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CD8+ tumor-infiltrating lymphocytes (TILs) are associated with improved survival in triple-negative breast cancer (TNBC) yet have no association with survival in estrogen receptor-positive (ER+) BC. The basis for these contrasting findings remains elusive. We identified subsets of BC tumors infiltrated by CD8+ T cells with characteristic features of exhausted T cells (TEX). Tumors with abundant CD8+ TEX exhibited a distinct tumor microenvironment marked by amplified interferon-γ signaling-related pathways and higher programmed death ligand 1 expression. Paradoxically, higher levels of tumor-infiltrating CD8+ TEX associated with decreased overall survival of patients with ER+ BC but not patients with TNBC. Moreover, high tumor expression of a CD8+ TEX signature identified dramatically reduced survival in premenopausal, but not postmenopausal, patients with ER+ BC. Finally, we demonstrated the value of a tumor TEX signature score in identifying high-risk premenopausal ER+ BC patients among those with intermediate Oncotype DX Breast Recurrence Scores. Our data highlight the complex relationship between CD8+ TILs, interferon-γ signaling, and ER status in BC patient survival. This work identifies tumor-infiltrating CD8+ TEX as a key feature of reduced survival outcomes in premenopausal patients with early-stage ER+ BC.

Background Recent estimates indicated substantially replacing cigarettes by e-cigarettes would, during 2016–2100, reduce US deaths and life-years lost (millions) by 6.6 and 86.7 (Optimistic Scenario) and 1.6 and 20.8 (Pessimistic). To provide additional insight we use alternative modelling based on a shorter period (1991–2040), four main smoking-associated diseases, deaths aged 30–79 years, and a full product history. We consider variations in: assumed effective dose of e-cigarettes versus cigarettes (F); their relative quitting rate (Q); proportions smoking after 10 years (X); and initiation rate (I) of vaping, relative to smoking. Methods We set F = 0.05, X = 5%, Q = 1.0 and I = 1.0 (Main Scenario) and F = 0.4, X = 10%, Q = 0.5 and I = 1.5 (Pessimistic Scenario). Sensitivity Analyses varied Main Scenario parameters singly; F from 0 to 0.4, X 0.01% to 15%, and Q and I 0.5 to 1.5. To allow comparison with prior work, individuals cannot be dual users, re-initiate, or switch except from cigarettes to e-cigarettes. Results Main Scenario reductions were 2.52 and 26.23 million deaths and life-years lost; Pessimistic Scenario reductions were 0.76 and 8.31 million. These were less than previously, due to the more limited age-range and follow-up, and restriction to four diseases. Reductions in deaths (millions) varied most for X, from 3.22 (X = 0.01%) to 1.31 (X = 15%), and F, 2.74 (F = 0) to 1.35 (F = 0.4). Varying Q or I had little effect. Conclusions Substantial reductions in deaths and life-years lost were observed even under pessimistic assumptions. Estimates varied most for X and F. These findings supplement literature indicating e-cigarettes can importantly impact health challenges from smoking.

Key Points Question Is immunotherapy targeting programmed cell death receptor 1/programmed cell death ligand 1 (PD-1/PD-L1) associated with the presence of liver metastasis at the time of therapy and outcomes among patients with treatment-resistant microsatellite stable (MSS) metastatic colorectal cancer? Findings This cohort study included 95 patients with MSS metastatic colorectal cancer. Patients without liver metastases had a significantly superior objective response rate (19.5% vs 0) and median progression-free survival (4.0 vs 1.5 months) compared with patients with liver metastases; multivariate analysis revealed that the presence of liver metastases was an independent prognostic factor associated with poor outcome of PD-1/PD-L1 therapy. Meaning This cohort study suggests that PD-1/PD-L1 inhibitors should be reinvestigated in prospective trials in patients with MSS metastatic colorectal cancer without liver involvement., Importance Microsatellite stable (MSS) metastatic colorectal cancer has been historically characterized as resistant to immunotherapy. Recent studies have demonstrated limited clinical activity of programmed cell death receptor 1/programmed death ligand 1 (PD-1/PD-L1) targeting in MSS metastatic colorectal cancer. The association of metastatic disease in the liver with treatment response has not been fully investigated. Objective To investigate the association of liver metastases with response to PD-1/PD-L1–targeting therapy in MSS metastatic colorectal cancer. Design, Setting, and Participants This single-center retrospective cohort study evaluated clinical responses to PD-1– or PD-L1–targeting therapy, with or without other investigational agents, in patients with MSS metastatic colorectal cancer and disease progression after standard of care therapy from January 1, 2014, to December 31, 2020. Main Outcomes and Measures Objective response rate (ORR) and progression-free survival (PFS), measured from initiation of PD-1/PD-L1–targeting therapy. Results Ninety-five patients with MSS metastatic colorectal cancer were identified (54 men [56.8%]; median age, 55 [interquartile range (IQR), 49-64] years). The overall ORR was 8.4% (8 of 95 patients). Eight of 41 patients without liver metastases achieved an ORR of 19.5%, and no response was observed in 54 patients with liver metastases. The disease control rate was 58.5% (24 of 41) in patients without liver metastasis and 1.9% (1 of 54) in patients with liver metastasis. Patients without liver metastases at the time of PD-1/PD-L1–targeting treatment had a superior median PFS compared with patients with liver metastases (4.0 [IQR, 2.0-7.5] vs 1.5 [IQR, 1.0-2.0] months; P, This cohort study analyzes the association of metastatic disease pattern with response to programmed cell death receptor 1/programmed cell death ligand 1–targeting therapy in patients with treatment-resistant microsatellite stable metastatic colorectal cancer.

The presence of lateral lymph node (LLN) metastasis was associated with higher local recurrence risk in patients with lower rectal cancer. The role of LLN dissection has not been fully determined despite prolonged debate that last for few decades. The practical difference between Japan and the West was the main culprit. Japanese used to rely on surgical removal of LLN as local control while the West believed that LLN dissection could be spared after giving neoadjuvant chemoradiotherapy. As time passed, it is getting more common to combine both treatments. With the quality improvement in magnetic resonance imaging, we can now predict the chance of LLN metastasis and evaluate the treatment response with good accuracy. Few large analyses have been published recently and provided us more insight into this topic. In this review, we summarized and provided an update on the latest evidence. We have proposed a treatment algorithm on the management of LLNs which may help clinical decision and provide idea for further research.

Aim There is current debate about the optimal management of lateral pelvic lymph nodes (LPLNs) in rectal cancer between Western and Eastern centres. This paper aims to report the rate of histologically proven positive LPLNs in a group of patients undergoing the conventional Western approach to primary and recurrent rectal cancer. Method A retrospective cohort review of all patients who underwent LPLN dissection at Royal Prince Alfred Hospital in Sydney, Australia. This included patients who underwent pelvic exenteration who had LPLNs excised either en bloc for laterally invasive or recurrent tumours or as part of selective node dissection for suspicious lymph nodes on preoperative imaging. Histopathological results for these patients were compared with node status at preoperative imaging. Results Seventy-one patients satisfied the inclusion criteria. Of those patients with positive nodes on histology, 27% (9/33) with radiologically positive LPLNs were treated with preoperative radiotherapy and 75% (9/12) with radiologically positive LPLNs were not treated with preoperative radiotherapy (P = 0.004). None of the 12 patients with radiologically negative nodes treated with radiotherapy had positive nodes; 25% (3/12) of the patients with radiologically negative nodes who were not treated with radiotherapy had positive nodes. Fifty-three per cent of patients developed postoperative complications. Conclusion Our study suggests that in patients with radiologically positive LPLNs chemoradiotherapy may not be enough to sterilize these extra-mesorectal lymph nodes as a large proportion (27%) will have residual viable adenocarcinoma cells. In patients with radiologically negative LPLNs, however, the addition of chemoradiotherapy may serve to adequately sterilize these lymph nodes without the need for prophylactic LPLN dissection.

Ti-containing micro-alloyed steels are often alloyed with molybdenum (Mo) to reduce nano-precipitate coarsening, although the mechanism is still disputed. Using small angle neutron scattering we characterised the precipitate composition and coarsening of Ti-alloyed and Ti-Mo-alloyed steels. The results demonstrate ~25 at.% of Ti is substituted by Mo in the (Ti, Mo)C precipitates, increasing both the precipitate volume percent and average size. Mo alloying did not retard precipitation coarsening, but improved lattice misfit between precipitate and matrix, contributing to better ageing resistance of the Ti-Mo-alloyed steel. This new understanding opens opportunities for designing ageing-resistant micro-alloyed steels with lean alloying elements.

The transdermal delivery of functional biomolecules has been widely achieved by microneedles in a non-invasive manner. However, establishing a simple and universal way to assure a stable loading of a large number of drugs is still imperative, particularly for the delivery of nucleic acid-based drugs. To address this issue, here, we present a universally applicable RNA membrane-coating system as a novel platform to manufacture purpose-oriented microneedles. Customization of RNA membrane-based microneedles is realized by large surface area, high cargo capacity, and controllable material properties of the RNA membrane and 3D-printing of customized scaffold microneedles in a purpose-oriented manner. In addition, simple covering with the RNA membrane facilitates the fabrication of RNA-coated microneedles regardless of the configuration and material of the scaffold. This study demonstrates the successful delivery of RNA along with various types of drugs by purpose-oriented microneedles. Taken together, our approach provides a general route towards the fabrication of tailor-made microneedles for efficient transdermal drug delivery.

Rylene dyes exhibit superior photophysical properties including outstanding chemical and photochemical stabilities as well as high fluorescence quantum yields (FQYs). However, the rylene chromophores have some limitations, such as high hydrophobicity and low solubility in aqueous solution, as a fluorescent tag for biological system. Herein, we present a general method to load the rylene dyes into triblock copolymer nanoparticles (NPs) and stabilize the core. The rylene dyes in confined hydrophobic core fairly preserve their FQYs in aqueous environment. Lumogen probe nanoparticles (PNPs) were prepared with four different commercial rylenes (Lumogen Violet, Yellow, Orange and Red) in the spectral region of visible and infrared (400–750 nm) and their photophysical properties were characterized. They exhibited enhanced photostability compared to commercial fluorescent dyes. Also the internalization of Lumogen PNPs in HeLa cell was confirmed by cell uptake test. These results indicate the Lumogen PNPs can be widely applicable in fluorescence detection and imaging such as flow cytometry and fluorescence microscopy.

The prognostic value of immune cell infiltration within the tumor microenvironment (TME) has been extensively investigated via histological and genomic approaches. Based on the positive prognostic value of T cell infiltration, Immunoscore has been developed and validated for predicting risk of recurrence for colorectal cancer (CRC). Also, association between a consensus T helper 1 (Th-1) immune response and favorable clinical outcomes has been observed across multiple cancer types. Here, we reanalyzed public genomic data sets from The Cancer Genome Atlas (TCGA) and NCBI Gene Expression Omnibus (NCBI-GEO) and performed multispectral immunohistochemistry (IHC) on a cohort of colorectal tumors. We identified and characterized a risk group, representing approximately 10% of CRC patients, with high intratumoral CD8(+) T cell infiltration, but poor prognosis. These tumors included both microsatellite instable (MSI) and stable (MSS) phenotypes and had a high density of tumor-associated macrophages (TAMs) that expressed CD274 (programmed death-ligand 1 [PD-L1]), TGF-β activation, and an immune overdrive signature characterized by the overexpression of immune response and checkpoint genes. Our findings illustrate that CRC patients may have poor prognosis despite high CD8(+) T cell infiltration and provide CD274 as a simple biomarker for identifying these patients.

Using data from the eBay car auction market, we test several predictions regarding warranties, seller reputation, and buyer experience in the determination of the final price. We find that the presence of a warranty generates a price premium, but that its magnitude decreases when the seller has a more established reputation. Compared to private sellers, professional dealers, who are ‘repeated-game players’ in the market, benefit less from a warranty and its substitutability for seller reputation is relatively small. In addition, a buyer with greater experience tends to pay less for a warranty or for a professional dealership.

High-strength copper conductor composites have been used in pulse magnet applications and as internal reinforcement in superconductor wires. The required property is high strength while maintaining high conductivity. Heavily worked pure copper has a strength of 450-500 MPa. Increasing the strength of copper by alloying additions without affecting the conductivity drastically is a significant challenge. Mixing pure copper with a higher modulus, higher strength tantalum alloys is an option to meet the challenge. This work reports on the use of a tantalum-tungsten alloy to strengthen high-purity copper through a multi-filament approach. The tantalum tungsten has a high modulus and very low solubility in copper. A composite wire containing 133 filaments of Ta-W (25% by volume) has a conductivity of 80% International Annealed Copper Standard and ultimate tensile strength of over 650 MPa with a modulus over 140 GPa. The wire has good ductility and toughness. These results are comparable or better than current options, and the potential to improve this product is explored.

Microstructures and pore systems in shales are key to understanding the role of shale in many energy applications. This study proposes a novel multi-stage upscaling procedure to comprehensively investigate the heterogeneous and complex microstructures and pore systems in a laminated and microfractured shale, utilizing 3D multi-scale imaging data. Five imaging techniques were used for characterisation from sub-nanoscale to macroscale (core-scale), spanning four orders of magnitude. Image data collected using X-ray tomography, Focused Ion Beam, and Electron Tomography techniques range in voxel size from 0.6 nm to 13 μm.Prior to upscaling, a novel two-step analysis was performed to ensure sub-samples were representative. Following this, a three-step procedure, based on homogenising descriptors and computed volume coefficients, was used to upscale the quantified microstructure and pore system. At the highest resolution (nanoscale), four distinct pore types were identified. At the sub-micron scale equations were derived for three pore-associated phases. At the microscale, the volume coefficients were recalculated to upscale the pore system to the macroscale (millimetre). The accuracy of the upscaling methodology was verified, predicting the total porosity within 7.2% discrepancy. The results provide a unique perspective to understand heterogeneous rock types, breaking though prior scale limitations in the pore system.

Regulatory T (Treg) cells play a major role in the development of an immunosuppressive tumor microenvironment. The origin of intratumoral Treg cells and their relationship with peripheral blood Treg cells remain unclear. Treg cells consist of at least three functionally distinct subpopulations. Here we show that peripheral blood CD45RA-FOXP3hi Treg cells (Treg II cells) are phenotypically closest to intratumoral Treg cells, including in their expression of CCR8. Analyses of T cell antigen receptor repertoires further support the hypothesis that intratumoral Treg cells may originate primarily from peripheral blood Treg II cells. Moreover, the signaling responsiveness of peripheral blood Treg II cells to immunosuppressive, T helper type 1 (TH1) and T helper type 2 (TH2) cytokines reflects intratumoral immunosuppressive potential, and predicts future relapse in two independent cohorts of patients with breast cancer. Together, our findings give important insights into the relationship between peripheral blood Treg cells and intratumoral Treg cells, and highlight cytokine signaling responsiveness as a key determinant of intratumoral immunosuppressive potential and clinical outcome.

This article examines why Asia-Pacific middle powers cooperate with each other on security issues. The article challenges the assumption that middle powers are primarily influenced by great-power s...

Pluronic® triblock copolymers, which spontaneously form nano-sized aggregates in water, have been considered as promising carriers for bioimaging and drug delivery. However, their use for applications in pharmacology and diagnostics is hindered by instability of polymer aggregates which are easily dissociated into unimers. Here we report a general method for stabilizing Pluronic® F127 micelles via semi-interpenetrating network (sIPN). The formation of sIPN within a core stabilizes the micelle upon temperature and concentration changes. We determined optimized methods for the preparation of F127 sIPN in the regime of chemical components. Importantly, F127 sIPNs are able to load various organic fluorescence probes, covering a panchromatic range of photoluminescence (350–850 nm; entire UV–Vis-NIR), without compromising their photophysical properties. Moreover, efficient cellular uptake of the fluorescence probes loaded sIPN is observed in human and mouse cells. After intravenous injection into mice, an infrared dye-loaded sIPNs are incorporated in multiple organs and have longer lifetime than a commercially available imaging probe. With the improvement of stability, Pluronic micelles with sIPN can be a powerful tool for building functional nanoprobes and in vivo fluorescence imaging for cancer cells and live animals.

Pluronic F127 forms spherical micelle with a defined number of molecules aggregated in aqueous environments. Such self-assembled micelles dissociate into unimers below certain concentration and temperature. We stabilized the micelles by semi-interpenetrating network (sIPN) formation within the hydrophobic core in the presence of a fluorescent dye. Additionally, by varying the mixing ratio of negatively charged and pristine F127s we prepared thermally stable polymeric nanoparticles with discrete surface charges within nearly same sizes. Using the nanomaterials with prescribed number of charges, we demonstrate that the electrophoretic mobility of nanoparticles is solely depending on number of surface charges. Finally, the aggregation number (Nagg) of F127 was further determined by electrophoresis.

Objective: To determine the utility of instillation negative pressure wound therapy (NPWT) in achieving eradication of infection and definitive wound closure in patients with infected left ventricular assist device (LVAD). Approach: A retrospective review was performed in a series of patients with infected and exposed LVADs who were treated with instillation NPWT in conjunction with surgical debridement. Results: Three consecutive patients were included who developed periprosthetic infection subsequent to LVAD implantation. In all cases, the utilization of a vacuum-assisted closure with instillation (VACi) along with surgical debridement and IV antibiotics eradicated infection resulting in successful retention of hardware. Cases 1 and 2 received definitive wound closure within 3 and 12 days of starting treatment, respectively. Case 3 initially deferred surgery in favor of local wound care. Eventually the patient elected for surgical treatment and underwent closure 164 days after initial presentation. All three patients healed completely without residual evidence of infection. Flap reconstruction with a pedicled rectus flap was used to achieve definitive closure in all patients. One patient subsequently required pump replacement secondary to thrombosis and mechanical pump failure. Innovation: LVAD infections are met with high morbidity and mortality rates, and timely salvage is critical. In this initial series, VACi has proven a viable therapy option to help control and eradicate infection without LVAD removal. Conclusion: This series illustrates the value of newer techniques such as VACi in combination with surgical debridement and antibiotic therapy in effectively salvaging LVADs that were infected.

Aims Cardiac optical mapping is the gold standard for measuring complex electrophysiology in ex vivo heart preparations. However, new methods for optical mapping in vivo have been elusive. We aimed at developing and validating an experimental method for performing in vivo cardiac optical mapping in pig models. Methods and results First, we characterized ex vivo the excitation-ratiometric properties during pacing and ventricular fibrillation (VF) of two near-infrared voltage-sensitive dyes (di-4-ANBDQBS/di-4-ANEQ(F)PTEA) optimized for imaging blood-perfused tissue (n = 7). Then, optical-fibre recordings in Langendorff-perfused hearts demonstrated that ratiometry permits the recording of optical action potentials (APs) with minimal motion artefacts during contraction (n = 7). Ratiometric optical mapping ex vivo also showed that optical AP duration (APD) and conduction velocity (CV) measurements can be accurately obtained to test drug effects. Secondly, we developed a percutaneous dye-loading protocol in vivo to perform high-resolution ratiometric optical mapping of VF dynamics (motion minimal) using a high-speed camera system positioned above the epicardial surface of the exposed heart (n = 11). During pacing (motion substantial) we recorded ratiometric optical signals and activation via a 2D fibre array in contact with the epicardial surface (n = 7). Optical APs in vivo under general anaesthesia showed significantly faster CV [120 (63–138) cm/s vs. 51 (41–64) cm/s; P = 0.032] and a statistical trend to longer APD90 [242 (217–254) ms vs. 192 (182–233) ms; P = 0.095] compared with ex vivo measurements in the contracting heart. The average rate of signal-to-noise ratio (SNR) decay of di-4-ANEQ(F)PTEA in vivo was 0.0671 ± 0.0090 min−1. However, reloading with di-4-ANEQ(F)PTEA fully recovered the initial SNR. Finally, toxicity studies (n = 12) showed that coronary dye injection did not generate systemic nor cardiac damage, although di-4-ANBDQBS injection induced transient hypotension, which was not observed with di-4-ANEQ(F)PTEA. Conclusions In vivo optical mapping using voltage ratiometry of near-infrared dyes enables high-resolution cardiac electrophysiology in translational pig models., Graphical Abstract Graphical Abstract

In our latest update of the evidence on smoking bans and heart disease we summarize 59 studies. We take account of the underlying trends in incidence rates as far as possible by using control data in eight studies, and by adjustment based on observed trends in cases pre- and post-ban in 40 studies, being unable to make an adjustment in the remaining 11 studies. Overall, based on 62 independent estimates from the 59 studies, we estimate that bans reduce incidence by 5.0% (95% CI 3.2-6.8%), though this estimate reduces to 2.9% (0.01-5.6%) when we exclude regional estimates where national estimates are available, and studies where trend adjustment is not possible. For 25 of the studies, quadratic rather than linear adjustment is possible, but this hardly affects the overall estimates. Ban effects are somewhat greater when the pre-ban period studied is relatively short, and in smaller studies. We compare our findings with those in other recent reviews, one of which totally ignored underlying trends and results from control populations. We discuss reasons why we believe there is likely to be a true small effect of smoking bans, and weaknesses in the data which preclude reaching any very confident conclusion.

INTRODUCTION: Experimental data suggest that nonsteroidal antiinflammatory drugs may prevent disease severity and mortality in acute pancreatitis (AP). The aim of this study was to compare the efficacy of rectal indomethacin vs placebo in reducing the systemic inflammatory response syndrome (SIRS) score in a high-risk AP population for clinical progression. METHODS: We conducted a single-center, quadruple-blinded, randomized, placebo-controlled trial. Eligible criteria were subjects with AP and SIRS within 72 hours of presentation and those without organ failure. Subjects were allocated in a 1:1 ratio to indomethacin or placebo using simple randomization. Both interventions were administered rectally every 8 hours for 6 doses and compared using both intention-to-treat and per-protocol analyses. RESULTS: A total of 42 subjects (mean age 52 years, 55% men) were randomized to indomethacin (n = 18) or placebo (n = 24). There was no significant difference between the indomethacin and placebo groups in the change of SIRS score, proportion of subjects with SIRS, and distribution of SIRS scores at 24, 48, and 72 hours from randomization. There were no significant differences in the change of C-reactive protein levels at 48 hours or clinical outcomes between both treatment groups. Indomethacin was as safe as placebo, with 2 adverse events occurring in the placebo and none in the indomethacin arm. DISCUSSION: Rectal indomethacin can be safely administered over 48 hours; however, it is not superior to placebo in reducing the SIRS or clinical progression in a high-risk population with AP (ClinicalTrials.gov: NCT02692391).

A new framework is presented for training neural networks that is based on the characterisation and stabilisation of measurement variations. The framework results in a number of useful properties that maximises the use of data as well as aiding in the interpretation of results in a principled manner. This is achieved via variance stabilisation and a subsequent standardisation step. The method is a general approach that may be used in any context where repeatability data is available. Standardisation in this manner allows goodness of fit to be quantified and measurement data to be interpreted from a statistical perspective. We demonstrate the utility of this framework in the analysis of advanced manufacturing data.

Keyhole porosity is a key concern in laser powder-bed fusion (LPBF), potentially impacting component fatigue life. However, some keyhole porosity formation mechanisms, e.g., keyhole fluctuation, collapse and bubble growth and shrinkage, remain unclear. Using synchrotron X-ray imaging we reveal keyhole and bubble behaviour, quantifying their formation dynamics. The findings support the hypotheses that: (i) keyhole porosity can initiate not only in unstable, but also in the transition keyhole regimes created by high laser power-velocity conditions, causing fast radial keyhole fluctuations (2.5–10 kHz); (ii) transition regime collapse tends to occur part way up the rear-wall; and (iii) immediately after keyhole collapse, bubbles undergo rapid growth due to pressure equilibration, then shrink due to metal-vapour condensation. Concurrent with condensation, hydrogen diffusion into the bubble slows the shrinkage and stabilises the bubble size. The keyhole fluctuation and bubble evolution mechanisms revealed here may guide the development of control systems for minimising porosity.

While tumor infiltration by CD8+ T cells is now widely accepted to predict outcomes, the clinical significance of intratumoral B cells is less clear. We hypothesized that spatial distribution rather than density of B cells within tumors may provide prognostic significance. We developed statistical techniques (fractal dimension differences and a box-counting method ‘occupancy’) to analyze the spatial distribution of tumor-infiltrating lymphocytes (TILs) in human triple-negative breast cancer (TNBC). Our results indicate that B cells in good outcome tumors (no recurrence within 5 years) are spatially dispersed, while B cells in poor outcome tumors (recurrence within 3 years) are more confined. While most TILs are located within the stroma, increased numbers of spatially dispersed lymphocytes within cancer cell islands are associated with a good prognosis. B cells and T cells often form lymphocyte clusters (LCs) identified via density-based clustering. LCs consist either of T cells only or heterotypic mixtures of B and T cells. Pure B cell LCs were negligible in number. Compared to tertiary lymphoid structures (TLS), LCs have fewer lymphocytes at lower densities. Both types of LCs are more abundant and more spatially dispersed in good outcomes compared to poor outcome tumors. Heterotypic LCs in good outcome tumors are smaller and more numerous compared to poor outcome. Heterotypic LCs are also closer to cancer islands in a good outcome, with LC size decreasing as they get closer to cancer cell islands. These results illuminate the significance of the spatial distribution of B cells and LCs within tumors.

Heart disease remains the leading cause of mortality globally, so further investigation is required to identify its underlying mechanisms and potential targets for treatment and prevention. Mitsugumin 53 (MG53), also known as TRIM72, is a TRIM family protein that was found to be involved in cell membrane repair and primarily found in striated muscle. Its role in skeletal muscle regeneration and myogenesis has been well documented. However, accumulating evidence suggests that MG53 has a potentially protective role in heart tissue, including in ischemia/reperfusion injury of the heart, cardiomyocyte membrane injury repair, and atrial fibrosis. This review summarizes the regulatory role of MG53 in cardiac tissues, current debates regarding MG53 in diabetes and diabetic cardiomyopathy, as well as highlights potential clinical applications of MG53 in treating cardiac pathologies.

Many soft tissues, such as the intervertebral disc (IVD), have a hierarchical fibrous composite structure which suffers from regional damage. We hypothesise that these tissue regions have distinct, inherent fibre structure and structural response upon loading. Here we used synchrotron computed tomography (sCT) to resolve collagen fibre bundles (∼5μm width) in 3D throughout an intact native rat lumbar IVD under increasing compressive load. Using intact samples meant that tissue boundaries (such as endplate-disc or nucleus-annulus) and residual strain were preserved; this is vital for characterising both the inherent structure and structural changes upon loading in tissue regions functioning in a near-native environment. Nano-scale displacement measurements along >10,000 individual fibres were tracked, and fibre orientation, curvature and strain changes were compared between the posterior-lateral region and the anterior region. These methods can be widely applied to other soft tissues, to identify fibre structures which cause tissue regions to be more susceptible to injury and degeneration. Our results demonstrate for the first time that highly-localised changes in fibre orientation, curvature and strain indicate differences in regional strain transfer and mechanical function (e.g. tissue compliance). This included decreased fibre reorientation at higher loads, specific tissue morphology which reduced capacity for flexibility and high strain at the disc-endplate boundary. STATEMENT OF SIGNIFICANCE: : The analyses presented here are applicable to many collagenous soft tissues which suffer from regional damage. We aimed to investigate regional intervertebral disc (IVD) structural and functional differences by characterising collagen fibre architecture and linking specific fibre- and tissue-level deformation behaviours. Synchrotron CT provided the first demonstration of tracking discrete fibres in 3D within an intact IVD. Detailed analysis of regions was performed using over 200k points, spaced every 8 μm along 10k individual fibres. Such comprehensive structural characterisation is significant in informing future computational models. Morphological indicators of tissue compliance (change in fibre curvature and orientation) and fibre strain measurements revealed localised and regional differences in tissue behaviour.

Issues and concerns regarding surgery of the sexual-reproductive anatomy during infancy and early childhood are discussed using four actual examples. A case of a 46, XX infant with 21 hydroxylase deficiency congenital adrenal hyperplasia (CAH) with atypical (ambiguous) genitalia is discussed regarding timing and potential harms and benefits of surgery. We present the perspective of balancing the child's rights to bodily autonomy and right to an open future versus parents' decision making authority regarding what they perceive as their child's future best interests. The second case is a newborn with complete androgen insensitivity syndrome and we discuss the harms, benefits and timing of gonadectomy. The third case examines the physical and psychological impact of penile shaft hypospadias, raising the question of whether surgery is justified to prevent what may or may not be considered a permanent disability. The fourth case involves an adult woman with classic CAH, born with a urogenital sinus and clitoromegaly, who never had genital surgery and is now requesting vaginoplasty, but not clitoral reduction. The primary message of this article, as the previous articles in this series, is to encourage patient-family centered care that individualizes treatment guided by shared decision making. ispartof: JOURNAL OF PEDIATRIC UROLOGY vol:17 issue:3 pages:338-345 ispartof: location:England status: published

This paper quantitatively characterises the microstructure in shales across five scales in 3D, builds a multi-scale model of CH 4 and CO 2 flow pathways and storage, and assesses the potential of enhanced gas recovery and CO 2 storage simultaneously. Injection of CO 2 into shale reservoirs to enhance gas recovery and simultaneously sequester greenhouse gases is a potential contributor towards the carbon-neutral target. It offers a low-carbon, low-cost, low-waste and large-scale solution during the energy transition period. A precondition to efficient gas storage and flow is a sound understanding of how the shale's micro-scale impacts on these phenomena. However, the heterogeneous and complex nature of shales limits the understanding of microstructure and pore systems, making feasibility analysis challenging. This study qualitatively and quantitatively investigates the Bowland shale microstructure in 3D at five length scales: artificial fractures at 10–100 μm scale, matrix fabric at 1–10 μm-scale, individual mineral grains and organic matter particles at 100 nm–1 μm scale, macropores and micro-cracks at 10–100 nm scale and organic matter and mineral pores at 1–10 nm-scale. For each feature, the volume fraction variations along the bedding normal orientation, the fractal dimensions and the degrees of anisotropy were analysed at all corresponding scales for a multi-scale heterogeneity analysis. The results are combined with other bulk laboratory measurements, including supercritical CO 2 and CH 4 adsorption at reservoir conditions, pressure-dependent permeability and nitrogen adsorption pore size distribution, to perform a comprehensive analysis on the storage space and flow pathways. A cross-scale pore size distribution, ranging from 2 nm to 3 μm, was calculated with quantified microstructure. The cumulative porosity is calculated to be 8%. The cumulative surface area is 17.6 m 2 g −1 . A model of CH 4 and CO 2 flow pathways and storage with quantified microstructure is presented and discussed. The feasibility of simultaneously enhanced gas recovery and subsurface CO 2 storage in Bowland shale, the largest shale gas potential formation in the UK, was assessed based using multi-scale microstructure analysis. The potential is estimated to store 19.0–21.2 Gt CO 2 as free molecules, together with 18.3–28.5 Gt CO 2 adsorbed onto pore surfaces, implying a theoretical maximum of 47.5–49.5 Gt carbon storage in the current estimate of 38 trillion cubic metres (∼1300 trillion cubic feet) of Bowland shale. Simple estimates suggest 6.0–15.8 Gt CO 2 may be stored in practice.

In recent years there has been an increasing effort in improving the performance of Nb3Sn for high-field applications, in particular for the fabrication of conductors suitable for the realization of the Future Circular Collider (FCC) at CERN. This challenging task has led to the investigation of new routes to advance the high-field pinning properties, the irreversibility and the upper critical fields (HIrr and Hc2, respectively). The effect of hafnium addition to the standard Nb-4Ta alloy has been recently demonstrated to be particularly promising and, in this paper, we investigate the origins of the observed improvements of the superconducting properties. Electron microscopy, Extended X-ray Absorption Fine Structure Spectroscopy (EXAFS) and Atom Probe Tomography (APT) characterization clearly show that, in presence of oxygen, both fine Nb3Sn grains and HfO2 nanoparticles form. Although EXAFS is unable to detect significant amounts of Hf in the A15 structure, APT does indeed reveal some residual intragrain metallic Hf. To investigate the layer properties in more detail, we created a microbridge from a thin lamella extracted by Focused Ion Beam (FIB) and measured the transport properties of Ta-Hf-doped Nb3Sn. Hc2(0) is enhanced to 30.8 T by the introduction of Hf, ~ 1 T higher than those of only Ta-doped Nb3Sn, and, even more importantly the position of the pinning force maximum exceeds 6 T, against the typical ~ 4.5–4.7 T of the only Ta-doped material. These results show that the improvements generated by Hf addition can significantly enhance the high-field performance, bringing Nb3Sn closer to the requirements necessary for FCC realization.

The multiple factors that determine outcomes for individuals with visible developmental errors and/or atypical development of the reproductive system are not fully understood. This case report of an individual with Bosma arhinia microphthalmia syndrome causing severe facial anomalies and hypogonadotropic hypogonadism is used to highlight factors that impacted his adjustment from childhood through adulthood. Key factors include his temperament, intact cognitive ability, and pragmatic approach for controlling his physical and social environment. His successful adjustment even in the face of significant early life challenges demonstrates that positive outcomes are attainable for individuals with significant developmental errors. His story and experiences with the health-care system offer insight into some factors that may be pertinent to resilience and lifelong adjustment for patients with similar conditions and the importance of continually seeking the patient’s perspective to tailor treatment across the lifespan.

A Lactobacillus-dominated vaginal microbiota (VMB) has been associated with health and considered an important host defense mechanism against urogenital infections. Conversely, depletion of lactobacilli and increased microbial diversity, or dysbiosis, increases the risk of adverse gynecologic and obstetric outcomes. A common clinical condition that exemplifies dysbiosis is bacterial vaginosis (BV). BV is currently treated with antibiotics, but frequently recurs, due in part to persistent dysbiosis and failure of endogenous lactobacilli to repopulate the vagina. New treatment options are therefore needed to address recurrent urogenital infections, including BV. The VMB represents an interesting case study for the development of microbiome-based therapeutics. Compared to the gut, the vaginal microbiota is relatively simple and optimally dominated by one or several species of one genus, i.e. Lactobacillus. Further, hydrogen peroxide (H2O2)-producing species, such as L. crispatus, show the strongest associations with vaginal health and are depleted in dysbiosis. Thus, replenishing the dysbiotic VMB with protective vaginal Lactobacillus species could be a promising approach to prevent recurrent infections and improve women's health. In this article we discuss confirmation of this approach with the microbiome-based biologic drug, LACTIN-V (Lactobacillus crispatus CTV-05), focusing on prevention of BV recurrence.

Purpose of review In this review, we outline the usage and formulations of gonadotropin-releasing hormone analogs (GnRHas) in central precocious puberty (CPP), short stature, and gender diverse individuals, as well as adverse effects, long-term outcomes, and monitoring of therapy. There is a particular focus on citing references published within the last 24 months. Recent findings Long-acting formulations of GnRHa now include Federal Drug Administration approval for subcutaneous injections. Significant adverse events continue to be rarely reported; extremely rare events include arterial hypertension and pseudotumor cerebri. There continue to be no significant long-term consequences including the impact upon body mass index and bone mineral density, which appear to be transient. GnRHas have been used in differences of sexual development (DSD) and increasingly in the treatment of adolescent transgender individuals. Summary GnRHas remain as the only fully efficacious therapy for CPP and effectively suppress pubertal hormones in other situations. The use of GnRHa therapy in gender incongruent individuals has proven beneficial and has become a standard of care, whereas use in those with DSDs should still be considered experimental. Video abstract http://links.lww.com/MOP/A62.

Shenzhen has been established as the technology and innovation center in China. The study reviews its economic development and environmental change over the past four decades. Specifically, it tests whether environmental Kuznets curve relationship between haze as a proxy indicator of environmental condition and gross domestic product (GDP) per capita holds in Shenzhen. The study also examines the contribution of Shenzhen’s secondary sector to its GDP and highlights some changes in the computer, communication and electronic product manufacturing industries over the years. We collected the official data from the Shenzhen Municipal Government. Economic, social and environmental changes in Shenzhen were identified using tables and stacked graphs. Environmental Kuznets curve revealed that the worst environmental condition appeared in Shenzhen during the period 2003–2004. Environmental analysis showed that Shenzhen’s computer, communication and electronic product manufacturing industries consumed 52,595 TJ of energy and produced 10.1 million tons CO2-eq in 2019. As gross output value of the industries was USD 336 billion in 2019, the industries had an energy efficiency of 156,716 MJ/million USD and an emission efficiency of 30.6 tons CO2-eq/million USD, improving by 74% and 65%, respectively, since 2008. Nevertheless, the industries should focus more on high value-added and low energy-intensive technologies and innovations. Additionally, the Shenzhen Government shall increase the use of clean energy sources such as nuclear, wind and solar power in order to sustain the continual improvement of energy and emission efficiencies for all industries.

In this review, we present an overview of significant developments in the field of in situ and operando (ISO) X-ray imaging of solidification processes. The objective of this review is to emphasize the key challenges in developing and performing in situ X-ray imaging of solidification processes, as well as to highlight important contributions that have significantly advanced the understanding of various mechanisms pertaining to microstructural evolution, defects, and semi-solid deformation of metallic alloy systems. Likewise, some of the process modifications such as electromagnetic and ultra-sound melt treatments have also been described. Finally, a discussion on the recent breakthroughs in the emerging technology of additive manufacturing, and the challenges thereof, are presented.

Dramatic variation in SARS-CoV-2 virulence and transmission between hosts has driven the COVID-19 pandemic. The complexity and dynamics of the immune response present a challenge to understanding variation in SARS-CoV-2 infections. To address this challenge, we apply control theory, a framework used to study complex feedback systems, to establish rigorous mathematical bounds on immune responses. Two mechanisms of SARS-CoV-2 biology are sufficient to create extreme variation between hosts: (1) a sparsely expressed host receptor and (2) potent, but not unique, suppression of interferon. The resulting model unifies disparate and unexplained features of the SARS-CoV-2 pandemic, predicts features of future viruses that threaten to cause pandemics, and identifies potential interventions.

Controversy continues over a proposed moratorium on elective genital surgery in childhood for disorders/differences of sex development (DSD). Empirical evidence on patient preference is needed to inform decision-making. We conducted a multicentre survey by cross-sectional questionnaire in 14 specialized clinics in six European countries. The sample comprised 459 individuals (≥ 16 years) with a DSD diagnosis, including individuals with congenital adrenal hyperplasia (CAH) (n = 192), XY DSD with prenatal androgen effect (A) (n = 150), and without (nA) (n = 117). Main outcome measures were level of agreement with given statements regarding genital surgery, including clitoris reduction, vaginoplasty, and hypospadias repair. A total of 66% of individuals with CAH and 60% of those with XY DSD-A thought that infancy or childhood were the appropriate age for genital surgery. Females with XY DSD were divided on this issue and tended to prefer vaginoplasty at a later age (XY DSD-A 39%, XY DSD-nA 32%). A total of 47% of males preferred early hypospadias surgery. Only 12% (CAH), 11% (XY DSD-A), and 21% (XY DSD-nA) thought they would have been better off without any surgery in childhood or adolescence. Individuals who had early genital surgery were more likely to approve of it. Outcome data failed to support a general moratorium on early elective genital surgery. Participant perspectives varied considerably by diagnostic category, gender, history of surgery, and contact with support groups. Case-by-case decision-making is better suited to grasping the ethical complexity of the issues at stake.Trial registration: German Clinical Trials Register DRKS00006072.

Monogenic hypertension is rare and caused by genetic mutations, but whether factors associated with mutations are disease-specific remains uncertain. Given two factors associated with high mutation rates, we tested how many previously known genes match with (i) proximity to telomeres or (ii) high adenine and thymine content in cardiovascular diseases (CVDs) related to vascular stiffening. We extracted genomic information using a genome data viewer. In human chromosomes, 64 of 79 genetic loci involving &gt, 25 rare mutations and single nucleotide polymorphisms satisfied (i) or (ii), resulting in an 81% matching rate. However, this high matching rate was no longer observed as we checked the two factors in genes associated with essential hypertension (EH), thoracic aortic aneurysm (TAA), and congenital heart disease (CHD), resulting in matching rates of 53%, 70%, and 75%, respectively. A matching of telomere proximity or high adenine and thymine content projects the list of loci involving rare mutations of monogenic hypertension better than those of other CVDs, likely due to adoption of rigorous criteria for true-positive signals. Our data suggest that the factor–disease matching rate is an accurate tool that can explain deleterious mutations of monogenic hypertension at a &gt, 80% match—unlike the relatively lower matching rates found in human genes of EH, TAA, CHD, and familial Parkinson’s disease.

Background CDK4/6 inhibitors modulate immune response in breast cancer. This phase I/II trial was designed to test the safety and efficacy of palbociclib, pembrolizumab and letrozole in women with hormone receptor positive (HR+) human epidermal growth factor receptor 2 negative (HER2−) metastatic breast cancer (MBC). Patients and methods Women with stage IV HR+ HER2− MBC were enrolled and treated with palbociclib, pembrolizumab and letrozole. Primary end-points were safety, tolerability and efficacy. Results Between November 2016 and July 2020, 23 patients were enrolled with 20 evaluable for response, including 4 patients in cohort 1 and 16 patients in cohort 2. Cohort 1 median age was 48 years (33–70) and cohort 2 median age was 55 (37–75). Cohort 1 closed early due to limited accrual. Grade III–IV adverse events were neutropenia (83%), leucopaenia (65%), thrombocytopenia (17%) and elevated liver enzymes (17%). In cohort 1, 50% achieved a partial response (PR) and 50% had stable disease (SD). In cohort 2, 31% achieved complete response (CR), 25% had PR and 31% had SD by Response Evaluation Criteria in Solid Tumours version 1.1. Median progression-free survival was 25.2 months (95% confidence interval [CI] 5.3, not reached) and median overall survival was 36.9 months (95% CI 36.9, not reached) in cohort 2 with a median follow-up of 24.8 months (95% CI 17.1, not reached). A correlative immune biomarker analysis was published separately. Conclusion The combination of palbociclib, pembrolizumab and letrozole is well tolerated, and a complete response rate of 31% was identified in HR+ MBC patients who received this combination as front-line therapy. Confirmatory trials are required to better understand the immune-priming effects of CDK4/6 inhibitors.

The governing mechanistic behaviour of Directed Energy Deposition Additive Manufacturing (DED-AM) is revealed by a combined in situ and operando synchrotron X-ray imaging and diffraction study of a nickel-base superalloy, IN718. Using a unique DAE-AM process replicator, real-space imaging enables quantification of the melt-pool boundary and flow dynamics during solidification. This imaging knowledge was also used to informed precise diffraction measurements of temporally resolved microstructural phases during transformation and stress development with a spatial resolution of 100 µm. The diffraction quantified thermal gradient enabled a dendritic solidification microstructure to be predicted and coupled to the stress orientation and magnitude. The fast cooling rate entirely suppressed the formation of secondary phases or recrystallisation in the solid-state. Upon solidification, the stresses rapidly increase to the yield strength during cooling. This insight, combined with the large solidification range of IN718 suggests that the accumulated plasticity exhausts the ductility of the alloy, causing liquation cracking. This study has revealed additional fundamental mechanisms governing the formation of highly non-equilibrium microstructures during DED-AM.

The Directed Energy Deposition Additive Manufacturing (DED-AM) of SS316L was studied using in situ and operando synchrotron X-ray imaging to quantitively understand the effect of processing parameters on the melt-pool morphology and surface quality. It was found that surface roughness of DED-AM builds can result from melt pool surface perturbations caused by changes in the melt flow and build stage motion perturbations. Process maps are developed that quantitatively correlate build quality to process parameters including powder feed rate, laser power and traverse speed. How the AM process parameters control build efficacy is clarified, and the processing conditions required to dampen surface perturbations leading to roughness were determined.