Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 596
Filtrar
2.
Pediatrics ; 2020 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-32144121

RESUMO

A previously healthy 9-year-old immigrant girl from Mexico was evaluated in the emergency department (ED) with one week of fatigue, fevers, rhinorrhea, and cough. She initially presented to her primary pediatrician, where a complete blood count revealed neutropenia, prompting referral to the ED. In the ED, she was found to be influenza A-positive. Because of dehydration, she received intravenous fluids and was admitted to the pediatric hospital medicine service. After 2 days, influenza symptoms improved, and oral intake increased. However, she was noted to have decreased bilateral lower-extremity strength, absent Achilles reflexes, decreased lower-extremity sensation and proprioception, a positive result on the Romberg sign, and abnormal heel-to-shin testing results. These findings prompted an urgent neurology consultation. After extensive imaging, laboratory evaluation, and further consultations, a diagnosis was established.

4.
Science ; 367(6481)2020 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-32029687

RESUMO

CRISPR-Cas9 gene editing provides a powerful tool to enhance the natural ability of human T cells to fight cancer. We report a first-in-human phase 1 clinical trial to test the safety and feasibility of multiplex CRISPR-Cas9 editing to engineer T cells in three patients with refractory cancer. Two genes encoding the endogenous T cell receptor (TCR) chains, TCRα (TRAC) and TCRß (TRBC), were deleted in T cells to reduce TCR mispairing and to enhance the expression of a synthetic, cancer-specific TCR transgene (NY-ESO-1). Removal of a third gene encoding programmed cell death protein 1 (PD-1; PDCD1), was performed to improve antitumor immunity. Adoptive transfer of engineered T cells into patients resulted in durable engraftment with edits at all three genomic loci. Although chromosomal translocations were detected, the frequency decreased over time. Modified T cells persisted for up to 9 months, suggesting that immunogenicity is minimal under these conditions and demonstrating the feasibility of CRISPR gene editing for cancer immunotherapy.

5.
Clin Pediatr (Phila) ; : 9922820902431, 2020 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-31994411
6.
Cell ; 180(3): 521-535.e18, 2020 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-31978320

RESUMO

Cortical layer 1 (L1) interneurons have been proposed as a hub for attentional modulation of underlying cortex, but the transformations that this circuit implements are not known. We combined genetically targeted voltage imaging with optogenetic activation and silencing to study the mechanisms underlying sensory processing in mouse barrel cortex L1. Whisker stimuli evoked precisely timed single spikes in L1 interneurons, followed by strong lateral inhibition. A mild aversive stimulus activated cholinergic inputs and evoked a bimodal distribution of spiking responses in L1. A simple conductance-based model that only contained lateral inhibition within L1 recapitulated the sensory responses and the winner-takes-all cholinergic responses, and the model correctly predicted that the network would function as a spatial and temporal high-pass filter for excitatory inputs. Our results demonstrate that all-optical electrophysiology can reveal basic principles of neural circuit function in vivo and suggest an intuitive picture for how L1 transforms sensory and modulatory inputs. VIDEO ABSTRACT.

7.
Langmuir ; 36(4): 889-896, 2020 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-31948231

RESUMO

Here, we report on the simple, catalyst-free preparation and application of carbon nanotube-silicon core-shell composite anodes on stainless steel. The stainless steel mesh structure acts as a self-catalyzing agent for the plasma-enhanced chemical vapor deposition (PECVD) growth of vertically aligned, dense, multiwalled carbon nanotube arrays. The carbon nanotube array then serves as a bed for silicon deposition by the decomposition of silane through chemical vapor deposition (CVD). This approach leads to the formation of highly conductive and stable composite anodes. Silicon deposition on the substrate is controlled in terms of the optimal silicon shell thickness, thus enhancing the performance of the cell. These extremely stable, binder-free composite electrodes were characterized as potential anodes in Li-ion batteries, exhibiting long cycle life (>700 cycles), high gravimetric capacity (>4000 mAh/gSi), low irreversible capacity (<10%), and high Coulombic efficiency (>99.5%). These composite anodes meet the requirements of Li-ion batteries for future portable electronics and electric vehicle applications.

8.
Br J Clin Pharmacol ; 86(1): 175-181, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31658494

RESUMO

Concentrations of drugs acting in the lungs are difficult to measure, resulting in relatively unknown local pharmacokinetics. The aim of this study is to assess the potential of exhaled breath condensate (EBC) as a matrix for pharmacokinetic analysis of inhaled and intravenous medication. A 4-way crossover study was conducted in 12 volunteers with tobramycin and salbutamol intravenously and via inhalation. EBC and plasma samples were collected postdose and analysed for drug concentrations. Sample dilution, calculated using urea concentrations, was used to estimate the epithelial lining fluid concentration. Salbutamol and tobramycin were largely undetectable in EBC after intravenous administration and were detectable after inhaled administration in all subjects in 50.8 and 51.5% of EBC samples, respectively. Correction of EBC concentrations for sample dilution did not explain the high variability. This high variability of EBC drug concentrations seems to preclude EBC as a matrix for pharmacokinetic analysis of tobramycin and salbutamol.

9.
Influenza Other Respir Viruses ; 14(1): 77-91, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31568678

RESUMO

INTRODUCTION: There are limited data on risk of severe disease or outcomes in patients with influenza and pulmonary tuberculosis (PTB) co-infection compared to those with single infection. METHODS: We conducted a systematic review of published literature on the interaction of influenza viruses and PTB. Studies were eligible for inclusion if they presented data on prevalence, disease association, presentation or severity of laboratory-confirmed influenza among clinically diagnosed or laboratory-confirmed PTB cases. We searched eight databases from inception until December 2018. Summary characteristics of each study were extracted, and a narrative summary was presented. Cohort or case-control studies were assessed for potential bias using the Newcastle-Ottawa scale. RESULTS: We assessed 5154 abstracts, reviewed 146 manuscripts and included 19 studies fulfilling selection criteria (13 human and six animal). Of seven studies reporting on the possible effect of the underlying PTB disease in patients with influenza, three of four analytical studies reported no association with disease severity of influenza infection in those with PTB, whilst one study reported PTB as a risk factor for influenza-associated hospitalization. An association between influenza infection and PTB disease was found in three of five analytical studies; whereas the two other studies reported a high frequency of PTB disease progression and complications among patients with seasonal influenza co-infection. CONCLUSION: Human analytical studies of an association between co-infection and severe influenza- or PTB-associated disease or increased prevalence of influenza co-infection in individuals' hospitalized for PTB were not conclusive. Data are limited from large, high-quality, analytical epidemiological studies with laboratory-confirmed endpoints.

10.
Bioessays ; 42(1): e1900142, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31823398

RESUMO

Cell membranes experience frequent stretching and poking: from cytoskeletal elements, from osmotic imbalances, from fusion and budding of vesicles, and from forces from the outside. Are the ensuing changes in membrane tension localized near the site of perturbation, or do these changes propagate rapidly through the membrane to distant parts of the cell, perhaps as a mechanical mechanism of long-range signaling? Literature statements on the timescale for membrane tension to equilibrate across a cell vary by a factor of ≈106 . This study reviews and discusses how apparently contradictory findings on tension propagation in cells can be evaluated in the context of 2D hydrodynamics and poroelasticity. Localization of tension in the cell membrane is likely critical in governing how membrane forces gate ion channels, set the subcellular distribution of vesicle fusion, and regulate the dynamics of cytoskeletal growth. Furthermore, in this study, it is proposed that cells can actively regulate the degree to which membrane tension propagates by modulating the density and arrangement of immobile transmembrane proteins. Also see the video abstract here https://youtu.be/T6K7AIAqqBs.

11.
Hand (N Y) ; 15(1): 59-63, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30003819

RESUMO

Background: Carpal tunnel syndrome is a common cause of upper extremity discomfort. Surgical release of the median nerve can be performed under general or local anesthetic, with or without a tourniquet. Wide-awake carpal tunnel release (CTR) (local anesthesia, no sedation) is gaining popularity. Tourniquet discomfort is a reported downside. This study reviews outcomes in wide-awake CTR and compares tourniquet versus no tourniquet use. Methods: Wide-awake, open CTRs performed from February 2013 to April 2016 were retrospectively reviewed. Patients were divided into 2 cohorts: with and without tourniquet. Demographics, comorbidities, tobacco use, operative time, estimated blood loss, complications and outcomes were compared. Results: A total of 304 CTRs were performed on 246 patients. The majority of patients were male (88.5%), and the mean age was 59.9 years. One hundred patients (32.9%) were diabetic, and 92 patients (30.2%) were taking antithrombotics. Seventy-five patients (24.7%) were smokers. A forearm tourniquet was used for 90 CTRs (29.6%). Mean operative time was 24.97 minutes with a tourniquet and 21.69 minutes without. Estimated blood loss was 3.16 mL with a tourniquet and 4.25 mL without. All other analyzed outcomes were not statistically significant. Conclusion: Operative time was statistically longer and estimated blood loss was statistically less with tourniquet use, but these findings are not clinically significant. This suggests that local anesthetic with epinephrine is a safe and effective alternative to tourniquet use in CTR. The overall rate of complications was low, and there were no major differences in postoperative outcomes between groups.

13.
Lancet Oncol ; 21(2): 207-221, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31859245

RESUMO

BACKGROUND: Belantamab mafodotin (GSK2857916), an immunoconjugate targeting B-cell maturation antigen, showed single-agent activity in the phase 1 DREAMM-1 study in heavily pre-treated patients with relapsed or refractory multiple myeloma. We further investigated the safety and activity of belantamab mafodotin in the DREAMM-2 study. METHODS: DREAMM-2 is an open-label, two-arm, phase 2 study done at 58 multiple myeloma specialty centres in eight countries. Patients (aged ≥18 years) with relapsed or refractory multiple myeloma with disease progression after three or more lines of therapy and who were refractory to immunomodulatory drugs and proteasome inhibitors, and refractory or intolerant (or both) to an anti-CD38 monoclonal antibody with an Eastern Cooperative Oncology Group performance status of 0-2 were recruited, centrally randomly assigned (1:1) with permuted blocks (block size 4), and stratified by previous lines of therapy (≤4 vs >4) and cytogenetic features to receive 2·5 mg/kg or 3·4 mg/kg belantamab mafodotin via intravenous infusion every 3 weeks on day 1 of each cycle until disease progression or unacceptable toxicity. The intention-to-treat population comprised all randomised patients, regardless of treatment administration. The safety population comprised all patients who received at least one dose of belantamab mafodotin. The primary outcome was the proportion of randomly assigned patients in the intention-to-treat population who achieved an overall response, as assessed by an independent review committee. This study is registered with ClinicalTrials.gov, NCT03525678, and is ongoing. FINDINGS: Between June 18, 2018, and Jan 2, 2019, 293 patients were screened and 196 were included in the intention-to-treat population (97 in the 2·5 mg/kg cohort and 99 in the 3·4 mg/kg cohort). As of June 21, 2019 (the primary analysis data cutoff date), 30 (31%; 97·5% CI 20·8-42·6) of 97 patients in the 2·5 mg/kg cohort and 34 (34%; 23·9-46·0) of 99 patients in the 3·4 mg/kg cohort achieved an overall response. The most common grade 3-4 adverse events in the safety population were keratopathy (in 26 [27%] of 95 patients in the 2·5 mg/kg cohort and 21 [21%] of 99 patients in the 3·4 mg/kg cohort), thrombocytopenia (19 [20%] and 33 [33%]), and anaemia (19 [20%] and 25 [25%]); 38 (40%) of 95 patients in the 2·5 mg/kg cohort and 47 (47%) of 99 in the 3·4 mg/kg cohort reported serious adverse events. Two deaths were potentially treatment related (one case of sepsis in the 2·5 mg/kg cohort and one case of haemophagocytic lymphohistiocytosis in the 3·4 mg/kg cohort). INTERPRETATION: Single-agent belantamab mafodotin shows anti-myeloma activity with a manageable safety profile in patients with relapsed or refractory multiple myeloma. FUNDING: GlaxoSmithKline.

14.
Hematology Am Soc Hematol Educ Program ; 2019(1): 266-272, 2019 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-31808859

RESUMO

The course of multiple myeloma (MM) from initial diagnosis to a relapsed/refractory state is characterized by acquisition of drug resistance as well as progressive immunologic dysfunction. Despite this, however, a number of novel therapies that work in part or solely via immune stimulation are in development for MM, with promising early clinical results. Several new whole-cell or multiepitope vaccine approaches are demonstrating immunologic efficacy in smoldering MM or as posttherapy consolidation, with trials ongoing to see whether this translates into delayed progression or elimination of minimal residual disease. Programmed death-1 (PD-1)/programmed death ligand-1 (PD-L1) inhibition in combination with immunomodulatory drugs demonstrated excessive toxicity in randomized trials; however, antibodies targeting PD-1/PD-L1 and other checkpoint molecules continue to be explored in combination with tumor-targeted antibodies and other T cell-directed therapies. B-cell maturation antigen (BCMA) has emerged as the next big antigen target, with multiple BCMA-specific antibody-drug conjugates (ADCs) and T cell-directed bispecific antibodies/bispecific therapeutic engagers (BiTEs) entering the clinic. In initial trials, the ADC GSK2857916 and the BiTE AMG 420 have demonstrated high response rates in relapsed/refractory patients, with depth and durability of responses that may end up rivaling chimeric antigen receptor T-cell therapies. These agents have unique toxicities that require close monitoring, but they are moving forward in larger registration studies and in combination with standard MM agents. Additional ADCs and bispecific antibodies targeting BCMA and other surface antigens (eg, CD38, CD46, CD48, FcRH5, and G protein-coupled receptor, class C group 5 member D) are moving forward in phase 1 trials and may provide even more options for MM patients.

16.
Eye Contact Lens ; 2019 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-31794541

RESUMO

OBJECTIVES: To report a novel case of Epipremnum aureum toxicity masquerading as bilateral infectious keratitis and review the literature on ocular manifestations of Epipremnum exposure. METHODS: Case report and literature review. RESULTS: A 70-year-old man with a history of photorefractive keratectomy presented with a 3-day history of bilateral eye pain. The patient reported exposure to plant debris while performing yard work and also water exposure while cleaning his coral fish tanks. Clinical examination revealed bilateral epitheliopathy progressing to frank epithelial defects with underlying stromal necrosis 6 days after exposure. Empiric topical antibiotic drops were initiated, but multiple cultures, corneal biopsy, and confocal microscopy were all negative for an infectious agent. Over a 2-week period, the epithelial defects worsened and a suspicion for a toxic etiology was raised. The patient later recalled rubbing his eyes after exposure to Epipremnum aureum (Golden Pothos/Devils Ivy) sap. He was thus treated conservatively with artificial tears, topical corticosteroids, and amniotic membrane. After 3 months, the epithelial defects resolved, but with corneal scarring, prominently in the left eye and underwent penetrating keratoplasty. Five years after presentation, best-corrected visual acuity with hard contact lenses was 20/25 in the right eye and 20/20 in the left eye. CONCLUSION: Epipremnum aureum toxicity is a rare cause of keratitis. It can mimic acanthamoeba keratitis or anesthetic abuse and should be considered in cases of culture negative nonhealing corneal ulcerations. Eliciting a history of plant sap exposure can facilitate appropriate supportive care for this toxic keratitis.

17.
CNS Oncol ; 8(4): CNS48, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31818130

RESUMO

Aim: Therapeutic targeting of BRAF alterations in primary brain tumor patients has demonstrated clinical activity in case reports and early trials; however, there is limited high-level evidence of the efficacy. Patients & results: Targeting BRAF V600E mutations with concurrent dabrafenib and trametinib in anaplastic pleomorphic xanthoastrocytoma resulted in a transient radiographic and clinical response and no therapeutic benefit in a patient with an epithelioid glioblastoma. Conclusion: BRAF/MEK inhibition did not produce a durable treatment effect in glioblastoma or pleomorphic xanthoastrocytoma with BRAF V600E alterations. Heterogenicity of related cases in the literature makes an evaluation of efficacy BRAF targeting therapies in gliomas difficult and requires additional investigation.

18.
Br J Clin Pharmacol ; 85(12): 2645-2648, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31828831
19.
Handb Exp Pharmacol ; 260: 371-397, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31707472

RESUMO

Clinical trials have been conducted since 500 BC. Currently, the methodological gold standard is the randomized controlled clinical trial, introduced by Austin Bradford Hill. This standard has produced enormous amounts of high-quality evidence, resulting in evidence-based clinical guidelines for physicians. However, the current trial paradigm needs to evolve because of the ongoing decrease of the incidence of hard endpoints and spiraling trial costs. While new trial designs, such as adaptive clinical trials, may lead to an increase in efficiency and decrease in costs, we propose a shift towards value-based trial design: a paradigm that mirrors value-based thinking in business and health care. Value-based clinical trials will use technology to focus more on symptoms and endpoints that patients care about, will incorporate fewer research centers, and will measure a state or consequence of disease at home or at work. Furthermore, they will measure the subjective experience of subjects in relation to other objective measurements. Ideally, the endpoints are suitable for individual assessment of the effect of an intervention. The value-based clinical trial of the future will have a low burden for participants, allowing for the inclusion of neglected populations such as children and the elderly, will be data-rich due to a high frequency of measurements, and can be conducted with technology that is already available.


Assuntos
Ensaios Clínicos como Assunto/normas , Projetos de Pesquisa/tendências , Humanos
20.
J Infect Dis ; 220(Supplement_4): S263-S265, 2019 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-31671435

RESUMO

Since the progressive introduction of the meningococcal serogroup A conjugate vaccine within Africa's meningitis belt beginning in 2010, the burden of meningitis due to Neisseria meningitidis serogroup A (NmA) has substantially decreased. Non-A serogroups C/W/X are now the most prevalent. Surveillance within the belt has historically focused on the clinical syndrome of meningitis, the classic presentation for NmA, and may not adequately capture other presentations of invasive meningococcal disease (IMD). The clinical presentation of infection due to serogroups C/W/X includes nonmeningeal IMD, and there is a higher case-fatality ratio associated with these non-A serogroups; however, data on the nonmeningeal IMD burden within the belt are scarce. Expanding surveillance to capture all cases of IMD, in accordance with the World Health Organization's updated vaccine-preventable disease surveillance standards and in preparation for the anticipated introduction of a multivalent meningococcal conjugate vaccine within Africa's meningitis belt, will enhance meningococcal disease prevention across the belt.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA