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Up to one in five early breast cancer patients develop chronic upper limb lymphedema after breast cancer treatments. This treatment complication is irreversible and can significantly impact the quality of life of breast cancer survivors. The model of prospective surveillance and early intervention has emerged as a potential strategy to prevent the development of this debilitating treatment-related complication. However, the widespread implementation of such programs worldwide is challenging. The aim of this review is to identify barriers of implementation, including selecting suitable patients to be enrolled, determining the optimal method for lymphedema screening, and choosing the most effective treatment to prevent progression when early or subclinical breast cancer-related arm lymphedema (BCRAL) is detected. Future research should develop accurate predictive models for the development of upper limb lymphedema using population based datasets with artificial intelligence and investigate the comparative efficacy of different screening methods and treatment options for early intervention for BCRAL. The medical community should also regularly review whether new treatments such as immunotherapy, targeted therapies and new surgical or radiation techniques could contribute to the development of arm lymphedema. By overcoming these barriers, we can improve the feasibility of implementing early prospective surveillance programs in clinical practice, ultimately improving the care and outcomes for breast cancer survivors at risk of treatment-related upper limb lymphedema.

The intricate network of protein-chaperone interactions is crucial for maintaining cellular function. Recent discoveries have unveiled the existence of specialized chaperone assemblies, known as epichaperomes, which serve as scaffolding platforms that orchestrate the reconfiguration of protein-protein interaction networks, thereby enhancing cellular adaptability and proliferation. This study explores the structural and regulatory aspects of epichaperomes, with a particular focus on the role of post-translational modifications (PTMs) in their formation and function. A key finding is the identification of specific PTMs on HSP90, particularly at residues Ser226 and Ser255 within an intrinsically disordered region, as critical determinants of epichaperome assembly. Our data demonstrate that phosphorylation of these serine residues enhances HSP90's interactions with other chaperones and co-chaperones, creating a microenvironment conducive to epichaperome formation. Moreover, we establish a direct link between epichaperome function and cellular physiology, particularly in contexts where robust proliferation and adaptive behavior are essential, such as in cancer and pluripotent stem cell maintenance. These findings not only provide mechanistic insights but also hold promise for the development of novel therapeutic strategies targeting chaperone assemblies in diseases characterized by epichaperome dysregulation, thereby bridging the gap between fundamental research and precision medicine., (© 2024. The Author(s).)

Purpose: Desmoplastic small round cell tumor (DSRCT) is a rare but highly aggressive soft tissue sarcoma that arises in the abdominopelvic cavity of young males. Since the discovery of EWSR1::WT1 fusion as the driver of DSRCT, no actionable genomic alterations have been identified, limiting disease management to a combination of surgery, chemotherapy, and radiation, with very poor outcomes. Herein, we evaluated ERBB2/HER2 expression in DSRCT as a therapeutic target., Experimental Design: ERBB2/HER2 expression was assessed in clinical samples and patient-derived xenografts (PDX) using RNA sequencing, RT-qPCR, and a newly developed HER2 IHC assay (clone 29D8). Responses to HER2 antibody-drug conjugates (ADC)-trastuzumab deruxtecan (T-DXd) and trastuzumab emtansine-were evaluated in DSRCT PDX, cell line, and organoid models. Drug internalization was demonstrated by live microscopy. Apoptosis was evaluated by Western blotting and caspase activity assays., Results: ERBB2/HER2 was detectable in DSRCT samples from patients and PDXs, with higher sensitivity RNA assays and improved IHC detectability using clone 29D8. Treatment of ERBB2/HER2-expressing DSRCT PDX, cell line, and organoid models with T-DXd or trastuzumab emtansine resulted in tumor regression. This therapeutic response was long-lasting in T-DXd-treated xenografts and was mediated by rapid HER2 ADC complex internalization and cytotoxicity, triggering p53-mediated apoptosis and growth arrest. Xenograft regression was associated with bystander payload effects triggering global tumor niche responses proportional to HER2 status., Conclusions: ERBB2/HER2 is a therapeutic target in DSRCT. HER2 ADCs may represent novel options for managing this exceptionally aggressive sarcoma, possibly fulfilling an urgent and historically unmet need for more effective clinical therapy., (©2024 American Association for Cancer Research.)

The intricate protein-chaperone network is vital for cellular function. Recent discoveries have unveiled the existence of specialized chaperone complexes called epichaperomes, protein assemblies orchestrating the reconfiguration of protein-protein interaction networks, enhancing cellular adaptability and proliferation. This study delves into the structural and regulatory aspects of epichaperomes, with a particular emphasis on the significance of post-translational modifications in shaping their formation and function. A central finding of this investigation is the identification of specific PTMs on HSP90, particularly at residues Ser226 and Ser255 situated within an intrinsically disordered region, as critical determinants in epichaperome assembly. Our data demonstrate that the phosphorylation of these serine residues enhances HSP90's interaction with other chaperones and co-chaperones, creating a microenvironment conducive to epichaperome formation. Furthermore, this study establishes a direct link between epichaperome function and cellular physiology, especially in contexts where robust proliferation and adaptive behavior are essential, such as cancer and stem cell maintenance. These findings not only provide mechanistic insights but also hold promise for the development of novel therapeutic strategies targeting chaperone complexes in diseases characterized by epichaperome dysregulation, bridging the gap between fundamental research and precision medicine., Competing Interests: COMPETING INTERESTS Memorial Sloan Kettering Cancer Center holds the intellectual rights to the epichaperome portfolio. G.C., A.R. and S.S. are inventors on the licensed intellectual property. All other authors declare no competing interests.

Background: Anaphylaxis is the most severe clinical presentation of acute systemic allergic reactions and can cause death. Given the prevalence of anaphylaxis within healthcare systems, it is a high priority public health issue. However, management of anaphylaxis - both acute and preventative - varies by region., Methods: The World Allergy Organization (WAO) Anaphylaxis Committee and the WAO Junior Members Steering Group undertook a global online survey to evaluate local practice in the diagnosis and management of anaphylaxis across regions., Results: Responses were received from WAO members in 66 countries. While intramuscular epinephrine (adrenaline) is first-line treatment for anaphylaxis, some countries continue to recommend alternative routes in contrast to guidelines. Epinephrine auto-injector (EAI) devices, prescribed to individuals at ongoing risk of anaphylaxis in the community setting, are only available in 60% of countries surveyed , mainly in high-income countries. Many countries in South America, Africa/Middle-East and Asian-Pacific regions do not have EAI available, or depend on individual importation. In countries where EAIs are commercially available, national policies regarding the availability of EAIs in public settings are limited to few countries (16%). There is no consensus regarding the time patients should be observed following emergency treatment of anaphylaxis., Conclusion: This survey provides a global snapshot view of the current management of anaphylaxis, and highlights key unmet needs including the global availability of epinephrine for self-injection as a key component of anaphylaxis management., Competing Interests: The authors declare that they do not have any conflict of interests related to the contents of this article., (© 2023 The Author(s).)

Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article.

Background: Annually, almost 2 billion peripheral intravenous cannulas (PIVCs) are placed worldwide. In response to concerns of infectious complications, chlorhexidine is increasingly utilised for maintenance decontamination of PIVC injection ports. Concomitantly, the allergenic potential of chlorhexidine exposures has been highlighted by several case reports, implicating it as a trigger when used for this seemingly innocuous process. Given how widespread this application is, elucidating potential chlorhexidine exposure is needed to gauge its risks and benefits., Objective: To examine and quantify if chlorhexidine is entrained when used for PIVC injection port cleaning., Methods: Twenty benchtop PIVC set-ups were cleaned with 2% chlorhexidine and 70% alcohol wipes, following three different pragmatic protocols. Each set-up was injected with 10 ml ultrapure water, and samples tested by liquid chromatography-electrospray tandem mass spectrometry for entrained chlorhexidine., Results: Chlorhexidine was detected in every sample. Mean concentrations and standard deviations from each protocol were 41.47 ppb (4.08), 54.76 ppb (17.46), and 65.84 ppb (7.01). One-way ANOVA indicated a statistical difference between at least two groups (df = 2, F = 24.11, p < .00001), with Tukey's testing verifying significantly different mean concentrations between all groups (p < .01)., Conclusions: Using 2% chlorhexidine and 70% alcohol swabs to decontaminate PIVC injection ports resulted in consistent entrainment of chlorhexidine, with varying amounts correlated to how it was applied. These results validate case reports attributing anaphylactic/allergic reactions to suspected intravenous chlorhexidine entrainment and should factor into future risk-benefit assessments for its use in PIVC maintenance antisepsis policies and protocols., (© 2022 The Authors. Acta Anaesthesiologica Scandinavica published by John Wiley & Sons Ltd on behalf of Acta Anaesthesiologica Scandinavica Foundation.)

Improved identification of anti-tumor T cells is needed to advance cancer immunotherapies. CD39 expression is a promising surrogate of tumor-reactive CD8 + T cells. Here, we comprehensively profiled CD39 expression in human lung cancer. CD39 expression enriched for CD8 + T cells with features of exhaustion, tumor reactivity, and clonal expansion. Flow cytometry of 440 lung cancer biospecimens revealed weak association between CD39 + CD8 + T cells and tumoral features, such as programmed death-ligand 1 (PD-L1), tumor mutation burden, and driver mutations. Immune checkpoint blockade (ICB), but not cytotoxic chemotherapy, increased intratumoral CD39 + CD8 + T cells. Higher baseline frequency of CD39 + CD8 + T cells conferred improved clinical outcomes from ICB therapy. Furthermore, a gene signature of CD39 + CD8 + T cells predicted benefit from ICB, but not chemotherapy, in a phase III clinical trial of non-small cell lung cancer. These findings highlight CD39 as a proxy of tumor-reactive CD8 + T cells in human lung cancer., Competing Interests: Declaration of interests C.A.K. received research funding support from Kite/Gilead and Intima Bioscience; is on the Scientific and/or Clinical Advisory Boards of Achilles Therapeutics, Aleta BioTherapeutics, Bellicum Pharmaceuticals, Catamaran Bio, Obsidian Therapeutics, and T-knife; and has performed consulting services for Bristol Myers Squibb, PACT Pharma, and Roche/Genentech. C.A.K. is a co-inventor on patent applications related to TCRs targeting public neoantigens unrelated to the current work. M.D.H. received a research grant from BMS; personal fees from Achilles, Arcus, AstraZeneca, Blueprint, BMS, Genentech/Roche, Genzyme, Immunai, Instil Bio, Janssen, Merck, Mirati, Natera, Nektar, Pact Pharma, Regeneron, Shattuck Labs, and Syndax; and equity options from Arcus, Factorial, Immunai, and Shattuck Labs. A patent filed by MSKCC related to the use of tumor mutational burden to predict response to immunotherapy (PCT/US2015/062208) is pending and licensed by PGDx. J.D.W. is a consultant for Amgen, Apricity, Ascentage Pharma, Astellas, AstraZeneca, Bicara Therapeutics, Boehringer Ingelheim, Bristol Myers Squibb, CellCarta, Chugai, Daiichi Sankyo, Dragonfly, Georgiamune, Idera, Imvaq, Larkspur, Maverick Therapeutics, Merck, Psioxus, Recepta, Tizona, Trishula, Sellas, Surface Oncology, and Werewolf Therapeutics. J.D.W. receives grant/research support from Bristol Myers Squibb and Sephora. J.D.W. has equity in Apricity, Arsenal IO, Ascentage, Beigene, Imvaq, Linneaus, Georgiamune, Maverick, Tizona Pharmaceuticals, and Trieza. J.D.W. is a co-inventor on the following patent application: xenogeneic (canine) DNA vaccines, myeloid-derived suppressor cell (MDSC) assay, anti-PD1 antibody, anti-CTLA4 antibodies, anti-GITR antibodies and methods of use thereof, Newcastle disease viruses for cancer therapy, and prediction of responsiveness to treatment with immunomodulatory therapeutics and method of monitoring abscopal effects during such treatment. J.D.W. and T.M. are co-inventors on patent applications related to CD40 and in situ vaccination (PCT/US2016/045970). T.M. is a consultant for Immunos Therapeutics and Pfizer. T.M. is a cofounder of and equity holder in IMVAQ Therapeutics. T.M. receives research funding from Bristol Myers Squibb, Surface Oncology, Kyn Therapeutics, Infinity Pharmaceuticals, Peregrine Pharmaceuticals, Adaptive Biotechnologies, Leap Therapeutics, and Aprea Therapeutics. T.M. is an inventor on patent applications related to work on oncolytic viral therapy, alpha virus-based vaccine, neoantigen modeling, CD40, GITR, OX40, PD-1, and CTLA-4. C.M.R. has consulted regarding oncology drug development with AbbVie, Amgen, Ascentage, AstraZeneca, BMS, Celgene, Daiichi Sankyo, Genentech/Roche, Ipsen, Loxo, and PharmaMar and is on the scientific advisory boards of Elucida, Bridge, and Harpoon. B.Y.N. and X.G. are employees and stockholders of Genentech/Roche., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Purpose: Stereotactic body radiation therapy (SBRT) is a recognized treatment for low- and intermediate-risk prostate cancer, with 36.25 Gy in 5 fractions the most commonly used regimen. We explored the preliminary efficacy, patient recorded toxicity, and decision regret in intermediate- and high-risk prostate cancer receiving SBRT with prostate-specific membrane antigen (PSMA)/magnetic resonance imaging (MRI) guided focal gross tumor volume boost to 45 Gy., Methods and Materials: Between July 2015 and June 2019, 120 patients received SBRT across 2 institutions with a uniform protocol. All patients had fiducial markers and hydrogel, MRI and PSMA positron emission tomography (PET) scan. All patients received a questionnaire asking the degree of urinary, bowel, and sexual bother experienced at set time points, including questions about treatment choice and decision regret., Results: One hundred twelve of 120 patients consented. Their median age was 72 years and median follow-up was 2.3 years. As per National Comprehensive Cancer Network guidelines, 78% had intermediate risk and 20% high risk. Androgen deprivation was combined with radiation in 6 patients. Most patients (74%) reported that receiving SBRT significantly influenced their choice of treatment. Five men (4%) expressed "quite a lot" (n = 4) or "very much" regret (n = 1) regarding their choice of treatment, while 89% expressed "no regret." Similar to pretreatment levels, "quite a lot" or "very much" urinary or bowel bother was expressed in 8% and 6% of patients, respectively. Two patients experienced nadir +2 biochemical failure, both found to have bone metastases. A third patient underwent PSMA PET at nadir +1.7 and had disease at the penile bulb, which was out of field. Three year estimated freedom from biochemical failure was 99% for intermediate and 85% for high-risk groups., Conclusions: We have demonstrated promising efficacy and low toxicity with PSMA/MRI-guided SBRT focal boost. Less than 5% of patients expressed significant decision regret for their choice of treatment., (Copyright © 2021 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.)

Strong and durable anticancer immune responses are associated with the generation of activated cancer-specific T cells in the draining lymph nodes. However, cancer cells can colonize lymph nodes and drive tumour progression. Here, we show that lymphocytes fail to penetrate metastatic lesions in lymph nodes. In tissue from patients with breast, colon, and head and neck cancers, as well as in mice with spontaneously developing breast-cancer lymph-node metastases, we found that lymphocyte exclusion from nodal lesions is associated with the presence of solid stress caused by lesion growth, that solid stress induces reductions in the number of functional high endothelial venules in the nodes, and that relieving solid stress in the mice increased the presence of lymphocytes in lymph-node lesions by about 15-fold. Solid-stress-mediated impairment of lymphocyte infiltration into lymph-node metastases suggests a therapeutic route for overcoming T-cell exclusion during immunotherapy., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Finite element analysis (FE) coupled with high-resolution peripheral quantitative computed tomography (HR-pQCT) allows for noninvasive in vivo assessment of fracture stiffness at peripheral locations including the distal radius. Previous studies have reported the ability of FE analysis to capture significant longitudinal changes in fracture stiffness. We hypothesized that continuum-based FE methods are necessary to capture significant changes in FE-estimated stiffness in men and women, with closed reductions and casting, over the course of their fracture healing process. The primary aim of the study was to evaluate the performance of 3 micro-FE (μFE) methods, 2 density-based (continuum) methods, and a homogeneous method. A total of 30 participants with stable distal radius fractures completed follow-ups at 2, 4, 6, 8, 12, and 26 weeks postfracture. Participants had their fractured wrist scanned using HR-pQCT at each follow-up; the contralateral wrist was also scanned at the initial assessment to represent baseline conditions. Images were used to generate continuum and homogeneous µFE models. Uniaxial compression and torsional tests were completed, with apparent stiffness determined as the primary outcome measure. Stiffness of the fractured wrist was compared to stiffness of the uninjured contralateral wrist to quantify the change in stiffness. Days since fracture significantly predicted change in stiffness for continuum and homogeneous µFE methods (p < 0.05). Continuum µFE methods appeared to account for partially mineralized tissues, resulting in a graduated recovery of stiffness (1% per week). Homogeneous µFE methods were more sensitive to stages of healing progression, resulting in a faster recovery of stiffness (3% per week). Our findings demonstrate the capability of µFE to capture the restoration of stiffness at the fractured side to prefracture stiffness in men and women, up to 6 months postfracture., (Copyright © 2020 The International Society for Clinical Densitometry. Published by Elsevier Inc. All rights reserved.)

Background: The purpose of this article is to document the normal arthroscopic appearance of the posterior ankle capsular and ligamentous structures, and variations in their anatomical relationships., Methods: 102 ankle arthroscopy videotapes were evaluated retrospectively for the configuration of the posterior capsuloligamentous structures. Based on these observations, the variations in the appearance and position of the posterior tibiofibular ligament (PTFL) and transverse (tibiofibular) ligament (TTFL) were documented. In addition, differences in the appearance of the flexor hallucis longus (FHL) were also noted., Results: All patients had evidence of both a PTFL and TTFL, which formed a labrum or meniscus-like addition to the posterior distal tibia. No patients demonstrated disruption of the PTFL; 3 had tears of the TTFL. We noted 4 distinct patterns of the PTFL and the TTFL. Thirty-four patients (33%) had a gap of ≥2 mm between the 2 ligamentous structures. Thirty-three (32.4%) had a gap <2 mm between the PTFL and TTFL. Twenty-six (25.5%) had a confluence of the 2 ligaments without a gap. Nine (9%) demonstrated a sizable gap between the 2 ligaments, and the TTFL appeared as a "cord-like" structure., Conclusion: To our knowledge, this is the first article to describe the variations in the arthroscopic normal posterior capsuloligamentous structures and FHL of the ankle., Level of Evidence: Level IV, case series., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. ICMJE forms for all authors are available online., (© The Author(s) 2021.)

Background and Objectives: Medical providers are significant drivers of care in post-acute long-term care (PALTC) settings, yet little research has examined the medical provider workforce and its role in ensuring quality of care., Research Design and Methods: This study examined the impact of nursing home medical staffing organization (NHMSO) dimensions on the quality of care in U.S. nursing homes. The principal data source was a survey specifically designed to study medical staff organization for post-acute care. Respondents were medical directors and attending physicians providing PALTC. We linked a number of medical provider and nursing home characteristics to the Centers for Medicaid and Medicare Services Nursing Home Compare quality measures hypothesized to be sensitive to input by medical providers., Results: From the sample of nursing home medical providers surveyed (n = 1,511), 560 responses were received, yielding a 37% response rate; 425 medical provider responses contained sufficient data for analysis. The results of the impact of NHMSO dimensions were mixed, with many domains not having any significance or having negative relationships between provider characteristics and quality measures. Respondents who reported having a formal process for granting privileges and nursing homes with direct employment of physicians reported significantly fewer emergency visits., Discussion and Implications: Further research is needed regarding what quality measures are sensitive to both medical provider characteristics and NHMSO characteristics., (© The Author(s) 2020. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: This study reports on olecranon osteotomy implant removal rates, fixation types, and associated complications., Design: Multicentre case series., Setting: Patients were identified through an electronic medical database at one Level 1 trauma center and three Level 2 trauma centers., Patients: Two hundred thirty-five patients were identified through the database, of which 92 patients met inclusion criteria., Intervention: Patients underwent olecranon osteotomy for fixation of distal humerus fractures and the implant used was at the surgeon's discretion., Main Outcome Measurement: Implant removal rate., Results: Thirty-four of 92 (37.0%) patients underwent removal of implant from their olecranon osteotomy. Implant removal rates were as follows: 28 of the 63 patients for tension band wiring (TBW) (44.4%), 6 of the 18 patients for plates (33.3%), 0 of the 1 patient for cable-pin, and 0 of the 10 patients for osteotomies fixed with a screw fixation. Screw fixation was removed less frequently than TBW (P = 0.01). Screws were less commonly removed than all other fixation types (P = 0.01). TBWs (28/63) were more commonly removed than all other implants (6/29) (P < 0.05). The nonunion rate for olecranon osteotomies was 3.3%. TBWs (18/18) are more likely to be removed for implant irritation than plates. TBWs had an odds ratio of 3.29 for requiring implant removal if they were left >1 mm off of the olecranon tip., Conclusion: In this study, 34 of the 92 (37%) patients undergoing an olecranon osteotomy for treatment of a distal humerus fracture required removal of olecranon implant. Screw fixation (0/10) was found to be removed less frequently than TBW fixation 28 of the 63 patients (44.4%)., Level of Evidence: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence., Competing Interests: The authors report no conflict of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Bone strength determined from finite element (FE) modelling provides an estimate of fracture healing progression following a distal radius fracture (DRF), but how these measures relate to patient-reported outcomes and functional outcomes remains unknown. We hypothesized that changes in bone stiffness and bone mineral density measured using high-resolution peripheral quantitative computed tomography (HR-pQCT) are associated with clinically available measures of functional and patient-reported outcomes. We also aimed to identify which clinical outcome measures best predict fracture stiffness and could therefore be used to inform cast removal. Participants ( n  = 30) with stable distal radius fractures were followed for two week intervals from the time of fracture until two months post-fracture, then at three months and six months post-fracture. At each follow-up, participants underwent clinical, radiographic, and functional assessments, as well as had their fractured wrist scanned using HR-pQCT. Recovery of bone stiffness during fracture healing was determined from micro-FE (μFE) models generated from HR-pQCT image data. During the DRF healing process, significant longitudinal changes were found in μFE-estimated stiffness, patient-reported outcomes, grip strength, range of motion (ROM), tenderness, number of cortices healed based on radiographs, and fracture line visibility ( p  < 0.05); however, no significant change was detected in HR-pQCT based total bone mineral density. Patient-reported outcomes, such as the Patient-Rated Wrist Evaluation (PRWE) and the Quick Disability of the Arm, Shoulder and Hand (QuickDASH) questionnaire, correlated strongly with μFE-estimated stiffness (0.61 ≥ r m  ≥ 0.66). Based on μFE-estimated stiffness, PRWE and QuickDASH are the best predictors of stiffness recovery ( p  < 0.05) and may be used to guide duration of cast immobilization in the clinical setting., Competing Interests: Phillip Spanswick – conflicts of interest: none. Danielle E. Whittier – conflicts of interest: none. Cory Kwong – conflicts of interest: none. Robert Korley – conflicts of interest: none. Dr. Steven Boyd – conflicts of interest: Numerics88 Solutions Ltd. – Co-founder. Dr. Prism Schneider – conflicts of interest: Amgen – Scientific Advisory Committee Member honorarium; Synthes – Teaching Honourarium., (© 2021 Published by Elsevier Inc.)

Purpose: To report the feasibility, toxicity, and preliminary outcomes (metabolic and biochemical) of 68 Ga-prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT)-directed focal prostate reirradiation using linear accelerator (LINAC)-based stereotactic body radiation treatment (SBRT)., Methods and Materials: From March 2016 to March 2019, 25 patients were enrolled in a prospective single institution trial (ACTRN12617000035325). Eligibility criteria included patients with biopsy proven isolated prostate recurrence after definitive irradiation, with concordant multiparametric MRI and 68 Ga-PSMA PET/CT findings, and a prostate-specific antigen of less than 15 ng/mL at the time of recurrence. The study included a sequential dose escalation component with the first 18 patients receiving 36 Gy in 6 fractions on alternate days with subsequent patients receiving 38 Gy in 6 fractions assuming acceptable toxicity., Results: Median age was 72 years (range, 62-83) with a median time between first radiation treatment and salvage SBRT of 8.3 years (range, 4.5- 13.6). Median prostate-specific antigen at reirradiation was 4.1 (range, 1.1-16.6). The median follow-up was 25 months (range, 13-46). Acute grade 1 and 2 genitourinary (GU) toxicity occurred in 6 (24%) and 1 (4%) men, respectively. Acute grade 1 gastrointestinal (GI) toxicity occurred in 8% with one acute grade 3 GI toxicity (4%) due to a rectal ulcer overlying the hydrogel. Late grade 1 and 2 GU toxicity occurred in 28% and 4%. Late grade 1 GI toxicity occurred in 8% with no grade 2 or greater toxicity. Twenty-four patients have undergone per-protocol 12-month 68 Ga-PSMA PET/CT, of which 23 (92%) demonstrated a complete metabolic response. Biochemical freedom from failure was 80% at 2 years with 3 out of 4 of the biochemical failures exhibiting recurrent local disease., Conclusions: PSMA-directed salvage focal reirradiation to the prostate using linear accelerator-based SBRT is feasible and safe. Toxicity was low, with very favorable short term local and biochemical control in a carefully selected cohort of patients., (Crown Copyright © 2020. Published by Elsevier Inc. All rights reserved.)

Surgical management for chronic lateral ankle ligament instability is useful when patients have failed nonoperative modalities. Open anatomic reconstruction is an effective method of stabilization. Ankle arthroscopy is a recommended to address intra-articular disorder before stabilization. An anatomic approach provides full range of motion, stability, and return to sport and activity. Allograft or suture tape augmentation can be useful for patients with generalized ligamentous laxity, patients with high body mass index, and elite athletes. Allograft reconstruction may be especially useful in revision procedures. Arthroscopic approach to lateral ankle ligament stabilization may provide good outcomes, with long-term data still limited., Competing Interests: Disclosure Dr E. Ferkel discloses that he is a consultant and instructor for Arthrex and Ferring Pharmaceuticals. Dr S. Nguyen and C. Kwong have nothing to disclose. Southern California Orthopedic Institute Sports Medicine and Arthroscopy Fellowship receives institutional support from Depuy Mitek and Smith & Nephew., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Lower respiratory tract infections, including hospital-acquired and ventilator-associated pneumonia, are common in hospitalized patient populations. Standard methods frequently fail to identify the infectious etiology due to the polymicrobial nature of respiratory specimens and the necessity of ordering specific tests to identify viral agents. The potential severity of these infections combined with a failure to clearly identify the causative pathogen results in administration of empirical antibiotic agents based on clinical presentation and other risk factors. We examined the impact of the multiplexed, semiquantitative BioFire FilmArray Pneumonia panel (PN panel) test on laboratory reporting for 259 adult inpatients submitting bronchoalveolar lavage (BAL) specimens for laboratory analysis. The PN panel demonstrated a combined 96.2% positive percent agreement (PPA) and 98.1% negative percent agreement (NPA) for the qualitative identification of 15 bacterial targets compared to routine bacterial culture. Semiquantitative values reported by the PN panel were frequently higher than values reported by culture, resulting in semiquantitative agreement (within the same log 10 value) of 43.6% between the PN panel and culture; however, all bacterial targets reported as >10 5 CFU/ml in culture were reported as ≥10 5 genomic copies/ml by the PN panel. Viral targets were identified by the PN panel in 17.7% of specimens tested, of which 39.1% were detected in conjunction with a bacterial target. A review of patient medical records, including clinically prescribed antibiotics, revealed the potential for antibiotic adjustment in 70.7% of patients based on the PN panel result, including discontinuation or de-escalation in 48.2% of patients, resulting in an average savings of 6.2 antibiotic days/patient., (Copyright © 2020 Buchan et al.)

The ability to provide timely identification of the causative agents of lower respiratory tract infections can promote better patient outcomes and support antimicrobial stewardship efforts. Current diagnostic testing options include culture, molecular testing, and antigen detection. These methods may require collection of various specimens, involve extensive sample treatment, and can suffer from low sensitivity and long turnaround times. This study assessed the performance of the BioFire FilmArray Pneumonia Panel (PN panel) and Pneumonia Plus Panel (PNplus panel), an FDA-cleared sample-to-answer assay that enables the detection of viruses, atypical bacteria, bacteria, and antimicrobial resistance marker genes from lower respiratory tract specimens (sputum and bronchoalveolar lavage [BAL] fluid). Semiquantitative results are also provided for the bacterial targets. This paper describes selected analytical and clinical studies that were conducted to evaluate performance of the panel for regulatory clearance. Prospectively collected respiratory specimens (846 BAL and 836 sputum specimens) evaluated with the PN panel were also tested by quantitative reference culture and molecular methods for comparison. The PN panel showed a sensitivity of 100% for 15/22 etiologic targets using BAL specimens and for 10/24 using sputum specimens. All other targets had sensitivities of ≥75% or were unable to be calculated due to low prevalence in the study population. Specificity for all targets was ≥87.2%, with many false-positive results compared to culture that were confirmed by alternative molecular methods. Appropriate adoption of this test could provide actionable diagnostic information that is anticipated to impact patient care and antimicrobial stewardship decisions., (Copyright © 2020 Murphy et al.)

Background: Education and training in Allergy and Clinical Immunology (A/I) are characterized by a great variability worldwide. However, objective and worldwide data regarding this topic are lacking., Methods: To investigate personal information, education, and involvement in scientific societies of juniors engaged in A/I field, a questionnaire was developed by representatives from the JMs' boards of the European Academy of Allergy and Clinical Immunology (EAACI), the American Academy of Allergy, Asthma, and Immunology (AAAAI), and the World Allergy Organization (WAO)., Results: A total of 543 questionnaires were collected from 76 regions of all continents. The geographic distribution of responders was as follows: Africa-Middle East 3.0%, Asia-Pacific 21.4%, Europe 48.2%, Latin America 12.1%, and North America 15.3%. 59.0% of responders declared that A/I is recognized as a separate specialty in their country, Europe mostly accounting for that proportion. Primary interest in the field represents the main motivation for choosing A/I specialty. Concerning involvement in scientific societies, 41.1% of responders ever attended an EAACI Congress, 20.6% an AAAAI Congress, and 20.4% a WAO Congress. According to 40.3% of responders, scientific societies do not provide enough opportunities for young members, and 96.4% believes in a more intensive cooperation between the A/I Societies., Conclusions: The survey provides the first worldwide perspective about A/I specialty. It represents the first ever example of a structured collaboration between the junior members (JMs) of the three main A/I Societies. The findings suggest the need for harmonization, at least in terms of training and formation in the field of A/I worldwide., (© 2020 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

Band-resolved frequency modulation spectroscopy is a common method to measure weak signals of radiative ensembles. When the optical depth of the medium is large, the signal drops exponentially and the technique becomes ineffective. In this situation, we show that a signal can be recovered when a larger modulation index is applied. Noticeably, this signal can be dominated by the natural linewidth of the resonance, regardless of the presence of inhomogeneous line broadening. We implement this technique on a cesium vapor, and then explore its main spectroscopic features. This work opens the road towards measurement of cooperative emission effects in bulk atomic ensemble.

Cubital tunnel syndrome (CuTS) is one of the most common compression neuropathies of the upper extremity. Conservative management of cubital tunnel syndrome is often considered first line therapy for mild or moderate symptoms; however, there is little evidence-based literature to guide physicians in this regard. As such, the objective of this study is to complete a comprehensive literature search of the conservative therapies available for treatment of CuTS. Additionally, we hope to assess the evidence for each therapy so that we can make evidence- based recommendations regarding the type and duration of optimal treatment. The databases MEDLINE, EMBASE, and CINAHL were search using a sensitive search strategy. Eligibility for studies included any studies or conference abstracts in which patients were treated conservatively for primary CuTS. Any form of non-operative treatment was acceptable. A data extraction form was developed to collect all information and outcomes of interest, including study design, level of evidence, number of patients, treatment modalities, follow- up time, patient reported outcomes, and electrophysiological markers. Qualitative and quantitative analysis was then completed based on the data extraction form. Given the heterogeneity of the included studies, results were summarized as best evidence available. Our sensitive literature search produced 6484 studies. Initial screening based on title and abstract resulted in the selection of 40 studies that underwent full text review. From these 19 studies were included for analysis in our systematic review. There were 3 level I studies, 4 level II studies, 3 level III studies, and 9 level IV studies. In total this included 844 patients. The most commonly reported outcomes included subjective patient reported outcomes and nerve conduction studies. The most common treatment modalities, from most to least common, included education and activity modification, splinting, steroid/lidocaine injection, nerve mobilization/gliding, pulsed ultrasound, laser therapy, non-steroidal antiinflammatory drugs, and physiotherapy. The most common duration of therapy was 3 months with a median follow-up time of 3 months. There was moderate strength evidence to recommend the use of education/activity modification or splinting in mild or moderate CuTS. There is a paucity of literature and highquality studies regarding the conservative management of CuTS. Regardless, there appears to be a role for non-operative management in CuTS, although further studies are needed to delineate this role further. In the cases of mild or moderate CuTS it is reasonable to trial education/activity modification or splinting as both appear to be equally effective., Competing Interests: Conflict of interest: the authors declare no potential conflict of interest.

Purpose: To demonstrate feasibility and toxicity of linear accelerator-based stereotactic radiation therapy boost (SBRT) for prostate cancer, mimicking a high-dose-rate brachytherapy boost., Methods and Materials: A phase 1 sequential dose escalation study of SBRT compared 20 Gy, 22 Gy, and 24 Gy to the prostate and 25 Gy, 27.5 Gy, and 30 Gy to the gross tumor volume in 2 fractions, combined with 46 Gy in 23 fractions of external beam radiation. Feasibility of dose escalation (volume receiving 125% and 150% of the dose) while meeting organ-at-risk dose constraints, grade 2 acute and late gastrointestinal and genitourinary toxicity, and freedom from biochemical failure were secondary endpoints., Results: Thirty-six men with intermediate- and high-risk prostate cancer were enrolled with a median follow-up of 24 months. Sixty-four percent of patients had high-risk features. Nine men were enrolled to dose level 1, 6 to level 2, and 6 to level 3. Another 15 patients were treated at dose level 3 on the continuation study. Dose level 3 achieved superior 125% (23.75 Gy) and 150% (28.5 Gy) dose compared to dose levels 1 and 2, with minimal differences in organ-at-risk doses. Kaplan-Meier estimate of freedom from biochemical failure at 3 years was 93.3%. There were no late grade 2 or 3 gastrointestinal events. The late grade 2 genitourinary toxicity at 2 years was 19.3%. Prostate-specific membrane antigen positron emission tomography was performed at 2 years with no local recurrences., Conclusions: We have shown that a linear accelerator-based SBRT boost for prostate cancer is feasible and can achieve doses comparable to high-dose-rate boost up to the 150% isodose volumes. Rectal, bladder, and urethral doses remained low, and long-term toxicity was the same as or better than previous reports from high-dose-rate or low-dose-rate boost protocols., (© 2019 Northern Sydney Local Health District.)

Background: The HAVOC score was previously developed to predict the risk of atrial fibrillation (AF) after cryptogenic stroke (CS) or transient ischemic attack (TIA). The purpose of this study was to apply the HAVOC score to patients who received insertable cardiac monitors (ICMs) in the CRYSTAL AF study., Methods: All patients from the CRYSTAL AF study who received an ICM were included. HAVOC score (one point each for peripheral vascular disease and obesity with body mass index >30, two points each for hypertension, age ⩾ 75, valvular heart disease, and coronary artery disease, 4 points for congestive heart failure) was computed for all patients. The primary endpoint was AF detection by 12 months of ICM monitoring., Results: A total of 214 patients who received ICM were included. AF was detected in 40 patients while the remaining 174 patients were AF negative. The HAVOC score was significantly higher among patients with AF [median 3.0 with interquartile range (IQR) 2-4] than those without AF [median 2.0 (IQR 0-3)], p = 0.01. AF increased significantly across the three HAVOC score groups: 11% in Group A (score 0-1), 18% in Group B (score 2-3), and 32 % in Group C (score ⩾ 4) with p = 0.02., Conclusions: The HAVOC score was shown in this post hoc analysis of CRYSTAL AF to successfully stratify AF risk post CS or TIA. The 11% AF rate in the lowest HAVOC score group highlights the significance of nontraditional contributors to AF and ischemic stroke., Competing Interests: Conflict of interest statement: PDZ and JLK are employees and shareholders of Medtronic, Inc. RSP reports speaker fees from Medtronic and Biotronik. SXZ, CK, and MHC report no relationships relevant to the contents of this paper to disclose.

Aim: To explore the utility of prostate specific membrane antigen (PSMA)-positron emission tomography (PET)/computed tomography (CT) in addition to conventional imaging prior to definitive external beam radiation treatment (EBRT) for prostate cancer., Methods: All men undergoing PSMA-PET/CT prior to definitive EBRT for intermediate and high-risk prostate cancer were included in our ethics approved prospective database. For each patient, clinical and pathological results, in addition to scan results including site of PSMA positive disease and number of lesions, were recorded. Results of conventional imaging (bone scan, CT and multiparametric magnetic resonance imaging [MRI]) were reviewed and included., Results: One hundred nine men underwent staging PSMA-PET/CT between May 2015 and June 2017; all patients had national comprehensive cancer network (NCCN) intermediate or high-risk prostate cancer and 87% had Gleason score (GS) 4 + 3 or higher. There was positive uptake corresponding to the primary in 108, equivocal in one. All patients with image detected nodal or bony lesions had GS 4 + 3 or more disease. Compared to conventional imaging with bone scan, CT and multiparametric MRI, PSMA-PET/CT upstaged an additional 7 patients (6.4%) from M0 to M1, 16 from N0M0 to N1M0 (14.7%) and downstaged 3 (2.8%) from M1 to M0 disease., Conclusion: PSMA-PET/CT identified the primary in 99% of patients, and altered staging in 21% of men with intermediate or high-risk prostate cancer referred for definitive EBRT compared to CT, bone scan and multiparametric MRI. Following this audit, we recommend the routine use of PSMA-PET/CT prior to EBRT in this patient group., (© 2018 John Wiley & Sons Australia, Ltd.)

Members of the bromodomain and extra-terminal domain (BET) family of proteins (bromodomain-containing (BRD) 2, 3, 4, and T) are widely expressed and highly conserved regulators of gene expression in eukaryotes. These proteins have been intimately linked to human disease, and more than a dozen clinical trials are currently underway to test BET-protein inhibitors as modulators of cancer. However, although it is clear that these proteins use their bromodomains to bind both histones and transcription factors bearing acetylated lysine residues, the molecular mechanisms by which BET family proteins regulate gene expression are not well defined. In particular, the functions of the other domains such as the ET domain have been less extensively studied. Here, we examine the properties of the ET domain of BRD3 as a protein/protein interaction module. Using a combination of pulldown and biophysical assays, we demonstrate that BRD3 binds to a range of chromatin-remodeling complexes, including the NuRD, BAF, and INO80 complexes, via a short linear "KIKL" motif in one of the complex subunits. NMR-based structural analysis revealed that, surprisingly, this mode of interaction is shared by the AF9 and ENL transcriptional coregulators that contain an acetyl-lysine-binding YEATS domain and regulate transcriptional elongation. This observation establishes a functional commonality between these two families of cancer-related transcriptional regulators. In summary, our data provide insight into the mechanisms by which BET family proteins might link chromatin acetylation to transcriptional outcomes and uncover an unexpected functional similarity between BET and YEATS family proteins., (© 2018 by The American Society for Biochemistry and Molecular Biology, Inc.)

Objectives: This study sought to characterize patients with methamphetamine-associated pulmonary arterial hypertension (MA-PAH) and cardiomyopathy (MA-CMP), to compare with MA controls (MA-CTL), users with structurally normal hearts, with the aim of identifying risk factors for these conditions., Background: MA-PAH and MA-CMP are 2 poorly understood cardiac complications in MA users., Methods: We retrospectively studied the clinical characteristics and outcomes of 50 MA-PAH, 296 MA-CMP, and 356 MA-CTL patients, whom we evaluated between 2010 and 2017., Results: After a median follow-up of 20.0 months (interquartile range [IQR]: 7.6 to 42.6 months), all-cause mortality was 18.0% for MA-PAH, 15.2% for MA-CMP, and 4.5% for MA-CTL group (p < 0.001). More women (58%) were in the MA-PAH group than in the MA-CMP (14%; p < 0.001) and MA-CTL (42%; p = 0.028) groups, whereas the MA-CMP group was predominantly male (86% vs. 58% in the MA-CTL group; p < 0.001). More MA-CMP patients had hypertension (p < 0.001) or alcoholism (p < 0.001) than MA-CTL patients. Logistic regression analyses identified male sex, alcoholism, and hypertension as independent factors associated with MA-CMP with the following respective adjusted odds ratios (OR) of 3.791 (95% confidence interval [CI]: 2.508 to 5.730), OR of 2.959 (95% CI: 2.084 to 4.203), and OR of 2.111 (95% CI: 1.486 to 2.999), whereas female sex was the only factor associated with MA-PAH., Conclusions: Both MA-PAH and MA-CMP patients carried significant disease burden and mortality risk. Male sex, hypertension, and alcoholism were strongly associated with MA-CMP, whereas female sex and other unknown factors may influence development of MA-PAH. This study adds to the understanding of MA-associated cardiac complications and highlights directions for future investigation., (Published by Elsevier Inc.)

ST-segment elevation is well known for its diagnostic value for transmural myocardial infarction due to acute thrombotic occlusion of a coronary artery, and often requires emergency reperfusion therapy. However, ST segment is by no means pathognomonic for acute coronary events. Here, we report a case of ST-segment elevation after hepatectomy secondary to an unusual etiology.

Purpose: To identify sites of failure with 68 Ga-PSMA-PET (PSMA-PET) imaging in patients who have Biochemical Failure (BF) following post-prostatectomy radiotherapy., Material and Methods: Between June 2006 and January 2016, 409 men received post prostatectomy intensity modulated radiation treatment (IMRT) with protocolised planning. 310 patients received radiation treatment (RT) to the Prostate Fossa (PF) alone and 99 patients received RT to PF and pelvic lymphatics (PF + LN) usually in combination with androgen deprivation (AD) therapy. Any failure not detected on conventional imaging was delineated with PSMA-PET scanning. Sites of failure were characterised as in-field (PF ± LN), or out of field (nodal alone, distant metastatic alone (visceral or bone) or multi-site failure). Nodal failure was further divided into pelvic failure and/or distant failure., Results: 119 men developed BF, defined as a PSA rise of >0.2 or greater, above post-RT nadir. Freedom from BF was 71% in the PF group and 70% in the PF + LN group, with median follow up of 52 and 44 months respectively. AD was used concomitantly in 13% of the PF group and 92% of the PF + LN group. 81 patients with BF (68%) had PSMA-PET imaging performed as per study intent, 67 (80%) of whom had PSMA avid disease identified. PSMA-PET delineated in-field failure occurred in 2/50 (4%) of the PF group and 1/17 (6%) in the PF + LN group. Nodal failure alone was 33/50 (66%) for the PF group vs 7/17 (41%) for the PF + LN group. For the nodal only failure patients, 18/33 (55%) had pelvic-only nodal failure in the PF group compared to 1/7 (14%) in the PF + LN group (p = 0.03). 16 (32%) of the PSMA avid failures in the PF group would have been encompassed by standard pelvic lymphatic radiotherapy volumes., Conclusion: Post-prostatectomy radiation treatment resulted in excellent in-field control rates. Isolated pelvic nodal failure was rare in those receiving radiotherapy to the prostatic fossa and pelvic nodes but accounted for one third of failures in those receiving PF alone treatment., (Copyright © 2017 Elsevier B.V. All rights reserved.)

The nucleosome remodelling and deacetylase (NuRD) complex is essential for the development of complex animals. NuRD has roles in regulating gene expression and repairing damaged DNA. The complex comprises at least six proteins with two or more paralogues of each protein routinely identified when the complex is purified from cell extracts. To understand the structure and function of NuRD, a map of direct subunit interactions is needed. Dozens of published studies have attempted to define direct inter-subunit connectivities. We propose that conclusions reported in many such studies are in fact ambiguous for one of several reasons. First, the expression of many NuRD subunits in bacteria is unlikely to lead to folded, active protein. Second, interaction studies carried out in cells that contain endogenous NuRD complex can lead to false positives through bridging of target proteins by endogenous components. Combining existing information on NuRD structure with a protocol designed to minimize false positives, we report a conservative and robust interaction map for the NuRD complex. We also suggest a 3D model of the complex that brings together the existing data on the complex. The issues and strategies discussed herein are also applicable to the analysis of a wide range of multi-subunit complexes., Enzymes: Micrococcal nuclease (MNase), EC 3.1.31.1; histone deacetylase (HDAC), EC 3.5.1.98., (© 2017 Federation of European Biochemical Societies.)

Howell-Jolly body-like inclusions in neutrophils have been reported in a handful of reports; however, their nuclear origin has never been confirmed to date. We report the presence of these cytoplasmic inclusions in two cases and confirm their DNA-based origin by fluorescent nuclear staining. Peripheral blood smears were manually reviewed by light microscopy and after 4',6-diamidino-2-phenylindole (DAPI) fluorescent staining via confocal microscopy. Methanol fixed peripheral blood smears were incubated with DAPI (Sigma Aldrich, St. Loius, MO, USA) and coverslipped with mounting media. DAPI-stained cells were imaged with a Leica SPE confocal microscope using a 405 nm excitation laser and a 63×/1.3 NA oil immersion objective. Optical sections spanning the entire cell thickness were acquired and maximum intensity projections were produced in ImageJ. Both cases described herein had Howell-Jolly body-like inclusions similar to those reported in the literature. Testing for relevant infectious etiologies was negative. Positive staining on fluorescence microscopy confirmed DNA-based origin of this cytoplasmic inclusion material. These DNA-based inclusions occur in the immunosuppressed patient and mimic infectious inclusions. While morphologically worrisome, recognition of these inclusions may prevent unnecessary treatment and testing in clinically appropriate patients., (Copyright 2017, Omman et al.)

Aim: In prostate cancer, fiducial marker image-guided radiotherapy (FMIGRT) allows correction of setup errors and interfraction physiological motion resulting in improved accuracy of target and sparing of at risk organs. We aim to report outcomes and toxicities observed in patients treated with dose escalation to 78Gy with FMIGRT in our center., Methods and Materials: Retrospective review of consecutive patients with histologically confirmed T1-4N0M0 localized prostate cancer treated with dose escalation to 78Gy with FMIGRT in our center. All patients had 3-D conformal radiotherapy. Duration of androgen deprivation therapy use was tailored to risk group. Toxicity was scored according to CTCAE.v04. Kaplan-Meier analysis was performed for freedom from biochemical failure (FFBF), prostate cancer-specific survival and overall survival., Results: Median follow-up was 48.6 months. Median duration of androgen deprivation therapy was 6 and 23 months in the intermediate- and high-risk group, respectively. FFBF at 5 years was 88.8%. FFBFs when stratified to risk groups were 100% for low risk, 88.9% for low-intermediate risk, 89.9% for high-intermediate risk and 85.4% for high risk, respectively. Acute severe toxicity (grade≥3) rate for both genitourinary (GU) and gastrointestinal (GI) was 1%. Late moderate-to-severe toxicity (grade≥2) rates for GU and GI were 15% and 17%, respectively, with severe (grade≥3) toxicity rate for GU and GI at 2% and 3%, respectively., Conclusion: Dose escalation to 78Gy with FMIGRT in our series achieved good FFBF at 5 years with low acute and late toxicity rates. These results provide a good comparator cohort to our current use of image-guided intensity modulated radiotherapy., (© 2016 John Wiley & Sons Australia, Ltd.)

Background and Purpose: We investigated the role of 68 Ga-PSMA-PET (PSMA) to determine the location of disease recurrence in those with a rising PSA following definitive external beam radiation treatment (EBRT)., Materials and Methods: 538men were treated with image guided EBRT to a dose of 78 or 82Gy between 2007 and 2014. Patients at least 24months post EBRT with biochemical failure (nadir+2) underwent PSMA scanning. Local recurrence (LR) was defined as increased uptake within the prostate or seminal vesicles. Distant disease included lymph node (LN), bone or visceral metastases., Results: 419men formed the study cohort. Median follow-up was 50months, 70 patients (17%) had biochemical failure (BF), 13 of whom have died. Of the 57 survivors, 5 had metastases detected on conventional scans; 2 were lost to follow up. 48men (of 50 candidates) underwent PSMA; in all cases, the PSMA was unequivocally positive. Of the 48 positive scans, 25 patients (52%) failed beyond the prostate - 5 in bones, 16LN, 3 in both, and 1 in the lungs. Fifteen men (31%) failed within the gland and in either LN (11), bones (3), or both (1). Eight (17%) had an isolated LR, which represents 2% of patients managed with definitive EBRT and followed for at least 2years., Conclusions: PSMA was positive in all patients with BF. Site of failure following dose-escalated EBRT was generally distant. Isolated LR (on PSMA) occurred in only 8 of 419 patients post-EBRT., (Crown Copyright © 2016. Published by Elsevier B.V. All rights reserved.)

Objectives: Detection of atrial fibrillation (AF) in post-cryptogenic stroke (CS) or transient ischemic attack (TIA) patients carries important therapeutic implications., Methods: To risk stratify CS/TIA patients for later development of AF, we conducted a retrospective cohort study using data from 1995 to 2015 in the Stanford Translational Research Integrated Database Environment (STRIDE)., Results: Of the 9,589 adult patients (age ≥40 years) with CS/TIA included, 482 (5%) patients developed AF post CS/TIA. Of those patients, 28.4, 26.3, and 45.3% were diagnosed with AF 1-12 months, 1-3 years, and >3 years after the index CS/TIA, respectively. Age (≥75 years), obesity, congestive heart failure, hypertension, coronary artery disease, peripheral vascular disease, and valve disease are significant risk factors, with the following respective odds ratios (95% CI): 1.73 (1.39-2.16), 1.53 (1.05-2.18), 3.34 (2.61-4.28), 2.01 (1.53-2.68), 1.72 (1.35-2.19), 1.37 (1.02-1.84), and 2.05 (1.55-2.69). A risk-scoring system, i.e., the HAVOC score, was constructed using these 7 clinical variables that successfully stratify patients into 3 risk groups, with good model discrimination (area under the curve = 0.77)., Conclusions: Findings from this study support the strategy of looking longer and harder for AF in post-CS/TIA patients. The HAVOC score identifies different levels of AF risk and may be used to select patients for extended rhythm monitoring., (© 2017 S. Karger AG, Basel.)

Purpose: To assess the relationship between quantitative measures of disc height and signal intensity with the Pfirrmann disc degeneration scoring system and to test the inter-rater reliability of the quantitative measures., Methods: Participants were 76 people who had recently recovered from their last episode of acute low back pain and underwent MRI scan on a single 3T machine. At all 380 lumbar discs, quantitative measures of disc height and signal intensity were made by 2 independent raters and compared to Pfirrmann scores from a single radiologist. For quantitative measures of disc height and signal intensity a "raw" score and 2 adjusted ratios were calculated and the relationship with Pfirrmann scores was assessed. The inter-tester reliability of quantitative measures was also investigated., Results: There was a strong linear relationship between quantitative disc signal intensity and Pfirrmann scores for grades 1-4, but not for grades 4 and 5. For disc height only, Pfirrmann grade 5 had significantly reduced disc height compared to all other grades. Results were similar regardless of whether raw or adjusted scores were used. Inter-rater reliability for the quantitative measures was excellent (ICC > 0.97)., Conclusions: Quantitative measures of disc signal intensity were strongly related to Pfirrmann scores from grade 1 to 4; however disc height only differentiated between grade 4 and 5 Pfirrmann scores. Using adjusted ratios for quantitative measures of disc height or signal intensity did not significantly alter the relationship with Pfirrmann scores.

Communication support tools (CST) improve patient outcomes in oncology including: knowledge, satisfaction, self-management, and adherence to planned treatment. Little is known about communication support tools use in patients with primary or secondary brain tumours. We aimed to explore cognitive function and communication support tool use in this population. This prospective survey involved patients, caregivers and health professionals. Questionnaires were completed after initial brain radiotherapy consultation and 1-2 weeks later. Patients completed the Montreal Cognitive Assessment (MoCA). Descriptive statistics are reported. Fifty-three patients participated, median age 62 years, ECOG status 0-2 (90 %), with 75 % having secondary brain metastasis. 21/53 (40 %) patients reported needing help reading medical information. Only 28 % patients had normal cognition (MoCA score ≥ 26/30). Initially, 82 % of patients and 87 % of caregivers reported the consultation was 'extremely/quite clear, and 69 % of their health professionals thought consultation 'extremely/quite clear' to patient. At follow-up, fewer patients (75 %) reported health professionals' explanation as 'extremely/quite clear'. Although patients recalled discussed illness and treatment details, 82 % recalled treatment-related side effects and management thereof by 46 %. CST use was reported by 22 % patients, 19 % caregivers, and 27 %health professionals. When used, tools improved understanding according to 92 % patients, 100 % caregivers, and 91 % health professionals. The majority of patients have some level of cognitive impairment. Information discussed appears clear to most patients, but this is not sustained, and recall of treatment toxicity management is poor. Few CSTs are used in consultations, but when used, are reported as helpful by all.

An optically thick cold atomic cloud emits a coherent flash of light in the forward direction when the phase of an incident probe field is abruptly changed. Because of cooperativity, the duration of this phenomena can be much shorter than the excited lifetime of a single atom. Repeating periodically the abrupt phase jump, we generate a train of pulses with short repetition time, high intensity contrast, and high efficiency. In this regime, the emission is fully governed by cooperativity even if the cloud is dilute.

Human identification using fingerprint impressions has been widely studied and employed for more than 2000 years. Despite new advancements in the 3D imaging technologies, widely accepted representation of 3D fingerprint features and matching methodology is yet to emerge. This paper investigates 3D representation of widely employed 2D minutiae features by recovering and incorporating (i) minutiae height z and (ii) its 3D orientation φ information and illustrates an effective matching strategy for matching popular minutiae features extended in 3D space. One of the obstacles of the emerging 3D fingerprint identification systems to replace the conventional 2D fingerprint system lies in their bulk and high cost, which is mainly contributed from the usage of structured lighting system or multiple cameras. This paper attempts to addresses such key limitations of the current 3D fingerprint technologies bydeveloping the single camera-based 3D fingerprint identification system. We develop a generalized 3D minutiae matching model and recover extended 3D fingerprint features from the reconstructed 3D fingerprints. 2D fingerprint images acquired for the 3D fingerprint reconstruction can themselves be employed for the performance improvement and have been illustrated in the work detailed in this paper. This paper also attempts to answer one of the most fundamental questions on the availability of inherent discriminable information from 3D fingerprints. The experimental results are presented on a database of 240 clients 3D fingerprints, which is made publicly available to further research efforts in this area, and illustrate the discriminant power of 3D minutiae representation and matching to achieve performance improvement.

We investigate the transient coherent transmission of light through an optically thick cold strontium gas. We observe a coherent superflash just after an abrupt probe extinction, with peak intensity more than three times the incident one. We show that this coherent superflash is a direct signature of the cooperative forward emission of the atoms. By engineering fast transient phenomena on the incident field, we give a clear and simple picture of the physical mechanisms at play.

Affective design is an important aspect of product development to achieve a competitive edge in the marketplace. A neural-fuzzy network approach has been attempted recently to model customer satisfaction for affective design and it has been proved to be an effective one to deal with the fuzziness and non-linearity of the modeling as well as generate explicit customer satisfaction models. However, such an approach to modeling customer satisfaction has two limitations. First, it is not suitable for the modeling problems which involve a large number of inputs. Second, it cannot adapt to new data sets, given that its structure is fixed once it has been developed. In this paper, a modified dynamic evolving neural-fuzzy approach is proposed to address the above mentioned limitations. A case study on the affective design of mobile phones was conducted to illustrate the effectiveness of the proposed methodology. Validation tests were conducted and the test results indicated that: (1) the conventional Adaptive Neuro-Fuzzy Inference System (ANFIS) failed to run due to a large number of inputs; (2) the proposed dynamic neural-fuzzy model outperforms the subtractive clustering-based ANFIS model and fuzzy c-means clustering-based ANFIS model in terms of their modeling accuracy and computational effort.

Cu, Ni and Fe oxides supported on ceria were investigated for their performance as oxygen carriers during the chemical looping combustion of biomass-derived syngas. A complex gas mixture containing CO, H2, CO2, CH4 and other hydrocarbons was used to simulate the complex fuel gas environment derived from biomass gasification. Results show that the transfer of the stored oxygen into oxidants for the supported Cu and Ni oxides at 800°C for the combustion of syngas was effective (>85%). The unsupported Cu oxide showed high oxygen carrying capacity but particle sintering was observed at 800°C. A reaction temperature of 950°C was required for the supported Fe oxides to transfer the stored oxygen into oxidants effectively. Also, for the complex fuel gas environment, the supported Ni oxide was somewhat effective in reforming CH4 and other light hydrocarbons into CO, which may have benefits for the reduction of tar produced during biomass pyrolysis., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Objective: Carotid endarterectomy (CEA) reduces the risk of cerebrovascular events due to the presence of atherosclerotic plaque in the internal carotid artery. Arterial stiffness is an indicator of cardiovascular risk and strongly associates with the development of atherosclerosis. This study aims to assess the short-term effect of CEA on arterial stiffness and haemodynamics., Design: Prospective observational study., Methods: Measurements of arterial stiffness and haemodynamics, including carotid-femoral pulse wave velocity (cfPWV), carotid-radial PWV (crPWV), augmentation pressure, augmentation index, subendocardial viability ratio, central pressures and pulse pressure amplification, were performed pre- and 6 weeks post-CEA on both surgical and non-surgical sides., Results: Fifty-nine patients completed the study (n = 46 men, age 68.9 ± 10.1 years). crPWV was decreased after CEA on the surgical (P = 0.01) and non-surgical side (P = 0.0008), AIx75 tended to decrease only on the surgical side (P = 0.06). cfPWV did not change significantly on either side., Conclusion: We assessed, for the first time, the short-term effect of CEA on arterial stiffness and haemodynamics. CEA improved peripheral but not central arterial stiffness. This study provides evidence for significant changes in certain arterial stiffness and haemodynamic parameters. Longer-term follow-up will assess whether these changes are sustained and whether CEA is associated with further haemodynamic benefits., (Copyright © 2013 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved.)

The vacuolar ATPase (V-ATPase) plays an important role in tumor progression and metastases. A novel peptide from the a2 isoform of V-ATPase called a2NTD has been shown to exert an immunoregulatory role in the tumor microenvironment by controlling the maturation of monocytes toward a tumor-associated macrophage phenotype. Our data indicate that a2NTD binds to the surface of monocytes. a2NTD was preferentially endocytosed by pro-inflammatory monocytes bearing a CD14 ++ CD16 + phenotype, which is associated with the monocyte-to-macrophage maturation process. Both a2NTD binding and internalization led to production of the pro-inflammatory cytokines interleukin (IL)-1α and IL-1β by CD14 ++ CD16 - (classical) and CD14 ++ CD16 + (intermediate) monocytes. a2NTD was internalized via a macropinocytosis mechanism utilizing scavenger receptors. However, the inhibition of a2NTD endocytosis did not reduce cytokine production by monocytes. This points to the existence of two receptors that respond to a2NTD: scavengers receptors that mediate cellular uptake and an hitherto unidentified receptor stimulating the production of inflammatory cytokines. Both of these monocyte receptors may be important in generating the localized inflammation that is often required to promote tumor growth and hence may constitute novel targets for the development of anticancer drugs.

At puberty, neurokinin B (NKB) and kisspeptin (Kiss1) may help to amplify GnRH secretion, but their precise roles remain ambiguous. We tested the hypothesis that NKB and Kiss1 are induced as a function of pubertal development, independently of the prevailing sex steroid milieu. We found that levels of Kiss1 mRNA in the arcuate nucleus (ARC) are increased prior to the age of puberty in GnRH/sex steroid-deficient hpg mice, yet levels of Kiss1 mRNA in wild-type mice remained constant, suggesting that sex steroids exert a negative feedback effect on Kiss1 expression early in development and across puberty. In contrast, levels of Tac2 mRNA, encoding NKB, and its receptor (NK3R; encoded by Tacr3) increased as a function of puberty in both wild-type and hpg mice, suggesting that during development Tac2 is less sensitive to sex steroid-dependent negative feedback than Kiss1. To compare the relative responsiveness of Tac2 and Kiss1 to the negative feedback effects of gonadal steroids, we examined the effect of estradiol (E(2)) on Tac2 and Kiss1 mRNA and found that Kiss1 gene expression was more sensitive than Tac2 to E(2)-induced inhibition at both juvenile and adult ages. This differential estrogen sensitivity was tested in vivo by the administration of E(2). Low levels of E(2) significantly suppressed Kiss1 expression in the ARC, whereas Tac2 suppression required higher E(2) levels, supporting differential sensitivity to E(2). Finally, to determine whether inhibition of NKB/NK3R signaling would block the onset of puberty, we administered an NK3R antagonist to prepubertal (before postnatal d 30) females and found no effect on markers of pubertal onset in either WT or hpg mice. These results indicate that the expression of Tac2 and Tacr3 in the ARC are markers of pubertal activation but that increased NKB/NK3R signaling alone is insufficient to trigger the onset of puberty in the mouse.

Problem: a2 isoform of vacuolar ATPase (Atp6v0a2) is important for maintaining the delicate immunological balance required for successful pregnancy. The objective of this investigation is to study the dynamic changes in spleen and blood that appear during spontaneous abortion in mice., Method of Study: Atp6v0a2 was measured in multiple immune cell populations from spleen and blood recovered from non-abortion-prone and abortion-prone mating combinations., Results: Atp6v0a2 expression was significantly lower (P ≤ 0.01) in the spleen recovered from abortion-prone ♀CBA × ♂DBA mating on days 12 and 16 of pregnancy when compared to non-abortion-prone ♀BALB/c × ♂BALB/c and ♀CBA × ♂BALB/c matings. Flow cytometric studies showed that significantly decreased expression of Atp6v0a2 in splenic CD4(+), CD8(+), CD19(+), and CD14(+) cells directly correlated with the high percentages of fetal resorption observed in abortion-prone mating on days 12 and 16 of pregnancy. In blood, CD4(+), CD8(+), and CD19(+) cells had a significantly reduced expression of Atp6v0a2 in abortion-prone mating compared to the non-abortion-prone mating combinations only on day 12., Conclusion: This deceased expression of Atp6v0a2 in the various immune cell populations of the spleen and blood suggests that the maternal environment is not supportive to fetus and leads to poor pregnancy outcome in the abortion-prone mating model., (© 2012 John Wiley & Sons A/S.)

Crystalline Co3O4 nanowire arrays freely supported on Ni foam are successfully synthesized using a template-free method. The effects of reaction time, concentration of reactants, and temperature on the morphology of the nanowires are studied. The results indicate that uniform Co3O4 nanowires could be synthesized at 90 degrees C, and a transformation of the samples' morphology from nanoparticles to nanowires to microrods is observed by controlling the concentration of the reactants. The well-ordered nanowires synthesized under the selected reaction conditions are composed of spinel Co3O4 with diameters of 500-580 nm and lengths of 6-8 microm. These nanowires show good catalytic activity for the ozone catalytic oxidation of toluene.

Cancer-related inflammation profoundly affects tumor progression. Tumor-associated macrophages (TAMs) are known regulators of that inflammation, but the factors that initiate cancer-related inflammation are poorly understood. Tumor invasiveness and poor clinical outcome are linked to increased expression of cell surface-associated vacuolar adenosine triphosphatases. The a2 isoform vacuolar adenosine triphosphatase is found on the surface on many solid tumors, and we have identified a peptide cleaved from a2 isoform vacuolar adenosine triphosphatase called a2NTD. a2NTD has properties necessary to induce monocytes into a pro-oncogenic TAM phenotype. The peptide upregulated both pro- and anti-inflammatory mediators. These included IL-1β and IL-10, which are important in promoting inflammation and immune escape by tumor cells. The secretion of inflammatory cytokine IL-1β was dependent on ATP, K(+) efflux, and reactive oxygen species, all mediators that activate the inflammasome. These findings describe a mechanism by which tumor cells affect the maturation of TAMs via a nontraditional cytokine-like signal, the a2NTD peptide.

In mammalian reproduction, two immunologically disparate entities, the mother and her fetus, co-exist in close proximity and mutually tolerate each other. The maternal immune system plays a major contributing role in the reproductive outcome. A coordinated set of immunological events takes place between the maternal and fetal cells to ensure fetal survival. Among these, cytokines secreted by proximal maternal immune cells as well as fetal trophoblast cells play a major role in feto-maternal tolerance. In this review, we describe the role of the vacuolar ATPase (and more specifically the a2 isoform, a2V-ATPase) in controlling the expression of these vital cytokines. a2V-ATPase is a key enzyme that controls the acidification of intracellular vesicles and the extracellular environment, processes that play a major role in cellular function. The localization of a2V-ATPase in tissues and immune cells of the reproductive tract which are essential for pregnancy will be described. Information will be provided on the role of a2V-ATPase on aspects of cell development in pregnancy, from fertilization to implantation and fetal growth. Particular emphasis will be placed on the role of a2V-ATPase in (a) regulating parts of the cytokine network at the implantation site and (b) attenuating the potentially harmful maternal immune response against trophoblast cells., (Copyright (c) 2009 Elsevier Ireland Ltd. All rights reserved.)