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Osteoarthritis (OA) causes bony shape changes within the knee. Furthermore, the risk of developing OA increases with age. However, age alone does not cause OA. It is therefore important to understand the healthy age-related trajectories of knee shape before attributing these changes to OA. The aim of this study was to determine the association between bony knee shape and age using statistical-shape modelling (SSM). 96 participants received a CT scan of their knee. Three-dimensional models were created using manual segmentation. Separate SSM's for the distal femur and proximal tibia were created. Linear regression models were used to assess the association between age and femoral and tibial shape. Fourteen modes of the femoral and tibial SSM's captured 68% and 73% shape variation, respectively. Only femoral mode 3 and tibial mode 7 were associated with age. Increasing age was related to larger femoral bone volume and deepening of the femoral trochlear groove. Furthermore, increased age was associated with medial tibial plateau expansion. Aspects of bony femoral and tibial shape were significantly associated with aging, including femoral and tibial bone size, femoral trochlear groove, and medial tibial plateau area. Changes in knee morphology occur as a normal process of aging without osteoarthritis development. This may be a response to mechanical loading over time. Further research investigating the effect of these changes on loading in the knee may provide valuable information for knee health in older age.
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Fluctuating arterial blood pressure during high-intensity interval exercise (HIIE) may challenge dynamic cerebral autoregulation (dCA), specifically after stroke after an injury to the cerebrovasculature. We hypothesized that dCA would be attenuated at rest and during a sit-to-stand transition immediately after and 30 min after HIIE in individuals poststroke compared with age- and sex-matched control subjects (CON). HIIE switched every minute between 70% and 10% estimated maximal watts for 10 min. Mean arterial pressure (MAP) and middle cerebral artery blood velocity (MCAv) were recorded. dCA was quantified during spontaneous fluctuations in MAP and MCAv via transfer function analysis. For sit-to-stand, time delay before an increase in cerebrovascular conductance index (CVCi = MCAv/MAP), rate of regulation, and % change in MCAv and MAP were measured. Twenty-two individuals poststroke (age 60 ± 12 yr, 31 ± 16 mo) and twenty-four CON (age 60 ± 13 yr) completed the study. Very low frequency (VLF) gain (P = 0.02, η2 = 0.18) and normalized gain (P = 0.01, η2 = 0.43) had a group × time interaction, with CON improving after HIIE whereas individuals poststroke did not. Individuals poststroke had lower VLF phase (P = 0.03, η2 = 0.22) after HIIE compared with CON. We found no differences in the sit-to-stand measurement of dCA. Our study showed lower dCA during spontaneous fluctuations in MCAv and MAP following HIIE in individuals poststroke compared with CON, whereas the sit-to-stand response was maintained.NEW & NOTEWORTHY This study provides novel insights into poststroke dynamic cerebral autoregulation (dCA) following an acute bout of high-intensity interval exercise (HIIE). In people after stroke, dCA appears attenuated during spontaneous fluctuations in mean arterial pressure (MAP) and middle cerebral artery blood velocity (MCAv) following HIIE. However, the dCA response during a single sit-to-stand transition after HIIE showed no significant difference from controls. These findings suggest that HIIE may temporarily challenge dCA after exercise in individuals with stroke.
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Ejercicio Físico , Accidente Cerebrovascular , Adulto , Humanos , Persona de Mediana Edad , Anciano , Ejercicio Físico/fisiología , Presión Arterial , Homeostasis/fisiología , Arteria Cerebral Media/fisiología , Circulación Cerebrovascular/fisiología , Presión Sanguínea/fisiología , Velocidad del Flujo Sanguíneo/fisiologíaRESUMEN
Objective: To evaluate data sources pertaining to the safety and efficacy of sodium-glucose cotransporter-2 (SGLT2) inhibitor use for diabetes management in patients following kidney transplantation. Data Sources: A literature search was conducted through PubMed (1966-January 2023), EMBASE (1973-January 2023), and clinicaltrials.gov databases using the search terms kidney transplantation, diabetes mellitus, and SGLT2 inhibitor or empagliflozin, dapagliflozin, and canagliflozin. Study Selection and Data Extraction: Studies evaluating human kidney transplant recipients (KTR) receiving SGLT2 inhibitors treatment and published in the English language were included. Eight case series or retrospective analyses, 4 prospective observational studies, and 1 randomized controlled trial were identified. Data Synthesis: Available literature provides evidence that the addition of SGLT2 inhibitors may provide modest benefits on glycemic control, body weight, and serum uric acid levels in certain KTR. Various studies and case reports found that incidence of urinary tract infections was low, but still present. Overall, there are limited data on mortality and graft survival; however, one study reported a benefit of SGLT2 inhibitor use in KTR relative to these outcomes. Conclusions: The current literature evaluated demonstrates that there may be benefit to the addition of SGLT2 inhibitors for diabetes management in select KTR. However, the limited evidence within a large diverse population and extended duration of treatment makes it difficult to definitively identify the true efficacy and safety of SGLT2 inhibitor use in this population.
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Deciphering the complex interplay of neutrophil extracellular traps (NETs) with the surrounding environment is a challenge with notable clinical implications. To bridge the gap in knowledge, we report our findings on the antibacterial activity against Pseudomonas aeruginosa of synthetic NET-mimetic materials composed of nanofibrillated DNA-protein complexes. Our synthetic system makes component-by-component bottom-up analysis of NET protein effects possible. When the antimicrobial enzyme neutrophil elastase (NE) is incorporated into the bactericidal DNA-histone complexes, the resulting synthetic NET-like structure exhibits an unexpected reduction in antimicrobial activity. This critical immune function is rescued upon treatment with alpha-1-antitrypsin (AAT), a physiological tissue-protective protease inhibitor. This suggests a direct causal link between AAT inhibition of NE and preservation of histone-mediated antimicrobial activity. These results help better understand the complex and, at times, contradictory observations of in vivo antimicrobial effects of NETs and AAT by excluding neutrophil, cytokine, and chemoattractant contributions.
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Antiinfecciosos , Trampas Extracelulares , Trampas Extracelulares/metabolismo , Histonas/metabolismo , Neutrófilos , Antibacterianos/farmacología , Antibacterianos/metabolismo , Antiinfecciosos/metabolismo , Antiinfecciosos/farmacología , ADN/metabolismoRESUMEN
This study analyzed the nuclease- and serum-driven degradation of millimeter-scale, circular DNA-histone mesostructures (DHMs). DHMs are bioengineered chromatin meshes of defined DNA and histone compositions designed as minimal mimetics of physiological extracellular chromatin structures, such as neutrophil extracellular traps (NETs). Taking advantage of the defined circular shape of the DHMs, an automated time-lapse imaging and image analysis method was developed and used to track DHM degradation and shape changes over time. DHMs were degraded well by 10 U/mL concentrations of deoxyribonuclease I (DNase I) but not by the same level of micrococcal nuclease (MNase), whereas NETs were degraded well by both nucleases. These comparative observations suggest that DHMs have a less accessible chromatin structure compared to NETs. DHMs were degraded by normal human serum, although at a slower rate than NETs. Interestingly, time-lapse images of DHMs revealed qualitative differences in the serum-mediated degradation process compared to that mediated by DNase I. Importantly, despite their reduced susceptibility to degradation and compositional simplicity, the DHMs mimicked NETs in being degraded to a greater extent by normal donor serum compared to serum from a lupus patient with high disease activity. These methods and insights are envisioned to guide the future development and expanded use of DHMs, beyond the previously reported antibacterial and immunostimulatory analyses, to extracellular chromatin-related pathophysiological and diagnostic studies.
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Cromatina , Trampas Extracelulares , Humanos , Cromatina/metabolismo , Histonas/metabolismo , Neutrófilos/metabolismo , Trampas Extracelulares/metabolismo , ADN/metabolismo , Desoxirribonucleasa I/metabolismoRESUMEN
BACKGROUND: Depression and anxiety are prevalent in youth populations and typically emerge during adolescence. Repetitive negative thinking (RNT) is a putative transdiagnostic mechanism with consistent associations with depression and anxiety. Targeting transdiagnostic processes like RNT for youth depression and anxiety may offer more targeted, personalised and effective treatment. METHODS: A meta-analysis was conducted to examine the effect of psychological treatments on RNT, depression and anxiety symptoms in young people with depression or anxiety, and a meta-regression to examine relationships between outcomes. RESULTS: Twenty-eight randomised controlled trials examining 17 different psychological interventions were included. Effect sizes were small to moderate across all outcomes (Hedge's g depression = -0.47, CI -0.77 to -0.17; anxiety = -0.42, CI -0.65 to -0.20; RNT = -0.45, CI -0.67 to -0.23). RNT-focused and non-RNT focused approaches had comparable effects; however, those focusing on modifying the process of RNT had significantly larger effects on RNT than those focusing on modifying negative thought content. Meta-regression revealed a significant relationship between RNT and depression outcomes only across all intervention types and with both depression and anxiety for RNT focused interventions only. CONCLUSION: Consistent with findings in adults, this review provides evidence that reducing RNT with psychological treatment is associated with improvements in depression and anxiety in youth. Targeting RNT specifically may not lead to better outcomes compared to general approaches; however, focusing on modifying the process of RNT may be more effective than targeting content. Further research is needed to determine causal pathways.
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Depresión , Pesimismo , Adulto , Humanos , Adolescente , Depresión/psicología , Pesimismo/psicología , Ansiedad/psicología , Trastornos de Ansiedad/terapia , Trastornos de Ansiedad/psicología , CogniciónRESUMEN
This study describes a novel, neutralizing monoclonal antibody (mAb), 11D7, discovered by mouse immunization and hybridoma generation, against the parental Wuhan-Hu-1 RBD of SARS-CoV-2. We further developed this mAb into a chimeric human IgG and recombinantly expressed it in plants to produce a mAb with human-like, highly homogenous N-linked glycans that has potential to impart greater potency and safety as a therapeutic. The epitope of 11D7 was mapped by competitive binding with well-characterized mAbs, suggesting that it is a Class 4 RBD-binding mAb that binds to the RBD outside the ACE2 binding site. Of note, 11D7 maintains recognition against the B.1.1.529 (Omicron) RBD, as well neutralizing activity. We also provide evidence that this novel mAb may be useful in providing additional synergy to established antibody cocktails, such as Evusheld™ containing the antibodies tixagevimab and cilgavimab, against the Omicron variant. Taken together, 11D7 is a unique mAb that neutralizes SARS-CoV-2 through a mechanism that is not typical among developed therapeutic mAbs and by being produced in ΔXFT Nicotiana benthamiana plants, highlights the potential of plants to be an economic and safety-friendly alternative platform for generating mAbs to address the evolving SARS-CoV-2 crisis.
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COVID-19 , Terapéutica Combinada de Anticuerpos , Humanos , Animales , Ratones , SARS-CoV-2 , Anticuerpos Monoclonales , Anticuerpos Neutralizantes , Anticuerpos AntiviralesAsunto(s)
Artritis Reumatoide , Microbiota , Ensayos Clínicos como Asunto , Dieta , Humanos , MetabolomaRESUMEN
We report 3 patients who presented with abnormal pancreatic contents that were initially nondiagnostic but were eventually found to have urate crystal deposition consistent with pancreatic tophaceous gout. Our first case involved an ICU patient who had fever of unknown origin and refractory pancreatic pseudocyst. The other 2 patients presented with abdominal pain associated with a pancreatic mass which mimicked malignancy. After further investigation, we were able to identify pancreatic tophaceous gout as the diagnosis. Initiation of therapy led to resolution of pancreatitis in the first patient and resolution of abdominal pain and decrease in size of a pancreatic mass in the other 2 patients. The recognition of clinical gout involving the pancreas has important implications in the evaluation and care of these patients who are at high risk for tophaceous gout. In addition, the importance of specimen preparation that preserves crystals for viewing is discussed.
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OBJECTIVE: Traditional nondigital methods of participant recruitment for clinical research studies in rheumatology can be costly and inefficient, particularly for recruitment of underserved populations. We aimed to address this need by evaluating two methods of online recruitment to an observational cohort of individuals at risk for rheumatoid arthritis, namely web and Facebook advertisements. METHODS: A 3-month countywide web-based recruitment campaign was conducted consisting of text and image-based advertisements. Similar advertisements were subsequently displayed on Facebook, initially in English for 5 months and later in Spanish for an additional 3 months. Individuals who clicked on advertisements were directed to a website landing page containing study information and could contact study personnel to schedule testing for anti-cyclic citrullinated peptide-3 (CCP3). The primary outcome measure for each campaign was the click-through rate. RESULTS: During the web campaign, 413,289 advertisement impressions were displayed, resulting in 428 clicks (click-through rate 0.10%) and only one screened participant. During the English Facebook campaign, 724,815 advertisements were displayed with 6765 clicks (click-through rate 0.93%) and 43 screened participants, significantly greater than the web campaign (P < 0.001). During the Spanish advertisement campaign, 255,730 Spanish advertisements were displayed, resulting in a click-through rate of 2.09% and 24 screened participants, a significantly higher rate than English advertisements. Of participants recruited through social media, 94% were female and 29.8% were Spanish speakers. CONCLUSION: Facebook advertisements were superior to web advertisements for participant recruitment. Spanish Facebook advertisements had a greater click-through rate than English Facebook advertisements. Facebook was an effective recruitment method, particularly for Spanish speakers.
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BACKGROUND: While many COVID-19 studies focus on acute effects of the infection, few examine the intermediate and long-term sequelae of the illness. Studies have shown that a good portion of patients have chronic effects in several body systems for several months or longer. Such effects can potentially adversely impact pilot performance in flight. We sought to determine the long-term effects of COVID-19 infection, how such effects can affect pilot performance, and how to best evaluate pilots for aeromedical flight clearance.METHODS: We used the PubMed literature search engine to review peer-reviewed articles that focused on the intermediate and long-term effects of COVID-19 infection. Chronic signs and symptoms were subdivided based on the particular body organ system affected. Merging information obtained from case reviews, article reviews, and aeromedical standards, we created a risk stratification guide to assist with the aeromedical disposition of affected pilots.RESULTS: Long-term effects of COVID-19 infection can last for several months or longer. The most common effects are fatigue, weakness, pulmonary diffusion defects, depression, and anxiety.DISCUSSION: This review article focuses on the most common intermediate- and long-term COVID-19 conditions of aeromedical significance and the corresponding course of actions recommended for the aeromedical examiner. Aeromedical evaluation should take into consideration factors related to the pilot, aircraft type, and specific aviation environment. Such evaluation may include diagnostic testing, medical specialist consultation, preflight simulation in an altitude chamber, human centrifuge testing, and/or a flight simulator checkride.Ko SY, Nguyen NK, Lee CL, Lee LA, Nguyen KUT, Lee EC. Aeromedical implications of long-term COVID-19 sequelae. Aerosp Med Hum Perform. 2021; 92(11):898-907.
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Medicina Aeroespacial , Ambulancias Aéreas , COVID-19 , Pilotos , Humanos , SARS-CoV-2RESUMEN
Neutrophil extracellular traps (NETs) is an antimicrobial cobweb-structured material produced by immune cells for clearance of pathogens in the body, but paradoxically associated with biofilm formation and exacerbated lung infections. To provide a better materials perspective on the pleiotropic roles played by NETs at diverse compositions/concentrations, a NETs-like material (called 'microwebs', abbreviated as µwebs) is synthesized for decoding the antimicrobial activity of NETs against Staphylococcus aureus in infection-relevant conditions. We show that µwebs composed of low-to-intermediate concentrations of DNA-histone complexes successfully trap and inhibit S. aureus growth and biofilm formation. However, with growing concentrations and histone proportions, the resulting microwebs appear gel-like structures accompanied by reduced antimicrobial activity that can even promote formation of S. aureus biofilms. Our simplified model of NETs provides a materials-based evidence on NETs-relevant pathology in the development of biofilms.
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CASE: We present the case of an otherwise healthy 77-year-old male retired firefighter and recreational pheasant hunter who presented with recurrent symptoms of carpal tunnel syndrome and tenosynovitis because of Mycobacterium szulgai. He was initially treated unsuccessfully for a presumed seronegative rheumatologic flare, followed by surgical diagnosis and treatment including revision carpal tunnel release with tenosynovectomy, and a secondary debridement and wound closure. His symptoms resolved after several months of multidrug antibiotic therapy with only mild residual median nerve deficit. CONCLUSION: Nontuberculous Mycobacterium infections of the upper extremity are extremely rare and challenging to diagnose/treat. This report highlights diagnostic and surgical challenges in this rarely reported infection.
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Síndrome del Túnel Carpiano , Infecciones por Mycobacterium no Tuberculosas , Tenosinovitis , Anciano , Síndrome del Túnel Carpiano/etiología , Síndrome del Túnel Carpiano/cirugía , Humanos , Masculino , Nervio Mediano/cirugía , Infecciones por Mycobacterium no Tuberculosas/diagnóstico , Infecciones por Mycobacterium no Tuberculosas/tratamiento farmacológico , Micobacterias no Tuberculosas , Tenosinovitis/diagnósticoRESUMEN
AIM: Diagnosing and monitoring vascular activity in giant cell arteritis (GCA) is difficult due to the paucity of specific serological biomarkers. We assessed the utility of 8 novel biomarkers in an inception cohort of newly suspected GCA patients. METHOD: Consecutive patients were enrolled between May 2016 and December 2017. Serum was collected within 72 hours of commencing corticosteroids and at 6 months. It was analyzed for levels of intra-cellular adhesion molecule 1, vascular endothelial growth factor (VEGF), pentraxin 3, von Willebrand factor and procalcitonin (5-plex R&D Systems multiplex assay) and interleukin (IL)6, IL12 and interferon-γ (high-sensitivity 3-plex ProcartaPlex multiplex assay). A GCA specific positron emission tomography / computed tomography (PET/CT) scan was performed at enrolment with uptake in each vascular territory graded and summed to derive a total vascular score (TVS). RESULTS: For the 63 patients enrolled, 12 (19%) had a final diagnosis of biopsy-positive GCA and a further 9 had a clinical diagnosis of biopsy-negative GCA. None of the 8 biomarkers was significantly higher in GCA patients compared with those with alternative diagnoses, or demonstrated a positive correlation with the PET/CT TVS. This was in contrast to the C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) which were higher in the biopsy-positive GCA cohort (P < .04) and showed weak positive correlations with the TVS (correlation coefficient 0.34, P < .01). Procalcitonin did not distinguish between GCA and infection. Concentrations of CRP, ESR, VEGF and pentraxin 3 decreased between diagnosis and 6 months in GCA patients. CONCLUSION: This study did not identify new serological biomarkers to assist in diagnosing or assessing the vasculitis burden in GCA.
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Biomarcadores/sangre , Arteritis de Células Gigantes/diagnóstico , Corticoesteroides/uso terapéutico , Anciano , Biopsia , Proteína C-Reactiva , Ensayo de Inmunoadsorción Enzimática , Fluorodesoxiglucosa F18/metabolismo , Arteritis de Células Gigantes/sangre , Arteritis de Células Gigantes/tratamiento farmacológico , Arteritis de Células Gigantes/patología , Humanos , Interferón gamma , Interleucina-12 , Interleucina-6/sangre , Masculino , Persona de Mediana Edad , Tomografía Computarizada por Tomografía de Emisión de Positrones , Polipéptido alfa Relacionado con Calcitonina/metabolismo , Sensibilidad y Especificidad , Componente Amiloide P Sérico , Factor A de Crecimiento Endotelial Vascular/sangre , Factor de von Willebrand/metabolismoRESUMEN
AIM: Positron emission tomography/computed tomography (PET/CT) can detect cranial and large vessel inflammation in giant cell arteritis (GCA). We aimed to determine the change and significance of vascular activity at diagnosis and 6 months. METHOD: Newly diagnosed GCA patients underwent time-of-flight fluorine-18-fluoro-2-deoxyglucose PET/CT from vertex to diaphragm within 72 hours of commencing corticosteroids and were followed for 12 months. A 6 months scan was performed in patients with inflammatory features on biopsy or CT aortitis. Vascular uptake was visually graded by 2 blinded readers across 18 artery segments from 0 (no increased uptake) to 3 (very marked uptake). Scores were summed to give a total vascular score (TVS). RESULTS: We enrolled 21 GCA patients and 15 underwent the serial scan. Twelve (57%) patients experienced a relapse and 5 of these had ischemic features of vision disturbance, jaw or limb claudication. The median TVS fell from 14 (interquartile range [IQR] 4-24) at baseline to 5 (IQR 0-10) at 6 months (P < .01) with reduction in both cranial and large artery scores. While the overall relapse rate was similar between patients with a high (≥10) and low baseline TVS, patients with high scores were numerically more likely to experience an ischemic relapse (33% vs 11%, P = .34). Five out of 15 patients had persistent uptake in at least 1 vessel on the serial PET/CT but none experienced a subsequent relapse. CONCLUSION: Vascular activity decreased in cranial and large arteries between diagnosis and 6 months. Persistent activity did not predict subsequent relapse.
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Arteritis de Células Gigantes/diagnóstico por imagen , Tomografía Computarizada por Tomografía de Emisión de Positrones , Corticoesteroides/uso terapéutico , Anciano , Anciano de 80 o más Años , Femenino , Fluorodesoxiglucosa F18/administración & dosificación , Arteritis de Células Gigantes/tratamiento farmacológico , Humanos , Masculino , Nueva Gales del Sur , Valor Predictivo de las Pruebas , Estudios Prospectivos , Radiofármacos/administración & dosificación , Recurrencia , Factores de Tiempo , Resultado del TratamientoRESUMEN
OBJECTIVES: There is uncertainty if varicella zoster virus (VZV) triggers GCA. This is based on discordant reports of VZV detection in GCA temporal artery biopsies. We conducted a multimodal evaluation for VZV in the inception Giant Cell Arteritis and PET Scan (GAPS) cohort. METHODS: Consecutive patients who underwent temporal artery biopsy for suspected GCA were clinically reviewed for active and past VZV infection and followed for 6 months. Serum was tested for VZV IgM and IgG. Temporal artery biopsy (TAB) sections were stained for VZV antigen using the VZV Mouse Cocktail Antibody (Cell Marque, Rocklin, CA, USA). A selection of GCA and control tissues were stained with the VZV gE antibody (Santa Cruz Biotechnology, Dallas, TX, USA), which was used in previous studies. RESULTS: A total of 58 patients met inclusion criteria, 12 (21%) had biopsy-positive GCA and 20 had clinically positive GCA. None had herpes zoster at enrolment and only one patient developed a VZV clinical syndrome (zoster ophthalmicus) on follow-up. There was no difference in VZV exposure between GCA and non-GCA patients. None of the 53 patients who had VZV serology collected had positive VZV IgM antibodies. VZV antigen was not convincingly demonstrated in any of the TAB specimens; 57 TABs stained negative and 1 stained equivocally positive. The Santa Cruz Biotechnology VZV antibody exhibited positive staining in a range of negative control tissues, questioning its specificity for VZV antigen. CONCLUSION: The absence of active infection markers argues against VZV reactivation being the trigger for GCA. Non-specific immunohistochemistry staining may account for positive findings in previous studies.
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Arteritis de Células Gigantes/virología , Herpesvirus Humano 3/aislamiento & purificación , Arterias Temporales/patología , Infección por el Virus de la Varicela-Zóster/diagnóstico , Anciano , Anciano de 80 o más Años , Femenino , Arteritis de Células Gigantes/patología , Humanos , Masculino , Persona de Mediana Edad , Infección por el Virus de la Varicela-Zóster/patologíaRESUMEN
CONTEXT: Uncertainty of antibiotic prophylaxis of type III open orthopedic fractures still exists. Controversy remains as using cefazolin as a single agent or the addition of an aminoglycoside for broader coverage to prevent infection. AIMS: The aim of the study was to determine if the combination of cefazolin and an aminoglycoside reduced infections compared with cefazolin alone. SUBJECTS AND METHODS: This was a retrospective study inclusive of patients with type III open fracture admitted between January 1, 2010, and August 31, 2014 at a level 1 trauma center, who were prophylactically treated with cefazolin alone or cefazolin and an aminoglycoside. STATISTICAL ANALYSIS USED: All analyses were performed using Microsoft Excel 2010. Chi-square or Fisher's exact tests were used for categorical data and Wilcoxon rank-sum test for skewed continuous data. Logistic regression analysis was performed on all confounding variables with P < 0.1. RESULTS: A significantly higher percentage in the combination group developed infection (6/15 [40%] vs. 8/53 [15.1%], P = 0.035). There was a trend toward a higher odds of infection in the combination group (odds ratio: 2.99, 95% confidence interval: 0.79-11.33, P = 0.107). Infection rates due to multidrug-resistant bacteria were statistically higher with the combination group (3/15 [20%] vs. 1/53 [1.9%], P = 0.046). There were no statistically significant differences in 30-day mortality, 1-year readmission rates due to fracture complication, or length of hospital stay. CONCLUSIONS: The results suggest that the addition of an aminoglycoside to cefazolin may not be necessary to prevent infection.
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May is a newly isolated myophage that infects multidrug-resistant strains of Klebsiella pneumoniae, a pathogen that is associated with antibiotic-resistant infections in humans. The genome of May has been shown to be similar to that of phage Vi01.
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The use of biochemical signaling to derive smooth muscle cells (SMCs) from mesenchymal stem cells (MSCs) has been explored, but the induction of a fully functional SMC phenotype remains to be a major challenge. Cell morphology has been shown to regulate MSC differentiation into various lineages, including SMCs. We engineered substrates with microgrooves to induce cell elongation to study the mechanism underlying the MSC shape modulation in SMC differentiation. In comparison to those on flat substrates, MSCs cultured on engineered substrates were elongated with increased aspect ratios for both cell body and nucleus, as well as augmented cytoskeletal tensions. Biochemical studies indicated that the microgroove-elongated cells expressed significantly higher levels of SMC markers. MicroRNA analyses showed that up-regulation of miR-145 and the consequent repression of KLF4 in these elongated cells promoted MSC-to-SMC differentiation. Rho/ROCK inhibitions, which impair cytoskeletal tension, attenuated cell and nuclear elongations and disrupted the miR-145/KLF4 regulation for SMC differentiation. Furthermore, cell traction force measurements showed that miR-145 is essential for the functional contractility in the microgroove-induced SMC differentiation. Collectively, our findings demonstrate that, through a Rho-ROCK/miR-145/KLF4 pathway, the elongated cell shape serves as a decisive geometric cue to direct MSC differentiation into functional SMCs.