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Sexual dysfunction (SD) is widely reported by cancer survivors. However, this is an issue underestimated by doctors and the contribution of anticancer therapies for the development of SD in cancer survivors is understudied and poorly understood. Sexual function involves the activation of a neurovascular system that leads to penile erection in males and clitoral engorgement in females. Anticancer therapies can cause damage to the neurovascular circuit responsible for normal sexual function and thus, individual or combined therapies could play a role in the development of SD in all types of cancer survivors and not only those affected by genital cancers. In this review, the pathophysiology of SD and possible mechanisms underlying SD induced by anticancer therapies will be discussed. The effects of chemotherapy, radiotherapy and surgical interventions on the vasculature and nerves as well as their effects on sex hormones and inflammatory processes could link the biological effects of these interventions with SD. In conclusion, this review reports evidence that, despite psychological aspects and the disease itself, anticancer therapies are able to induce direct and indirect effects in males and females that could lead to SD in cancer survivors even after the end of the treatment.

Background & Hypothesis We sought to assess the reliability of 4 different shoulder arthroplasty 3-dimensional preoperative planning programs. Comparison was also made to manual measurements conducted by 2 fellowship-trained musculoskeletal radiologists. We hypothesized that there would be significant variation in measurements of glenoid anatomy affected by glenoid deformity. Methods A retrospective review of computed tomography (CT) scans of patients undergoing shoulder arthroplasty was undertaken. A total of 76 computed tomographies were analyzed for glenoid version and inclination by 4 templating software systems (VIP, Blueprint, TrueSight, ExactechGPS). Inter-rater reliability was assessed via intra-class correlation coefficient (ICC). For those shoulders with glenohumeral arthritis (58/76), ICC was also calculated when sub-grouping by modified Walch classification. Lin's concordance correlation coefficient was calculated for each system with 2 musculoskeletal-trained radiologists’ measurements. Results Measurements of glenoid version and inclination differed between at least 2 programs by 5o-10o in 75% and 92% of glenoids respectively, and by >10o in 18% and 45% respectively. ICC was excellent for version but only moderate for inclination. ICC was highest among Walch A glenoids for both version (near excellent) and inclination (good), and lowest among Walch D for version (near poor) and Walch B for inclination (moderate). When measuring version, VIP had the highest concordance with manual measurement; Blueprint had the lowest. For inclination Blueprint had the highest concordance; ExactechGPS had the lowest. Discussion & Conclusion Despite overall high reliability for measures of glenoid version between 4 frequently utilized shoulder arthroplasty templating softwares, this reliability is significantly affected by glenoid deformity. The programs were overall less reliable when measuring inclination, and a similar trend of decreasing reliability with increasing glenoid deformity emerged that was not statistically significant. Concordance with manual measurement is also variable. Further research is needed to understand how this variability should be accounted for during shoulder arthroplasty preoperative planning. Level of Evidence Level III; Retrospective Comparative Study

Background The global distribution of melioidosis is under considerable scrutiny, with both unmasking of endemic disease in African and Pacific nations and evidence of more recent dispersal in the Americas. Because of the high incidence of disease in tropical northern Australia, The Darwin Prospective Melioidosis Study commenced in October, 1989. We present epidemiology, clinical features, outcomes, and bacterial genomics from this 30-year study, highlighting changes in the past decade. Methods The present study was a prospective analysis of epidemiological, clinical, and laboratory data for all culture-confirmed melioidosis cases from the tropical Northern Territory of Australia from Oct 1, 1989, until Sept 30, 2019. Cases were identified on the basis of culture-confirmed melioidosis, a laboratory-notifiable disease in the Northern Territory of Australia. Patients who were culture-positive were included in the study. Multivariable analysis determined predictors of clinical presentations and outcome. Incidence, survival, and cluster analyses were facilitated by population and rainfall data and genotyping of Burkholderia pseudomallei, including multilocus sequence typing and whole-genome sequencing. Findings There were 1148 individuals with culture-confirmed melioidosis, of whom 133 (12%) died. Median age was 50 years (IQR 38–60), 48 (4%) study participants were children younger than 15 years of age, 721 (63%) were male individuals, and 600 (52%) Indigenous Australians. All but 186 (16%) had clinical risk factors, 513 (45%) had diabetes, and 455 (40%) hazardous alcohol use. Only three (2%) of 133 fatalities had no identified risk. Pneumonia was the most common presentation occurring in 595 (52%) patients. Bacteraemia occurred in 633 (56%) of 1135 patients, septic shock in 240 (21%) patients, and 180 (16%) patients required mechanical ventilation. Cases correlated with rainfall, with 80% of infections occurring during the wet season (November to April). Median annual incidence was 20·5 cases per 100 000 people; the highest annual incidence in Indigenous Australians was 103·6 per 100 000 in 2011–12. Over the 30 years, annual incidences increased, as did the proportion of patients with diabetes, although mortality decreased to 17 (6%) of 278 patients over the past 5 years. Genotyping of B pseudomallei confirmed case clusters linked to environmental sources and defined evolving and new sequence types. Interpretation Melioidosis is an opportunistic infection with a diverse spectrum of clinical presentations and severity. With early diagnosis, specific antimicrobial therapy, and state-of-the-art intensive care, mortality can be reduced to less than 10%. However, mortality remains much higher in the many endemic regions where health resources remain scarce. Genotyping of B pseudomallei informs evolving local and global epidemiology. Funding The Australian National Health and Medical Research Council.

OBJECTIVE: To describe the protocol and statistical analysis plan for the Treatment of Invasively Ventilated Adults with Early Activity and Mobilisation (TEAM III) trial. DESIGN: An international, multicentre, parallel-group, randomised controlled phase 3 trial. SETTING: Intensive care units (ICUs) in Australia, New Zealand, Germany, Ireland, the United Kingdom and Brazil. PATIENTS: 750 adult patients expected to receive mechanical ventilation for more than 48 hours. INTERVENTIONS: Early activity and mobilisation delivered to critically ill patients in an ICU for up to 28 days compared with standard care. MAIN OUTCOME MEASURES: The primary outcome is the number of days alive and out of hospital at 180 days after randomisation. Secondary outcomes include ICU-free days, ventilator-free days, delirium-free days, all-cause mortality at 28 and 180 days after randomisation, and functional outcome at 180 days after randomisation. RESULTS: Recruitment at 46 research sites passed 576 patients in March 2021. Final collection of all 180-day outcome data for the target of 750 patients is anticipated by May 2022. CONCLUSIONS: Consistent with international guidelines, a detailed protocol and prospective analysis plan has been developed for the TEAM III trial. This plan specifies the statistical models for evaluating primary and secondary outcomes, defines covariates for adjusted analyses, and defines methods for exploratory analyses. Application of this protocol and statistical analysis plan to the forthcoming TEAM III trial will facilitate unbiased analyses of the clinical data collected. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT03133377.

Concussions and chronic traumatic encephalopathy (CTE) related to professional football has received much attention within emergency care and sports medicine. Research suggests that some of this may be due to a greater likelihood of initial helmet contact (IHC), however this association has not been studied across all age groups. This study aims to investigate the association between player age and IHC in American football.Retrospective review of championship games between 2016 and 2018 at 6 levels of amateur tackle football as well as the National Football League (NFL). Trained raters classified plays as IHC using pre-specified criteria. A priori power analysis established the requisite impacts needed to establish non-inferiority of the incidence rate of IHC across the levels of play.Thirty-seven games representing 2912 hits were rated. The overall incidence of IHC was 16% across all groups, ranging from 12.6% to 18.9%. All but 2 of the non-NFL divisions had a statistically reduced risk of IHC when compared with the NFL, with relative risk ratios ranging from 0.55-0.92. IHC initiated by defensive participants were twice as high as offensive participants (RR 2.04, p0.01) while 6% [95% CI 5.4-7.2] of all hits were helmet-on-helmet contact.There is a high rate of IHC with a lower relative risk of IHC at most levels of play compared to the NFL. Further research is necessary to determine the impact of IHC; the high rates across all age groups suggests an important role for education and prevention.

Background Ductal adenocarcinoma is an uncommon prostate cancer variant. Previous studies suggest that ductal variant histology may be associated with worse clinical outcomes, but these are difficult to interpret. To address this, we performed an international, multi-institutional study to describe the characteristics of ductal adenocarcinoma, particularly focussing on the effect of presence of ductal variant cancer on metastasis-free survival. Methods Patients with ductal variant histology from two institutional databases who underwent radical prostatectomies were identified and compared with an independent acinar adenocarcinoma cohort. After propensity score matching, the effect of the presence of ductal adenocarcinoma on time to biochemical recurrence, initiation of salvage therapy and the development of metastatic disease was determined. Deep whole-exome sequencing was performed for selected cases (n = 8). Results A total of 202 ductal adenocarcinoma and 2037 acinar adenocarcinoma cases were analysed. Survival analysis after matching demonstrated that patients with ductal variant histology had shorter salvage-free survival (8.1 versus 22.0 months, p = 0.03) and metastasis-free survival (6.7 versus 78.6 months, p Conclusions The presence of any ductal variant adenocarcinoma at the time of prostatectomy portends a worse clinical outcome than pure acinar cancers, with significantly shorter times to initiation of salvage therapies and the onset of metastatic disease. These features appear to be driven by uncoupling of chromosomal duplication from cell division, resulting in widespread copy number aberration with specific gain of genes implicated in treatment resistance.

Metformin reduces the incidence of placental-mediated disease (PMD) in pregnancies with and without diabetes, but the mechanism through which it exerts these effects is not yet fully understood. We performed a systematic review and meta-analysis to examine the effect of metformin on biomarkers implicated in the pathogenesis of PMD. We searched Medline, Embase and the Cochrane Library for studies of metformin and biomarkers of PMD in pregnancy. Meta-analysis was undertaken where comparable data were obtained from two or more studies. 12 studies were included in the final review. Meta-analysis of 2 studies including 323 pregnant women showed significantly reduced CRP levels following treatment with metformin compared to placebo [mean difference = −1.72, 95% CI (−2.97; −0.48); p = 0.007]. Metformin exposure was also associated with decreased levels of the inflammatory cytokines TNFα, IL-1a, IL-1b and IL-6 in serum, placenta and omental tissue taken from pregnant women. Metformin significantly decreased the release of anti-angiogenic factors sFlt-1 and sEng from ex-vivo placental and umbilical vein tissue, and increased maternal serum levels of non-phosphorylated IGFBP-1. Overall, our findings show that metformin mediates several molecular pathways implicated in the pathogenesis of pre-eclampsia and intrauterine growth retardation. Metformin therefore has exciting potential as a therapeutic, as well as preventative, agent in the treatment of PMD, which warrants further investigation.

Objective Lumbo-pelvic landmark palpation is widely used by manual practitioners as part of a clinical assessment. However, research has not clearly described or established the validity of landmark palpation as a diagnostic tool; we aimed to analyse and synthesise data on the validity of lumbo-pelvic landmark palpation compared to an imaging modality reference standard. Methods and results Nine studies met the inclusion criteria (43 practitioners assessing 364 subjects). Mean palpatory accuracy ranged from 42 to 71%; four studies reported kappa values, ranging from 0.20 (no agreement) to 0.81 (strong); two studies could not be directly compared. The use of multiple palpation techniques improved palpation accuracy, however, no specific technique or technique combination was more accurate than another. Methodological quality was assessed using the QUADAS-2 check-list tool; eight studies were rated as having a risk of bias and/or concerns regarding applicability. Conclusion The use of lumbo-pelvic landmark palpation does not reach clinically acceptable levels of validity; however, heterogeneity in the included studies’ methods and data reporting limited between trial comparisons. These results accord with other reviews and suggest the necessity of a shift away from over-reliance on landmark palpation to align manual therapy with practise guidelines.

Objective We recently showed that tumors with an immunologically ‘cold’ phenotype are enriched for expression of stemness-associated genes and PVR/CD155, the ligand of the immunosuppressive molecule TIGIT. To explore the therapeutic implications of this finding, we investigated the relationship between PVR/CD155 expression, tumor-infiltrating lymphocytes (TIL), and prognosis in high-grade serous ovarian cancer (HGSC) and other cancers. Methods Expression of CD155, TIGIT, PD-1, PD-L1, and other immune markers in HGSC was assessed by high-dimensional flow cytometry, multi-color histological imaging, and/or gene expression profiling. The prognostic significance of PVR/CD155 and CD274/PD-L1 expression was assessed bioinformatically in HGSC and 32 other cancers in The Cancer Genome Atlas. Results T cells from HGSC frequently co-expressed TIGIT and PD-1, and the ratio of TIGIT to PD-1 expression increased markedly after in vitro expansion with a clinically relevant protocol. CD155 was commonly expressed on malignant epithelium in HGSC and showed a negative or non-significant association with TIL. In contrast, PD-L1 was predominantly expressed by tumor-associated macrophages and positively associated with TIL. These contrasts between CD155 and PD-L1 were seen across HGSC patients, across metastatic sites within individual patients, and even within individual tumor deposits. PVR/CD155 and CD274/PD-L1 exhibited divergent prognostic associations across diverse cancer types in TCGA, including HGSC. Conclusions CD155 and PD-L1 exhibit contrasting expression patterns, TIL associations and prognostic significance, suggesting they represent non-redundant immunosuppressive mechanisms. The CD155/TIGIT pathway represents a compelling immunotherapeutic target for HGSC and for immunologically cold tumors in general.

Mycoplasma species (spp.) bacteria can infect cell cultures, posing a potential threat to recipients of cell therapy products. Conventional Mycoplasma testing methods are highly sensitive but typically require a minimum of 28 days to produce results. This delay is problematic if rapid results are needed to inform treatment decisions. Nucleic acid amplification technique (NAT) methods have been gaining favor for Mycoplasma testing due to their speed and specificity; however, they must first be qualified as meeting or exceeding the sensitivity of the compendial method. We present herein a NAT method for the detection of Mycoplasma that circumvents the need for live Mycoplasma spp. in the test procedure by instead being qualified using Mycoplasma spp. genomic DNA. We have demonstrated a lower limit of detection that exceeds the regulatory requirements set by Health Canada. This assay is now being used to screen clinical cell therapy products manufactured at our center.

James A. Arrighi, MD, FACC, Chair Lisa A. Mendes, MD, FACC, Co-Chair Jesse E. Adams iii, MD, FACC[∗][1] John E. Brush, Jr, MD, FACC[∗][1] G. William Dec, Jr, MD, FACC Ali Denktas, MD, FACC Susan M. Fernandes, LPD, PA-C Sanjeev A. Francis, MD, FACC Rosario Freeman, MD, MS, FACC[∗][1

Background and Aims: Recent studies have unveiled an association between ADAMTS7 gene variation and coronary artery disease (CAD) caused by atherosclerosis. We investigated if the ADAMTS7 Serine214-to-Proline substitution arising from a CAD-associated variant affected angiogenesis, since neovascularization plays an important role in atherosclerosis. Methods and Results: ADAMTS7 knockdown in vascular endothelial cells (ECs) attenuated their angiogenesis potential, whereas augmented ADAMTS7-Ser214 expression had the opposite effect, leading to increased ECs migratory and tube formation ability. Proteomics analysis showed an increase in thrombospondin-1, a reported angiogenesis inhibitor, in culture media conditioned by ECs with ADAMTS7 knockdown and a decrease of thrombospondin-1 in media conditioned by ECs with ADAMTS7-Ser214 overexpression. Cleavage assay indicated that ADAMTS7 possessed thrombospondin-1 degrading activity, which was reduced by the Ser214-to-Pro substitution. The pro-angiogenic effect of ADAMTS7-Ser214 diminished in the presence of a thrombospondin-1 blocking antibody. Conclusions: The ADAMTS7 Ser217-to-Pro substitution as a result of ADAMTS7 polymorphism affects thrombospondin-1 degradation, thereby promoting atherogenesis through increased EC migration and tube formation.

The Anderson-Hynes technique has been the treatment of choice for primary ureteropelvic junction obstruction in children. Laparoscopic approach has shown similar outcomes to open, with advantages of shorter hospital stay and less pain. We reviewed the experience of 11 geographically diverse, tertiary pediatric urology institutions focusing on the outcomes and complications of laparoscopic pyeloplasty.A descriptive, retrospective study was conducted evaluating patients undergoing Anderson-Hynes dismembered laparoscopic pyeloplasty. Centers from four different continents participated. Demographic data, perioperative management, results, and complications are described.Over a 9-year period, 744 laparoscopic pyeloplasties were performed in 743 patients. Mean follow-up was 31 months (6-120m). Mean age at surgery was 82 months (1 w-19 y). Median operative time was 177 min. An internal stent was placed in 648 patients (87%). A catheter was placed for bladder drainage in 702 patients (94%). Conversion to open pyeloplasty was necessary in seven patients. Average length of hospital stay was 2.8 days. Mean time of analgesic requirement was 3.2 days. Complications, according to Clavien-Dindo classification, were observed in 56 patients (7.5%); 10 (1%) were Clavien-Dindo IIIb. Treatment failure occurred in 35 cases with 30 requiring redo pyeloplasty (4%) and 5 cases requiring nephrectomy (0.6%).We have described the laparoscopic pyeloplasty experience of institutions with diverse cultural and economic backgrounds. They had very similar outcomes, in agreement with previously published data. Based on these findings, we conclude that laparoscopic pyeloplasty is safe and successful in diverse geographics areas of the world.

To conduct a Chinese translation and validation of the Friedman Life Balance Scale (FLBS).Prevalence of mental disorders is high among nursing students. Life balance is important for nursing students, which may help them increase efficiency in their studies and develop physical and psychological health. Yet, little is known about life balance in nursing students. Therefore, it is crucial to evaluate the status of life balance of the students to lay the foundation for exploring its associated factors.A multi-centre cross-sectional design.The study was comprised of 420 nursing students from 15 hospitals and two educational institutes in East, North and Northeast China from July 2021 to January 2022. The Chinese version of the FLBS was translated and adapted based on published, standardized, international guidelines. Psychometric evaluation included floor and ceiling effects, factorial validity, convergent validity, discriminant validity, internal consistency, test-retest reliability, diagnosis accuracy and calibration. The tests used for validity included floor and ceiling effects, confirmatory factor analysis, average extracted variance (AVE) value, composite reliability, correlations with life satisfaction and subjective well-being. The tests used for reliability incudes Cronbach's alpha and intraclass correlation coefficients. Diagnosis accuracy was tested by the area under the curve and calibration was tested by Hosmer-Lemeshow goodness-of-fit test.The Chinese version of the Friedman life balance scale did not demonstrate floor or ceiling effect, showing content validity is not limited. Confirmatory factor analysis showed acceptable model fit after it was modified. Convergent validity and discriminant validity of the Friedman life balance scale were supported, except subscales two and three were not discriminated well by AVE technique. The internal consistency was acceptable and the test-retest reliability was good with 0.858. The area under the curve was 0.762 and the optimal cut-off point for depressive symptoms was 44. Hosmer-Lemeshow goodness-of-fit test showed the calibration to be acceptable. Life balance is moderate among Chinese nursing students. The subscale "self-forgive, compassion, love" had the highest correlations with well-being and life satisfaction.The Chinese version of the Friedman life balance scale is a suitable instrument for assessing life balance in Chinese-speaking contexts. It also may have potential utility in identifying nursing students with or without depressive symptoms that may need further examination. Future work should examine additional samples of Chinese nursing students, as well as, perhaps other student populations to determine the extent to which the psychometric properties of the FLBS generalize to other students and contexts.

NEXT Collaboration: et al., Radio-frequency (RF) carpets with ultra-fine pitches are examined for ion transport in gases at atmospheric pressures and above. We develop new analytic and computational methods for modeling RF ion transport at densities where dynamics are strongly influenced by buffer gas collisions. An analytic description of levitating and sweeping forces from phased arrays is obtained, then thermodynamic and kinetic principles are used to calculate ion loss rates in the presence of collisions. This methodology is validated against detailed microscopic SIMION simulations. We then explore a parameter space of special interest for neutrinoless double beta decay experiments: transport of barium ions in xenon at pressures from 1 to 10 bar. Our computations account for molecular ion formation and pressure dependent mobility as well as finite temperature effects. We discuss the challenges associated with achieving suitable operating conditions, which lie beyond the capabilities of existing devices, using presently available or near-future manufacturing techniques., The University of Texas at Arlington NEXT group is supported by the Department of Energy, USA under Early Career Award number DE-SC0019054 (BJPJ), by Department of Energy, USA Award DE-SC0019223 (DRN), the National Science Foundation, USA under award number NSF CHE 2004111 (FWF), and the Robert A Welch Foundation, Y-2031-20200401 (FWF). The NEXT Collaboration acknowledges support from the following agencies and institutions: the European Research Council (ERC) under the Advanced Grant 339787-NEXT; the European Union’s Framework Programme for Research and Innovation Horizon 2020 (2014–2020) under the Grant Agreements No. 674896, 690575 and 740055; the Ministerio de Economía Competitividad and the Ministerio de Ciencia, Innovación Universidades of Spain under grants FIS2014-53371-C04, RTI2018-095979, the Severo Ochoa Program grants SEV-2014-0398 and CEX2018-000867-S, and the María de Maeztu Program MDM-2016-0692; from Fundacion Bancaria la Caixa (ID 100010434), grant code LCF/BQ/PI19/11690012; the Generalitat Valenciana of Spain under grants PROMETEO/2016/120 and SEJI/2017/011; the Portuguese FCT under project PTDC/FIS-NUC/2525/2014 and under projects UID/FIS/04559/2020 to fund the activities of LIBPhys-UC; the Pazy Foundation (Israel) under grants 877040 and 877041; the US Department of Energy under contracts number DE-AC02-06CH11357 (Argonne National Laboratory, USA), DE-AC02-07CH11359 (Fermi National Accelerator Laboratory), DE-FG02-13ER42020 (Texas A&M). DGD acknowledges support from the Ramón y Cajal program (Spain) under contract number RYC-2015-18820. JM-A acknowledges support from Fundación Bancaria la Caixa (ID 100010434), grant code LCF/BQ/PI19/11690012, and from the Plan GenT program of the Generalitat Valenciana , grant code CIDEGENT/2019/049.

The outcome for children with high-risk neuroblastoma is poor despite intensive multi-modal treatment protocols. Toxicity from current treatments is significant, and novel approaches are needed to improve outcome. Cyclophosphamide (CPM) is a key component of current chemotherapy regimens and is known to have immunomodulatory effects. However, this has not been investigated in the context of tumor infiltrating lymphocytes in neuroblastoma. Using murine models of neuroblastoma, the immunomodulatory effects of low-dose CPM were investigated using detailed immunophenotyping. We demonstrated that CPM resulted in a specific depletion of intratumoral T regulatory cells by apoptosis, and when combined with anti-PD-1 antibody therapy, this resulted in improved therapeutic efficacy. CPM combined with anti-PD-1 therapy was demonstrated to be an effective combinational therapy, with metronomic CPM found to be more effective than single dosing in more resistant tumor models. Overall, this pre-clinical data strongly support clinical evaluation of such combination strategies in neuroblastoma.

Acetaldehyde is a major wine oxidation product. Here, three Cabernet Sauvignon wines, containing different levels of acetaldehyde from different micro-oxygenation (mOx) regimes, including yeast-mediated treatments, were aged under closures differing in oxygen ingress. Oxygen, phenolics, carbonyls and heterocyclic acetals were measured. Acetaldehyde levels at bottling was a significant factor in the phenolic compound profile after one year, with anthocyanins most affected, then flavonols, flavonoids and hydroxycinnamic acids, but there were negligible effects on benzoic acids. The effect of bottle closures with increased oxygen ingress had a similar trend. Increased acetaldehyde levels and oxygen ingress also yielded higher levels of the heterocyclic acetals from glycerol. These changes reflect aging, and suggest that managing mOx during production could be used to reduce the time needed to achieve some aged wine characteristics.

Aims Incorrectly fitting shoes are implicated in callus formation and a significant proportion of diabetic foot ulcers, yet remain surprisingly prevalent. We review the current shoe fit guidelines for consistency and discuss ways in which technology may assist us in standardising methods of footwear assessment. Methods Narrative review. Results Incorrectly fitted shoes are implicated in the development of some diabetic foot ulcers yet surprisingly there’s no consensus on shoe fit, despite substantial spending on prescription footwear. Suggested toe gaps vary from 6 to 20 mm and measurement methods also vary from Brannock Devices and callipers to manual measurement. Conclusions To prevent fit-related foot ulceration, we need to standardise our biomechanical definition of fit. Future research should (1) evaluate the potential use of 3D scanning technology to provide a standardised means of capturing foot morphology; (2) develop a working biomechanical definition of fit, including toe gap through the identification of key physiological markers that capture and predict dynamic foot shape changes during different physical activities and body weight loading conditions; and (3) determine whether changes in dynamic foot shape of those with diabetes differs from those without, impacting on their shoe fitting needs, potentially necessitating specialist footwear at an earlier stage to avoid ulceration.

The liquid sampling – atmospheric pressure glow discharge (LS-APGD) microplasma was paired with a monochromatic imaging spectrometer (MIS) to interrogate relevant plasma species/elements. The coupling of the LS-APGD source to the MIS allows for the generation of spatial emission profiles at specific analyte and background species' wavelengths. A major goal of this work was to utilize these emission profiles to gain an understanding of the species' location in the plasma as well as the effects of plasma gas flow on these emission profiles. It was found that as sheath gas and counter gas flow rates were increased, there were visible differences in intensity and distribution of emission from the monitored species in the plasma. Silver was used as the representative (test) analyte for this work due to its good sensitivity, wavelength positioning, and ability to provide continuity for comparison to previous works. The majority of analyte emission was found to occur at the tip of the solution electrode, where solutes are introduced to the plasma, whereas various background species emitted throughout the plasma. In addition to aiding in the understanding of plasma operation based on spatial emission characteristics, these studies also aided in optimizing the gas flow parameters for analyte emission intensity, signal-to-background (S/B), and signal-to-noise (S/N) values. The optimized gas flow parameters were found to be 0.7 and 0.1 L min−1 for the sheath and counter gas respectively.

Cardiovascular disease is one of the leading causes of death in the world. A characteristic symptom of cardiovascular disease is occlusion of vessels. Once vascular occlusion occurs there is a critical need to re-establish flow to prevent ischemia in the downstream tissues. In the most advanced cases, flow is re-established by creating a secondary flow path around the blockage, bypass grafting. For large diameter applications, synthetic conduits are successfully implanted, however in small diameter applications re-occlusion occurs and there is a critical need for new vascular grafts. There are many strategies and approaches that are being employed to design an effective and successful vascular graft. However, to date, there are no clinically available small diameter vascular grafts that are consistently successful in vivo long term (>7 years). As an effort to develop a successful graft there are several tissue engineering approaches: cell sheets, synthetic and natural biomaterial platforms, and decellularized extracellular matrices that are being investigated. While each area has its advantages, scaffold-based approaches are among the most widely studied. Scaffold based approaches are extensively studied due to tailorability and the availability of synthetic and natural polymers. Within the area of scaffold-based approaches, biomimicry has become an increasingly studied area, and structural biomimicry is one of the many approaches. The focus of this review paper is to analyze scaffold-based approaches. Particularly the advantages and disadvantages of using multi-layer scaffold-based approaches to engineer conduits for small diameter applications.

Background: Morbidity and mortality rates from seasonal and pandemic influenza occur disproportionately in high-risk groups, including Indigenous people globally. Although vaccination against influenza is recommended for those most at risk, studies on immune responses elicited by seasonal vaccines in Indigenous populations are largely missing, with no data available for Indigenous Australians and only one report published on antibody responses in Indigenous Canadians. Methods: We recruited 78 Indigenous and 84 non-Indigenous Australians vaccinated with the quadrivalent influenza vaccine into the LIFT-V cohort, and collected blood to define baseline, early (day 7) and memory (day 28) immune responses. We performed in-depth analyses of T and B cell activation, formation of memory B cells and antibody profiles, and investigated host factors that could contribute to vaccine responses. Findings:We found robust antibody responses to influenza vaccination induced in Indigenous Australians, with activation profiles of circulating T follicular helper type-1 (cT FH 1) cells at the acute response strongly correlating with total change of antibody vaccine titres induced by vaccination. Formation of influenza-specific haemagglutinin (HA)-binding memory B cells was significantly higher in seroconverters compared to non-seroconverters. Back-boosting of antibodies towards previously circulating influenza strains was observed following influenza vaccination. In-depth antibody characterisation revealed a reduction in IgG3 pre- and post-vaccination in the Indigenous Australian population, potentially linked to the increased frequency of G3m21* allotype. Interpretation: Overall, our data provide the first evidence that Indigenous populations elicit robust, broad and prototypical immune responses following immunisation with seasonal inactivated influenza vaccines. Our work strongly supports the recommendation of influenza vaccination to protect Indigenous populations from severe seasonal influenza virus infections and its subsequent complications. Funding: This work was funded by the Australian National Health and Medical Research Council (NHMRC) Program Grant (#1071916) to KK, NHMRC Project Grant (#1122524) to KK, ST, AM, NHMRC Project Grant (#1141840) to MP, KLF, Clifford Craig Foundation Grant (#145) to KLF, and NHMRC Investigator Grant (#1173871) to KK supported this work. EBC is a NHMRC Peter Doherty Fellow. ST is a NHMRC Career Development Fellow (#1145033). This work is supported by the NHMRC program grant 111 #1149990 (SJK), NHMRC project grant #1162760 (AKW). KK is supported by a NHMRC Senior Research Fellowship (#1102792) and SJK by a NHMRC Senior Principal Research Fellowship (#1136322). LH is supported by the Melbourne International Research Scholarship the Melbourne International Fee Remission Scholarship from The University of Melbourne. CES has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 792532. The Melbourne WHO Collaborating Centre for Reference Research on Influenza is supported by the Australian Government Department of Health. Declaration of Interest: None to declare. Ethical Approval: All experiments were conducted according to the Declaration of Helsinki principles and NHMRC Code of practice and approved by the University of Melbourne Human Research Ethics Committee (#1955465 and #1441452), the Human Research Ethics Committee of the Northern Territory Department of Health and Menzies School of Health Research (#2012-1928), and the Tasmanian Human Research Ethics Committee (#H0015460).

Circadian entrainment is the process by which internal circadian oscillators staying in synchronization with the local environmental rhythms. Circadian clocks are entrained by adjusting phase and period in response to environmental and metabolic signals. In Arabidopsis thaliana, light and sugar signals differentially affect the circadian phase; the former advances the phase in the late of the subjective night and delays around dusk, while the latter advances the phase mainly in the morning, which is optimal to maintain sucrose homeostasis. We have proposed that the phase adjustment of the A. thaliana circadian oscillator by sugar signals contributes to the realization of carbon homeostasis and the increase of plant growth under fluctuating day-night cycles. However, which genes in the circadian oscillator are targets of sucrose signals and how the potential target genes should be regulated by sucrose to realize sucrose homeostasis has not been studied from the theoretical perspective. Here we investigate the effect of sugar on the phase response property of the plant circadian oscillator using clock gene-regulatory network models. We simulated phase response curves (PRCs) to sucrose pulses, which were compared with an experimental PRC. Our analyses of the gene-regulatory network model demonstrated that target genes of the sugar signal could be members of the PSEUDO-RESPONSE REGULATOR gene family and the evening complex components. We also examined the phase response property using a single feedback-loop model and elucidated how phase advance is induced in the subjective morning under certain conditions of a target clock gene of sucrose and its regulatory property.

Spectral UV records of solar irradiance at stations over Europe, Canada, and Japan were used to study long-term trends at 307.5 nm for a 25-year period, from 1992 to 2016. Ground-based measurements of total ozone, as well as satellite measurements of the Aerosol Index, the Total Cloud Cover and the surface reflectivity were also used in order to attribute the estimated changes of the UV to the corresponding changes of these factors. The present study shows that over the Northern Hemisphere, the long-term changes in UV-B radiation reaching the Earth’s surface vary significantly over different locations, and that the main drivers of these variations are changes in aerosols and total ozone. At high latitudes, part of the observed changes may also be attributed to changes in the surface reflectivity. Over Japan, the UV-B irradiance at 307.5 nm has increased significantly by 3%/decade during the past 25 years, possibly due to the corresponding significant decrease of its absorption by aerosols. It was found that the greatest part of this increase took place before the mid-2000s. The only European station, over which UV radiation increases significantly, is that of Thessaloniki, Greece. Analysis of the clear-sky irradiance for the particular station shows increasing irradiance at 307.5 nm by 3.5%/decade during the entire period of study, with an increasing rate of change during the last decade, possibly again due to the decreasing absorption by aerosols.

Background Coronary artery disease (CAD) has substantial heritability and a polygenic architecture. However, the potential of genomic risk scores to help predict CAD outcomes has not been evaluated comprehensively, because available studies have involved limited genomic scope and limited sample sizes. Objectives This study sought to construct a genomic risk score for CAD and to estimate its potential as a screening tool for primary prevention. Methods Using a meta-analytic approach to combine large-scale, genome-wide, and targeted genetic association data, we developed a new genomic risk score for CAD (metaGRS) consisting of 1.7 million genetic variants. We externally tested metaGRS, both by itself and in combination with available data on conventional risk factors, in 22,242 CAD cases and 460,387 noncases from the UK Biobank. Results The hazard ratio (HR) for CAD was 1.71 (95% confidence interval [CI]: 1.68 to 1.73) per SD increase in metaGRS, an association larger than any other externally tested genetic risk score previously published. The metaGRS stratified individuals into significantly different life course trajectories of CAD risk, with those in the top 20% of metaGRS distribution having an HR of 4.17 (95% CI: 3.97 to 4.38) compared with those in the bottom 20%. The corresponding HR was 2.83 (95% CI: 2.61 to 3.07) among individuals on lipid-lowering or antihypertensive medications. The metaGRS had a higher C-index (C = 0.623; 95% CI: 0.615 to 0.631) for incident CAD than any of 6 conventional factors (smoking, diabetes, hypertension, body mass index, self-reported high cholesterol, and family history). For men in the top 20% of metaGRS with >2 conventional factors, 10% cumulative risk of CAD was reached by 48 years of age. Conclusions The genomic score developed and evaluated here substantially advances the concept of using genomic information to stratify individuals with different trajectories of CAD risk and highlights the potential for genomic screening in early life to complement conventional risk prediction.

Aquatic carbon exports are an understudied component of catchment carbon budgets. For drained agroecosystems, the role of this aquatic pathway in offsetting the terrestrial carbon sink is unknown. Here, we present findings on the complete annual carbon budget of a subtropical agricultural floodplain in Australia. We quantified net ecosystem exchange (NEE) using eddy covariance, and aquatic carbon fluxes from drainage canals over an annual cycle, including atmospheric exchange of aquatic CO2 and CH4, as well as lateral exports of dissolved organic, inorganic and particulate carbon. The floodplain was a large atmospheric CO2 sink, with an annual NEE of −900 g C m−2 yr−1 driven by the sugarcane growing season. Aquatic carbon fluxes were estimated at 24, 16, and 0.05 g C m−2 yr−1 for lateral export, CO2 and CH4 evasion, respectively. Between 70% and 91% of aquatic carbon was lost during flood events which occurred only 12% of the time. From these measurements and estimates of other carbon inputs and outputs from farm operations, the net ecosystem carbon budget was close to neutral at −100 (error range −289 to 215) g C m−2 yr−1. Compared to other drained wetlands, the aquatic carbon flux was a minor component of the carbon budget.

Peripheral arterial disease is a leading cause of morbidity and mortality. The most commonly utilized prosthetic material for peripheral bypass grafting is expanded polytetrafluoroethylene (ePTFE) yet it continues to exhibit poor performance from restenosis due to neointimal hyperplasia, especially in femoral distal bypass procedures. Recently, we demonstrated that periadventitial delivery of all-trans retinoic acid (atRA) immobilized throughout porous poly(1,8 octamethylene citrate) (POC) membranes inhibited neointimal formation in a rat arterial injury model. Thus, the objective of this study was to investigate whether atRA immobilized throughout the lumen of ePTFE vascular grafts would inhibit intimal formation following arterial bypass grafting. Utilizing standard ePTFE two types of atRA-containing ePTFE vascular grafts were fabricated and evaluated: grafts whereby all-trans retinoic acid was directly immobilized on ePTFE (atRA-ePTFE) and grafts where all-trans retinoic acid was immobilized onto ePTFE grafts coated with POC (atRA-POC-ePTFE). All grafts were characterized by SEM, HPLC, and FTIR and physical chararcteristics were evaluated in vitro. Modification of these grafts, did not significantly alter their physical characteristics or biocompatibility, and resulted in inhibition of intimal formation in a rat aortic bypass model, with atRA-POC-ePTFE inhibiting intimal formation at both the proximal and distal graft sections. In addition, treatment with atRA-POC-ePTFE resulted in increased graft endothelialization and decreased inflammation when compared to the other treatment groups. This work further confirms the biocompatibility and efficacy of locally delivered atRA to inhibit intimal formation in a bypass setting. Thus, atRA-POC-ePTFE grafts have the potential to improve patency rates in small diameter bypass grafts and warrant further investigation.

Global food security is at a tipping point. After decades of both absolute and relative improvement in food security worldwide, climate change, market disruptions and declining productivity have reversed the trend. After four decades of improving food security, both more people and a larger portion of the global population are hungry today than in 2015. In response, researchers and their funders, governments, industries and interest groups are urging renewed collaboration and partnerships to recover and return to accelerate food production and to improve food distribution. Recently some public academics and civil society organizations are opposing these public-private partnerships (P3s). The article reviews the context, discusses the logic for P3s and explores the range of P3s that have been used and their impacts on the global agri-food system. We conclude that rather than reversing direction, the use of both strategic and tactical partnerships should be accelerated in order to improve global food security.

Epstein - Barr virus positive Mucocutaenous ulcer (EBVMCU) is a relatively new entity of the lymphoproliferative disorders, recognised by the WHO in 2017. The usual presentation is of a self-limiting ulcer which can affect the oropharynx, gastrointestinal tract and cutaneous skin. We present an unusual diagnosis of (EBVMCU). The patient had two separate presentations of the same disease: the first followed the expected pathogenesis of EBVMCU with full recovery; the second highlights a complication of the disease resulting in maxillary osteonecrosis.

The purpose of this investigation was to better define the anatomical features of the biceps tendon sheath, including the distance the sheath extends below the inferior margin of the subscapularis tendon and below the termination of the bony bicipital groove. A total of 110 magnetic resonance and computed tomography arthrograms performed during 1-year period at our institution were retrospectively reviewed, and the length of the biceps tendon sheath and distances from the inferior margin of the subscapularis tendon and from the termination of the bicipital groove to the inferior margin of the biceps tendon sheath were measured by 3 radiologists. The mean length of the biceps tendon sheath was 47.5mm. The mean distances from the inferior margin of the subscapularis tendon and from the inferior margin of the bicipital groove to the distal extent of the biceps tendon sheath were 24.5mm and 11.9mm, respectively. The relationships among these 3 anatomical measurements and biological confounders of sex and age were investigated while controlling for measurement variability. The anatomical relationships between the biceps tendon sheath and surrounding structures may have implications for needle placement when attempting to inject into the biceps tendon sheath for diagnostic or therapeutic purposes.

A series of four thiosemicarbazones from 6-nitropiperonal along with the corresponding copper complexes were synthesized. The biophysical characteristics of the complexes were investigated by the binding to DNA and human serum albumin. The binding to DNA is moderate; the binding constants run from (0.49–7.50) × 10 4 M − 1 . In relation to HSA, the complexes interact strongly with binding constants on the order of 10 5 M − 1 . The complexes also display antioxidant behavior as determined by the ability to scavenge diphenylpicrylhydrazyl (dpph) and nitric oxide radicals. The antimicrobial profiles of the compounds, tested against a panel of microbes including five of the ESKAPE pathogens ( Staphylococcus aureus , MRSA , Escherichia coli , Klebsiella pneumoniae , MDR , Acinetobacter baumannii , Pseudomonas aeruginosa ) and two yeasts ( Candida albicans and Cryptococcus neoformans var. grubii ), are also described. The compounds contain a core moiety that is similar to oxolinic acid, a quinolone antibiotic that targets DNA gyrase and topoisomerase (IV). The binding interaction between the complexes and these important antibacterial targets were studied by computational methods, chiefly docking studies. The calculated dissociation constants for the interaction with DNA gyrase B (from Staphylococcus aureus ) range from 4.32 to 24.65 μM; the binding was much stronger to topoisomerase IV, with dissociation constants ranging from 0.37 to 1.27 μM.

A novel antifungal strategy targeting the inhibition of calcineurin is described. To develop a calcineurin based inhibitor of pathogenic fungi, analogs of FK506 were synthesized that were able to permeate mammalian but not fungal cells. Antagonists in combination with FK506 were not immunosuppressive and retained antifungal activity in A. fumigatus. To reduce the dosage burden of the antagonist, murine oral PK was improved an order of magnitude relative to previous FK506 antagonists.

To investigate the association of 4 anthropometric measurements with cardiometabolic risk factors in a UK biethnic sample of South Asians (SAs) and white Europeans (WEs).Baseline data were collected from adults of WE and SA origin participating in the Leicester arm of the Anglo-Danish-Dutch Study of Intensive Treatment in People with Screen Detected Diabetes in Primary Care (ADDITION-Leicester) study between August 2004 and December 2007. Overall, 6268 WE and SA adults had measures of body mass index, waist circumference, waist-to-hip ratio, and waist-to-height ratio assessed between June 18, 2004, and December 4, 2007. Hypertension, dyslipidemia, and dysglycemia were established from venous blood samples using standard definitions. Crude and adjusted (covariates used were age, sex, ethnicity, smoking, and alcohol consumption) odds ratios were calculated using multivariate logistic regression. Receiver operating characteristic curves and the area under the curve were used to calculate optimal cut points for the whole cohort and for both ethnic groups.Increases in all anthropometric measurements resulted in a higher odds ratio for each of the risk factors in both the crude and adjusted models (P.001). The adjusted odds ratios for dyslipidemia, hypertension, and dysglygemia ranged from 1.30 to 1.35, from 1.36 to 1.52, and from 1.62 to 1.75 (P.001 for all), respectively, in WEs. The adjusted odds ratio for dyslipidemia, hypertension, and dysglygemia ranged from 1.50 to 1.65 (P.01), from 1.40 to 1.60 (P.01), and from 1.96 to 2.11 (P.001 for all), respectively, in SAs. The areas under the receiver operating characteristic curves for all the anthropometric measurements had low accuracy (P.70) for the whole cohort and when stratified by ethnicity and sex.There is insufficient evidence to recommend replacing body mass index with another anthropometric measurement for the ethnically diverse population in the United Kingdom.clinicaltrials.gov Identifier: NCT00318032.

Primary total hip arthroplasty (THA) and conversion THA may result in substantial blood loss, sometimes necessitating transfusion. Despite the complexities of the latter, both are grouped in the same category for quality assessment and reimbursement. This study's purpose was to compare both blood loss and transfusion risk in primary and conversion THA and identify their associated predictors.A total of 1616 patients who underwent primary and conversion THA at a single hospital from 2009-2013 were reviewed (primary THA = 1575; conversion THA = 41). Demographics, comorbidities, and perioperative data were collected from electronic records. Blood loss was calculated using a validated method. Transfusion triggers were based on standardized criteria. Separate multivariable regression models for blood loss and transfusion were performed.Conversion THA patients were younger (P = .002), had lower age-adjusted Charlson scores (P = .006), longer surgeries (P.001), higher blood loss (P.001), and more transfusions (P.001). Primary and conversion THA groups were different in terms of surgical approach (P.001), anesthesia type (P = .002), and venous thromboembolism prophylaxis (P = .01). Compared to primary THA, conversion THA had an average 478.9 mL higher blood loss (P = .003) and increased adjusted odds ratio of 3.2 (P = .019) for transfusion.Conversion THA leads to higher blood loss and transfusion compared with primary THA. These differences were quantified in the present study and showed consistent results between the 2 metrics. The differences between these procedures should be addressed during quality assurance because conversion THA is associated with higher resource utilization, which is important in the allocation of resources and tiered reimbursement strategies.

Enveloped viruses utilize fusion (F) proteins studding the surface of the virus to facilitate membrane fusion with a target cell membrane. Fusion of the viral envelope with a cellular membrane is required for release of viral genomic material, so the virus can ultimately reproduce and spread. To drive fusion, the F protein undergoes an irreversible conformational change, transitioning from a metastable pre-fusion conformation to a more thermodynamically stable post-fusion structure. Understanding the elements that control stability of the pre-fusion state and triggering to the post-fusion conformation is important for understanding F protein function. Mutations in F protein transmembrane (TM) domains implicated the TM domain in the fusion process, but the structural and molecular details in fusion remain unclear. Previously, analytical ultracentrifugation was utilized to demonstrate that isolated TM domains of Hendra virus F protein associate in a monomer-trimer equilibrium (Smith, E. C., Smith, S. E., Carter, J. R., Webb, S. R., Gibson, K. M., Hellman, L. M., Fried, M. G., and Dutch, R. E. (2013) J. Biol. Chem. 288, 35726–35735). To determine factors driving this association, 140 paramyxovirus F protein TM domain sequences were analyzed. A heptad repeat of β-branched residues was found, and analysis of the Hendra virus F TM domain revealed a heptad repeat leucine-isoleucine zipper motif (LIZ). Replacement of the LIZ with alanine resulted in dramatically reduced TM-TM association. Mutation of the LIZ in the whole protein resulted in decreased protein stability, including pre-fusion conformation stability. Together, our data suggest that the heptad repeat LIZ contributed to TM-TM association and is important for F protein function and pre-fusion stability.

The Nucleosome Remodeling and Deacetylase (NuRD) complex is essential for development in complex animals but has been refractory to biochemical analysis. We present the first integrated analysis of the architecture of the native mammalian NuRD complex, combining quantitative mass spectrometry, covalent cross-linking, protein biochemistry and electron microscopy. NuRD is built around a 2:2:4 pseudo-symmetric deacetylase module comprising MTA, HDAC and RBBP subunits. This module interacts asymmetrically with a remodeling module comprising one copy each of MBD, GATAD2 and CHD subunits. The previously enigmatic GATAD2 controls the asymmetry of the complex and directly recruits the ATP-dependent CHD remodeler. Unexpectedly, the MTA-MBD interaction acts as a point of functional switching. The transcriptional regulator PWWP2A modulates NuRD assembly by competing directly with MBD for binding to the MTA-HDAC-RBBP subcomplex, forming a ‘moonlighting’ PWWP2A-MTA-HDAC-RBBP complex that likely directs deacetylase activity to PWWP2A target sites. Taken together, our data describe the overall architecture of the intact NuRD complex and reveal aspects of its structural dynamics and functional plasticity.

There is a general consensus that Mars is the next high priority destination for human space exploration. There has been no lack of analysis and recommendations for human missions to Mars, including, for example, the NASA Design Reference Architectures and the Mars Direct proposal. These studies and others usually employ the traditional approach of selecting a baseline mission architecture and running individual trade studies. However, this can cause blind spots, as not all combinations are explored. An alternative approach is to holistically analyze the entire architectural trade-space such that all of the possible system interactions are identified and measured. In such a framework, an optimal design is sought by minimizing cost for maximal value. While cost is relatively easy to model for manned spaceflight, value is more difficult to define. In our efforts to develop a surface base architecture for the MIT Mars 2040 project, we explored several methods for quantifying value, including technology development benefits, challenge, and various metrics for measuring scientific return. We developed a science multi-score method that combines astrobiology and geologic research goals, which is weighted by the crew-member hours that can be used for scientific research rather than other activities.