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1.
Eur J Orthop Surg Traumatol ; 34(6): 2933-2940, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38814449

RESUMO

BACKGROUND: The use of subtalar arthroereisis as an adjunct to the surgical treatment of stage 1 flexible progressive collapsing foot deformity (PCFD) is controversial. The aim was to investigate the clinical outcomes and report the implant removal rate of subtalar arthroereisis as an adjunct for stage 1 PCFD. METHODS: A retrospective study of 212 consecutive feet undergoing operative management of stage 1 PCFD with adjunctive subtalar arthroereisis between October 2010 and April 2018. The primary outcome was the Foot and Ankle Outcome Score (FAOS). Secondary outcomes included Foot and Ankle Disability Index (FADI), Euroqol-5D-5L Index and implant removal rate. RESULTS: Post-operative clinical FAOS outcomes were collected for 153 feet (72.2%). At mean 2.5-year follow-up, the mean ± standard deviation FAOS for each domain was as follows; Pain: 81.5 ± 18.5, Symptoms: 79.5 ± 12.9, Activities of Daily Living: 82.5 ± 15.4 and Quality of Life: 64.2 ± 23.7. EQ-5D-5L Index was 0.884 ± 0.152. Pre-operative scores were available for 20 of these feet demonstrating a statistically significant improvement in all FAOS, FADI and EQ-5D-5L domains (p < 0.05). The implant removal rate for persistent sinus tarsi pain was 48.1% (n = 102). CONCLUSION: Use of a subtalar arthroereisis implant as an adjunct to conventional procedures in stage 1 flexible PCFD can result in significant improvement in pain and function. Patients should be counselled as to the relatively frequent rate of subsequent implant removal. LEVEL OF EVIDENCE: IV.


Assuntos
Qualidade de Vida , Articulação Talocalcânea , Humanos , Feminino , Estudos Retrospectivos , Masculino , Articulação Talocalcânea/cirurgia , Pessoa de Meia-Idade , Resultado do Tratamento , Adulto , Atividades Cotidianas , Remoção de Dispositivo/métodos , Idoso
2.
Blood ; 143(19): 1887-1888, 2024 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-38722656
3.
Int J Obstet Anesth ; 59: 104210, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38781778

RESUMO

Women with pulmonary hypertension (PH) have increased mortality during pregnancy and the peripartum period. An increasing number of publications suggest improvements in maternal outcomes, so we conducted a systematic review focusing on disease severity and maternal survival. After screening 9097 potential studies from 1967 to 2021, we identified 66 relevant publications. Outcomes improved continuously over time and mortality fell from 11.6% in studies published before 2015 to 8.2% in studies published after 2015. Mortality was lower in patients with mild disease (0.8%) than in those with Eisenmenger syndrome (26.2%) or idiopathic pulmonary arterial hypertension (7.4-24.0%). One major drawback of the published studies is that they define severity using echocardiographic-estimated pulmonary artery pressures, without considering more contemporary parameters. This systematic review provides new insights for preconception counseling on pregnancy risks related to PH and suggests that PH classification and severity should be carefully considered in determining an individual's pregnancy-associated risk.


Assuntos
Hipertensão Pulmonar , Complicações Cardiovasculares na Gravidez , Resultado da Gravidez , Índice de Gravidade de Doença , Feminino , Humanos , Gravidez , Hipertensão Pulmonar/complicações
4.
Blood Adv ; 8(17): 4714-4726, 2024 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-38669344

RESUMO

ABSTRACT: Blood endothelial cells control the hemostatic and inflammatory response by secreting von Willebrand factor (VWF) and P-selectin from storage organelles called Weibel-Palade bodies (WPBs). Actin-associated motor proteins regulate this secretory pathway at multiple points. Before fusion, myosin Va forms a complex that anchors WPBs to peripheral actin structures, allowing for the maturation of content. After fusion, an actomyosin ring/coat is recruited and compresses the WPB to forcibly expel the largest VWF multimers. Here, we provide, to our knowledge, the first evidence for the involvement of class I myosins during regulated VWF secretion. We show that the unconventional myosin-1C (Myo1c) is recruited after fusion via its pleckstrin homology domain in an actin-independent process. This provides a link between the actin ring and phosphatidylinositol 4,5-bisphosphate (PIP2) at the membrane of the fused organelle and is necessary to ensure maximal VWF secretion. This is an active process requiring Myo1c ATPase activity because inhibition of class I myosins using the inhibitor pentachloropseudilin or expression of an ATPase-deficient Myo1c rigor mutant perturbs the expulsion of VWF and alters the kinetics of the exocytic actin ring. These data offer a novel insight into the control of an essential physiological process and provide a new way in which it can be regulated.


Assuntos
Actomiosina , Membrana Celular , Miosina Tipo I , Fator de von Willebrand , Humanos , Fator de von Willebrand/metabolismo , Membrana Celular/metabolismo , Actomiosina/metabolismo , Miosina Tipo I/metabolismo , Células Endoteliais/metabolismo , Corpos de Weibel-Palade/metabolismo
5.
J Thromb Haemost ; 22(7): 1867-1879, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38608731

RESUMO

BACKGROUND: Carfilzomib (CFZ) is a second-generation proteasome inhibitor used to treat multiple myeloma. Potent inhibition of the proteasome results in chronic proteotoxic endoplasmic reticulum (ER) stress, leading to apoptosis. While CFZ has improved survival rates in multiple myeloma, it is associated with an increased risk of cardiovascular adverse effects. While this has been putatively linked to cardiotoxicity, CFZ could potentially also exhibit adverse effects on the endothelium. OBJECTIVES: To investigate the effects of CFZ on the endothelium. METHODS: Human umbilical vein endothelial cells (HUVECs) were treated with CFZ, and expression of relevant markers of ER stress, inflammation, and thrombosis was measured and functionally assessed. RESULTS: CFZ failed to induce ER stress in HUVECs but induced the expression of Kruppel-like factor 4, endothelial nitric oxide synthase, tissue plasminogen activator, and thrombomodulin and reduced tumor necrosis factor alpha (TNFα)-mediated intercellular adhesion molecule 1 and tissue factor expression, suggesting a potential protective effect on the endothelium. Consistent with these observations, CFZ reduced leukocyte adhesion under shear stress and reduced factor Xa generation and fibrin clot formation on the endothelium following TNFα treatment and inhibited von Willebrand factor (VWF) and angiopoietin-2 exocytosis from Weibel-Palade bodies. Subsequently, CFZ inhibited the formation of VWF-platelet strings, and moreover, media derived from myeloma cell lines induced VWF release, a process also inhibited by CFZ. CONCLUSION: These data demonstrate that CFZ is unable to induce ER stress in confluent resting endothelial cells and can conversely attenuate the prothrombotic effects of TNFα on the endothelium. This study suggests that CFZ does not negatively alter HUVECs, and proteasome inhibition of the endothelium may offer a potential way to prevent thrombosis.


Assuntos
Anti-Inflamatórios , Estresse do Retículo Endoplasmático , Fibrinolíticos , Células Endoteliais da Veia Umbilical Humana , Oligopeptídeos , Inibidores de Proteassoma , Humanos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Oligopeptídeos/farmacologia , Inibidores de Proteassoma/farmacologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Fibrinolíticos/farmacologia , Anti-Inflamatórios/farmacologia , Adesão Celular/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Molécula 1 de Adesão Intercelular/metabolismo , Tromboplastina/metabolismo , Leucócitos/efeitos dos fármacos , Leucócitos/metabolismo , Trombose/prevenção & controle , Trombose/induzido quimicamente , Trombose/metabolismo , Células Cultivadas , Inflamação/metabolismo , Trombomodulina
6.
Sci Total Environ ; 926: 172020, 2024 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-38547987

RESUMO

Climate change has disproportional effects on Arctic-boreal ecosystems, as the increase of air temperatures in these northern regions is several times higher than the global average. Ongoing warming and drying have resulted in recent record-breaking fire years in Arctic-boreal ecosystems, resulting in substantial carbon emissions that might accelerate climate change. While recent trends in Arctic-boreal burned area have been well documented, it is still unclear how fire intensity has changed. Fire intensity relates to the energy release from combustion and to a large extent drives the impact of a fire on the vegetation and soils, the emission of various gasses and the combustion completeness of different fuels. Here, we used the active fire product from the Moderate Resolution Imaging Spectroradiometer (MODIS) to examine trends in fire radiative power (FRP) over the entire Arctic-boreal region. We found a significant increase in annual median fire intensity between 2003 and 2022 in Eurasian boreal forests, for both daytime (increase of 0.392 MW/km2 per year, R2 = 0.56, p < 0.001) and nighttime fires (increase of 0.175 MW/km2 per year, R2 = 0.47, p < 0.001), while no general trend in FRP was observed in boreal North America. This increase in FRP in Eurasian boreal forests was strongly associated with simultaneous increases in air temperature, vapour pressure deficit, fire weather and fuel availability. We estimated that for Eurasia with each degree increase in air temperature, annual median daytime FRP increases with 1.58 MW/km2 in the tundra and 0.94 MW/km2 in the taiga. Climate change has thus resulted in a widespread and clear increase in fire intensity in central and eastern Eurasia while we could not discern clear trends in Arctic-boreal North America. Arctic-boreal fire intensity may further increase with climate change, with potentially major consequences for fire regimes, carbon emissions and society.

8.
Front Immunol ; 14: 1186134, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37936695

RESUMO

Introduction: Following the emergence of SARS-CoV-2 in 2020, care homes were disproportionately impacted by high mortality and morbidity of vulnerable elderly residents. Non-pharmaceutical interventions (NPIs) and improved infection control measures together with vaccination campaigns have since improved outcomes of infection. We studied the utility of past infection status, recent vaccination and anti-S antibody titres as possible correlates of protection against a newly emergent Omicron variant infection. Methods: Prospective longitudinal surveillance of nine sentinel London care homes from April 2020 onwards found that all experienced COVID-19 outbreaks due to Omicron (BA.1) during December 2021 and January 2022, despite extensive prior SARS-CoV-2 exposure and high COVID-19 vaccination rates, including booster vaccines (>70% residents, >40% staff). Results: Detailed investigation showed that 46% (133/288) of Omicron BA.1 infections were SARS-CoV-2 reinfections. Two and three COVID-19 vaccine doses were protective against Omicron infection within 2-9 weeks of vaccination, though protection waned from 10 weeks post-vaccination. Prior infection provided additional protection in vaccinated individuals, approximately halving the risk of SARS-CoV-2 infection. Discussion: Anti-S antibody titre showed a dose-dependent protective effect but did not fully account for the protection provided by vaccination or past infection, indicating that other mechanisms of protection are also involved.


Assuntos
Vacinas contra COVID-19 , COVID-19 , Idoso , Humanos , Estudos Prospectivos , Reinfecção , Anticorpos , COVID-19/epidemiologia , COVID-19/prevenção & controle , SARS-CoV-2
9.
NanoImpact ; 32: 100483, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37734653

RESUMO

A roadmap was developed to strengthen standardisation activities for risk governance of nanotechnology. Its baseline is the available standardised and harmonised methods for nanotechnology developed by the International Organization for Standardization (ISO), the European Committee for Standardization (CEN), and the Organisation for Economic Co-operation and Development (OECD). In order to identify improvements and needs for new themes in standardisation work, an analysis of the state-of-the-art concepts and interpretations of risk governance of nanotechnology was performed. Eleven overall areas of action were identified, each including a subset of specific topics. Themes addressed include physical chemical characterisation, assessment of hazard, exposure, risk and socio-economic factors, as well as education & training and social dialogue. This has been visualised in a standardisation roadmap spanning a timeframe of ten years and including key outcomes and highlights of the analysis. Furthermore, the roadmap indicates potential areas of action for harmonisation and standardisation (H&S) for nanomaterials and nanotechnology. It also includes an evaluation of the current level (limited, moderate, intense) of ongoing H&S activities and indicates the time horizon for the different areas of action. As the identified areas differ in their state of development, the number and type of actions varied widely amongst the different actions towards achieving standardisation. Thus, priority areas were also identified. The overall objective of these actions is to strengthen risk governance towards a safe use of nanomaterials and nano-related products. Though not explicitly addressed, risk-based legislation and policies are supported via the proposed H&S actions.


Assuntos
Nanoestruturas , Nanotecnologia , Fatores Econômicos , Escolaridade , Padrões de Referência
10.
J Thromb Haemost ; 21(7): 1802-1812, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-37011710

RESUMO

BACKGROUND: The von Willebrand factor (VWF) is a multimeric plasma glycoprotein essential for hemostasis, inflammation, and angiogenesis. The majority of VWF is synthesized by endothelial cells (ECs) and stored in Weibel-Palade bodies (WPB). Among the range of proteins shown to co-localize to WPB is angiopoietin-2 (Angpt-2), a ligand of the receptor tyrosine kinase Tie-2. We have previously shown that VWF itself regulates angiogenesis, raising the hypothesis that some of the angiogenic activity of VWF may be mediated by its interaction with Angpt-2. METHODS: Static-binding assays were used to probe the interaction between Angpt-2 and VWF. Binding in media from cultured human umbilical vein ECs s and in plasma was determined by immunoprecipitation experiments. Immunofluorescence was used to detect the presence of Angpt-2 on VWF strings, and flow assays were used to investigate the effect on VWF function. RESULTS: Static-binding assays revealed that Angpt-2 bound to VWF with high affinity (KD,app ∼3 nM) in a pH and calcium-dependent manner. The interaction was localized to the VWF A1 domain. Co-immunoprecipitation experiments demonstrated that the complex persisted following stimulated secretion from ECs and was present in plasma. Angpt-2 was also visible on VWF strings on stimulated ECs. The VWF-Angpt-2 complex did not inhibit the binding of Angpt-2 to Tie-2 and did not significantly interfere with VWF-platelet capture. CONCLUSIONS: Together, these data demonstrate a direct binding interaction between Angpt-2 and VWF that persists after secretion. VWF may act to localize Angpt-2; further work is required to establish the functional consequences of this interaction.


Assuntos
Corpos de Weibel-Palade , Fator de von Willebrand , Humanos , Fator de von Willebrand/metabolismo , Corpos de Weibel-Palade/metabolismo , Angiopoietina-2/metabolismo , Exocitose , Células Endoteliais da Veia Umbilical Humana/metabolismo , Células Cultivadas
11.
Blood ; 141(10): 1102-1103, 2023 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-36893008
12.
Foot Ankle Int ; 44(2): 104-117, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36692121

RESUMO

BACKGROUND: Recent large studies of third-generation minimally invasive hallux valgus surgery (MIS) have demonstrated significant improvement in clinical and radiologic outcomes. It remains unknown whether these clinical and radiologic outcomes are maintained in the medium to long term. The aim of this study was to investigate the minimum 5-year clinical and radiologic outcomes following third-generation MIS hallux valgus surgery in the hands of a high-volume MIS surgeon. METHODS: A retrospective observational single highly experienced MIS surgeon case series of consecutive patients undergoing primary isolated third-generation percutaneous chevron and Akin osteotomies (PECA) for hallux valgus with a minimum 60-month clinical and radiographic follow-up. Primary outcome was radiographic assessment of the hallux valgus angle (HVA) and intermetatarsal angle (IMA) preoperatively, 6 months, and ≥60 months following PECA. Secondary outcomes included the Manchester-Oxford Foot Questionnaire, patient satisfaction, EuroQol-5D visual analog scale and the visual analog scale for pain. RESULTS: Between 2012 and 2014, 126 consecutive feet underwent isolated third-generation PECA, with complete data available for 78 (61.9%) feet. The median follow-up was 65.0 (IQR 64-69; range 60-88) months. There was a significant improvement in radiographic deformity correction; the median IMA improved from 12.0 degrees (interquartile range [IQR]: 10.8-14.2) to 6.0 degrees (IQR: 4.2-7.3) (P < .001), and the median HVA improved from 27.2 degrees (IQR: 20.6-34.4) to 7.2 degrees (IQR: 3.4-11.6). Median MOXFQ Index score at ≥60-month follow-up was 2.3 (IQR: 0.0-7.8). The radiographic recurrence rate (defined as HVA >15 degrees) was 7.7% at final follow-up. The complication rate was 4.8%. CONCLUSION: Radiologic deformity correction for the 78 feet we were able to follow that had third-generation PECA performed by a single highly experienced MIS surgeon was found to be maintained at a mean follow-up of average 66.8 months, with a radiographic recurrence rate of 7.7%. Clinical PROMs and patient satisfaction levels were high and comparable to other third-generation studies with shorter duration of follow-up. LEVEL OF EVIDENCE: Level IV, retrospective cohort study.


Assuntos
Joanete , Hallux Valgus , Humanos , Seguimentos , Hallux Valgus/diagnóstico por imagem , Hallux Valgus/cirurgia , Osteotomia , Estudos Retrospectivos , Resultado do Tratamento
13.
Domest Anim Endocrinol ; 82: 106773, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36375404

RESUMO

The majority of beef cattle in the United States often receive at least one anabolic implant resulting in improved growth, feed efficiency, and environmental and economic sustainability. However, the physiological and molecular mechanisms through which anabolic implants increase skeletal muscle growth of beef cattle remain elusive. The objective of this study was to identify transcriptional changes occurring in skeletal muscle of steers receiving anabolic implants containing different steroid hormones. Forty-eight steers were stratified by weight into 1 of 4 (n = 12/treatment) implant treatment groups: (1) estradiol (ImpE2; 25.7 mg E2; Compudose, Elanco Animal Health, Greenfield, IN), (2) trenbolone acetate (ImpTBA; 200 mg TBA; Finaplix-H, Merck Animal Health, Madison, NJ), (3) combination (ImpETBA; 120 mg TBA + 24 mg E2; Revalor-S, Merck Animal Health), or (4) no implant (CON). Skeletal muscle biopsies were taken from the longissimus 2 and 10 d post-implantation. The mRNA abundance of 94 genes associated with skeletal muscle growth was examined. At 10 d post-implantation, steers receiving ImpETBA had greater (P = 0.02) myoblast differentiation factor 1 transcript abundance than CON. Citrate synthase abundance was increased (P = 0.04) in ImpETBA steers compared to CON steers. In ImpE2 steers 10 d post-implantation, muscle RING finger protein 1 decreased (P = 0.05) compared to CON steers, and forkhead box protein O4 decreased (P = 0.05) in ImpETBA steers compared to CON steers. Interleukin-6 abundance tended to be increased (P = 0.09) in ImpE2 steers compared to both ImpETBA and CON steers. Furthermore, interleukin-10 mRNA abundance tended to be increased (P = 0.06) in ImpTBA steers compared to ImpETBA steers. Leptin receptor abundance was reduced (P = 0.01) in both ImpE2 and ImpTBA steers when compared to CON steers. Abundance of phosphodiesterase 4B was increased (P = 0.04) in ImpTBA steers compared to CON steers 2 d post-implantation. Taken together, the results of this research demonstrate that estradiol increases skeletal muscle growth via pathways related to nutrient partitioning and mitochondria function, while trenbolone acetate improves steer skeletal muscle growth via pathways related to muscle growth.


Assuntos
Doenças dos Bovinos , Acetato de Trembolona , Animais , Bovinos , RNA Mensageiro/genética , Acetato de Trembolona/farmacologia , Inflamação/veterinária , Músculo Esquelético , Estradiol
14.
AJNR Am J Neuroradiol ; 43(11): 1615-1620, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36229166

RESUMO

BACKGROUND AND PURPOSE: Flow diversion has gradually become a standard treatment for intracranial aneurysms of the anterior circulation. Recently, the off-label use of the flow diverters to treat posterior circulation aneurysms has also increased despite initial concerns of rupture and the suboptimal results. This study aimed to explore the change in complication rates and treatment outcomes across time for posterior circulation aneurysms treated using flow diversion and to further evaluate the mechanisms and variables that could potentially explain the change and outcomes. MATERIALS AND METHODS: A retrospective review using a standardized data set at multiple international academic institutions was performed to identify patients with ruptured and unruptured posterior circulation aneurysms treated with flow diversion during a decade spanning January 2011 to January 2020. This period was then categorized into 4 intervals. RESULTS: A total of 378 procedures were performed during the study period. Across time, there was an increasing tendency to treat more vertebral artery and fewer large vertebrobasilar aneurysms (P = .05). Moreover, interventionalists have been increasingly using fewer overlapping flow diverters per aneurysm (P = .07). There was a trend toward a decrease in the rate of thromboembolic complications from 15.8% in 2011-13 to 8.9% in 2018-19 (P = .34). CONCLUSIONS: This multicenter experience revealed a trend toward treating fewer basilar aneurysms, smaller aneurysms, and increased usage of a single flow diverter, leading to a decrease in the rate of thromboembolic and hemorrhagic complications.


Assuntos
Embolização Terapêutica , Procedimentos Endovasculares , Aneurisma Intracraniano , Humanos , Procedimentos Endovasculares/métodos , Curva de Aprendizado , Aneurisma Intracraniano/diagnóstico por imagem , Aneurisma Intracraniano/cirurgia , Resultado do Tratamento , Estudos de Coortes , Estudos Retrospectivos , Embolização Terapêutica/métodos , Stents
15.
Foot Ankle Int ; 43(9): 1157-1166, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35652729

RESUMO

BACKGROUND: Coronal and sagittal plane deformities of the lesser toes are common yet challenging to treat. Traditional open releases and translational Weil osteotomies can be unpredictable and lead to postoperative stiffness. We present the results of a percutaneous closing wedge extracapsular osteotomy of the proximal phalanx to treat valgus deformity of the second toe. METHODS: Thirty-one patients underwent 40 percutaneous osteotomies at a median age of 58.6±9.4 years. Using a small dorsomedial incision, a percutaneous proximal metaphyseal medial closing-wedge extracapsular osteotomy of the second toe is performed, leaving the dorsolateral cortex intact. An irrigated low-speed, high-torque 2- × 8-mm burr is used under image guidance. The osteotomy is then closed to correct deformity and taped for 2 weeks. Patient-reported outcomes and weightbearing radiographs were obtained. RESULTS: Questionnaire data was available for 89.7% (n=35) of cases. Most cases (91.4%) were either satisfied or extremely satisfied with the procedure. Radiographs were available for 90.0% of osteotomies, with a median length from surgery to radiographic follow-up of 1.6 years (range 0.5-6.3; SD ±1.5). Median second-toe valgus angle (STVA) decreased from 16.2±10.7 degrees to 5.0±7.0 degrees (P < .001) at final follow-up. All osteotomies united with no delayed union. There were no wound complications or infections. We found 2 cases of radiographic recurrence. CONCLUSION: Percutaneous proximal phalanx base metaphyseal closing wedge extracapsular osteotomies of lesser toes to correct coronal plane deformity is useful adjunct to first-ray corrective surgery and is associated with high levels of patient satisfaction. LEVEL OF EVIDENCE: Level IV, retrospective case series.


Assuntos
Hallux Valgus , Idoso , Hallux Valgus/cirurgia , Humanos , Pessoa de Meia-Idade , Osteotomia/métodos , Radiografia , Estudos Retrospectivos , Dedos do Pé , Resultado do Tratamento
16.
Am J Physiol Heart Circ Physiol ; 322(1): H87-H93, 2022 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-34890277

RESUMO

The 2019 coronavirus disease (COVID-19) is the disease caused by SARS-CoV-2 infection. Although this infection has been shown to affect the respiratory system, a high incidence of thrombotic events has been observed in severe cases of COVID-19 and in a significant portion of COVID-19 nonsurvivors. Although prior literature has reported on both the coagulopathy and hypercoagulability of COVID-19, the specifics of coagulation have not been fully investigated. Observations of microthrombosis in patients with COVID-19 have brought attention to potential inflammatory endothelial injury. Von Willebrand factor (VWF) and its protease, A disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13), play an important homeostatic role in responding to endothelial injury. This report provides an overview of the literature investigating the role the VWF/ADAMTS13 axis may have in COVID-19 thrombotic events and suggests potential therapeutic strategies to prevent the progression of coagulopathy in patients with COVID-19.


Assuntos
Proteína ADAMTS13/metabolismo , Transtornos da Coagulação Sanguínea/metabolismo , COVID-19/sangue , Fator de von Willebrand/metabolismo , Coagulação Sanguínea , Transtornos da Coagulação Sanguínea/etiologia , COVID-19/complicações , Humanos
17.
Haematologica ; 107(3): 668-679, 2022 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33763999

RESUMO

Terminal sialylation determines the plasma half-life of von Willebrand factor (VWF). A role for macrophage galactose lectin (MGL) in regulating hyposialylated VWF clearance has recently been proposed. In this study, we showed that MGL influences physiological plasma VWF clearance. MGL inhibition was associated with a significantly extended mean residence time and 3-fold increase in endogenous plasma VWF antigen levels (P<0.05). Using a series of VWF truncations, we further demonstrated that the A1 domain of VWF is predominantly responsible for enabling the MGL interaction. Binding of both full-length and VWF-A1-A2-A3 to MGL was significantly enhanced in the presence of ristocetin (P<0.05), suggesting that the MGL-binding site in A1 is not fully accessible in globular VWF. Additional studies using different VWF glycoforms demonstrated that VWF O-linked glycans, clustered at either end of the A1 domain, play a key role in protecting VWF against MGLmediated clearance. Reduced sialylation has been associated with pathological, increased clearance of VWF in patients with von Willebrand disease. Herein, we demonstrate that specific loss of α2-3 linked sialylation from O-glycans results in markedly increased MGL-binding in vitro, and markedly enhanced MGL-mediated clearance of VWF in vivo. Our data further show that the asialoglycoprotein receptor (ASGPR) does not have a significant role in mediating the increased clearance of VWF following loss of O-sialylation. Conversely however, we observed that loss of N-linked sialylation from VWF drives enhanced circulatory clearance predominantly via the ASGPR. Collectively, our data support the hypothesis that in addition to regulating physiological VWF clearance, the MGL receptor works in tandem with ASGPR to modulate enhanced clearance of aberrantly sialylated VWF in the pathogenesis of von Willebrand disease.


Assuntos
Galactose , Ácido N-Acetilneuramínico , Fator de von Willebrand , Galactose/metabolismo , Humanos , Lectinas/metabolismo , Macrófagos/metabolismo , Ácido N-Acetilneuramínico/metabolismo , Polissacarídeos/metabolismo , Fator de von Willebrand/metabolismo
18.
Lancet Healthy Longev ; 2(12): e811-e819, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34873592

RESUMO

BACKGROUND: Understanding the duration of protection and risk of reinfection after natural infection is crucial to planning COVID-19 vaccination for at-risk groups, including care home residents, particularly with the emergence of more transmissible variants. We report on the duration, neutralising activity, and protection against the alpha variant of previous SARS-CoV-2 infection in care home residents and staff infected more than 6 months previously. METHODS: We did this prospective observational cohort surveillance in 13 care homes in Greater London, England. All staff and residents were included. Staff and residents had regular nose and throat screening for SARS-CoV-2 by RT-PCR according to national guidelines, with ad hoc testing of symptomatic individuals. From January, 2021, antigen lateral flow devices were also used, but positive tests still required RT-PCR confirmation. Staff members took the swab samples for themselves and the residents. The primary outcome was SARS-CoV-2 RT-PCR positive primary infection or reinfection in previously infected individuals, as determined by previous serological testing and screening or diagnostic RT-PCR results. Poisson regression and Cox proportional hazards models were used to estimate protective effectiveness of previous exposure. SARS-CoV-2 spike, nucleoprotein, and neutralising antibodies were assessed at multiple timepoints as part of the longitudinal follow-up. FINDINGS: Between April 10 and Aug 3, 2020, we recruited and tested 1625 individuals (933 staff and 692 residents). 248 participants were lost to follow-up (123 staff and 125 residents) and 1377 participants were included in the follow-up period to Jan 31, 2021 (810 staff and 567 residents). There were 23 reinfections (ten confirmed, eight probable, five possible) in 656 previously infected individuals (366 staff and 290 residents), compared with 165 primary infections in 721 susceptible individuals (444 staff and 277 residents). Those with confirmed reinfections had no or low neutralising antibody concentration before reinfection, with boosting of titres after reinfection. Kinetics of binding and neutralising antibodies were similar in older residents and younger staff. INTERPRETATION: SARS-CoV-2 reinfections were rare in older residents and younger staff. Protection from SARS-CoV-2 was sustained for longer than 9 months, including against the alpha variant. Reinfection was associated with no or low neutralising antibody before reinfection, but significant boosting occurred on reinfection. FUNDING: Public Health England.


Assuntos
COVID-19 , SARS-CoV-2 , Idoso , Anticorpos Neutralizantes , Vacinas contra COVID-19 , Humanos , Reinfecção
19.
PLoS One ; 16(10): e0257160, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34613999

RESUMO

Social desirability reporting leads to over estimations of church attendance. To date, researchers have treated over-reporting of church attendance as a general phenomenon, and have been unable to determine the demographic correlates of inaccuracy in these self-reports. By comparing over eight months of observational data on church attendance (n = 48 services) to self-report in a rural Fijian village, we find that 1) self-report does not reliably predict observed attendance, 2) women with two or more children (≥ 2) are more likely to over-report their attendance than women with fewer children (≤ 1), and 3) self-report of religiosity more reliably predicts observed church attendance than does self-report of church attendance. Further, we find that third-party judgements of church attendance by fellow villagers are more reliably associated with observed church attendance than self-report. Our findings suggest that researchers interested in estimating behavioral variation, particularly in domains susceptible to social desirability effects, should consider developing and employing third-party methods to mitigate biases inherent to self-report.


Assuntos
Religião , Autorrelato , Adulto , Idoso , Feminino , Fiji , Humanos , Julgamento , Masculino , Pessoa de Meia-Idade , População Rural , Adulto Jovem
20.
Foot Ankle Int ; 42(9): 1106-1114, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33870760

RESUMO

BACKGROUND: There are many options for incision closure in forefoot surgery. The aim of this study was to compare topical skin adhesive (2-octyl-cyanoacrylate) to simple interrupted nylon sutures. METHODS: A prospective randomized controlled trial comparing topical skin adhesive (TSA) and nylon sutures (NSs) for elective open forefoot surgery. Primary outcome was Hollander Wound Evaluation Scale (HWES) assessed 2 weeks following surgery. Secondary objectives included time taken for wound closure, wound assessment, patient satisfaction with wound cosmesis, incision pain, and infection rate. RESULTS: Between January and December 2018, 84 feet (70 patients) underwent hallux valgus scarf/Akin osteotomy or first metatarsophalangeal arthrodesis and were randomized to receive either intervention (topical skin adhesive) or control (3/0 nylon sutures). We found worse HWES scores when using TSA compared to NSs (1.07 vs 0.60). Incision closure time was slower for TSA (mean, 272 vs 229 seconds). At 2 weeks postoperatively, wound care was faster for TSA (mean 71 secs) vs NSs (mean 120), and patient-reported pain was less with TSA (visual analog scale: TSA 1.2 vs NSs 2.1). A high degree of overall patient satisfaction was reported in both groups, without significant difference. CONCLUSION: Closure of elective forefoot surgery incisions with topical skin adhesive or interrupted nylon sutures offers high satisfaction rates, low pain scores, and low complications. However, topical skin adhesive was associated with more inflammation and areas of wound separation compared to nylon sutures. We recommend the use of sutures for wound closure in forefoot surgery. LEVEL OF EVIDENCE: Level I, randomized controlled trial.


Assuntos
Nylons , Adesivos Teciduais , Adesivos , Humanos , Estudos Prospectivos , Técnicas de Sutura , Suturas , Cicatrização
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