7,553 research outputs found
Random Function Descent
While gradient based methods are ubiquitous in machine learning, selecting
the right step size often requires "hyperparameter tuning". This is because
backtracking procedures like Armijo's rule depend on quality evaluations in
every step, which are not available in a stochastic context. Since optimization
schemes can be motivated using Taylor approximations, we replace the Taylor
approximation with the conditional expectation (the best estimator) and
propose "Random Function Descent" (RFD). Under light assumptions common in
Bayesian optimization, we prove that RFD is identical to gradient descent, but
with calculable step sizes, even in a stochastic context. We beat untuned Adam
in synthetic benchmarks. To close the performance gap to tuned Adam, we propose
a heuristic extension competitive with tuned Adam
Hypertrophic Cardiomyopathy: Surgical Perspectives
Hypertrophic cardiomyopathy is a unique myocardial disorder that can present in all ages from neonate to adults and has strong genetic basis. Several key features characterize hypertrophic cardiomyopathy. These include: the presence of left ventricular hypertrophy that can not be explained by another etiology, and left ventricular outflow tract obstruction secondary to systolic anterior motion of the anterior mitral valve leaflet with varying degrees of mitral valve regurgitation. Surgical septal myectomy continues to be the standard line of treatment when medical therapy fails or become intolerable. We summarize in the current chapter the technical tips and pitfall of septal myectomy, its alternatives/adjuncts and its outcomes
Feature Papers in Compounds
This book represents a collection of contributions in the field of the synthesis and characterization of chemical compounds, natural products, chemical reactivity, and computational chemistry. Among its contents, the reader will find high-quality, peer-reviewed research and review articles that were published in the open access journal Compounds by members of the Editorial Board and the authors invited by the Editorial Office and Editor-in-Chief
Utilisation of Emulsion-based Techniques to Prepare Polymeric Nanocomposites with different Graphene Derivatives as Fillers
Due to the extraordinary mechanical, electrical, and thermal properties, graphene has been used for incorporation with a wide range of natural and synthetic polymers for the fabrication of advanced composites. However, the inertness of graphene induces ineffective interactions with a lot of polymer matrices, which hinders its applicability. Therefore, graphene derivatives with various surface modifications have been studied and developed to enhance these interactions, as well as introduce new unique properties and further broaden the applications. Synthesis of polymeric nanocomposites with graphene and its derivatives has however been facing serious challenges in achieving homogeneous dispersion and avoiding filler aggregation. Furthermore, more simplified and environmentally friendly methods have been prioritised to avoid dangerous chemical hazards and reduce consumption from energy-intensive processes.
Graphene quantum dot (GQD) and carbon nanotube (CNT) are the focused graphene-based materials due to their distinct differences in morphology and intrinsic properties. With large specific surface area, high loading capacity and similar amphiphilicity as graphene oxide (GO), GQD has been reported to effectively stabilise oil-in-water emulsions. Yet, exploitation of its capability as alternative surfactants in heterogeneous polymerisation systems is rather limited, and its effect on the polymeri-sation kinetics and mechanisms needs to be more elaborated. As for CNT, both covalently and non-covalently functionalised CNT has been utilised in the fabrication of conductive composites via emulsion-based polymerisation and latex technology. Aggregation problem was somewhat elevated and homogeneous distribution was achieved, but CNT concentrations remained relatively low and enhancement in physical properties of the as-developed composites was not significant.
Therefore, this Thesis presents in-depth investigations to tackle the mentioned issues for each type of graphene derivatives, with the basis of utilising water-based heterogeneous polymerisation techniques and latex technology. Firstly, carboxylated GQDs (cGQD) were selected as a species of GQD, and its effectiveness in stabilising waterborne polymer particles was scrutinised in various miniemulsion polymerisation systems using eight different monomers, and two initiators with contrasting water solubility. cGQD can replace conventional surfactants in these systems as polymer particles are colloidally stable at cGQD concentrations of higher than 5 wt.%. Additionally, the nature of monomers and initiators was demonstrated as major factors significantly altering the miniemulsion polymerisation kinetics. Secondly, multiwalled carbon nanotubes (MWNT) as a type of CNT were non-covalently functionalised using two surfactants with different ionicity separately, which were subsequently incorporated in the fabrication of MWNT/polymer nanocomposites through in situ miniemulsion polymerisation (MP) and physical mixing (PM). MP films exhibited elastomeric behaviours with low tensile strength and extremely high stretchability, whereas PM films yielded exceptional electrical conductivity up to 164.28 S/cm at 5 wt.% MWNT, which lies in the top percentage for CNT-based polymer composites regardless of polymer matrix, fabrication method and CNT type.
In conclusion, these results illustrate the efficacy of emulsion-based polymerisation techniques and latex technology in producing homogeneous nanocomposite latexes and films with remarkable functionalities, offering more facile pathways in designing and nanoengineering graphene-based composite materials for specific applications
Writing Facts
»Fact« is one of the most crucial inventions of modern times. Susanne Knaller discusses the functions of this powerful notion in the arts and the sciences, its impact on aesthetic models and systems of knowledge. The practice of writing provides an effective procedure to realize and to understand facts. This concerns preparatory procedures, formal choices, models of argumentation, and narrative patterns. By considering »writing facts« and »writing facts«, the volume shows why and how »facts« are a result of knowledge, rules, and norms as well as of description, argumentation, and narration. This approach allows new perspectives on »fact« and its impact on modernity
Estudo da remodelagem reversa miocárdica através da análise proteómica do miocárdio e do líquido pericárdico
Valve replacement remains as the standard therapeutic option for aortic
stenosis patients, aiming at abolishing pressure overload and triggering
myocardial reverse remodeling. However, despite the instant hemodynamic
benefit, not all patients show complete regression of myocardial hypertrophy,
being at higher risk for adverse outcomes, such as heart failure. The current
comprehension of the biological mechanisms underlying an incomplete reverse
remodeling is far from complete. Furthermore, definitive prognostic tools and
ancillary therapies to improve the outcome of the patients undergoing valve
replacement are missing. To help abridge these gaps, a combined myocardial
(phospho)proteomics and pericardial fluid proteomics approach was followed,
taking advantage of human biopsies and pericardial fluid collected during
surgery and whose origin anticipated a wealth of molecular information
contained therein.
From over 1800 and 750 proteins identified, respectively, in the myocardium
and in the pericardial fluid of aortic stenosis patients, a total of 90 dysregulated
proteins were detected. Gene annotation and pathway enrichment analyses,
together with discriminant analysis, are compatible with a scenario of increased
pro-hypertrophic gene expression and protein synthesis, defective ubiquitinproteasome system activity, proclivity to cell death (potentially fed by
complement activity and other extrinsic factors, such as death receptor
activators), acute-phase response, immune system activation and fibrosis.
Specific validation of some targets through immunoblot techniques and
correlation with clinical data pointed to complement C3 β chain, Muscle Ring
Finger protein 1 (MuRF1) and the dual-specificity Tyr-phosphorylation
regulated kinase 1A (DYRK1A) as potential markers of an incomplete
response. In addition, kinase prediction from phosphoproteome data suggests
that the modulation of casein kinase 2, the family of IκB kinases, glycogen
synthase kinase 3 and DYRK1A may help improve the outcome of patients
undergoing valve replacement. Particularly, functional studies with DYRK1A+/-
cardiomyocytes show that this kinase may be an important target to treat
cardiac dysfunction, provided that mutant cells presented a different response
to stretch and reduced ability to develop force (active tension).
This study opens many avenues in post-aortic valve replacement reverse
remodeling research. In the future, gain-of-function and/or loss-of-function
studies with isolated cardiomyocytes or with animal models of aortic bandingdebanding will help disclose the efficacy of targeting the surrogate therapeutic
targets. Besides, clinical studies in larger cohorts will bring definitive proof of
complement C3, MuRF1 and DYRK1A prognostic value.A substituição da válvula aórtica continua a ser a opção terapêutica de
referência para doentes com estenose aórtica e visa a eliminação da
sobrecarga de pressão, desencadeando a remodelagem reversa miocárdica.
Contudo, apesar do benefício hemodinâmico imediato, nem todos os pacientes
apresentam regressão completa da hipertrofia do miocárdio, ficando com maior
risco de eventos adversos, como a insuficiência cardíaca. Atualmente, os
mecanismos biológicos subjacentes a uma remodelagem reversa incompleta
ainda não são claros. Além disso, não dispomos de ferramentas de
prognóstico definitivos nem de terapias auxiliares para melhorar a condição
dos pacientes indicados para substituição da válvula. Para ajudar a resolver
estas lacunas, uma abordagem combinada de (fosfo)proteómica e proteómica
para a caracterização, respetivamente, do miocárdio e do líquido pericárdico
foi seguida, tomando partido de biópsias e líquidos pericárdicos recolhidos em
ambiente cirúrgico.
Das mais de 1800 e 750 proteínas identificadas, respetivamente, no miocárdio
e no líquido pericárdico dos pacientes com estenose aórtica, um total de 90
proteínas desreguladas foram detetadas. As análises de anotação de genes,
de enriquecimento de vias celulares e discriminativa corroboram um cenário de
aumento da expressão de genes pro-hipertróficos e de síntese proteica, um
sistema ubiquitina-proteassoma ineficiente, uma tendência para morte celular
(potencialmente acelerada pela atividade do complemento e por outros fatores
extrínsecos que ativam death receptors), com ativação da resposta de fase
aguda e do sistema imune, assim como da fibrose.
A validação de alguns alvos específicos através de immunoblot e correlação
com dados clínicos apontou para a cadeia β do complemento C3, a Muscle
Ring Finger protein 1 (MuRF1) e a dual-specificity Tyr-phosphoylation
regulated kinase 1A (DYRK1A) como potenciais marcadores de uma resposta
incompleta. Por outro lado, a predição de cinases a partir do fosfoproteoma,
sugere que a modulação da caseína cinase 2, a família de cinases do IκB, a
glicogénio sintase cinase 3 e da DYRK1A pode ajudar a melhorar a condição
dos pacientes indicados para intervenção. Em particular, a avaliação funcional
de cardiomiócitos DYRK1A+/- mostraram que esta cinase pode ser um alvo
importante para tratar a disfunção cardíaca, uma vez que os miócitos mutantes
responderam de forma diferente ao estiramento e mostraram uma menor
capacidade para desenvolver força (tensão ativa).
Este estudo levanta várias hipóteses na investigação da remodelagem reversa.
No futuro, estudos de ganho e/ou perda de função realizados em
cardiomiócitos isolados ou em modelos animais de banding-debanding da
aorta ajudarão a testar a eficácia de modular os potenciais alvos terapêuticos
encontrados. Além disso, estudos clínicos em coortes de maior dimensão
trarão conclusões definitivas quanto ao valor de prognóstico do complemento
C3, MuRF1 e DYRK1A.Programa Doutoral em Biomedicin
Recommended from our members
MODELING CHAIN PACKING IN COMPLEX PHASES OF SELF-ASSEMBLED BLOCK COPOLYMERS
Block copolymer (BCP) melts undergo microphase seperation and form ordered soft matter crystals with varying domain shapes and symmetries. We study the con- nection between diblock copolymer molecular designs and thermodynamic selection of ordered crystals by modeling features of variable sub-domain geometry filled with individual blocks within non-canonical sphere-like and network phases that together with layered, cylindrical and canonical spherical phases forms “natural forms” of self- assembled amphiphilic soft matter at large. First, we present a model to revise our understanding of optimal Frank-Kasper sphere-like morphologies by advancing the- ory to account for varying domain volumes. We then develop generic approaches to quantify local changes to domain thickness or packing frustration using medial sets and show its application to morphologies with arbitrary domain topologies and sym- metries in both theoretical models and experimental data. We further use medial sets as a proxy for terminal boundaries of blocks within different domains and revise thermodynamic models of BCP assembly in the strong segregation limit. Finally, we use this revised model to study effect of elastic stiffness asymmetry on relaxing packing frustration experienced by BCPs in tubular and matrix domains leading to equilibrium double gyroid network morphology in diblock copolymers
Nonunion of the clavicle: novel use of clinical recovery and ultrasound to improve our ability to predict fracture healing
The aim of this thesis was to progress our understanding of clavicle nonunion and the ability
to accurately predict fracture healing in order to improve the current management of these
injuries.
Although only one in seven fractures go onto nonunion, these are challenging to predict. It is
unclear if the recent widespread increase in the use of acute plate fixation for displaced
fractures is justified on current evidence. It is unknown whether the early accurate prediction
of fractures at high risk of nonunion is advantageous. Currently the perceived risk of nonunion
is largely based on factors available at time of injury alone. The evaluation of clinical recovery
following non-operative management and the novel use of ultrasound may advance our ability
to accurately predict fracture healing for these injuries.
The cost-effectiveness of acute clavicle plate fixation versus non-operative treatment was
estimated from randomized controlled trial data that had been previously published. This was
completed prior to the start of this thesis and the author was not involved in the original trial.
A large retrospective review of clavicle fracture fixations was undertaken to determine whether
delayed clavicle fixation has an increased risk of complications compared to acute operative
management. A prospective study of displaced midshaft fractures was carried out over a two-year period to determine the influence of functional recovery on the ability to predict fracture
healing. The influence of clavicle fracture management on the early functional recovery was
evaluated with data from a randomized controlled trial and second prospective cohort. Finally,
the novel use of ultrasound to detect early callus formation and determine whether this allows
accurate prediction of fracture healing was evaluated for a cohort of clavicle and tibia fractures.
The estimated cost per quality-of-life adjusted year of acute plate fixation over non-operative
treatment is £480,309.41/QALY. For a threshold of £20,000/QALY the benefit of acute
fixation would need to be present for 24 years to be cost-effective over conservative treatment.
Linear regression analysis identified nonunion as the only factor to negatively influence the
SF-6D at 12-months (p<0.001).
A ten-year cohort of 259 clavicle plate fixations found failed primary surgery requiring revision
fixation occurred in 7.7% of all patients. Smoking (p<0.001), presence of a post-operative
infection (<0.001), increasing age (p=0.018), and greater time delay from injury to surgery
(p=0.015) was identified as significant independent predictors on regression analysis. Receiver
operating curve analysis (ROC) revealed that surgery beyond 96 days from injury has an
increased rate of major complications and revision surgery. Using a matched case cohort of
cases before (n=67) and after the ‘safe window’ (n=77), the risk of post-operative infection
increased (Odds ratio (OR) 7.7, p=0.028), fixation failure (OR 3.8, p=0.017) and revision
surgery (OR 4.8 p=0.004). A delay to operative fixation beyond 3 months following injury
would appear to be associated with an increased risk of major operative complications and
revision surgery.
A large prospective cohort of 200 patients managed non-operatively with a displaced midshaft
clavicle fracture were recruited. Regression modelling found a QuickDASH ≥40 (p=0.001), no
callus on radiograph (p=0.004) and fracture movement on examination (p=0.001) were
significant predictors of nonunion. If none were present the predicted nonunion risk was 3%,
found in 40% of the cohort. Conversely if two or more of the predictors were present, found in
23.5% of the cohort, the predicted nonunion risk was 60%. The delayed assessment nonunion
model appeared to have superior accuracy when compared to the estimation of nonunion at
time of injury alone healing on ROC curve analysis (Area Under Curve analysis; 87.3% vs
64.8% respectively).
Data from a randomized controlled trial was used to compare 86 patients who underwent
operative fixation against 76 patients that united with non-operative treatment. The recovery
of normal shoulder function, as defined by a DASH score within the predicted 95% confidence
interval for each respective patient was similar between each group at six-weeks (operative
26.7% vs non-operative 25.0%, p=0.80), three-months (52.3% vs 44.2%, p=0.77) and six-months post-injury (86.0% vs 90.8%, p=0.35). The mean DASH score and return to work was
also comparable at each time point. Regression analysis found no specific patient, injury or
fracture predictor was associated with an early return of function following non-operative
management at six or twelve weeks.
From a pilot study of twenty clavicle fractures, six-week sonographic bridging callus appeared
to be the most accurate, and repeatable, predictor of fracture healing with a strong agreement
on intra class correlation (ICC) between four reviewers (ICC 0.82, 95% confidence interval
0.68-0.91). In a large prospective study of 112 patients, sonographic bridging callus was
detected in 62.5% (n=70/112) of the cohort at six weeks post-injury. If present, union occurred
in 98.6% of the fractures (n=69/70). If absent, nonunion developed in 40.5% of cases
(n=17/42). The sensitivity to predict union with sonographic bridging callus at six weeks was
73.4% and the specificity was 94.4%. Three-dimensional fracture reconstruction can be created
using multiple ultrasound images in order to evaluate the presence of bridging callus. This
imaging modality has the potential to enhance the usability and accuracy of identification of
fracture healing at an early stage following injury.
Nonunion following a displaced midshaft clavicle fractures accounts for the majority of poor
functional recovery and impaired quality of life over the first-year post-injury. Prediction of
clavicle fracture healing at six weeks following injury maybe a safe and effective strategy to
identify patients at greatest risk of nonunion. The use of functional recovery enables a more
accurate estimation of nonunion risk compared to conventional prediction at time of injury
alone. The use of ultrasound may further refine our ability to predict fracture healing
- …