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We describe the synthesis of pro-antimicrobial networks via degradable acetals (PANDAs) as a new paradigm for sequestration and triggered release of volatile, bioactive aldehydes. PANDAs derived from diallyl p-chlorobenzaldehyde acetal degrade and release p-chlorobenzaldehyde as an antibacterial and antifungal agent under mild conditions (pH 7.4/high humidity). We show that PANDAs enable facile access to materials with tunable release profiles, potent antimicrobial activity without triggering antimicrobial resistance, and minimal cytotoxicity.

We describe the design and synthesis of degradable, dual-release, pro-antimicrobial poly(thioether acetal) networks derived from synergistic pairs of aromatic terpene aldehydes. Initially, we identified pairs of aromatic terpene aldehyde derivatives exhibiting a synergistic antimicrobial activity against Pseudomonas aeruginosa by determining fractional inhibitory concentrations. Synergistic aldehydes were converted into dialkene acetal monomers and copolymerized at various ratios with a multifunctional thiol via thiol–ene photopolymerization. The step-growth nature of the thiol–ene polymerization ensures every cross-link junction contains a degradable acetal linkage enabling a fully cross-linked polymer network to revert into its small molecule constituents upon hydrolysis, releasing the synergistic aldehydes as active antimicrobial compounds. A three-pronged approach was used to characterize the poly(thioether acetal) materials: (i) determination of the degradation/aldehyde release behavior, (ii) evaluat...

Recent research has indicated a significant potential for providing demand response using Economic Model Predictive Control (E-MPC) of radiators in residential space heating systems. Previous studies indicate the need for distinct temperatures in different rooms, which would require an E-MPC with different temperature constraints across the dwelling. Studies on E-MPC concepts for this purpose often assume that it is possible to measure the heating power delivered to each room separately. However, this assumption is not valid in typical existing residential buildings heated by hydronic radiators; they only have one heat meter measuring the heating use of the entire housing unit. This study presents a simulation-based study of a novel dual-zone E-MPC scheme that relies on indoor air temperature measurements in individual rooms of the housing unit, and only one heat meter measuring the total heating use for space heating and domestic hot water. The results indicate that the proposed scheme has the same load shifting potential as an E-MPC using room-level heat metering. The proposed scheme thus reduces the additional hardware and data infrastructure needed for the practical realization of E-MPC of residential space heating systems for demand response purposes.

Current crisis, causing structural long-term changes in the economy and society, is offering a challenge to the insurance sector, whose primary role lies in the protection of individuals and productive activities. The insurance industry can take this opportunity towards achieving the objective of social well-being with the design of new insurance products and incentives. In this work we propose a particular type of securitization scheme where the health risk in a broad sense is transferred to capital market. For example, this tool can be exploited by firms to cover the risks of damage to the health of workers and office workers. Certain discount policies by insurance companies may encourage activities aimed at improving the health system and the work safety. An appropriate morbidity index is used to price this type of policy. Numerical results are offered and discussed.

Recent simulation-based studies have indicated that load shifting using Economic Model Predictive Control (E-MPC) of radiators for residential space heating can be utilized for demand response purposes in energy systems. However, there is a lack of studies on whether this load shift potential can be realized in real, inhabited buildings. This paper reports on a field experiment aiming at realizing load shifting of space heating in a single-family house with a hydronic radiator system connected to the local district heating. Radiators in a limited number of ‘active’ rooms were controlled using set-point schedules mimicking the typical behavior of E-MPC. The results indicate that it was possible to load shift heating consumption in the ‘active’ rooms but that the load shift for the building as a whole was limited due to the hydronics of the radiator system. The paper also reports on the several practical issues encountered during the experiments – issues that in different ways are barriers to the practical realization of demand response from E-MPC of hydronic space heating systems.

Let $\Omega\subset\mathbb{R}^n$, $n\geq 2$, be a bounded, open and convex set and let $f$ be a positive and non-increasing function depending only on the distance from the boundary of $\Omega$. We consider the $p-$torsional rigidity associated to $\Omega$ for the Poisson problem with Dirichlet boundary conditions, denoted by $T_{f,p}(\Omega)$. Firstly, we prove a P\'olya type lower bound for $T_{f,p}(\Omega)$ in any dimension; then, we consider the planar case and we provide two quantitative estimates in the case $f\equiv 1 $., Comment: 18 pages, 4 figures

Obesity is correlated with breast tumor desmoplasia, leading to diminished chemotherapy response and disease-free survival. Obesity causes chronic, macrophage-driven inflammation within breast tissue, initiated by chemokine ligand 2 (CCL2) signaling from adipose stromal cells. To understand how CCL2-induced inflammation alters breast tumor pathology, we transplanted oncogenically transformed human breast epithelial cells with breast stromal cells expressing CCL2 or empty vector into murine mammary glands and examined tumor formation and progression with time. As tumors developed, macrophages were rapidly recruited, followed by the emergence of cancer-associated fibroblasts (CAFs) and collagen deposition. Depletion of CD11b + myeloid lineage cells early in tumor formation reduced tumor growth, CAF numbers, and collagen deposition. CCL2 expression within developing tumors also enhanced recruitment of myeloid progenitor cells from the bone marrow into the tumor site. The myeloid progenitor cell population contained elevated numbers of fibrocytes, which exhibited platelet-derived growth factor receptor-alpha (PDGFR&alpha, )-dependent colony formation and growth in vitro. Together, these results suggest that chronic inflammation induced by CCL2 significantly enhances tumor growth and promotes the formation of a desmoplastic stroma through early recruitment of macrophages and fibrocytes into the tumor microenvironment. Fibrocytes may be a novel target in the tumor microenvironment to reduce tumor fibrosis and enhance treatment responses for obese breast cancer patients.

Plant-derived aldehydes are constituents of essential oils that possess broad-spectrum antimicrobial activity and kill microorganisms without promoting resistance. In our previous study, we incorporated p-anisaldehyde from star anise into a polymer network called proantimicrobial networks via degradable acetals (PANDAs) and used it as a novel drug delivery platform. PANDAs released p-anisaldehyde upon a change in pH and humidity and controlled the growth of the multidrug-resistant pathogen Pseudomonas aeruginosa PAO1. In this study, we identified the cellular pathways targeted by p-anisaldehyde by generating 10,000 transposon mutants of PAO1 and screened them for hypersensitivity to p-anisaldehyde. To improve the antimicrobial efficacy of p-anisaldehyde, we combined it with epigallocatechin gallate (EGCG), a polyphenol from green tea, and demonstrated that it acts synergistically with p-anisaldehyde in killing P. aeruginosa. We then used transcriptome sequencing to profile the responses of P. aeruginosa to p-anisaldehyde, EGCG, and their combination. The exposure to p-anisaldehyde altered the expression of genes involved in modification of the cell envelope, membrane transport, drug efflux, energy metabolism, molybdenum cofactor biosynthesis, and the stress response. We also demonstrate that the addition of EGCG reversed many p-anisaldehyde-coping effects and induced oxidative stress. Our results provide insight into the antimicrobial activity of p-anisaldehyde and its interactions with EGCG and may aid in the rational identification of new synergistically acting combinations of plant metabolites. Our study also confirms the utility of the thiol-ene polymer platform for the sustained and effective delivery of hydrophobic and volatile antimicrobial compounds. IMPORTANCE Essential oils (EOs) are plant-derived products that have long been exploited for their antimicrobial activities in medicine, agriculture, and food preservation. EOs represent a promising alternative to conventional antibiotics due to their broad-range antimicrobial activity, low toxicity to human commensal bacteria, and capacity to kill microorganisms without promoting resistance. Despite the progress in the understanding of the biological activity of EOs, our understanding of many aspects of their mode of action remains inconclusive. The overarching aim of this work was to address these gaps by studying the molecular interactions between an antimicrobial plant aldehyde and the opportunistic human pathogen Pseudomonas aeruginosa. The results of this study identify the microbial genes and associated pathways involved in the response to antimicrobial phytoaldehydes and provide insights into the molecular mechanisms governing the synergistic effects of individual constituents within essential oils.

Obese women diagnosed with breast cancer have an increased risk for metastasis, and the underlying mechanisms are not well established. Within the mammary gland, adipose-derived stromal cells (ASCs) are heterogeneous cells with the capacity to differentiate into multiple mesenchymal lineages. To study the effects of obesity on ASCs, mice were fed a control diet (CD) or high-fat diet (HFD) to induce obesity, and ASCs were isolated from the mammary glands of lean and obese mice. We observed that obesity increased ASCs proliferation, decreased differentiation potential, and upregulated expression of α-smooth muscle actin, a marker of activated fibroblasts, compared to ASCs from lean mice. To determine how ASCs from obese mice impacted tumor growth, we mixed ASCs isolated from CD- or HFD-fed mice with mammary tumor cells and injected them into the mammary glands of lean mice. Tumor cells mixed with ASCs from obese mice grew significantly larger tumors and had increased invasion into surrounding adipose tissue than tumor cells mixed with control ASCs. ASCs from obese mice demonstrated enhanced tumor cell invasion in culture, a phenotype associated with increased expression of insulin-like growth factor-1 (IGF-1) and abrogated by IGF-1 neutralizing antibodies. Weight loss induced in obese mice significantly decreased expression of IGF-1 from ASCs and reduced the ability of the ASCs to induce an invasive phenotype. Together, these results suggest that obesity enhances local invasion of breast cancer cells through increased expression of IGF-1 by mammary ASCs, and weight loss may reverse this tumor-promoting phenotype.

The synthesis of a fully degradable, bio-based, sustained release, pro-antimicrobial polymer network comprised of degradable acetals (PANDA) is reported. The active antimicrobial agent - p-anisaldehyde (pA) (an extract from star anise) - was converted into a UV curable acetal containing pro-antimicrobial monomer and subsequently photopolymerized into a homogenous thiol-ene network. Under neutral to acidic conditions (pH 8), the PANDAs undergo surface erosion and exhibit sustained release of pA over 38 days. The release of pA from PANDAs was shown to be effective against both bacterial and fungal pathogens. From a combination of confocal microscopy and transmission electron microscopy, we observed that the released pA disrupts the cell membrane. Additionally, we demonstrated that PANDAs have minimal cytotoxicity towards both epithelial cells and macrophages. Although a model platform, these results point to promising pathways for the design of fully degradable sustained-release antimicrobial systems with potential applications in agriculture, pharmaceuticals, cosmetics, household/personal care, and food industries.With the increasing number of patients prescribed immunosuppressants coupled with the rise in antibiotic resistance - life-threatening microbial infections are a looming global threat. With limited success within the antibiotic pipeline, nature-based essential oils (EOs) are being investigated for their multimodal effectiveness against microbes. Despite the promising potential of EOs, difficulties in their encapsulation, limited water solubility, and high volatility limit their use. Various studies have shown that covalent attachment of these EO derivatives to polymers can mitigate these limitations. The current study presents the synthesis of a fully-degradable, sustained release, cytocompatible, pro-antimicrobial acetal network derived from p-anisaldehyde. This polymer network design provides a pathway toward application-specific EO releasing materials with quantitative encapsulation efficiencies, sustained release, and broad-spectrum antimicrobial activity.

Objective Rare genetic and non-genetic diseases are often associated with high risk of malnutrition[1]. The purpose of the study is to evaluated rare diseases among patients on Home Artificial Nutrition (HAN) and prescriptions registered at Local Health Care Unit Naples 3, Italy. Methods and procedures Data were collected from 231 patients (M=131; F=100) recorded in 2019 (1st January-31st December). Oral Nutritional Supplements (ONS), Enteral Nutrition (HEN), Parenteral Nutrition (HPN) were included; complications of pregnancy and childbirth were excluded. Results Adults were 182 (78.8%), Pediatrics 49 (21.2% ). Rare diseases of the nervous system were 177 (76.7%), congenital anomalies 25 (10.8%) and inborn errors of metabolism 8 (3%). Respiratory, hematologic, immunologic, and skin diseases, primitive glomerulopathies and intestinal disorders, rare tumors were found in fewer cases (9.1%). Amyotrophic Lateral Sclerosis was the most frequent diagnosis (43.3%; 94 ALS and 6 ALS-Juvenile). Spinal Muscolar Atrophy (SMA) was found in 23.8% of pediatrics, Progressive Supranuclear Palsy (PSP) and Duchenne Muscular Dystrophy (DMD) in 8.4% and 4.5% of adult patients. ONS were 123, mainly prescribed to adults (87%); HEN were 100, administered through Percutaneous Endoscopy Gastrostomy (86%) and nasogastric tube feeding (14%), HPN were only 9 prescriptions. Conclusion Nutritional impairment in patient with rare neurologic diseases is frequent. HAN could improve clinical management of symptoms worsening quality of life of patients. Further research is needed to evaluate the impact of nutritional intervention on individual clinical outcome[1].

Supplemental Digital Content is available in the text., Background: The HeartLogic algorithm combines multiple implantable cardioverter-defibrillator sensors to identify patients at risk of heart failure (HF) events. We sought to evaluate the risk stratification ability of this algorithm in clinical practice. We also analyzed the alert management strategies adopted in the study group and their association with the occurrence of HF events. Methods: The HeartLogic feature was activated in 366 implantable cardioverter-defibrillator and cardiac resynchronization therapy implantable cardioverter-defibrillator patients at 22 centers. The median follow-up was 11 months [25th–75th percentile: 6–16]. The HeartLogic algorithm calculates a daily HF index and identifies periods IN alert state on the basis of a configurable threshold. Results: The HeartLogic index crossed the threshold value 273 times (0.76 alerts/patient-year) in 150 patients. The time IN alert state was 11% of the total observation period. Patients experienced 36 HF hospitalizations, and 8 patients died of HF during the observation period. Thirty-five events were associated with the IN alert state (0.92 events/patient-year versus 0.03 events/patient-year in the OUT of alert state). The hazard ratio in the IN/OUT of alert state comparison was (hazard ratio, 24.53 [95% CI, 8.55–70.38], P

Background Obesity is correlated with an increased risk for developing postmenopausal breast cancer. Since obesity rates continue to rise worldwide, it is important to understand how the obese microenvironment influences normal mammary tissue to increase breast cancer risk. We hypothesized that obesity increases the proportion of luminal progenitor cells, which are thought to be the cells of origin for the most common types of breast cancer, potentially leading to an increased risk for breast cancer. Methods To study the obese microenvironment within the mammary gland, we used a high-fat diet mouse model of obesity and human breast tissue from reduction mammoplasty surgery. We identified changes in breast epithelial cell populations using flow cytometry for cell surface markers, in vitro functional assays and expression of markers on breast tissue sections. Results In both obese female mice and women, mammary epithelial cell populations demonstrated significant decreases in basal/myoepithelial cells, using either flow cytometry or cell-type-specific markers (SMA and p63). Estrogen receptor alpha (ERα) expression was significantly increased in luminal cells in obese mammary tissue, compared with control mice or breast tissue from lean women. Functional assays demonstrated significantly enhanced mammary epithelial progenitor activity in obese mammary epithelial cells and elevated numbers of ERα-positive epithelial cells that were co-labeled with markers of proliferation. Weight loss in a group of obese mice reversed increases in progenitor activity and ERα expression observed in obese mammary tissue. Conclusions Obesity enhances ERα-positive epithelial cells, reduces the number of basal/myoepithelial cells, and increases stem/progenitor activity within normal mammary tissue in both women and female mice. These changes in epithelial cell populations induced by obesity are reversible with weight loss. Our findings support further studies to examine how obesity-induced changes in stem/progenitor cells impact breast tumor incidence and histologic tumor types. Electronic supplementary material The online version of this article (doi:10.1186/s13058-017-0921-7) contains supplementary material, which is available to authorized users.

Background/Objectives: The aim of this study was to compare resting energy expenditure (REE) measured (MREE) by indirect calorimetry (IC) and REE predicted (PREE) from established predictive equations in a large sample of obese Caucasian adults. Subjects/Methods: We evaluated 1851 obese patients (body mass index (BMI)>30 kg m−2) aged between 18a and 65 years. Data were obtained by comparing MREE with PREE, derived from different equations, within and between normal weight and obese groups. The mean differences between PREE and MREE as well as the accuracy prediction within ±10% level were investigated in the whole sample and in three subgroups, classified by BMI (Group 1=30–39.9 kg m−2; Group 2=40–49.9 kg m−2; Group 3>50 kg m−2). Results: We observed that FAO, Henry and Muller3 (body composition (BC)) equations provided good mean PREE–MREE (bias −0.7, −0.3 and 0.9% root mean standard error (RMSE) 273, 263 and 269 kcal per day, respectively); HB and Henry equations were more accurate individually (57 and 56.9%). Only the Muller1 (BC) equation gave the lowest PREE–MREE difference (bias −1.7% RMSE 228 kcal per day) in females, while Johnstone and De Lorenzo equations were the most accurate (55.1 and 54.8%). When the sample was split into three subgroups according to BMI, no differences were found in males; however, the majority of the equations included in this study failed to estimate REE in severely obese females (BMI>40 kg m−2). Overall, prediction accuracy was low (~55%) for all predictive equations, regardless of BMI. Conclusions: Different established equations can be used for estimating REE at the population level in both sexes. However, the accuracy was very low for all predictive equations used, particularly among females and when BMI was high, limiting their use in clinical practice. Our findings suggest that the validation of new predictive equations would improve the accuracy of REE prediction, especially for severely obese subjects (BMI>40 kg m−2).

Thiol-ene chemistry was exploited in droplet-based microfluidics to fabricate advanced microcapsules with tunable encapsulation, degradation, and thermal properties. In addition, by utilizing the thiol-ene photopolymerization with tunable cross-link density, we demonstrate the importance of monomer conversion on the retention of omniphilic cargo in double emulsion templated microcapsules. Furthermore, we highlight the rapid cure kinetics afforded by thiol-ene chemistry in a continuous flow photopatterning device for hemispherical microparticle production.

Post-polymerization modification (PPM) has been broadly employed to achieve functional polymer brush surfaces via immobilization of functional moieties on the brush using efficient organic tranformations. Here, we demonstrate the amine-anhydride reaction as a modular PPM route to functional brush surfaces using poly(styrene–maleic anhydride) (pSMA) copolymer brushes as a platform. The amine-anhydride reaction on pSMA surfaces proceeds to high conversions, with rapid kinetics, under ambient reaction conditions, and exploits a readily available library of functional amines. Using cystamine as a modifier, a convenient route to thiol-functionalized brushes was developed that enables sequential PPM modifications with a large library of alkenes using both base-catalyzed thiol-Michael and radical-mediated thiol–ene reactions. The high fidelity PPM reactions were demonstrated via the development of multifunctional, micropatterned brush surfaces.

OBJECTIVE Although it is known that the airway has bacterial contamination that seeds the surgical site during microlaryngeal surgery, literature on the use of postoperative antibiotics is lacking. We performed a retrospective analysis of open phonosurgical and phonomicrosurgical cases at a single institution to assess whether use of postoperative antibiotics impacts the incidence of surgical site infections (SSI). METHODS In this retrospective cohort study, we reviewed 228 phonomicrosurgery and 53 open phonosurgery cases performed for benign diseases. Surgeries were performed by two laryngologists between February 2016 and August 2018. The surgeons differ in their postoperative antibiotic regimens: no antibiotics versus a 5- to 7-day postoperative course. Data collected include demographics, medical comorbidities, type of benign laryngeal disease, and surgical procedure. The primary outcome measure was postoperative infection, defined as the patient requiring a new prescription for antibiotics, an extended course of antibiotics, or any mention of infection at follow-up/emergency visits within the first month postoperatively. RESULTS The overall rate of SSI was 3.1% and 0% for phonomicrosurgery and open phonosurgery cases, respectively. For phonomicrosurgery, there was no difference in the rate of SSI for patients who received or did not receive antibiotics perioperatively: 2.9% versus 3.2% (P = 0.99). Similarly, there was no difference in the infection rate for open phonosurgical cases. CONCLUSION Infection rates after endoscopic and open phonosurgery are low. In this study, we found no evidence to suggest a protective effect associated with postoperative use of antibiotics. LEVEL OF EVIDENCE 4 Laryngoscope, 130:1128-1131, 2020.

The term Economic Zones includes a wide range of related types, including free trade zones, free ports, export processing zones, special economic zones (SEZ), areas of economic and trade cooperation, processing zones, economic and free zones. Despite the numerous variations of name and form, all these typologies recall the idea of demarcated geographical areas, placed within the national borders of a country, in which the rules of the economic and business environment are di erent from those prevailing in the national territory. is set of di erential rules generally concerns, as a matter of priority, the investment conditions, customs, taxation and the regulatory context. In the area, an environment is granted for the economic activities that choose it as a localization that appears to be more liberal and generally, more e cient from an administrative point of view than that found in the rest of the national territory. Considering all this, the paper intends to analyze the size of the SEZ phenomenon with particular regard to the EU member States and to Southern Italy, its di usion and the di erent choices of governance, as well as any barriers to development and the ability to become attractors of foreign direct investment.