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1.
Am J Surg ; : 115822, 2024 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-39003092

RESUMO

INTRODUCTION: Delta-9-tetraydrocannabinol (THC) usage is associated with venous thromboembolic events (VTE) in trauma patients. We hypothesized that THC â€‹+ â€‹trauma patients would have less platelet inhibition than THC - patients using thromboelastography with platelet mapping (TEG-PM). METHODS: Results from initial TEG- PM assays and patient's UDS were reviewed between 2019 and 2023. Mean levels of arachidonic acid (AA) and adenosine diphosphate (ADP) percent inhibition were compared by THC status. RESULTS: 793 patients had TEG-PM and UDS data. Mean levels of arachidonic acid (AA) percentage inhibition were 32.6 â€‹± â€‹34.2. AA inhibition was lower for THC â€‹+ â€‹vs THC- patients (THC+ 23.9 â€‹± â€‹27.0 vs THC- 34.3 â€‹± â€‹35.3, P â€‹< â€‹0.001). There was no association between THC status and ADP inhibition (THC+ 32.5 â€‹± â€‹27.1 vs THC- 30.8 â€‹± â€‹28.4, P â€‹= â€‹0.536). DISCUSSION: To our knowledge, our data are the first to suggest a clinically measurable increase in platelet reactivity in THC â€‹+ â€‹trauma patients. More work is needed to determine if addition of aspirin to the chemoprophylaxis strategy for THC â€‹+ â€‹patients would mitigate the known association of THC with VTE.

2.
J Biomech Eng ; 146(11)2024 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-38766990

RESUMO

During vaginal delivery, the delivery requires the fetal head to mold to accommodate the geometric constraints of the birth canal. Excessive molding can produce brain injuries and long-term sequelae. Understanding the loading of the fetal brain during the second stage of labor (fully dilated cervix, active pushing, and expulsion of fetus) could thus help predict the safety of the newborn during vaginal delivery. To this end, this study proposes a finite element model of the fetal head and maternal canal environment that is capable of predicting the stresses experienced by the fetal brain at the onset of the second phase of labor. Both fetal and maternal models were adapted from existing studies to represent the geometry of full-term pregnancy. Two fetal positions were compared: left-occiput-anterior and left-occiput-posterior. The results demonstrate that left-occiput-anterior position reduces the maternal tissue deformation, at the cost of higher stress in the fetal brain. In both cases, stress is concentrated underneath the sutures, though the location varies depending on the presentation. In summary, this study provides a patient-specific simulation platform for the study of vaginal delivery and its effect on both the fetal brain and maternal anatomy. Finally, it is suggested that such an approach has the potential to be used by obstetricians to support their decision-making processes through the simulation of various delivery scenarios.


Assuntos
Encéfalo , Análise de Elementos Finitos , Segunda Fase do Trabalho de Parto , Humanos , Feminino , Gravidez , Encéfalo/fisiologia , Encéfalo/embriologia , Segunda Fase do Trabalho de Parto/fisiologia , Feto/fisiologia , Estresse Mecânico , Suporte de Carga , Fenômenos Biomecânicos
3.
ACS Chem Biol ; 19(4): 938-952, 2024 04 19.
Artigo em Inglês | MEDLINE | ID: mdl-38565185

RESUMO

Phenotypic assays have become an established approach to drug discovery. Greater disease relevance is often achieved through cellular models with increased complexity and more detailed readouts, such as gene expression or advanced imaging. However, the intricate nature and cost of these assays impose limitations on their screening capacity, often restricting screens to well-characterized small compound sets such as chemogenomics libraries. Here, we outline a cheminformatics approach to identify a small set of compounds with likely novel mechanisms of action (MoAs), expanding the MoA search space for throughput limited phenotypic assays. Our approach is based on mining existing large-scale, phenotypic high-throughput screening (HTS) data. It enables the identification of chemotypes that exhibit selectivity across multiple cell-based assays, which are characterized by persistent and broad structure activity relationships (SAR). We validate the effectiveness of our approach in broad cellular profiling assays (Cell Painting, DRUG-seq, and Promotor Signature Profiling) and chemical proteomics experiments. These experiments revealed that the compounds behave similarly to known chemogenetic libraries, but with a notable bias toward novel protein targets. To foster collaboration and advance research in this area, we have curated a public set of such compounds based on the PubChem BioAssay dataset and made it available for use by the scientific community.


Assuntos
Descoberta de Drogas , Ensaios de Triagem em Larga Escala , Bibliotecas de Moléculas Pequenas , Descoberta de Drogas/métodos , Ensaios de Triagem em Larga Escala/métodos , Quimioinformática/métodos , Bibliotecas de Moléculas Pequenas/química , Relação Estrutura-Atividade
4.
Emerg Radiol ; 31(2): 193-201, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38374481

RESUMO

PURPOSE: Blunt bowel and/or mesenteric injury requiring surgery presents a diagnostic challenge. Although computed tomography (CT) imaging is standard following blunt trauma, findings can be nonspecific. Most studies have focused on the diagnostic value of CT findings in identifying significant bowel and/or mesenteric injury (sBMI). Some studies have described scoring systems to assist with diagnosis. Little attention, has been given to radiologist interpretation of CT scans. This study compared the discriminative ability of scoring systems (BIPS and RAPTOR) with radiologist interpretation in identifying sBMI. METHODS: We conducted a retrospective chart review of trauma patients with suspected sBMI. CT images were reviewed in a blinded fashion to calculate BIPS and RAPTOR scores. Sensitivity and specificity were compared between BIPS, RAPTOR, and the admission CT report with respect to identifying sBMI. RESULTS: One hundred sixty-two patients were identified, 72 (44%) underwent laparotomy and 43 (26.5%) had sBMI. Sensitivity and specificity were: BIPS 49% and 87%, AUC 0.75 (0.67-0.81), P < 0.001; RAPTOR 46% and 82%, AUC 0.72 (0.64-0.79), P < 0.001; radiologist impression 81% and 71%, AUC 0.82(0.75-0.87), P < 0.001. The discriminative ability of the radiologist impression was higher than RAPTOR (P = 0.04) but not BIPS (P = 0.13). There was not a difference between RAPTOR vs. BIPS (P = 0.55). CONCLUSION: Radiologist interpretation of the admission CT scan was discriminative of sBMI. Although surgical vigilance, including evaluation of the CT images and patient, remains fundamental to early diagnosis, the radiologist's impression of the CT scan can be used in clinical practice to simplify the approach to patients with abdominal trauma.


Assuntos
Traumatismos Abdominais , Ferimentos não Penetrantes , Humanos , Estudos Retrospectivos , Intestino Delgado/diagnóstico por imagem , Intestino Delgado/lesões , Intestinos/lesões , Tomografia Computadorizada por Raios X/métodos , Traumatismos Abdominais/diagnóstico por imagem , Traumatismos Abdominais/cirurgia , Ferimentos não Penetrantes/diagnóstico por imagem , Ferimentos não Penetrantes/cirurgia
5.
J Back Musculoskelet Rehabil ; 37(2): 305-315, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-37781790

RESUMO

BACKGROUND: Despite wobble board use being common in physiotherapy the effect of certain factors, essential to clinical reasoning, have not been investigated. OBJECTIVE: To determine the effect of biological sex, anthropometrics, footwear and dual tasking (DT) on wobble board balance performance. METHODS: Eighty-six healthy participants (44 females) had their wobble board performance measured during double-leg-stance (DLS) with eyes open (DLSEO), closed (DLSEC) and single-leg-stance (SLS) tasks, with and without footwear and a DT added. Anthropometrics were also measured. RESULTS: Females outperformed males during most tasks, with some large effect sizes (ES). Performance was moderately related to weight and shoulder, waist and hip circumference. Overall, there were no differences between footwear and no footwear, except for males during SLS. DT made little difference, except during DLSEO and SLS, where single task was better than DT, though only females had a large ES. CONCLUSION: During wobble board tasks, biological sex differences were observed and a modest correlation between anthropometrics and performance noted. DT and footwear had minimal effect.


Assuntos
Equilíbrio Postural , Humanos , Masculino , Adulto Jovem , Feminino
6.
Mater Horiz ; 10(12): 5931-5941, 2023 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-37873969

RESUMO

Deformable electroluminescent devices (DELDs) with mechanical adaptability are promising for new applications in smart soft electronics. However, current DELDs still present some limitations, including having stimuli-insensitive electroluminescence (EL), untunable mechanical properties, and a lack of versatile stimuli response properties. Herein, a facile approach for fabricating in situ interactive and multi-stimuli responsive DELDs with optical/photothermal/mechanical tunability was proposed. A polyvinyl alcohol (PVA)/polydopamine (PDA)/graphene oxide (GO) adaptable hydrogel exhibiting optical/photothermal/mechanical tunability was used as the top ionic conductor (TIC). The TIC can transform from a viscoelastic state to an elastic state via a special freezing-salting out-rehydration (FSR) process. Meanwhile, it endows the DELDs with a photothermal response and thickness-dependent light shielding properties, allowing them to dynamically demonstrate "on" or "off" or "gradually change" EL response to various mechanical/photothermal stimuli. Thereafter, the DELDs with a viscoelastic TIC can be utilized as pressure-responsive EL devices and laser-engravable EL devices. The DELDs with an elastic TIC can withstand both linear and out-of-plane deformation, enabling the designs of various interactive EL devices/sensors to monitor linear sliders, human finger bending, and pneumatically controllable bulging. This work offers new opportunities for developing next-generation EL-responsive devices with widespread application based on adaptable hydrogel systems.

7.
Faraday Discuss ; 239(0): 70-84, 2022 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-35822567

RESUMO

Cu2ZnSn(S,Se)4 (CZTSSe) is a promising material for thin-film photovoltaics, however, the open-circuit voltage (VOC) deficit of CZTSSe prevents the device performance from exceeding 13% conversion efficiency. CZTSSe is a heavily compensated material that is rich in point defects and prone to the formation of secondary phases. The landscape of these defects is complex and some mitigation is possible by employing non-stoichiometric conditions. Another route used to reduce the effects of undesirable defects is the doping and alloying of the material to suppress certain defects and improve crystallization, such as with germanium. The majority of works deposit Ge adjacent to a stacked metallic precursor deposited by physical vapour deposition before annealing in a selenium rich atmosphere. Here, we use an established hot-injection process to synthesise Cu2ZnSnS4 nanocrystals of a pre-determined composition, which are subsequently doped with Ge during selenisation to aid recrystallisation and reduce the effects of Sn species. Through Ge incorporation, we demonstrate structural changes with a negligible change in the energy bandgap but substantial increases in the crystallinity and grain morphology, which are associated with a Ge-Se growth mechanism, and gains in both the VOC and conversion efficiency. We use surface energy-filtered photoelectron emission microscopy (EF-PEEM) to map the surface work function terrains and show an improved electronic landscape, which we attribute to a reduction in the segregation of low local effective work function (LEWF) Sn(II) chalcogenide phases.

8.
Front Chem ; 10: 920676, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35844645

RESUMO

Developing effective device architectures for energy technologies-such as solar cells, rechargeable batteries or fuel cells-does not only depend on the performance of a single material, but on the performance of multiple materials working together. A key part of this is understanding the behaviour at the interfaces between these materials. In the context of a solar cell, efficient charge transport across the interface is a pre-requisite for devices with high conversion efficiencies. There are several methods that can be used to simulate interfaces, each with an in-built set of approximations, limitations and length-scales. These methods range from those that consider only composition (e.g. data-driven approaches) to continuum device models (e.g. drift-diffusion models using the Poisson equation) and ab-initio atomistic models (developed using e.g. density functional theory). Here we present an introduction to interface models at various levels of theory, highlighting the capabilities and limitations of each. In addition, we discuss several of the various physical and chemical processes at a heterojunction interface, highlighting the complex nature of the problem and the challenges it presents for theory and simulation.

9.
J Am Chem Soc ; 144(14): 6227-6236, 2022 04 13.
Artigo em Inglês | MEDLINE | ID: mdl-35364811

RESUMO

Tryptophan (Trp) plays a variety of critical functional roles in protein biochemistry; however, owing to its low natural frequency and poor nucleophilicity, the design of effective methods for both single protein bioconjugation at Trp as well as for in situ chemoproteomic profiling remains a challenge. Here, we report a method for covalent Trp modification that is suitable for both scenarios by invoking photo-induced electron transfer (PET) as a means of driving efficient reactivity. We have engineered biaryl N-carbamoyl pyridinium salts that possess a donor-acceptor relationship that enables optical triggering with visible light whilst simultaneously attenuating the probe's photo-oxidation potential in order to prevent photodegradation. This probe was assayed against a small bank of eight peptides and proteins, where it was found that micromolar concentrations of the probe and short irradiation times (10-60 min) with violet light enabled efficient reactivity toward surface exposed Trp residues. The carbamate transferring group can be used to transfer useful functional groups to proteins including affinity tags and click handles. DFT calculations and other mechanistic analyses reveal correlations between excited state lifetimes, relative fluorescence quantum yields, and chemical reactivity. Biotinylated and azide-functionalized pyridinium salts were used for Trp profiling in HEK293T lysates and in situ in HEK293T cells using 440 nm LED irradiation. Peptide-level enrichment from live cell labeling experiments identified 290 Trp modifications, with 82% selectivity for Trp modification over other π-amino acids, demonstrating the ability of this method to identify and quantify reactive Trp residues from live cells.


Assuntos
Proteoma , Triptofano , Elétrons , Células HEK293 , Humanos , Luz , Peptídeos/química , Sais , Triptofano/química
10.
Am J Surg ; 224(1 Pt B): 590-594, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35379483

RESUMO

BACKGROUND: The current literature offers mixed conclusions regarding the effect of increased body mass index (BMI) on outcomes after trauma laparotomy. This study evaluated the impact of obesity on outcomes and cost for patients undergoing trauma laparotomy at a level 1 trauma center. STUDY DESIGN: Data on patients requiring trauma laparotomy in 2016 were prospectively collected and patients were stratified by BMI. Statistical analyses were used to determine variables significantly associated with patient morbidity and length of stay. RESULTS: 313 patients underwent trauma laparotomy: 225 non-obese, 69 obese, and 19 morbidly obese. Obese and morbidly obese patients had longer ICU and hospital lengths of stay (LOS), more ventilator days, larger hospital costs, and higher morbidity compared to non-obese patients. Obesity was an independent predictor for patient morbidity, ICU, and hospital LOS. CONCLUSIONS: Morbidity and length of stay increased with worsening obesity after trauma laparotomy, contributing to rising hospital costs.


Assuntos
Obesidade Mórbida , Índice de Massa Corporal , Humanos , Laparotomia , Tempo de Internação , Morbidade , Obesidade Mórbida/complicações , Obesidade Mórbida/cirurgia , Estudos Retrospectivos , Centros de Traumatologia
11.
Am Surg ; 88(7): 1504-1509, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35341346

RESUMO

INTRODUCTION: The role of serial computed tomography (CT) in the nonoperative management of blunt splenic injuries (NOMSIs) remains unclear. The purpose of the study was to determine the utility of serial CT of Grade 2-5 NOMSI in the modern era. METHODS: Blunt splenic injuries were identified over a 3.5-year period, ending in 6/2020. Our institutional protocol for NOMSI mandates a repeat 24-hour CT for Grade 2-5 injuries. Patients age<18, Grade 1 injuries and patients that underwent intervention prior to repeat scan were excluded. Demographics, comorbidities, timing of events (admission, CTs, splenectomy, and angiography), injury details, procedural details, total transfusion requirements, complications, length of stay, mortality, and discharge disposition were recorded. Descriptive statistics were performed. RESULTS: 219 patients with Grade 2-5 NOMSI had both an initial and 24-hour CT after exclusions. 24-hour CT identified 14 patients with new PSA(s) and 11 (5%) went to angiography within 24 hours with 9 (4%) undergoing angioembolization and 4 (2%) had splenectomy. Two hundred and four (93%) had no intervention though eventually 12 went on to angiography and 6 went for splenectomy. The 24-hour CT rarely altered management in the absence of clinical indication or prior PSA on initial CT with 5 (2%) receiving a therapeutic embolization and 2 (1%) had a nontherapeutic angiogram. No deaths were attributable to splenic injury. CONCLUSIONS: Routine 24-hour CT for NOMSI did not impact management. Clinical status and change in exam may warrant repeat CT in select cases in the setting of a plausible alternate explanation. Prompt angioembolization or splenectomy is more appropriate in clear-cut cases of failed NOMSI.


Assuntos
Traumatismos Abdominais , Embolização Terapêutica , Ferimentos não Penetrantes , Traumatismos Abdominais/complicações , Adolescente , Embolização Terapêutica/métodos , Humanos , Escala de Gravidade do Ferimento , Masculino , Antígeno Prostático Específico , Estudos Retrospectivos , Esplenectomia , Tomografia Computadorizada por Raios X , Ferimentos não Penetrantes/complicações , Ferimentos não Penetrantes/diagnóstico por imagem , Ferimentos não Penetrantes/terapia
12.
Proc Natl Acad Sci U S A ; 119(4)2022 01 25.
Artigo em Inglês | MEDLINE | ID: mdl-35042819

RESUMO

Inspired by the intriguing adaptivity of natural life, such as squids and flowers, we propose a series of dynamic and responsive multifunctional devices based on multiscale structural design, which contain metal nanocoating layers overlaid with other micro-/nanoscale soft or rigid layers. Since the optical/photothermal properties of a metal nanocoating are thickness dependent, metal nanocoatings with different thicknesses were chosen to integrate with other structural design elements to achieve dynamic multistimuli responses. The resultant devices demonstrate 1) strain-regulated cracked and/or wrinkled topography with tunable light-scattering properties, 2) moisture/photothermal-responsive structural color coupled with wrinkled surface, and 3) mechanically controllable light-shielding properties attributed to the strain-dependent crack width of the nanocoating. These devices can adapt external stimuli, such as mechanical strain, moisture, light, and/or heat, into corresponding changes of optical signals, such as transparency, reflectance, and/or coloration. Therefore, these devices can be applied as multistimuli-responsive encryption devices, smart windows, moisture/photothermal-responsive dynamic optics, and smartphone app-assisted pressure-mapping sensors. All the devices exhibit high reversibility and rapid responsiveness. Thus, this hybrid system containing ultrathin metal nanocoatings holds a unique design flexibility and adaptivity and is promising for developing next-generation multifunctional devices with widespread application.

13.
Methods Mol Biol ; 2396: 187-195, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34786684

RESUMO

Lipids play an essential role in plants, and historically manipulating their levels and composition has been an important target for metabolic engineering. A variety of analytical techniques, many based on mass spectrometry, have been utilized for lipid profiling, but the analysis of complex lipid mixtures still poses significant analytical challenges. Recent advances in technology have revived the supercritical fluid chromatography (SFC) as a promising separation technique for lipid analysis. Utilization of sub-2-µm particle columns improves the separation efficiency and robustness of the SFC systems. The combination of SFC with sub-2-µm particle separation, commonly referred as ultra-performance convergence chromatography, has been successfully used for separation of both polar and neutral lipids. In this chapter, we present a simple method for lipid class separation using Sub-2-µm particle CO2-based chromatography coupled to mass spectrometry. The supercritical fluid chromatography methodology is flexible and can be altered to provide greater retention and separation of lipid classes or individual lipids within class.


Assuntos
Cromatografia com Fluido Supercrítico , Espectrometria de Massas , Dióxido de Carbono , Lipídeos
14.
J Trauma Acute Care Surg ; 90(3): 421-425, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33306601

RESUMO

INTRODUCTION: In certain regions of the United States, there has been a dramatic proliferation of trauma centers. The goal of our study was to evaluate transport times during this period of trauma center proliferation. METHODS: Aggregated data summarizing level I trauma center admissions in Arizona between 2009 and 2018 were provided to our institution by the Arizona Department of Health Services. We evaluated patient demographics, transport times, and injury severity for both rural and urban injuries. RESULTS: Data included statistics summarizing 266,605 level I trauma admissions in the state of Arizona. The number of state-designated trauma centers during this time increased from 14 to 47, with level I centers increasing from 8 to 13. Slight decreases in mean Injury Severity Score (rural, 9.4 vs. 8.4; urban, 7.9 vs. 7.0) were observed over this period. Median transport time for cases transported from the injury scene directly to a level I center remained stable in urban areas at 0.9 hours in both 2009 and 2018. In rural areas, transport times for these cases were approximately double but also stable, with median times of 1.8 and 1.9 hours. Transport times for cases requiring interfacility transfer before admission at a level I center increased by 0.3 hours for urban injuries (5.3-5.6 hours) and 0.9 hours for rural injuries (5.6-6.5 hours). CONCLUSION: Despite the threefold increase in the number of state-designated trauma centers, transport time has not decreased in urban or rural areas. This finding highlights the need for regulatory oversight regarding the number and geographic placement of state-designated trauma centers. LEVEL OF EVIDENCE: Care management, level IV, Epidemiological, level III.


Assuntos
Serviços de Saúde Rural/provisão & distribuição , Transporte de Pacientes/estatística & dados numéricos , Centros de Traumatologia/provisão & distribuição , Serviços Urbanos de Saúde/provisão & distribuição , Ferimentos e Lesões/epidemiologia , Adulto , Arizona , Feminino , Humanos , Escala de Gravidade do Ferimento , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Tempo , Ferimentos e Lesões/terapia , Adulto Jovem
15.
Cell Chem Biol ; 28(1): 4-13.e17, 2021 01 21.
Artigo em Inglês | MEDLINE | ID: mdl-32966806

RESUMO

MYC is a major oncogenic transcriptional driver of most human cancers that has remained intractable to direct targeting because much of MYC is intrinsically disordered. Here, we have performed a cysteine-reactive covalent ligand screen to identify compounds that could disrupt the binding of MYC to its DNA consensus sequence in vitro and also impair MYC transcriptional activity in situ in cells. We have identified a covalent ligand, EN4, that targets cysteine 171 of MYC within a predicted intrinsically disordered region of the protein. We show that EN4 directly targets MYC in cells, reduces MYC and MAX thermal stability, inhibits MYC transcriptional activity, downregulates multiple MYC transcriptional targets, and impairs tumorigenesis. We also show initial structure-activity relationships of EN4 and identify compounds that show improved potency. Overall, we identify a unique ligandable site within an intrinsically disordered region of MYC that leads to inhibition of MYC transcriptional activity.


Assuntos
Cisteína/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-myc/antagonistas & inibidores , Células Cultivadas , Cisteína/metabolismo , Relação Dose-Resposta a Droga , Humanos , Ligantes , Estrutura Molecular , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo
16.
Trauma Surg Acute Care Open ; 5(1): e000583, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33305006

RESUMO

BACKGROUND: Although helmets are associated with reduction in mortality from motorcycle collisions, many states have failed to adopt universal helmet laws for motorcyclists, in part on the grounds that prior research is limited by study design (historical controls) and confounding variables. The goal of this study was to evaluate the association of helmet use in motorcycle collisions with hospital charges and mortality in trauma patients with propensity score analysis in a state without a universal helmet law. METHODS: Motorcycle collision data from the Arizona State Trauma Registry from 2014 to 2017 were propensity score matched by regressing helmet use on patient age, sex, race/ethnicity, alcohol intoxication, illicit drug use, and comorbidities. Linear and logistic regression models were used to evaluate the impact of helmet use. RESULTS: Our sample consisted of 6849 cases, of which 3699 (54.0%) were helmeted and 3150 (46.0%) without helmets. The cohort was 88.1% male with an average age of 40.9±16.0 years. Helmeted patients were less likely to be admitted to the intensive care unit (20.3% vs. 23.7%, OR 0.82 (0.72-0.93)) and ventilated (7.8% vs. 12.0%, OR 0.62 (0.52-0.75)). Propensity-matched analyses consisted of 2541 pairs and demonstrated helmet use to be associated with an 8% decrease in hospital charges (B -0.075 (0.034)) and a 56% decrease in mortality (OR 0.44 (0.31-0.58)). DISCUSSION: In a state without mandated helmet use for all motorcyclists, the burden of the unhelmeted rider is significant with respect to lives lost and healthcare charges incurred. Although the helmet law debate with respect to civil liberties is complex and unsettled, it appears clear that helmet use is strongly associated with both survival and less economic encumbrance on the state. LEVEL OF EVIDENCE: Level III, prognostic and epidemiological.

17.
Nat Chem Biol ; 16(11): 1189-1198, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32572277

RESUMO

Molecular glues are an intriguing therapeutic modality that harness small molecules to induce interactions between proteins that typically do not interact. However, such molecules are rare and have been discovered fortuitously, thus limiting their potential as a general strategy for therapeutic intervention. We postulated that natural products bearing one or more electrophilic sites may be an unexplored source of new molecular glues, potentially acting through multicovalent attachment. Using chemoproteomic platforms, we show that members of the manumycin family of polyketides, which bear multiple potentially reactive sites, target C374 of the putative E3 ligase UBR7 in breast cancer cells, and engage in molecular glue interactions with the neosubstrate tumor-suppressor TP53, leading to p53 transcriptional activation and cell death. Our results reveal an anticancer mechanism of this natural product family, and highlight the potential for combining chemoproteomics and multicovalent natural products for the discovery of new molecular glues.


Assuntos
Antineoplásicos/química , Neoplasias da Mama/tratamento farmacológico , Polienos/química , Policetídeos/química , Alcamidas Poli-Insaturadas/química , Proteína Supressora de Tumor p53/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Reagentes de Ligações Cruzadas/química , Descoberta de Drogas , Feminino , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Conformação Molecular , Estrutura Molecular , Polienos/farmacologia , Alcamidas Poli-Insaturadas/farmacologia , Eletricidade Estática , Relação Estrutura-Atividade , Proteína Supressora de Tumor p53/genética , Ubiquitina-Proteína Ligases/genética
18.
Front Microbiol ; 10: 2665, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31849856

RESUMO

The enteric pathogen, Salmonella enterica is a major cause of human gastroenteritis globally and with increasing bacterial resistance to antibiotics, alternative solutions are urgently needed. Single domain antibodies (sdAbs), the smallest antibody fragments that retain antigen binding specificity and affinity, are derived from variable heavy-chain only fragments (VHH) of camelid heavy-chain-only immunoglobulins. SdAbs typically contain a single disulfide bond simplifying recombinant protein production in microbial systems. These factors make sdAbs ideally suited for the development of effective anti-bacterial therapeutics. To this end, we generated an anti-Salmonella VHH library from which we screened for high affinity sdAbs. We present a novel sdAb (Abi-Se07) that targets the Salmonella virulence factor, FliC, required for bacterial motility and invasion of host cells. We demonstrate that Abi-Se07 bound FliC with a K D of 16.2 ± 0.1 nM. In addition, Abi-Se07 exhibited cross-serovar binding to whole cells of S. enterica serovar Typhimurium, Heidelberg, and Hadar. Abi-Se07 significantly inhibited bacterial motility and significantly reduced S. enterica colonization in a more native environment of chicken jejunum epithelium. Taken together, we have identified a novel anti-Salmonella sdAb and discuss future efforts toward therapeutic development.

19.
J Trauma Acute Care Surg ; 87(5): 1214-1219, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31389918

RESUMO

BACKGROUND: Although the impact of health literacy (HL) on trauma patient outcomes remains unclear, recent studies have demonstrated that trauma patients with deficient HL have poor understanding of their injuries, are less likely to comply with follow-up, and are relatively less satisfied with physician communication. In this study, we sought to determine if HL deficiency was associated with comprehension of discharge instructions. METHODS: In this prospective study, hospitalized trauma patients underwent evaluation of HL prior to discharge. Newest Vital Sign (NVS) instrument was used to score HL as deficient, marginal, or proficient. Three days postdischarge, patients were telephonically administered a six-point scored questionnaire regarding comprehension of discharge instructions. A general linear model was used to determine the association between HL and comprehension of discharge instructions. RESULTS: Sixty-three patients were administered both NVS and discharge instruction questionnaire. Ten (15.9%) patients scored as deficient in HL on the NVS screen, 16 (25.4%) as marginally proficient, and 37 (58.7%) as proficient. The HL proficiency significantly predicted follow-up score with increasing proficiency associated with higher scores on the discharge comprehension assessment (p < 0.001). Adjusted mean scores (± SE) for deficient, marginal, and proficient patients were 2.8 ± 0.5, 3.2 ± 0.4, and 4.7 ± 0.2. Post hoc comparisons demonstrated significant differences between proficient with marginal proficiency (p = 0.002) and deficient proficiency (p = 0.001). CONCLUSION: Performance on bedside test of HL among trauma inpatients predicted ability to comprehend instructions following hospital discharge. This study supports the value of HL screening prior to discharge. The HL-deficient patients may benefit from a transitional care program to improve comprehension of discharge instructions after leaving the hospital. LEVEL OF EVIDENCE: Therapeutic/Care Management, level III.


Assuntos
Compreensão , Letramento em Saúde/estatística & dados numéricos , Pacientes Internados/psicologia , Cooperação do Paciente/psicologia , Ferimentos e Lesões/terapia , Adulto , Feminino , Humanos , Pacientes Internados/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Cooperação do Paciente/estatística & dados numéricos , Alta do Paciente , Estudos Prospectivos , Inquéritos e Questionários/estatística & dados numéricos , Cuidado Transicional/organização & administração , Adulto Jovem
20.
Arch Dis Child ; 104(8): 793-801, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31164375

RESUMO

BACKGROUND: Performing high-quality chest compressions during cardiopulmonary resuscitation (CPR) requires achieving of a target depth, release force, rate and duty cycle. OBJECTIVE: This study evaluates whether 'real time' feedback could improve infant CPR performance in basic life support-trained (BLS) and lay rescuers. It also investigates whether delivering rescue breaths hinders performing high-quality chest compressions. Also, this study reports raw data from the two methods used to calculate duty cycle performance. METHODOLOGY: BLS (n=28) and lay (n=38) rescuers were randomly allocated to respective 'feedback' or 'no-feedback' groups, to perform two-thumb chest compressions on an instrumented infant manikin. Chest compression performance was then investigated across three compression algorithms (compression only; five rescue breaths then compression only; five rescue breaths then 15:2 compressions). Two different routes to calculate duty cycle were also investigated, due to conflicting instruction in the literature. RESULTS: No-feedback BLS and lay groups demonstrated <3% compliance against each performance target. The feedback rescuers produced 20-fold and 10-fold increases in BLS and lay cohorts, respectively, achieving all targets concurrently in >60% and >25% of all chest compressions, across all three algorithms. Performing rescue breaths did not impede chest compression quality. CONCLUSIONS: A feedback system has great potential to improve infant CPR performance, especially in cohorts that have an underlying understanding of the technique. The addition of rescue breaths-a potential distraction-did not negatively influence chest compression quality. Duty cycle performance depended on the calculation method, meaning there is an urgent requirement to agree a single measure.


Assuntos
Reanimação Cardiopulmonar/instrumentação , Retroalimentação , Parada Cardíaca/terapia , Manequins , Efeito Espectador , Serviços de Saúde da Criança , Simulação por Computador , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Resultado do Tratamento
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