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Objective: Pulmonary involvement is commonly observed in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), presenting with manifestations such as diffuse alveolar hemorrhage, inflammatory infiltrates, pulmonary nodules, and tracheobronchial disease. We aimed to identify distinct subgroups of tracheobronchial disease patterns in patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) using latent class analysis (LCA), and to evaluate their clinical characteristics and outcomes. Methods: We conducted a retrospective cohort study using electronic medical records of patients aged >18 years diagnosed with AAV and tracheobronchial disease between 1 January 2002 and 6 September 2022. Patients with follow-up Results: Among 136 identified AAV patients assessed for tracheobronchial involvement, 111 (81.6%) were included after excluding 25 without tracheal or bronchial disease. Predominant findings included subglottic stenosis (91.0%), lower tracheal stenosis (16.2%), and bronchial stenosis (17.1%). LCA identified a three-class model as optimal: tracheal predominant (n = 94), tracheobronchial (n = 12), and bronchial predominant (n = 5). Tracheal predominant patients showed reduced risk of ear, eye, and lower respiratory manifestations, with milder obstruction on pulmonary function testing (PFT). Tracheobronchial-class patients were prone to saddle nose deformity (50%), extensive lower respiratory involvement (91.7%), and renal disease (66.7%). Bronchial predominant patients exhibited severe obstructive disease (median forced expiratory volume in 1 s (FEV1)% predicted: 58, IQR 34–66; FEV1/forced vital capacity (FVC) ratio: 56.9, interquartile range (IQR) 43–63.3) but lacked systemic AAV manifestations. LCA classes did not predict outcomes such as endoscopic intervention, tracheostomy, recurrent tracheobronchial narrowing, or mortality. Conclusion: LCA shows promise in subtype stratification of AAV patients, yet its utility in predicting outcomes and guiding treatment remains limited based on our analysis. Future studies with enhanced phenotypic data and larger cohorts are warranted to improve predictive accuracy.

Abstract Objective Antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (AAV) is a group of illnesses that cause inflammation and alterations to small vessels in the body. Some of the most common and detrimental manifestations, including alveolar hemorrhage and glomerulonephritis, are caused by this capillary inflammation. We sought to clarify whether patients with AAV would have abnormal nailfold capillaries when evaluated with nailfold videocapillaroscopy. Methods Patients with a current diagnosis of AAV and a control group were identified for enrollment. Nailfold videocapillaroscopy images were used for a semiquantitative analysis on capillary density, morphology, dilation, and microhemorrhage after review by 2 rheumatologists. Disease characteristics, occurrence of recent disease flare, and presence of ANCA were recorded. Results Thirty-three patients with a diagnosis of AAV and 21 controls were recruited. The AAV group had a median age of 59 and 17 (52%) were women. Granulomatosis with polyangiitis was the most common diagnosis (19 [58%]), followed by eosinophilic granulomatosis with polyangiitis (7 [21%]) and microscopic polyangiitis (7 [21%]). Twenty-seven patients (82%) had positive ANCA tests. After assessment of capillary density, dilation, morphology, microhemorrhages, and disorganization, there were no statistically significant differences between the 2 groups. Conclusion There was no evidence of differences in nailfold capillaroscopy abnormalities between those diagnosed with AAV and the control group. While this cohort was relatively small, we did not find a high enough prevalence or specific phenotype of capillary abnormalities that could aid in diagnosis or prognostication of these diseases in the clinical setting.

Abstract Background Persistent monoarthritis in otherwise well-controlled rheumatoid arthritis presents a therapeutic challenge. Intra-articular (IA) steroids are a mainstay of treatment, though some have queried whether IA disease modifying anti-rheumatic drugs (DMARD) and biologics can be used in those who fail steroid injections. Methods A systematic literature review was conducted using four medical databases to identify randomized, controlled trials assessing IA therapies in RA patients. Included studies underwent Cochrane Risk of Bias 2 assessment for quality. Results Twelve studies were included, 6 of which examined intra-articular (IA) TNF inhibitors (TNFi), and 6 studies evaluating IA methotrexate. Of those evaluating IA TNFi, one study reported statistical improvement in TNFi therapy when compared with placebo. The remaining 5 studies compared IA TNFi therapy with steroid injections. IA TNFi had statistically improved symptom scores and clinical assessments comparable with IA steroid treatments. In the 6 studies evaluating IA methotrexate, the addition of methotrexate to steroid intra-articular therapy was not found to be beneficial, and singular methotrexate injection was not superior to the control arms (saline or triamcinolone). Risk-of-bias (ROB) assessment with the Revised Cochrane ROB tool indicated that 2 of 6 TNFi studies were at some risk or high risk for bias, compared with 5 out of 6 methotrexate studies. Conclusion For persistent monoarthritis in rheumatoid arthritis, IA methotrexate was not found to have clinical utility. Intra-articular TNFi therapy appears to have equal efficacy to IA steroids, though the optimal dose and frequency of injections is yet unknown.

Artificial intelligence models have been increasingly used in the analysis of tumor histology to perform tasks ranging from routine classification to identification of molecular features. These approaches distill cancer histologic images into high-level features, which are used in predictions, but understanding the biologic meaning of such features remains challenging. We present and validate a custom generative adversarial network-HistoXGAN-capable of reconstructing representative histology using feature vectors produced by common feature extractors. We evaluate HistoXGAN across 29 cancer subtypes and demonstrate that reconstructed images retain information regarding tumor grade, histologic subtype, and gene expression patterns. We leverage HistoXGAN to illustrate the underlying histologic features for deep learning models for actionable mutations, identify model reliance on histologic batch effect in predictions, and demonstrate accurate reconstruction of tumor histology from radiographic imaging for a "virtual biopsy."

Objectives: To define the prevalence, distribution, and characteristics of patients with VEXAS who have confirmed vasculitis., Methods: Patients with VEXAS syndrome, verified by positive UBA1 mutation, were included. Chart review was performed to identify., Patient: characteristics and outcomes. Vasculitis diagnosis was based on either histopathology showing vascular inflammation or non-invasive angiography findings. Summary statistics were calculated., Results: Eighty-nine patients met inclusion criteria. All were male with a median age of onset of 66.9 years (IQR 60.1, 72.7). Median (IQR) follow up was 3.8(2.2-5.5) years during which 21 patients (23.6%) had evidence of vasculitis. Vasculitis subtypes included small vessel vasculitis (19.1%), cutaneous medium vessel vasculitis (2.2%), and large vessel vasculitis (2.2%). No patient had more than one vessel size involved. Histopathology in small vessel vasculitis patients was consistent with cutaneous leukocytoclastic vasculitis in the majority, though one patient had leukocytoclastic peritubular capillaritis on renal biopsy. Cranial symptoms (headache, vision changes, or jaw pain) were noted in 18.0%. Two additional patients not experiencing cranial symptoms exhibited large vessel involvement with confirmed carotid thickening on non-invasive angiography; one of these had a positive temporal artery biopsy., Conclusion: VEXAS syndrome manifests as a variable vessel vasculitis in a quarter of patients, with cutaneous small and medium vessel involvement being particularly common. Some patients may have positive ANCA serologies or even renal vasculitis leading to misdiagnosis. Cranial symptoms are common and may mimic giant cell arteritis, though documented large vessel inflammation is rare., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Cattle in regions with high ambient temperatures are at risk of heat stress. Early detection is important to allow action to be taken to minimise the risks to cattle exposed to thermal stress. This study aimed to investigate the impact of heat stress on IRT-Eye temperature and its association with the behavioural and physiological responses of heat-stressed Angus steers (n = 24) on finisher and or substituted diets. Overall, 2 cohorts of 12 Angus steers were individually housed in a climate-controlled facility to examine responses to heat stress when fed on a standard finisher diet, based on a high percentage of cereal grains, and on a substituted diet in which 8% of the grains were replaced by an isoenergetic amount of lucerne hay. Exposing feedlot cattle to hot environmental conditions increased IRT-Eye temperature, which had a strong association with behaviour and physiology. There was no evidence of differences between the different dietary cohorts. The cattle with increased IRT-Eye temperature showed stress-related responses, including a downward-facing head, ears directed backwards, and other indicators of heat stress such as increased panting, standing, and increased rumen temperature. The strong association of IRT-Eye temperature with stress-related behaviours, as well as with rumen temperature and panting behaviour, highlights the potential for IRT-Eye to be utilised as a non-invasive tool to assess cattle responses in hot conditions.

Cattle are increasingly exposed to hot temperatures as a result of climate change, and a better understanding of behavioural responses could be beneficial for the diagnosis of heat loads. The changes in the positioning of key body parts, feeding behaviour, body maintenance, and respiratory dynamics were assessed in 24 Black Angus steers individually exposed to hot conditions and fed a finisher diet based on cereal grain or a substituted diet (8% of the grain replaced by an isoenergetic amount of lucerne hay). Increased respiration rate during the heat load period, compared to the recovery period, was associated with increased stepping, especially by left limbs. Cattle also reduced eating, grooming, and scratching during the heat load period. The lowered head, backward ear, vertical or raised tail, and increased respiration rate and panting persisted in cattle during the heat load period. Cattle on the cereal grain diet stood for longer and were more likely to hold their ears backward and tail vertical than those on the substituted diet. We conclude that these behaviours could be used to detect animals that are most affected and that changing from a cereal-based diet to a substituted diet containing a higher amount of fibre, such as lucerne hay, can reduce hyperthermic behavioural responses to a heat load.

Given high costs of Oncotype DX (ODX) testing, widely used in recurrence risk assessment for early-stage breast cancer, studies have predicted ODX using quantitative clinicopathologic variables. However, such models have incorporated only small cohorts. Using a cohort of patients from the National Cancer Database (NCDB, n = 53,346), we trained machine learning models to predict low-risk (0-25) or high-risk (26-100) ODX using quantitative estrogen receptor (ER)/progesterone receptor (PR)/Ki-67 status, quantitative ER/PR status alone, and no quantitative features. Models were externally validated on a diverse cohort of 970 patients (median follow-up 55 months) for accuracy in ODX prediction and recurrence. Comparing the area under the receiver operating characteristic curve (AUROC) in a held-out set from NCDB, models incorporating quantitative ER/PR (AUROC 0.78, 95% CI 0.77-0.80) and ER/PR/Ki-67 (AUROC 0.81, 95% CI 0.80-0.83) outperformed the non-quantitative model (AUROC 0.70, 95% CI 0.68-0.72). These results were preserved in the validation cohort, where the ER/PR/Ki-67 model (AUROC 0.87, 95% CI 0.81-0.93, p = 0.009) and the ER/PR model (AUROC 0.86, 95% CI 0.80-0.92, p = 0.031) significantly outperformed the non-quantitative model (AUROC 0.80, 95% CI 0.73-0.87). Using a high-sensitivity rule-out threshold, the non-quantitative, quantitative ER/PR and ER/PR/Ki-67 models identified 35%, 30% and 43% of patients as low-risk in the validation cohort. Of these low-risk patients, fewer than 3% had a recurrence at 5 years. These models may help identify patients who can forgo genomic testing and initiate endocrine therapy alone. An online calculator is provided for further study., (© 2024. The Author(s).)

Background: Urinary incontinence is a growing issue among adult women globally. Limited data exist examining the impact of occupational, environmental, and behavioral factors on urinary incontinence., Objective: This quantitative, cross-sectional pilot study examined the workplace behaviors of adult women experiencing urinary incontinence. It was hypothesized that specific jobs and work environments would be associated with increased urinary incontinence and urgency based on identified behaviors and work-related conditions., Design: This study is a quantitative, cross-sectional survey., Methods: Adult women (18 years and older) with a history of urinary incontinence were recruited from August 2022 to February 2023 to complete a one-time survey consisting of multiple-choice and short answer questions identifying specific workplace behaviors and symptoms of urinary incontinence. Descriptive statistics and data categorization were used to observe outcomes and examine relationships between urinary incontinence and particular professions., Results: Urinary incontinence and urgency-related symptoms affected healthcare and business professionals at a higher prevalence. The most commonly reported behaviors across all professions consisted of withholding urine and utilizing absorbance products., Conclusion: The results of this study will help guide women's health practitioners in exploring current workplace behaviors that may contribute to urinary incontinence in adult women. With this knowledge, practitioners can provide meaningful education to employers and employees to prioritize toileting behaviors in the workplace.

When evaluating the last 25 yr of morbidity and mortality from adult chimpanzees managed within the Association of Zoo and Aquarium Chimpanzee Species Survival Plan® for North American zoos, only two female chimpanzees were diagnosed with mammary neoplasia: one incidentally antemortem and one with a terminal metastatic neoplasia. When comparing this observation of prevalence of mammary neoplasia to humans, a substantial disparity is apparent. Mammary neoplasia is the second most common cancer in adult female humans, with a lifetime risk of 1:8 in the United States. The reason for the disparity between humans and chimpanzees, as closely related species, is unknown. The true prevalence in chimpanzees may be higher than currently noted, because routine examination of mammary tissue in chimpanzees is generally less complete than for other tissues postmortem, and antemortem assessment is generally limited to mammary palpation. This study was performed on intact, bilateral mammary glands harvested at postmortem examination of adult female chimpanzees ( n = 7) from six institutions. With mammography, complete histopathologic sectioning, and genetic evaluation, the risk of mammary neoplasia was evaluated more thoroughly than during a typical postmortem exam in zoo populations during 2017-2019. No chimpanzees in the study were diagnosed with mammary neoplasia. Overall, this study supports the previous impression that chimpanzees do not develop mammary neoplasia at a similar rate as humans, even when comparable diagnostic modalities for evaluation are used.

Context.—: Pembrolizumab is used in patients with metastatic head and neck squamous cell carcinoma contingent upon the programmed death ligand-1 (PD-L1) combined positive score (CPS)., Objective.—: To compare PD-L1 CPS scores derived from paired resected primary tumors (PTs) and lymph node metastases (LMs) in patients with p16+ oropharyngeal squamous cell carcinoma (OPSCC)., Design.—: We identified 38 resected p16+ OPSCCs for which paired PTs and LMs were available. PD-L1 immunohistochemistry using the SP263 antibody clone was done on both the PT and the LM. CPS scoring was performed by 4 observers, and data were analyzed at the CPS cut points of greater than or equal to 1 and 20 in regard to interobserver and interspecimen agreement., Results.—: Overall agreement between consensus CPS scoring of PT and LM was seen in 76% of paired specimens (κ = 0.53). No specimen received a negative consensus score. Interobserver agreement for both PT and LM was fair to substantial (κ = 0.54 and 0.51, respectively) and was inferior to that seen in a prospective series of unselected head and neck squamous carcinoma cases evaluated at our institution (κ = 0.84)., Conclusions.—: Given the high rates of interobserver and interspecimen variability, evaluation of additional material or by additional observers may be of value in performing CPS scoring in cases of p16+ OPSCC. This is particularly the case when a negative or low-positive result is being evaluated in a patient who is otherwise a good candidate for immunotherapy., (© 2023 College of American Pathologists.)

Cattle change their behaviour in response to hot temperatures, including by engaging in stepping that indicates agitation. The automated recording of these responses would be helpful in the timely diagnosis of animals experiencing heat loading. Behavioural responses of beef cattle to hot environmental conditions were studied to investigate whether it was possible to assess behavioural responses by video-digitised image analysis. Open-source automated behavioural quantification software was used to record pixel changes in 13 beef cattle videorecorded in a climate-controlled chamber during exposure to a simulated typical heat event in Queensland, Australia. Increased digitised movement was observed during the heat event, which was related to stepping and grooming/scratching activities in standing animals. The 13 cattle were exposed in two cohorts, in which the first group of cattle ( n = 6) was fed a standard finisher diet based on a high percentage of cereal grains, and the second group of cattle ( n = 7) received a substituted diet in which 8% of the grains were replaced by lucerne hay. The second group displayed a smaller increase in digitised movements on exposure to heat than the first, suggesting less discomfort under hot conditions. The results suggest that cattle exposed to heat display increased movement that can be detected automatically by video digitisation software, and that replacing some cereal grain with forage in the diet of feedlot cattle may reduce the measured activity responses to the heat., Competing Interests: The authors declare no conflicts of interest.

Alzheimer's disease (AD) and high blood pressure (BP) are prevalent age-related diseases with significant unexplained heritability. A thorough analysis of genetic pleiotropy between AD and BP will lay a foundation for the study of the associated molecular mechanisms, leading to a better understanding of the development of each phenotype. We used the conditional false discovery rate (cFDR) method to identify novel genetic loci associated with both AD and BP. The cFDR approach improves the effective sample size for association testing by combining GWAS summary statistics for correlated phenotypes. We identified 50 pleiotropic SNPs for AD and BP, 7 of which are novel and have not previously been reported to be associated with either AD or BP. The novel SNPs located at STK3 are particularly noteworthy, as this gene may influence AD risk via the Hippo signaling network, which regulates cell death. Bayesian colocalization analysis demonstrated that although AD and BP are associated, they do not appear to share the same causal variants. We further performed two sample Mendelian randomization analysis, but could not detect a causal effect of BP on AD. Despite the inability to establish a causal link between AD and BP, our findings report some potential novel pleiotropic loci that may influence disease susceptibility. In summary, we identified 7 SNPs that annotate to 4 novel genes which have not previously been reported to be associated with AD nor with BP and discuss the possible role of one of these genes, STK3 in the Hippo signaling network., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The U.S. National Oceanic and Atmospheric Administration's Office of National Marine Sanctuaries manages a system of marine protected areas encompassing more than 2,000,000 km 2 . U.S. National Marine Sanctuaries (NMS) have been designated to provide protection for their conservation, recreational, ecological, historical, scientific, cultural, archaeological, educational, or aesthetic qualities. Due to the large variability of attributes among NMS, designing coordinated system-wide monitoring to support diverse resource protection goals can be challenging. Underwater sound monitoring is seeing increasing application to marine protected area management because it is able to support this wide variety of information needs. Passive acoustics are providing invaluable autonomous information regarding habitat associations, identifying species spatial and temporal use, and highlighting patterns in conditions that are otherwise difficult to survey. Using standardized equipment and analysis methods this study collected ambient underwater sound data and derived measurements to investigate temporal changes in sound pressure levels and power spectral density, identify presence of select species of importance and support within and among site comparison of ambient underwater sound among eight sites within four U.S. NMS. Broadband sound pressure levels of ambient sound (10-24,000 Hz) varied as much as 24 dB re 1 µPa (max difference 100-124 dB re 1 µPa) among the recording sites, sanctuaries, and seasons. Biotic signals, such as snapping shrimp snaps and vocalizations of fishes, exhibited distinct diel and seasonal patterns and showed variation among sites. Presence of anthropogenic signals, such as vessel passage, also varied substantially among sites, ranging from on average 1.6-21.8 h/d. The study identified measurements that effectively summarized baseline soundscape attributes and prioritized future opportunities for integrating non-acoustic and acoustic variables in order to inform area-specific management questions within four ecologically varying U.S. National Marine Sanctuaries., (© 2021 by the Ecological Society of America.)

Introduction: Core symptoms of depression are likely universal, however cultural groups differ in their experience of the condition. The purpose of this study was to examine differences and similarities of depression symptom groupings between broad cultural groups., Method: 6,982 adults took part in an online multilingual depression screening study, and completed an 18-item major depression screener. Participants were categorized into five broad cultural groups by language and country of residence: Spanish speakers from Latin America (n = 3,411); English speakers from Southeast Asia (n = 1,265); Russian speakers from the former Soviet bloc (n = 642); English speakers from English-speaking Western countries (n = 999); and Chinese speakers from China (n = 665). Principal components analysis with promax rotation was used., Results: Both similarities and noteworthy differences in symptom clustering between groups were observed. For instance, though suicide-related items formed a separate cluster for most cultures, for the Latin-American group, worthlessness loaded with suicidality. Changes in appetite and changes in weight tended to load on different factors (except for Chinese and Russian groups). Hypersomnia tended to load with psychomotor agitation, and core depression symptoms tended to load with physical symptoms (except for the Russian group)., Limitations: Depression was assessed by a self-report measure aligned to DSM-IV., Conclusion: The analysis contributes to a nuanced understanding of depression manifestations of various cultures, which may inform culturally sensitive clinical practice., (Copyright © 2020. Published by Elsevier B.V.)

The physiology of hyperthermia or heat stress in mammals is complex. It is a totally systemic condition that in varying degrees involves all organs, tissues and body fluid compartments. The nature and magnitude of the response is influenced by animal specific characteristics (e.g. age, diet, body condition, gender, reproductive stage), environment and animal management. Given the multifaceted nature of heat stress, and the varied ruminant production systems based in varied geoclimatic zones, it has been difficult to find appropriate measures of heat stress for production ruminants. This has become an urgent challenge as production systems intensify globally in a warming climate. Bioclimatic indices such as the Temperature-Humidity Index (THI) have evolved to incorporate some measure of animal physiology. However, these indices do not have strong relationships with core temperature trajectories and altered respiratory dynamics of animals with excessive heat load. In recent decades, the careful physiology studies of the 1950-80s, have given way to numerous studies trialling a plethora of new technologies and computational approached to measure heat stress. Infrared thermography of body surface temperatures, automated measures of respiration rate and radiotelemetry of internal body temperatures are the most intensively researched. The common goal has been to find the 'holy grail' decision-making threshold or timepoint as to the animal's wellbeing. Are we making any progress?, (Crown Copyright © 2020. Published by Elsevier Inc. All rights reserved.)

Cattle are susceptible to heat stress, especially those kept on high levels of nutrition for the purpose of maximising growth rates, which leads to a significant heat increment in their bodies. Consequences include compromised health and productivity and mortalities during extreme events, as well as serious economic loss. Some measures of heat stress, such as plasma cortisol and temperature in the rectum, vagina, or rumen, are invasive and therefore unlikely to be used on farms. These may cause additional stress to the animal due to handling, and that stress in itself can confound the measure. Consequently, it is desirable to find non-invasive alternatives. Panting score (PS), cortisol metabolites in faeces, milk, or hair, and the infrared temperature of external body surfaces are all potentially useful. Respiratory indicators are difficult and time consuming to record accurately, and cortisol metabolites are expensive and technically difficult to analyse. Infrared temperature appears to offer the best solution but requires further research to determine the thresholds that define when corrective actions are required to ensure optimal health and productivity. Research in this area has the potential to ultimately improve the welfare and profitability of cattle farming.

We report here the development of oncolytic adenoviruses (Ads) that have reduced toxicity, enhanced tumor tropism, produce strong antitumor response, and can overcome resistance to immune checkpoint inhibitor therapy in breast cancer. We have shown that LyP-1 receptor (p32) is highly expressed on the surface of breast cancer cells and tumors from cancer patients, and that increased stromal expression of transforming growth factor β-1 (TGFβ-1) is associated with triple-negative breast cancer. Therefore, we constructed oncolytic Ads, AdLyp.sT and mHAdLyp.sT, in which the p32-binding LyP-1 peptide was genetically inserted into the adenoviral fiber protein. Both AdLyp.sT and mHAdLyp.sT express sTGFβRIIFc, a TGFβ decoy that can inhibit TGFβ pathways. mHAdLyp.sT is an Ad5/48 chimeric hexon virus in which hypervariable regions (HVRs 1-7) of Ad5 are replaced with the corresponding Ad48 HVRs. AdLyp.sT and mHAdLyp.sT exhibited better binding, replication, and produced higher sTGFβRIIFc protein levels in breast cancer cell lines compared with Ad.sT or mHAd.sT control viruses without LyP-1 peptide modification. Systemic delivery of mHAdLyp.sT in mice resulted in reduced hepatic/systemic toxicity compared with Ad.sT and AdLyp.sT. Intravenous delivery of AdLyp.sT and mHAdLyp.sT elicited a strong antitumor response in a human MDA-MB-231 bone metastasis model in mice, as indicated by bioluminescence imaging, radiographic tumor burden, serum TRACP 5b and calcium, and body weight analyses. Furthermore, intratumoral delivery of AdLyp.sT in 4T1 model in immunocompetent mice inhibited tumor growth and metastases, and augmented anti-PD-1 and anti-CTLA-4 therapy. Based on these studies, we believe that AdLyp.sT and mHAdLyp.sT can be developed as potential targeted immunotherapy agents for the treatment of breast cancer.

Purpose: Although survival rates for patients with localized breast cancer have increased, patients with metastatic breast cancer still have poor prognosis. Understanding key factors involved in promoting breast cancer metastasis is imperative for better treatments. In this study, we investigated the role of syndecan-1 (Sdc1) in breast cancer metastasis., Methods: To assess the role of Sdc1 in breast cancer metastasis, we silenced Sdc1 expression in the triple-negative breast cancer human MDA-MB-231 cell line and overexpressed it in the mouse mammary carcinoma 4T1 cell line. Intracardiac injections were performed in an experimental mouse metastasis model using both cell lines. In vitro transwell blood-brain barrier (BBB) and brain section adhesion assays were utilized to specifically investigate how Sdc1 facilitates brain metastasis. A cytokine array was performed to evaluate differences in the breast cancer cell secretome when Sdc1 is silenced., Results: Silencing expression of Sdc1 in breast cancer cells significantly reduced metastasis to the brain. Conversely, overexpression of Sdc1 increased metastasis to the brain. We found that silencing of Sdc1 expression had no effect on attachment of breast cancer cells to brain endothelial cells or astrocytes, but migration across the BBB was reduced as well as adhesion to the perivascular regions of the brain. Loss of Sdc1 also led to changes in breast cancer cell-secreted cytokines/chemokines, which may influence the BBB., Conclusions: Taken together, our study demonstrates a role for Sdc1 in promoting breast cancer metastasis to the brain. These findings suggest that Sdc1 supports breast cancer cell migration across the BBB through regulation of cytokines, which may modulate the BBB. Further elucidating this mechanism will allow for the development of therapeutic strategies to combat brain metastasis.

In an effort to develop a new therapy for cancer and to improve antiprogrammed death inhibitor-1 (anti-PD-1) and anticytotoxic T lymphocyte-associated protein (anti-CTLA-4) responses, we have created a telomerase reverse transcriptase promoter-regulated oncolytic adenovirus rAd.sT containing a soluble transforming growth factor receptor II fused with human IgG Fc fragment (sTGFβRIIFc) gene. Infection of breast and renal tumor cells with rAd.sT produced sTGFβRIIFc protein with dose-dependent cytotoxicity. In immunocompetent mouse 4T1 breast tumor model, intratumoral delivery of rAd.sT inhibited both tumor growth and lung metastases. rAd.sT downregulated the expression of several transforming growth factor β (TGFβ) target genes involved in tumor growth and metastases, inhibited Th2 cytokine expression, and induced Th1 cytokines and chemokines, and granzyme B and perforin expression. rAd.sT treatment also increased the percentage of CD8 + T lymphocytes, promoted the generation of CD4 + T memory cells, reduced regulatory T lymphocytes (Tregs), and reduced bone marrow-derived suppressor cells. Importantly, rAd.sT treatment increased the percentage of CD4 + T lymphocytes, and promoted differentiation and maturation of antigen-presenting dendritic cells in the spleen. In the immunocompetent mouse Renca renal tumor model, similar therapeutic effects and immune activation results were observed. In the 4T1 mammary tumor model, rAd.sT improved the inhibition of tumor growth and lung and liver metastases by anti-PD-1 and anti-CTLA-4 antibodies. Analysis of the human breast and kidney tumors showed that a significant number of tumor tissues expressed high levels of TGFβ and TGFβ-inducible genes. Therefore, rAd.sT could be a potential enhancer of anti-PD-1 and anti-CTLA-4 therapy for treating breast and kidney cancers.

Feeding low-fiber and high-energy diets to dairy cows is one approach to ameliorate heat stress (HS) by reducing heat increment (HI) during digestion. However, rapidly and slowly fermentable cereal grains differ in their HI. The aim of this experiment was to quantify if feeding slowly fermentable grains ameliorated the physiological responses to HS and improved milk production (MP) in dairy cows. Holstein-Friesian lactating dairy cows were housed in shaded pens and were fed either a total mixed ration (TMR) plus wheat (TMRW), a TMR plus wheat treated with 2% of a commercial starch-binding agent (TMRB), or a TMR plus corn (TMRC) (n = 8 cows per diet) during summer in Queensland, Australia. Respiration rate (RR) and panting score (PS) were measured four times a day; rumen temperature (RuT) was recorded every 20 min, and rectal temperature (RT) and milk samples were obtained every 4 days. Cows fed slowly fermentable grains had higher milk production (MP) than cows fed TMRW, and cows fed TMRC had lower RT than those fed TMRW and TMRB (P < 0.001). Rumen temperature was positively correlated with temperature-humidity index and negatively correlated with MP (P < 0.05). In summary, feeding TMRC ameliorated HS as indicated by lower RT and improved MP in dairy cows. Milk production was improved with starch-binding agents; however, this was not associated with efficient thermoregulatory responses. Furthermore, determination of RuT enabled the prediction of changes in physiological variables and productive responses due to HS in lactating dairy cows.

Background: A preponderance of periapical radiolucencies are of inflammatory etiology (radicular cysts or periapical granulomas) secondary to pulpal disease. In some instances, however, a suspected periapical inflammatory lesion is not a consequence of pulpal disease but instead represents a lesion of noninflammatory origin. The differential diagnosis for such lesions is broad, ranging from odontogenic cysts and tumors to metastatic disease. As the biological behavior of such lesions is varied, the distinction between inflammatory odontogenic periapical lesions and lesions of noninflammatory origin in a periapical location is critical., Methods: A retrospective study of 5,993 archival periapical biopsies over a span of 15 years from the database of the Oral Pathology Biopsy Service in the Henry M. Goldman School of Dental Medicine at Boston University recorded the incidence of various lesions in a periapical location., Results: Of the cases studied, 97.2% represented lesions of inflammatory origin with histopathologic diagnoses as follows: periapical granuloma (60.0%), radicular cyst (36.7%), periapical fibrous scar (0.27 %), and periapical abscess (0.23 %). The remaining 2.8% cases were lesions of noninflammatory origin with histopathologic diagnoses of odontogenic keratocyst (also known as keratocystic odontogenic tumor), benign fibro-osseous lesions, and ameloblastoma. One patient had Langerhans cell disease, and 1 had central giant cell granuloma., Conclusions: Although most periapical specimens biopsied represented expected inflammatory periapical lesions, the biological behavior of underdiagnosed lesions may have considerable consequences for both the patient and the clinician., Practical Implications: This article serves to inform clinicians regarding the diversity of lesions arising in the periapical region of the jaws, to assist in the formulation of differential diagnoses, and to highlight the importance of submission of lesional tissue for histopathologic evaluation and definitive diagnosis when biopsy is clinically indicated., (Copyright © 2016 American Dental Association. Published by Elsevier Inc. All rights reserved.)

Background: Appropriate thromboprophylaxis for patients with atrial fibrillation (AF) remains a national challenge., Methods: We hypothesized that provision of decision support in the form of an Atrial Fibrillation Decision Support Tool (AFDST) would improve thromboprophylaxis for AF patients. We conducted a cluster randomized trial involving 15 primary care practices and 1,493 adults with nonvalvular AF in an integrated health care system between April 2014 and February 2015. Physicians in the intervention group received patient-level treatment recommendations made by the AFDST. Our primary outcome was the proportion of patients with antithrombotic therapy that was discordant from AFDST recommendation., Results: Treatment was discordant in 42% of 801 patients in the intervention group. Physicians reviewed reports for 240 patients. Among these patients, thromboprophylaxis was discordant in 63%, decreasing to 59% 1 year later (P = .02). In nonstratified analyses, changes in discordant care were not significantly different between the intervention group and control groups. In multivariate regression models, assignment to the intervention group resulted in a nonsignificant trend toward decreased discordance (P = .29), and being a patient of a resident physician (P = .02) and a higher HAS-BLED score predicted decreased discordance (P = .03), whereas female gender (P = .01) and a higher CHADSVASc score (P = .10) predicted increased discordance., Conclusions: Among patients whose physicians reviewed recommendations of the decision support tool discordant therapy decreased significantly over 1 year. However, in nonstratified analyses, the intervention did not result in significant improvements in discordant antithrombotic therapy., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objectives: To assess the appropriateness of oral anticoagulant therapy (OAT) in women and elderly adults, looking for patterns of undertreatment or unnecessary treatment., Design: Retrospective cohort study., Setting: Primary care practices of an academic healthcare system., Participants: Adults (aged 28-93) with nonvalvular atrial fibrillation (AF) seen between March 2013 and February 2014 (N = 1,585)., Measurements: Treatment recommendations were made using an AF decision support tool (AFDST) based on projections of quality-adjusted life expectancy calculated using a decision analytical model that integrates individual-specific risk factors for stroke and hemorrhage., Results: Treatment was discordant from AFDST-recommended treatment in 45% (326/725) of women and 39% (338/860) of men (P = .02). Although current treatment was discordant from recommended in 35% (89/258) of participants aged 85 and older and in 43% (575/1,328) of those younger than 85 (P = .01), many undertreated elderly adults were receiving aspirin as the sole antithrombotic agent., Conclusion: Physicians should understand that female sex is a significant risk factor for AF-related stroke and incorporate this into decision-making about thromboprophylaxis. Treating older adults with aspirin instead of OAT exposes them to significant risk of bleeding with little to no reduction in AF-related stroke risk., (© 2016, Copyright the Authors Journal compilation © 2016, The American Geriatrics Society.)

Background: Guidelines for anticoagulant therapy in patients with atrial fibrillation are based on stroke risk as calculated by either the CHADS2 or the CHA2DS2VASc scores and do not integrate bleeding risk in an explicit, quantitative manner. Our objective was to quantify the net clinical benefit resulting from improved decision making about antithrombotic therapy., Methods and Results: This study is a retrospective cohort study of 1876 adults with nonvalvular atrial fibrillation or flutter seen in primary care settings of an integrated healthcare delivery system between December 2012 and January 2014. Projections for quality-adjusted life expectancy reported as quality-adjusted life-years were calculated by a decision analytic model that integrates patient-specific risk factors for stroke and hemorrhage and examines strategies of no antithrombotic therapy, aspirin, or oral anticoagulation with warfarin. Net clinical benefit was defined by the gain or loss in quality-adjusted life expectancy between current treatment and treatment recommended by an Atrial Fibrillation Decision Support Tool. Current treatment was discordant from treatment recommended by the Atrial Fibrillation Decision Support Tool in 931 patients. A clinically significant gain in quality-adjusted life expectancy (defined as ≥0.1 quality-adjusted life-years) was projected in 832 patients. Subgroups were examined. For example, oral anticoagulant therapy was recommended for 188 who currently were receiving no antithrombotic therapy. For the entire cohort, a total of 736 quality-adjusted life-years could be gained were treatment changed to that recommended by the Atrial Fibrillation Decision Support Tool., Conclusions: Use of a decision support tool that integrates patient-specific stroke and bleeding risk could result in significant gains in quality-adjusted life expectancy for a primary care population of patients with atrial fibrillation., (© 2014 American Heart Association, Inc.)

The receptor activator of nuclear factor-κB ligand (RANKL) acts as a paracrine factor in progesterone-induced mammary epithelial proliferation and tumorigenesis. This evidence comes mainly from mouse models. Our aim was to examine whether RANKL expression in human normal and malignant breast is under the control of progesterone throughout the menstrual cycle. Breast epithelial samples were obtained by random fine needle aspiration (rFNA) of the contralateral unaffected breasts (CUB) of 18 breast cancer patients, with simultaneous serum hormone measurements. Genes correlated with serum progesterone levels were identified through Illumina microarray analysis. Validation was performed using qRT-PCR in rFNA samples from CUB of an additional 53 women and using immunohistochemistry in tissue microarrays of 61 breast cancer samples. Expression of RANKL, DIO2, and MYBPC1 was correlated with serum progesterone in CUB, and was significantly higher in luteal phase. RANKL and MYBPC1 mRNA expression were highly correlated between CUB and matched tumor samples. RANKL protein expression was also significantly increased in the luteal phase and highly correlated with serum progesterone levels in cancer samples, especially in hormone receptor positive tumors. The regulatory effects of progesterone on the expression of RANKL, DIO2, and MYBPC1 were confirmed in three-dimensional cultures of normal breast organoids. In normal breast and in breast cancer, RANKL mRNA and protein expression fluctuate with serum progesterone with highest levels in the luteal phase, suggesting that RANKL is a modulator of progesterone signaling in normal and malignant breast tissue and a potential biomarker of progesterone action and blockade.

Ductal carcinoma in situ (DCIS) is a noninvasive cancer that accounts for 25% of all breast cancers diagnosed in the United States. DCIS is a heterogeneous disease process with varied clinical manifestations and a broad spectrum of imaging findings. With advances in technology, the ability to detect early-stage cancers has improved, and understanding the role of ultrasonography (US) in the multimodality era of detection and diagnosis is paramount. When calcifications are identified at mammography, US can be performed to evaluate for an invasive component and to allow possible US-guided biopsy. Use of high-frequency transducers, spectral compounding, and speckle reduction algorithms can aid in the detection of calcifications. Calcified DCIS most commonly manifests as echogenic foci located within a mass or duct, associated with internal microlobulations, or distributed in a branch pattern. Noncalcified DCIS, which is more often identified in symptomatic patients, may manifest as a hypoechoic mass with microlobulated margins and no posterior acoustic features, or it may have a "pseudomicrocystic" appearance. Harmonic imaging and coronal reconstruction may improve detection of noncalcified DCIS. The appearance of DCIS at "second-look" US can be subtle and may warrant a lower threshold for detection, given a higher pretest probability of malignancy. US features are nonspecific, and careful correlation with respect to lesion location, size, shape, and depth is needed. The presence of internal vascularity can help increase the positive predictive value of US in this setting. US is a useful adjunct to mammography and magnetic resonance imaging, and recognizing the US appearance of DCIS will aid in the detection and diagnosis of this disease entity.

Unlabelled: INTODUCTION AND HYPOTHESIS: The vaginal wound healing process is a major determinant of surgical outcome following pelvic reconstructive surgery. Since the majority of these surgeries are performed in peri- and postmenopausal women, it is essential to understand how estrogen deficiency affects this process. We aimed to histologically evaluate the vaginal incisional wound healing process in a rabbit menopause model., Methods: Sixty three rabbits were utilized and divided into 3 groups: Twenty one underwent bilateral oophorectomy, 21 underwent a sham surgery, and 21 served as controls. Eight weeks later, standardized full-thickness 6 mm circular segments were excised from the vagina of all rabbits and spontaneous healing was recorded. Animals were euthanized sequentially, before wounding, and at 0, 4, 7, 14, 21 and 35 days after wounding, and their wounds were harvested and assessed histologically for wound healing using a validated scoring system., Results: Oophorectomized rabbits showed significantly delayed wound closure (p < 0.02), neovascularization (p < 0.01), granulation tissue accumulation and maturation (p < 0.02), collagen deposition (p < 0.01) and re-epithelialization (p < 0.01), however acute and chronic inflammation were significantly enhanced (p < 0.02)., Conclusion: Oophorectomized rabbits show protracted incisional vaginal wound healing by all histologic criteria, however, inflammation is significantly enhanced.

Mucocele-like lesion (MLL) is a rare mucinous lesion of the breast with highly variable upgrade rates to atypia or malignancy on excision. This spectrum of data has led to differing opinions on the need for surgical excision. We evaluated 50 core biopsy specimens diagnosed as having MLLs and correlated the findings with those of excision pathology. Thirty-eight patients underwent surgical excision and 29 were benign (76%), 4 had atypical ductal hyperplasia (11%), and 5 had ductal carcinoma in situ (13%), with an overall upgrade rate of 13%. However, the risk of upgrade was exclusively associated with the presence of atypia as seen on the needle core biopsy. All 22 MLLs without atypia had benign excisions, while 5 (31%) of the 16 patients with MLLs with atypia were upgraded to ductal carcinoma in situ on excision. No invasive carcinoma was identified. We believe it is reasonable that women with the core biopsy diagnosis of MLL without atypia and no associated mass be offered close clinical follow-up as an alternative to surgery.

We aimed to compare the histologic characteristics of vaginal vs. abdominal surgical wound healing in the rabbit. Bilateral 6 mm full-thickness circular segments were excised from the vagina and abdominal skin in 34 New Zealand white female rabbits. Animals were euthanized on the day of and 4, 7, 10, 14, 21, 28, and 35 days after wounding, and their wounds were evaluated using a modified scoring system. The inter- and intraobserver agreements of the scoring system were good (weighted kappa 0.63 and 0.71, respectively). A transient fibrinous crust was evident in 75% of the abdominal and in none of the vaginal wound specimens on days 4-7 after wounding (p=0.01). Acute inflammation peaked at day 4 in both the vaginal and abdominal wounds, while chronic inflammation peaked at days 4-7 and 14-21 in the abdomen and vagina, respectively. Both neovascularization and the amount of granulation tissue peaked at days 4 and 7 in the vagina and abdomen, respectively. Maturation of granulation tissue and collagen deposition increased persistently in both tissues until postwounding day 35. Reepithelialization increased after wounding, and was completed by day 14 in both tissues. The surgical wound-healing process in both the vagina and abdomen includes transient acute and chronic inflammation, fibroblast proliferation, and neovascularization, as well as progressive maturation of granulation tissue, reepithelialization, and collagen deposition. A transient fibrinous crust forms in the abdomen but not in the vagina 4-7 days after wounding. The modified histologic scoring system described here was found to be reliable and reproducible.