guideline document. The panel has also added recommendations for managing intra-abdominal infection in children, particularly where such management differs from that of adults; for appendicitis in patients of all ages; and for necrotizing enterocolitis in neonates.
Perivascular adipose tissue (PVAT) exerts an anticontractile effect in response to various vasoconstrictor agonists, and this is lost in obesity. A recent study reported that bariatric surgery ...reverses the damaging effects of obesity on PVAT function. However, PVAT function has not been characterized after weight loss induced by caloric restriction, which is often the first line treatment for obesity.
Contractility studies were performed using wire myography on small mesenteric arteries with and without PVAT from control, diet-induced obese, calorie restricted and sustained weight loss rats. Changes in the PVAT environment were assessed using immunohistochemistry. PVAT from healthy animals elicited an anticontractile effect in response to norepinephrine. This was abolished in diet-induced obesity through a mechanism involving increased local tumor necrosis factor-α and reduced nitric oxide bioavailability within PVAT. Sustained weight loss led to improvement in PVAT function associated with restoration of adipocyte size, reduced tumor necrosis factor-α, and increased nitric oxide synthase function. This was associated with reversal of obesity-induced hypertension and normalization of plasma adipokine levels, including leptin and insulin.
We have shown that diet-induced weight loss reverses obesity-induced PVAT damage through a mechanism involving reduced inflammation and increased nitric oxide synthase activity within PVAT. These data reveal inflammation and nitric oxide synthase, particularly endothelial nitric oxide synthase, as potential targets for the treatment of PVAT dysfunction associated with obesity and metabolic syndrome.
PDF
