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Collectively, we have chosen to explore an Australian First Nations-first approach to understanding the chemical elements. We believe that engagement with cultural heritage, ongoing cultures, and the knowledges of this place—the lands on which we work, live, and study—will lead to new ways of understanding the elements and change the way we practice chemistry. The “First Nations first” phrase and approach comes from understanding the unique place that Aboriginal and Torres Strait Islander peoples have in the Australian context. In this paper we explore how a First Nations-first approach could take place in Sydney on Aboriginal lands. This approach is led by Aboriginal people, engages with culture, and is produced with local knowledge holders. So far, the work has entailed two years of meeting, conversing, and sharing space to determine appropriate ways of working together, interrogating the complexities of the ideas, and to refining our approach to the work. To appreciate the significant shift that a First Nations-first approach represents for chemistry, we consider the legacy of the Periodic Table. We share some reflections on how Indigenous knowledges can contribute to an expanded chemistry curriculum through the recognition of productive cultural tension.

This study examined how talker accentedness affects the recognition of noise-vocoded speech by native English listeners and how contextual information interplays with talker accentedness during this process. The listeners included 20 native English-speaking, normal-hearing adults aged between 19 and 23 years old. The stimuli were English Hearing in Noise Test (HINT) and Revised Speech Perception in Noise (R-SPIN) sentences produced by four native Mandarin talkers (two males and two females) who learned English as a second language. Two talkers (one in each sex) had a mild foreign accent and the other two had a moderate foreign accent. A six-channel noise vocoder was used to process the stimulus sentences. The vocoder-processed and unprocessed sentences were presented to the listeners. The results revealed that talkers’ foreign accents introduced additional detrimental effects besides spectral degradation and that the negative effect was exacerbated as the foreign accent became stronger. While the contextual information provided a beneficial role in recognizing mildly accented vocoded speech, the magnitude of contextual benefit decreased as the talkers’ accentedness increased. These findings revealed the joint influence of talker variability and sentence context on the perception of degraded speech.

PURPOSE: The purpose of this study was to explore (1) patterns in physical activity behaviors and (2) the meaning and personal significance of social cognitive theory (SCT) constructs on physical activity, across gender and income groups among people with type 2 diabetes (T2DM). METHODS: Albertans, 18 years and older (x- = 63, SD = 12.08) with T2DM (N = 1614) completed self-report measures of demographic characteristics and physical activity. Two-way, between-groups analyses of variance (ANOVAs) assessed main and interaction effects of gender and income on leisure time physical activity (LTPA). A subsample of these participants (n = 20) subsequently completed qualitative telephone interviews to provide contextual understanding of the quantitative data and to explore salient SCT influences on physical activity. RESULTS: Significant findings indicated that men participate in more LTPA than women do, and those from the highest income group participate in more LTPA than low- or middle-income groups (P < .01). Interview results suggested that walking is the most popular form of physical activity; however, gender and income groups differ in other leisure and nonleisure physical activities. Furthermore, patterns for SCT constructs related to physical activity were apparent across gender and income, most noticeably for self-efficacy and environmental and situational influences. Specifically among men, noteworthy differences existed between income groups for self-control and reinforcement strategies. CONCLUSIONS: The study highlights the need for more sensitive self-report measures and objective measures of physical activity to help distinguish whether true differences exist between certain demographic groups. Moreover, interventions that promote walking may be beneficial for people with T2DM, provided that appropriate environmental and policy changes occur to accommodate walking and other physical activity behaviors. [ABSTRACT FROM AUTHOR]

OBJECTIVES: To identify demographic, health, and behavioral factors associated with smoking behavior in adults with diabetes. METHODS: Canadian adults 18+ years with type 1 (n=697) or type 2 (n=1621) were investigated. Logistic regression analyses were conducted separately for both diabetes subgroups. RESULTS: When comparing never versus ever smokers, never versus current smokers, and former smokers who quit versus current smokers, similarities and differences for demographic, health, and behavioral factors were found for the 2 diabetes subgroups. CONCLUSIONS: Diabetes type, demographic, health, and behavioral factors should be considered when tailoring smoking cessation and prevention programs. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Depression scales that are responsive to changes in clinical symptoms are important for clinical monitoring and outcomes assessment in longitudinal studies. We evaluated the psychometric properties and responsiveness to clinical change of the 13- and 20-item versions of the Hopkins Symptom Checklist Depression Scale (HSCL-D). METHODS: A secondary data analysis from a large 11-week, multicenter clinical trial, comparing three treatments was performed. Adult patients with minor depression or dysthymia and a score of > or = 10 on the Hamilton Depression Rating Scale (HDRS) were recruited from primary care clinics. Item-total correlations and Cronbach alphas were computed for HSCL-D-13 and HSCL-D-20. Clinical response at 11 weeks was defined by a Hamilton Depression Rating Scale (HDRS) < 10, clinical remission by a HDRS < 7, and criterion symptom remission by < or = 1 DSM-III-R criterion symptoms. Standardized effect sizes and Guyatt's responsiveness statistic were determined for the 13- and 20-item HSCL-D. RESULTS: Of the 656 subjects enrolled, 511 (77.9%) had complete data and were included in the analysis. Patients were 61.1 +/- 15.0 years old; minor depression was diagnosed in 238, dysthymia in 273. Both scales had good internal consistency; Cronbach's alpha = 0.835 and 0.859 for the 13- and 20-items questionnaires respectively. Standardized effect sizes for clinical response (0.62 for the HSCL-D-13; 0.66 for the HSCL-D-20), clinical remission (0.69 and 0.70), and criterion symptom remission (0.65 and 0.67) showed moderate to large effects and did not differ significantly for the two versions. Responsiveness was virtually identical for patients with minor depression and dysthymia but responsiveness was substantially lower for ethnic minorities. CONCLUSION: The HSCL-D-13 and 20-item versions have similar responsiveness to change. For use in European Americans, we recommend the HSCL-D-13 if response burden is the preeminent consideration. To more fully capture DSM criterion symptoms, we recommend the HSCL-D-20. [ABSTRACT FROM AUTHOR]

Abstract Background Physicians, nurses and hospital pharmacists were surveyed to assess attitudes of hospital-based pediatric caregivers regarding the dosing of medicine to children. Our objectives were to gauge how current resources are utilized to guide the management of pediatric pharmacotherapy, assess drugs and drug classes where guidance is most critical and examine the prevalence and practice of dose adjustment in pediatric patients. Methods Questionnaire categories included demographics, pharmacotherapy resources, dosing adjustment and modification, and valuation of additional tools to provide improved pharmacotherapy guidance. The questionnaire was developed in collaboration with representative nurse, pharmacist and physician team members using the SurveyMonkey.com site and survey tool. The survey link was distributed to caregivers via email. The questionnaire results of 303 respondents were collected into MS Excel and imported into SAS for data summarization. Results A total of 313 responses were obtained. Physician and nurse practitioner groups comprised the majority of the responses. Approximately 80% of the responders considered dosing adjustment important in pediatric pharmacotherapy. While there was general satisfaction with available resources, nearly 75% responded in support of access to predictive tools that facilitate individualized patient pharmacotherapy. The majority of respondents (> 65%) indicated that dosing outside standard practice occurs in 1-20% of their patients, while still a substantial number of respondents (a range of 8 to 20% reflecting the resident and fellow categories) estimated between 20 and 50% of their patients required adjustments outside the standard practice. Conclusions Differences in prescribing habits based on caregiver role, specialty and location were small and likely require further exploration. Existing resources are generally viewed as helpful but inadequate to guide recommendations for individual patients. Decision support systems connected to hospital-based electronic medical records offer the promise of informative and individualized pharmacotherapy guidance.

Abstract Background Inflammatory cytokines play a crucial role in coronary artery disease (CAD). We investigated the association between 48 coding and three non-coding single nucleotide polymorphisms (SNPs) from 35 inflammatory genes and the development of CAD, using a large discordant sibship collection (2699 individuals in 891 families). Methods Family-based association tests (FBAT) and conditional logistic regression (CLR) were applied to single SNPs and haplotypes and, in CLR, traditional risk factors of CAD were adjusted for. Results An association was observed between CAD and a common three-locus haplotype in the interleukin one (IL-1) cluster with P = 0.006 in all CAD cases, P = 0.01 in myocardial infarction (MI) cases and P = 0.0002 in young onset CAD cases (P = 0.05) in young onset CAD cases, more so (P = 0.002) when hypercholesterolaemia was excluded. As many as 82% of individuals affected by CAD had hypercholesterolaemia compared to only 29% of those unaffected, making the two phenotypes difficult to separate. Conclusion Despite the multiple hypotheses tested, the robustness of family design to population confoundings and the consistency with previous findings increase the likelihood of true association. Further investigation using larger data sets is needed in order for this to be confirmed. See the related commentary by Keavney: http://www.biomedcentral.com/1741-7015/8/6

Abstract Background Proteomic profiling using mass spectrometry (MS) is one of the most promising methods for the analysis of complex biological samples such as urine, serum and tissue for biomarker discovery. Such experiments are often conducted using MALDI-TOF (matrix-assisted laser desorption/ionisation time-of-flight) and SELDI-TOF (surface-enhanced laser desorption/ionisation time-of-flight) MS. Using such profiling methods it is possible to identify changes in protein expression that differentiate disease states and individual proteins or patterns that may be useful as potential biomarkers. However, the incorporation of quality control (QC) processes that allow the identification of low quality spectra reliably and hence allow the removal of such data before further analysis is often overlooked. In this paper we describe rigorous methods for the assessment of quality of spectral data. These procedures are presented in a user-friendly, web-based program. The data obtained post-QC is then examined using variance components analysis to quantify the amount of variance due to some of the factors in the experimental design. Results Using data from a SELDI profiling study of serum from patients with different levels of renal function, we show how the algorithms described in this paper may be used to detect systematic variability within and between sample replicates, pooled samples and SELDI chips and spots. Manual inspection of those spectral data that were identified as being of poor quality confirmed the efficacy of the algorithms. Variance components analysis demonstrated the relatively small amount of technical variance attributable to day of profile generation and experimental array. Conclusion Using the techniques described in this paper it is possible to reliably detect poor quality data within proteomic profiling experiments undertaken by MS. The removal of these spectra at the initial stages of the analysis substantially improves the confidence of putative biomarker identification and allows inter-experimental comparisons to be carried out with greater confidence.

Abstract Background Recent genome-wide association (GWA) studies have provided compelling evidence of association between genetic variants and common complex diseases. These studies have made use of cases and controls almost exclusively from populations of European ancestry and little is known about the frequency of risk alleles in other populations. The present study addresses the transferability of disease associations across human populations by examining levels of population differentiation at disease-associated single nucleotide polymorphisms (SNPs). Methods We genotyped ~1000 individuals from 53 populations worldwide at 25 SNPs which show robust association with 6 complex human diseases (Crohn's disease, type 1 diabetes, type 2 diabetes, rheumatoid arthritis, coronary artery disease and obesity). Allele frequency differences between populations for these SNPs were measured using Fst. The Fst values for the disease-associated SNPs were compared to Fst values from 2750 random SNPs typed in the same set of individuals. Results On average, disease SNPs are not significantly more differentiated between populations than random SNPs in the genome. Risk allele frequencies, however, do show substantial variation across human populations and may contribute to differences in disease prevalence between populations. We demonstrate that, in some cases, risk allele frequency differences are unusually high compared to random SNPs and may be due to the action of local (i.e. geographically-restricted) positive natural selection. Moreover, some risk alleles were absent or fixed in a population, which implies that risk alleles identified in one population do not necessarily account for disease prevalence in all human populations. Conclusion Although differences in risk allele frequencies between human populations are not unusually large and are thus likely not due to positive local selection, there is substantial variation in risk allele frequencies between populations which may account for differences in disease prevalence between human populations.

Abstract Background Decision analysis in hospital-based settings is becoming more common place. The application of modeling and simulation approaches has likewise become more prevalent in order to support decision analytics. With respect to clinical decision making at the level of the patient, modeling and simulation approaches have been used to study and forecast treatment options, examine and rate caregiver performance and assign resources (staffing, beds, patient throughput). There us a great need to facilitate pharmacotherapeutic decision making in pediatrics given the often limited data available to guide dosing and manage patient response. We have employed nonlinear mixed effect models and Bayesian forecasting algorithms coupled with data summary and visualization tools to create drug-specific decision support systems that utilize individualized patient data from our electronic medical records systems. Methods Pharmacokinetic and pharmacodynamic nonlinear mixed-effect models of specific drugs are generated based on historical data in relevant pediatric populations or from adults when no pediatric data is available. These models are re-executed with individual patient data allowing for patient-specific guidance via a Bayesian forecasting approach. The models are called and executed in an interactive manner through our web-based dashboard environment which interfaces to the hospital's electronic medical records system. Results The methotrexate dashboard utilizes a two-compartment, population-based, PK mixed-effect model to project patient response to specific dosing events. Projected plasma concentrations are viewable against protocol-specific nomograms to provide dosing guidance for potential rescue therapy with leucovorin. These data are also viewable against common biomarkers used to assess patient safety (e.g., vital signs and plasma creatinine levels). As additional data become available via therapeutic drug monitoring, the model is re-executed and projections are revised. Conclusion The management of pediatric pharmacotherapy can be greatly enhanced via the immediate feedback provided by decision analytics which incorporate the current, best-available knowledge pertaining to dose-exposure and exposure-response relationships, especially for narrow therapeutic agents that are difficult to manage.

Abstract Background Cigarette smoking and chemical occupational exposure are the main known risk factors for bladder transitional cell carcinoma (TCC). Oxidative DNA damage induced by carcinogens present in these exposures requires accurate base excision repair (BER). The XRCC1 protein plays a crucial role in BER by acting as a scaffold for other BER enzymes. Variants in the XRCC1 gene might alter protein structure or function or create alternatively spliced proteins which may influence BER efficiency and hence affect individual susceptibility to bladder cancer. Recent epidemiological studies have shown inconsistent associations between these polymorphisms and bladder cancer. To clarify the situation, we conducted a comprehensive analysis of 14 XRCC1 polymorphisms in a case-control study involving more than 1100 subjects. Results We found no evidence of an association between any of the 14 XRCC1 polymorphisms and bladder cancer risk. However, we found carriage of the variant Arg280His allele to be marginally associated with increased bladder cancer risk compared to the wild-type genotype (adjusted odds ratio [95% confidence interval], 1.50 [0.98–2.28], p = 0.06). The association was stronger for current smokers such that individuals carrying the variant 280His allele had a two to three-fold increased risk of bladder cancer compared to those carrying the wildtype genotype (p = 0.09). However, the evidence for gene-environment interaction was not statistically significant (p = 0.45). Conclusion We provide no evidence of an association between polymorphisms in XRCC1 and bladder cancer risk, although our study had only limited power to detect the association for low frequency variants, such as Arg280His.

The relationship between acute pain and the cardiovascular system was recognized approximately 50 years ago following the initial observation, along with several subsequent experimental studies, that hypertension can result in decreases in the perception of pain. These studies provided a strong impetus to study potential mechanisms to clarify commonalities between the regulatory pathways associated with pain and the cardiovascular system. Attention subsequently shifted to an emphasis on the impact of chronic pain on cardiovascular diseases and mortality with several large meta-analyses of longitudinal studies providing clear evidence that chronic widespread pain increases the risk for developing cardiovascular disease and is associated with excess morbidity and mortality. Cardiovascular associated mortality from myocardial infarction and stroke appears to be directly related to the duration and severity of chronic pain, a result often characterized as a 'dose-response' relationship. The availability and reproducibility of extensive large-scale observational and retrospective studies have emphasized the critical need for more research, including prospective studies, along with the need for the development of preclinical animal models, to better understand the relationship(s) and underlying mechanisms between chronic pain, associated comorbidities, and cardiovascular disease. Elucidation and a deeper understanding of these relationships, including a focus on the link between chronic pain, cardiovascular disease, and depression, could provide valuable information to guide the development of potential treatment interventions to aid in attenuating pain while preventing pain-associated cardiovascular disease, comorbidities, and mortality., 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 © 2024 Elsevier Inc. All rights reserved.)

Endometrial cancer (EC) is the most prevalent gynaecological cancer in high-income countries and its incidence is continuing to rise sharply. Simple and objective tools to reliably detect women with EC are urgently needed. We recently developed and validated the DNA methylation (DNAme)-based women's cancer risk identification-quantitative polymerase chain reaction test for endometrial cancer (WID-qEC) test that could address this need. Here, we demonstrate that the stability of the WID-qEC test remains consistent regardless of: (i) the cervicovaginal collection device and sample media used (Cervex brush and PreservCyt or FLOQSwab and eNAT), (ii) the collector of the specimen (gynaecologist- or patient-based), and (iii) the precise sampling site (cervical, cervicovaginal and vaginal). Furthermore, we demonstrate sample stability in eNAT medium for 7 days at room temperature, greatly facilitating the implementation of the test into diagnostic laboratory workflows. When applying FLOQSwabs (Copan) in combination with the eNAT (Copan) sample collection media, the sensitivity and specificity of the WID-qEC test to detect uterine (i.e., endometrial and cervical) cancers in gynaecologist-taken samples was 92.9% (95% confidence interval [CI] = 75.0%-98.8%) and 98.6% (95% CI = 91.7%-99.9%), respectively, whilst the sensitivity and specificity in patient collected self-samples was 75.0% (95% CI = 47.4%-91.7%) and 100.0% (95% CI = 93.9%-100.0%), respectively. Taken together these data confirm the robustness and clinical potential of the WID-qEC test., (© 2024 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Anxiety is a part of the human condition and has been managed by psychoactive substances for centuries. The current medical need and societal demand for anxiolytic medicines has not abated. The present overview provides a brief historical introduction to the discovery of modern age anxiolytics that include the benzodiazepines together with a discussion of the continuing medical need for new antianxiety medications. The paper also discusses the use and impact of behavioral pharmacology in the preclinical development of anxiolytics. The review then highlights the diversity of mechanisms for creating a new generation of anxiolytics through mechanisms beyond the potentiation of GABA A receptors and the blockade of monoamine uptake. A discussion then follows on the behavioral specificity of action of anxiolytics that includes the concept of creating an anxioselective drug, one that targets anxiety without producing untoward effects that include sedation and dependence. The use of anxiolytics in the treatment of other conditions such as substance use disorder is also briefly reviewed. Finally, a brief summary of the current status of anxiolytic drug development is provided. The review concludes with the idea that despite a host of anxiolytic drugs, the lack of efficacy in some patients and the side-effects and safety issues associated with some of these medications demands alternative medicines. Current preclinical and clinical research is ongoing with the goal of identifying such compounds., Competing Interests: Declaration of competing interest The authors have no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Cervical cancer (CC) screening in women comprises human papillomavirus (HPV) testing followed by cytology triage of positive cases. Drawbacks, including cytology's low reproducibility and requirement for short screening intervals, raise the need for alternative triage methods. Here we used an innovative triage technique, the WID-qCIN test, to assess the DNA methylation of human genes DPP6, RALYL and GSX1 in a real-life cohort of 28,017 women aged ≥30 years who attended CC screening in Stockholm between January and March 2017. In the analysis of all 2,377 HPV-positive samples, a combination of WID-qCIN (with a predefined threshold) and HPV16 and/or HPV18 (HPV16/18) detected 93.4% of cervical intraepithelial neoplasia grade 3 and 100% of invasive CCs. The WID-qCIN/HPV16/18 combination predicted 69.4% of incident cervical intraepithelial neoplasia grade 2 or worse compared with 18.2% predicted by cytology. Cytology or WID-qCIN/HPV16/18 triage would require 4.1 and 2.4 colposcopy referrals to detect one cervical intraepithelial neoplasia grade 2 or worse, respectively, during the 6 year period. These findings support the use of WID-qCIN/HPV16/18 as an improved triage strategy for HPV-positive women., (© 2024. The Author(s).)

Drylands are unique among terrestrial ecosystems in that they have a significant proportion of primary production facilitated by non-vascular plants such as colonial cyanobacteria, moss, and lichens, i.e., biocrusts, which occur on and in the surface soil. Biocrusts inhabit all continents, including Antarctica, an increasingly dynamic continent on the precipice of change. Here, we describe in-situ field surveying and sampling, remote sensing, and modeling approaches to assess the habitat suitability of biocrusts in the Lake Fryxell basin of Taylor Valley, Antarctica, which is the main site of the McMurdo Dry Valleys Long-Term Ecological Research Program. Soils suitable for the development of biocrusts are typically wetter, less alkaline, and less saline compared to unvegetated soils. Using random forest models, we show that gravimetric water content, electrical conductivity, and snow frequency are the top predictors of biocrust presence and biomass. Areas most suitable for the growth of dense biocrusts are soils associated with seasonal snow patches. Using geospatial data to extrapolate our habitat suitability model to the whole basin predicts that biocrusts are present in 2.7 × 10 5 m 2 and contain 11-72 Mg of aboveground carbon, based on the 90% probability of occurrence. Our study illustrates the synergistic effect of combining field and remote sensing data for understanding the distribution and biomass of biocrusts, a foundational community in the carbon balance of this region. Extreme weather events and changing climate conditions in this region, especially those influencing snow accumulation and persistence, could have significant effects on the future distribution and abundance of biocrusts and therefore soil organic carbon storage in the McMurdo Dry Valleys., Competing Interests: The authors declare that they have no competing interests., (© 2024 The Author(s). Ecology and Evolution published by John Wiley & Sons Ltd.)

Oxycodone, a semisynthetic derivative of naturally occurring thebaine, an opioid alkaloid, has been available for more than 100 years. Although thebaine cannot be used therapeutically due to the occurrence of convulsions at higher doses, it has been converted to a number of other widely used compounds that include naloxone, naltrexone, buprenorphine, and oxycodone. Despite the early identification of oxycodone, it was not until the 1990s that clinical studies began to explore its analgesic efficacy. These studies were followed by the pursuit of several preclinical studies to examine the analgesic effects and abuse liability of oxycodone in laboratory animals and the subjective effects in human volunteers. For a number of years oxycodone was at the forefront of the opioid crisis, playing a significant role in contributing to opioid misuse and abuse, with suggestions that it led to transitioning to other opioids. Several concerns were expressed as early as the 1940s that oxycodone had significant abuse potential similar to heroin and morphine. Both animal and human abuse liability studies have confirmed, and in some cases amplified, these early warnings. Despite sharing a similar structure with morphine and pharmacological actions also mediated by the μ -opioid receptor, there are several differences in the pharmacology and neurobiology of oxycodone. The data that have emerged from the many efforts to analyze the pharmacological and molecular mechanism of oxycodone have generated considerable insight into its many actions, reviewed here, which, in turn, have provided new information on opioid receptor pharmacology. SIGNIFICANCE STATEMENT: Oxycodone, a μ -opioid receptor agonist, was synthesized in 1916 and introduced into clinical use in Germany in 1917. It has been studied extensively as a therapeutic analgesic for acute and chronic neuropathic pain as an alternative to morphine. Oxycodone emerged as a drug with widespread abuse. This article brings together an integrated, detailed review of the pharmacology of oxycodone, preclinical and clinical studies of pain and abuse, and recent advances to identify potential opioid analgesics without abuse liability., (Copyright © 2023 by The American Society for Pharmacology and Experimental Therapeutics.)

The impact of a pathogen on host disease can only be studied in samples covering the entire spectrum of pathogenesis. Persistent oncogenic human papilloma virus (HPV) infection is the most common cause for cervical cancer. Here, we investigate HPV-induced host epigenome-wide changes prior to development of cytological abnormalities. Using cervical sample methylation array data from disease-free women with or without an oncogenic HPV infection, we develop the WID (Women's cancer risk identification)-HPV, a signature reflective of changes in the healthy host epigenome related to high-risk HPV strains (AUC = 0.78, 95% CI: 0.72-0.85, in nondiseased women). Looking at HPV-associated changes across disease development, HPV-infected women with minor cytological alterations (cervical intraepithelial neoplasia grade 1/2, CIN1/2), but surprisingly not those with precancerous changes or invasive cervical cancer (CIN3+), show an increased WID-HPV index, indicating the WID-HPV may reflect a successful viral clearance response absent in progression to cancer. Further investigation revealed the WID-HPV is positively associated with apoptosis (ρ = 0.48; P < .001) and negatively associated with epigenetic replicative age (ρ = -0.43; P < .001). Taken together, our data suggest the WID-HPV captures a clearance response associated with apoptosis of HPV-infected cells. This response may be dampened or lost with increased underlying replicative age of infected cells, resulting in progression to cancer., (© 2023 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

The incidence of endometrial cancer is rising. Measures to identify women at risk and to detect endometrial cancer earlier are required to reduce the morbidity triggered by the aggressive treatment required for advanced endometrial cancer. We developed the WID-EC (Women's cancer risk IDentification-Endometrial Cancer) test, which is based on DNA methylation at 500 CpG sites, in a discovery set of cervical liquid-based cytology samples from 1086 women with and without an endometrial cancer (217 cancer cases and 869 healthy controls) with a worse prognosis (grade 3 or ≥stage IB). We validated the WID-EC test in an independent external validation set of 64 endometrial cancer cases and 225 controls. We further validated the test in 150 healthy women (prospective set) who provided a cervical sample as part of the routine Swedish cervical screening programme, 54 of whom developed endometrial cancer within 3 years of sample collection. The WID-EC test identified women with endometrial cancer with a receiver operator characteristic area under the curve (AUC) of 0.92 (95% CI: 0.88-0.97) in the external set and of 0.82 (95% CI: 0.74-0.89) in the prospective validation set. Using an optimal cutoff, cancer cases were detected with a sensitivity of 86% and a specificity of 90% in the external validation set, and a sensitivity and specificity of 52% and 98% respectively in the prospective validation set. The WID-EC test can identify women with or at risk of endometrial cancer., (© 2022 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Variation in microbial use of soil carbon compounds is a major driver of biogeochemical processes and microbial community composition. Available carbon substrates in soil include both low molecular weight-dissolved organic carbon (LMW-DOC) and volatile organic compounds (VOCs). To compare the effects of LMW-DOC and VOCs on soil chemistry and microbial communities under different moisture regimes, we performed a microcosm experiment with five levels of soil water content (ranging from 25 to 70% water-holding capacity) and five levels of carbon amendment: a no carbon control, two dissolved compounds (glucose and oxalate), and two volatile compounds (methanol and α-pinene). Microbial activity was measured throughout as soil respiration; at the end of the experiment, we measured extractable soil organic carbon and total extractable nitrogen and characterized prokaryotic communities using amplicon sequencing. All C amendments increased microbial activity, and all except oxalate decreased total extractable nitrogen. Likewise, individual phyla responded to specific C amendments-e.g., Proteobacteria increased under addition of glucose, and both VOCs. Further, we observed an interaction between moisture and C amendment, where both VOC treatments had higher microbial activity than LMW-DOC treatments and controls at low moisture. Across moisture and C treatments, we identified that Chloroflexi, Nitrospirae, Proteobacteria, and Verrucomicrobia were strong predictors of microbial activity, while Actinobacteria, Bacteroidetes, and Thaumarcheota strongly predicted soil extractable nitrogen. These results indicate that the type of labile C source available to soil prokaryotes can influence both microbial diversity and ecosystem function and that VOCs may drive microbial functions and composition under low moisture conditions., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Cervical screening using primary human papilloma virus (HPV) testing and cytology is being implemented in several countries. Cytology as triage for colposcopy referral suffers from several shortcomings. HPV testing overcomes some of these but lacks specificity in women under 30. Here, we aimed to develop and validate an automatable triage test that is highly sensitive and specific independently of age and sample heterogeneity, and predicts progression to CIN3+ in HPV+ patients., Results: The WID™-qCIN, assessing three regions in human genes DPP6, RALYL, and GSX1, was validated in both a diagnostic (case-control) and predictive setting (nested case-control), in a total of 761 samples. Using a predefined threshold, the sensitivity of the WID™-qCIN test was 100% and 78% to detect invasive cancer and CIN3, respectively. Sensitivity to detect CIN3+ was 65% and 83% for women < and ≥ 30 years of age. The specificity was 90%. Importantly, the WID™-qCIN test identified 52% of ≥ 30-year-old women with a cytology negative (cyt-) index sample who were diagnosed with CIN3 1-4 years after sample donation., Conclusion: We identified suitable DNAme regions in an epigenome-wide discovery using HPV+ controls and CIN3+ cases and established the WID™-qCIN, a PCR-based DNAme test. The WID™-qCIN test has a high sensitivity and specificity that may outperform conventional cervical triage tests and can in an objective, cheap, and scalable fashion identify most women with and at risk of (pre-)invasive cervical cancer. However, evaluation was limited to case-control settings and future studies will assess performance and generalisability in a randomised controlled trial., (© 2022. The Author(s).)

Neuropathic pain, a disease of the somatosensory nervous system, afflicts many individuals and adequate management with current pharmacotherapies remains elusive. The glutamatergic system of neurons, receptors and transporters are intimately involved in pain but, to date, there have been few drugs developed that therapeutically modulate this system. Glutamate transporters, or excitatory amino acid transporters (EAATs), remove excess glutamate around pain transmitting neurons to decrease nociception suggesting that the modulation of glutamate transporters may represent a novel approach to the treatment of pain. This review highlights and summarizes (1) the physiology of the glutamatergic system in neuropathic pain, (2) the preclinical evidence for dysregulation of glutamate transport in animal pain models, and (3) emerging novel therapies that modulate glutamate transporters. Successful drug discovery requires continuous focus on basic and translational methods to fully elucidate the etiologies of this disease to enable the development of targeted therapies. Increasing the efficacy of astrocytic EAATs may serve as a new way to successfully treat those suffering from this devastating disease., 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 © 2022 Elsevier Ltd. All rights reserved.)

Background: Cervical screening is transitioning from primary cytology to primary human papillomavirus (HPV) testing. HPV testing is highly sensitive but there is currently no high-specificity triage method for colposcopy referral to detect cervical intraepithelial neoplasia grade 3 or above (CIN3+) in women positive for high-risk (hr) HPV subtypes. An objective, automatable test that could accurately perform triage, independently of sample heterogeneity and age, is urgently required., Methods: We analyzed DNA methylation at ~850,000 CpG sites across the genome in a total of 1254 cervical liquid-based cytology (LBC) samples from cases of screen-detected histologically verified CIN1-3+ (98% hrHPV-positive) and population-based control women free from any cervical disease (100% hrHPV-positive). Samples were provided by a state-of-the-art population-based cohort biobank and consisted of (i) a discovery set of 170 CIN3+ cases and 202 hrHPV-positive/cytology-negative controls; (ii) a diagnostic validation set of 87 CIN3+, 90 CIN2, 166 CIN1, and 111 hrHPV-positive/cytology-negative controls; and (iii) a predictive validation set of 428 cytology-negative samples (418 hrHPV-positive) of which 210 were diagnosed with CIN3+ in the upcoming 1-4 years and 218 remained disease-free., Results: We developed the WID-CIN (Women's cancer risk IDentification-Cervical Intraepithelial Neoplasia) test, a DNA methylation signature consisting of 5000 CpG sites. The receiver operating characteristic area under the curve (AUC) in the independent diagnostic validation set was 0.92 (95% CI 0.88-0.96). At 75% specificity (≤CIN1), the overall sensitivity to detect CIN3+ is 89.7% (83.3-96.1) in all and 92.7% (85.9-99.6) and 65.6% (49.2-82.1) in women aged ≥30 and &lt;30. In hrHPV-positive/cytology-negative samples in the predictive validation set, the WID-CIN detected 54.8% (48.0-61.5) cases developing 1-4 years after sample donation in all ages or 56.9% (47.6-66.2) and 53.5% (43.7-63.2) in ≥30 and &lt;30-year-old women, at a specificity of 75%., Conclusions: The WID-CIN test identifies the vast majority of hrHPV-positive women with current CIN3+ lesions. In the absence of cytologic abnormalities, a positive WID-CIN test result is likely to indicate a significantly increased risk of developing CIN3+ in the near future., (© 2022. The Author(s).)

Background: Breast cancer is a leading cause of death in premenopausal women. Progesterone drives expansion of luminal progenitor cells, leading to the development of poor-prognostic breast cancers. However, it is not known if antagonising progesterone can prevent breast cancers in humans. We suggest that targeting progesterone signalling could be a means of reducing features which are known to promote breast cancer formation., Methods: In healthy premenopausal women with and without a BRCA mutation we studied (i) estrogen and progesterone levels in saliva over an entire menstrual cycle (n = 20); (ii) cancer-free normal breast-tissue from a control population who had no family or personal history of breast cancer and equivalently from BRCA1/2 mutation carriers (n = 28); triple negative breast cancer (TNBC) biopsies and healthy breast tissue taken from sites surrounding the TNBC in the same individuals (n = 14); and biopsies of ER+ve/PR+ve stage T1-T2 cancers and healthy breast tissue taken from sites surrounding the cancer in the same individuals (n = 31); and (iii) DNA methylation and DNA mutations in normal breast tissue (before and after treatment) from clinical trials that assessed the potential preventative effects of vitamins and antiprogestins (mifepristone and ulipristal acetate; n = 44)., Results: Daily levels of progesterone were higher throughout the menstrual cycle of BRCA1/2 mutation carriers, raising the prospect of targeting progesterone signalling as a means of cancer risk reduction in this population. Furthermore, breast field cancerization DNA methylation signatures reflective of (i) the mitotic age of normal breast epithelium and (ii) the proportion of luminal progenitor cells were increased in breast cancers, indicating that luminal progenitor cells with elevated replicative age are more prone to malignant transformation. The progesterone receptor antagonist mifepristone reduced both the mitotic age and the proportion of luminal progenitor cells in normal breast tissue of all control women and in 64% of BRCA1/2 mutation carriers. These findings were validated by an alternate progesterone receptor antagonist, ulipristal acetate, which yielded similar results. Importantly, mifepristone reduced both the TP53 mutation frequency as well as the number of TP53 mutations in mitotic-age-responders., Conclusions: These data support the potential usage of antiprogestins for primary prevention of poor-prognostic breast cancers., Trial Registration: Clinical trial 1 Mifepristone treatment prior to insertion of a levonorgestrel releasing intrauterine system for improved bleeding control - a randomized controlled trial, clinicaltrialsregister.eu, 2009-009014-40 ; registered on 20 July 2009. Clinical trial 2 The effect of a progesterone receptor modulator on breast tissue in women with BRCA1 and 2 mutations, clinicaltrials.gov, NCT01898312 ; registered on 07 May 2013. Clinical trial 3 A pilot prevention study of the effects of the anti- progestin Ulipristal Acetate (UA) on surrogate markers of breast cancer risk, clinicaltrialsregister.eu, 2015-001587-19 ; registered on 15 July 2015., (© 2022. The Author(s).)

Spironolactone, a potassium-sparing diuretic and aldosterone antagonist, is a mineralocorticoid hormone commonly prescribed to patients suffering from heart failure, hirsutism, dermatological afflictions, and hypertension. Interestingly, relatively little work has been done on the development of vertebrate embryos after exposure to this compound. Here, we treat zebrafish embryos with spironolactone at 10 -6 M, 10 -7 M, or 10 -8 M, and observe them after three to seven days of exposure. While no effect was observed in mortality, we did detect differences in cardiovascular development at 3 dpf and craniofacial development at 5 dpf. At 10 -6 M, smaller atria, ventricles, and blood vessels were observed. The highest concentrations also caused a longer ceratohyal/Meckel's distance, longer palatoquadrate, and smaller angles between the palatoquadrate and both the ceratohyal and Meckel's. Further research of spironolactone's effects on embryonic development could lead to a better understanding of the compound resulting in improved public and environmental health., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: A variety of epigenetic clocks utilizing DNA methylation changes have been developed; these clocks are either tissue-independent or designed to predict chronological age based on blood or saliva samples. Whether discordant tick rates between tissue-specific and general epigenetic clocks play a role in health and disease has not yet been explored., Results: Here we analyze 1941 cervical cytology samples, which contain a mixture of hormone-sensitive cervical epithelial cells and immune cells, and develop the WID general clock (Women's IDentification of risk), an epigenetic clock that is shared by epithelial and immune cells and optimized for cervical samples. We then develop the WID epithelial clock and WID immune clock, which define epithelial- and immune-specific clocks, respectively. We find that the WID-relative-epithelial-age (WID-REA), defined as the difference between the epithelial and general clocks, is significantly reduced in cervical samples from pre-menopausal women with breast cancer (OR 2.7, 95% CI 1.28-5.72). We find the same effect in normal breast tissue samples from pre-menopausal women at high risk of breast cancer and show that potential risk reducing anti-progesterone drugs can reverse this. In post-menopausal women, this directionality is reversed. Hormone replacement therapy consistently leads to a significantly lower WID-REA in cancer-free women, but not in post-menopausal women with breast or ovarian cancer., Conclusions: Our findings imply that there are multiple epigenetic clocks, many of which are tissue-specific, and that the differential tick rate between these clocks may be an informative surrogate measure of disease risk., (© 2022. The Author(s).)

The vast majority of epithelial ovarian cancer arises from tissues that are embryologically derived from the Müllerian Duct. Here, we demonstrate that a DNA methylation signature in easy-to-access Müllerian Duct-derived cervical cells from women with and without ovarian cancer (i.e. referred to as the Women's risk IDentification for Ovarian Cancer index or WID-OC-index) is capable of identifying women with an ovarian cancer in the absence of tumour DNA with an AUC of 0.76 and women with an endometrial cancer with an AUC of 0.81. This and the observation that the cervical cell WID-OC-index mimics the epigenetic program of those cells at risk of becoming cancerous in BRCA1/2 germline mutation carriers (i.e. mammary epithelium, fallopian tube fimbriae, prostate) further suggest that the epigenetic misprogramming of cervical cells is an indicator for cancer predisposition. This concept has the potential to advance the field of risk-stratified cancer screening and prevention., (© 2022. The Author(s).)

Genetic and non-genetic factors contribute to breast cancer development. An epigenome-based signature capturing these components in easily accessible samples could identify women at risk. Here, we analyse the DNA methylome in 2,818 cervical, 357 and 227 matched buccal and blood samples respectively, and 42 breast tissue samples from women with and without breast cancer. Utilising cervical liquid-based cytology samples, we develop the DNA methylation-based Women's risk IDentification for Breast Cancer index (WID-BC-index) that identifies women with breast cancer with an AUROC (Area Under the Receiver Operator Characteristic) of 0.84 (95% CI: 0.80-0.88) and 0.81 (95% CI: 0.76-0.86) in internal and external validation sets, respectively. CpGs at progesterone receptor binding sites hypomethylated in normal breast tissue of women with breast cancer or in BRCA mutation carriers are also hypomethylated in cervical samples of women with poor prognostic breast cancer. Our data indicate that a systemic epigenetic programming defect is highly prevalent in women who develop breast cancer. Further studies validating the WID-BC-index may enable clinical implementation for monitoring breast cancer risk., (© 2022. The Author(s).)

Toll-like receptors were discovered as proteins playing a crucial role in the dorsoventral patterning during embryonic development in the Drosophila melanogaster (D. melanogaster) almost 40 years ago. Subsequently, further research also showed a role of the Toll protein or Toll receptor in the recognition of Gram-positive bacterial and fungal pathogens infecting D. melanogaster. In 1997, the human homolog was reported and the receptor was named the Toll-like receptor 4 (TLR4) that recognizes lipopolysaccharide (LPS) of the Gram-negative bacteria as a pathogen-associated molecular pattern (PAMP). Identification of TLR4 in humans filled the long existing gap in the field of infection and immunity, addressing the mystery surrounding the recognition of foreign pathogens/microbes by the immune system. It is now known that mammals (mice and humans) express 13 different TLRs that are expressed on the outer cell membrane or intracellularly, and which recognize different PAMPs or microbe-associated molecular patterns (MAMPs) and death/damage-associated molecular patterns (DAMPs) to initiate the protective immune response. However, their dysregulation generates profound and prolonged pro-inflammatory immune responses responsible for different inflammatory and immune-mediated diseases. This chapter provides an overview of TLRs in the control of the immune response, their association with different diseases, including TLR single nucleotide polymorphisms (SNPs), interactions with microRNAs (miRs), use in drug development and vaccine design, and expansion in neurosciences to include pain, addiction, metabolism, reproduction, and wound healing., (© 2022. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Despite ever-increasing availability of detailed information about microbial community structure, relationships of microbial diversity with ecosystem functioning remain unclear. We investigated these relationships at the Coweeta Hydrologic Laboratory, where past forest disturbances (e.g., clear-cut) have altered both ecosystem processes (e.g., increased N export) and microbial communities (e.g., increased bacterial diversity). We sampled soils from disturbed and adjacent reference forests, characterized resident microbial communities, and measured several microbial C-cycle and N-cycle process rates. Microbial communities from historically disturbed soils exhibited altered ecosystem functioning, including generally higher rates of C- and N-cycle processes. Disturbed soil microbial communities also exhibited altered ecosystem multifunctionality, a composite variable consisting of all measured process rates as well as extracellular enzyme activities. Although we found few relationships between ecosystem functions and microbial alpha diversity, all functions were correlated with microbial community composition metrics, particularly r:K strategist ratios of bacterial phyla. Additionally, for both ecosystem multifunctionality and specific processes (i.e., C- and N-mineralization), microbial metrics significantly improved models seeking to explain variation in process rates. Our work sheds light on the links between microbial communities and ecosystem functioning and identifies specific microbial metrics important for modeling ecosystem responses to environmental change., (© 2021 by the Ecological Society of America.)

Aims: We have shown that chemokines injected into the periaqueductal gray region of the brain blocks opioid-induced analgesia in the rat cold-water tail flick test (CWTF). The present experiments tested whether chemokine receptor antagonists (CRAs), in combination with sub-analgesic doses of morphine, would provide maximal analgesia in the CWTF test and the mouse formalin pain assay. The effect of CRAs on respiratory depression was also evaluated., Main Methods: One, two or four CRAs (AMD3100/CXCR4, maraviroc/CCR5, RS504393/CCR2 orAZD8797/CX3CR1) were used in combination with sub-analgesic doses of morphine, all given systemically. Pain was assessed using the rat CWTF test or formalin injection into the paw of mice scored by licking. Respiration and oxygen saturation were measured in rats using a MouseOX® Plus - pulse oximeter., Key Findings: In the CWTF test, a sub-maximal dose of morphine in combination with maraviroc alone, maraviroc plus AMD3100, or with the four chemokine receptor antagonists, produced synergistic increases in antinociception. In the formalin test, the combination of four CRAs plus a sub-maximal dose of morphine resulted in increased antinociception in both male and female mice. AMD3100 had an additive effect with morphine in both sexes. Coadministration of CRAs with morphine did not potentiate the opioid respiratory depressive effect., Significance: These results support the conclusion that combinations of CRAs can increase the potency of sub-analgesic doses of morphine analgesia without increasing respiratory depression. The results support an "opioid sparing" strategy for alleviation of pain using reduced doses of opioids in combination with CRAs to achieve maximal analgesia., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Despite the abundance of studies demonstrating the effects of drought on soil microbial communities, the role of land use legacies in mediating these drought effects is unclear. To assess historical land use influences on microbial drought responses, we conducted a drought-rewetting experiment in soils from two adjacent and currently forested watersheds with distinct land use histories: an undisturbed 'reference' site and a 'disturbed' site that was clear-cut and converted to agriculture ~60 years prior. We incubated intact soil cores at either constant moisture or under a drought-rewet treatment and characterized bacterial and fungal communities using amplicon sequencing throughout the experiment. Bacterial alpha diversity decreased following drought-rewetting while fungal diversity increased. Bacterial beta diversity also changed markedly following drought-rewetting, especially in historically disturbed soils, while fungal beta diversity exhibited little response. Additionally, bacterial beta diversity in disturbed soils recovered less from drought-rewetting compared with reference soils. Disturbed soil communities also exhibited notable reductions in nitrifying taxa, increases in putative r-selected bacteria, and reductions in network connectivity following drought-rewetting. Overall, our study reveals historical land use to be important in mediating responses of soil bacterial communities to drought, which will influence the ecosystem-scale trajectories of these environments under ongoing and future climate change., (© 2021 Society for Applied Microbiology and John Wiley & Sons Ltd.)

Land use change has long-term effects on the structure of soil microbial communities, but the specific community assembly processes underlying these effects have not been identified. To investigate effects of historical land use on microbial community assembly, we sampled soils from several currently forested watersheds representing different historical land management regimes (e.g., undisturbed reference, logged, converted to agriculture). We characterized bacterial and fungal communities using amplicon sequencing and used a null model approach to quantify the relative importance of selection, dispersal, and drift processes on bacterial and fungal community assembly. We found that bacterial communities were structured by both selection and neutral (i.e., dispersal and drift) processes, while fungal communities were structured primarily by neutral processes. For both bacterial and fungal communities, selection was more important in historically disturbed soils compared with adjacent undisturbed sites, while dispersal processes were more important in undisturbed soils. Variation partitioning identified the drivers of selection to be changes in vegetation communities and soil properties (i.e., soil N availability) that occur following forest disturbance. Overall, this study casts new light on the effects of historical land use on soil microbial communities by identifying specific environmental factors that drive changes in community assembly., (© 2021. The Author(s).)

Objectives: To assess the impact of variable drug response and measurement error on SBP control., Methods: We simulated a treat-to-target strategy for populations with different pretreatment SBP, whereby medications were added sequentially until measured SBP (mSBP) less than 140 mmHg. Monte Carlo simulations determined variability of both drug response (drugeff ± σdrug; 10 ± 5 mmHg base case) and measurement error (σmeas; 10 mmHg base case) of true SBP (tSBP). The primary outcome measure was the proportion of individuals who achieved target less than 140 mmHg., Results: Decision-making based on mSBP resulted in 35.0% of individuals with initial tSBP 150 mmHg being either inappropriately given, or inappropriately denied a second drug. When the simulation was run for multiple drug titrations, measurement error limited tSBP control for all populations tested. A strategy of drug titration based on a second measurement for individuals at risk of incorrect decisions (mSBP 120-150 mmHg; σmeas 15 mmHg) reduced the proportion above target from 40.1 to 30.0% when initial tSBP 160 mmHg. When the measurement variability for the second reading was reduced below that usually seen in clinical practice (σmeas 5 mmHg), the proportion above target decreased further to 17.4%., Conclusion: In this simulation, measurement error had the greatest impact on the proportion of individuals achieving their SBP target. Efforts to reduce this error through repeated measures, alternative measurement techniques or changing thresholds, are promising strategies to reduce cardiovascular morbidity and mortality and should be investigated in clinical trials. Here we have shown that Monte Carlo simulations are a useful technique to investigate the influence of uncertainty for different hypertension management strategies.

Background: The phase III MRC COIN trial showed no statistically significant benefit from adding the EGFR-target cetuximab to oxaliplatin-based chemotherapy in first-line treatment of advanced colorectal cancer. This study exploits additional information on HER2-HER3 dimerization to achieve patient stratification and reveal previously hidden subgroups of patients who had differing disease progression and treatment response., Methods: HER2-HER3 dimerization was quantified by fluorescence lifetime imaging microscopy in primary tumor samples from 550 COIN trial patients receiving oxaliplatin and fluoropyrimidine chemotherapy with or without cetuximab. Bayesian latent class analysis and covariate reduction was performed to analyze the effects of HER2-HER3 dimer, RAS mutation, and cetuximab on progression-free survival and overall survival (OS). All statistical tests were two-sided., Results: Latent class analysis on a cohort of 398 patients revealed two patient subclasses with differing prognoses (median OS = 1624 days [95% confidence interval [CI] = 1466 to 1816 days] vs 461 days [95% CI = 431 to 504 days]): Class 1 (15.6%) showed a benefit from cetuximab in OS (hazard ratio = 0.43, 95% CI = 0.25 to 0.76, P = .004). Class 2 showed an association of increased HER2-HER3 with better OS (hazard ratio = 0.64, 95% CI = 0.44 to 0.94, P = .02). A class prediction signature was formed and tested on an independent validation cohort (n = 152) validating the prognostic utility of the dimer assay. Similar subclasses were also discovered in full trial dataset (n = 1630) based on 10 baseline clinicopathological and genetic covariates., Conclusions: Our work suggests that the combined use of HER dimer imaging and conventional mutation analyses will be able to identify a small subclass of patients (>10%) who will have better prognosis following chemotherapy. A larger prospective cohort will be required to confirm its utility in predicting the outcome of anti-EGFR treatment., (© The Author(s) 2019. Published by Oxford University Press.)

Large-scale electronic health records (EHRs) present an opportunity to quickly identify suitable individuals in order to directly invite them to participate in an observational study. EHRs can contain data from millions of individuals, raising the question of how to optimally select a cohort of size n from a larger pool of size N. In this article, we propose a simple selective recruitment protocol that selects a cohort in which covariates of interest tend to have a uniform distribution. We show that selectively recruited cohorts potentially offer greater statistical power and more accurate parameter estimates than randomly selected cohorts. Our protocol can be applied to studies with multiple categorical and continuous covariates. We apply our protocol to a numerically simulated prospective observational study using an EHR database of stable acute coronary disease patients from 82 089 individuals in the U.K. Selective recruitment designs require a smaller sample size, leading to more efficient and cost-effective studies., (© 2020 The Authors. Statistics in Medicine published by John Wiley & Sons, Ltd.)

We investigated whether motor fascicles of the ulnar nerve can be reliably identified proximal to the wrist. In 17 cadaveric upper limbs, the anterior interosseous nerve was transected at its arborization in the pronator quadratus and transposed to the palmar aspect of the ulnar nerve. The motor fascicular bundle was identified at this level after distinguishing the intraneural epineural involution by microsurgical probing. The motor branch was identified in Guyon's canal and traced retrograde via intraneural dissection to assess accuracy of the original identification. The motor fascicular bundle was found to have been correctly identified in all specimens. We conclude that local anatomic landmarks allow for the motor fascicular group to be correctly identified. Therefore, retrograde, internal dissection of the ulnar nerve is not likely to be required for reliable transfer of anterior interosseous nerve to ulnar nerve motor fascicles.

Post-traumatic stress disorder (PTSD) is a debilitating mental disorder with a prevalence of more than 7% in the US population and 12% in the military. An interaction of childhood trauma with FKBP5 (a glucocorticoid-regulated immunophilin) has been reported to be associated with PTSD in the general population. However, there are few reports on the association of FKBP5 with PTSD, particularly in important high-risk population such as the military. Here, we examined the association between four single-nucleotide polymorphisms (SNPs; rs3800373, rs9296158, rs1360780, rs9470080) covering the FKBP5 gene and probable PTSD in US service members deployed to Iraq and Afghanistan, a high-risk military population (n = 3890) (Hines et al., 2014). We found that probable PTSD subjects were significantly more likely to carry the A-allele of rs3800373, G-allele of rs9296158, C-allele of rs1360780, and C-allele of rs9470080. Furthermore, the four SNPs were in one block of strong pairwise linkage disequilibrium (r = 0.91-0.96). Within the block there were two major haplotypes of CATT and AGCC (rs3800373-rs9296158-rs1360780-rs9470080) that account for 99% of haplotype diversity. The distribution of the AGCC haplotype was significantly higher in probable PTSD subjects compared to non-PTSD (p<.05). The diplotype-based analysis indicated that the AGCC carriers tended to be probable PTSD. In this study, we demonstrated the association between FKBP5 and probable PTSD in US service members deployed to Iraq and Afghanistan, indicating that FKBP5 might be a risk factor for PTSD., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Published by Elsevier Ltd.)

Background: Ankle fractures are a common cause of morbidity that have increased in incidence over the past decade. The purpose of this study was to compare the outcomes and prognosis of various fracture subtypes by using 2 validated patient-reported outcome measures: the Patient-Reported Outcome Measurement Information System (PROMIS) Physical Function (PF) and Pain Interference (PI) Computer Adaptive Tests (CATs)., Methods: Twelve-month postoperative PF and PI CATs were collected for 126 ankle fracture patients presenting between 2014 and 2017. Patients were stratified by ankle fracture subtype and refined by the presence/absence of concomitant deltoid injury or posterior malleolar fracture. Patients defined as members of vulnerable populations and patients presenting more than 2 weeks from time of injury or with prior acute ipsilateral fracture were excluded. The distribution of PF and PI T scores were assessed via a Shapiro-Wilk test and a 1-way analysis of variance. If significant differences were found between groups, pairwise comparisons were tested via Dwass, Steel, and Critchlow-Fligner multiple comparison analysis., Results: Mean values for the PROMIS PF and PI for each fracture subtype were calculated and compared to reference population mean (SD) T scores of 50 (10): isolated lateral malleolar (PF: 50/PI: 51), isolated medial malleolar (PF: 52/PI: 49), bimalleolar (PF: 48/PI: 50), trimalleoar (PF: 47/PI: 51), isolated posterior malleolar (PF: 53/PI: 44), and isolated syndesmotic injury (PF: 60/PI: 46). Shapiro-Wilk test indicated a nonnormal distribution for the postoperative PROMIS PF T scores across all fracture patients ( P = .0421)., Conclusion: Operative fixation of an ankle fracture was able to return most patients to the population mean with regard to PROMIS function and pain regardless of fracture type., Level of Evidence: Level II, prospective comparative study.

In Appalachian ecosystems, forest disturbance has long-term effects on microbially driven biogeochemical processes such as nitrogen (N) cycling. However, little is known regarding long-term responses of forest soil microbial communities to disturbance in the region. We used 16S and ITS sequencing to characterize soil bacterial (16S) and fungal (ITS) communities across forested watersheds with a range of past disturbance regimes and adjacent reference forests at the Coweeta Hydrologic Laboratory in the Appalachian mountains of North Carolina. Bacterial communities in previously disturbed forests exhibited consistent responses, including increased alpha diversity and increased abundance of copiotrophic (e.g., Proteobacteria) and N-cycling (e.g., Nitrospirae) bacterial phyla. Fungal community composition also showed disturbance effects, particularly in mycorrhizal taxa. However, disturbance did not affect fungal alpha diversity, and disturbance effects were not consistent at the fungal class level. Co-occurrence networks constructed for bacteria and fungi showed that disturbed communities were characterized by more connected and tightly clustered network topologies, indicating that disturbance alters not only community composition but also potential ecological interactions among taxa. Although bacteria and fungi displayed different long-term responses to forest disturbance, our results demonstrate clear responses of important bacterial and fungal functional groups (e.g., nitrifying bacteria and mycorrhizal fungi), and suggest that both microbial groups play key roles in the long-term alterations to biogeochemical processes observed following forest disturbance in the region., (Copyright © 2019 Osburn, McBride, Aylward, Badgley, Strahm, Knoepp and Barrett.)

With the success rate of drugs for CNS indications at an all-time low, new approaches are needed to turn the tide of failed clinical trials. This paper reviews the history of CNS drug Discovery over the last 60 years and proposes a new paradigm based on the lessons learned. The initial wave of successful therapeutics discovered using careful clinical observations was followed by an emphasis on a phenotypic target-agnostic approach, often leading to successful drugs with a rich pharmacology. The subsequent introduction of molecular biology and the focus on a target-driven strategy has largely dominated drug discovery efforts over the last 30 years, but has not increased the probability of success, because these highly selective molecules are unlikely to address the complex pathological phenotypes of most CNS disorders. In many cases, reliance on preclinical animal models has lacked robust translational power. We argue that Quantitative Systems Pharmacology (QSP), a mechanism-based computer model of biological processes informed by preclinical knowledge and enhanced by neuroimaging and clinical data could be a new powerful knowledge generator engine and paradigm for rational polypharmacy. Progress in the academic discipline of computational neurosciences, allows one to model the effect of pathology and therapeutic interventions on neuronal circuit firing activity that can relate to clinical phenotypes, driven by complex properties of specific brain region activation states. The model is validated by optimizing the correlation between relevant emergent properties of these neuronal circuits and historical clinical and imaging datasets. A rationally designed polypharmacy target profile will be discovered using reverse engineering and sensitivity analysis. Small molecules will be identified using a combination of Artificial Intelligence methods and computational modeling, tested subsequently in heterologous cellular systems with human targets. Animal models will be used to establish target engagement and for ADME-Tox, with the QSP approach complemented by in vivo preclinical models that can be further refined to increase predictive validity. The QSP platform can also mitigate the variability in clinical trials with the concept of virtual patients. Because the QSP platform integrates knowledge from a wide variety of sources in an actionable simulation, it offers the possibility of substantially improving the success rate of CNS R&D programs while, at the same time, reducing both cost and the number of animals.

Unlike other macroecological principles, relationships between productivity and diversity have not been effectively tested for microbial communities. Here we describe an experiment in which the availability of resources to soil bacterial communities was manipulated in a model system, the McMurdo Dry Valleys of Antarctica. Mannitol additions were used to simulate a productivity gradient such that a response in bacterial biomass production, taxonomic diversity and functioning (e.g., enzyme activity) were induced. Resource amendment induced a positive linear response in microbial productivity (P < 0.001) but a unimodal (hump-shaped) response in microbial diversity at multiple taxonomic scales (P = 0.035). Putative oligotrophic (e.g., phyla Nitrospirae and Cyanobacteria) and copiotrophic (e.g., phylum Proteobacteria) taxa were apparent through substantial community turnover along the resource gradient. Soil enzyme activity was inversely related to bacterial biomass but positively related to diversity, suggesting the latter may be a stronger control over enzyme-mediated decomposition. The mechanisms behind this pattern are consistent with macroecological theory of a shift from environmental (e.g., stress tolerance) to biotic (e.g., competition) drivers with increasing resource availability. This evidence is among the first of its kind to document a significant unimodal productivity-diversity relationship for soil bacteria., (© 2019 Society for Applied Microbiology and John Wiley & Sons Ltd.)

Background: Therapeutic plasma exchange (PE) or plasmapheresis is an extracorporeal procedure employed to treat immunological disorders. Exosomes, nanosized vesicles of endosomal origin, mediate intercellular communication by transferring cargo proteins and nucleic acids and regulate many pathophysiological processes. Exosomal miRNAs are potential biomarkers due to their stability and dysregulation in diseases including complex regional pain syndrome (CRPS), a chronic pain disorder with persistent inflammation. A previous study showed that a subset of CRPS patients responded to PE., Methods: As a proof-of-concept, we investigated the PE-induced exosomal miRNA changes in six CRPS patients. Plasma cytokine levels were measured by HPLC and correlated with miRNA expression. Luciferase assay following co-transfection of HEK293 cells with target 3'UTR constructs and miRNA mimics was used to evaluate miRNA mediated gene regulation of target mRNA. Transient transfection of THP-1 cells with miRNA mimics followed by estimation of target gene and protein expression was used to validate the findings., Results: Comparison of miRNAs in exosomes from the serum of three responders and three poor-responders showed that 17 miRNAs differed significantly before and after therapy. Of these, poor responders had lower exosomal hsa-miR-338-5p. We show that miR-338-5p can bind to the interleukin 6 (IL-6) 3' untranslated region and can regulate IL-6 mRNA and protein levels in vitro. PE resulted in a significant reduction of IL-6 in CRPS patients., Conclusions: We propose that lower pretreatment levels of miR-338-5p in poor responders are linked to IL-6 levels and inflammation in CRPS. Our data suggests the feasibility of exploring exosomal miRNAs as a strategy in patient stratification for maximizing therapeutic outcome of PE.