SIRT2 as a potential new therapeutic target for Alzheimer's disease

Alzheimer's disease is the most common cause of dementia globally with an increasing incidence over the years,bringing a heavy burden to individuals and society due to the lack of an effective treatment.In this context,sirtuin 2,the sirtuin with the highest expression in the brain,has emerged as a potential therapeutic target for neurodegenerative diseases.This review summarizes and discusses the complex roles of sirtuin 2 in different molecular mechanisms involved in Alzheimer's disease such as amyloid and tau pathology,microtubule stability,neuroinflammation,myelin formation,autophagy,and oxidative stress.The role of sirtuin 2 in all these processes highlights its potential implication in the etiology and development of Alzheimer's disease.However,its presence in different cell types and its enormous variety of substrates leads to apparently contra dictory conclusions when it comes to understanding its specific functions.Further studies in sirtuin 2 research with selective sirtuin2 modulators targeting specific sirtuin 2 substrates are necessary to clarify its specific functions under different conditions and to validate it as a novel pharmacological target.This will contribute to the development of new treatment strategies,not only for Alzheimer's disease but also for other neurodegenerative diseases.

Context-dependent role of sirtuin 2 in inflammation

Sirtuin 2 is a member of the sirtuin family nicotinamide adenine dinucleotide(NAD~+)-dependent deacetylases, known for its regulatory role in different processes, including inflammation. In this context, sirtuin 2 has been involved in the modulation of key inflammatory signaling pathways and transcription factors by deacetylating specific targets, such as nuclear factor κB and nucleotide-binding oligomerization domain-leucine-rich-repeat and pyrin domain-containing protein 3(NLRP3). However, whether sirtuin 2-mediated pathways induce a pro-or an anti-inflammatory response remains controversial. Sirtuin 2 has been implicated in promoting inflammation in conditions such as asthma and neurodegenerative diseases, suggesting that its inhibition in these conditions could be a potential therapeutic strategy. Conversely, arthritis and type 2 diabetes mellitus studies suggest that sirtuin 2 is essential at the peripheral level and, thus, its inhibition in these pathologies would not be recommended. Overall, the precise role of sirtuin 2 in inflammation appears to be context-dependent, and further investigation is needed to determine the specific molecular mechanisms and downstream targets through which sirtuin 2 influences inflammatory processes in various tissues and pathological conditions. The present review explores the involvement of sirtuin 2 in the inflammation associated with different pathologies to elucidate whether its pharmacological modulation could serve as an effective strategy for treating this prevalent symptom across various diseases.

Interactivity software tools for teaching in ophthalmology

The use of interactive audience software,such as audience response systems(ARS),in medical education has become increasingly popular in recent years.This technology allows instructors to engage students in real time,encouraging active participation and promoting effective learning.The benefits of interactive audience software in medical education include increased student engagement,promotion of active learning,and enhanced learning outcomes.However,there are also several challenges to its implementation,including technical difficulties,careful planning and preparation,over-reliance on technology,and ethical concerns related to privacy and data security.The cost of implementing interactive audience software may also be a barrier for some institutions.This paper specifically reviews six interactive software platforms,including Socrative,Quizizz,Pear Deck,Slido,Wooclap and ClassPoint.These platforms allow for real-time assessment of student understanding,feedback,and participation.They also enable instructors to adjust their teaching strategies based on student responses and feedback.Overall,interactive audience software has shown great potential to enhance learning and engagement in medical education.It is important for instructors to carefully consider the benefits and challenges of its implementation.While the cost of implementing interactive audience software may be a barrier for some institutions,there are free and low-cost options available.

A texture-modified dessert with high nutritional value designed for people with dysphagia:effect of refrigeration and frozen storage

Dysphagia is commonly associated with malnutrition and an increased choking risk.To overcome these complications,food designed for people with dysphagia should have an appropriate texture and a high nutritional value.In this study,six formulations of a strawberry dessert enriched in protein(calcium caseinate)and fiber(wheat dextrin or inulin)were developed using different hydrocolloids(xanthan gum,carboxymethyl cellulose or modified starch)to provide desirable texture and stability.Nutritional value was calculated and total phenolic content and antioxidant activity of the samples were analyzed.Back-extrusion test,rheological measurements and sensory analysis were performed in refrigerated and frozen samples to characterize their textural and viscoelastic properties.The high content in protein(14.7 g/100 g)and fiber(7.9-8.7 g/100 g)made possible to use the claims“high protein”and“high fiber”.Phytochemicals supplied by strawberries contributed to the antioxidant properties of the dessert.Loss tangent ranged 0.28-0.35 for all the formulations,indicating a weak gel behavior,which could be considered safe to swallow.The formulations with dextrin in combination with carboxymethyl cellulose or xanthan gum seemed to be less susceptible to structural changes during frozen storage.This work provides insights for the development of a nutrient-dense dessert that meets the requirements of people with dysphagia.

Resilience to structural and molecular changes in excitatory synapses in the hippocampus contributes to cognitive function recovery in Tg2576 mice

Plaques of amyloid-β(Aβ)and neurofibrillary tangles are the main pathological characteristics of Alzheimer’s disease(AD).However,some older adult people with AD pathological hallmarks can retain cognitive function.Unraveling the factors that lead to this cognitive resilience to AD offers promising prospects for identifying new therapeutic targets.Our hypothesis focuses on the contribution of resilience to changes in excitatory synapses at the structural and molecular levels,which may underlie healthy cognitive performance in aged AD animals.Utilizing the Morris Water Maze test,we selected resilient(asymptomatic)and cognitively impaired aged Tg2576 mice.While the enzyme-linked immunosorbent assay showed similar levels of Aβ42 in both experimental groups,western blot analysis revealed differences in tau pathology in the pre-synaptic supernatant fraction.To further investigate the density of synapses in the hippocampus of 16-18 month-old Tg2576 mice,we employed stereological and electron microscopic methods.Our findings indicated a decrease in the density of excitatory synapses in the stratum radiatum of the hippocampal CA1 in cognitively impaired Tg2576 mice compared with age-matched resilient Tg2576 and non-transgenic controls.Intriguingly,through quantitative immunoelectron microscopy in the hippocampus of impaired and resilient Tg2576 transgenic AD mice,we uncovered differences in the subcellular localization of glutamate receptors.Specifically,the density of GluA1,GluA2/3,and mGlu5 in spines and dendritic shafts of CA1 pyramidal cells in impaired Tg2576 mice was significantly reduced compared with age-matched resilient Tg2576 and non-transgenic controls.Notably,the density of GluA2/3 in resilient Tg2576 mice was significantly increased in spines but not in dendritic shafts compared with impaired Tg2576 and non-transgenic mice.These subcellular findings strongly support the hypothesis that dendritic spine plasticity and synaptic machinery in the hippocampus play crucial roles in the mechanisms of cognitive resilience in Tg2576 mice.

Exercise training-induced changes in exerkine concentrations may be relevant to the metabolic control of type 2 diabetes mellitus patients:A systematic review and meta-analysis of randomized controlled trials

Background:This study investigates the effects of exercise training on exerkines in patients with type 2 diabetes mellitus to determine the optimal exercise prescription.Methods:A systematic search for relevant studies was performed in 3 databases.Randomized controlled trials investigating the effects of exercise training on at least one of the following exerkines were included:adiponectin,apelin,brain-derived neurotrophic factor,fetuin-A,fibroblast growth factor-21,follistatin,ghrelin,interleukin(IL)-6,IL-8,IL-10,IL-15,IL-18,leptin,myostatin,omentin,resistin,retinol-binding protein 4,tumor necrosis factor-α,and visfatin.Results:Forty randomized controlled trials were selected for data extraction(n=2160).Exercise training induces changes in adiponectin,fetuin-A,fibroblast growth factor-21,IL-6,IL-10,leptin,resistin,and tumor necrosis factor-a levels but has no significant effects on apelin,IL-18,and ghrelin compared to controls.Physical exercise training favored large and positive changes in pooled exerkines(i.e.,an overall effect size calculated from several exerkine s)(Hedge’s g=1.02,95%confidence interval(95%CI):0.76-1.28),which in turn were related to changes in glycated hemoglobin(mean difference(MD)=-0.81%,95%CI:-0.95%to-0.67%),fasting glucose(MD=-23.43 mg/dL,95%CI:-30.07 mg/dL to-16.80 mg/dL),waist circumference(MD=-3.04 cm,95%CI:-4.02 cm to-2.07 cm),and body mass(MD=-1.93 kg,95%CI:-2.00 kg to-1.86 kg).Slightly stronger effects were observed with aerobic,resistance,or high-intensity interval protocols at moderate-to vigorous-intensity and with programs longer than 24 weeks that comprise at least 3 sessions per week and more than 60 min per session.Conclusion:Exercise training represents an anti-inflammatory therapy and metabolism-improving strategy with minimal side effects for patients with type 2 diabetes mellitus.

Twenty-four-hour movement guidelines during middle adolescence and their association with glucose outcomes and type 2 diabetes mellitus in adulthood

Purpose:The aim of the present study was to determine the association between adherence to the 24-h movement guidelines during middle adolescence and glucose outcomes(glycated hemoglobin and fasting glucose)and type 2 diabetes mellitus(T2DM)in adulthood,14 and 22 years later.Methods:We analyzed data from apparently healthy adolescents aged 12-18 years who participated in WavesⅠandⅡ(1994-1996,n=14,738),WaveⅣ(2008-2009,n=8913),and Wave V(2016-2018,n=3457)of the National Longitudinal Study of Adolescent to Adult Health(Add Health)in the United States.Physical activity,screen time,and sleep duration were measured using questionnaires,and the 24-h guidelines were defined as:5 or more times moderate-to-vigorous physical activity per week,≤2 h per day of screen time,and 9-11 h of sleep for 12-13 years and 8-10 h for 14-17 years.Capillary and venous whole blood was collected and analyzed to determine glycated hemoglobin and fasting glucose for WavesⅣandⅤ,respectively.Results:Only 2.1%of the adolescents met all the 3 guidelines,and 37.8%met none of them.In both wavesⅣandⅤ,adolescents who met physical activity and screen time guidelines had lower odds of T2DM in adulthood than those who did not meet any of these guidelines(WaveⅣ;prevalence ratio(PR)=0.57,95%confidence interval(95%CI):0.21-0.89;Wave V:PR=0.43,95%CI:0.32-0.74).Only for Wave V did adolescents who met all 3 guidelines have lower odds of T2DM at follow-up compared with those who did not meet any of these guidelines(PR=0.47,95%CI:0.24-0.91).Also,for each increase in meeting one of the 24-h recommendations,the odds of T2DM decreased by 18%(PR=0.82,95%CI:0.61-0.99)and 15%(PR=0.85,95%CI:0.65-0.98)in adulthood for WavesⅣandⅤ,respectively.Conclusion:Promoting all 24-h movement guidelines in adolescence,especially physical activity and screen time,is important for lowering the potential risk of T2DM in adulthood.

Olfactory proteotyping: towards the enlightenment of the neurodegeneration

Although phylogenetically ancient,the olfactory system has received less attention than other sensorial systems.However,olfactory dysfunction is considered an early prodromal event in neurodegenerative diseases(NDs)(Doty,2012;Attems et al.,2014),which may vary from severe smell loss(e.g.,Alzheimer’s and Parkinson’s diseases)to relatively moderate loss(e.g.,progressive supranuclear palsy)(Doty,2017).Recently,a cluster of neuropathological and functional discoveries has evidenced the relevant role of the olfactory bulb(OB)during the neurodegenerative process(Attems et al.,2014;Rey et al.,2018).For instance,the double-transgenic APP/PS1 mouse model of Alzheimer’s disease(AD)develops early proteomic disturbances accompanied by a specific modulation of the focal adhesion kinase(FAK)and mitogen-activated protein kinase(MAPK)dynamics at the level of the OB,demonstrating that olfactory molecular alterations occur prior toβ-amyloid plaque appearance and memory impairments in APP/PS1 transgenic mice(Lachen-Montes et al.,2016).

Cardiorespiratory fitness measured with cardiopulmonary exercise testing and mortality in patients with cardiovascular disease:A systematic review and meta-analysis

Background Cardiorespiratory fitness(CRF)is inversely associated with mortality in apparently healthy subjects and in some clinical populations,but evidence for the association between CRF and all-cause and/or cardiovascular disease(CVD)mortality in patients with established CVD is lacking.This study aimed to quantify this association.Methods We searched for prospective cohort studies that measured CRF with cardiopulmonary exercise testing in patients with CVD and that examined all-cause and CVD mortality with at least 6 months of follow-up.Pooled hazard ratios(HRs)were calculated using random-effect inverse-variance analyses.Results Data were obtained from 21 studies and included 159,352 patients diagnosed with CVD(38.1%female).Pooled HRs for all-cause and CVD mortality comparing the highest vs.lowest category of CRF were 0.42(95%confidence interval(95%CI):0.28–0.61)and 0.27(95%CI:0.16–0.48),respectively.Pooled HRs per 1 metabolic equivalent(1-MET)increment were significant for all-cause mortality(HR=0.81;95%CI:0.74–0.88)but not for CVD mortality(HR=0.75;95%CI:0.48–1.18).Coronary artery disease patients with high CRF had a lower risk of all-cause mortality(HR=0.32;95%CI:0.26–0.41)than did their unfit counterparts.Each 1-MET increase was associated with lower all-cause mortality risk among coronary artery disease patients(HR=0.83;95%CI:0.76–0.91)but not lower among those with heart failure(HR=0.69;95%CI:0.36–1.32).Conclusion A better CRF was associated with lower risk of all-cause mortality and CVD.This study supports the use of CRF as a powerful predictor of mortality in this population.

Is device-measured vigorous physical activity associated with health-related outcomes in children and adolescents? A systematic review and meta-analysis

Objective:This study sought to analyze the prospective association between vigorous-intensity physical activity(VPA)and health-related outcomes in children and adolescents.Methods:Studies reporting associations between device-measured VPA and health-related factors in children and adolescents aged 318 years were identified through database searches(MEDLINE,EMBASE,and SPORTDiscus).Correlation coefficients were pooled if outcomes were reported by at least 3 studies,using DerSimonian-Laird random effects models.Results:Data from 23 studies including 13,674 participants were pooled using random effects models.Significant associations were found between VPA at baseline and overall adiposity(r=0.09,95%confidence interval(95%CI):0.15 to0.03;p=0.002;I^(2)=89.8%),cardiometabolic risk score(r=0.13,95%CI:0.24 to0.02,p=0.020;I^(2)=69.6%),cardiorespiratory fitness(r=0.25,95%CI:0.150.35;p<0.001;I^(2)=57.2%),and total body bone mineral density(r=0.16,95%CI:0.06 to 0.25;p=0.001;I^(2)=0%).Conclusion:VPA seems to be negatively related to adiposity and cardiometabolic risk score and positively related to cardiorespiratory fitness and total body bone mineral density among children and adolescents at follow-up.Therefore,our findings support the need to strengthen physical activity recommendations regarding VPA due to its health benefits in children and adolescents.

Prevalence of meeting 24-Hour Movement Guidelines from pre-school to adolescence: A systematic review and meta-analysis including 387,437 participants and 23 countries

Background:Meeting the 24-Hour Movement Guidelines(physical activity,screen time,and sleep duration) has been associated with positive health indicators.However,there are no previous meta-analyses that have examined the overall adherence to the 24-Hour Movement Guidelines from pre-school to adolescence across the world.Therefore,the main purpose of this systematic review and meta-analysis was to examine the overall(non)adherence to the 24-Hour Movement Guidelines among preschoolers,children,and adolescents worldwide.Methods:Four electronic databases(MEDLINE,Scopus,Web of Science,and Cochrane Database of Systematic Reviews) were searched for quantitative studies published in Spanish and English between January 2016 and May 2021.Studies that were conducted with apparently healthy participants and reported the overall(non)adherence to the 24-Hour Movement Guidelines in preschoolers and/or children and/or adolescents were included.Results:Sixty-three studies comprising 387,437 individuals(51% girls) aged 3-18 years from 23 countries were included.Overall,7.12%(95%confidence interval(95%CI):6.45%-7.78%) of youth met all three 24-Hour Movement Guidelines,and 19.21%(95%CI:16.73%-21.69%)met none of the 3 recommendations.Concerning sex,adherence to all recommendations was significantly lower in girls(3.75%,95%CI:3.23%-4.27%) than in boys(6.89%,95%CI:5.89%-7.89%)(p <0.001).However,there were no sex differences regarding adherence to any of the 3 individual recommendations(girls,15.66%,95%CI:8.40%-22.92%;boys,12.95%,95%CI:6.57%-19.33%).In terms of age group,adherence to the 3 recommendations was 11.26%(95%CI:8.68%-13.84%),10.31%(95%CI:7.49%-13.12%),and 2.68%(95%CI:1.78%-3.58%) in preschoolers,children,and adolescents,respectively.Conversely,8.81%(95%CI:5.97%-11.64%) of preschoolers,15.57%(95%CI:11.60%-19.54%) of children,and 28.59%(95%CI:22.42%-34.75%) of adolescents did not meet any of the recommendations.South America was the region with the lowest adherence(all:2.93%;none:31.72%).Overall adherence to the 24-Hour Movement Guidelines was positively related to country Human Development Index(β=-0.37,95%CI:-0.65 to-0.09;p=0.010).Conclusion:Most young people fail to meet the three 24-Hour Movement Guidelines,particularly adolescents,girls,and those who are from countries with a lower Human Development Index.Moreover,1 in 5 young people did not meet any of these recommendations.Therefore,these results highlight the need to develop age-and sex-specific strategies to promote these movement behaviors from the early stages of life.

The effects of plyometric jump training on physical fitness attributes in basketball players:A meta-analysis`

Background:There is a growing body of experimental evidence examining the effects of plyometric jump training(PJT)on physical fitness attributes in basketball players;however,this evidence has not yet been comprehensively and systematically aggregated.Therefore,our objective was to meta-analyze the effects of PJT on physical fitness attributes in basketball players,in comparison to a control condition.Methods:A systematic literature search was conducted in the databases PubMed,Web of Science,and Scopus,up to July 2020.Peer-reviewed controlled trials with baseline and follow-up measurements investigating the effects of PJT on physical fitness attributes(muscle power,i.e.,jumping performance,linear sprint speed,change-of-direction speed,balance,and muscle strength)in basketball players,with no restrictions on their playing level,sex,or age.Hedge’s g effect sizes(ES)were calculated for physical fitness variables.Using a random-effects model,potential sources of heterogeneity were selected,including subgroup analyses(age,sex,body mass,and height)and single training factor analysis(program duration,training frequency,and total number of training sessions).Computation of metaregression was also performed.Results:Thirty-two studies were included,involving 818 total basketball players.Significant(p<0.05)small-to-large effects of PJT were evident on vertical jump power(ES=0.45),countermovement jump height with(ES=1.24)and without arm swing(ES=0.88),squat jump height(ES=0.80),drop jump height(ES=0.53),horizontal jump distance(ES=0.65),linear sprint time across distances≤10 m(ES=1.67)and>10 m(ES=0.92),change-of-direction performance time across distances≤40 m(ES=1.15)and>40 m(ES=1.02),dynamic(ES=1.16)and static balance(ES=1.48),and maximal strength(ES=0.57).The meta-regression revealed that training duration,training frequency,and total number of sessions completed did not predict the effects of PJT on physical fitness attributes.Subgroup analysis indicated greater improvements in older compared to younger players in horizontal jump distance(>17.15 years,ES=2.11;≤17.15 years,ES=0.10;p<0.001),linear sprint time>10 m(>16.3 years,ES=1.83;≤16.3 years,ES=0.36;p=0.010),and change-of-direction performance time≤40 m(>16.3 years,ES=1.65;≤16.3 years,ES=0.75;p=0.005).Greater increases in horizontal jump distance were apparent with>2 compared with≤2 weekly PJT sessions(ES=2.12 and ES=0.39,respectively;p<0.001).Conclusion:Data from 32 studies(28 of which demonstrate moderate-to-high methodological quality)indicate PJT improves muscle power,linear sprint speed,change-of-direction speed,balance,and muscle strength in basketball players independent of sex,age,or PJT program variables.However,the beneficial effects of PJT as measured by horizontal jump distance,linear sprint time>10 m,and change-of-direction performance time≤40 m,appear to be more evident among older basketball players.

Healthy diet,depression and quality of life:A narrative review of biological mechanisms and primary prevention opportunities

Unipolar depressive disorder(UDD)affects more than 264 million people worldwide and was projected well before the severe acute respiratory syndrome coronavirus 2 pandemic to be the leading cause of disability-adjusted life years lost in 2030.It is imperative for leading economies to implement preventive strategies targeted towards UDD,given consistent policies are currently lacking.Recently established similarities between the aetiological hypotheses of depression and cardiometabolic diseases are shifting paradigms within this field.It is believed that dietary practices could potentially reduce the incidence of depression;similar to their effects on metabolism.Thus,the aim of this review was to compile current evidence on healthy dietary patterns as suitable contributors towards primary prevention strategies against UDD.Most of the well-known biological mechanisms behind depression have been positively associated with healthful diets and dietary patterns to varying degrees.Interestingly,a common factor of UDD is the production and overall effects of inflammatory cytokines,such as interleukin-6,tumor necrosis factor-α,and Creactive protein.These compounds have been associated with depressive symptoms,disturbances in neuroendocrine function,leaky gut,monoamine activity and brain function,while also being key factors in the development of cardiometabolic diseases.The Mediterranean diet(MD)in particular,is well supported by first-level evidence regarding its preventive qualities against metabolic and cardiovascular diseases and thus considered a model for healthy eating by various organizations.In one of the few clinical trials investigating these associations,the PREDIMED trial,individuals with diabetes assigned to a MD supplemented with mixed tree nuts experienced a 41%relative risk reduction for developing depression.Lastly,there is a need to include health related quality of life as an indicator of physical and mental well-being,considering its putative associations with depression and suicide risk.Going forward,focusing on clinical trials,using precise nutritional assessments,and identifying nutritional biomarkers which may be related to depression are needed to fully support the implementation of dietary recommendations in the field of psychiatry.

GOECP/SEOR radiotherapy guidelines for thymic epithelial tumours

Thymic epithelial tumours(TET)are rare,heterogeneous neoplasms that range from resectable indolent tumours to aggressive thymic carcinomas with a strong tendency to metastasize.The pathological diagnosis is complex,in part due to the management of TETs is scant and mainly based on non-randomised studies and retrospective series.Consequently,the clinical management of TETs tends to be highly heterogenous,which makes it difficult to improve the evidence level.The role of technological advances in the field of radiotherapy and new systemic therapies in the treatment of TETs has received little attention to date.In the present clinical guidelines,developed by the GOECP/SEOR,we review recent developments in the diagnosis and classification of TETs.We also present a consensus-based therapeutic strategy for each disease stage that takes into consideration the best available evidence.These guidelines focus primarily on the role of radiotherapy,including recent advances,in the management of TETs.The main aim of this document is to promote the standardisation of clinical practice and lay the foundations for future studies to clarify the main unresolved questions related to the optimal management of TET.

LIBRA:an adaptative integrative tool for paired single-cell multi-omics data

Background:Single-cell multi-omics technologies allow a profound system-level biology understanding of cells and tissues.However,an integrative and possibly systems-based analysis capturing the different modalities is challenging.In response,bioinformatics and machine learning methodologies are being developed for multi-omics single-cell analysis.It is unclear whether current tools can address the dual aspect of modality integration and prediction across modalities without requiring extensive parameter fine-tuning.Methods:We designed LIBRA,a neural network based framework,to learn translation between paired multi-omics profiles so that a shared latent space is constructed.Additionally,we implemented a variation,aLIBRA,that allows automatic fine-tuning by identifying parameter combinations that optimize both the integrative and predictive tasks.All model parameters and evaluation metrics are made available to users with minimal user iteration.Furthermore,aLIBRA allows experienced users to implement custom configurations.The LIBRA toolbox is freely available as R and Python libraries at GitHub(TranslationalBioinformaticsUnit/LIBRA).Results:LIBRA was evaluated in eight multi-omic single-cell data-sets,including three combinations of omics.We observed that LIBRA is a state-of-the-art tool when evaluating the ability to increase cell-type(clustering)resolution in the integrated latent space.Furthermore,when assessing the predictive power across data modalities,such as predictive chromatin accessibility from gene expression,LIBRA outperforms existing tools.As expected,adaptive parameter optimization(aLIBRA)significantly boosted the performance of learning predictive models from paired data-sets.Conclusion:LIBRA is a versatile tool that performs competitively in both“integration”and“prediction”tasks based on single-cell multi-omics data.LIBRA is a data-driven robust platform that includes an adaptive learning scheme.

Mutated trimeric RBD vaccines:a platform against variants of concern

He et al.recently reported in Nature Communications1 the development of a protein vaccine against SASR-CoV-2 Omicron variant consisting of a trimer of the spike protein receptor-binding domain(RBD)of the Delta variant fused to heptad-repeat sequences 1 and 2.This vaccine induced broad-spectrum neutralizing antibodies and fully protected mice and non-human primates against challenge with live Delta and Omicron virus.

Novel hybrid biocomposites for tendon grafts:The addition of silk to polydioxanone and poly(lactide-co-caprolactone)enhances material properties,in vitro and in vivo biocompatibility

Biopolymers play a critical role as scaffolds used in tendon and ligament(TL)regeneration.Although advanced biopolymer materials have been proposed with optimised mechanical properties,biocompatibility,degradation,and processability,it is still challenging to find the right balance between these properties.Here,we aim to develop novel hybrid biocomposites based on poly(p-dioxanone)(PDO),poly(lactide-co-caprolactone)(LCL)and silk to produce high-performance grafts suitable for TL tissue repair.Biocomposites containing 1-15%of silk were studied through a range of characterisation techniques.We then explored biocompatibility through in vitro and in vivo studies using a mouse model.We found that adding up to 5%silk increases the tensile properties,degradation rate and miscibility between PDO and LCL phases without agglomeration of silk inside the composites.Furthermore,addition of silk increases surface roughness and hydrophilicity.In vitro experiments show that the silk improved attachment of tendon-derived stem cells and proliferation over 72 h,while in vivo studies indicate that the silk can reduce the expression of pro-inflammatory cytokines after six weeks of implantation.Finally,we selected a promising biocomposite and created a prototype TL graft based on extruded fibres.We found that the tensile properties of both individual fibres and braided grafts could be suitable for anterior cruciate ligament(ACL)repair applications.

Robotic versus laparoscopic liver resection for huge (≥10 cm) liver tumors: an international multicenter propensity-score matched cohort study of 799 cases

Background:The use of laparoscopic(LLR)and robotic liver resections(RLR)has been safely performed in many institutions for liver tumours.A large scale international multicenter study would provide stronger evidence and insight into application of these techniques for huge liver tumours≥10 cm.Methods:This was a retrospective review of 971 patients who underwent LLR and RLR for huge(≥10 cm)tumors at 42 international centers between 2002-2020.Results:One hundred RLR and 699 LLR which met study criteria were included.The comparison between the 2 approaches for patients with huge tumors were performed using 1:3 propensity-score matching(PSM)(73 vs.219).Before PSM,LLR was associated with significantly increased frequency of previous abdominal surgery,malignant pathology,liver cirrhosis and increased median blood.After PSM,RLR and LLR was associated with no significant difference in key perioperative outcomes including media operation time(242 vs.290 min,P=0.286),transfusion rate rate(19.2%vs.16.9%,P=0.652),median blood loss(200 vs.300 mL,P=0.694),open conversion rate(8.2%vs.11.0%,P=0.519),morbidity(28.8%vs.21.9%,P=0.221),major morbidity(4.1%vs.9.6%,P=0.152),mortality and postoperative length of stay(6 vs.6 days,P=0.435).Conclusions:RLR and LLR can be performed safely for selected patients with huge liver tumours with excellent outcomes.There was no significant difference in perioperative outcomes after RLR or LLR.

Diagnostic performance of serum interleukin-6 in pediatric acute appendicitis:a systematic review

Background Despite the radiological and analytical advances of the last decades,there is still a significant rate of diagnostic error in pediatric acute appendicitis.In recent years,multiple biomarkers have emerged as potential diagnostic tools.This study aimed to examine the diagnostic performance of serum interleukin-6 in pediatric acute appendicitis.Methods We conducted a systematic review of the literature that involved an extensive search in the main databases of medical bibliography(Medline,PubMed,Web of Science and SciELO).Two independent reviewers selected the relevant articles based on the previously defined inclusion and exclusion criteria.Methodological quality of the selected article was rated using the QUADAS2 index.Data extraction was performed by two independent reviewers.Results The research in the medical bibliography databases resulted in 68 articles.We removed 26 duplicates.Among the remaining 42 articles,we excluded 33 following the inclusion and exclusion criteria.Of the final 9 studies included in this review,8 provided measured serum interleukin-6 values,and all of them reported significant differences between groups,but inconsistent results regarding sensitivity and specificity.Conclusions The diagnostic performance of interleukine-6 alone for the diagnosis of acute appendicitis in children is limited.The sensitivity and specificity of interleukine-6 for the diagnosis of non-complicated acute appendicitis in the pediatric population are moderate but increased in complicated appendicitis.There seems to be a direct relationship between serum level of interleukin-6 and the hours of evolution of abdominal pain in children with acute appendicitis.The increasingly widespread use of non-operative management of acute appendicitis warrants further exploration of the classificatory potential of this marker between complicated and uncomplicated appendicitis.We consider that this may be an avenue of research to explore in the future.

NLRP3 inflammasome blockade reduces adipose tissue inflammation and extracellular matrix remodeling

The NLRP3-IL-1β pathway plays an important role in adipose tissue(AT)-induced inflammation and the development of obesityassociated comorbidities.We aimed to determine the impact of NLRP3 on obesity and its associated metabolic alterations as well as its role in adipocyte inflammation and extracellular matrix(ECM)remodeling.Samples obtained from 98 subjects were used in a case-control study.The expression of different components of the inflammasome as well as their main effectors and inflammation-and ECM remodeling-related genes were analyzed.The impact of blocking NLRP3 using siRNA in lipopolysaccharide(LPS)-mediated inflammation and ECM remodeling signaling pathways was evaluated.We demonstrated that obesity(P<0.01),obesity-associated T2D(P<0.01)and NAFLD(P<0.05)increased the expression of different com ponents of the inflammasome as well as the expression and release of IL-1β and IL-18 in AT.We also found that obese patients with T2D exhibited increased(P<0.05)hepatic gene expression levels of NLRP3,IL1B and IL18.We showed that NLRP3,but not NLRP1,is regulated by inflammation and hypoxia in visceral adipocytes.We revealed that the inhibition of NLRP3 in human visceral adipocytes significantly blocked(P<0.01)LPS-induced inflammation by downregulating the mRNA levels of CCL2,IL1B,IL6,IL8,S100A8,S100A9,TLR4 and TNF as well as inhibiting(P<0.01)the secretion of IL1-β into the culture medium.Furthermore,blocking NLRP3 attenuated(P<0.01)the LPS-induced expression of important molecules involved in AT fibrosis(COL1A1,COL4A3,COL6A3 and MMP2).These novel findings provide evidence that blocking the expression of NLRP3 reduces AT inflammation with significant fibrosis attenuation.