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Previous clinical studies indicate that monoamine oxidase-B (MAO-B) inhibition by blackcurrants must be predominantly attributed to bioactives other than anthocyanins. In this natural products discovery study, MAO-A/B inhibitory phytochemicals were isolated from blackcurrants, and a double-blind crossover study investigated the efficacy of freeze-dried whole-fruit blackcurrant powder in inhibiting MAO-B compared with blackcurrant juice in healthy adults. Platelet MAO-B inhibition was comparable between powder (89% ± 6) and juice (91% ± 4), and it was positively correlated with MAO-modulated plasma catecholamines, subjective alertness, and reduced mental fatigue, assessed using the Bond-Lader questionnaire. Sarmentosin, a nitrile glycoside, and its hydroxycinnamoyl esters were identified as novel MAO-A/B inhibitors from blackcurrant in vitro , and sarmentosin was demonstrated to inhibit platelet MAO-B activity in vivo . These findings confirm sarmentosin as the primary bioactive for MAO-A/B inhibition in blackcurrants, as well as its bioavailability and stability during freeze-drying, and suggest that consuming blackcurrant powder and juice may positively affect mood in healthy adults.

Background: Gastrointestinal enteroendocrine cells express chemosensory bitter taste receptors that may play an important role in regulating energy intake (EI) and gut function., Objectives: To determine the effect of a bitter hop extract (Humulus lupulus L.) on acute EI, appetite, and hormonal responses., Methods: Nineteen healthy-weight men completed a randomized 3-treatment, double-blind, crossover study with a 1-wk washout between treatments. Treatments comprised either placebo or 500 mg of hop extract administered in delayed-release capsules (duodenal) at 11:00 h or quick-release capsules (gastric) at 11:30 h. Ad libitum EI was recorded at the lunch (12:00 h) and afternoon snack (14:00 h), with blood samples taken and subjective ratings of appetite, gastrointestinal (GI) discomfort, vitality, meal palatability, and mood assessed throughout the day., Results: Total ad libitum EI was reduced following both the gastric (4473 kJ; 95% CI: 3811, 5134; P = 0.006) and duodenal (4439 kJ; 95% CI: 3777, 5102; P = 0.004) hop treatments compared with the placebo (5383 kJ; 95% CI: 4722, 6045). Gastric and duodenal treatments stimulated prelunch ghrelin secretion and postprandial cholecystokinin, glucagon-like peptide 1, and peptide YY responses compared with placebo. In contrast, postprandial insulin, glucose-dependent insulinotropic peptide, and pancreatic polypeptide responses were reduced in gastric and duodenal treatments without affecting glycemia. In addition, gastric and duodenal treatments produced small but significant increases in subjective measures of GI discomfort (e.g., nausea, bloating, abdominal discomfort) with mild to severe adverse GI symptoms reported in the gastric treatment only. However, no significant treatment effects were observed for any subjective measures of appetite or meal palatability., Conclusions: Both gastric and duodenal delivery of a hop extract modulates the release of hormones involved in appetite and glycemic regulation, providing a potential "bitter brake" on EI in healthy-weight men., (© The Author(s) 2022. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Background: Extreme, prolonged wildfire smoke (WFS) events are becoming increasingly frequent phenomena across the Western United States. Rural communities, dependent on contributions of nature to people's quality of life, are particularly hard hit. While prior research has explored the physical health impacts of WFS exposure, little work has been done to assess WFS impacts on mental health and wellbeing, or potential adaptation solutions., Methods: Using qualitative methods, we explore the mental health and wellbeing impacts experienced by community members in a rural Washington State community that has been particularly hard hit by WFS in recent years, as well as individual, family, and community adaptation solutions. We conducted focus groups with residents and key informant interviews with local health and social service providers., Results: Participants identified a variety of negative mental health and wellbeing impacts of WFS events, including heightened anxiety, depression, isolation, and a lack of motivation, as well as physical health impacts (e.g., respiratory issues and lack of exercise). Both positive and negative economic and social impacts, as well as temporary or permanent relocation impacts, were also described. The impacts were not equitably distributed; differential experiences based on income level, outdoor occupations, age (child or elderly), preexisting health conditions, housing status, and social isolation were described as making some residents more vulnerable to WFS-induced physical and mental health and wellbeing challenges than others. Proposed solutions included stress reduction (e.g., meditation and relaxation lessons), increased distribution of air filters, development of community clean air spaces, enhancing community response capacity, hosting social gatherings, increasing education, expanding and coordination risk communications, and identifying opportunities for volunteering. Findings were incorporated into a pamphlet for community distribution. We present a template version herein for adaptation and use in other communities., Conclusions: Wildfire smoke events present significant mental health and wellbeing impacts for rural communities. Community-led solutions that promote stress reduction, physical protection, and community cohesion have the opportunity to bolster resilience amid this growing public health crisis., (© 2022. The Author(s).)

Objectives: This research focused on osteoarthritis (OA) lesions on modern patients to 1) identify consistently observed lesions not included within current paleopathological measures of OA, 2) assess the correspondence of bone and cartilage lesions with clinical OA diagnostic criteria, and 3) discuss the correspondence of bone lesions with sources of pain reported in clinical literature., Materials: Tibial plateaus from 62 patients undergoing total knee replacement surgery due to OA were examined., Methods: Plateaus were scored for several non-standard OA criteria, including non-articular and X-ray visible lesions and pre-maceration cartilage lesions, as well as articular surface criteria standard in paleopathology., Results: Proliferative bone in the intercondylar region was present in 95 % of specimens, while areas of dense trabecular bone and lytic defects, both on the inferior side of the plateaus, were present in 98 % and 83 %, respectively., Conclusions: The inferior lytic defects may be physical evidence of bone marrow lesions (BML), a clinical OA indicator visible via MRI. Previous research has linked BML to pain, inflammation, and ligament pathology. The latter conditions have also been associated with intercondylar enthesophytes and third intercondylar tubercle of Parsons (TITP), both of which were observed in the intercondylar regions., Significance: Several non-articular lesions not currently included in paleopathological measures of OA were consistently observed., Suggestions for Future Research: A similar analysis of a control sample of non-OA tibial plateaus would better contextualize these results., Limitations: The sample's high average age (65.8 years) and severe OA stage may hamper generalizability to archaeological collections., (Copyright © 2020 Elsevier Inc. All rights reserved.)

One of the goals of the Critical Path Institute's Predictive Safety Testing Consortium (PSTC) is to promote best practices for evaluating novel markers of drug induced injury. This includes the use of sound statistical methods. For rat studies, these practices have centered around comparing the area under the receiver-operator characteristic curve for each novel injury biomarker to those for the standard markers. In addition, the PSTC has previously used the net reclassification index (NRI) and integrated discrimination index (IDI) to assess the increased certainty provided by each novel injury biomarker when added to the information already provided by the standard markers. Due to their relatively simple interpretations, NRI and IDI have generally been popular measures of predictive performance. However recent literature suggests that significance tests for NRI and IDI can have inflated false positive rates and thus, tests based on these metrics should not be relied upon. Instead, when parametric models are employed to assess the added predictive value of a new marker, following (Pepe, M. S., Kerr, K. F., Longton, G., and Wang, Z. (2013). Testing for improvement in prediction model performance. Stat. Med. 32, 1467-1482), the PSTC recommends that likelihood based methods be used for significance testing., (© The Author 2016. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

One mechanism to advance the application of novel safety assessment methodologies in drug development, including in silico or in vitro approaches that reduce the use of animals in toxicology studies, is regulatory qualification. Regulatory qualification, a formal process defined at the the U. S. Food and Drug Administration and the European Medicines Agency, hinges on a central concept of stating an appropriate "context of use" for a novel drug development tool (DDT) that precisely defines how that DDT can be used to support decision making in a regulated drug development setting. When accumulating the data to support a particular "context-of-use," the concept of "fit-for-purpose" often guides assay validation, as well as the type and amount of data or evidence required to evaluate the tool. This paper will review pathways for regulatory acceptance of novel DDTs and discuss examples of safety projects considered for regulatory qualification. Key concepts to be considered when defining the evidence required to formally adopt and potentially replace animal-intensive traditional safety assessment methods using qualified DDTs are proposed. Presently, the use of qualified translational kidney safety biomarkers can refine and reduce the total numbers of animals used in drug development. We propose that the same conceptual regulatory framework will be appropriate to assess readiness of new technologies that may eventually replace whole animal models., (© The Author 2016. Published by Oxford University Press on behalf of the Institute for Laboratory Animal Research. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Traditional kidney biomarkers are insensitive indicators of acute kidney injury, with meaningful changes occurring late in the course of injury. The aim of this work was to demonstrate the diagnostic potential of urinary osteopontin (OPN) and neutrophil gelatinase-associated lipocalin (NGAL) for drug-induced kidney injury (DIKI) in rats using data from a recent regulatory qualification submission of translational DIKI biomarkers and to compare performance of NGAL and OPN to five previously qualified DIKI urinary biomarkers. Data were compiled from 15 studies of 11 different pharmaceuticals contributed by Critical Path Institute's Predictive Safety Testing Consortium (PSTC) Nephrotoxicity Working Group (NWG). Rats were given doses known to cause DIKI or other target organ toxicity, and urinary levels of the candidate biomarkers were assessed relative to kidney histopathology and serum creatinine (sCr) and blood urea nitrogen (BUN).OPN and NGAL outperformed sCr and BUN in identifying DIKI manifested as renal tubular epithelial degeneration or necrosis. In addition, urinary OPN and NGAL, when used with sCr and BUN, increased the ability to detect renal tubular epithelial degeneration or necrosis. NGAL and OPN had comparable or improved performance relative to Kim-1, clusterin, albumin, total protein, and beta-2 microglobulin. Given these data, both urinary OPN and NGAL are appropriate for use with current methods for assessing nephrotoxicity to identify and monitor DIKI in regulatory toxicology studies in rats. These data also support exploratory use of urinary OPN and NGAL in safety monitoring strategies of early clinical trials to aid in the assurance of patient safety., (© The Author 2016. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Novel skeletal muscle (SKM) injury biomarkers that have recently been identified may outperform or add value to the conventional SKM injury biomarkers aspartate transaminase (AST) and creatine kinase (CK). The relative performance of these novel biomarkers of SKM injury including skeletal troponin I (sTnI), myosin light chain 3 (Myl3), CK M Isoform (Ckm), and fatty acid binding protein 3 (Fabp3) was assessed in 34 rat studies including both SKM toxicants and compounds with toxicities in tissues other than SKM. sTnI, Myl3, Ckm, and Fabp3 all outperformed CK or AST and/or added value for the diagnosis of drug-induced SKM injury (ie, myocyte degeneration/necrosis). In addition, when used in conjunction with CK and AST, sTnI, Myl3, CKm, and Fabp3 individually and collectively improved diagnostic sensitivity and specificity, as well as diagnostic certainty, for SKM injury and responded in a sensitive manner to low levels of SKM degeneration/necrosis in rats. These findings support the proposal that sTnI, Myl3, Ckm, and Fabp3 are suitable for voluntary use, in conjunction with CK and AST, in regulatory safety studies in rats to monitor drug-induced SKM injury and the potential translational use of these exploratory biomarkers in early clinical trials to ensure patient safety., (© The Author 2015. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Regulatory science, the science of developing new tools, standards, and approaches to assess the safety, efficacy, quality, and performance of regulated medical products, has advanced over time due to a number of factors. The FDA, the EMA, and the Pharmaceuticals and Medical Devices Agency (PMDA) have recently formalized voluntary data submission processes for the regulatory "qualification" of novel tools and methodologies for use in drug development. While recognizing that other mechanisms exist within the research community for driving scientific consensus on novel tools and methodologies, this article focuses on the formal regulatory process that addresses a tool's acceptability for incorporation by any sponsor into novel medical product development. Guidances, regulatory qualification opinions, and publications were reviewed to allow a systematic comparison of the process, content, and volume of submissions at the FDA, EMA, and PMDA. Qualification of new tools by regulatory agencies and subsequent adoption by drug developers are anticipated to speed therapeutic development for patients in need, build scientific consensus as to the usefulness and readiness of novel methodologies for understanding disease and therapeutic development, and decrease uncertainty between the regulators and sponsors regarding the appropriate application of new tools.

We evaluated the potential of apple to reduce inflammation. Phenolic compounds and triterpenes were analyzed in 109 apple cultivars. Total phenolics ranged from 29 to 7882 μg g(-1) of fresh weight (FW) in the flesh and from 733 to 4868 μg g(-1) FW in the skin, with flavanols including epicatechin and procyanidins as major components. Ursolic (44.7 to 3522 μg g(-1) FW) and oleanolic (47.2 to 838 μg g(-1) FW) acids dominated the skin triterpene profile. Five chemically contrasting cultivars were fractionated and their immune-modulating activity measured using two cell-based assays targeting key points in the inflammation process. Cultivars exhibiting high contents of procyanidins were the most potent at inhibiting NF-κB while triterpene-rich fractions reduced the promoter activity of the gene of TNFα. This study provides new insights into how apple genetic diversity could be used to alleviate inflammation.

Purpose: General surgeons have decreased as a proportion of the total U.S. surgical workforce. Given the likelihood of increasing shortages of general surgeons, the authors evaluated available expansion capacity of existing general surgery residency programs., Method: In November 2009, the authors e-mailed a Web-based questionnaire to the program directors and coordinators of the 246 U.S. general surgery residency programs that were then certified by the Accreditation Council for Graduate Medical Education., Results: Of the 246 programs the authors contacted, 123 (50%) completed the survey. Community hospital programs and academic programs had similar response rates (52% and 50%, respectively). Of the 115 program directors who responded to the relevant question, 92 (80%) reported sufficient existing case volume capacity to accommodate additional surgery residents. Both community and academic program directors reported modest expansion capacity: an average of 1.7 and 2.0 additional residents per year, respectively. Across all programs, the average additional capacity reported was 1.9 additional residents per year. An expansion of this size would increase the number of general surgery residency positions from 1,137 to 1,515 annually. After accounting for subspecialization, this increase of 378 residents would result in approximately 249 additional general surgeons entering the workforce per year after five years., Conclusions: Expansion capacity within existing approved general surgery residency programs is insufficient to meet the expected demand for general surgeons in the United States. Strategies to alleviate shortages include developing new training programs, cultivating new medical education funding streams, and changing the surgical training paradigm., (Copyright © by the Association of American medical Colleges.)

Helicobacter pylori is a gram-negative bacterium that colonizes the stomach of nearly half of the world's population. Genotypic characterization of H. pylori strains involves the analysis of virulence-associated genes, such as vacA, which has multiple alleles. Previous phylogenetic analyses have revealed a connection between modern H. pylori strains and the movement of ancient human populations. In this study, H. pylori DNA was amplified from the stomach tissue of the Kwäday Dän Ts'ìnchi individual. This ancient individual was recovered from the Samuel Glacier in Tatshenshini-Alsek Park, British Columbia, Canada on the traditional territory of the Champagne and Aishihik First Nations and radiocarbon dated to a timeframe of approximately AD 1670 to 1850. This is the first ancient H. pylori strain to be characterized with vacA sequence data. The Tatshenshini H. pylori strain has a potential hybrid vacA m2a/m1d middle (m) region allele and a vacA s2 signal (s) region allele. A vacA s2 allele is more commonly identified with Western strains, and this suggests that European strains were present in northwestern Canada during the ancient individual's time. Phylogenetic analysis indicated that the vacA m1d region of the ancient strain clusters with previously published novel Native American strains that are closely related to Asian strains. This indicates a past connection between the Kwäday Dän Ts'ìnchi individual and the ancestors who arrived in the New World thousands of years ago.

A study was conducted on decomposition and insect succession in the Prairie Ecozone of Saskatchewan in the year 2000. Eighteen domestic pig carcasses (42-79 kg) were employed as human models for applications to future homicide investigations in this region. Two major variables were considered including the effect of season and habitat (sun versus shade). Research was conducted over 25 weeks, spanning three seasons: spring, summer and fall. Ambient temperature, internal carcass temperature, faunistic succession over time, and the rate of decay were all compared for each experimental variable. Results indicated that habitat was only a factor in the decompositional rate of carrion in the spring season. The ambient temperature was the chief factor determining the seasonal variations in decay rate. Maximum internal carcass temperatures always coincided with the presence of 3rd instar larvae. Patterns of insect succession occurred in a predictable sequence that varied across different habitats and seasons and was unique compared to previously published studies. Carcasses placed in spring and fall attracted a more diverse assemblage of insects than summer-placed carrion. Sun-exposed carrion also had greater variation in fauna than shaded carrion in spring and fall. Members of Silphidae were the first coleopteran colonizers in all habitats and seasons. This paper also marks the first record for Cochliomyia macellaria (Fabricius) in Saskatchewan.