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BACKGROUND: Randomised trials are essential to reliably assess medical interventions. Nevertheless, interpretation of such studies, particularly when considering absolute effects, is enhanced by understanding how the trial population may differ from the populations it aims to represent. METHODS: We compared baseline characteristics and mortality of RECOVERY participants recruited in England (n = 38,510) with a reference population hospitalised with COVID-19 in England (n = 346,271) from March 2020 to November 2021. We used linked hospitalisation and mortality data for both cohorts to extract demographics, comorbidity/frailty scores, and crude and age- and sex-adjusted 28-day all-cause mortality. RESULTS: Demographics of RECOVERY participants were broadly similar to the reference population, but RECOVERY participants were younger (mean age [standard deviation]: RECOVERY 62.6 [15.3] vs reference 65.7 [18.5] years) and less frequently female (37% vs 45%). Comorbidity and frailty scores were lower in RECOVERY, but differences were attenuated after age stratification. Age- and sex-adjusted 28-day mortality declined over time but was similar between cohorts across the study period (RECOVERY 23.7% [95% confidence interval: 23.3-24.1%]; vs reference 24.8% [24.6-25.0%]), except during the first pandemic wave in the UK (March-May 2020) when adjusted mortality was lower in RECOVERY. CONCLUSIONS: Adjusted 28-day mortality in RECOVERY was similar to a nationwide reference population of patients admitted with COVID-19 in England during the same period but varied substantially over time in both cohorts. Therefore, the absolute effect estimates from RECOVERY were broadly applicable to the target population at the time but should be interpreted in the light of current mortality estimates. TRIAL REGISTRATION: ISRCTN50189673- Feb. 04, 2020, NCT04381936- May 11, 2020.
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COVID-19 , Hospitalização , Humanos , COVID-19/mortalidade , COVID-19/epidemiologia , Masculino , Inglaterra/epidemiologia , Feminino , Pessoa de Meia-Idade , Idoso , Hospitalização/estatística & dados numéricos , Idoso de 80 Anos ou mais , SARS-CoV-2 , Comorbidade , Adulto , Ensaios Clínicos Controlados Aleatórios como Assunto , Fragilidade/epidemiologia , Fragilidade/diagnóstico , Fragilidade/mortalidadeRESUMO
ANCA-associated vasculitides (AAV) are rare autoimmune diseases causing inflammation and damage to small blood vessels. New autoantibody biomarkers are needed to improve the diagnosis and treatment of AAV patients. In this study, we aimed to profile the autoantibody repertoire of AAV patients using in-house developed antigen arrays to identify previously unreported antibodies linked to the disease per se, clinical subgroups, or clinical activity. A total of 1743 protein fragments representing 1561 unique proteins were screened in 229 serum samples collected from 137 AAV patients at presentation, remission, and relapse. Additionally, serum samples from healthy individuals and patients with other type of vasculitis and autoimmune-inflammatory conditions were included to evaluate the specificity of the autoantibodies identified in AAV. Autoreactivity against members of the kinesin protein family were identified in AAV patients, healthy volunteers, and disease controls. Anti-KIF4A antibodies were significantly more prevalent in AAV. We also observed possible associations between anti-kinesin antibodies and clinically relevant features within AAV patients. Further verification studies will be needed to confirm these findings.
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Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos , Autoanticorpos , Humanos , Cinesinas , Biomarcadores , Proteínas/uso terapêutico , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/diagnósticoRESUMO
Polymers are extensively used in various industries due to their versatility, durability and cost-effectiveness. To ensure functionality and longevity, polymer parts must have sufficient strength to endure external forces without deformation or breakage. Traditional approaches to increasing part strength involve adding more material; however, balancing strength to weight relationships is challenging. This paper explorers the viability of manufacturing lightweight components using a microcellular foaming polymer. Microcellular foaming has emerged as a helpful tool to achieve an optimal strength-to-weight ratio; offering advantages such as lightweight, improved mechanical properties, reduced material usage, better insulation and improved cost-effectiveness. It can also contribute to improved fuel efficiency and reduced carbon emissions, making them environmentally favourable. The combination of additive manufacturing (AM) and microcellular foaming has opened new possibilities for design innovation. This text highlights the challenges and efforts in incorporating foaming techniques into 3D printing processes, specifically fused filament fabrication (FFF). This study reveals that microcellular polymers are a viable option when balancing part strength and weight. The experiments completed during the formulation of this paper demonstrated that lightweight LW-PLA parts were significantly lighter than standard PLA parts and that a design of experiments approach can be used to optimise strength properties and provide insights into optimising manufacturability. Microcellular polymers present an opportunity for lighter and stronger 3D printed parts, offering potential energy and material savings for sustainable manufacturing practices.
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BACKGROUND: Traumatic lumbosacral instability is a rare but potentially devastating injury. These injuries are frequently associated with neurologic injury and often result in long-term disability. Despite their severity, radiographic findings can be subtle, and multiple reports exist in which these injuries were not recognized on initial imaging. Transverse process fractures, high-energy mechanisms, and other injury features have been suggested as indications for advanced imaging, which has a high degree of sensitivity in detecting unstable injuries. CASE PRESENTATION: A 21-year-old man presented to our level I trauma center after being ejected in a rollover motor vehicle collision. He sustained multiple injuries, including multiple lumbar transverse process fractures and a unilateral superior articular facet fracture of S1. PRIMARY OUTCOMES: Initial supine computed tomography (CT) images showed no displacement of the fracture and no listhesis or instability. Subsequent upright imaging in a brace, however, demonstrated significant displacement of the fracture with dislocation of the contralateral L5-S1 facet joint and significant anterolisthesis. The patient underwent open posterior reduction and stabilization of L4-S1 followed by L5-S1 anterior lumbar interbody fusion. The patient demonstrated excellent alignment on postoperative imaging. At 3 months postoperatively, he had returned to work, was ambulating without assistance, and reported minimal back discomfort and no lower extremity pain, numbness, or weakness. CONCLUSION: This case serves as a warning that supine CT imaging alone may not be sufficient to rule out unstable lumbar spine injuries, such as traumatic L5-S1 instability, and that upright radiographs in these potentially unstable injuries may represent a hazard to patients. Fractures involving the pedicle, pars, or facet joints as well as multiple transverse process fractures and/or a high-energy mechanism of injury should all raise suspicion of instability and warrant additional imaging. CLINICAL RELEVANCE: This article provides guidance on approaching treatment for patients with potential traumatic lumbosacral instability.
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Fused Filament Fabrication (FFF) 3D printing is an additive technology used to manufacture parts. Used in the engineering industry for prototyping polymetric parts, this disruptive technology has been adopted commercially and there are affordable printers on the market that allow for at-home printing. This paper examines six methods of reducing the energy and material consumption of 3D printing. Using different commercial printers, each approach was investigated experimentally, and the potential savings were quantified. The modification most effective at reducing energy consumption was the hot-end insulation, with savings of 33.8-30.63%, followed by the sealed enclosure, yielding an average power reduction of 18%. For material, the most influential change was noted using 'lightning infill', reducing material consumption by 51%. The methodology includes a combined energy- and material-saving approach in the production of a referenceable 'Utah Teapot' sample object. Using combined techniques on the Utah Teapot print, the material consumption was reduced by values between 55.8% and 56.4%, and power consumption was reduced by 29% to 38%. The implementation of a data-logging system allowed us to identify significant thermal management and material usage opportunities to minimise power consumption, providing solutions for a more positive impact on the sustainable manufacturing of 3D printed parts.
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Pauci-immune focal necrotizing glomerulonephritis (piFNGN) involves asynchronous onset and progression of injurious lesions in biopsies. Pathologists can describe this heterogeneity within a biopsy, but translating the information into prognostic or expression analyses is challenging. Understanding the underlying molecular processes could improve treatment; however, bulk or single-cell transcriptomic analyses of dissociated tissue disregard the heterogeneity of glomerular injury. We characterize protein and mRNA expression of individual glomeruli in 20 biopsies from 18 patients with antineutrophil cytoplasmic antibody-associated piFNGN using the NanoString digital spatial profiling (DSP) platform. For this purpose, circular annotations of glomeruli were analyzed using protein, immuno-oncology RNA, and Cancer Transcriptome Atlas panels (n=120, 72, and 48 glomeruli, respectively). Histologic evaluation of glomerular patterns of injury was performed in adjacent serial sections. Expression data were processed by log2 transformation, quantile normalization, and batch adjustment. DSP revealed distinct but overlapping gene expression profiles relating to the morphological evolution of injurious lesions, including dynamic expression of various immune checkpoint regulators. Enrichment analysis indicated deregulated pathways that underline known and highlight novel potential mechanisms of disease. Moreover, by capturing individual glomeruli, DSP describes heterogeneity between and within biopsies. We demonstrate the benefit of spatial profiling for characterization of heterogeneous glomerular injury, indicating novel molecular correlates of glomerular injury in piFNGN.
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Glomerulonefrite por IGA , Glomerulonefrite , Necrose do Córtex Renal , Humanos , Glomerulonefrite/genética , Glomerulonefrite/patologia , Glomérulos Renais/química , Glomérulos Renais/patologia , Glomerulonefrite por IGA/patologia , Anticorpos Anticitoplasma de Neutrófilos/análise , Necrose do Córtex Renal/patologia , Expressão GênicaRESUMO
Management of partial hand amputations is a notable clinical challenge. Historically, myoelectric prostheses have not allowed for independent digital control, resulting in unsatisfactory function and high rejection rates among upper extremity amputees. The Starfish Procedure was developed for patients who sustained loss of multiple digits through the level of the base of the proximal phalanx or distal metacarpal. The procedure involves the pedicled transfer of 1 or more dorsal interosseous muscles to a subcutaneous location. This allows for a myoelectric sensor to capture the signals generated by these transferred muscles, thereby enabling intuitive, independent, digital prosthetic flexion and extension. In this article, we detail the relevant anatomy, indications, and technique for performing the Starfish Procedure. Given our patients' promising outcomes to date, we hope this technique paper will encourage upper extremity surgeons of all training backgrounds to perform this relatively straightforward procedure, thereby allowing patients with life-altering finger amputations to regain meaningful function by enhancing control of digital prostheses.
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Membros Artificiais , Humanos , Desenho de Prótese , Mãos , Dedos/cirurgia , Extremidade SuperiorRESUMO
Chronic recurrent multifocal osteomyelitis (CRMO) is an idiopathic autoinflammatory disease of the bone that typically occurs in children and adolescents. CRMO is characterized by recurrent periods of exacerbation and remission of symptomatic, osteolytic/sclerotic sterile bone lesions and is often a diagnosis of exclusion. Treatment consists of multimodal anti-inflammatory medication management by rheumatology and rarely involves surgery. This review summarizes the clinical presentation, pathophysiology, diagnosis, and management of this disease and highlights the role of the orthopedic surgeon. With increased familiarity with CRMO, clinicians will be able to diagnose and treat the condition in a more timely manner. [Orthopedics. 2023;46(3):e149-e155.].
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Osteomielite , Criança , Adolescente , Humanos , Osteomielite/terapia , Osteomielite/tratamento farmacológico , Diagnóstico Diferencial , Doença CrônicaRESUMO
Small extracellular vesicles (sEV) purified from blood have great potential clinically as biomarkers for systemic disease; however interpretation is complicated by release of sEV ex vivo after blood taking. To quantify the problem and devise ways to minimise it, we characterised sEV in paired serum, plasma and platelet poor plasma (PPP) samples from healthy donors. Immunoblotting showed twofold greater abundance of CD9 in sEV fractions from fresh serum than from fresh plasma or PPP. MACSPlex confirmed this, and showed that proteins expressed on platelet sEV, either exclusively (CD41b, CD42a and CD62P) or more widely (HLA-ABC, CD24, CD29 and CD31) were also twofold more abundant; by contrast non-platelet proteins (including CD81) were no different. Storage of plasma (but not serum) increased abundance of platelet and selected leukocyte sEV proteins to at least that of serum, and this could be recapitulated by activating cells in fresh plasma by Ca2+, an effect abrogated in PPP. This suggests that a substantial proportion of sEV in serum and stored plasma were generated ex vivo, which is not the case for fresh plasma or PPP. Thus we provide strategies to minimise ex vivo sEV generation and criteria for identifying those that were present in vivo.
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INTRODUCTION: Unsolicited patient complaints (UPCs) about surgeons correlate with surgical complications and malpractice claims. Analysis of UPCs in orthopedics is limited. METHODS: Patient complaint reports recorded at 36 medical centers between January 1, 2015 and December 31, 2018 were coded using a previously validated coding algorithm Patient Advocacy Reporting System. RESULTS: A total of 33,174 physicians had 4 consecutive years of data across the 36 participating medical centers and met other inclusion criteria. CONCLUSIONS: Orthopedists with high numbers of UPCs may benefit from being made aware of their elevated risk status in ways that invite reflection on underlying causes.
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Procedimentos Ortopédicos , Ortopedia , Humanos , Procedimentos Ortopédicos/efeitos adversos , Satisfação do Paciente , Relações Médico-Paciente , Estudos RetrospectivosRESUMO
Autophagy is a central mechanism for maintaining cellular homeostasis in health and disease as it provides the critical energy through the breakdown and recycling of cellular components and molecules within lysosomes. One of the three types of autophagy is chaperone-mediated autophagy (CMA), a degradation pathway selective for soluble cytosolic proteins that contain a targeting motif related to KFERQ in their amino acid sequence. This motif marks them as CMA substrate and is, in the initial step of CMA, recognised by the heat shock protein 70 (Hsc70). The protein complex is then targeted to the lysosomal membrane where the interaction with the splice variant A of the lysosomal-associated membrane protein-2 (LAMP-2A) results in its unfolding and translocation into the lysosome for degradation. Altered levels of CMA have been reported in a wide range of pathologies including many cancer types that upregulate CMA as part of the pro-tumorigenic phenotype, while in aging a decline is observed and associated with a decrease of LAMP-2 expression. The potential of altering CMA to modify a physiological or pathological process has been firmly established through genetic manipulation in animals and chemical interference with this pathway. However, its use for therapeutic purposes has remained limited. Compounds used to target and modify CMA have been applied successfully to gain a better understanding of its cellular mechanisms, but they are mostly not specific, also influence other autophagic pathways and are associated with high levels of toxicity. Here, we will focus on the molecular mechanisms involved in CMA regulation as well as on potential ways to intersect them, describe modulators successfully used, their mechanism of action and therapeutic potential. Furthermore, we will discuss the potential benefits and drawbacks of CMA modulation in diseases such as cancer.
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Autofagia Mediada por Chaperonas , Neoplasias , Animais , Proteínas de Choque Térmico HSC70/metabolismo , Lisossomos/metabolismo , Chaperonas Moleculares/metabolismo , Neoplasias/metabolismoRESUMO
The frequency and intensity of cyanobacterial blooms is increasing worldwide. Multiple factors are implicated, most of which are anthropogenic. New Zealand provides a useful location to study the impacts of human settlement on lake ecosystems. The first humans (Polynesians) arrived about 750 years ago. Following their settlement, there were marked landscape modifications which intensified after European settlement about 150 years ago. The aims of this study were to reconstruct cyanobacterial communities in six lakes over the last 1000 years and explore key drivers of change. Cyanobacterial environmental DNA was extracted from sediment cores and analysed using metabarcoding and droplet digital PCR. Cyanobacteria, including potentially toxic or bloom forming species, were already present in these lakes prior to human arrival, however their overall abundance was low. Total cyanobacteria abundance and richness increased in all lakes after European settlement but was very pronounced in four lakes, where bloom-forming taxa became dominant. These shifts occurred concomitant with land-use change. The catchment of one deteriorated lake is only moderately modified, thus the introduction of non-native fish is posited as the key factor driving this change. The paleolimnological approach used in this study has enabled new insights into timing and potential causes of changes in cyanobacterial communities.
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Cianobactérias , Lagos , Animais , Cianobactérias/genética , Ecossistema , Eutrofização , Humanos , Lagos/microbiologia , Nova Zelândia , Reação em Cadeia da PolimeraseRESUMO
BACKGROUND: Elbow fractures are the most common pediatric fractures requiring operative treatment. Although recent reports have suggested that the COVID-19 pandemic has markedly reduced the incidence of pediatric fractures, no study has specifically evaluated the impact on pediatric elbow fractures. This study aimed to evaluate changes in the incidence, severity, and resource utilization for managing pediatric elbow fractures during the COVID-19 pandemic, compared with prepandemic years. METHODS: A prepandemic (2007 to 2017) cohort and a COVID-19 pandemic period (March 2020 to March 2021) cohort of pediatric elbow injuries from a single tertiary hospital were retrospectively examined and compared. Exclusion criteria included outside treatment or lack of diagnosis by an orthopedist. Presentation information, injury patterns, transport, and treatment requirements were collected. RESULTS: Although the incidence of pediatric elbow fractures and rate of neurovascular injury were comparable, seasonal patterns were not sustained and the rate of fracture displacement was found to be significantly elevated in the COVID-19 period compared with nonpandemic years. Likewise, marked changes to where patients first presented (emergency department vs. Clinic), how the patients were transported, and the distance traveled for care were observed. Specifically, patients were more likely to present to the clinic, were more likely to self-transport instead of using emergency medical service transportation, and traveled a greater distance for care, on average. Aligning with these changes, the resources utilized for the treatment of pediatric elbow fracture markedly changed during the COVID-19 period. This study found that there was an increase in the overall number of surgeries performed, the total operative time required to treat elbow fractures, and the number of patients requiring admission during the COVID-19 period. CONCLUSIONS: These data provide a contrasting viewpoint to prior reports, illustrating that the incidence of elbow fractures remained consistent during the COVID-19 period, whereas the operative volume and need for hospital admission increased compared with years prior. Furthermore, this study demonstrated how the COVID-19 pandemic altered the interface between pediatric patients with elbow fractures and our institution regarding the location of presentation and transportation. LEVEL OF EVIDENCE: Level III-retrospective cohort study.
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Traumatismos do Braço , COVID-19 , Fraturas Ósseas , COVID-19/epidemiologia , Criança , Fraturas Ósseas/epidemiologia , Fraturas Ósseas/terapia , Humanos , Incidência , Pandemias , Estudos Retrospectivos , Lesões no CotoveloRESUMO
Background: Prosthetic hip dislocation remains one of the most frequent complications following total hip replacement. Dislocations are predominantly managed by a closed reduction in the emergency department (ED) or the operating room (OR). This study aimed to evaluate how the location of an initial closed reduction attempt impacts a patient's course of care including length of stay (LOS) and cost of care. Material and methods: A retrospective chart review was performed on all patients presenting to a single ED with a unilateral prosthetic hip dislocation from 2009 to 2019. A total of 108 patients were identified. Data collected included patient demographics, ED/hospital course, and hospital charges. Results: Seventy-four patients (69%) had initial reduction attempted in the ED (65/74, 88% were successful), while 34 patients (31%) went directly to OR (100% successful with closed reduction). Failed closed reduction in ED or direct to OR resulted in a greater LOS and rate of placement to a skilled nursing facility following discharge. Median hospital charges for successful ED reduction were $6,837, while failed ED closed reduction or direct to OR resulted in median charges of $27,317 and $20,481, respectively. Conclusion: Many patients successfully underwent closed reduction in the ED, and there was no difference in complications, independent of where the reduction was first performed. Patients undergoing reduction in the OR had greater LOS and cost of care, independent of whether a reduction attempt was performed and failed in the ED, than those successfully reduced in the ED.
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BACKGROUND: Nonaccidental trauma (NAT) is a rising source of morbidity and mortality in the pediatric population. Fractures are often the first cause for presentation to health care providers in the case of NAT but can be misidentified as accidental. Given that elbow fractures are the most common accidental injuries among pediatric patients, they are not traditionally associated with NAT. This study aims to determine the prevalence of NAT among elbow fractures and identify common features in nonaccidental elbow fractures. METHODS: Current Procedural Terminology (CPT) codes were used to retrospectively identify all pediatric (0 to 17) elbow fractures at a single, tertiary children's hospital between 2007 and 2017. Among these, all fractures for which an institutional child abuse evaluation team was consulted were identified. The medical record was then used to determine which of these fractures were due to NAT. Standard injury radiographs of all victims of NAT as well as all patients under 1 year of age were blinded and radiographically evaluated for fracture type by a pediatric orthopaedic surgeon. RESULTS: The prevalence of nonaccidental elbow fractures across the 10-year study period was 0.4% (N=18). However, the prevalence of nonaccidental elbow fractures in those patients below 1 year of age was markedly higher at 30.3% (10/33). Among all elbow fractures in patients below 1 year of age, supracondylar humerus fractures were the most common fracture type (19/33, 57.6%), yet transphyseal fractures (6/33, 18.1%) were most commonly the result of NAT (5/6, 83.3%). In children over 1 year of age, fracture type was not an indicator of NAT. CONCLUSIONS: The vast majority of pediatric elbow fractures (99.6%) are accidental. However, certain factors, namely age below 1 year and transphyseal fractures increase the likelihood that these fractures may be a result of NAT. LEVEL OF EVIDENCE: Level IV: retrospective case series.
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Maus-Tratos Infantis , Fraturas do Úmero , Acidentes , Criança , Maus-Tratos Infantis/diagnóstico , Cotovelo , Humanos , Fraturas do Úmero/diagnóstico por imagem , Fraturas do Úmero/epidemiologia , Lactente , Estudos RetrospectivosRESUMO
STUDY DESIGN: Retrospective analysis on prospectively collected data. OBJECTIVE: The aim of this study was to construct a clinical prediction model for 90-day mortality in elderly patients with traumatic spine injuries. SUMMARY OF BACKGROUND DATA: Spine trauma in the elderly population is increasing. Comparing elderly spine trauma patients to younger patients with similar injuries proves challenging due to the extensive comorbidities and frailty found in the elderly. There is a paucity of evidence to predict survival of elderly patients following traumatic spinal injuries. METHODS: All patients 65+ with spine trauma presenting to a level I trauma center from 2010 to 2019 were reviewed from a prospectively maintained trauma registry. Retrospective chart review was performed to record injury, frailty scores, comorbidities, presence of spinal cord injury, imaging evidence of sarcopenia and osteopenia, mortality, and complications. We preselected 13 variables for our multivariable logistic regression model: hypotension on admission, gender, marital status, age, max Abbreviated Injury Scale, Modified Frailty Index, surgical treatment, hematocrit, white blood count, spinal cord injury, closed head injury, injury level and presence of high energy mechanism. The performance of the prediction model was evaluated using a concordance index and calibration plot. The model was internally validated via bootstrap approach. RESULTS: Over the 9-year period, 1746 patients met inclusion criteria; 359 (20.6%) patients died within 90 days after presenting with spine trauma. The most important predictors for 90-day mortality were age, hypotension, closed head injury, max Abbreviated Injury Scale and hematocrit. There was an optimism-corrected C-index of 0.77. A calculator was created to predict a personalized mortality risk. CONCLUSION: The incidence of spine trauma in elderly patients continues to increase. Previous publications described preexisting conditions that imply increased mortality, but ours is the first to develop a predictive calculator. Prospective research is planned to externally validate this model to better determine its predictive value and utility in the clinical setting.
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Fragilidade , Traumatismos Cranianos Fechados , Hipotensão , Traumatismos da Medula Espinal , Traumatismos da Coluna Vertebral , Idoso , Fragilidade/diagnóstico , Humanos , Modelos Estatísticos , Prognóstico , Estudos Prospectivos , Estudos Retrospectivos , Traumatismos da Medula Espinal/terapia , Traumatismos da Coluna Vertebral/epidemiologia , Centros de TraumatologiaRESUMO
OBJECTIVE: To evaluate the baseline level and demographic predictors of statistical literacy in orthopaedic patients who sustained traumatic injuries. DESIGN: Prospective observational. SETTING: Level 1 trauma center. PATIENTS: One hundred ninety-eight patients presenting to the orthopaedic trauma clinic. INTERVENTION: Berlin Numeracy Test (BNT) and General Health Numeracy Test-6 (GHNT-6). RESULTS: When assessed using the BNT, 67% of patients had results that placed them into the lowest quartile of objective numeracy skills. Only 3.5% of patients had results that scored in the top quartile. Our multivariate ordinal regression model demonstrated lower education level ( P = 0.01), and older age ( P = 0.03) were significant predictors of poor performance on the BNT. The mean score on the GHNT-6 was 36% (SD 30%). CONCLUSIONS: In a cohort of traumatically injured patients, poor statistical literacy was common, occurring in more than two-thirds of patient surveyed. Older age and lower levels of education were predictive of poor BNT performance and should be considered when discussing surgical options, associated risks, and likelihood of potential complications.
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Letramento em Saúde , Ortopedia , Estudos de Coortes , Escolaridade , Humanos , Inquéritos e QuestionáriosRESUMO
Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) are severe inflammatory disorders that often involve focal necrotizing glomerulonephritis (FNGN) and consequent glomerular scarring, interstitial fibrosis, and chronic kidney disease. Robust murine models of scarring in FNGN that may help to further our understanding of deleterious processes are still lacking. Here, we present a murine model of severe FNGN based on combined administration of antibodies against the glomerular basement membrane (GBM) and myeloperoxidase (MPO), and bacterial lipopolysaccharides (LPS), that recapitulates acute injury and was adapted to investigate subsequent glomerular and interstitial scarring. Hematuria without involvement of other organs occurs consistently and rapidly, glomerular necrosis and crescent formation are evident at 12 days, and consequent glomerular and interstitial scarring at 29 days after initial treatment. Using mass-spectrometric proteome analysis, we provide a detailed overview of matrisomal and cellular changes in our model. We observed increased expression of the matrisome including collagens, fibronectin, tenascin-C, in accordance with human AAV as deduced from analysis of gene expression microarrays and tissue staining. Moreover, we observed tissue infiltration by neutrophils, macrophages, T cells and myofibroblasts upon injury. Experimental inhibition of CXCR4 using AMD3100 led to a sustained histological presence of fibrin extravasate, reduced chemokine expression and leukocyte activation, but did not markedly affect ECM composition. Altogether, we demonstrate an adapted FNGN model that enables the study of matrisomal changes both in disease and upon intervention, as exemplified via CXCR4 inhibition.
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Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos , Glomerulonefrite , Receptores CXCR4 , Animais , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/genética , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/metabolismo , Anticorpos Anticitoplasma de Neutrófilos , Membrana Basal Glomerular/metabolismo , Glomerulonefrite/genética , Glomerulonefrite/patologia , Humanos , Camundongos , Peroxidase/genética , Peroxidase/metabolismo , Receptores CXCR4/antagonistas & inibidores , Receptores CXCR4/genética , Receptores CXCR4/metabolismoRESUMO
Lakes and their catchments have been subjected to centuries to millennia of exploitation by humans. Efficient monitoring methods are required to promote proactive protection and management. Traditional monitoring is time consuming and expensive, which limits the number of lakes monitored. Lake surface sediments provide a temporally integrated representation of environmental conditions and contain high microbial biomass. Based on these attributes, we hypothesized that bacteria associated with lake trophic states could be identified and used to develop an index that would not be confounded by non-nutrient stressor gradients. Metabarcoding (16S rRNA gene) was used to assess bacterial communities present in surface sediments from 259 non-saline lakes in New Zealand encompassing a range of trophic states from alpine microtrophic lakes to lowland hypertrophic lakes. A subset of lakes (n = 96) with monitoring data was used to identify indicator amplicon sequence variants (ASVs) associated with different trophic states. A total of 10,888 indicator taxa were identified and used to develop a Sediment Bacterial Trophic Index (SBTI), which signficantly correlated (r2 = 0.842, P < 0.001) with the Trophic Lake Index. The SBTI was then derived for the remaining 163 lakes, providing new knowledge of the trophic state of these unmonitored lakes. This new, robust DNA-based tool provides a rapid and cost-effective method that will allow a greater number of lakes to be monitored and more effectively managed in New Zealand and globally. The SBTI could also be applied in a paleolimnological context to investigate changes in trophic status over centuries to millennia.
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Bactérias , Lagos , Bactérias/genética , Sedimentos Geológicos , Humanos , Nova Zelândia , RNA Ribossômico 16SRESUMO
PURPOSE: The presence of soft tissue injury in pediatric supracondylar humerus fractures (SCHFs) has been shown to be an independent predictor of any neurovascular injury. Potentially expanding this concept, the specific neurovascular structure injured around the elbow is thought to be dependent upon the direction and magnitude of fracture displacement and subsequent soft tissue injury. Therefore, it was hypothesized that the bruise location following SCHF is indicative of the anatomic location of maximal soft tissue injury and therefore is a specific prognosticator of which neurovascular structure may be injured. METHODS: Retrospective chart review of all SCHFs treated at a tertiary pediatric hospital from 2007 to 2017 collected information on bruise location, neurovascular injury patterns, and outcomes. Bruise location was classified as anterior, anterolateral, anteromedial, or posterior. Injury radiographs were reviewed by a blinded pediatric orthopaedic surgeon to neurovascular structure injured. RESULTS: Of 2845 SCHFs identified, 267 (9.4%) had concomitant neurovascular injury-of which 128 (47.9%) met inclusion criteria. Among the vascular injuries, all bruising was anteromedial (28/45, 62.2%, P<0.05) or anterior (17/45, 37.8%, P>0.05). Fractures with anteromedial bruising correlated with median nerve injury (24/27, 88.9%, P<0.05), whereas fractures with anterolateral bruising correlated with radial nerve injuries (24/25, 96.0%, P<0.05). Bruising or radiographic evaluation correctly identified 60.2% and 64.1% of neurovascular injuries, respectively, whereas the combination identified 82.0% of neurovascular injuries correctly. Bruise location identified 23 neurovascular injuries not predicted by radiographic evaluation alone. CONCLUSION: Bruise location is an important physical examination finding that can be used as an adjunct to improve the diagnostic accuracy of neurovascular injury in SCHFs in conjunction with neurovascular physical examination and radiographic evaluation. SCHFs with anterior or anteromedial bruising should raise concern for vascular injury. In addition, anteromedial bruising is predictive of a median nerve injury and anterolateral bruising is predictive of radial nerve injury. This adjunct diagnostic is particularly helpful in a noncooperative child or if performed by a clinician with limited experience in diagnosing neurovascular injuries or interpreting pediatric elbow radiographs. LEVEL OF EVIDENCE: Level IV, case series.