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Polymeric biomaterials treated by nanostructured metal coatings are very efficient against a wide spectrum of nosocomial pathogens. One of the most effective ways for the preparation of such metal/polymer composites is the combination of excimer laser modification of polymeric materials and vacuum evaporation of noble metals. By this way, we successfully prepared palladium nanowire arrays (PdNWs) supported on biocompatible polyethylene naphthalate (PEN). The characterization of prepared PdNWs on the surface of PEN was accomplished by various methods, such as X-ray Photoelectron Spectroscopy (XPS), Focussed Ion Beam Scanning Electron Microscopy (FIB-SEM), and Atomic Force Microscopy (AFM). PdNWs were preferentially formed from one side of underlying ripples. Pd release in antibacterial testing was measured by Inductively coupled plasma mass spectrometry (ICP-MS). Then, the antibacterial and cytotoxic effects were evaluated by (i) drop plate method using E. coli (G–) and S. epidermidis (G+ bacteria), and (ii) WST-1 cytotoxicity assay with three model cell lines (L929, NIH 3T3, RAW 264.7), respectively. Pd-treated samples exhibited significant antibacterial effects, increasing with cultivation time. Cytotoxicity assay showed that the absorbance of PEN/PdNWs samples was mildly decreased, suggesting considerably low cytotoxic effects of PdNWs.

Corporations, industries and non-governmental organizations have become increasingly concerned with growing water risks in many parts of the world. Most of the focus has been on water scarcity and competition for the resource between agriculture, urban users, ecology and industry. However, water risks are multi-dimensional. Water-related hazards include flooding due to extreme rainfall, persistent drought and pollution, either due to industrial operations themselves, or to the failure of infrastructure. Most companies have risk management plans at each operational location to address these risks to a certain design level. The residual risk may or may not be managed, and is typically not quantified at a portfolio scale, i.e. across many sites. Given that climate is the driver of many of these extreme events, and there is evidence of quasi-periodic climate regimes at inter-annual and decadal timescales, it is possible that a portfolio is subject to persistent, multi-year exceedances of the design level. In other words, for a multi-national corporation, it is possible that there is correlation in the climate-induced portfolio water risk across its operational sites as multiple sites may experience a hazard beyond the design level in a given year. Therefore, from an investor's perspective, a need exists for a water risk index that allows for an exploration of the possible space and/or time clustering in exposure across many sites contained in a portfolio. This paper represents a first attempt to develop an index for financial exposure of a geographically diversified, global portfolio to the time-varying risk of climatic extremes using long daily global rainfall datasets derived from climate re-analysis models. Focusing on extreme daily rainfall amounts and using examples from major mining companies, we illustrate how the index can be developed. We discuss how companies can use it to explore their corporate exposure, and what they may need to disclose to investors and regulators to promote transparency as to risk exposure and mitigation efforts. For the examples of mining companies provided, we note that the actual exposure is substantially higher than would be expected in the absence of space and time correlation of risk as is usually tacitly assumed. We also find evidence for the increasing exposure to climate-induced risk, and for decadal variability in exposure. The relative vulnerability of different portfolios to multiple extreme events in a given year is also demonstrated.

Abstract Introduction Cardiac amyloidosis is a rarely reported and potentially fatal variant of the systemic disease. Its early diagnosis could potentially lead to significantly improved clinical outcomes. Case presentation A 56-year-old female presented with dyspnea and palpitations. Her physical exam and non-invasive evaluation with cardiac magnetic resonance imaging (CMRI) revealed restrictive cardiomyopathy, and the bone marrow biopsy results showed systemic amyloidosis. Discussion The diagnosis of cardiac amyloidosis is not always straightforward, and delay can cause the progression of the disease and an increased risk of morbidity and mortality. Electrocardiograms, echocardiograms, cardiac magnetic resonance imaging, and histopathologic evaluation are the main methods for diagnosing cardiac amyloidosis. The treatment consists of controlling heart failure symptoms and disease-modifying interventions, including medical and surgical therapeutic methods. Clinical learning point (conclusion) Cardiac involvement is the main cause of death in systemic amyloidosis. Early suspicion, diagnosis, and treatment are crucial in improving patients’ survival. CMRI can play an essential role in the diagnosis of cardiac Amyloidosis. A graphical abstract is provided for visual summary. Graphical Abstract

Background: Empirical decisions to select therapies for psoriasis (PSO) and atopic dermatitis (AD) can lead to delays in disease control and increased health care costs. However, routine molecular testing for AD and PSO are lacking. Objective: To examine (1) how clinicians choose systemic therapies for patients with PSO and AD without molecular testing and (2) to determine how often the current approach leads to patients switching medications. Methods: A 20-question survey designed to assess clinician strategies for systemic treatment of AD and PSO was made available to attendees of a national dermatology conference in 2022. Results: Clinicians participating in the survey (265/414, 64% response rate) ranked “reported efficacy” as the most important factor governing treatment choice (P

The study of excimer laser treatment of polystyrene surface was performed. The influence of laser fluence and number of laser pulses on surface chemistry and morphology was determined. The surface morphology and roughness were studied with atomic force microscopy. Surface wettability and aging studies were characterized by the water contact angle measurements. Surface oxygen concentration and chemistry were evaluated from X-ray photoelectron spectroscopy and zeta potential measurements. The optimal polystyrene treatment parameters for the most regular pattern were determined. The foils with optimal ripple pattern were subsequently sputtered with gold nano-layers of 100 nm thickness. It was found that the surface roughness of PS strongly depends on number of pulses. The aging study revealed that the higher contact angle achieve the samples treated with higher laser fluence. The deposition of gold nano-layer increases the surface roughness of nano-patterned surface. It was proved that the oxygen concentration is significantly influenced by the KrF laser exposure.

Abstract Atrial fibrillation (AF) often escapes detection, given its frequent paroxysmal and asymptomatic presentation. Deep learning of transthoracic echocardiograms (TTEs), which have structural information, could help identify occult AF. We created a two-stage deep learning algorithm using a video-based convolutional neural network model that (1) distinguished whether TTEs were in sinus rhythm or AF and then (2) predicted which of the TTEs in sinus rhythm were in patients who had experienced AF within 90 days. Our model, trained on 111,319 TTE videos, distinguished TTEs in AF from those in sinus rhythm with high accuracy in a held-out test cohort (AUC 0.96 (0.95–0.96), AUPRC 0.91 (0.90–0.92)). Among TTEs in sinus rhythm, the model predicted the presence of concurrent paroxysmal AF (AUC 0.74 (0.71–0.77), AUPRC 0.19 (0.16–0.23)). Model discrimination remained similar in an external cohort of 10,203 TTEs (AUC of 0.69 (0.67–0.70), AUPRC 0.34 (0.31–0.36)). Performance held across patients who were women (AUC 0.76 (0.72–0.81)), older than 65 years (0.73 (0.69–0.76)), or had a CHA2DS2VASc ≥2 (0.73 (0.79–0.77)). The model performed better than using clinical risk factors (AUC 0.64 (0.62–0.67)), TTE measurements (0.64 (0.62–0.67)), left atrial size (0.63 (0.62–0.64)), or CHA2DS2VASc (0.61 (0.60–0.62)). An ensemble model in a cohort subset combining the TTE model with an electrocardiogram (ECGs) deep learning model performed better than using the ECG model alone (AUC 0.81 vs. 0.79, p = 0.01). Deep learning using TTEs can predict patients with active or occult AF and could be used for opportunistic AF screening that could lead to earlier treatment.

Abstract Introduction The validated 40-gene expression profile (40-GEP) test independently stratifies risk of regional or distant metastasis for cutaneous squamous cell carcinoma (cSCC) tumors with high-risk clinicopathologic features. This study evaluated the stratification of risk by the 40-GEP test in a large cohort of tumors with one or more high-risk factors and in clinically relevant subgroups, including tumors within National Comprehensive Cancer Network (NCCN) high- and very-high-risk groups, lower-stage BWH T1 and T2a tumors, and patients > 65 years old. Methods This multicenter (n = 58) performance study of the 40-GEP included 897 patients. Kaplan-Meier analyses were performed to assess risk stratification profiles for 40-GEP Class 1 (low), Class 2A (higher) and Class 2B (highest) risk groups, while nested Cox regression models were used to compare risk prediction of clinicopathologic risk classification systems versus risk classification systems in combination with 40-GEP. Results Patients classified as 40-GEP Class 1, Class 2A, or Class 2B had significantly different metastatic risk profiles (p

The University of Connecticut Extension Sustainable Landscapes program seeks to develop an invasive plant training program to equip stakeholder groups of varied experiential backgrounds with the information needed to evaluate, manage, and mitigate populations of invasive species in Connecticut. A mixed methods needs assessment was conducted to explore diverse viewpoints about invasive plant education. Data were collected from 233 survey respondents and three focus group interviews. Landscape professional/contractors and municipal employees totaled 41.1% of respondents when combined, and home gardeners totaled 27.9%. The greatest programmatic need identified by survey respondents was invasive plant management options and strategies, with Japanese knotweed considered the most problematic invasive plant from a list of 16 species. Focus group participants expressed enthusiasm about targeted educational programming, such as efforts focused on land management principles, species identification, state regulatory agencies, and pesticide application. Many shared the need for enhanced public education efforts and resource availability. A hybrid approach, including virtual and in-person components, was recommended as the ideal delivery modality for an invasive plant training program.

Wildfire in California is an increasing threat to life and property. The expansion of urban and suburban development into wildlands limits risk-reduction options like prescribed burning, whereas large-scale mechanical and herbicide treatments can be cost prohibitive and unpalatable to the public. Cattle grazing is a low risk, affordable treatment not frequently considered for use explicitly for fuels reduction in California. To examine the impact of cattle grazing on fire in Napa and Sonoma Counties, California, we quantified its effects as change in average annual burn probability. Probabilities were calculated for 2001–2017 using mixed-effect regression models in combination with a range of grazing intensities and extents. These grazing scenarios were designed to represent current grazing conditions, ungrazed conditions, adding grazing to high priority landscapes, and grazing the full study area. We estimated that under current grazing conditions, cattle grazing reduces average annual burn probability 45% (from 9.9% to 5.4%) compared to ungrazed conditions. Adding grazing to high priority landscapes as identified by the California Department of Forestry and Fire Protection (CAL FIRE) decreased their average annual burn probability by 82% (from 7.6% to 1.4%) compared to under current grazing conditions. Of the scenarios assessed, grazing high priority landscapes heavily while maintaining the current extent and intensity of grazing on other rangelands provided the best return in terms of decreased burn probability per additional area grazed. Finally, we demonstrated how our methodologies can be utilized by fuel managers and planners to identify key areas for treatment with cattle grazing. Our findings suggest cattle grazing provides benefits to the study area by reducing overall burn probability, and that extending its use to treat fuels in priority areas in and around the wildland urban interface could provide further fire-risk reduction on community-adjacent lands. Land managers may find cattle grazing a valuable long term fuel-management tool at the landscape scale.

Continuous gold layers of increasing thickness were prepared by the vacuum deposition method on pristine and plasma modified sheets of PE, PET and PTFE. Various surface profiles were obtained. The surface morphology was studied using atomic force microscopy (AFM). The continuity of the metal layer on the polymer surface was validated by measuring its electrical resistance. Changes in the wettability of the plasma treated polymers were evaluated by measuring the aging curves. These were obtained as the dependence of contact angle on ageing time.

IntroductionDeep brain stimulation (DBS) has shown remarkable success treating neurological and psychiatric disorders including Parkinson’s disease, essential tremor, dystonia, epilepsy, and obsessive-compulsive disorder. DBS is now being explored to improve cognitive and functional outcomes in other psychiatric conditions, such as those characterized by reduced N-methyl-D-aspartate (NMDA) function (i.e., schizophrenia). While DBS for movement disorders generally involves high-frequency (>100 Hz) stimulation, there is evidence that low-frequency stimulation may have beneficial and persisting effects when applied to cognitive brain networks.MethodsIn this study, we utilize a novel technology, functional ultrasound imaging (fUSI), to characterize the cerebrovascular impact of medial septal nucleus (MSN) DBS under conditions of NMDA antagonism (pharmacologically using Dizocilpine [MK-801]) in anesthetized male mice.ResultsImaging from a sagittal plane across a variety of brain regions within and outside of the septohippocampal circuit, we find that MSN theta-frequency (7.7 Hz) DBS increases hippocampal cerebral blood volume (CBV) during and after stimulation. This effect was not present using standard high-frequency stimulation parameters [i.e., gamma (100 Hz)].DiscussionThese results indicate the MSN DBS increases circuit-specific hippocampal neurovascular activity in a frequency-dependent manner and does so in a way that continues beyond the period of electrical stimulation.

MicroRNAs (miRNAs) are small non-coding RNAs that alter the expression of target genes at the post-transcriptional level, influencing diverse outcomes in metabolism, cell differentiation, proliferation, cell survival, and cell death. Dysregulated miRNA expression is implicated in various rheumatic conditions, including ankylosing spondylitis (AS), gout, juvenile idiopathic arthritis (JIA), osteoarthritis (OA), psoriatic arthritis, rheumatoid arthritis (RA), Sjogren’s syndrome, systemic lupus erythematosus (SLE) and systemic sclerosis. For this review, we used an open-source programming language- PowerShell, to scan the massive number of existing primary research publications on PubMed on miRNAs in these nine diseases to identify and count unique co-occurrences of individual miRNAs and the disease name. These counts were used to rank the top seven most relevant immuno-miRs based on their research volume in each rheumatic disease. Individual miRNAs were also screened for publication with the names of immune cells, cytokines, and pathological processes involved in rheumatic diseases. These occurrences were tabulated into matrices to identify hotspots for research relevance. Based on this information, we summarize the basic and clinical findings for the top three miRNAs — miR-146, miR-155, and miR-21 — whose relevance spans across multiple rheumatic diseases. Furthermore, we highlight some unique miRNAs for each disease and why some rheumatic conditions lack research in this emerging epigenetics field. With the overwhelming number of publications on miRNAs in rheumatic diseases, this review serves as a ‘relevance finder’ to guide researchers in selecting miRNAs based on the compiled existing knowledge of their involvement in disease pathogenesis. This approach applies to other disease contexts with the end goal of developing miRNA-based therapeutics.

Abstract Background Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy. Thus, there is an urgent need for safe and effective novel therapies. PDAC’s excessive reliance on glucose metabolism for its metabolic needs provides a target for metabolic therapy. Preclinical PDAC models have demonstrated that targeting the sodium-glucose co-transporter-2 (SGLT2) with dapagliflozin may be a novel strategy. Whether dapagliflozin is safe and efficacious in humans with PDAC is unclear. Methods We performed a phase 1b observational study (ClinicalTrials.gov ID NCT04542291; registered 09/09/2020) to test the safety and tolerability of dapagliflozin (5 mg p.o./day × 2 weeks escalated to 10 mg p.o./day × 6 weeks) added to standard Gemcitabine and nab-Paclitaxel (GnP) chemotherapy in patients with locally advanced and/or metastatic PDAC. Markers of efficacy including Response Evaluation Criteria in Solid Tumors (RECIST 1.1) response, CT-based volumetric body composition measurements, and plasma chemistries for measuring metabolism and tumor burden were also analyzed. Results Of 23 patients who were screened, 15 enrolled. One expired (due to complications from underlying disease), 2 dropped out (did not tolerate GnP chemotherapy) during the first 4 weeks, and 12 completed. There were no unexpected or serious adverse events with dapagliflozin. One patient was told to discontinue dapagliflozin after 6 weeks due to elevated ketones, although there were no clinical signs of ketoacidosis. Dapagliflozin compliance was 99.4%. Plasma glucagon increased significantly. Although abdominal muscle and fat volumes decreased; increased muscle-to-fat ratio correlated with better therapeutic response. After 8 weeks of treatment in the study, partial response (PR) to therapy was seen in 2 patients, stable disease (SD) in 9 patients, and progressive disease (PD) in 1 patient. After dapagliflozin discontinuation (and chemotherapy continuation), an additional 7 patients developed the progressive disease in the subsequent scans measured by increased lesion size as well as the development of new lesions. Quantitative imaging assessment was supported by plasma CA19-9 tumor marker measurements. Conclusions Dapagliflozin is well-tolerated and was associated with high compliance in patients with advanced, inoperable PDAC. Overall favorable changes in tumor response and plasma biomarkers suggest it may have efficacy against PDAC, warranting further investigation.

Abstract This article outlines an Interpersonal Neurobiology (IPNB) perspective on the fundamental components that comprise mental health and promote well-being. The central aim of this paper is to answer essential but often overlooked questions related to the field of mental health, such as: What is the mind? What is the basis of well-being? What is the self and how does it develop? We will offer scientific support for the IPNB position that the mind is relational and embodied and that integration is the basis of mental health. It will also describe how the self extends beyond the individual, arising from and inextricably connected to the social, cultural and planetary systems in which we exist. IPNB is not a form of therapy; rather, it is a framework that focuses on deepening our understanding of the mind and human development across the lifespan. Drawing from interdisciplinary principles from a range of fields including physics, mathematics, neuroscience, and psychology, we will provide a practical view of the underlying basis of mental suffering and the scientific mechanisms of change to improve mental well-being. These core principles are building blocks of clinical evaluation and treatment that can be applied across multiple theoretical orientations and client populations. The special emphasis in this article is on the issue of psychache as an underlying cause of suicide and its relationship to personal, public and planetary health.

Abstract Objective Although most patients diagnosed with early‐stage cutaneous melanoma (CM) have excellent outcomes, because of the large number diagnosed each year, many will experience recurrence or death. Prognostic testing for CM using the 31‐gene expression profile (31‐GEP) test can benefit patients by helping guide risk‐appropriate treatment and surveillance plans. We sought to evaluate patients' attitudes toward prognostic testing with the 31‐GEP and assess whether patients experience decision regret about having 31‐GEP testing. Methods A 43‐question survey was distributed by the Melanoma Research Foundation in June–August 2021 to CM patients enrolled in their database. Patients were asked questions regarding their decision to undergo 31‐GEP testing and the extent to which they experienced decision regret using a validated set of Decision Regret Scale questions. Results We analyzed responses from patients diagnosed in 2014 or later (n = 120). Of these, 28 had received 31‐GEP testing. Most respondents (n = 108, 90%) desired prognostic information when diagnosed. Of those who received 31‐GEP testing, most felt the results were useful (n = 22 out of 24) and had regret scores significantly less than neutral regret, regardless of their test results (Class 1: p

Background There are limited data on repeat mitral transcatheter edge‐to‐edge repair for recurrent significant mitral regurgitation (MR). Methods and Results We conducted a single‐center, retrospective analysis of consecutive patients referred to a second mitral transcatheter edge‐to‐edge repair after a technically successful first procedure. Clinical, laboratory, and echocardiographic measures were assessed up to 1 year after the intervention. The composite of all‐cause death or heart failure (HF) hospitalizations constituted the primary outcome. A total of 52 patients (median age, 81 [interquartile range, 76–87] years, 29 [55.8%] men, 26 [50.0%] with functional MR) met the inclusion criteria. MR recurrences were mostly related to progression of the underlying cardiac pathology. All procedures were technically successful. At 1 year, most patients with available records (n=24; 96.0%) experienced improvement in MR severity or New York Heart Association functional class that was statistically significant but numerically modest. Fourteen (26.9%) patients died or were hospitalized due to HF. These were higher‐risk cases with predominantly functional MR who mostly underwent an urgent procedure and exhibited more severe HF indices before the intervention, as well as an attenuated 1‐month clinical and echocardiographic response. Overall, 1‐year course was comparable to that experienced by patients who underwent only a first transcatheter edge‐to‐edge repair at our institution (n=902). Tricuspid regurgitation of greater than moderate grade was the only baseline parameter to independently predict the primary outcome. Conclusions Repeat mitral transcatheter edge‐to‐edge repair is feasible, safe, and clinically effective, especially in non‐functional MR patients without concomitant significant tricuspid regurgitation.

BackgroundThere are scarce data regarding the post-mitral transcatheter edge-to-edger repair (TEER) course in different racial groups.ObjectiveTo assess the impact of race on outcomes following TEER for mitral regurgitation (MR).MethodsThis is a single-center, retrospective analysis of consecutive TEER procedures performed during 2013–2020. The primary outcome was the composite of all-cause mortality or heart failure (HF) hospitalizations along the first postprocedural year. Secondary outcomes included individual components of the primary outcome, New York Heart Association (NYHA) class, MR grade, and left ventricular mass index (LVMi).ResultsOut of 964 cases, 751 (77.9%), 88 (9.1%), 68 (7.1%), and 57 (5.9%) were whites, blacks, Asians, and Hispanics, respectively. At baseline, non-whites and blacks were younger and more likely be female, based in lower socioeconomic areas, not fully insured, diagnosed with functional MR, and affected by biventricular dysfunction. Intra-procedurally, more devices were implanted in blacks. At 1-year, non-whites (vs. whites) and blacks (vs. non-blacks or whites) experienced higher cumulative incidence of the primary outcome (32.9% vs. 22.5%, p = 0.002 and 38.6% vs. 23.4% or 22.5%, p = 0.002 or p = 0.001, respectively), which were accounted for by hospitalizations in the functional MR sub-cohort (n = 494). NYHA class improved less among blacks with functional MR. MR severity and LVMi equally regressed in all groups. White race (HR 0.62, 95% CI 0.39–0.99, p = 0.047) and black race (HR 2.07, 95% CI 1.28–3.35, p = 0.003) were independently associated with the primary outcome in functional MR patients only.ConclusionMitral TEER patients of different racial backgrounds exhibit major differences in baseline characteristics. Among those with functional MR, non-whites and blacks also experience a less favorable 1-year clinical outcome.

Introduction: Image-guided percutaneous microwave ablation (MWA) is becoming a more common treatment option for patients with primary and metastatic lung malignancies. Nevertheless, there is limited literature on the safety and efficacy of MWA compared with standard-of-care therapy, including surgical resection and radiation. This study will report the long-term outcomes after MWA for pulmonary malignancies and investigate the factors related to efficacy, including lesion size, location, and ablation power. Methods: Retrospective single-center study analyzing 93 patients who underwent percutaneous MWA for primary or metastatic lung malignancies. Outcomes included immediate technical success, local tumor recurrence, overall survival, disease-specific survival, and complications. Results: At a single institution, 190 lesions (81 primary and 109 metastatic) were treated in 93 patients. Immediate technical success was achieved in all cases. Freedom from local recurrence was 87.6%, 75.3%, and 69.2% and overall survival was 87.7%, 76.2%, and 74.3% at 1 year, 2 years, and 3 years, respectively. Disease-specific survival was 92.6%, 81.8%, and 81.8%. The most common complication was pneumothorax, which occurred in 54.7% (104 of 190) of procedures, with 35.2% (67 of 190) requiring a chest tube. No life-threatening complications occurred. Conclusions: Percutaneous MWA seems safe and effective for treatment of primary and metastatic lung malignancies and should be considered for patients with limited metastatic burden and lesions less than 3 cm in size.

Aim: This study explored uveal melanoma patient experiences and regret following molecular prognostic testing using a 15-gene expression profile (GEP) test. Materials & methods: A retrospective, cross-sectional survey study was conducted through an online questionnaire capturing patient-reported experiences with prognostic biopsy/molecular testing. Results: Of 177 respondents, 159 (90%) wanted prognostic information at diagnosis. Most 15-GEP-tested patients who shared their results (99%) reported gaining value from testing, as did patients tested with other methods. Patients who received prognostic testing experienced lower decision regret than those who opted out. Decision regret did not differ based on GEP class. Conclusion: Most uveal melanoma patients desire prognostic testing and gain value from the GEP, independent of a high- or low-risk result.

Coronary artery fistula (CAF) is an abnormal connection between a coronary artery and a heart chamber resulting in left-to-right shunt. A large CAF was an unexpected cause of heart failure in a 58-year-old woman who underwent transcatheter closure of the CAF with improvement in symptoms but complicated by myocardial infarction. (Level of Difficulty: Beginner.)

Glasses are promising electrolytes for solid-state lithium batteries; however, due to their amorphous structure, the ionic conduction mechanism remains poorly understood. Here, atomic-scale modeling reveals that lithium migration occurs via concerted hopping of Li-ions coupled to quasi-permanent rotations of tetrahedral anions.

Abstract Background The p66ShcA redox protein is the longest isoform of the Shc1 gene and is variably expressed in breast cancers. In response to a variety of stress stimuli, p66ShcA becomes phosphorylated on serine 36, which allows it to translocate from the cytoplasm to the mitochondria where it stimulates the formation of reactive oxygen species (ROS). Conflicting studies suggest both pro- and anti-tumorigenic functions for p66ShcA, which prompted us to examine the contribution of tumor cell-intrinsic functions of p66ShcA during breast cancer metastasis. Methods We tested whether p66ShcA impacts the lung-metastatic ability of breast cancer cells. Breast cancer cells characteristic of the ErbB2+/luminal (NIC) or basal (4T1) subtypes were engineered to overexpress p66ShcA. In addition, lung-metastatic 4T1 variants (4T1-537) were engineered to lack endogenous p66ShcA via Crispr/Cas9 genomic editing. p66ShcA null cells were then reconstituted with wild-type p66ShcA or a mutant (S36A) that cannot translocate to the mitochondria, thereby lacking the ability to stimulate mitochondrial-dependent ROS production. These cells were tested for their ability to form spontaneous metastases from the primary site or seed and colonize the lung in experimental (tail vein) metastasis assays. These cells were further characterized with respect to their migration rates, focal adhesion dynamics, and resistance to anoikis in vitro. Finally, their ability to survive in circulation and seed the lungs of mice was assessed in vivo. Results We show that p66ShcA increases the lung-metastatic potential of breast cancer cells by augmenting their ability to navigate each stage of the metastatic cascade. A non-phosphorylatable p66ShcA-S36A mutant, which cannot translocate to the mitochondria, still potentiated breast cancer cell migration, lung colonization, and growth of secondary lung metastases. However, breast cancer cell survival in the circulation uniquely required an intact p66ShcA S36 phosphorylation site. Conclusion This study provides the first evidence that both mitochondrial and non-mitochondrial p66ShcA pools collaborate in breast cancer cells to promote their maximal metastatic fitness.

Background: The prognostic significance of pulmonary venous (PV) flow reversal in degenerative mitral regurgitation (dMR) is not well-established. Objective: We aimed to assess whether reversed PV flow is associated with adverse outcomes in patients with significant dMR. Methods: We retrospectively analyzed consecutive patients referred to a tertiary center for evaluation of dMR of greater than moderate degree, who had normal sinus rhythm, had a left ventricular ejection fraction of above 60%, and did not suffer from any other major valvular disorders. The primary outcome was the combined rate of all-cause mortality, mitral intervention, or new-onset atrial fibrillation (AF) at 5 years following index echocardiogram. Secondary outcomes included individual components of the primary outcome. Results: Overall, 135 patients (median age 68 (IQR, 58–74) years; 93 (68.9%) males; 89 (65.9%) with severe MR) met the inclusion criteria and were followed for 115.2 (IQR, 60.0–155.0) months. Patients with a reversed PV flow pattern (PVFP) (n = 34) more often presented with severe MR compared to those with a normal (n = 49) and non-reversed PVFP (n = 101) (RR = 2.03 and 1.59, respectively, all p < 0.001). At 5 years, they experienced the highest cumulative incidence of the primary outcome (80.2% vs. 59.2% and 67.3%, p = 0.008 and 0.018, respectively). Furthermore, a reversed PVFP was independently associated with a higher risk of the primary outcome compared to normal PVFP (HR 2.53, 95% CI 1.21–5.31, p = 0.011) and non-reversed PVFP (HR 2.14, 95% CI 1.12–4.10, p = 0.022). Conclusion: PV flow reversal is associated with a worse 5-year composite of mortality, mitral intervention, or AF in patients with significant dMR.

Historically, administration of dacarbazine to sarcoma patients was limited by frequent treat-ment-related nausea/vomiting and neutropenia. These toxicities are now largely preventable with contemporary antiemetics and growth factor support. In this single-arm, phase II study, dacarbazine 850 mg/m 2 was given on day 1 of each 3-week cycle until disease progression or intolerance with prophylactic serotonin-3 receptor, neurokinin-1 antagonists, corticosteroids, and pegfilgrastim. Coprimary endpoints included clinical benefit rate (CBR), and any grade of nausea/vomiting and/or grade 3–4 neutropenia. With a sample size of 80 patients, >24 patients with clinical benefit would indicate that the CBR exceeds the historical (

Summary: The H2 capacities of a diverse set of 918,734 metal-organic frameworks (MOFs) sourced from 19 databases is predicted via machine learning (ML). Using only 7 structural features as input, ML identifies 8,282 MOFs with the potential to exceed the capacities of state-of-the-art materials. The identified MOFs are predominantly hypothetical compounds having low densities (5,300 m2 g−1), void fractions (∼0.90), and pore volumes (>3.3 cm3 g−1). The relative importance of the input features are characterized, and dependencies on the ML algorithm and training set size are quantified. The most important features for predicting H2 uptake are pore volume (for gravimetric capacity) and void fraction (for volumetric capacity). The ML models are available on the web, allowing for rapid and accurate predictions of the hydrogen capacities of MOFs from limited structural data; the simplest models require only a single crystallographic feature. The bigger picture: The efficient storage of hydrogen fuel remains a barrier to the adoption of fuel cell vehicles. Although many storage technologies have been proposed, adsorptive storage in metal-organic frameworks (MOFs) holds promise due to the low operating pressures, fast kinetics, reversibility, and high gravimetric densities typical of MOFs. Nevertheless, the volumetric storage densities of known MOFs are generally low; hence, new MOFs with improved volumetric performance are desired. Identifying optimal MOFs remains a challenge, however, because relatively few MOFs have been characterized experimentally, and the building-block structure of MOFs suggests that the number of possible materials is limitless. To accelerate the discovery process, this study develops machine learning models that predict the hydrogen capacity of MOFs. The models identify promising materials, clarify structure-property relations, and can be used—on the web or through an API—to predict the performance of new MOFs.

Considering the large number of existing synthesised and hypothesised metal-organic frameworks, determining which materials perform best for given applications remains a challenge. Here, the authors screen the usable hydrogen uptake capacities of nearly 500,000 MOFs, and find that three frameworks outperform the current record-holder.

Transcatheter techniques for the treatment of tricuspid regurgitation (TR) are being more frequently used and several new devices are in development. Since 90% of patients with TR have secondary TR, catheter based systems which reduce the dilated tricuspid annulus area are of particular interest. In order to perform an annuloplasty procedure effectively and safely, knowledge about the anatomy of the tricuspid valve apparatus and especially of the annulus in relation to the important neighboring structures such as the aortic root, the RCA, the electrical pathways and the CS is fundamental. In addition, comprehensive understanding of the device itself, the delivery system, its maneuverability and the individual procedural steps is required. Furthermore, the use of multi-modality imaging is important. For each step of the procedure the appropriate imaging modality as well as the optimal; imaging planes are crucial to provide the necessary information to best guide the individual procedural step.

Background: The incidence of acute cardiac injury in COVID-19 patients is very often subclinical and can be detected by cardiac magnetic resonance imaging. The aim of this study was to assess if subclinical myocardial dysfunction could be identified using left ventricular global longitudinal strain (LV-GLS) in patients hospitalized with COVID-19. Methods: We performed a search of COVID-19 patients admitted to our institution from January 1st, 2020 to June 8th, 2020, which revealed 589 patients (mean age = 66 ± 18, male = 56%). All available 60 transthoracic echocardiograms (TTE) were reviewed and off-line assessment of LV-GLS was performed in 40 studies that had sufficient quality images and the views required to calculate LV-GLS. We also analyzed electrocardiograms and laboratory findings including inflammatory markers, Troponin-I, and B-type natriuretic peptide (BNP). Results: Of 589 patients admitted with COVID-19 during our study period, 60 (10.1%) underwent TTE during hospitalization. Findings consistent with overt myocardial involvement included reduced ejection fraction (23%), wall motion abnormalities (22%), low stroke volume (82%) and increased LV wall thickness (45%). LV-GLS analysis was available for 40 patients and was abnormal in 32 patients (80%). All patients with LV dysfunction had elevated cardiac enzymes and positive inflammatory biomarkers. Conclusions: Subclinical myocardial dysfunction as measured via reduced LV-GLS is frequent, occurring in 80% of patients hospitalized with COVID-19, while prevalent LV function parameters such as reduced EF and wall motion abnormalities were less frequent findings. The mechanism of cardiac injury in COVID-19 infection is the subject of ongoing research.

Approximately one in 45 children have been diagnosed with Autism Spectrum Disorder (ASD), which is characterized by social/communication impairments. Recent studies have linked a subset of familial ASD to mutations in the Protocadherin 10 (Pcdh10) gene. Additionally, Pcdh10's expression pattern, as well as its known role within protein networks, implicates the gene in ASD. Subsequently, the neurobiology of mice heterozygous for Pcdh10 (Pcdh10+/−) has been investigated as a proxy for ASD. Male Pcdh10+/− mice have demonstrated sex-specific deficits in social behavior, recapitulating the gender bias observed in ASD. Furthermore, in vitro slice preparations of these Pcdh10+/− mice demonstrate selective decreases to high frequency electrophysiological responses, mimicking clinical observations. The direct in vivo ramifications of such decreased in vitro high frequency responses are unclear. As such, Pcdh10+/− mice and their wild-type (WT) littermates underwent in vivo electrocorticography (ECoG), as well as ex vivo amino acid concentration quantification using High Performance Liquid Chromatography (HPLC). Similar to the previously observed reductions to in vitro high frequency electrophysiological responses in Pcdh10+/− mice, male Pcdh10+/− mice exhibited reduced gamma-band (30–80 Hz), but not lower frequency (10 and 20 Hz), auditory steady state responses (ASSR). In addition, male Pcdh10+/− mice exhibited decreased signal-to-noise-ratio (SNR) for high gamma-band (60–100 Hz) activity. These gamma-band perturbations for both ASSR and SNR were not observed in females. Administration of a GABAB agonist remediated these electrophysiological alterations among male Pcdh10+/−mice. Pcdh10+/− mice demonstrated increased concentrations of GABA and glutamine. Of note, a correlation of auditory gamma-band responses with underlying GABA concentrations was observed in WT mice. This correlation was not present in Pcdh10+/− mice. This study demonstrates the role of Pcdh10 in the regulation of excitatory-inhibitory balance as a function of GABA in ASD.