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The aim of this study was to evaluate the effect of Lepidium meyenii (maca) in chemically and physically subfertile mice. After 35 days, the following groups of mice were evaluated: control, sham, chemical subfertility, chemical subfertility-maca-supplemented, physical subfertility, physical subfertility-maca-supplemented and maca-supplemented only. Motility (32.36% ± 5.34%) and sperm count (44.4 ± 5.37 × 106/ml) in the chemically and physically subfertile mice (11.81% ± 4.06%, 17.34 ± 13.07 × 106/ml) decreased compared to the control (75.53% ± 2.97% and 57.4 ± 19.6 106/ml) and sham (53.5% ± 7.86% and 58.4 ± 14.10 106/ml). Maca was able to reverse the deleterious effect of motility (76.36 ± 1.97) as well as sperm count (53.5 ± 9.18 × 106/ml) on chemical subfertility. In contrast, maca did not reverse the effects of induced physical subfertility nor motility (18.78% ± 14.41%) or sperm count (20.17 ± 11.20 × 106/ml). The percentage of sperm DNA fragmentation in the physically subfertile mice increased (11.1% ± 19.29%) compared to the control (0.84% ± 0.85%). However, in the physically subfertile group, maca decreased sperm DNA fragmentation (2.29% ± 2.30%) closer to the sham (1.04% ± 0.62%) and the control (0.84% ± 0.85%). The group supplemented only with maca showed 0.54% ± 0.50% of spermatozoa with DNA fragmentation. Yet, the differences observed were statistically not significant. In conclusion, it appears that maca activates the cytochrome P450 system after chemically induced subfertility. However, it does not reverse the low mitochondrial membrane potential in spermatozoa compromised in the physical subfertility group. [ABSTRACT FROM AUTHOR]

Mansonella ozzardi, a filarioid parasite, causes human mansonellosis in the Americas. We identified raccoons (Procyon lotor) as wildlife reservoirs of M. ozzardi in Costa Rica. Noting the sympatry of free-ranging raccoons and humans, we conclude that mansonellosis is a considerable public health risk in the region.

Purpose: To evaluate high-risk histopathological features (HRHF) following primary enucleation of eyes with retinoblastoma (RB) and assess the patient outcomes across continents., Methods: Retrospective study of 1426 primarily enucleated RB eyes from five continents., Results: Of all, 923 (65%) were from Asia (AS), 27 (2%) from Australia (AUS), 120 (8%) from Europe (EUR), 162 (11%) from North America (NA), and 194 (14%) from South America (SA). Based on the continent (AS vs. AUS vs. EUR vs. NA vs. SA), the histopathology features included massive choroidal invasion (31% vs. 7% vs. 13% vs. 19% vs. 27%, p=0.001), post-laminar optic nerve invasion (27% vs. 0% vs. 16% vs. 21% vs. 19%, p=0.0006), scleral infiltration (5% vs. 0% vs. 4% vs. 2% vs. 7%, p=0.13), and microscopic extrascleral infiltration (4% vs. 0% vs. <1% vs. <1% vs. 4%, p=0.68). Adjuvant chemotherapy with/without orbital radiotherapy was given in 761 (53%) patients. Based on Kaplan-Meier estimates in different continents (AS vs. AUS vs. EUR vs. NA vs. SA), the 6-year risk of orbital tumor recurrence was 5% vs. 2% vs. 0% vs. 0% vs. 12% (p<0.001), systemic metastasis was reported in 8% vs. 5% vs. 2% vs. 0% vs. 13% (p=0.001), and death in 10% vs. 3% vs. 2% vs. 0% vs. 11% (p<0.001) patients., Conclusion: There is a wide variation in the infiltrative histopathology features of RB across continents, resulting in variable outcomes. SA and AS had a higher risk of orbital tumor recurrence, systemic metastasis, and death compared to AUS, EUR, and NA., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Opthalmic Communications Society, Inc.)

Study Design: This is a retrospective study using the Nationwide Emergency Department Sample., Objective: Facial laceration repairs are one of the most common procedures performed in the emergency department (ED). The goal of this study was to describe the patient's characteristics and healthcare cost associated with ED encounters for facial lacerations using the largest nationally representative database in the United States., Methods: This is a retrospective study using the Nationwide Emergency Department Sample. The data was collected between January and December of 2019. Patients with either a primary or secondary diagnosis of facial laceration were included. The primary outcome was patient characteristics. The secondary outcomes were ED characteristics, number and type of procedures performed and total encounter charges. Diagnoses and procedures were identified using ICD-10 CM codes., Results: There were 2,548,944 ED encounters for facial lacerations in the United States. Of those, laceration was the chief complaint in 75%. 80% of lacerations were unintentional, 8% were due to assaults, and <1% due to suicidal attempts. The most common laceration location was the scalp (21%) followed by the lip (11%) and eyelid (11%). The mean patient age was 38 years. Most patients were adults (69%), male (62%), Caucasian (64%, African American 14%, Hispanic 14%, Other 4%, Asian 2%), from low income levels ($1-$45,999: 29%, $46,000- $58,999: 24%, $59,000-$78,999: 24%, $79,000 or more: 23%), with private insurance (32%, Medicaid 25%, Medicare 24%, self-pay 12%, other 6%). Most encounters were during summer (June, July, August) at large metropolitan areas with at least 1 million residents (52%, small metropolitan: 30%, micropolitan: 10%, other: 7%) at teaching hospitals (65%) located in the southern region of the United States (37%, Midwest: 23%, west: 21%, northeast: 19%). Almost half of the encounters were at non-trauma-designated hospitals (48%, Level 1 trauma center: 21%, Level 2 trauma center: 17%, Level 3 trauma center: 13%). The number of procedures during each encounter was: none: 4%, one: 17%, two: 23%, three: 11%, four: 11%, five or more: 28%. The most frequent laceration repair was a simple repair of superficial wounds of the face, ears, eyelids, nose, lips, and/or mucous membranes 2.5 cm or less, followed by simple repair of superficial wounds to the scalp, neck, axillae, external genitalia, trunk, and/or extremities 2.5 cm or less. Most emergency department visits were billed as a Level 3 encounter, followed by Level 2 then Level 4. CT scan of the head was the most common imaging modality. Of all patients, <1% were admitted to the hospital and 87% were discharged home. The average total emergency department charges were $5,733., Conclusions: Facial laceration is a common complaint in the emergency department. It is costly, and disproportionately affects the impoverished. Most lacerations are classified as simple, less than 2.5 cm, involving the scalp, unintentional, with the discharge disposition being home. Thus, exploring pathways to treat facial lacerations outside of the ED can potentially reduce both healthcare cost and ED crowding., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2024.)

Microbial sensors play an essential role in maintaining cellular homoeostasis. Our knowledge is limited on how microbial sensing helps in differential immune response and its link to inflammatory diseases. Recently we have confirmed that ELMO1 (Engulfment and Cell Motility Protein-1) present in cytosol is involved in pathogen sensing, engulfment, and intestinal inflammation. Here, we show that ELMO1 interacts with another sensor, NOD2 (Nucleotide-binding oligomerization domain-containing protein 2), that recognizes bacterial cell wall component muramyl dipeptide (MDP). The polymorphism of NOD2 is linked to Crohn's disease (CD) pathogenesis. Interestingly, we found that overexpression of ELMO1 and mutant NOD2 (L1007fs) were not able to clear the CD-associated adherent invasive E. coli (AIEC -LF82). The functional implications of ELMO1-NOD2 interaction in epithelial cells were evaluated by using enteroid-derived monolayers (EDMs) from ELMO1 and NOD2 KO mice. Subsequently we also assessed the immune response in J774 macrophages depleted of either ELMO1 or NOD2 or both. The infection of murine EDMs with AIEC -LF82 showed higher bacterial load in ELMO1-KO, NOD2 KO EDMs, and ELMO1 KO EDMs treated with NOD2 inhibitors. The murine macrophage cells showed that the downregulation of ELMO1 and NOD2 is associated with impaired bacterial clearance that is linked to reduce pro-inflammatory cytokines and reactive oxygen species. Our results indicated that the crosstalk between microbial sensors in enteric infection and inflammatory diseases impacts the fate of the bacterial load and disease pathogenesis.

Porcine circovirus type 3 (PCV3) is a nonenveloped virus of the Circoviridae family. This virus has been identified in pigs of different ages and pigs with several clinical manifestations of the disease or even in apparently healthy pigs. While PCV3 was first reported in 2015, several retrospective studies have reported the virus before that year. The earliest report indicates that PCV3 has been circulated in swine farms since 1996. In this study, we evaluated the presence of PCV3 in samples collected in Mexico in 2008, 2015, 2020, and 2021. This study assessed PCV3 DNA by qPCR and antibodies against CAP protein by indirect ELISA. The results showed that PCV3 (DNA and anti-CAP antibodies) was detected in the samples collected from 2008 to 2021. The highest prevalence was in 2008 (100%), and the lowest was in 2015 (negative). Genetic analysis of ORF2 showed that the virus identified belonged to genotype a, as most of the viruses identified thus far. PCV3 was detected in samples from piglets with respiratory signs and growth retardation, sows with reproductive failure, or asymptomatic piglets and sows. Pigs with respiratory signs, growth retardation, or reproductive failure had a higher prevalence of antibodies and qPCR-positive samples. In conclusion, this study showed that PCV3 has been circulating in Mexico since 2008 and that PCV3 DNA and antibodies were more prevalent in samples from pigs with clinical manifestations of diseases.

Aim: To evaluate the relevance of incidental prostate [ 18 F]FDG uptake (IPU) and to explore the potential of radiomics and machine learning (ML) to predict prostate cancer (PCa)., Methods: We retrieved [ 18 F]FDG PET/CT scans with evidence of IPU performed in two institutions between 2015 and 2021. Patients were divided into PCa and non-PCa, according to the biopsy. Clinical and PET/CT-derived information (comprehensive of radiomic analysis) were acquired. Five ML models were developed and their performance in discriminating PCa vs non-PCa IPU was evaluated. Radiomic analysis was investigated to predict ISUP Grade., Results: Overall, 56 IPU were identified and 31 patients performed prostate biopsy. Eighteen of those were diagnosed as PCa. Only PSA and radiomic features (eight from CT and nine from PET images, respectively) showed statistically significant difference between PCa and non-PCa patients. Eight features were found to be robust between the two institutions. CT-based ML models showed good performance, especially in terms of negative predictive value (NPV 0.733-0.867). PET-derived ML models results were less accurate except the Random Forest model (NPV = 0.933). Radiomics could not accurately predict ISUP grade., Conclusions: Paired with PSA, radiomic analysis seems to be promising to discriminate PCa/non-PCa IPU. ML could be a useful tool to identify non-PCa IPU, avoiding further investigations.

Background: Androgens are generally thought to cause prostate cancer, but the data from animal studies suggest that they must be aromatized to estrogen and act in concert with genotoxic estrogen metabolites. The objective of this study was to determine whether treatment with testosterone (T) combined with a nonestrogenic estrogen metabolite and a nongenotoxic estrogenic compound would all be necessary and sufficient for the induction of a high incidence of prostate cancer in the susceptible NBL rat strain., Methods: NBL rats were treated with low-dose testosterone via slow-release Silastic implants and with the marginally estrogenic genotoxic catechol estrogen 4-hydroxyestradiol (4OH-E2) and the nongenotoxic estrogen 2-fluoroestradiol (2F-E2) and in one experiment the aromatase inhibitor letrozole via custom-made slow-release pellets. Animals were euthanized 52 weeks after implantation and their pituitaries and prostate complexes weighed and fixed in formalin. Hematoxylin and eosin (H&E)-stained step sections were prepared and examined microscopically for proliferative lesions., Results: Animals treated with 2F-E2, with or without the other compounds, had enlarged pituitaries demonstrating its estrogenicity. Animals treated with T, with or without the other compounds, had enlarged prostates consistent with its androgenicity. Rats treated with T plus 2F-E2 and 4OH-E2 developed a high incidence of prostatic cancer (89%), while, surprisingly, rats treated with T plus only 2F-E2 also had a high incidence of prostate cancer (95%) contradicting our initial hypothesis. To test whether the formation of E2 from T by aromatase could lead to estrogen genotoxicity and prostate carcinogenesis we then rats treated with T and 2F-E2 also with letrozole and found that it reduced prostate cancer incidence by about 50%., Conclusions: These findings indicate that long-term treatment with a nongenotoxic estrogen (2F-E2) and T as well as uninhibited prostatic aromatase activity generating genotoxic E2 are all required for induction of a high incidence of prostatic adenocarcinomas in NBL rats. These and previous data indicate that androgen receptor-mediated action, estrogen receptor mediation, and estrogen genotoxicity are all required and sufficient for hormonal carcinogenesis in the NBL rat prostate. Interference with the estrogen genotoxicity is a potential approach to prostate cancer chemoprevention., (© 2023 The Authors. The Prostate published by Wiley Periodicals LLC.)

Purpose: A photon Monte Carlo (MC) model was commissioned for flattened (FF) and flattening filter free (FFF) 6 MV beam energy. The accuracy of this model, as a single model to be used for three beam matched LINACs, was evaluated., Methods: Multiple models were created in RayStation v.10A for three linacs equipped with Elekta "Agility" collimator. A clinically commissioned collapsed cone (CC) algorithm (GoldCC), a MC model automatically created from the CC algorithm without further optimization (CCtoMC) and an optimized MC model (GoldMC) were compared with measurements. The validation of the model was performed by following the recommendations of IAEA TRS 430 and comprised of basic validation in a water tank, validation in a heterogeneous phantom and validation of complex IMRT/VMAT paradigms using gamma analysis of calculated and measured dose maps in a 2D-Array., Results: Dose calculation with the GoldMC model resulted in a confidence level of 3% for point measurements in water tank and heterogeneous phantom for measurements performed in all three linacs. The same confidence level resulted for GoldCC model. Dose maps presented an agreement for all models on par to each other with γ criteria 2%/2mm., Conclusions: The GoldMC model showed a good agreement with measured data and is determined to be accurate for clinical use for all three linacs in this study., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Associazione Italiana di Fisica Medica e Sanitaria. Published by Elsevier Ltd. All rights reserved.)

Sulfones and carboxylic acids are prominent motifs widely present in the chemical structure of agrochemicals, pharmaceuticals and many other highly valuable compounds. Herein, we describe a conjunctive strategy for the precise installation of these functionalities onto styrenes using sodium sulfinates and CO 2 as coupling partners. The protocol allowed the preparation of carboxy-sulfonylated compounds in good yields and broad functional group tolerance. Additionally, taking advantage of the leaving group ability of the sulfone moiety, a one-pot photocatalytic carboxy-sulfonylation-elimination strategy was developed for the synthesis of α-aryl-acrylates., (© 2022 Wiley-VCH GmbH.)

Background: Behavioral health outpatients are at risk for self-harm. Identifying individuals or combination of risk factors could discriminate those at elevated risk for self-harm., Methods: The study population (N = 248,491) included New York State Medicaid-enrolled individuals aged 10 to 64 with mental health clinic services between November 1, 2015 to November 1, 2016. Self-harm episodes were defined using ICD-10 codes from emergency department and inpatient visits. Multi-predictor logistic regression models were fit on a subsample of the data and compared to a testing sample based on discrimination performance (Area Under the Curve or AUC)., Results: Of N = 248,491 patients, 4,224 (1.70%) had an episode of intentional self-harm. Factors associated with increased self-harm risk were age 17-25, being female and having recent diagnoses of depression (AOR=4.3, 95%CI: 3.6-5.0), personality disorder (AOR=4.2, 95%CI: 2.9-6.1), or substance use disorder (AOR=3.4, 95%CI: 2.7-4.3) within the last month. A multi-predictor logistic regression model including demographics and new psychiatric diagnoses within 90 days prior to index date had good discrimination and outperformed competitor models on a testing sample (AUC=0.86, 95%CI:0.85-0.87)., Limitations: New York State Medicaid data may not be generalizable to the entire U.S population. ICD-10 codes do not allow distinction between self-harm with and without intent to die., Conclusions: Our results highlight the usefulness of recency of new psychiatric diagnoses, in predicting the magnitude and timing of intentional self-harm risk. An algorithm based on this finding could enhance clinical assessments support screening, intervention and outreach programs that are at the heart of a Zero Suicide prevention model., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Dermatomyositis (DM) and polymyositis (PM) are forms of idiopathic inflammatory myopathies (IIMs), which are associated with the production of autoantibodies that are useful in the diagnosis and prognosis of the disease., Objective: The aim of this study was to determine the frequency of antinuclear autoantibodies (ANAs), myositis-specific autoantibodies (MSAs), and myositis-associated autoantibodies (MAAs) in 6 Latin American countries., Methods: Two hundred ten patients with IIM were included in this cross-sectional study from 2014 to 2017: 112 from Mexico, 46 from Colombia, 20 from Peru, 16 from the Dominican Republic, 10 from Argentina, and 6 from Guatemala. Antinuclear autoantibodies were detected by indirect immunofluorescence on HEp-2 cells. MSAs and MAAs were tested by a line immunoassay method. Mann-Whitney U and χ2 tests were used for statistical analysis., Results: Of the 210 IIM patients, 139 (66.2%) had DM, 59 (28%) PM, and 12 (5.7%) juvenile DM. The mean age was 43.5 (6-79 years); 158 (75.2%) were female, and 52 (24.8%) were male. The overall frequency of ANA was 60%. The most frequent patterns were fine speckled (AC-4) (78.3%) and cytoplasmic (AC-19) (6.45%). The most frequent MSA were anti-Mi-2 (38.5%) and anti-Jo-1 (11.9%). Anti-Mi-2 was more frequent in patients from Colombia (40.1%). The MAA more frequent were anti-Ro-52/TRIM21 (17.6%) and anti-PM-Scl75 (7.5%)., Conclusions: This is the first study of ANA, MSA, and MAA in patients from 6 countries from the Panamerican League against Rheumatism myositis study group. We observed a general prevalence of 60% of ANA. In relation to MSA and MAA, anti-Mi-2 was the more frequent (38.5%)., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: The communication between the brain and the immune system is a cornerstone in animal physiology. This interaction is mediated by immune factors acting in both health and pathogenesis, but it is unclear how these systems molecularly and mechanistically communicate under changing environmental conditions. Behavioural fever is a well-conserved immune response that promotes dramatic changes in gene expression patterns during ectotherms' thermoregulatory adaptation, including those orchestrating inflammation. However, the molecular regulators activating the inflammatory reflex in ectotherms remain unidentified., Methods: We revisited behavioural fever by providing groups of fish a thermal gradient environment during infection. Our novel experimental setup created temperature ranges in which fish freely moved between different thermal gradients: (1) wide thermoregulatory range; T° = 6.4 °C; and (2) restricted thermoregulatory range; T° = 1.4 °C. The fish behaviour was investigated during 5-days post-viral infection. Blood, spleen, and brain samples were collected to determine plasmatic pro- and anti-inflammatory cytokine levels. To characterize genes' functioning during behavioural fever, we performed a transcriptomic profiling of the fish spleen. We also measured the activity of neurotransmitters such as norepinephrine and acetylcholine in brain and peripheral tissues., Results: We describe the first set of the neural components that control inflammatory modulation during behavioural fever. We identified a neuro-immune crosstalk as a potential mechanism promoting the fine regulation of inflammation. The development of behavioural fever upon viral infection triggers a robust inflammatory response in vivo, establishing an activation threshold after infection in several organs, including the brain. Thus, temperature shifts strongly impact on neural tissue, specifically on the inflammatory reflex network activation. At the molecular level, behavioural fever causes a significant increase in cholinergic neurotransmitters and their receptors' activity and key anti-inflammatory factors such as cytokine Il10 and Tgfβ in target tissues., Conclusion: These results reveal a cholinergic neuronal-based mechanism underlying anti-inflammatory responses under induced fever. We performed the first molecular characterization of the behavioural fever response and inflammatory reflex activation in mobile ectotherms, identifying the role of key regulators of these processes. These findings provide genetic entry points for functional studies of the neural-immune adaptation to infection and its protective relevance in ectotherm organisms.

The objective of this quantitative retrospective study is to understand healthcare patterns prior to self-harm, which may inform prevention efforts and identify intervention sites. Medicaid claims within 30, 60, 90, and 365 days prior to hospital-treated self-harm between 11/1/2015 and 11/1/2016 in New York State (N = 7492) were examined. Numbers and proportions were calculated for all service types. Participants were predominately 15-34, female, and White. Most (97%) had prior-year services, 94% outpatient care (73% behavioral health, 90% medical), 69% emergency department (37% behavioral health, 59% medical), and 42% inpatient services (34% behavioral health, 20% medical). About 86% received services within 90 days and 80% within 60 days. Utilization was high within 30 days prior, with 69% having one or more services. Medical services were more common than behavioral health (94% versus 79% in prior year); outpatient (94%) was more common than emergency (69%) and inpatient (42%) care. Given that most patients received health services within 30 days and almost all saw providers within the year prior, the findings indicate that improved prevention efforts within the healthcare system can reduce the incidence of self-harm.

Objective: The aim of this study was to compare patient and physician (MD) assessment of disease activity in systemic lupus erythematosus patients., Methods: This cross-sectional study was conducted between August 2016 and December 2017 at 2 Peruvian hospitals. One group assessed disease activity using a visual analog scale (VAS, 0-100 mm) and the other one using a numerical rating scale (NRS, 0-4), before and after their MD's visit. MDs assessed it with the Mexican Systemic Lupus Erythematosus Disease Activity (Mex-SLEDAI) (0-32) and with the SLICC/ACR Damage Index (SDI) for damage. Health-related quality of life was ascertained with the LupusQoL. Visual analog scale and NRS were compared using the Wilcoxon signed-rank test and the correlation between disease activity as assessed by the patient and the Mex-SLEDAI, SDI, and LupusQoL with the Spearman rank correlation., Results: Two hundred forty patients were included; mean (SD) age at diagnosis was 34.9 (12.9) years; most patients were Mestizo. Disease duration was 10.1 (7.0) years. The Mex-SLEDAI was 1.9 (2.7) and the SDI 1.2 (1.5). Disease activity as assessed by the patient, either by VAS or NRS, did not correlate with the Mex-SLEDAI or the SDI. In contrast, patient assessment of disease activity, by VAS or NRS, significantly correlated with several components of the LupusQoL (physical health, pain, planning, emotional health, and fatigue)., Conclusions: Physician's and patient's assessments of disease activity are discrepant; overall, patients score higher than their MDs. Patients score how they perceive the disease is affecting them, rather than disease activity per se. The VAS could be more useful than the NRS as a measurement of disease activity.

Objective: To determine the reliability of SLE patients' disease activity measurements., Methods: This was a cross-sectional study conducted (August 2016-December 2017) at 2 main public Peruvian hospitals, 1 with a comprehensive lupus care program. Patients assessed their disease activity with a visual analog scale (VAS) (0-100 mm) or a numerical rating scale (NRS) (0-4) before and after their physician's (MD's) assessment. Demographic and disease-related characteristics were recorded. Reliability of patients' disease activity before and after MD's assessment was determined using Spearman rank correlation. Factors possibly associated with this variability were examined with Spearman rank correlation and Mann-Whitney U test., Results: Two hundred forty, mostly Mestizo, SLE patients were included; mean (SD) age and disease duration (diagnosis) were 34.9 (12.9) years and 10.1 (7.0) years, respectively. The Mexican version of the Systemic Lupus Erythematosus Disease Activity Index was 1.9 (2.7), and the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index was 1.2 (1.5). The correlations between NRS and VAS before and after the MD's assessment were ρ = 0.839; p < 0.001; and ρ = 0.872; p < 0.001, respectively. Visual analog scale and NRS were higher before than after the MD's assessment (VAS 29.3 [26.5] and 26.5 [24.9], p = 0.052; and NRS (1.5 [1.2] and 1.3 [1.1], p = 0.003); only the comprehensive program explained this variability (p = 0.043). The reliability of VAS and NRS was ρ = 0.917 and ρ = 0.861, p < 0.001, before and after for the comprehensive program and ρ = 0.710 and ρ = 0.785, p < 0.001, for before and after for the regular program., Conclusions: Both VAS an NRS are highly reliable. Patients scored higher before than after their physicians' assessment but that these differences were smaller for the patients in the comprehensive care program than in the regular one.

Objective: Treating chronic low back pain (CLBP) with spine-focused interventions is common, potentially dangerous, and often ineffective. This preliminary trial tests the feasibility and efficacy of caring for CLBP in older adults as a geriatric syndrome in Aging Back Clinics (ABC)., Design: Randomized controlled trial., Setting: Outpatient clinics of two VA Medical Centers., Subjects: Fifty-five English-speaking veterans aged 60-89 with CLBP and no red flags for serious underlying illness, prior back surgery, dementia, impaired communication, or uncontrolled psychiatric illness., Methods: Participants were randomized to ABC care or usual care (UC) and followed for six months. ABC care included 1) a structured history and physical examination to identify pain contributors, 2) structured participant education, 3) collaborative decision-making, and 4) care guided by condition-specific algorithms. Primary outcomes were low back pain severity (0-10 current and seven-day average/worst pain) and pain-related disability (Roland Morris). Secondary outcomes included the SF-12 and health care utilization., Results: ABC participants experienced significantly greater reduction in seven-day average (-1.22 points, P = 0.023) and worst pain (-1.70 points, P = 0.003) and SF-12 interference with social activities (50.0 vs 11.5%, P = 0.0030) at six months. ABC participants were less likely to take muscle relaxants (16.7 vs 42.3%, P = 0.0481). Descriptively, UC participants were more likely to experience pain-related emergency room visits (45.8% vs 30.8%) and to be exposed to non-COX2 nonsteroidal anti-inflammatory drugs (73.1% vs 54.2%)., Conclusions: These preliminary data suggest that ABC care for older veterans with CLBP is feasible and may reduce pain and exposure to other potential morbidity., (2019 American Academy of Pain Medicine. This work is written by US Government employees and is in the public domain in the US.)

Hematoxylin and eosin (H&E) staining is a well-established technique in histopathology. However, immunohistochemistry (IHC) interpretation is done exclusively with hematoxylin counterstaining. Our goal was to investigate the potential of H&E as counterstaining (H&E-IHC) to allow for visualization of a marker while confirming the diagnosis on the same slide. The quality of immunostaining and the fast-technical performance were the main criteria to select the final protocol. We stained multiple diagnostic tissues with class I IHC tests with different subcellular localization markers (anti-CK7, CK20, synaptophysin, CD20, HMB45, and Ki-67) and with double-staining on prostate tissues with anti-high molecular weight keratins/p63 (DAB detection) and p504s (alkaline phosphatase detection). To validate the efficacy of the counterstaining, we stained tissue microarrays from the Canadian Immunohistochemistry Quality Control (cIQc) with class II IHC tests (ER, PR, HER2, and p53 markers). Interobserver and intraobserver concordance was assessed by κ statistics. Excellent agreement of H&E-IHC interpretation was observed in comparison with standard IHC from our laboratory (κ, 0.87 to 1.00), and with the cIQc reference values (κ, 0.81 to 1.00). Interobserver and intraobserver agreement was excellent (κ, 0.89 to 1.00 and 0.87 to 1.00, respectively). We therefore show for the first time the potential of using H&E counterstaining for IHC interpretation. We recommend the H&E-IHC protocol to enhance diagnostic precision for the clinical workflow and research studies.

Tattooing is a ubiquitous body modification involving the injection of ink and/or dye pigments into the dermis. Biosensors in the form of tattoos can be used to monitor metabolites in interstitial fluid. Here, minimally invasive, injectable dermal biosensors were developed for measuring pH, glucose, and albumin concentrations. The dermal pH sensor was based on methyl red, bromothymol blue, and phenolphthalein, which responded to a pH range from 5.0 to 9.0. The dermal glucose sensor consisted of glucose oxidase, 3,3',5,5'-tetramethylbenzidine, and peroxidase that detected concentrations up to 50.0 mmol L -1 . The dermal albumin sensor consisted of 3',3'',5',5''-tetrachlorophenol-3,4,5,6-tetrabromosulfophthalein to measure concentrations up to 5.0 g L -1 . The sensors were multiplexed in ex vivo skin tissue and quantitative readouts were obtained using a smartphone camera. These sensors can be used to manage of acid-base homeostasis, diabetes, and liver failure in point-of-care settings., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Objective: To describe key peripheral and central nervous system (CNS) conditions in a group of older adults with chronic low back pain (CLBP) and their association with pain severity and self-reported and performance-based physical function., Design: Cross-sectional., Setting: Outpatient VA clinics., Subjects: Forty-seven community-dwelling veterans with CLBP (age 68.0 ± 6.5 years, range = 60-88 years, 12.8% female, 66% white) participated., Methods: Data were collected on peripheral pain generators-body mass index, American College of Rheumatology hip osteoarthritis criteria, neurogenic claudication (i.e., spinal stenosis), sacroiliac joint (SIJ) pain, myofascial pain, leg length discrepancy (LLD), and iliotibial band pain; and CNS pain generators-anxiety (GAD-7), depression (PHQ-9), insomnia (Insomnia Severity Index), maladaptive coping (Fear Avoidance Beliefs Questionnaire, Cognitive Strategies Questionnaire), and fibromyalgia (fibromyalgia survey). Outcomes were pain severity (0 to 10 scale, seven-day average and worst), self-reported pain interference (Roland Morris [RM] questionnaire), and gait speed., Results: Approximately 96% had at least one peripheral CLBP contributor, 83% had at least one CNS contributor, and 80.9% had both peripheral and CNS contributors. Of the peripheral conditions, only SIJ pain and LLD were associated with outcomes. All of the CNS conditions and SIJ pain were related to RM score. Only depression/anxiety and LLD were associated with gait speed., Conclusions: In this sample of older veterans, CLBP was a multifaceted condition. Both CNS and peripheral conditions were associated with self-reported and performance-based function. Additional investigation is required to determine the impact of treating these conditions on patient outcomes and health care utilization., (2018 American Academy of Pain Medicine.)

Androgens are thought to cause prostate cancer, but the underlying mechanisms are unclear. Data from animal studies suggest that for androgens to cause prostate cancer, they must be aromatized to estrogen and act in concert with estrogen metabolites. We tested the hypothesis that androgen-receptor and estrogen receptor-mediated effects of androgen and estrogen are necessary, as well as genotoxicity of estrogen metabolites. NBL rats were treated with androgenic and estrogenic compounds for 16-75 weeks through slow-release silastic implants or pellets. Testosterone alone induced cancer in the prostate of 37% of rats. 5α-Dihydrotestosterone, which cannot be converted to estradiol or testosterone, did not cause a significant prostate cancer incidence (4%). Addition of estradiol to 5α-dihydrotestosterone treatment did not markedly enhance prostate cancer incidence (14%), unlike adding estradiol to testosterone treatment which induced a 100% tumor incidence. Testosterone plus estradiol treatment induced a DNA adduct detectable by 32 P-postlabeling, oxidative DNA damage (8-hydroxyguanosine), and lipid peroxidation at the site within the prostate where this treatment causes cancers, preceding later cancer formation. The non-estrogenic 4-hydroxy metabolite of estradiol, when combined with testosterone, induced prostatic dysplasia within 16 weeks and, after long-term treatment, a very low incidence of prostate cancer (21%). When an estrogen that cannot be hydroxylated (2-fluoroestradiol) was added to this combined treatment with testosterone and 4-hydroxyestradiol, dysplasia frequency after 16 weeks was doubled. These results strongly support the hypothesis, but additional definitive studies are needed which may identify new targets to interfere with these mechanisms that are clinically feasible in humans.

Electronic (e)-cigarettes theoretically may be safer than conventional tobacco. However, our prior studies demonstrated direct adverse effects of e-cigarette vapor (EV) on airway cells, including decreased viability and function. We hypothesize that repetitive, chronic inhalation of EV will diminish airway barrier function, leading to inflammatory protein release into circulation, creating a systemic inflammatory state, ultimately leading to distant organ injury and dysfunction. C57BL/6 and CD-1 mice underwent nose only EV exposure daily for 3-6 mo, followed by cardiorenal physiological testing. Primary human bronchial epithelial cells were grown at an air-liquid interface and exposed to EV for 15 min daily for 3-5 days before functional testing. Daily inhalation of EV increased circulating proinflammatory and profibrotic proteins in both C57BL/6 and CD-1 mice: the greatest increases observed were in angiopoietin-1 (31-fold) and EGF (25-fold). Proinflammatory responses were recapitulated by daily EV exposures in vitro of human airway epithelium, with EV epithelium secreting higher IL-8 in response to infection (227 vs. 37 pg/ml, respectively; P < 0.05). Chronic EV inhalation in vivo reduced renal filtration by 20% ( P = 0.017). Fibrosis, assessed by Masson's trichrome and Picrosirius red staining, was increased in EV kidneys (1.86-fold, C57BL/6; 3.2-fold, CD-1; P < 0.05), heart (2.75-fold, C57BL/6 mice; P < 0.05), and liver (1.77-fold in CD-1; P < 0.0001). Gene expression changes demonstrated profibrotic pathway activation. EV inhalation altered cardiovascular function, with decreased heart rate ( P < 0.01), and elevated blood pressure ( P = 0.016). These data demonstrate that chronic inhalation of EV may lead to increased inflammation, organ damage, and cardiorenal and hepatic disease.

Background: More than 80% of intestinal neoplasia is associated with the adenomatous polyposis coli (APC) mutation. Doublecortin-like kinase 1 (Dclk1), a kinase protein, is overexpressed in colorectal cancer and specifically marks tumor stem cells (TSCs) that self-renew and increased the tumor progeny in Apc Min/+ mice. However, the role of Dclk1 expression and its contribution to regulating pro-survival signaling for tumor progression in Apc mutant cancer is poorly understood., Methods: We analyzed DCLK1 and pro-survival signaling gene expression datasets of 329 specimens from TCGA Colon Adenocarcinoma Cancer Data. The network of DCLK1 and pro-survival signaling was analyzed utilizing the GeneMANIA database. We examined the expression levels of Dclk1 and other stem cell-associated markers, pro-survival signaling pathways, cell self-renewal in the isolated intestinal epithelial cells of Apc Min/+ mice with high-grade dysplasia and adenocarcinoma. To determine the functional role of Dclk1 for tumor progression, we knocked down Dclk1 and determined the pro-survival signaling pathways and stemness. We used siRNA technology to gene silence pro-survival signaling in colon cancer cells in vitro. We utilized FACS, IHC, western blot, RT-PCR, and clonogenic (self-renewal) assays., Results: We found a correlation between DCLK1 and pro-survival signaling expression. The expression of Dclk1 and stem cell-associated markers Lgr5, Bmi1, and Musashi1 were significantly higher in the intestinal epithelial cells of Apc Min/+ mice than in wild-type controls. Intestinal epithelial cells of Apc Min/+ mice showed increased expression of pro-survival signaling, pluripotency and self-renewal ability. Furthermore, the enteroids formed from the intestinal Dclk1 + cells of Apc Min/+ mice display higher pluripotency and pro-survival signaling. Dclk1 knockdown in Apc Min/+ mice attenuates intestinal adenomas and adenocarcinoma, and decreases pro-survival signaling and self-renewal. Knocking down RELA and NOTCH1 pro-survival signaling and DCLK1 in HT29 and DLD1 colon cancer cells in vitro reduced the tumor cells' ability to self-renew and survive., Conclusion: Our results indicate that Dclk1 is essential in advancing intestinal tumorigenesis. Knocking down Dclk1 decreases tumor stemness and progression and is thus predicted to regulate pro-survival signaling and tumor cell pluripotency. This study provides a strong rationale to target Dclk1 as a treatment strategy for colorectal cancer.

The complex nature of atherosclerosis demands high-resolution approaches to identify subtle thrombogenic lesions and define the risk of plaque rupture. Here, we report the proof-of-concept use of a multimodal scanning fiber endoscope (SFE) consisting of a single optical fiber scanned by a piezoelectric drive that illuminates tissue with red, blue, and green laser beams, and digitally reconstructs images at 30 Hz with high resolution and large fields-of-view. By combining laser-induced reflectance and fluorescence emission of intrinsic fluorescent constituents in arterial tissues, the SFE allowed us to co-generate endoscopic videos with a label-free biochemical map to derive a morphological and spectral classifier capable of discriminating early, intermediate, advanced, and complicated atherosclerotic plaques. We demonstrate the capability of scanning fiber angioscopy for the molecular imaging of vulnerable atherosclerosis by targeting proteolytic activity with a fluorescent probe activated by matrix metalloproteinases. We also show that the SFE generates high-quality spectral images in vivo in an animal model with medium-sized arteries. Multimodal laser-based angioscopy could become a platform for the diagnosis, prognosis, and image-guided therapy of atherosclerosis., Competing Interests: COMPETING FINANCIAL INTERESTS E.S. participates in royalty sharing with his employer, the University of Washington, which has ownership of patents that may gain or lose financially through this publication. The remaining authors declare no competing financial interests.

Archeological ceramic paste material typically consists of a mix of a clay matrix and various millimeter and sub-millimeter sized mineral inclusions. Micro X-ray fluorescence (XRF) is a standard compositional classification tool and in this work we propose and demonstrate an improved fluorescence map processing protocol where the mineral inclusions are automatically separated from the clay matrix to allow independent statistical analysis of the two parts. Application of this protocol allowed us to enhance the discrimination between different ceramic shards compared with the standard procedure of working with only the spatially averaged elemental concentrations. Using the new protocol, we performed an initial compositional classification of a set of 83 ceramic shards from the western slopes of the south central Andean region in the Arica y Parinacota region (Chile). Comparing the classifications obtained using the new versus the old (average concentrations only) protocols, we found that some samples were erroneously classified with the old protocol. From an archaeological perspective, a broad and heterogeneous regional sample set was used in this experimental study due to the fact that this was the first such analysis to be performed on ceramics from this region. This allowed a general overview to be obtained, however further work on more specific sample sets will be necessary to extract concrete archaeological conclusions., (© The Author(s) 2016.)

Two studies examined the effects of dietary astaxanthin on Hanlbm Wistar (SPF) rats. Male and female rats receiving astaxanthin concentrations up to 1.52% of the feed for 13 weeks showed no evidence of toxicity; no effects were noted in the offspring of female rats exposed to astaxanthin at up to 1.39% of the feed during the period of organogenesis (GD 7-16). Discoloration of the feces and yellow pigmentation of adipose tissue was seen in the 13-week study, an intrinsic property of the substance, and not a sign of toxicity. Differences between the control and astaxanthin groups, some of which reached statistical significance, were generally sporadic (i.e., transient and/or not related to astaxanthin concentration) and not considered of biological or toxicological significance. Blood cholesterol levels, for example, were greater in animals receiving astaxanthin for 13 weeks, but remained within the normal range. The highest dietary concentration of astaxanthin in each of the studies is proposed as a no-observable-adverse-effect level (NOAEL). Specifically, 1.52% for the 13-week study, corresponding to a mean intake of 1033 mg/kg bw/day (range: 880-1240 mg/kg bw/day), and 1.39% for the developmental toxicity study, corresponding to a mean intake of approximately 830 mg/kg bw/day (range: 457-957 mg/kg bw/day)., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Can the application of local anesthetics (Neural Therapy, NT) alone durably improve pain symptoms in referred patients with chronic and refractory pain? If the application of local anesthetics does lead to an improvement that far exceeds the duration of action of local anesthetics, we will postulate that a vicious circle of pain in the reflex arcs has been disrupted (hypothesis)., Methods: Case series design. We exclusively used procaine or lidocaine. The inclusion criteria were severe pain and chronic duration of more than three months, pain unresponsive to conventional medical measures, written referral from physicians or doctors of chiropractic explicitly to NT. Patients with improvement of pain who started on additional therapy during the study period for a reason other than pain were excluded in order to avoid a potential bias. Treatment success was measured after one year follow-up using the outcome measures of pain and analgesics intake., Results: 280 chronic pain patients were included; the most common reason for referral was back pain. The average number of consultations per patient was 9.2 in the first year (median 8.0). After one year, in 60 patients pain was unchanged, 52 patients reported a slight improvement, 126 were considerably better, and 41 pain-free. At the same time, 74.1% of the patients who took analgesics before starting NT needed less or no more analgesics at all. No adverse effects or complications were observed., Conclusions: The good long-term results of the targeted therapeutic local anesthesia (NT) in the most problematic group of chronic pain patients (unresponsive to all evidence based conventional treatment options) indicate that a vicious circle has been broken. The specific contribution of the intervention to these results cannot be determined. The low costs of local anesthetics, the small number of consultations needed, the reduced intake of analgesics, and the lack of adverse effects also suggest the practicality and cost-effectiveness of this kind of treatment. Controlled trials to evaluate the true effect of NT are needed.

Background: Reviewing clinical trial site performance identifies strategies to control outcomes. Performance across 5 geographical regions (36 sites across Asia, Australia, Europe, North America and Latin America) was investigated in a study that randomised 322 HIV-infected individuals., Methods: Regional performance was compared using descriptive analysis for time to site opening, recruitment, quality of data and laboratory samples. Follow-up consisted of 10 visits (96 weeks), electronic data collection (EDC) within 7 days of a visit and serious adverse events (SAEs) reported within 24 hours of site awareness., Results: Median days to site opening was 250 (188 to 266), ranging from 177 (158 to 200) (Australia) to 265 (205 to 270) (Europe). Median days to ethics and regulatory approval was 182 (120 to 241) and 218 (182 to 341) days, respectively. Within regions, time to approval ranged from 187 (91 to 205) days (Australia) to 276 (175 to 384) days (Europe). Time to first randomisation ranged from 282 (250 to 313) days (Australia) to 426 (420 to 433) days (North America). Recruitment was lower than forecasted in Asia, Australia, Europe and North America at 89%, 77%, 91% and 43%, respectively. The converse was true in Latin America where despite ethics, regulatory and contractual delays, recruitment was 104% of predicted. Median days to EDC was 7 (3 to 16), ranging from 3 (1 to 16) (Asia) to 13 (8 to 14) days (North America). Median days for initial SAE submission to sponsor was 6 (2 to 20), ranging from 4 (2 to 18) (Latin America) to 24 (5 to 46) days (Australia). Sites took longer to submit final reports, overall median of 28 (7 to 91) days, ranging from 7 days (Australia) to 67 (23 to 103) days (Europe)., Conclusions: Population availability and time to ethics and regulatory approvals influence recruitment; therefore accurate feasibility assessments are critical to site selection. Time to ethics and regulatory approval may not limit site inclusion if compensated by rapid recruitment. Identifying potential delays and methods for reduction can decrease time and costs for sponsors., Trial Registration: Clinical Trials.Gov identifier: NCT00335322. Date of registration: 8 June 2006.