Soft-tissue sarcoma in adults: An update on the current state of histiotype-specific management in an era of personalized medicine.

AbstractSoft‐tissue sarcomas (STS) are rare tumors that account for 1% of all adult malignancies, with over 100 different histologic subtypes occurring predominately in the trunk, extremity, and retroperitoneum. This low incidence is further complicated by their variable presentation, behavior, and long‐term outcomes, which emphasize the importance of centralized care in specialized centers with a multidisciplinary team approach. In the last decade, there has been an effort to improve the quality of care for patients with STS based on anatomic site and histology, and multiple ongoing clinical trials are focusing on tailoring therapy to histologic subtype. This report summarizes the latest evidence guiding the histiotype‐specific management of extremity/truncal and retroperitoneal STS with regard to surgery, radiation, and chemotherapy

Seventeenth-century building engineering in the central Mediterranean : A case study from Malta

Masonry and architecture are synonymous in built heritage which is erected in local stone. The Maltese archipelago, located in the central Mediterranean, is no exception. Malta is geo-culturally rich in architectural heritage dating back to the Neolithic Period and reaching a peak during the rule of the Hospitaller Order of St John. This paper studies the engineering and construction of seventeenth-century residential architecture in Malta through a representative case-study of the period: Casa Ippolito, an aristocratic country residence erected in local limestone. The limestone walls were roofed by slabs laid on masonry arches or timber beams. These slabs had an overlying layer of fill and flagstones to uniformly distribute the loading. The parts of the roof exposed to the elements were finished in an impervious layer.peer-reviewe

A Cutoff Procedure and Counterterms for Differential Renormalization

Explicit divergences and counterterms do not appear in the differential renormalization method, but they are concealed in the neglected surface terms in the formal partial integration procedure used. A systematic real space cutoff procedure for massless $\phi^4$ theory is therefore studied in order to test the method and its compatibility with unitarity. Through 3-loop order, it is found that cutoff bare amplitudes are equal to the renormalized amplitudes previously obtained using the formal procedure plus singular terms which can be consistently cancelled by adding conventional counterterms to the Lagrangian. Renormalization group functions $\beta (g)$ and $\gamma (g)$ obtained in the cutoff theory also agree with previous results.Comment: 28 pages, CTP#2099-DTP/92/40-UBECMPF/92/13, 2 figures (not included). (Tex problems solved and information about number of pages and figures added

Frailty in Indigenous populations: A scoping review

Background: Indigenous populations experience high rates of age-related illness when compared to their non-Indigenous counterparts. Frailty is a challenging expression of aging and an important public health priority. The purpose of this review was to map what the existing literature reports around frailty in Indigenous populations and to highlight the current gaps in frailty research within the Indigenous landscape. Method: Scoping review of English language original research articles focusing on frailty within Indigenous adult populations in settler colonial countries (Australia, Canada, New Zealand and USA). Ten electronic databases and eight relevant institutional websites were searched from inception to October 2020. Results: Nine articles met our inclusion criteria, finding this population having a higher prevalence of frailty and frailty occurring at younger ages when compared to their non-Indigenous counterparts, but two did not use a formal frailty tool. Females presented with higher levels of frailty. No culturally specific frailty tool was identified, and the included articles did not assess strategies or interventions to manage or prevent frailty in Indigenous peoples. Conclusions: There was little definitive evidence of the true frailty prevalence, approaches to frailty screening and of potential points of intervention to manage or prevent the onset of frailty. Improvements in the quality of evidence are urgently needed, along with further research to determine the factors contributing to higher rates of frailty within Indigenous populations. Incorporation of Indigenous views of frailty, and instruments and programs that are led and designed by Indigenous communities, are crucial to address this public health priority

Levels of frailty and frailty progression in older urban- and regional-living First Nations Australians

OBJECTIVES: To explore the prevalence of frailty, association between frailty and mortality, and transitions between frailty states in urban- and regional-living First Nations Australians.STUDY DESIGN: Secondary analysis of longitudinal data from the Koori Growing Old Well Study. First Nations Australians aged 60 years or more from five non-remote communities were recruited in 2010-2012 and followed up six years later (2016-2018). Data collected at both visits were used to derive a 38-item Frailty Index (FI). The FI (range 0-1.0) was classified as robust (&lt;0.1), pre-frail (0.1- &lt; 0.2), mildly (0.2- &lt; 0.3), moderately (0.3- &lt; 0.4) or severely frail (≥0.4).MAIN OUTCOME MEASURES: Association between frailty and mortality, examined using logistic regression and transitions in frailty (the percentage of participants who changed frailty category) during follow-up.RESULTS: At baseline, 313 of 336 participants (93 %) had sufficient data to calculate a FI. Median FI score was 0.26 (interquartile range 0.21-0.39); 4.79 % were robust, 20.1 % pre-frail, 31.6 % mildly frail, 23.0 % moderately frail and 20.5 % severely frail. Higher baseline frailty was associated with mortality among severely frail participants (adjusted odds ratio 7.11, 95 % confidence interval 2.51-20.09) but not moderately or mildly frail participants. Of the 153 participants with a FI at both baseline and follow-up, their median FI score increased from 0.26 to 0.28.CONCLUSIONS: Levels of frailty in this First Nations cohort are substantially higher than in similar-aged non-Indigenous populations. Screening for frailty before the age of 70 years may be warranted in First Nations Australians. Further research is urgently needed to determine the factors that are driving such high levels of frailty and propose solutions to prevent or manage frailty in this population.</p

β-Secretase 1’s Targeting Reduces Hyperphosphorilated Tau, Implying Autophagy Actors in 3xTg-AD Mice

β-site APP cleaving enzyme 1 (BACE1) initiates APP cleavage, which has been reported to be an inducer of tau pathology by altering proteasome functions in Alzheimer's disease (AD). However, the exact relationship between BACE1 and PHF (Paired Helical Filaments) formation is not clear. In this study, we confirm that BACE1 and Hsc70 are upregulated in the brains of AD patients, and we demonstrate that both proteins show enhanced expression in lipid rafts from AD-affected triple transgenic mouse brains. BACE1 targeting increased Hsc70 levels in the membrane and cytoplasm fractions and downregulated Hsp90 and CHIP in the nucleus in the hippocampi of 3xTg-AD mice. However, these observations occurred in a proteasome-independent manner in vitro. The BACE1miR-induced reduction of soluble hyperphosphorylated tau was associated with a decrease in MAPK activity. However, the BACE1 RNAi-mediated reduction of hyperphosphorylated tau was only blocked by 3-MA (3-methyladenine) in vitro, and it resulted in the increase of Hsc70 and LAMP2 in lipid rafts from hippocampi of 3xTg-AD mice, and upregulation of survival and homeostasis signaling. In summary, our findings suggest that BACE1 silencing neuroprotects reducing soluble hyperphosphorylated tau, modulating certain autophagy-related proteins in aged 3xTg-AD mice

Predicting the artificial immunity induced by RUTI&#174; vaccine against tuberculosis using universal immune system simulator (UISS)

BACKGROUND: Tuberculosis (TB) represents a worldwide cause of mortality (it infects one third of the world's population) affecting mostly developing countries, including India, and recently also developed ones due to the increased mobility of the world population and the evolution of different new bacterial strains capable to provoke multi-drug resistance phenomena. Currently, antitubercular drugs are unable to eradicate subpopulations of Mycobacterium tuberculosis (MTB) bacilli and therapeutic vaccinations have been postulated to overcome some of the critical issues related to the increase of drug-resistant forms and the difficult clinical and public health management of tuberculosis patients. The Horizon 2020 EC funded project "In Silico Trial for Tuberculosis Vaccine Development" (STriTuVaD) to support the identification of new therapeutic interventions against tuberculosis through novel in silico modelling of human immune responses to disease and vaccines, thereby drastically reduce the cost of clinical trials in this critical sector of public healthcare

The impact of failure to achieve symptom control after resection of functional neuroendocrine tumors: An 8â institution study from the US Neuroendocrine Tumor Study Group

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/147162/1/jso25306_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/147162/2/jso25306.pd

Impact of a prospective feedback loop on care review activities in older patients at the end of life. A stepped-wedge randomised trial

Background: Hospitalisation rates for older people are increasing, with end-of-life care becoming a more medicalised experience. Innovative approaches are warranted to support early identification of the end-of-life phase, communicate prognosis, provide care consistent with people’s preferences, and improve the use of healthcare resources. The Intervention for Appropriate Care and Treatment (InterACT) trial aimed to increase appropriate care and treatment decisions for older people at the end of life, through implementation of a prospective feedback loop. This paper reports on the care review outcomes. Methods: A stepped-wedge randomised controlled trial was conducted in three large acute hospitals in Queensland, Australia between May 2020 and June 2021. The trial identified older people nearing the end of life using two validated tools for detecting deterioration and short-term death. Admitting clinical teams were provided with details of patients identified as at-risk with the goal of increasing awareness that end of life was approaching to facilitate appropriate patient centred care and avoid non-beneficial treatment. We examined the time between when the patient was identified as ‘at-risk’ and three outcomes: clinician-led care review discussions, review of care directive measures and palliative care referrals. These were considered useful indicators of appropriate care at the end of life. Results: In two hospitals there was a reduction in the review of care directive measures during the intervention compared with usual care at 21 days (reduced probability of − 0.08; 95% CI: − 0.12 to − 0.04 and − 0.14; 95% CI: − 0.21 to − 0.06). In one hospital there was a large reduction in clinician-led care review discussions at 21 days during the intervention (reduced probability of − 0.20; 95% CI: − 0.28 to − 0.13). There was little change in palliative care referrals in any hospital, with average probability differences at 21 days of − 0.01, 0.02 and 0.04. Discussion: The results are disappointing as an intervention designed to improve care of hospitalised older people appeared to have the opposite effect on care review outcomes. The reasons for this may be a combination of the intervention design and health system challenges due to the pandemic that highlight the complexity of providing more appropriate care at the end of life. Trial registration: Australia New Zealand Clinical Trial Registry, ACTRN12619000675123 (registered 6 May 2019).</p

Moving forward through the in silico modeling of tuberculosis : a further step with UISS-TB

In 2018, about 10 million people were found infected by tuberculosis, with approximately 1.2 million deaths worldwide. Despite these numbers have been relatively stable in recent years, tuberculosis is still considered one of the top 10 deadliest diseases worldwide. Over the years, Mycobacterium tuberculosis has developed a form of resistance to first-line tuberculosis treatments, specifically to isoniazid, leading to multi-drug-resistant tuberculosis. In this context, the EU and Indian DBT funded project STriTuVaD-In Silico Trial for Tuberculosis Vaccine Development-is supporting the identification of new interventional strategies against tuberculosis thanks to the use of Universal Immune System Simulator (UISS), a computational framework capable of predicting the immunity induced by specific drugs such as therapeutic vaccines and antibiotics. Here, we present how UISS accurately simulates tuberculosis dynamics and its interaction within the immune system, and how it predicts the efficacy of the combined action of isoniazid and RUTI vaccine in a specific digital population cohort. Specifically, we simulated two groups of 100 digital patients. The first group was treated with isoniazid only, while the second one was treated with the combination of RUTI vaccine and isoniazid, according to the dosage strategy described in the clinical trial design. UISS-TB shows to be in good agreement with clinical trial results suggesting that RUTI vaccine may favor a partial recover of infected lung tissue. In silico trials innovations represent a powerful pipeline for the prediction of the effects of specific therapeutic strategies and related clinical outcomes. Here, we present a further step in UISS framework implementation. Specifically, we found that the simulated mechanism of action of RUTI and INH are in good alignment with the results coming from past clinical phase IIa trials