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BackgroundHome assessment is a critical component of successful home modifications, enabling individuals with functional limitations to age in place comfortably. A high-quality home assessment tool should facilitate a valid and reliable assessment involving health care and housing professionals, while also engaging and empowering consumers and their caregivers who may be dealing with multiple functional limitations. Unlike traditional paper-and-pencil assessments, which require extensive training and expert knowledge and can be alienating to consumers, mobile health (mHealth) apps have the potential to engage all parties involved, empowering and activating consumers to take action. However, little is known about which apps contain all the necessary functionality, quality appraisal, and accessibility. ObjectiveThis study aimed to assess the functionality, overall quality, and accessibility of mHealth home assessment apps. MethodsmHealth apps enabling home assessment for aging in place were identified through a comprehensive search of scholarly articles, the Apple (iOS) and Google Play (Android) stores in the United States, and fnd.io. The search was conducted between November 2022 and January 2023 following a method adapted from PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses). Reviewers performed a content analysis of the mobile app features to evaluate their functionality, overall quality, and accessibility. The functionality assessment used a home assessment component matrix specifically developed for this study. For overall quality, the Mobile Application Rating Scale (MARS) was used to determine the apps’ effectiveness in engaging and activating consumers and their caregivers. Accessibility was assessed using the Web Content Accessibility Guidelines (WCAG) 2.1 (A and AA levels). These 3 assessments were synthesized and visualized to provide a comprehensive evaluation. ResultsA total of 698 apps were initially identified. After further screening, only 6 apps remained. Our review revealed that none of the apps used thoroughly tested assessment tools, offered all the functionality required for reliable home assessment, achieved the “good” quality threshold as measured by the MARS, or met the accessibility criteria when evaluated against WCAG 2.1. However, DIYModify received the highest scores in both the overall quality and accessibility assessments. The MapIt apps also showed significant potential due to their ability to measure the 3D environment and the inclusion of a desktop version that extends the app’s functionality. ConclusionsOur review revealed that there are very few apps available within the United States that possess the necessary functionality, engaging qualities, and accessibility to effectively activate consumers and their caregivers for successful home modification. Future app development should prioritize the integration of reliable and thoroughly tested assessment tools as the foundation of the development process. Furthermore, efforts should be made to enhance the overall quality and accessibility of these apps to better engage and empower consumers to take necessary actions to age in place.

The human mammary gland is the major organ involved in lactation. In the mammary gland, alveoli secrete milk and myoepithelial cells contract to propel the milk through branched structures called ducts and eventually to the nipple. It is through this process of lactation that infants receive milk, which is essential for proper infant growth and development. The lactation process is comprised of sophisticated interactive networks at the cellular level that are not well understood. Whereas the majority of published mammary gland lactation studies have relied on mouse mammary glands, recent advancements in techniques to study mammary glands enable in vitro reproduction of lactation using human-representative frameworks. Currently, the 3D breast organoid is the state-of-the-art model in human mammary gland research, utilizing induced pluripotent stem cells (iPSCs) or processed patient-derived breast tissues embedded in a special matrix that are then able to grow into complex structures that recapitulate aspects of native human breast tissue. Gaining comprehensive biological insight into the process of lactation through these breast tissue-mimetic 3D models is essential for further studies on lactation-associated human mammary gland diseases, human milk composition, and potential solutions to challenges in maternal milk accessibility. In this short review, the benefits and potential utility of 3D breast organoids in understanding the underlying science of lactation and advancing further human mammary gland studies are discussed.

AbstractBeing a teacher or a student in a class with a large enrollment can be intimidating. Often, teachers view comforts that are common to small classes as unattainable in a larger class, including knowing students’ names, using active learning, employing group work, and creating group discussion. Students in large classes may find that the class size leads to isolation. At Utah State University, we offer introductory statistics classes for various audiences using a large lecture format. The authors have collectively led these large lectures dozens of times and found that, despite its shortcomings, the large lecture format can be an asset when teaching statistics. With an active learning approach such as recommended by the revised GAISE College report, large class sizes permit realistic sampling, facilitate student-driven simulation, and provide bountiful opportunities for experimentation. In this article, we discuss the benefits of large classes for statistics teaching and present examples of using large class sizes to create an engaging environment that where students are involved in active learning and collecting real data to foster statistical thinking.

Abstract Background Hypercholesterolemia is associated with tendon pathology, but the reasons underpinning this relationship are not well understood. Cholesterol can accumulate in the tendon non-collagenous matrix which may affect both global and local tissue mechanics. Changes to the local strain environment within tendon may have significant implications for mechanosensitive tenocytes. Here, we investigated the association between elevated blood cholesterol and presence of tendon lipids in the Achilles tendon. We expected lipids to be localised in the proteoglycan-rich inter-sub-tendon matrix (ISTM), therefore we also sought to examine the impact of this on the biomechanical and viscoelastic properties of the ISTM. Methods The Achilles tendons of 32 young wild-type (SD) and 32 apolipoprotein E knock-out rats (ApoE −/− ) were harvested at 15.6 ± 2.3 weeks of age. 32 specimens underwent histological examination to assess the distribution of lipids throughout sub-tendons and ISTM. The remaining specimens were prepared for biomechanical testing, where the ISTM between the gastrocnemius and soleus sub-tendons was subjected to shear load mechanical testing. A sub-set of tests were video recorded to enable a strain analysis. Results ApoE −/− serum cholesterol was double that of SD rats (mean 2.25 vs. 1.10 mg/ml, p

Abstract BackgroundThe Augmented Reality Home Assessment Tool (ARHAT) is a mobile app developed to provide rapid, highly accurate assessments of the home environment. It uses 3D-capture technologies to help people identify and address functional limitations and environmental barriers. ObjectiveThis study was conducted to gain stakeholder feedback on the acceptability and appropriateness of the ARHAT for identifying and addressing barriers within home environments. MethodsA qualitative descriptive study was conducted because it allows for variability when obtaining data and seeks to understand stakeholders’ insights on an understudied phenomenon. Each stakeholder group (occupational therapists, housing professionals, and aging adult and caregiver “dyads”) participated in a 60-minute, web-based focus group via a secure Zoom platform. Focus group data were analyzed by 2 trained qualitative research team members using a framework method for analysis. ResultsA total of 19 stakeholders, aged from 18 to 85+ years, were included in the study. Of the occupational therapists (n=5, 26%), housing professionals (n=3, 16%), and dyads (n=11, 58%), a total of 32% (n=6) were male and 68% (n=13) were female, with most living in the Midwestern United States (n=10, 53%). The focus group data demonstrate the acceptability and appropriateness of the workflow, style, measurement tools, and impact of the ARHAT. All stakeholders stated that they could see the ARHAT being used at many different levels and by any population. Dyads specifically mentioned that the ARHAT would allow them to do forward planning and made them think of home modifications in a new light. ConclusionsStakeholders found the ARHAT to be acceptable and appropriate for identifying and addressing functional limitations and barriers in the home environment. This study highlights the importance of considering the workflow, style, measurement tools, and potential impact of home assessment technology early in the developmental process.

Abstract Sustained elevation in neutrophil‐to‐lymphocyte ratio (NLR) after initial chemoradiotherapy (CRT) has been shown to correlate with worse prognosis in a number of solid organ malignancies. Here, we conducted a retrospective observational cohort study involving six sites across Sydney, Australia, including all patients with unresectable stage III NSCLC treated with CRT and consolidation durvalumab between January 2018 and September 2021. Patients had NLR collected prior to CRT and prior to cycle one of durvalumab. We used an NLR value of 3 to stratify patients into high and low groups. Patients with sustained NLR were defined as those with values ≥3 at both timepoints. A total of 145 patients were included in the study. The median age of patients was 66 years with median follow‐up of 15.1 months. The median PFS was 17.6 months in the pre‐CRT NLR high cohort and not reached (NR) in the pre‐CRT NLR low cohort (HR 1.99; p = 0.01). The median OS was 35.5 months in the high pre‐CRT NLR cohort compared with 42.0 months in the low pre‐CRT NLR cohort (HR 2.62; 95% CI: 1.23–5.56, p

Metastatic cutaneous squamous cell carcinoma (CSCC) is a highly morbid disease requiring radical surgery and adjuvant therapy, which is associated with a poor prognosis. Yet, compared to other advanced malignancies, relatively little is known of the genomic landscape of metastatic CSCC. We have previously reported the mutational signatures and mutational patterns of CCCTC-binding factor (CTCF) regions in metastatic CSCC. However, many other genomic components (indel signatures, non-coding drivers, and structural variants) of metastatic CSCC have not been reported. To this end, we performed whole genome sequencing on lymph node metastases and blood DNA from 25 CSCC patients with regional metastases of the head and neck. We designed a multifaceted computational analysis at the whole genome level to provide a more comprehensive perspective of the genomic landscape of metastatic CSCC. In the non-coding genome, 3′ untranslated region (3′UTR) regions of EVC (48% of specimens), PPP1R1A (48% of specimens), and ABCA4 (20% of specimens) along with the tumor-suppressing long non-coding RNA (lncRNA) LINC01003 (64% of specimens) were significantly functionally altered (Q-value < 0.05) and represent potential non-coding biomarkers of CSCC. Recurrent copy number loss in the tumor suppressor gene PTPRD was observed. Gene amplification was much less frequent, and few genes were recurrently amplified. Single nucleotide variants driver analyses from three tools confirmed TP53 and CDKN2A as recurrently mutated genes but also identified C9 as a potential novel driver in this disease. Furthermore, indel signature analysis highlighted the dominance of ID signature 13 (ID13) followed by ID8 and ID9. ID9 has previously been shown to have no association with skin melanoma, unlike ID13 and ID8, suggesting a novel pattern of indel variation in metastatic CSCC. The enrichment analysis of various genetically altered candidates shows enrichment of “TGF-beta regulation of extracellular matrix” and “cell cycle G1 to S check points.” These enriched terms are associated with genetic instability, cell proliferation, and migration as mechanisms of genomic drivers of metastatic CSCC.

The supply of, and demand for, housing in Aotearoa, New Zealand, is in a state of crisis. With all other areas of social deprivation, Māori are impacted disproportionately in the housing space, and have been locked out of the housing market. In order to address this crisis, a range of government, community and iwi initiatives have been established in Tāmaki Makaurau (Auckland) to provide various housing interventions, from emergency housing, accommodation supplements and subsidies to transitional housing, home ownership programmes and papakāinga (Māori settlement, village) development opportunities. Marae Ora, Kāinga Ora (MOKO) is a Kaupapa Māori (Māori approach) research project created to explore the role of marae (cultural centre) and kāinga (village, settlement) in supporting the wellbeing of whānau (family group), hapū (extended kinship grouping), iwi (extended kinship–tribal grouping) and communities, which includes the potential provision of housing. Five marae in the South Auckland landscape are partners in this research and bring to life the prospect of their contribution to housing solutions for their local Māori communities. This article presents some valuable insights into the aspirations of each whānau involved with the five marae with regard to their perspectives and developments with marae-led housing provision.

Abstract Background/aim In the beginning of 2020, the novel Coronavirus disease (COVID-19) caused by the SARS-CoV-2 virus, became a public health emergency in the U.S. and rapidly escalated into a global pandemic. Because the SARS-CoV-2 virus is highly contagious, physical distancing was enforced and indoor public spaces, including schools and educational institutions, were abruptly closed and evacuated to ensure civilian safety. Accordingly, educational institutions rapidly transitioned to remote learning. We investigated the impacts of the COVID-19 pandemic on domestic U.S. college students, ages 18–24 years. Methods Through Pollfish®’s survey research platform, we collected data from 200 domestic U.S. college students in this age range (N = 200) regarding the physical, emotional, and social impacts of COVID-19 as well as key background information (e.g. whether or not they are first-generation or if they identify with the LGBTQIA+ community). Results Our results indicate that students closer to graduating faced increases in anxiety (60.8%), feeling of loneliness (54.1%), and depression (59.8%). Many reported worries for the health of loved ones most impacted their mental health status (20.0%), and the need to take care of family most affected current and future plans (31.8%). Almost one-half of students took to exercising and physical activity to take care of their mental health (46.7%). While a third did not have strained familial relationships (36.5%), almost one half did (45.7%). A majority found it harder to complete the semester at home (60.9%), especially among those who had strained relationships with family (34.1%). Seventy percent spent time during the pandemic watching television shows or movies. Significantly more men, first-generation, and low-income students gained beneficial opportunities in light of the pandemic, whereas their counterparts reported no impact. First-generation students were more likely to take a gap year or time off from school. Conclusions Although students found ways to take care of themselves and spent more time at home, the clear negative mental health impacts call for schools and federal regulations to accommodate, support, and make mental health care accessible to all students.

Background & Aims: Serum microRNA (miRNA) levels are known to change in non-alcoholic fatty liver disease (NAFLD) and may serve as useful biomarkers. This study aimed to profile miRNAs comprehensively at all NAFLD stages. Methods: We profiled 2,083 serum miRNAs in a discovery cohort (183 cases with NAFLD representing the complete NAFLD spectrum and 10 population controls). miRNA libraries generated by HTG EdgeSeq were sequenced by Illumina NextSeq. Selected serum miRNAs were profiled in 372 additional cases with NAFLD and 15 population controls by quantitative reverse transcriptase PCR. Results: Levels of 275 miRNAs differed between cases and population controls. Fewer differences were seen within individual NAFLD stages, but miR-193a-5p consistently showed increased levels in all comparisons. Relative to NAFL/non-alcoholic steatohepatitis (NASH) with mild fibrosis (stage 0/1), 3 miRNAs (miR-193a-5p, miR-378d, and miR378d) were increased in cases with NASH and clinically significant fibrosis (stages 2–4), 7 (miR193a-5p, miR-378d, miR-378e, miR-320b, miR-320c, miR-320d, and miR-320e) increased in cases with NAFLD activity score (NAS) 5–8 compared with lower NAS, and 3 (miR-193a-5p, miR-378d, and miR-378e) increased but 1 (miR-19b-3p) decreased in steatosis, activity, and fibrosis (SAF) activity score 2–4 compared with lower SAF activity. The significant findings for miR-193a-5p were replicated in the additional cohort with NAFLD. Studies in Hep G2 cells showed that following palmitic acid treatment, miR-193a-5p expression decreased significantly. Gene targets for miR-193a-5p were investigated in liver RNAseq data for a case subgroup (n = 80); liver GPX8 levels correlated positively with serum miR-193a-5p. Conclusions: Serum miR-193a-5p levels correlate strongly with NAFLD activity grade and fibrosis stage. MiR-193a-5p may have a role in the hepatic response to oxidative stress and is a potential clinically tractable circulating biomarker for progressive NAFLD. Lay summary: MicroRNAs (miRNAs) are small pieces of nucleic acid that may turn expression of genes on or off. These molecules can be detected in the blood circulation, and their levels in blood may change in liver disease including non-alcoholic fatty liver disease (NAFLD). To see if we could detect specific miRNA associated with advanced stages of NAFLD, we carried out miRNA sequencing in a group of 183 patients with NAFLD of varying severity together with 10 population controls. We found that a number of miRNAs showed changes, mainly increases, in serum levels but that 1 particular miRNA miR-193a-5p consistently increased. We confirmed this increase in a second group of cases with NAFLD. Measuring this miRNA in a blood sample may be a useful way to determine whether a patient has advanced NAFLD without an invasive liver biopsy.

Summary: Many steps of the MHC class I antigen processing pathway can be predicted using computational methods. Here we show that epitope predictions can be further improved by considering abundance levels of peptides' source proteins. We utilized biophysical principles and existing MHC binding prediction tools in concert with abundance estimates of source proteins to derive a function that estimates the likelihood of a peptide to be an MHC class I ligand. We found that this combination improved predictions for both naturally eluted ligands and cancer neoantigen epitopes. We compared the use of different measures of antigen abundance, including mRNA expression by RNA-Seq, gene translation by Ribo-Seq, and protein abundance by proteomics on a dataset of SARS-CoV-2 epitopes. Epitope predictions were improved above binding predictions alone in all cases and gave the highest performance when using proteomic data. Our results highlight the value of incorporating antigen abundance levels to improve epitope predictions.

Abstract Background Kratom is a habit-forming opioid-like substance with an acute toxidrome of various symptoms such as diaphoresis, dizziness, nausea, and vomiting. Chronic users require increasing dosages for the analgesic effects. Although kratom use dates back to the 1800s in Asia, kratom intoxication is still a novel (but increasing) toxidrome in the Western world. Here, we present a novel case of acute toxicity from overdose in a kratom-naïve patient, taking place through recommendation by a family member who chronically takes this substance. Case presentation We present the case of a 62-year-old woman arriving to the emergency department (ED) with a chief complaint of intractable vomiting after ingestion of kratom. After a day of yard work, she was in pain, secondary to her osteoporotic joints. She was recommended kratom from a family member, who stated he was using kratom to transition away from opioid dependence. She took two “scoops.” She proceeded to have multiple episodes of vomiting at home. She came to the ED, where she required multiple rounds of anti-emetic medication for resolution of her symptoms. Discussion We present a classic case of a novel acute toxicity: kratom. A unique aspect of this case is the circumstance by which this toxicity took place: a family member who chronically takes this substance (that requires increasing dosages to remain effective) recommended a dosage to this kratom-naïve patient, leading to overdose. This opioid family alternative substance is gaining popularity across the USA in the era of the opioid crisis. Further documentation of case reports and research is required to learn the associated risks of the use of this substance.

Abstract Background Advance care planning (ACP) facilitates identification and documentation of patients’ treatment preferences. Its goal aligns with that of palliative care – optimizing quality of life of seriously ill patients. However, concepts of ACP and palliative care remain poorly recognized in Chinese population. This study aims at exploring barriers to ACP from perspective of seriously ill patients and their family caregivers. Methods This is a qualitative study conducted in a Palliative Day Care Centre of Hong Kong between October 2016 and July 2017. We carried out focus groups and individual interviews for the seriously ill patients and their family caregivers. A semi-structured interview guide was used to explore participants’ experiences and attitudes about ACP. Qualitative content analysis was adopted to analyze both manifest content and latent content. Results A total of 17 patients and 13 family caregivers participated in our study. The qualitative analysis identified four barriers to ACP: 1) limited patients’ participation in autonomous decision making, 2) cognitive and emotional barriers to discussion, 3) lack of readiness and awareness of early discussion, and 4) unprepared healthcare professionals and healthcare system. Conclusions Participations of seriously ill patients, family caregivers and healthcare workers in ACP initiation are lacking respectively. A series of interventions are necessary to resolve the barriers.

As generalist parasitoid wasps, Leptopilina heterotoma are highly successful on many species of fruit flies of the genus Drosophila. The parasitoids produce specialized multi-strategy extracellular vesicle (EV)-like structures in their venom. Proteomic analysis identified several immunity-associated proteins, including the knottin peptide, LhKNOT, containing the structurally conserved inhibitor cysteine knot (ICK) fold, which is present in proteins from diverse taxa. Our structural and docking analysis of LhKNOT’s 36-residue core knottin fold revealed that in addition to the knottin motif itself, it also possesses a Cation–Polar–Cation (CPC) clip. The CPC clip motif is thought to facilitate antimicrobial activity in heparin-binding proteins. Surprisingly, a majority of ICKs tested also possess the CPC clip motif, including 75 bona fide plant and arthropod knottin proteins that share high sequence and/or structural similarity with LhKNOT. Like LhKNOT and these other 75 knottin proteins, even the Drosophila Drosomycin antifungal peptide, a canonical target gene of the fly’s Toll-NF-kappa B immune pathway, contains this CPC clip motif. Together, our results suggest a possible defensive function for the parasitoid LhKNOT. The prevalence of the CPC clip motif, intrinsic to the cysteine knot within the knottin proteins examined here, suggests that the resultant 3D topology is important for their biochemical functions. The CPC clip is likely a highly conserved structural motif found in many diverse proteins with reported heparin binding capacity, including amyloid proteins. Knottins are targets for therapeutic drug development, and insights into their structure–function relationships will advance novel drug design.

Abstract Background The use of Complementary Medicines (CMs) has significantly increased in Australia over the last decade. This study attempts to determine the extent to which complementary and alternative medicines are recorded, ceased or initiated in the acute hospital setting and investigate which health professionals have a role in this process. Methods A cross-sectional study of inpatients was conducted at a major tertiary teaching hospital. Patient’s medical records were examined to determine the rates of complementary medicine (CM) use and recording on medication charts and discharge prescriptions. Patient progress notes were audited to determine which health professionals were involved with the initiation or cessation of CMs during the inpatient stay. Results Three hundred and forty-one patients were included for analysis of which 44.3% (n = 151) participants were recorded as utilizing a CM. Patients were admitted on a mean of 2 (±1.4[Sd]; 0–9[range]) CMs and discharged on a mean of 1.7 CMs (±1.3[Sd]; 0–5[range]). 274 individual CMs were recorded on inpatient medication reconciliation forms with multivitamins, magnesium, fish oil and cholecalciferol recorded the most frequently. One hundred and fifty-eight changes to patient CM usage were recorded during the patient hospitalisation. One hundred and seven of these changes (68%) were not accounted for in the patient progress notes. Conclusion Patients use of CM in this hospital setting do not reflect the national estimated usage. On the occasions that CM products are included in patient records, they are subsequently deprescribed following patient examination in hospital. It is currently unclear which health professionals have a role in this deprescribing process.

Abstract Aims/Introduction Older people with diabetes mellitus are at high risk for cognitive impairment or dementia. The clinical predictors for cognitive decline in older people with diabetes mellitus were elucidated. Materials and Methods This was a secondary analysis of a vitamin B12 intervention trial in older people with diabetes mellitus. A total of 271 non‐demented individuals were followed up at 9‐month intervals for 27 months. We explored the association between baseline clinical features with changes in cognitive measures (Clinical Dementia Rating scale, Neuropsychological Test Battery including executive function z‐scores, psychomotor speed z‐scores and memory z‐scores). Results A total of 152 participants had normal cognition (Clinical Dementia Rating 0) and 119 had cognitive impairment (Clinical Dementia Rating 0.5) at baseline. After 27 months, 41 participants had cognitive decline, 36 of whom were cognitively normal at baseline. Multiple logistic regression showed no significant clinical predictor of global cognitive decline. Higher high‐density lipoprotein cholesterol (HDL‐C) was associated with better executive performance at month 27 (β = 0.359, P < 0.001). Multilevel modeling showed that the highest tertile of HDL‐C was associated with better executive function z‐scores than the lowest tertile of HDL‐C at all time‐points. Conclusions Among older people with diabetes mellitus, higher serum HDL‐C was associated with better executive function.

Background and purpose: Dose escalation has improved cancer outcomes for patients with localized prostate cancer. Targeting subprostatic tumor regions for dose intensification may further improve outcomes. Apparent Diffusion Coefficient (ADC) maps may enable early radiation response assessment and dose adaptation. This study was a proof-of-principle investigation of early changes in ADC radiomics features for patients undergoing radiotherapy with dose escalation to the gross tumor volume (GTV). Materials and methods: Fifty-nine patients were enrolled on a prospective tumor dose-escalation trial. Multi-parametric MRI was performed at baseline and week six, corresponding to the time of peak ADC change. GTV and prostate contours were deformably registered between baseline and week six T2-weighted images, and applied to ADC maps, to account for diminished image contrast post-EBRT and possible differences in prostate gland volume, shape, and orientation. A total of 101 radiomics features were tested for significant change post-EBRT using two-tailed Student’s t-test. All ADC features of the prostate and GTV volumes were correlated using Pearson’s coefficient (p

Abstract Background Complex multicellularity requires elaborate developmental mechanisms, often based on the versatility of heterodimeric transcription factor (TF) interactions. Homeobox TFs in the TALE superclass are deeply embedded in the gene regulatory networks that orchestrate embryogenesis. Knotted-like homeobox (KNOX) TFs, homologous to animal MEIS, have been found to drive the haploid-to-diploid transition in both unicellular green algae and land plants via heterodimerization with other TALE superclass TFs, demonstrating remarkable functional conservation of a developmental TF across lineages that diverged one billion years ago. Here, we sought to delineate whether TALE-TALE heterodimerization is ancestral to eukaryotes. Results We analyzed TALE endowment in the algal radiations of Archaeplastida, ancestral to land plants. Homeodomain phylogeny and bioinformatics analysis partitioned TALEs into two broad groups, KNOX and non-KNOX. Each group shares previously defined heterodimerization domains, plant KNOX-homology in the KNOX group and animal PBC-homology in the non-KNOX group, indicating their deep ancestry. Protein-protein interaction experiments showed that the TALEs in the two groups all participated in heterodimerization. Conclusions Our study indicates that the TF dyads consisting of KNOX/MEIS and PBC-containing TALEs must have evolved early in eukaryotic evolution. Based on our results, we hypothesize that in early eukaryotes, the TALE heterodimeric configuration provided transcription-on switches via dimerization-dependent subcellular localization, ensuring execution of the haploid-to-diploid transition only when the gamete fusion is correctly executed between appropriate partner gametes. The TALE switch then diversified in the several lineages that engage in a complex multicellular organization.

IntroductionAssociation between elevated cytokeratin 18 (CK-18) levels and hepatocyte death has made circulating CK-18 a candidate biomarker to differentiate non-alcoholic fatty liver from non-alcoholic steatohepatitis (NASH). Yet studies produced variable diagnostic performance. We aimed to provide summary estimates with increased precision for the accuracy of CK-18 (M30, M65) in detecting NASH and fibrosis among non-alcoholic fatty liver disease (NAFLD) adults.MethodsWe searched five databases to retrieve studies evaluating CK-18 against a liver biopsy in NAFLD adults. Reference screening, data extraction and quality assessment (QUADAS-2) were independently conducted by two authors. Meta-analyses were performed for five groups based on the CK-18 antigens and target conditions, using one of two methods: linear mixed-effects multiple thresholds model or bivariate logit-normal random-effects model.ResultsWe included 41 studies, with data on 5,815 participants. A wide range of disease prevalence was observed. No study reported a pre-defined cut-off. Thirty of 41 studies provided sufficient data for inclusion in any of the meta-analyses. Summary AUC [95% CI] were: 0.75 [0.69-0.82] (M30) and 0.82 [0.69-0.91] (M65) for NASH; 0.73 [0.57-0.85] (M30) for fibrotic NASH; 0.68 (M30) for significant (F2-4) fibrosis; and 0.75 (M30) for advanced (F3-4) fibrosis. Thirteen studies used CK-18 as a component of a multimarker model.ConclusionsFor M30 we found lower diagnostic accuracy to detect NASH compared to previous meta-analyses, indicating a limited ability to act as a stand-alone test, with better performance for M65. Additional external validation studies are needed to obtain credible estimates of the diagnostic accuracy of multimarker models.

Efficiency corrected single ratios of neutron and proton spectra in central Sn112+112Sn and Sn124+124Sn collisions at 120 MeV/u are combined with double ratios to provide constraints on the density and momentum dependencies of the isovector mean-field potential. Bayesian analyses of these data reveal that the isoscalar and isovector nucleon effective masses, ms⁎−mv⁎ are strongly correlated. The linear correlation observed in ms⁎−mv⁎ yields a nearly independent constraint on the effective mass splitting Δmnp⁎=(mn⁎−mp⁎)/mN=−0.05−0.09+0.09δ. The correlated constraint on the standard symmetry energy, S0 and the slope, L at saturation density yields the values of symmetry energy S(ρs)=16.8−1.2+1.2 MeV at a sensitive density of ρs/ρ0=0.43−0.05+0.05. Keywords: Symmetry energy, Heavy-ion collisions, Bayesian analysis

The prevalence and severity of non-alcoholic fatty liver disease (NAFLD) is increasing, yet adequately validated tests for care paths are limited and non-invasive markers of disease progression are urgently needed. The aim of this work was to summarize the performance of Pro-C3, a biomarker of active fibrogenesis, in detecting significant fibrosis (F ≥ 2), advanced fibrosis (F ≥ 3), cirrhosis (F4) and non-alcoholic steatohepatitis (NASH) in patients with NAFLD. A sensitive search of five databases was performed in July 2021. Studies reporting Pro-C3 measurements and liver histology in adults with NAFLD without co-existing liver diseases were eligible. Meta-analysis was conducted by applying a bivariate random effects model to produce summary estimates of Pro-C3 accuracy. From 35 evaluated reports, eight studies met our inclusion criteria; 1568 patients were included in our meta-analysis of significant fibrosis and 2058 in that of advanced fibrosis. The area under the summary curve was 0.81 (95% CI 0.77–0.84) in detecting significant fibrosis and 0.79 (95% CI 0.73–0.82) for advanced fibrosis. Our results support Pro-C3 as an important candidate biomarker for non-invasive assessment of liver fibrosis in NAFLD. Further direct comparisons with currently recommended non-invasive tests will demonstrate whether Pro-C3 panels can outperform these tests, and improve care paths for patients with NAFLD.

Marae Ora, Kainga Ora (MOKO) is a three-year research study established as a marae-led intervention project to strengthen the provision of housing with five urban marae in South Auckland, Aotearoa New Zealand. In brief, marae are primarily places for cultural gatherings and are the centres of activity for Māori communities. Though just one of the marae involved is part of a pre-European tribal settlement, the four other marae were established to meet the cultural needs of Māori who had relocated many decades ago from their tribal areas outside of the Auckland region. The project works with Marae Research Coordinators (MRC) nominated by each marae to build research and development capacity and capability through the sharing of skills, information, and resources. Each MRC is affiliated with their respective marae, either through whakapapa (genealogical links) or through their contributions of service and leadership. The role of the MRC is critical in capturing the lived realities, experiences, and aspirations of their marae community. This was evident in the first year of the project (2020) when three of the five marae actively responded to the needs of their communities during COVID-19 lockdowns in Auckland. While the project has a housing focus, the marae involved demonstrate, in their own distinctive ways, how health and wellbeing is intrinsic to their core function.

The study of the origin of asymmetries in mirror β decay is extremely important to understand the fundamental nuclear force and the nuclear structure. The experiment was performed at the National Laboratory of Heavy Ion Research Facility in Lanzhou (HIRFL) to measure the β-delayed γ rays of 26P by silicon array and Clover-type high-purity Germanium (HPGe) detectors. Combining with results from the β decay of 26P and its mirror nucleus 26Na, the mirror asymmetry parameter δ ( ≡ft+/ft−− 1) was determined to be 46(13)% for the transition feeding the first excited state in the daughter nucleus. Our independent results support the conclusion that the large mirror asymmetry is close to the proton halo structure in 26P.

Early detection of liver fibrosis is crucial to select the correct care path for patients with non-alcoholic fatty liver disease (NAFLD). Here, we systematically review the evidence on the performance of FibroMeter versions in detecting different levels of fibrosis in patients with NAFLD. We searched four databases (Medline, Embase, the Cochrane library, and Web of Science) to find studies that included adults with NAFLD and biopsy-confirmed fibrosis (F1 to F4), compared with any version of FibroMeter. Two independent researchers screened the references, collected the data, and assessed the methodological quality of the included studies. We used a bivariate logit-normal random effects model to produce meta-analyses. From 273 references, 12 studies were eligible for inclusion, encompassing data from 3425 patients. Meta-analyses of the accuracy in detecting advanced fibrosis (F ≥ 3) were conducted for FibroMeter Virus second generation (V2G), NAFLD, and vibration controlled transient elaFS3stography (VCTE). FibroMeter VCTE showed the best diagnostic accuracy in detecting advanced fibrosis (sensitivity: 83.5% (95%CI 0.58–0.94); specificity: 91.1% (95%CI 0.89–0.93)), followed by FibroMeter V2G (sensitivity: 83.1% (95%CI 0.73–0.90); specificity: 84.4% (95%CI 0.62–0.95)) and FibroMeter NAFLD (sensitivity: 71.7% (95%CI 0.63–0.79); specificity: 82.8% (95%CI 0.71–0.91)). No statistically significant differences were found between the different FibroMeter versions. FibroMeter tests showed acceptable sensitivity and specificity in detecting advanced fibrosis in patients with NAFLD, but an urge to conduct head-to-head comparison studies in patients with NAFLD of the different FibroMeter tests remains.

In 2003, Aotearoa New Zealand (NZ) passed the Prostitution Reform Act 2003 (PRA), which decriminalized sex work for NZ citizens and holders of permanent residency (PR) while excluding migrant sex workers (MSWs) from its protection. This is due to Section 19 (s19) of the PRA, added at the last minute against advice by the Aotearoa New Zealand Sex Workers’ Collective (NZPC) as an anti-trafficking clause. Because of s19, migrants on temporary visas found to be working as sex workers are liable to deportation by Immigration New Zealand (INZ). Drawing on original ethnographic and interview data gathered over 24 months of fieldwork, our study finds that migrant sex workers in New Zealand are vulnerable to violence and exploitation, and are too afraid to report these to the police for fear of deportation, corroborating earlier studies and studies completed while we were collecting data.

(1) Background: FibroTest™ is a multi-marker panel, suggested by guidelines as one of the surrogate markers with acceptable performance for detecting fibrosis in patients with non-alcoholic fatty liver disease (NAFLD). A number of studies evaluating this test have been published after publication of the guidelines. This study aims to produce summary estimates of FibroTest™ diagnostic accuracy. (2) Methods: Five databases were searched for studies that evaluated FibroTest™ against liver biopsy as the reference standard in NAFLD patients. Two authors independently screened the references, extracted data, and assessed the quality of included studies. Meta-analyses of the accuracy in detecting different levels of fibrosis were performed using the bivariate random-effects model and the linear mixed-effects multiple thresholds model. (3) Results: From ten included studies, seven were eligible for inclusion in our meta-analysis. Five studies were included in the meta-analysis of FibroTest™ in detecting advanced fibrosis and five in significant fibrosis, resulting in an AUC of 0.77 for both target conditions. The meta-analysis of three studies resulted in an AUC of 0.69 in detecting any fibrosis, while analysis of three other studies showed higher accuracy in cirrhosis (AUC: 0.92). (4) Conclusions: Our meta-analysis showed acceptable performance (AUC > 0.80) of FibroTest™ only in detecting cirrhosis. We observed more limited performance of the test in detecting significant and advanced fibrosis in NAFLD patients. Further primary studies with high methodological quality are required to validate the reliability of the test for detecting different fibrosis levels and to compare the performance of the test in different settings.

Naratuximab emtansine (IMGN529) is an investigational antibody-drug conjugate consisting of a CD37-targeting antibody conjugated to the maytansine-derived microtuble disruptor, DM1. IMGN529 has shown promising preclinical and clinical activity in non-Hodgkin lymphoma, including diffuse large B-cell lymphoma (DLBCL). Due to the aggressive nature of the disease, DLBCL is often treated with combination therapies to maximize clinical outcomes; therefore, we investigated the potential of combining IMGN529 with both standard-of-care and emerging therapies against multiple oncology-relevant targets and pathways. The strongest enhancement in potency was seen with anti-CD20 antibodies, including rituximab. The combination of IMGN529 and rituximab was more potent than either agent alone, and this combinatorial benefit was associated with increased apoptotic induction and cell death. Additional studies revealed that rituximab treatment increased the internalization and degradation of the CD37-targeting antibody moiety of IMGN529. The combination of IMGN529 and rituximab was highly efficacious in multiple xenograft models, with superior antitumor efficacy seen compared to either agent alone or treatment with R-CHOP therapy. These findings suggest a novel mechanism whereby the potency of IMGN529 can be enhanced by CD20 binding, which results in the increased internalization and degradation of IMGN529 leading to the generation of greater amounts of cytotoxic catabolite. Overall, these data provide a biological rationale for the enhanced activity of IMGN529 in combination with rituximab and support the ongoing clinical evaluation of IMGN529 in combination with rituximab in patients with relapsed and/or refractory DLBCL.

While angiotensin II (ang II) has been implicated in the pathogenesis of cardiac cachexia (CC), the molecules that mediate ang II's wasting effect have not been identified. It is known TNF-α level is increased in patients with CC, and TNF-α release is triggered by ang II. We therefore hypothesized that ang II induced muscle wasting is mediated by TNF-α. Ang II infusion led to skeletal muscle wasting in wild type (WT) but not in TNF alpha type 1 receptor knockout (TNFR1KO) mice, suggesting that ang II induced muscle loss is mediated by TNF-α through its type 1 receptor. Microarray analysis identified cholesterol 25-hydroxylase (Ch25h) as the down stream target of TNF-α. Intraperitoneal injection of 25-hydroxycholesterol (25-OHC), the product of Ch25h, resulted in muscle loss in C57BL/6 mice, accompanied by increased expression of atrogin-1, MuRF1 and suppression of IGF-1/Akt signaling pathway. The identification of 25-OHC as an inducer of muscle wasting has implications for the development of specific treatment strategies in preventing muscle loss.

Identification of neighborhoods is an important, financially-driven topic in real estate. It is known that the real estate industry uses ZIP (postal) codes and Census tracts as a source of land demarcation to categorize properties with respect to their price. These demarcated boundaries are static and are inflexible to the shift in the real estate market and fail to represent its dynamics, such as in the case of an up-and-coming residential project. Delineated neighborhoods are also used in socioeconomic and demographic analyses where statistics are computed at a neighborhood level. Current practices of delineating neighborhoods have mostly ignored the information that can be extracted from property appraisals. This paper demonstrates the potential of using only the distance between subjects and their comparable properties, identified in an appraisal, to delineate neighborhoods that are composed of properties with similar prices and features. Using spatial filters, we first identify regions with the most appraisal activity, and through the application of a spatial clustering algorithm, generate neighborhoods composed of properties sharing similar characteristics. Through an application of bootstrapped linear regression, we find that delineating neighborhoods using geolocation of subjects and comparable properties explains more variation in a property’s features, such as valuation, square footage, and price per square foot, than ZIP codes or Census tracts. We also discuss the ability of the neighborhoods to grow and shrink over the years, due to shifts in each housing submarket.

Upon publication of the original article [1], it was noticed that Alexandra Z. Worden’s affiliation is not complete. The full affiliation information for Alexandra Z. Worden is can be found below and in the complete affiliation list of this Correction article.

Purpose: Little is known about the effectiveness of bright white light therapy (BWL) for depressive symptoms in cancer survivors, many of whom prefer non-pharmacological treatments. The purpose of this study was to compare the effectiveness of BWL versus dim red light therapy (DRL) on depressive symptoms within individual cancer survivors using personalized (N-of-1) trials. Methods: Cancer survivors with at least mild depressive symptoms were randomized to one of two treatment sequences consisting of counterbalanced crossover comparisons of three-weeks of lightbox-delivered BWL (intervention) or DRL (sham) for 30 min each morning across 12 weeks. A smartphone application guided cancer survivors through the treatment sequence and facilitated data collection. Cancer survivors tracked end-of-day depressive symptoms (primary outcome) and fatigue using visual analog scales. Within-patient effects of BWL were assessed using an autoregressive model with adjustment for linear time trends. Results: Eight of nine cancer survivors completed the 12-week protocol. Two survivors reported significantly (i.e., p < 0.05) lower depressive symptoms (−1.3 ± 0.5 and −1.30 ± 0.9 points on a 10-point scale), five reported no difference in depressive symptoms, and one reported higher depressive symptoms (+1.7 ± 0.6 points) with BWL versus DRL. Eight of nine cancer survivors recommended personalized trials of BWL to others. Conclusions: There were heterogeneous effects of three-week BWL on self-reported depressive symptoms among cancer survivors, with some finding a benefit but others finding no benefit or even harm. Implications for Cancer Survivors: Personalized trials can help cancer survivors learn if BWL is helpful for improving their depressive symptoms.

Spectroscopic information has been extracted on the hole-states of 55Ni, the least known of the quartet of nuclei (55Ni, 57Ni, 55Co and 57Cu), one nucleon away from 56Ni, the N=Z=28 double magic nucleus. Using the H1(Ni56,d)Ni55 transfer reaction in inverse kinematics, neutron spectroscopic factors, spins and parities have been extracted for the f7/2, p3/2 and the s1/2 hole-states of 55Ni. These new data provide a benchmark for large basis calculations that include nucleonic orbits in both the sd and pf shells. State of the art calculations have been performed to describe the excitation energies and spectroscopic factors of the s1/2 hole-state below Fermi energy.

Parkinson disease (PD) is a common and disabling disorder. No current therapy can slow or reverse disease progression. An important aspect of research in this field is target validation, a systematic approach to evaluating the likelihood that modification of a certain molecule, mechanism or biological pathway may be useful for the development of pharmacological or molecular treatments for the disease. TorsinA, a member of the AAA+ family of chaperone proteins, has been proposed as a potential target of neuroprotective therapy. TorsinA is found in Lewy bodies in human PD, and can suppress toxicity in cellular and invertebrate models of PD. Here, we evaluated the neuroprotective properties of torsinA in mouse models of PD based on intoxication with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) as well as recombinant adeno associated virus (rAAV) induced overexpression of alpha-synuclein (α-syn). Using either transgenic mice with overexpression of human torsinA (hWT mice) or mice in which torsinA expression was induced using an rAAV vector, we found no evidence for protection against acute MPTP intoxication. Similarly, genetic deletion of the endogenous mouse gene for torsinA (Dyt1) using an rAAV delivered Cre recombinase did not enhance the vulnerability of dopaminergic neurons to MPTP. Overexpression of α-syn using rAAV in the mouse substantia nigra lead to a loss of TH positive neurons six months after administration, and no difference in the degree of loss was observed between transgenic animals expressing forms of torsinA and wild type controls. Collectively, we did not observe evidence for a protective effect of torsinA in the mouse models we examined. Each of these models has limitations, and there is no single model with established predictive value with respect to the human disease. Nevertheless, these data do seem to support the view that torsinA is unlikely to be successfully translated as a target of therapy for human PD.

Being a teacher or a student in a class with a large enrollment can be intimidating. Often, teachers view comforts that are common to small classes as unattainable in a larger class, including knowing students' names, using active learning, employing group work, and creating group discussion. Students in large classes may find that the class size leads to isolation. At Utah State University, we offer introductory statistics classes for various audiences using a large lecture format. The authors have collectively led these large lectures dozens of times and found that, despite its shortcomings, the large lecture format can be an asset when teaching statistics. With an active learning approach such as recommended by the revised GAISE College report, large class sizes permit realistic sampling, facilitate student-driven simulation, and provide bountiful opportunities for experimentation. In this article, we discuss the benefits of large classes for statistics teaching and present examples of using large class sizes to create an engaging environment that where students are involved in active learning and collecting real data to foster statistical thinking.

This article discus- ses the public debate about pasteurization in Sweden from the 1880s to the 1940s. It attempts to discern the intricate interaction between scientific knowledge, commercial interests, and political agendas in policy-making and legislation from an actor–network perspective. The article discusses how the different alliances were formed, that finally ensured the success of compulsory pasteurization. These alliances were in part dependent on an institutional framework that evolved over time. The threat of tuberculosis remained important throughout the whole period and helps us understand why pasteurization became such an issue. Notions of quality also play a part in understanding the history of pasteurization and the history of the urban milk supply, with its commercial and municipal actors. From the 1880s to the 1920s, a semi-consensus is established within the scientific community. There is agreement that bacteria do exist, that milk may indeed transmit infections – in particular tuberculosis – and that pasteurization is a practical and comparatively cheap way of making milk safe. The technical difficulties in the pasteurization process are also overcome during this period. But the commercial interest in pasteurization is weak. The political initiative is also lacking. Not until the 1930s does a strong pasteurization lobby appear, that joins commercial, political, and scientific interests. The downturn of the world economy helps bring about this change of attitude, but it is the conjuncture of commercial, political, and medical aspects that tips the scales in favour of pasteurization.

A biomechanical model-based deformable image registration incorporating specimen-specific changes in material properties is optimized and evaluated for correlating histology of clinical prostatectomy specimens with in vivo MRI. In this methodology, a three-step registration based on biomechanics calculates the transformations between histology and fixed, fixed and fresh, and fresh and in vivo states. A heterogeneous linear elastic material model is constructed based on magnetic resonance elastography (MRE) results. The ex vivo tissue MRE data provide specimen-specific information for the fresh and fixed tissue to account for the changes due to fixation. The accuracy of the algorithm was quantified by calculating the target registration error (TRE) by identifying naturally occurring anatomical points within the prostate in each image. TRE were improved with the deformable registration algorithm compared to rigid registration alone. The qualitative assessment also showed a good alignment between histology and MRI after the proposed deformable registration.