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1.
West Afr J Med ; 41(4): 436-451, 2024 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-39003518

RESUMO

INTRODUCTION: Community-based prevalence studies are known to be more accurate than hospital-based records. However, such community-based prevalence studies are uncommon in low- and middle-income countries including Nigeria. Allocation of resources and prioritization of health care needs by policy makers require data from such community-based studies to be meaningful and sustainable. This study aims to assess the prevalence of common surgical conditions amongst adults in Nigeria. METHODS: A descriptive cross-sectional community-based study to determine the prevalence of congenital and acquired surgical conditions in adults in a mixed rural-urban area of Lagos was conducted. The study population comprised resident members in the Ikorodu Local Government Area (LGA) of Lagos State. Data was collected using a modified version of the interviewer-administered questionnaire, the Surgeons OverSeas Assessment of Surgical Need (SOSAS) survey tool. Data was analysed using the REDCap analytic tool. RESULTS: Eight hundred and fifty-six households were surveyed with a yield of 1,992 adults. There were 95 adults who complained of surgical conditions giving a prevalence rate of 5%. Vast majority of reported conditions were acquired deformities (n=94) while only 1 congenital deformity was reported. Others included breast lumps, anterior neck swelling, and groin swellings. CONCLUSION: The most common surgical complaints in our setting among adults were acquired conditions of the extremities and open wounds/sores. With an estimated population of 90 million adults and approximately 1,200 orthopaedic and general surgeons respectively, the surgeon-to-affected population ratio is 1:10,000. There is a large gap to be filled in terms of surgical manpower development.


INTRODUCTION: Les études de prévalence communautaires sont connues pour être plus précises que les dossiers hospitaliers. Cependant, de telles études de prévalence communautaires sont rares dans les pays à revenu faible et intermédiaire, y compris le Nigeria. L'allocation des ressources et la priorisation des besoins de santé par les décideurs nécessitent des données issues de telles études communautaires pour être significatives et durables. Cette étude vise à évaluer la prévalence des affections chirurgicales courantes chez les adultes au Nigeria. MÉTHODES: Une étude descriptive transversale basée sur la communauté pour déterminer la prévalence des conditions chirurgicales congénitales et acquises chez les adultes dans une zone rurale-urbaine mixte de Lagos a été menée. La population étudiée comprenait des membres résidents de la zone de gouvernement local (LGA) d'Ikorodu, dans l'État de Lagos. Les données ont été collectées à l'aide d'une version modifiée du questionnaire administré par un enquêteur, l'outil d'enquête Surgeons OverSeas Assessment of Surgical Need (SOSAS). Les données ont été analysées à l'aide de l'outil analytique REDCap. RÉSULTATS: Huit cent cinquante-six ménages ont été enquêtés, ce qui a donné 1 992 adultes. Quatre-vingt-quinze adultes se sont plaints de conditions chirurgicales, donnant un taux de prévalence de 5 %. La grande majorité des conditions rapportées étaient des déformations acquises (n=94) tandis qu'une seule déformation congénitale a été signalée. Les autres incluaient des nodules mammaires, des gonflements antérieurs du cou et des gonflements inguinaux. CONCLUSION: Les plaintes chirurgicales les plus courantes dans notre cadre parmi les adultes étaient des conditions acquises des extrémités et des plaies ouvertes/ulcères. Avec une population estimée à 90 millions d'adultes et environ 1 200 chirurgiens orthopédiques et généralistes respectivement, le ratio chirurgien-population affectée est de 1:10,000. Il y a un grand écart à combler en termes de développement de la main-d'œuvre chirurgicale. MOTS CLÉS: Prévalence, Charge de morbidité, Chirurgie, Plaies.


Assuntos
População Rural , População Urbana , Humanos , Nigéria/epidemiologia , Estudos Transversais , Adulto , Feminino , Masculino , População Rural/estatística & dados numéricos , Pessoa de Meia-Idade , População Urbana/estatística & dados numéricos , Adulto Jovem , Prevalência , Inquéritos e Questionários , Adolescente , Procedimentos Cirúrgicos Operatórios/estatística & dados numéricos , Necessidades e Demandas de Serviços de Saúde , Idoso , Avaliação das Necessidades
2.
Cutis ; 113(3): 125-131, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38648584

RESUMO

Wound healing is crucial for survival, prevention of infection, and restoration of tissue function. The immune system drives this process with 3 main phases: inflammation, proliferation, and remodeling. Keloids and hypertrophic scars reveal disruptions in these phases, underscoring the balance needed for healing. Limb amputation, a life-changing event, demands careful consideration for healing and function. Factors such as amputation level, surgical technique, and prosthetic fitting shape outcomes, while complications such as heterotopic ossification challenge recovery. Treatment advances including statins and stem cell therapy hold promise, with dermatologists poised to contribute substantially to postamputation care.


Assuntos
Amputação Cirúrgica , Cicatrização , Humanos , Cicatrização/fisiologia , Queloide/terapia , Queloide/etiologia
3.
ACS Appl Polym Mater ; 5(1): 775-783, 2023 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-37033151

RESUMO

Flexible, dry skin electrodes represent a potentially superior alternative to standard Ag/AgCl metal electrodes for wearable devices used in long-term monitoring. Herein, such electrodes were formed using a facile method for dispersing carbon nanotubes (CNTs) in a silicone matrix using custom amphiphilic dispersive additives (DSPAs). Using only brief mixing and without the use of solvents or surface modification of CNTs, twelve poly(ethylene oxide)-silanes (PEO-SAs) of varying crosslinkability, architecture, siloxane tether length, and molar ratio of siloxane:PEO were combined with an addition cure silicone and CNTs. Nearly all PEO-SA modified silicone-CNT composites demonstrated improved conductivity compared to the unmodified composite. Best conductivities correlated to composites prepared with PEO-SAs that formed micelles of particular sizes (d ~ 200 - 300 nm) and coincided to PEO-SAs with a siloxane:PEO molar ratio of ~ 0.75 - 3.00. Superior dispersion of CNT by such PEO-SAs was exemplified by scanning electron microscopy (SEM). Advantageously, modified composites retained their moduli, rather than becoming more rigid. Resultant electrodes fabricated with modified composites showed skin-electrode impedance comparable to that of Ag/AgCl electrodes. Combined, these results demonstrate the potential of silicone-CNT composites prepared with PEO-SA DSPAs as flexible, dry electrodes as a superior alternative to traditional electrodes.

4.
Am J Surg ; 226(1): 128-132, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-37121787

RESUMO

INTRODUCTION: Effects of pulmonary function test (PFT) results on perioperative outcomes were investigated after robotic-assisted video-thoracoscopic (RAVT) pulmonary lobectomy. METHODS: We retrospectively analyzed 706 consecutive patients who underwent RAVT lobectomy by one surgeon over 10.8 years. Preoperative (preop) forced expiratory volume in 1 s as a percent of predicted (FEV1%) was used to group patients as having normal FEV1% (≥80%) versus reduced FEV1% (<80%). Demographics, preop comorbidities, intraoperative (intraop) and postoperative (postop) complications, perioperative outcomes, and median survival time (MST) were compared across patients with normal vs. reduced FEV1% using Chi-Square (X2), Fisher's Exact test, Student's t-test, Kruskal-Wallis test, or Kaplan-Meier analysis respectively, with significance at p ≤ 0.05. Multivariable analysis was performed for perioperative outcomes to investigate the differences across patients in the FEV1% groups. RESULTS: There were 470 patients with normal FEV1% and 236 patients with reduced FEV1%. The two FEV1% groups did not differ in intraop or postop complication rates, except for higher postop other arrhythmia requiring intervention (p = 0.004), prolonged air leak >5 days (p = 0.002), mucous plug formation (p = 0.009), hypoxia (p < 0.001), and pneumonia (p = 0.002), and total postop complications (p < 0.001) in reduced-FEV1% patients. Reduced FEV1% correlated with increased intraop estimated blood loss (p < 0.0001) and skin-to-skin operative time (p < 0.0001). Median overall survival in patients with normal FEV1% was 93.20 months (95% CI: 76.5-126.0) versus 58.9 months (95% CI: 50.4-68.4) in patients with reduced FEV1% (p = 0.0004). CONCLUSION: Patients should have PFTs conducted before surgery to determine at-risk patients. However, RAVT pulmonary lobectomy is feasible and safe even in patients with reduced FEV1%.


Assuntos
Pulmão , Procedimentos Cirúrgicos Robóticos , Humanos , Pneumopatias/cirurgia , Neoplasias Pulmonares/cirurgia , Pneumonectomia/métodos , Estudos Retrospectivos , Cirurgia Torácica Vídeoassistida
5.
Artigo em Inglês | MEDLINE | ID: mdl-38248488

RESUMO

The occurrence of severe and extreme weather events that have been attributed to a changed climate system and the widespread dissemination of the impacts of these events in the media can lead people to experience concern, worry, and anxiety, which we examined in two studies. In Study 1, we observed that people more frequently expressed worry than anxiety about the impacts of climate change in six areas. People were more frequently worried and anxious about the effects of climate change on future generations and about societal responses (or lack of a response) to climate change. The levels of anxiety that people expressed were significantly higher than the worry people reported when anxiety was their modal response. In Study 2, we observed that both climate change worry and anxiety were negatively correlated with psychological distance from climate change. Overall, climate change worry and psychological distance significantly predicted climate-sustainable behaviors. Our study was among the first to use developed measures of climate change worry, anxiety, and psychological distance to examine peoples' responses across some of the possible impact and consequence areas of climate change.


Assuntos
Mudança Climática , Clima Extremo , Humanos , Ansiedade/epidemiologia , Transtornos de Ansiedade , Distância Psicológica
6.
Surg Oncol ; 44: 101843, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36067629

RESUMO

BACKGROUND: Evaluate whether the Breast Cancer Locator™ (BCL), a novel guidance system based on supine MRI images, can be safely and effectively deployed by several surgeons at multiple sites. METHODS: Patients with palpable breast cancer underwent supine MRI at their local institution. A three dimensional (3D) digital image of the tumor in the breast was derived from supine MRI images and used to generate 1) an interactive 3D virtual image of the tumor in the breast (Visualizer) and 2) a plastic bra-like form that allowed the surgeon to place a central wire and bracketing wires in the breast (BCL). The primary objective was to determine the proportion of patients who had the central localization wire deployed within the cancer on specimen mammogram. RESULTS: Fourteen patients were enrolled at 4 different sites by 6 surgeons. BCLs were successfully manufactured for all patients. The central wire was deployed within the tumor on specimen mammogram in 12 of the 13 patients who had a central wire placed (92%). The cancer was excised with negative margins in 14/14 cases (100%). No adverse events occurred. CONCLUSIONS: Supine MRI image acquisition was accomplished successfully across multiple sites. Multiple surgeons utilized the BCL system to localize cancers accurately and safely.


Assuntos
Neoplasias da Mama , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/patologia , Neoplasias da Mama/cirurgia , Feminino , Humanos , Imageamento por Ressonância Magnética/métodos , Mamografia , Mastectomia Segmentar/métodos , Plásticos
8.
Microbiol Resour Announc ; 11(9): e0063622, 2022 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-35969062

RESUMO

Subcluster L3 bacteriophage Finnry was isolated from soil collected in Charleston, South Carolina, using Mycobacterium smegmatis mc2155 as a host. The genome of this temperate siphovirus is 75,632 bp long (130 predicted protein-coding genes, 9 tRNAs, and no transfer-messenger RNAs), and BLASTn alignment revealed 99.86% identity with the genome of L3 mycobacteriophage Samty.

9.
S Afr Med J ; 112(2): 13501, 2022 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-35139989

RESUMO

BACKGROUND: In South Africa (SA), >2.4 million cases of COVID­19 and >72 000 deaths were recorded between March 2020 and 1 August 2021, affecting the country's 52 districts to various extents. SA has committed to a COVID­19 vaccine roll-out in three phases, prioritising frontline workers, the elderly, people with comorbidities and essential workers. However, additional actions will be necessary to support efficient allocation and equitable access for vulnerable, access-constrained communities. OBJECTIVES: To explore various determinants of disease severity, resurgence risk and accessibility in order to aid an equitable, effective vaccine roll-out for SA that would maximise COVID­19 epidemic control by reducing the number of COVID­19 transmissions and resultant deaths, while at the same time reducing the risk of vaccine wastage. METHODS: For the 52 districts of SA, 26 COVID­19 indicators such as hospital admissions, deaths in hospital and mobility were ranked and hierarchically clustered with cases to identify which indicators can be used as indicators for severity or resurgence risk. Districts were then ranked using the estimated COVID­19 severity and resurgence risk to assist with prioritisation of vaccine roll-out. Urban and rural accessibility were also explored as factors that could limit vaccine roll-out in hard-to-reach communities. RESULTS: Highly populated urban districts showed the most cases. Districts such as Buffalo City, City of Cape Town and Nelson Mandela Bay experienced very severe first and second waves of the pandemic. Districts with high mobility, population size and density were found to be at highest risk of resurgence. In terms of accessibility, we found that 47.2% of the population are within 5 km of a hospital with ≥50 beds, and this percentage ranged from 87.0% in City of Cape Town to 0% in Namakwa district. CONCLUSIONS: The end goal is to provide equal distribution of vaccines proportional to district populations, which will provide fair protection. Districts with a high risk of resurgence and severity should be prioritised for vaccine roll-out, particularly the major metropolitan areas. We provide recommendations for allocations of different vaccine types for each district that consider levels of access, numbers of doses and cold-chain storage capability.


Assuntos
Vacinas contra COVID-19/administração & dosagem , COVID-19/prevenção & controle , Vacinação em Massa/organização & administração , Acessibilidade aos Serviços de Saúde , Hospitalização , Humanos , Gravidade do Paciente , África do Sul , Populações Vulneráveis
11.
Can J Neurol Sci ; 49(6): 746-760, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-34511142

RESUMO

Endovascular thrombectomy (EVT) has significantly improved outcomes for patients with acute ischemic stroke due to large vessel occlusion. However, despite advances, more than half of patients remain functionally dependent 3 months after their initial stroke. Anesthetic strategy may influence both the technical success of the procedure and overall outcomes. Conventionally, general anesthesia (GA) has been widely used for neuroendovascular procedures, particularly for the distal intracranial circulation, because the complete absence of movement has been considered imperative for procedural success and to minimize complications. In contrast, in patients with acute stroke undergoing EVT, the optimal anesthetic strategy is controversial. Nonrandomized studies suggest GA negatively affects outcomes while the more recent anesthesia-specific RCTs report improved or unchanged outcomes in patients managed with versus without GA, although these findings cannot be generalized to other EVT capable centers due to a number of limitations. Potential explanations for these contrasting results will be addressed in this review including the effect of different anesthetic strategies on cerebral and systemic hemodynamics, revascularization times, and periprocedural complications.


Assuntos
Isquemia Encefálica , Procedimentos Endovasculares , AVC Isquêmico , Acidente Vascular Cerebral , Humanos , Isquemia Encefálica/complicações , Procedimentos Endovasculares/métodos , Resultado do Tratamento , Trombectomia/métodos , Acidente Vascular Cerebral/etiologia , Anestesia Geral/métodos
12.
J Forensic Sci ; 66(6): 2307-2318, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34462924

RESUMO

Death investigations in aquatic ecosystems are challenging due to abiotic and biotic factors that may influence the estimation of a postmortem submersion interval (PMSI). In this study, we examined bacterial changes throughout the decomposition process on porcine carcasses submerged in a tidal-influenced river and identified predictors of epinecrotic community succession. Fetal porcine (Sus scrofa) carcasses (N = 6) were submerged with epinecrotic samples collected every 3 days (6 collections) over a period of 19 days (~7415 accumulated degree hours (ADH)). Amplicon sequencing was performed using the Illumina MiSeq platform (16S V4 region, 2 × 250 bp format) to identify changes in bacterial relative abundance and diversity. To match bacterial succession with rough taphonomy, carcasses were visually assessed at each sampling time point to determine the decomposition stage. Notably, the three most abundant families were Moraxellaceae, Burkholderiaceae (Proteobacteria), and Clostridiaceae (Firmicutes), though communities composition varied significantly across decomposition stages. Greater bacterial phylogenetic diversity was observed in in latter decomposition stages (advanced floating decay, sunken remains). Random Forest Models were built to predict ADH and explained 77%-80.8% of variation in ADH with an error rate of +/-1943.2 ADH (Root Mean Square Error) or approx. ±2.7 days at the mean water temperature of this study. This study provided a useful model that could be used to estimate a PMSI in this river system utilizing bacterial community succession, and thus, potentially improve the accuracy of such estimations to be used in the court of law.


Assuntos
Restos Mortais , Imersão , Microbiota , Mudanças Depois da Morte , Rios/microbiologia , Animais , DNA Bacteriano/análise , Medicina Legal , Sequenciamento de Nucleotídeos em Larga Escala , Modelos Animais , Filogenia , Suínos
13.
Br J Surg ; 108(8): 892-897, 2021 08 19.
Artigo em Inglês | MEDLINE | ID: mdl-34297806

RESUMO

BACKGROUND: Bariatric surgery is an established treatment for severe obesity; however, fewer than 1 per cent of eligible patients undergo surgery. The perceived risk of surgery may contribute to the low uptake. The aim of this study was to determine perioperative mortality associated with bariatric surgery, comparing different operation types and data sources. METHODS: A literature search of Ovid MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials was conducted to identify studies published between 1 January 2014 and 31 July 2020. Inclusion criteria were studies of at least 1000 patients reporting short-term mortality after bariatric surgery. Data were collected on RCTs. Meta-analysis was performed to establish overall mortality rates across different study types. The primary outcome measure was perioperative mortality. Different operation types were compared, along with study type, in subgroup analyses. The study was registered at PROSPERO (2019: CRD 42019131632). RESULTS: Some 4356 articles were identified and 58 met the inclusion criteria. Data were available on over 3.6 million patients. There were 4707 deaths. Pooled analysis showed an overall mortality rate of 0.08 (95 per cent c.i. 0.06 to 0.10; 95 per cent prediction interval 0 to 0.21) per cent. In subgroup analysis, there was no statistically significant difference between overall, 30-day, 90-day or in-hospital mortality (P = 0.29). There was no significant difference in reported mortality for RCTs, large studies, national databases or registries (P = 0.60). The pooled mortality rates by procedure type in ascending order were: 0.03 per cent for gastric band, 0.05 per cent for sleeve gastrectomy, 0.09 per cent for one-anastomosis gastric bypass, 0.09 per cent for Roux-en-Y gastric bypass, and 0.41 per cent for duodenal switch (P < 0.001 between operations). CONCLUSION: Bariatric surgery is safe, with low reported perioperative mortality rates.


Weight loss surgery helps patients with severe obesity. This study looked at the risk of dying after weight loss surgery in over 3.6 million patients. The risk was less than 1 in 1000 (0.08 per cent). The risk was lowest for gastric band and sleeve gastrectomy, then for gastric bypasses and highest for the duodenal switch operation. This shows that weight loss surgery is safe, with a low risk of dying similar to that of other common operations.


Assuntos
Cirurgia Bariátrica/mortalidade , Obesidade Mórbida/cirurgia , Cirurgia Bariátrica/métodos , Saúde Global , Humanos , Laparoscopia/mortalidade , Obesidade Mórbida/mortalidade , Obesidade Mórbida/fisiopatologia , Período Perioperatório , Taxa de Sobrevida/tendências , Redução de Peso/fisiologia
14.
Mol Ther Methods Clin Dev ; 21: 656-669, 2021 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-34141821

RESUMO

Clinical application of somatic genome editing requires therapeutics that are generalizable to a broad range of patients. Targeted insertion of promoterless transgenes can ensure that edits are permanent and broadly applicable while minimizing risks of off-target integration. In the liver, the Albumin (Alb) locus is currently the only well-characterized site for promoterless transgene insertion. Here, we target the Apoa1 locus with adeno-associated viral (AAV) delivery of CRISPR-Cas9 and achieve rates of 6% to 16% of targeted hepatocytes, with no evidence of toxicity. We further show that the endogenous Apoa1 promoter can drive robust and sustained expression of therapeutic proteins, such as apolipoprotein E (APOE), dramatically reducing plasma lipids in a model of hypercholesterolemia. Finally, we demonstrate that Apoa1-targeted fumarylacetoacetate hydrolase (FAH) can correct and rescue the severe metabolic liver disease hereditary tyrosinemia type I. In summary, we identify and validate Apoa1 as a novel integration site that supports durable transgene expression in the liver for gene therapy applications.

15.
PLoS One ; 16(3): e0247972, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33684160

RESUMO

INTRODUCTION: Delayed graft function (DGF) following renal transplantation is a manifestation of acute kidney injury (AKI) leading to poor long-term outcome. Current treatments have limited effectiveness in preventing DGF. Interleukin-18 (IL18), a biomarker of AKI, induces interferon-γ expression and immune activation. GSK1070806, an anti-IL18 monoclonal antibody, neutralizes activated (mature) IL18 released from damaged cells following inflammasome activation. This phase IIa, single-arm trial assessed the effect of a single dose of GSK1070806 on DGF occurrence post donation after circulatory death (DCD) kidney transplantation. METHODS: The 3 mg/kg intravenous dose was selected based on prior studies and physiologically based pharmacokinetic (PBPK) modeling, indicating the high likelihood of a rapid and high level of IL18 target engagement when administered prior to kidney allograft reperfusion. Utilization of a Bayesian sequential design with a background standard-of-care DGF rate of 50% based on literature, and confirmed via extensive registry data analyses, enabled a statistical efficacy assessment with a minimal sample size. The primary endpoint was DGF frequency, defined as dialysis requirement ≤7 days post transplantation (except for hyperkalemia). Secondary endpoints included safety, pharmacokinetics and pharmacodynamic biomarkers. RESULTS: GSK1070806 administration was associated with IL18-GSK1070806 complex detection and increased total serum IL18 levels due to IL18 half-life prolongation induced by GSK1070806 binding. Interferon-γ-induced chemokine levels declined or remained unchanged in most patients. Although the study was concluded prior to the Bayesian-defined stopping point, 4/7 enrolled patients (57%) had DGF, exceeding the 50% standard-of-care rate, and an additional two patients, although not reaching the protocol-defined DGF definition, demonstrated poor graft function. Six of seven patients experienced serious adverse events (SAEs), including two treatment-related SAEs. CONCLUSION: Overall, using a Bayesian design and extensive PBPK dose modeling with only a small sample size, it was deemed unlikely that GSK1070806 would be efficacious in preventing DGF in the enrolled DCD transplant population. TRIAL REGISTRATION: NCT02723786.


Assuntos
Injúria Renal Aguda , Anticorpos Monoclonais Humanizados , Função Retardada do Enxerto , Interleucina-18/sangue , Transplante de Rim , Doadores de Tecidos , Injúria Renal Aguda/sangue , Injúria Renal Aguda/tratamento farmacológico , Adulto , Idoso , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/farmacocinética , Função Retardada do Enxerto/sangue , Função Retardada do Enxerto/tratamento farmacológico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto
16.
Circulation ; 143(19): 1874-1890, 2021 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-33682427

RESUMO

BACKGROUND: Diastolic dysfunction (DD) is associated with the development of heart failure and contributes to the pathogenesis of other cardiac maladies, including atrial fibrillation. Inhibition of histone deacetylases (HDACs) has been shown to prevent DD by enhancing myofibril relaxation. We addressed the therapeutic potential of HDAC inhibition in a model of established DD with preserved ejection fraction. METHODS: Four weeks after uninephrectomy and implantation with deoxycorticosterone acetate pellets, when DD was clearly evident, 1 cohort of mice was administered the clinical-stage HDAC inhibitor ITF2357/Givinostat. Echocardiography, blood pressure measurements, and end point invasive hemodynamic analyses were performed. Myofibril mechanics and intact cardiomyocyte relaxation were assessed ex vivo. Cardiac fibrosis was evaluated by picrosirius red staining and second harmonic generation microscopy of left ventricle (LV) sections, RNA sequencing of LV mRNA, mass spectrometry-based evaluation of decellularized LV biopsies, and atomic force microscopy determination of LV stiffness. Mechanistic studies were performed with primary rat and human cardiac fibroblasts. RESULTS: HDAC inhibition normalized DD without lowering blood pressure in this model of systemic hypertension. In contrast to previous models, myofibril relaxation was unimpaired in uninephrectomy/deoxycorticosterone acetate mice. Furthermore, cardiac fibrosis was not evident in any mouse cohort on the basis of picrosirius red staining or second harmonic generation microscopy. However, mass spectrometry revealed induction in the expression of >100 extracellular matrix proteins in LVs of uninephrectomy/deoxycorticosterone acetate mice, which correlated with profound tissue stiffening based on atomic force microscopy. ITF2357/Givinostat treatment blocked extracellular matrix expansion and LV stiffening. The HDAC inhibitor was subsequently shown to suppress cardiac fibroblast activation, at least in part, by blunting recruitment of the profibrotic chromatin reader protein BRD4 (bromodomain-containing protein 4) to key gene regulatory elements. CONCLUSIONS: These findings demonstrate the potential of HDAC inhibition as a therapeutic intervention to reverse existing DD and establish blockade of extracellular matrix remodeling as a second mechanism by which HDAC inhibitors improve ventricular filling. Our data reveal the existence of pathophysiologically relevant covert or hidden cardiac fibrosis that is below the limit of detection of histochemical stains such as picrosirius red, highlighting the need to evaluate fibrosis of the heart using diverse methodologies.


Assuntos
Matriz Extracelular/fisiologia , Sopros Cardíacos/tratamento farmacológico , Inibidores de Histona Desacetilases/uso terapêutico , Remodelação Ventricular/fisiologia , Animais , Modelos Animais de Doenças , Feminino , Inibidores de Histona Desacetilases/farmacologia , Humanos , Masculino , Camundongos
17.
J Thromb Haemost ; 19(2): 358-369, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33075181

RESUMO

BACKGROUND: Von Willebrand factor (VWF) contains a number of free thiols, the majority of which are located in its C-domains, and these have been shown to alter VWF function, However, the impact of free thiols on function following acute exposure of VWF to collagen under high and pathological shear stress has not been determined. METHODS: VWF free thiols were blocked with N-ethylmaleimide and flow assays performed under high and pathological shear rates to determine the impact on platelet capture and collagen binding function. Atomic force microscopy (AFM) was used to probe the interaction of VWF with collagen and molecular simulations conducted to determine the effect of free thiols on the flexibility of the VWF-C4 domain. RESULTS: Blockade of VWF free thiols reduced VWF-mediated platelet capture to collagen in a shear-dependent manner, with platelet capture virtually abolished above 5000 s-1 and in regions of stenosis in microfluidic channels. Direct visualization of VWF fibers formed under extreme pathological shear rates and analysis of collagen-bound VWF attributed the effect to altered binding of VWF to collagen. AFM measurements showed that thiol-blockade reduced the lifetime and strength of the VWF-collagen bond. Pulling simulations of the VWF-C4 domain demonstrated that with one or two reduced disulphide bonds the C4 domain has increased flexibility and the propensity to undergo free-thiol exchange. CONCLUSIONS: We conclude that free thiols in the C-domains of VWF enhance the flexibility of the molecule and enable it to withstand high shear forces following collagen binding, demonstrating a previously unrecognized role for VWF free thiols.


Assuntos
Compostos de Sulfidrila , Fator de von Willebrand , Plaquetas/metabolismo , Colágeno/metabolismo , Humanos , Adesividade Plaquetária , Ligação Proteica , Estresse Mecânico , Fator de von Willebrand/metabolismo
18.
BJS Open ; 4(5): 977-984, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-33179875

RESUMO

BACKGROUND: RCTs provide the scientific basis upon which treatment decisions are made. To facilitate critical review, it is important that methods and results are reported transparently. The aim of this study was to explore transparency in surgical RCTs with respect to trial registration, disclosure of funding sources, declarations of investigator conflicts and data-sharing. METHODS: This was a cross-sectional review of published surgical RCTs. Ten high-impact journals were searched systematically for RCTs published in years 2009, 2012, 2015 and 2018. Four domains of transparency were explored: trial registration, disclosure of funding, disclosure of investigator conflicts, and a statement relating to data-sharing. RESULTS: Of 611 RCTs, 475 were eligible for analysis. Some 397 RCTs (83.6 per cent) were registered on a trial database, of which 190 (47·9 per cent) had been registered prospectively. Prospective registration increased over time (26 per cent in 2009, 33·0 per cent in 2012, 54 per cent in 2015, and 72·7 per cent in 2018). Funding disclosure was present in 55·0, 65·0, 69·4 and 75·4 per cent of manuscripts respectively. Conflict of interest disclosure was present in 49·5, 89·1, 94·6 and 98·3 per cent of manuscripts across the same time periods. Data-sharing statements were present in only 15 RCTs (3·2 per cent), 11 of which were published in 2018. CONCLUSION: Trial registration, disclosure of funding and disclosure of investigator conflicts in surgical RCTs have improved markedly over the past 10 years. Disclosure of data-sharing plans is exceptionally low. This may contribute to research waste and represents a target for improvement.


ANTECEDENTES: Los ensayos clínicos aleatorizados y controlados (randomized controlled trials, RCT) proporcionan la base científica para la toma de decisiones terapéuticas. Es importante que los métodos y los resultados se presenten de forma transparente para facilitar la revisión crítica. El objetivo de este estudio fue investigar la transparencia en los RCTs del ámbito quirúrgico según su registro, declaraciones de las fuentes de financiación del estudio y conflicto de interés de los investigadores, así como información referente a compartir los datos. MÉTODOS: Revisión transversal de RCTs quirúrgicos publicados. Se realizó una búsqueda sistemática de los RCTs publicados en 10 revistas de alto impacto en los años 2009, 2012, 2015 y 2018. Se exploraron cuatro dominios de transparencia: el registro de los ensayos, la declaración de los fondos utilizados, la declaración de los conflictos de los investigadores y la información referente a la forma de compartir los datos. RESULTADOS: De 611 RCTs, se incluyeron en el análisis 475. Un total de 397 (83,6%) estudios se registraron en una base de datos de ensayos clínicos, de forma prospectiva en 190 (47,9%). El registro prospectivo aumentó a lo largo del tiempo (26,0% en 2009, 33,0% en 2012, 53,5% en 2015 y 72,7% en 2018). Se mencionaban las fuentes de financiación en el 55%, 65%, 69,4% y 75,4% de los manuscritos, respectivamente. La declaración de conflictos de interés estuvo presente en el 49,5%, 89,1%, 94,6% y 98,3% de los manuscritos en esos mismos períodos de tiempo. Las declaraciones relativas a compartir los datos de la investigación constaban en solo 15 (3,2%) RCTs, 11 de los cuales fueron publicados en el 2018. CONCLUSIÓN: En los últimos 10 años ha mejorado de forma notable el registro de los ensayos y las declaraciones de las fuentes de financiación y conflicto de interés en los RCTs quirúrgicos. La declaración referente a compartir los datos es excepcionalmente baja, lo que puede contribuir al desperdicio de la investigación y constituye un objetivo de mejora.


Assuntos
Conflito de Interesses , Revelação , Cirurgia Geral , Publicações Periódicas como Assunto/estatística & dados numéricos , Ensaios Clínicos Controlados Aleatórios como Assunto/economia , Estudos Transversais , Políticas Editoriais , Humanos , Fator de Impacto de Revistas , Publicações Periódicas como Assunto/normas , Ensaios Clínicos Controlados Aleatórios como Assunto/ética , Apoio à Pesquisa como Assunto
19.
Adv Skin Wound Care ; 33(6): 294-300, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32427785

RESUMO

GENERAL PURPOSE: To provide wound care information that considers the specific physiology of neonates. TARGET AUDIENCE: This continuing education activity is intended for physicians, physician assistants, nurse practitioners, and nurses with an interest in skin and wound care. LEARNING OBJECTIVES/OUTCOMES: After participating in this educational activity, the participant will:1. Differentiate the use of hydrocolloids, hydrogels, foam dressings, and barrier creams in the neonatal population.2. Identify issues related to the use of solvents, alginates, collagen dressings, and negative-pressure wound therapy in neonates. ABSTRACT: OBJECTIVETo discuss what is known about the wound milieu in premature and full-term neonates, including the unique challenges pediatric clinicians face, the therapies that have proven effective, and the therapies contraindicated for use in neonatal wound healing to guide treatment that accounts for the specific physiological characteristics of this often overlooked population. DATA SOURCES: Data were collected on neonatal wound healing from a wide variety of sources, including PubMed, Google Scholar, journals, and textbooks. STUDY SELECTION: Selection criteria included publications focused on the differences and nuances of wound healing in neonates in comparison with all other age groups. DATA EXTRACTION: Data were extracted based on articles covering wound healing therapies with proven effectiveness in neonates. Terms for neonatal wound care were compiled, and then a comprehensive literature search was performed by the authors. DATA SYNTHESIS: Although many therapies are safe for treatment of older children and adolescents, most have not been explicitly tested for neonatal use. This article reviews therapies with proven effectiveness and/or specific concerns in the neonatal population. CONCLUSION: This review sheds light on the advantages and disadvantages of current standards of care regarding wound healing for neonates to direct researchers and clinicians toward developing treatments specifically for this delicate population.


To discuss what is known about the wound milieu in premature and full-term neonates, including the unique challenges pediatric clinicians face, the therapies that have proven effective, and the therapies contraindicated for use in neonatal wound healing to guide treatment that accounts for the specific physiological characteristics of this often overlooked population. Data were collected on neonatal wound healing from a wide variety of sources, including PubMed, Google Scholar, journals, and textbooks. Selection criteria included publications focused on the differences and nuances of wound healing in neonates in comparison with all other age groups. Data were extracted based on articles covering wound healing therapies with proven effectiveness in neonates. Terms for neonatal wound care were compiled, and then a comprehensive literature search was performed by the authors. Although many therapies are safe for treatment of older children and adolescents, most have not been explicitly tested for neonatal use. This article reviews therapies with proven effectiveness and/or specific concerns in the neonatal population. This review sheds light on the advantages and disadvantages of current standards of care regarding wound healing for neonates to direct researchers and clinicians toward developing treatments specifically for this delicate population.


Assuntos
Cicatriz/prevenção & controle , Desbridamento/enfermagem , Fármacos Dermatológicos/uso terapêutico , Higiene da Pele/enfermagem , Cicatrização/fisiologia , Ferimentos e Lesões/enfermagem , Adolescente , Bandagens/estatística & dados numéricos , Criança , Humanos , Recém-Nascido , Tratamento de Ferimentos com Pressão Negativa/métodos , Pomadas/uso terapêutico
20.
Artigo em Inglês | MEDLINE | ID: mdl-32021696

RESUMO

PURPOSE: The purpose of this study is to assess the feasibility of conducting a large, multicentre randomised controlled trial (RCT) comparing needle fasciotomy with limited fasciectomy for treatment of Dupuytren's contractures. DESIGN: The design of this study is a parallel, two-arm, multicentre, randomised feasibility trial with embedded QuinteT Recruitment Intervention. PARTICIPANTS: Patients aged 18 years or over who were referred from primary to secondary care for treatment of a hand with Dupuytren's contractures of one or more fingers of more than 30° at the metacarpophalangeal (MCP) and/or proximal interphalangeal (PIP) joints and well-defined cord(s). Patients were excluded if they had undergone previous Dupuytren's contracture surgery on the same hand. METHODS: Potential participants were screened for eligibility. Recruited participants randomised (1:1) to treatment with either needle fasciotomy or limited fasciectomy and followed-up for up to 6 months after treatment. Data on recruitment rates, completion of follow-up, and procedure costs were collected. Four patient reported outcome measures (PROMs) and objective outcome measures were collected before intervention and 6 weeks and 6 months afterwards. RESULTS: One hundred and fifty-three of 267 (57%) primary-care referrals for Dupuytren's contractures met the eligibility criteria for the study. Seventy-one of the 153 (46%) agreed to participate and were randomly allocated to treatment with needle fasciotomy or limited fasciectomy. Sixty-seven of these underwent their allocated treatment, two were crossovers from limited fasciectomy to needle fasciotomy, and two (both allocated limited fasciectomy) received no treatment. Fifty-nine participants (85%) completed 6-month follow-up PROMs. Participants felt the MYMOP, PEM and URAM PROMs allowed them to better describe how their treatment affected their hand function than the DASH PROM. The estimated costs of limited fasciectomy (in an operating theatre) and needle fasciotomy (in a clinic room) were £777 and £111 respectively. CONCLUSION: A large RCT comparing treatment of Dupuytren's contractures by needle fasciotomy and limited fasciectomy is feasible. Data from this study will help determine the number of sites and duration of recruitment required to complete an adequately powered RCT and will assist the selection of PROMs in future studies on the treatment of Dupuytren's contractures. (Level 1 feasibility study). TRIAL REGISTRATION: Trial registered with ISRCTN (registration number: ISRCTN11164292), date assigned - 28/08/2015.

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