We investigate the presence of helical character and chirality using a vector-based charge density perspective instead of energetic or structural measures. The vector-based perspective of the chemical bonding, constructed using the most preferred direction of charge density accumulation, finds the presence of induced symmetry-breaking for α,ω-disubstituted [4]cumulenes as the end groups are torsioned. The stress tensor trajectories Tσ(s) are used to provide the additional symmetry-breaking required to quantify the degree and nature of the chirality and helical character. We find an absence of chirality for [4]cumulene but a very significant degree of axiality as demonstrated by the purely axial form of the Tσ(s) indicating a lack of helical character. The S-1,5-dimethyl-[4]cumulene contains a very low degree of chiral character but significant axiality(helicity) resulting in a weakly helical morphology of the corresponding Tσ(s). The (-)S(-), (+)S(-) and (+)S(+) conformations of S-1,5-diamino-[4]cumulene contain very significant degrees of both chirality and helical character resulting in helical morphology of the corresponding Tσ(s). The chirality assignments are in agreement with the Cahn–Ingold–Prelog (CIP) classifications for the (-)S(-), (+)S(-) and (+)S(+) conformations of S-1,5-diamino-[4]cumulene. We discuss the consequences for the Tσ(s) in locating chiral character in these molecules in future experiment investigations.

Metformin is one of the first-line and widely-used drugs in patients with T2DM due to its safety profile, clinical efficacy and cheap cost. It is clearly that metformin has benefits on lowering hyperglycemia and diabetes-related complications in clinical use. The classic effect of metformin is to reduce hepatic glucose production by inhibiting gluconeogenesis in liver and increase glucose utilization in peripheral tissues. Metformin targets mitochondrial respiratory chain complex I to specifically reduce reactive oxygen species generation to protect cells against oxidative stress-induced cell apoptosis. AMPK complex is a key factor in the action of metformin; however it is inconclusive that whether metformin activate AMPK directly or indirectly. In addition, more and more studies showed that metformin act on gut microbiota to exert anti-hyperglycemia effect. Emerging evidence showed that metformin has off-label function on antitumor therapy; however the underlying mechanism of this property of metformin still remains elusive. Taken together, in this review we provide a new perspective on metformin and repurpose its novel and promising application in antitumor therapy.

Objectives: Paediatric patients living with tracheostomies are a medically vulnerable group. During the COVID-19 pandemic, there may be apprehension about their susceptibility to SARS-CoV-2 infection with unknown consequences. Healthcare workers managing this cohort can be anxious about viral transmission from respiratory secretions and aerosols emerging from the open airway. Our objective is to share a systematic approach to minimise incidental mismanagement, avoid iatrogenic airway injury, reduce aerosolisation and decrease staff exposure when treating these patients. Methods: A COVID-19 emergency management plan was created for paediatric patients with tracheostomies in the event of presentation with unknown, suspected or proven SARS-CoV-2 infection. Three documents were developed: a generic tracheostomy management plan detailing troubleshooting measures to reduce air leak from around the tube; a personalised management plan with customised recommendations; a guide for tracheostomy tube change with emphasis on minimising aerosol production. Results: Our plan was distributed to 31 patients (age range 11 months - 17 years) including 23 (74.2%) with uncuffed tubes and 9 (29%) on long term ventilation. There have been 10 occasions in which the plan was utilised and influenced care, including 4 situations where successful troubleshooting avoided tube manipulation and 6 situations where an uncuffed tube was safely replaced with a pre-selected cuffed tube to reduce air leak. Conclusions: A structured approach to emergency presentations during the COVID-19 pandemic may safeguard paediatric patients from unnecessary manipulation of their tracheostomy tube and airway trauma, as well as provide guidance to minimise viral exposure and allow provision of expeditious care.

Patients diagnosed with COVID-19 infection undergoing surgical procedures have been reported to have increased post-operative complications and mortality. These findings are important when considering cardiac surgical procedures, specifically coronary artery bypass grafting (CABG). This case series describes the clinical course following a CABG procedure in two patients that went on to develop COVID-19 infection post-operatively, having previously tested negative. We aim to illustrate the similarities in clinical presentation, but differences in eventual outcomes for both patients and hypothesize the reasons for the differences. Patients with comorbidities such as advanced age, diabetes mellitus, obesity, hypertension, and COPD are possibly at increased risk of adverse outcomes should they contract the infection, and special care should be taken in this population. Early institution of VV-ECMO may be beneficial, but further studies are needed in this matter.

image, and the arrow area is the focus area; D shows the MRI T1 image, the arrow area is the focus area, showing high signal, the low signal shadow can be seen in the middle of the focus, and the

As a rapidly growing field of community ecology, the study of meta-communities provides an effective framework to unravel community assembly mechanisms by focusing on the relative contributions of environmental screening and spatial processes. While macroinvertebrates have been extensively investigated in many river ecosystems, meta-community ecology perspectives in high mountain stream networks are very limited. In this study, we assessed the role of ecological determinants and temporal dynamics in the macroinvertebrate meta-community assembly of an alpine stream situated in a dry-hot valley of Baima Snow Mountain, Northwest Yunnan. Our results show significant differences in the macroinvertebrate community composition across time periods. Spatial structuring and environmental filtering jointly drive the configuration of macroinvertebrate meta-community, with relative contributions to the variance in community composition varying over time. Redundancy Analysis (RDA) and variation partitioning indicate that environmental variables are the most important predictors of community organization in most scenarios, whereas spatial determinants also play a significant role. Moreover, the explanatory power, identity, and the relative significance of ecological indicators change over time. Particularly, in the years 2018 and 2019, stronger environmental filtering was found shaping community assembly, suggesting that deterministic mechanisms predominated in driving community dynamics in such a specific environment of the stream. However, spatial factors had a stronger predictive power on meta-community structures in 2017, implying conspicuous dispersal mechanisms which may be owing to increased connectivity amongst locations. Thereby, we inferred that the stream macroinvertebrate metacommunity composition can be regulated by the interaction of both spatial processes and environmental filtering, with relative contributions varying over time. Based on these findings, we suggest that community ecology studies in aquatic systems should be designed beyond single snapshot investigations.

Spontaneous isolated superior mesenteric artery dissection (SISMAD) is a rare and potentially fatal cause diagnosis presenting with acute abdominal; however, because of its rarity, the pathogenic factors of SISMAD remain unknown and no clear cause has been found. Moreover, there is a lack of evidence-based treatment guidelines.

Hyperdontia involving the premolar teeth can be single or multiple or even related to a syndrome. These are frequently encountered in permanent dentition, but their occurrence has ranged between 0.09 to 0.64% in the general population. These are rarely found between the first and second premolars.

Background The ideal aortic valve replacement strategy in young- and middle-aged adults remains up for debate. Clinical practice guidelines recommend mechanical prostheses for most patients less than 50 years of age undergoing aortic valve replacement. However, risks of major hemorrhage and thromboembolism associated with long-term anticoagulation may make the pulmonary autograft technique, or Ross procedure, a preferred approach in select patients. Methods Data were retrospectively collected for patients 18 to 50 years of age who underwent either the Ross procedure or mechanical aortic valve replacement (mAVR) between January 2000 and December 2016 at a single institution. Propensity score matching was performed and yielded 32 well-matched pairs from a total of 216 eligible patients. Results Demographic and preoperative characteristics were similar between the two groups. Median follow-up was 7.3 and 6.9 years for Ross and mAVR, respectively. There were no early mortalities in either group and no statistically significant differences were observed with respect to perioperative outcomes or complications. Major hemorrhage and stroke events were significantly more frequent in the mAVR population ( p < 0.01). Overall survival ( p = 0.93), freedom from reintervention and valve dysfunction free survival ( p = 0.91) were equivalent. Conclusions In this mid-term propensity score-matched analysis, the Ross procedure offers similar perioperative outcomes, freedom from reintervention or valve dysfunction as well as overall survival compared to traditional mAVR but without the morbidity associated with long-term anticoagulation. At specialized centers with sufficient expertise, the Ross procedure should be strongly considered in select patients requiring aortic valve replacement.

Odontomas are common occurrences in the oral cavity and can be classified as complex or compound. Erupted peripheral compound odontomas are rare and are present in the extra-osseous soft tissues. In this case the odontoma led to the impaction of permanent teeth for which removal of the lesion was advised.

Objectives. The efficiency of Covid-19 vaccination is determined by cellular and humoral immune responses, and for the latter, by the balance between neutralizing and infection-enhancing antibodies. Here we analyzed the evolution of neutralizing and facilitating epitopes in the spike protein among SARS-CoV-2 variants. Methods. Amino acid alignments were performed on 929,203 spike sequences over the 4 last months. Molecular modeling studies of the N-terminal domain (NTD) and rod-like regions of the spike protein were performed on a representative panel of SARS-CoV-2 variants that were structurally compared with the original Wuhan strain. Results. D614, which belongs to an antibody-dependent-enhancement (ADE) epitope common to SARS-CoV-1 and SARS-CoV-2, has rapidly mutated to D614G in the first months of 2020, explaining why ADE has not been detected following mass vaccination. We show that this epitope is conformationally linked to the main ADE epitope of the SARS-CoV-2 NTD which is highly conserved among most variants. In contrast, the neutralizing epitope of the NTD showed extensive variations in SARS-CoV-2 variants. Conclusions. This molecular epidemiology study coupled with structural analysis of the spike protein indicates that the balance between facilitating and neutralizing antibodies in vaccinated people is in favor of neutralization for the Wuhan strain, alpha and beta variants, but not for gamma, delta, lambda and mu. The evolution of SARS-CoV-2 has dramatically affected the ADE/neutralization balance which is nowadays in favor of ADE. Future vaccines should consider these data to design new formulations adapted to SARS-CoV-2 variants and lacking ADE epitopes in the spike protein.

High interindividual variability in pharmacokinetics coupled with concentration-effect relationship make sunitinib an ideal candidate for therapeutic drug monitoring (TDM). The feasibility of TDM of sunitinib in patients with metastatic renal cell carcinoma (mRCC) was evaluated in this prospective observational study. Seventy patients with mRCC treated with sunitinib 50mg OD were enrolled. Total trough levels (TTL) of sunitinib and N-desethyl sunitinib were measured between days 10-14 of cycle 1. The discriminatory potential of TTL of sunitinib for the prediction of responders and occurrence of grade ≥3 toxicity was determined using receiver operating characteristic (ROC) curve. Threshold concentrations obtained from ROC analysis showed that TTL ≥60.75ng/mL was associated with higher response rates and TTL ≥82.3ng/mL was associated with higher incidence of grade ≥3 toxicity compared with lower exposures (31/34 versus 5/12, P=0.001 and 9/24 versus 4/36; P=0.024 respectively). More than 50% of patients in our cohort attained TTL outside the optimal range of 60.75-82.3 ng/mL demonstrating the feasibility of TDM.

COVID-19 has spread globally, affecting almost 160 million individuals. Elderly and pre-existing patients (such as diabetes, heart disease and asthma), seems more susceptible to serious illness with COVID-19. Roflumilast was licensed for usage in the European Union in July 2010 as a phosphodiesterase-4 (PDE4) inhibitor. Roflumilast has been shown to decrease bleomycin-induced lung fibrosis, lung hydroxyproline, right heart thickning in animal prophylactic. The current study reviewed existing data that the PDE-4 inhibitor protects not just renal tissues but also other major organ systems after COVID-19 infection by decreasing immune cell infiltration. These immune-balancing effects of roflumilast were related with a decrease in oxidative and inflammatory burden, caspase-3 suppression, and increased PKA/cAMP levels in renal and other organ tissue.

A novel aerial tracer particle distribution system has been developed. This system is mounted on an Unmanned Aerial Vehicle (UAV) and flown upstream from where surface velocimetry measurements are conducted. This enables surface velocimetry techniques to be applied in rivers and channels lacking sufficient natural tracer particles or surface features. Lack of tracers is a common problem during low flows, in lowland rivers, or in artificial channels. This is particularly problematic for analysis conducted using Particle Image Velocimetry (PIV) techniques where dense tracer particles are required. Techniques for colouring tracer particles with biodegradable dye have also been developed, along with methods for extracting them from Red Green Blue (RGB) imagery in the Hue Saturation Value (HSV) colour space. The use of coloured tracer particles enables flow measurements in situations where sunglint, surface waves, moving shadows, or dappled lighting on riverbeds can interfere with and corrupt results using surface velocimetry techniques. These developments further expand the situations where surface velocimetry can be applied, as well as improving the accuracy of the results.

Spin projected wave functions are known as generalizations of the Hartree-Fock wave function. Among them, the Half-Projected Hartree-Fock (HPHF) model represents a good compromise between the restricted (RHF) and unrestricted (UHF) Hartree-Fock methods. The HPHF wave function is a nearly pure wave function of spin and recovers a small part of the spin correlation energy. This paper reviews the history of the HPHF theory, not only from the conceptual point of view but also providing a compilation of the publications of this method over the years until now. In addition, the extension of the HPHF method to the calculation of non-orthogonal excited states to the ground state will be treated. The variational collapse during the calculation of singlet excited states with the same symmetry as the ground state is avoided by orthogonalizing the excited orbital to the corresponding occupied orbital. As an example, the potential energy surface of the S0 ground and 1S1(n, π∗) first excited state of the formic acid HCOOH are calculated. Formic acid exhibits complex energy surfaces with respect two large amplitude motions, the torsional rotation of the O-H group and the waving out-of-plane angle of the H atom. In the excited state, the molecule adopts a pyramidal structure. The obtained energy results are fitted to curves that can be used for the calculation of the theoretical spectrum.

1. Species performance in the realised niche is jointly shaped by both abiotic and biotic processes. Moreover, interactions between and within abiotic and biotic processes generate non-additivities, resulting in density dependence that varies in strength or even direction across environments. If ignored, these non-additivities can lead to inaccurate predictions of species responses to changes in environment and community composition. 2. There are increasing empirical efforts to test the constancy of pairwise biotic interactions along environmental and compositional gradients, but rarely along both. We address this gap using nationwide forest inventory data that span broad ambient temperature and moisture gradients throughout New Zealand. 3. We analysed tree diameter growth of six focal tree species as a function of neighbour densities and climate, while accounting for potential abiotic and biotic non-additivities arising from neighbour × climate and neighbour × neighbour statistical interactions, respectively. We kept the large number of parameters manageable using Bayesian shrinkage priors and interpretable using average predictive comparisons. 4. We found that the most complex model—featuring biotic interactions that changed with climate and higher-order interactions with intermediary species—had the highest predictive accuracy of tree diameter growth. Compared to climate, biotic interactions typically had stronger effects on tree diameter growth, especially when they were subjected to non-additivities from local climate and the density of a third species. Most non-additivities tended to weakly exacerbate pairwise competition, whereas the few strong non-additivities tended to alleviate pairwise competition or even produce pairwise facilitation. 5. _Synthesis:_ Our study highlights the importance of the interplay between abiotic and biotic processes when predicting how biotic interactions may structure communities under global change. When quantifying the relative importance of biotic and abiotic processes on species performance, we show that the conclusion varies depending on whether we are looking at direct or indirect effects. With accumulating evidence of non-additive biotic interactions, the next crucial step is to uncover their underlying mechanisms.

The components of complex differentiable functions define solutions for the Laplace's equation, and in a simply connected domain each solution of this equation is the first component of a complex analytic function. In this paper we generalize this result; for each PDE of the form Au xx +Bu xy +Cu yy = 0 and for each affine planar vector field ϕ, we give an associative and commutative 2D algebra with unit A, with respect to which the components of all functions of the form L • ϕ define solutions for this PDE, where L is differentiable in the sense of Lorch with respect to A. By using the generalized Cauchy-Riemann equations associated with ϕA-differentiability we show that each solution of these PDEs is a component of a ϕA-differentiable function. In the same way, for each PDE of the form Au xx + Bu xy + Cu yy + Du x + Eu y + F u = 0, the components of the exponential function e ϕ defined with respect to A, define solutions for this PDE. Also, solutions for two independent variables 3 th order PDEs and 4 th order PDE are constructed; among these are the bi-harmonic, bi-wave, and bi-telegraph equations.

Soft fluidic actuators produce continuous and life-like motions that are intrinsically safe, but current designs are not yet mature enough to enable large deployment with high force and low-cost fabrication methods. Here, soft fluidic actuators with two superimposed origami architectures are reported. Driven by a fluid input, the presented dual-origami soft actuators produce quasi-sequential deployment and bending motion that is guided by unsymmetric unfolding of low-stretchable origami components. The dominance between the deployment and bending can be shifted by varying the unfolding behavior, enabling pre-programming of the motion. The proposed origami-inspired soft actuators are directly fabricated by low-cost fused deposition modeling 3D-printing, and subjected to a heat treatment post-processing to enhance the fluid sealing performance. Finally, soft gripper applications are presented and they successfully demonstrate gripping tasks that each requires strength, delicacy, precision and dexterity. The dual-origami approach offers a design guidance for soft robots to embody grow-and-retract motion with a small initial form factor, promising for applications in next-generation soft robotic systems.

Telehealth has become an increasingly popular method of delivery of health-related services. Under the umbrella of telehealth lies telemental health (TMH). Although this type of modality has been around for quite some time, it was not until the arrival of Covid-19 during 2020-2021 that the United States healthcare system began to fully accept, embrace, and implement TMH. Due to public health restrictions related to Covid-19, in person therapy and other social services were prohibited (or restricted) thus relying on TMH. This article discusses the link between a racial justice lens, minority stress theory, health equity and identifies barriers/challenges in telemental health that do not reflect equity in health for racial minorities including Black, Indigenous, Hispanic, and Latinx communities, and all communities of color. 

Most patients presenting with allergies are first seen by primary care health professionals. The perceived knowledge gaps and educational needs were recently assessed in response to which the LOGOGRAM Task Force was established with the remit of constructing pragmatic flow-diagrams for common allergic conditions in line with an earlier EAACI proposal to develop simplified pathways for the diagnosis and management of allergic diseases in primary care. To address the lack of accessible and pragmatic guidance, we designed flow-diagrams for five major clinical allergy conditions: asthma, anaphylaxis, food allergy, drug allergy and urticaria. Existing established allergy guidelines were collected and iteratively distilled to produce five pragmatic and accessible tools to aid diagnosis and management of these common allergic problems. Ultimately, they should now be validated prospectively in primary care settings.

Schistosomiasis is a neglected tropical disease of humans caused by blood flukes of the genus Schistosoma – the only dioecious parasitic flatworms. Although aspects of sex determination, differentiation and reproduction have been studied in some Schistosoma species, almost nothing is understood for Schistosoma japonicum - the causative agent of schistosomiasis japonica. This relates mainly to a lack of high-quality genomic and transcriptomic resources for this species. As current draft genomes for S. japonicum are highly fragmented, we assembled here a chromosome-level reference genome (seven autosomes, the Z-chromosome and partial W-chromosome), achieving a substantially enhanced gene annotation. Utilising this genome, we discovered that the sex chromosomes of S. japonicum and its congener S. mansoni independently suppressed recombination during evolution, forming four and two ‘strata’, respectively. By exploring the W-chromosome and sex-specific transcriptomes, we identified 35 W-linked genes and 257 female-preferentially transcribed genes (FTGs) and identified a signature for sex determination and differentiation in S. japonicum. These FTGs cluster within autosomes or the Z-chromosome and exhibit a highly dynamic transcription profile during the pairing of female and male schistosomules (advanced juveniles), representing a critical phase for the maturation of the female worms, suggesting distinct layers of regulatory control of gene transcription at this stage of development. Collectively, these data provide a valuable resource for further functional genomic characterisation of S. japonicum, shed light on the evolution of sex chromosomes in this highly virulent human blood fluke and provide a pathway to identify novel targets for development of intervention tools against schistosomiasis.

Aim: nlmixr offers first-order conditional estimation with or without interaction (FOCE or FOCEi) and stochastic approximation estimation-maximisation (SAEM) to fit nonlinear mixed-effect models (NLMEM). We modelled metformin’s population pharmacokinetics with flip-flop characteristics within nlmixr framework and investigated SAEM and FOCEi’s performance with respect to bias, precision, and robustness. Method: Compartmental pharmacokinetic models were fitted. The final model was determined based on the lowest objective function value and visual inspection of goodness-of-fit plots. To examine flip-flop pharmacokinetics, k_a values of a typical concentration-time profile based on the final model were perturbed and changes in the steepness of the terminal elimination phase were evaluated. The bias and precision of parameter estimates were compared between SAEM and FOCEi using stochastic simulations and estimations. For robustness, parameters were re-estimated as the initial estimates were perturbed 100-times and resultant changes evaluated. Results: A one-compartment model with transit compartment for absorption best described the data. At low n, Stirling’s approximation of n! over-approximated plasma concentration unlike the log-gamma function. Flip-flop pharmacokinetics were evident as the steepness of the terminal elimination phase changed with k_a. Mean rRMSE for fixed-effect parameters was 0.932. When initial estimates were perturbed, FOCEi estimates of k_a and food effect on k_a appeared bimodal and were upward biased. Discussion: nlmixr is reliable for NLMEM even if flip-flop is present but caution should be exercised when using Stirling’s approximation for n! in the transit compartment model. SAEM was marginally superior to FOCEi in bias and precision, but SAEM was superior against initial estimate perturbations.

Considerable calcification and stenosis frequently occur in the radial artery (RA) in diabetic nephropathy. PTA was performed successfully using balloon to expand and restrictively tear the longitudinal axis of the RA. Serendipity,the method indicates it may be a useful measure of promoting maturation of AVF in diabetic nephropathy

Renal involvement in spondyloarthritis is dominated by amyloidosis, IgA nephropathy and urolithiasis. Other nephropathies are rare . A patient followed for SpA consults with edema , hydrocele and a pleural effusion. A FSGS was confirmed by renal biopsy and the etiological investigation has ruled out the causes of secondary FSGS.