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Abstract We conducted a longitudinal randomized controlled experiment between September 2021 and May 2022 to evaluate whether anti-tobacco industry beliefs and attitudes mediate the effect of culturally tailored anti-smoking messages on quit intentions among US young adult sexual minority women (SMW) ages 18–30 who smoke. Participants were randomized to view up to a total of 20 tailored versus non-tailored messages over one month. Outcomes were assessed at baseline and one-month follow-up. We fit a structural equation model testing the effect of LGBTQ + community-tailored, anti-smoking messages on quit intentions and mediating roles of anti-industry attitudes and beliefs (n = 966). Anti-industry beliefs (indirect effect size = 0.024, 95% confidence interval [CI] = [0.040, 0.056]) and attitudes (indirect effect size = 0.034, 95% CI = [0.006, 0.077]) significantly mediated the effect of the tailored condition on quit intentions. These findings suggest that LGBTQ + -tailored cues in anti-smoking messaging may promote quit intentions indirectly through influencing young adult SMW’s beliefs and attitudes about the tobacco industry. Future campaigns to promote quitting among young adult SMW who smoke should consider incorporating themes to change their beliefs and attitudes about the tobacco industry. Trial registration This study was registered in ClinicalTrials.gov (NCT04812795) on 24/03/2021.

Abstract Purpose To assess the diagnostic performance of prostate MRI by estimating the proportion of clinically significant prostate cancer (csPCa) in patients without prostate pathology. Materials and methods This three-center retrospective study included prostate MRI examinations performed for clinical suspicion of csPCa (Grade group ≥ 2) between 2018 and 2022. Examinations were divided into two groups: pathological diagnosis within 1 year after the MRI (post-MRI pathology) is present and absent. Risk prediction models were developed using the extracted eleven common predictive variables from the patients with post-MRI pathology. Then, the csPCa proportion in the patients without post-MRI pathology was estimated by applying the model. The area under the receiver operating characteristic curve (AUC), sensitivity, specificity, and positive and negative predictive values (PPV/NPV) of prostate MRI in diagnosing csPCa were subsequently calculated for patients with and without post-MRI prostate pathology (estimated statistics) with a positive threshold of PI-RADS ≥ 3. Results Of 12,191 examinations enrolled (mean age, 65.7 years ± 8.4 [standard deviation]), PI-RADS 1–2 was most frequently assigned (55.4%) with the lowest pathological confirmation rate of 14.0–18.2%. Post-MRI prostate pathology was found in 5670 (46.5%) examinations. The estimated csPCa proportions across facilities were 12.6–15.3%, 18.4–31.4%, 45.7–69.9%, and 75.4–88.3% in PI-RADS scores of 1–2, 3, 4, and 5, respectively. The estimated (observed) performance statistics were as follows: AUC, 0.78–0.81 (0.76–0.79); sensitivity, 76.6–77.3%; specificity, 67.5–78.6%; PPV, 49.8–66.6% (52.0–67.7%); and NPV, 84.4–87.2% (82.4–86.6%). Conclusion We proposed a method to estimate the probabilities harboring csPCa for patients who underwent prostate MRI examinations, which allows us to understand the PI-RADS diagnostic performance with several metrics. Clinical relevance statement The reported estimated performance metrics are expected to aid in understanding the true diagnostic value of PI-RADS in the entire prostate MRI population performed with clinical suspicion of prostate cancer. Key Points Calculating performance metrics only from patients who underwent prostate biopsy may be biased due to biopsy selection criteria, especially in PI-RADS 1–2. The estimated area under the receiver operating characteristic curve of PI-RADS in the entire prostate MRI population ranged from 0.78 to 0.81 at three facilities. The estimated statistics are expected to help us understand the true PI-RADS performance and serve as a reference for future studies. Graphical Abstract

Tissue engineering and regenerative medicine (TERM) is an emerging field that has provided new therapeutic opportunities by delivering innovative solutions. The development of nontraditional therapies for previously unsolvable diseases and conditions has brought hope and excitement to countless individuals globally. Many regenerative medicine therapies have been developed and delivered to patients clinically. The technology platforms developed in regenerative medicine have been expanded to various medical areas; however, their applications in colorectal surgery remain limited. Applying TERM technologies to engineer biological tissue and organ substitutes may address the current therapeutic challenges and overcome some complications in colorectal surgery, such as inflammatory bowel diseases, short bowel syndrome, and diseases of motility and neuromuscular function. This review provides a comprehensive overview of TERM applications in colorectal surgery, highlighting the current state of the art, including preclinical and clinical studies, current challenges, and future perspectives. This article synthesizes the latest findings, providing a valuable resource for clinicians and researchers aiming to integrate TERM into colorectal surgical practice.

Abstract Understanding the impact of the relativistic motion of a chiral molecule on its optical response is a prime challenge for fundamental science, but it also has a direct practical relevance in our search for extraterrestrial life. To contribute to these significant developments, we describe a multi–scale computational framework that combines quantum chemistry calculations and full–wave optical simulations to predict the chiral optical response from molecules moving at relativistic speeds. Specifically, the effect of a relativistic motion on the transmission circular dichroism (TCD) of three life–essential biomolecules, namely, B–DNA, chlorophyll a, and chlorophyll b, is investigated. Inspired by previous experiments to detect interstellar chiral molecules, we assume that the molecules move between a stationary observer and a light source, and we study the rotationally averaged TCD as a function of the speed of the molecule.We find that the TCD spectrum that contains the signatures of the molecules shifts with increasing speed to shorter wavelengths, with the effects already being visible for moderate velocities.

In vivo delivery of mRNA is promising for the study of gene expression and the treatment of diseases. Lipid nanoparticles (LNPs) enable efficient delivery of mRNA constructs, but protein expression has been assumed to be limited to the liver. With specialized LNPs, delivery to extrahepatic tissue occurs in small animal models; however, it is unclear if global delivery of mRNA to all major organs is possible in humans because delivery may be affected by differences in innate immune response and relative organ size. Furthermore, limited studies with LNPs have been performed in large animal models, such as swine, due to their sensitivity to complement activation-related pseudoallergy (CARPA). In this study, we found that exogenous protein expression occurred in all major organs when swine were injected intravenously with a relatively low dose of mRNA encapsulated in a clinically relevant LNP formulation. Exogenous protein was detected in the liver, spleen, lung, heart, uterus, colon, stomach, kidney, small intestine, and brain of the swine without inducing CARPA. Furthermore, protein expression was detected in the bone marrow, including megakaryocytes, hematopoietic stem cells, and granulocytes, and in circulating white blood cells and platelets. These results show that nearly all major organs contain exogenous protein expression and are viable targets for mRNA therapies.

Abstract Purpose To characterize current lesbian, gay, bisexual, transgender, queer, and intersex (LGBTQI +) health-related undergraduate medical education (UME) curricular content and associated changes since a 2011 study and to determine the frequency and extent of institutional instruction in 17 LGBTQI + health-related topics, strategies for increasing LGBTQI + health-related content, and faculty development opportunities. Method Deans of medical education (or equivalent) at 214 allopathic or osteopathic medical schools in Canada and the United States were invited to complete a 36-question, Web-based questionnaire between June 2021 and September 2022. The main outcome measured was reported hours of LGBTQI + health-related curricular content. Results Of 214 schools, 100 (46.7%) responded, of which 85 (85.0%) fully completed the questionnaire. Compared to 5 median hours dedicated to LGBTQI + health-related in a 2011 study, the 2022 median reported time was 11 h (interquartile range [IQR], 6–16 h, p

Abstract Background Invasive mechanical ventilation contributes to bronchopulmonary dysplasia (BPD), the most common complication of prematurity and the leading respiratory cause of childhood morbidity. Non-invasive ventilation (NIV) may limit invasive ventilation exposure and can be either synchronized or non-synchronized (NS). Pooled data suggest synchronized forms may be superior. Non-invasive neurally adjusted ventilatory assist (NIV-NAVA) delivers NIV synchronized to the neural signal for breathing, which is detected with a specialized catheter. The DIVA (Diaphragmatic Initiated Ventilatory Assist) trial aims to determine in infants born 240/7–276/7 weeks’ gestation undergoing extubation whether NIV-NAVA compared to non-synchronized nasal intermittent positive pressure ventilation (NS-NIPPV) reduces the incidence of extubation failure within 5 days of extubation. Methods This is a prospective, unblinded, pragmatic, multicenter phase III randomized clinical trial. Inclusion criteria are preterm infants 24–276/7 weeks gestational age who were intubated within the first 7 days of life for at least 12 h and are undergoing extubation in the first 28 postnatal days. All sites will enter an initial run-in phase, where all infants are allocated to NIV-NAVA, and an independent technical committee assesses site performance. Subsequently, all enrolled infants are randomized to NIV-NAVA or NS-NIPPV at extubation. The primary outcome is extubation failure within 5 days of extubation, defined as any of the following: (1) rise in FiO2 at least 20% from pre-extubation for > 2 h, (2) pH ≤ 7.20 or pCO2 ≥ 70 mmHg; (3) > 1 apnea requiring positive pressure ventilation (PPV) or ≥ 6 apneas requiring stimulation within 6 h; (4) emergent intubation for cardiovascular instability or surgery. Our sample size of 478 provides 90% power to detect a 15% absolute reduction in the primary outcome. Enrolled infants will be followed for safety and secondary outcomes through 36 weeks’ postmenstrual age, discharge, death, or transfer. Discussion The DIVA trial is the first large multicenter trial designed to assess the impact of NIV-NAVA on relevant clinical outcomes for preterm infants. The DIVA trial design incorporates input from clinical NAVA experts and includes innovative features, such as a run-in phase, to ensure consistent technical performance across sites. Trial registration www.ClinicalTrials.gov , trial identifier NCT05446272 , registered July 6, 2022.

Objective: To assess pathways to parenthood, pregnancy outcomes, future pregnancy desire, and fertility counseling experiences among a cross-sectional sample of transgender men and gender diverse individuals assigned female or intersex at birth in the United States Methods: Participants were recruited from The Population Research in Identity and Disparities for Equality (PRIDE) Study and the general public. Eligible participants for this analysis were able to read and understand English, assigned female or intersex at birth, US residents, 18+ years old, and identified as transgender, nonbinary, or gender diverse. We analyzed responses to close-ended survey questions, overall and stratified by gender identity, race/ethnicity, and testosterone use. We also qualitatively assessed open-text responses on fertility counseling. Results: Among the 1694 participants, median age was 27 years (range: 18–72), 12% had ever been pregnant, and 12% were parents. Carrying a pregnancy where the individual was the egg source (36%) was the most common pathway to parenthood. Individuals with an exclusively binary gender identity (ie, transgender man or man) more often reported becoming parents through adoption than individuals with gender diverse identities (19% vs 12%). A third of individuals did not receive fertility counseling prior to initiating testosterone; individuals who exclusively reported nonbinary identities were recommended to investigate fertility preservation options less often (36%) compared to transgender men (50%). Conclusion: Transgender men and gender diverse individuals who were assigned female or intersex at birth build their families through a variety of pathways, including pregnancy, stepparenting, and adoption. Clinicians should avoid making assumptions about reproductive desires in these populations based on gender identities or testosterone use and should provide consistent fertility counseling prior to and after hormone initiation.

Abstract Ratios of glycerol dialkyl glycerol tetraethers (GDGT), which are membrane lipids of bacteria and archaea, are at the base of several paleoenvironmental proxies. They are frequently applied to soils as well as lake‐ and marine sediments to generate records of past temperature and soil pH. To derive meaningful environmental information from these reconstructions, high analytical reproducibility is required. Based on submitted results by 39 laboratories from across the world, which employ a diverse range of analytical and quantification methods, we explored the reproducibility of brGDGT‐based proxies (MBT′5ME, IR, and #ringstetra) measured on four soil samples and four soil lipid extracts. Correct identification and integration of 5‐ and 6‐methyl brGDGTs is a prerequisite for the robust calculation of proxy values, but this can be challenging as indicated by the large inter‐interlaboratory variation. The exclusion of statistical outliers improves the reproducibility, where the remaining uncertainty translates into a temperature offset from median proxy values of 0.3–0.9°C and a pH offset of 0.05–0.3. There is no apparent systematic impact of the extraction method and sample preparation steps on the brGDGT ratios. Although reported GDGT concentrations are generally consistent within laboratories, they vary greatly between laboratories. This large variability in brGDGT quantification may relate to variations in ionization efficiency or specific mass spectrometer settings possibly impacting the response of brGDGTs masses relative to that of the internal standard used. While ratio values of GDGT are generally comparable, quantities can currently not be compared between laboratories.

In both plant breeding and crop management, interpretability plays a crucial role in instilling trust in AI-driven approaches and enabling the provision of actionable insights. The primary objective of this research is to explore and evaluate the potential contributions of deep learning network architectures that employ stacked LSTM for end-of-season maize grain yield prediction. A secondary aim is to expand the capabilities of these networks by adapting them to better accommodate and leverage the multi-modality properties of remote sensing data. In this study, a multi-modal deep learning architecture that assimilates inputs from heterogeneous data streams, including high-resolution hyperspectral imagery, LiDAR point clouds, and environmental data, is proposed to forecast maize crop yields. The architecture includes attention mechanisms that assign varying levels of importance to different modalities and temporal features that, reflect the dynamics of plant growth and environmental interactions. The interpretability of the attention weights is investigated in multi-modal networks that seek to both improve predictions and attribute crop yield outcomes to genetic and environmental variables. This approach also contributes to increased interpretability of the model's predictions. The temporal attention weight distributions highlighted relevant factors and critical growth stages that contribute to the predictions. The results of this study affirm that the attention weights are consistent with recognized biological growth stages, thereby substantiating the network's capability to learn biologically interpretable features. Accuracies of the model's predictions of yield ranged from 0.82-0.93 R2ref in this genetics-focused study, further highlighting the potential of attention-based models. Further, this research facilitates understanding of how multi-modality remote sensing aligns with the physiological stages of maize. The proposed architecture shows promise in improving predictions and offering interpretable insights into the factors affecting maize crop yields, while demonstrating the impact of data collection by different modalities through the growing season. By identifying relevant factors and critical growth stages, the model's attention weights provide valuable information that can be used in both plant breeding and crop management. The consistency of attention weights with biological growth stages reinforces the potential of deep learning networks in agricultural applications, particularly in leveraging remote sensing data for yield prediction. To the best of our knowledge, this is the first study that investigates the use of hyperspectral and LiDAR UAV time series data for explaining/interpreting plant growth stages within deep learning networks and forecasting plot-level maize grain yield using late fusion modalities with attention mechanisms.

Abstract Dwarfism is a useful trait in many crop plants because it contributes to improved lodging resistance and harvest index. The mutant allele dw3‐ref (dwarf3‐reference) of sorghum [Sorghum bicolor (L.) Moench] is characterized by an 882 bp tandem duplication in the fifth exon of the gene that is unstable and reverts to wild‐type at a frequency greater than 0.001 in many genetic backgrounds. The goal of this research was to identify stable alleles of dw3 (dwarf3) that could be backcrossed into elite parent lines to improve height stability of the crop. To discover new alleles of dw3, a panel consisting mostly of sorghum conversion lines (SC‐lines) was screened by polymerase chain reaction for the 882 bp tandem duplication in the fifth exon of dw3‐ref. Sanger sequencing was used to characterize the DNA sequence of this fragment in genotypes that did not contain the 882 bp tandem duplication. Sequence analysis identified three indel mutations, including an 82 bp deletion, a 6 bp duplication, and a 15 bp deletion in this region of the gene. Field trials of the donor genotypes with these new alleles indicated no wild‐type revertants of dw3‐sd3 (dwarf3‐stable dwarf), dw3‐sd4, and dw3‐sd5. These alleles were backcrossed into Tx430. Field trials of backcross progeny (BC2F4) with the dw3‐sd3, dw3‐sd4, and dw3‐sd5 alleles indicated no revertants. The plant height and flowering time characteristics of the backcross progeny were similar or slightly shorter and earlier than the recurrent parent. These findings demonstrate that dw3‐sd3, dw3‐sd4, and dw3‐sd5 alleles will be useful in breeding for the stable dwarf trait.

Introduction: Risk of complications due to gestational diabetes mellitus is increasing in the U.S., particularly among individuals from racial minorities. Research has focused largely on clinical interventions to prevent complications, rarely on individuals’ residential environments. This retrospective cohort study aims to examine the association between individuals’ neighborhoods and complications of gestational diabetes mellitus. Methods: Demographic and clinical data were extracted from electronic health records and linked to American Community Survey data from the U.S. Census Bureau for 2,047 individuals who had 2,164 deliveries in 2014–2018. Data were analyzed in 2021–2022 using Wilcoxon rank sum test and chi-square test for bivariate analyses and logistic regression for analysis of independent effects. All census tract–based variables used in the model were dichotomized at the median. Results: Bivariate analysis showed that the average percentage of adults earning 25 years with less than high school diploma had a higher likelihood of complications than those who lived in areas with

Abstract Background Increasing physical activity (PA) is an effective strategy to slow reductions in cortical volume and maintain cognitive function in older adulthood. However, PA does not exist in isolation, but coexists with sleep and sedentary behaviour to make up the 24-hour day. We investigated how the balance of all three behaviours (24-hour time-use composition) is associated with grey matter volume in healthy older adults, and whether grey matter volume influences the relationship between 24-hour time-use composition and cognitive function. Methods This cross-sectional study included 378 older adults (65.6 ± 3.0 years old, 123 male) from the ACTIVate study across two Australian sites (Adelaide and Newcastle). Time-use composition was captured using 7-day accelerometry, and T1-weighted magnetic resonance imaging was used to measure grey matter volume both globally and across regions of interest (ROI: frontal lobe, temporal lobe, hippocampi, and lateral ventricles). Pairwise correlations were used to explore univariate associations between time-use variables, grey matter volumes and cognitive outcomes. Compositional data analysis linear regression models were used to quantify associations between ROI volumes and time-use composition, and explore potential associations between the interaction between ROI volumes and time-use composition with cognitive outcomes. Results After adjusting for covariates (age, sex, education), there were no significant associations between time-use composition and any volumetric outcomes. There were significant interactions between time-use composition and frontal lobe volume for long-term memory (p = 0.018) and executive function (p = 0.018), and between time-use composition and total grey matter volume for executive function (p = 0.028). Spending more time in moderate-vigorous PA was associated with better long-term memory scores, but only for those with smaller frontal lobe volume (below the sample mean). Conversely, spending more time in sleep and less time in sedentary behaviour was associated with better executive function in those with smaller total grey matter volume. Conclusions Although 24-hour time use was not associated with total or regional grey matter independently, total grey matter and frontal lobe grey matter volume moderated the relationship between time-use composition and several cognitive outcomes. Future studies should investigate these relationships longitudinally to assess whether changes in time-use composition correspond to changes in grey matter volume and cognition.

Objectives HFE haemochromatosis genetic variants have an uncertain clinical penetrance, especially to older ages and in undiagnosed groups. We estimated p.C282Y and p.H63D variant cumulative incidence of multiple clinical outcomes in a large community cohort.Design Prospective cohort study.Setting 22 assessment centres across England, Scotland, and Wales in the UK Biobank (2006–2010).Participants 451 270 participants genetically similar to the 1000 Genomes European reference population, with a mean of 13.3-year follow-up through hospital inpatient, cancer registries and death certificate data.Main outcome measures Cox proportional HRs of incident clinical outcomes and mortality in those with HFE p.C282Y/p.H63D mutations compared with those with no variants, stratified by sex and adjusted for age, assessment centre and genetic stratification. Cumulative incidences were estimated from age 40 years to 80 years.Results 12.1% of p.C282Y+/+ males had baseline (mean age 57 years) haemochromatosis diagnoses, with a cumulative incidence of 56.4% at age 80 years. 33.1% died vs 25.4% without HFE variants (HR 1.29, 95% CI: 1.12 to 1.48, p=4.7×10-4); 27.9% vs 17.1% had joint replacements, 20.3% vs 8.3% had liver disease, and there were excess delirium, dementia, and Parkinson’s disease but not depression. Associations, including excess mortality, were similar in the group undiagnosed with haemochromatosis. 3.4% of women with p.C282Y+/+ had baseline haemochromatosis diagnoses, with a cumulative incidence of 40.5% at age 80 years. There were excess incident liver disease (8.9% vs 6.8%; HR 1.62, 95% CI: 1.27 to 2.05, p=7.8×10-5), joint replacements and delirium, with similar results in the undiagnosed. p.C282Y/p.H63D and p.H63D+/+ men or women had no statistically significant excess fatigue or depression at baseline and no excess incident outcomes.Conclusions Male and female p.C282Y homozygotes experienced greater excess morbidity than previously documented, including those undiagnosed with haemochromatosis in the community. As haemochromatosis diagnosis rates were low at baseline despite treatment being considered effective, trials of screening to identify people with p.C282Y homozygosity early appear justified.

Acetaminophen (APAP) is a widely used drug, but overdose can cause severe acute liver injury. The first reports of APAP hepatotoxicity in humans were published in 1966, shortly after the development of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) as the first biomarkers of liver injury as opposed to liver function. Thus, the field of liver injury biomarkers has evolved alongside the growth in APAP hepatotoxicity incidence. Numerous biomarkers have been proposed for use in the management of APAP overdose patients in the intervening years. Here, we comprehensively review the development of these markers from the 1960s to the present day and briefly discuss possible future directions.

Higher education institutions around the world were impacted by the COVID-19 pandemic that began in early 2020. Because U.S. community colleges focus on two-year degrees and workforce development, they were affected differently than their four-year counterparts. This study examined how academic administrators at different rural community colleges in Virginia, United States, perceived enrollment management practices that were implemented or changed due to the pandemic. This sequential explanatory study’s first phase was quantitative and measured mid- to senior-level administrators’ views of how the pandemic affected their colleges’ enrollment management practices. The second qualitative phase resulted in five themes surrounding COVID-related enrollment management practices: a) COVID-19 led to crisis management and operations in phases; b) managing student onboarding during COVID-19; c) COVID-19 created unique challenges for community college students; d) COVID-19 affected decision-making procedures; and e) COVID-19 resulted in work/life balance issues and COVID fatigue. Implications and future directions are provided to ensure that community college enrollment managers and policymakers understand how to continue to pivot to ensure student services are maintained or enhanced during a crisis.

Abstract Background Although the Eating Disorder Examination-Questionnaire (EDE-Q) is one of the most widely used self-report assessments of eating disorder symptoms, evidence indicates potential limitations with its original factor structure and associated psychometric properties in a variety of populations, including sexual minority populations. The aims of the current investigation were to explore several previously published EDE-Q factor structures and to examine internal consistency and measurement invariance of the best-fitting EDE-Q model in a large community sample of cisgender gay men and cisgender lesbian women. Methods Data were drawn from 1624 adults (1060 cisgender gay men, 564 cisgender lesbian women) who participated in The PRIDE Study, a large-scale longitudinal cohort study of sexual and gender minorities from the United States. A series of confirmatory factor analyses (CFAs) were conducted to explore the fit of eight proposed EDE-Q models; internal consistency (Cronbach’s alphas, Omega coefficients) and measurement invariance (multi-group CFA) were subsequently evaluated. Results A brief seven-item, three-factor (dietary restraint, shape/weight overvaluation, body dissatisfaction) model of the EDE-Q from Grilo et al. (Obes Surg. 23:657–662, 2013), consistently evidenced the best fit across cisgender gay men and lesbian women. The internal consistencies of the three subscales were adequate in both groups, and measurement invariance across the groups was supported. Conclusions Taken together, these findings support the use of the seven-item, three-factor version of the EDE-Q for assessing eating disorder symptomatology in cisgender gay men and lesbian women. Future studies can confirm the current findings in focused examinations of the seven-item, three-factor EDE-Q in diverse sexual minority samples across race, ethnicity, socioeconomic status, and age ranges.

Water and nitrogen (N) are major factors in plant growth and agricultural production. However, these are often confounded and produce overlapping symptoms of plant stress. The objective of this study is to verify whether the different levels of N treatment influence water status prediction and vice versa with hyperspectral modeling. We cultivated 108 maize plants in a greenhouse under three-level N treatments in combination with three-level water treatments. Hyperspectral images were collected from those plants, then Relative Water Content (RWC), as well as N content, was measured as ground truth. A Partial Least Squares (PLS) regression analysis was used to build prediction models for RWC and N content. Then, their accuracy and robustness were compared according to the different N treatment datasets and different water treatment datasets, respectively. The results demonstrated that the PLS prediction for RWC using hyperspectral data was impacted by N stress difference (Ratio of Performance to Deviation; RPD from 0.87 to 2.27). Furthermore, the dataset with water and N dual stresses improved model accuracy and robustness (RPD from 1.69 to 2.64). Conversely, the PLS prediction for N content was found to be robust against water stress difference (RPD from 2.33 to 3.06). In conclusion, we suggest that water and N dual treatments can be helpful in building models with wide applicability and high accuracy for evaluating plant water status such as RWC.

Climate change-induced heat stress combines two challenges: high day- and nighttime temperatures, and physiological water deficit due to demand-side drought caused by increase in vapor-pressure deficit. It is one of the major factors in low productivity of maize in rainfed stress-prone environments in South Asia, affecting a large population of smallholder farmers who depend on maize for their sustenance and livelihoods. The International Maize and Wheat Improvement Center (CIMMYT) maize program in Asia, in partnership with public-sector maize research institutes and private-sector seed companies in South Asian countries, is implementing an intensive initiative for developing and deploying heat-tolerant maize that combines high yield potential with resilience to heat and drought stresses. With the integration of novel breeding tools and methods, including genomics-assisted breeding, doubled haploidy, field-based precision phenotyping, and trait-based selection, new maize germplasm with increased tolerance to heat stress is being developed for the South Asian tropics. Over a decade of concerted effort has resulted in the successful development and release of 20 high-yielding heat-tolerant maize hybrids in CIMMYT genetic backgrounds. Via public–private partnerships, eight hybrids are presently being deployed on over 50,000 ha in South Asian countries, including Bangladesh, Bhutan, India, Nepal, and Pakistan.

Abstract Background Gender minority (GM; individuals whose gender is not aligned with that traditionally associated with the sex that was assigned to them at birth) people have widely reported mistreatment in healthcare settings. Mistreatment is enacted by individuals within society who hold stigmatizing beliefs. However, the relationship between healthcare mistreatment and societal stigma (i.e., the degree to which society disapproves of GM people) is unclear and not measured consistently. Methods We analyzed data from 2,031 GM participants in The Population Research in Identity and Disparities for Equality (PRIDE) Study’s 2019 Annual Questionnaire to determine whether societal stigma was associated with participants’ past-year reports of mistreatment (defined as denial of healthcare services and/or lower quality care) in medical or mental healthcare settings. We created a proxy measure of societal stigma by incorporating variables validated in existing literature. Participants reported whether they had experienced mistreatment in medical and mental health settings independently. Results Healthcare denial and/or lower quality care during the past year was reported by 18.8% of our sample for medical settings and 12.5% for mental health settings. We found no associations between the societal stigma variables and past-year reports of healthcare denial and/or lower quality care in medical or mental healthcare settings. Conclusions Although a high proportion of GM people reported past-year healthcare mistreatment in both medical and mental health settings, mistreatment had no relationship with societal stigma. Factors other than societal stigma may be more important predictors of healthcare mistreatment, such as healthcare workers’ knowledge of and attitudes toward GM people. However, other measures of societal stigma, or different types of mistreatment, may show stronger associations. Identifying key factors that contribute to mistreatment can serve as targets for intervention in communities and healthcare settings.

Abstract Background The first telomere-to-telomere (T2T) human genome assembly (T2T-CHM13) release is a milestone in human genomics. The T2T-CHM13 genome assembly extends our understanding of telomeres, centromeres, segmental duplication, and other complex regions. The current human genome reference (GRCh38) has been widely used in various human genomic studies. However, the large-scale genomic differences between these two important genome assemblies are not characterized in detail yet. Results Here, in addition to the previously reported “non-syntenic” regions, we find 67 additional large-scale discrepant regions and precisely categorize them into four structural types with a newly developed website tool called SynPlotter. The discrepant regions (~ 21.6 Mbp) excluding telomeric and centromeric regions are highly structurally polymorphic in humans, where the deletions or duplications are likely associated with various human diseases, such as immune and neurodevelopmental disorders. The analyses of a newly identified discrepant region—the KLRC gene cluster—show that the depletion of KLRC2 by a single-deletion event is associated with natural killer cell differentiation in ~ 20% of humans. Meanwhile, the rapid amino acid replacements observed within KLRC3 are probably a result of natural selection in primate evolution. Conclusion Our study provides a foundation for understanding the large-scale structural genomic differences between the two crucial human reference genomes, and is thereby important for future human genomics studies.

Tyrosine kinase inhibitors (TKIs) are increasingly popular drugs used to treat more than a dozen different diseases including some forms of cancer. Despite having fewer adverse effects than traditional chemotherapies, they are not without risks. Liver injury is a particular concern. Of the FDA-approved TKIs, approximately 40% cause hepatotoxicity. However, little is known about the underlying pathophysiology. The leading hypothesis is that TKIs are converted by cytochrome P450 3A4 (CYP3A4) to reactive metabolites that damage proteins. Indeed, there is strong evidence for this bioactivation of TKIs in in vitro reactions. However, the actual toxic effects are underexplored. Here, we measured the cytotoxicity of several TKIs in primary mouse hepatocytes, HepaRG cells and HepG2 cells with and without CYP3A4 modulation. To our surprise, the data indicate that CYP3A4 increases resistance to sorafenib and lapatinib hepatotoxicity. The results have implications for the mechanism of toxicity of these drugs in patients and underline the importance of selecting an appropriate experimental model.

BACKGROUND: Although 10% to 20% of cisgender women aged 18 to 40 years have a sexual minority identity (eg, bisexual, lesbian, and queer), there is limited research on the family building and pregnancy experiences of sexual minority cisgender women. Improving our understanding of the family building and pregnancy experiences of cisgender sexual minority women is critical for improving the perinatal health of this population. OBJECTIVE: This study aimed to compare the mode of family building, past pregnancy experiences, and future pregnancy intentions among cisgender sexual minority women by sexual orientation. STUDY DESIGN: This is an observational study which was conducted using cross-sectional data collected in 2019 from a national sample of 1369 cisgender sexual minority women aged 18 to 45 years. RESULTS: Most participants (n=794, 58%) endorsed multiple sexual orientations, most commonly queer (n=641, 47%), lesbian (n=640, 47%), and/or bisexual (n=583, 43%). There were 243 (18%) cisgender sexual minority women who were parents. Pregnancy was used by 74% (181/243) of women to build their families. Among participants who used pregnancy, 60% (108/181) became pregnant through sexual activity with another parent of the child, whereas 27% (64/243) of women used donor sperm. An additional 10% (n=24) became parents through second-parent adoption, 10% (n=25) through adoption, and 14% (n=35) through step-parenting. Bisexual women more often used sexual activity to become parents (61/100, 61%) compared with queer (40/89, 45%) and lesbian women (40/130, 31%). In contrast, lesbian (50/130, 39%) and queer (25/89, 27%) women more often used donor sperm to become parents compared with bisexual women (11/100, 11%). Among the 266 (19%) cisgender sexual minority women who had ever been pregnant, there were 545 pregnancies (mean, 2.05 pregnancies per woman). Among those pregnancies, 59% (n=327) resulted in live birth, 23% (n=126) resulted in miscarriage, 15% (n=83) resulted in abortion, and 2% (n=9) resulted in ectopic pregnancy. A quarter of women had future pregnancy intentions, with no differences by sexual orientation. Overall, few participants (16%) reported that all of their healthcare providers were aware of their sexual orientation. CONCLUSION: Cisgender sexual minority women primarily built their families through pregnancy and a quarter have future pregnancy desires. In addition, there were important differences in family building methods used by sexual orientation. Providers should be aware of the pregnancy and family-building patterns, plans, and needs of cisgender sexual minority women.

Curative bone marrow transplantation (BMT) therapies for sickle cell disease (SCD) can cause infertility. The Fertility Preservation Program (FPP) in Pittsburgh cryopreserves testicular tissues for SCD patients prior to BMT in anticipation that those tissues can be thawed in the future and matured to produce sperm. Here, we generated and validated two isogenic patient-derived induced pluripotent stem cell (iPSC) lines from testicular biopsy fibroblasts of a 12-year-old SCD patient.

Sickle cell disease (SCD) is a hemoglobin disorder and the most common genetic disorder that affects 100,000 Americans and millions worldwide. Adults living with SCD have pain so severe that it often requires opioids to keep it in control. Depression is a major global public health concern associated with an increased risk in chronic medical disorders, including in adults living with sickle cell disease (SCD). A strong relationship exists between suicidal ideation, suicide attempts, and depression. Researchers enrolling adults living with SCD in pragmatic clinical trials are obligated to design their methods to deliberately monitor and respond to symptoms related to depression and suicidal ideation. This will offer increased protection for their participants and help clinical investigators meet their fiduciary duties. This article presents a review of this sociotechnical milieu that highlights, analyzes, and offers recommendations to address ethical considerations in the development of protocols, procedures, and monitoring activities related to suicidality in depressed patients in a pragmatic clinical trial.

Abstract Background Clear cell renal cell cancer (ccRCC), the 8th leading cause of cancer-related death in the US, is challenging to treat due to high level intratumoral heterogeneity (ITH) and the paucity of druggable driver mutations. CcRCC is unusual for its high frequency of epigenetic regulator mutations, such as the SETD2 histone H3 lysine 36 trimethylase (H3K36me3), and low frequency of traditional cancer driver mutations. In this work, we examined epigenetic level ITH and defined its relationships with pathologic features, aspects of tumor biology, and SETD2 mutations. Results A multi-region sampling approach coupled with EPIC DNA methylation arrays was conducted on a cohort of normal kidney and ccRCC. ITH was assessed using DNA methylation (5mC) and CNV-based entropy and Euclidian distances. We found elevated 5mC heterogeneity and entropy in ccRCC relative to normal kidney. Variable CpGs are highly enriched in enhancer regions. Using intra-class correlation coefficient analysis, we identified CpGs that segregate tumor regions according to clinical phenotypes related to tumor aggressiveness. SETD2 wild-type tumors overall possess greater 5mC and copy number ITH than SETD2 mutant tumor regions, suggesting SETD2 loss contributes to a distinct epigenome. Finally, coupling our regional data with TCGA, we identified a 5mC signature that links regions within a primary tumor with metastatic potential. Conclusion Taken together, our results reveal marked levels of epigenetic ITH in ccRCC that are linked to clinically relevant tumor phenotypes and could translate into novel epigenetic biomarkers.

Olfactory receptors (ORs) represent one of the largest yet least investigated families of G protein-coupled receptors in mammals. While initially believed to be functionally restricted to the detection and integration of odors at the olfactory epithelium, accumulating evidence points to a critical role for ectopically expressed ORs in the regulation of cellular homeostasis in extranasal tissues. This review aims to summarize the current state of knowledge on the expression and physiological functions of ectopic ORs in the cardiovascular system, kidneys, and primary metabolic organs and emphasizes how altered ectopic OR signaling in those tissues may impact cardiovascular–kidney–metabolic health.

Objective: Mitochondrial pyruvate is a critical intermediary metabolite in gluconeogenesis, lipogenesis, and NADH production. As a result, the mitochondrial pyruvate carrier (MPC) complex has emerged as a promising therapeutic target in metabolic diseases. Clinical trials are currently underway. However, recent in vitro data indicate that MPC inhibition diverts glutamine/glutamate away from glutathione synthesis and toward glutaminolysis to compensate for loss of pyruvate oxidation, possibly sensitizing cells to oxidative insult. Here, we explored this in vivo using the clinically relevant acetaminophen (APAP) overdose model of acute liver injury, which is driven by oxidative stress. Methods: We used pharmacological and genetic approaches to inhibit MPC2 and alanine aminotransferase 2 (ALT2), individually and concomitantly, in mice and cell culture models and determined the effects on APAP hepatotoxicity. Results: We found that MPC inhibition sensitizes the liver to APAP-induced injury in vivo only with concomitant loss of alanine aminotransferase 2 (ALT2). Pharmacological and genetic manipulation of neither MPC2 nor ALT2 alone affected APAP toxicity, but liver-specific double knockout (DKO) significantly worsened APAP-induced liver damage. Further investigation indicated that DKO impaired glutathione synthesis and increased urea cycle flux, consistent with increased glutaminolysis, and these results were reproducible in vitro. Finally, induction of ALT2 and post-treatment with dichloroacetate both reduced APAP-induced liver injury, suggesting new therapeutic avenues. Conclusions: Increased susceptibility to APAP toxicity requires loss of both the MPC and ALT2 in vivo, indicating that MPC inhibition alone is insufficient to disrupt redox balance. Furthermore, the results from ALT2 induction and dichloroacetate in the APAP model suggest new metabolic approaches to the treatment of liver damage.

Abstract Objective Home blood pressure monitoring (HBPM) is an increasingly important tool in managing hypertension (HTN); however, its efficacy depends on its accuracy. This study aimed to explore the differences between blood pressure (BP) measurements conducted by patients and medical professionals and the patient demographic factors correlating with inaccurate self-measured BP levels. Methods One hundred hypertensive patients completed a questionnaire inquiring about their health status and HBPM procedures and were filmed while measuring their BP using their own devices. A researcher then measured the patients' BP using a calibrated sphygmomanometer to assess the accuracy of patient-performed readings. This cross-sectional study was conducted in five primary healthcare centers in Kraków, Poland. Results The mean differences in systolic and diastolic BP readings by patients and researchers were 8.36 mmHg (SD = 10.90 mmHg) and 2.16 mmHg (SD = 9.12 mmHg), respectively. Inaccuracies in patient BP measurements were associated with a less than high school education level, patients’ age, and a family history of HTN. Conclusion Patient self-measured BP levels were higher than researcher values, likely due to a higher patient error rate. Healthcare providers must increase training regarding correct HBPM techniques offered to patients; such efforts should be directed at all hypertensive patients, emphasizing the most error-prone demographics.

Genotype-by-environment interaction (GEI) is among the greatest challenges for maize breeding programs. Strong GEI limits both the prediction of genotype performance across variable environmental conditions and the identification of genomic regions associated with grain yield. Incorporating GEI into yield prediction models has been shown to improve prediction accuracy of yield; nevertheless, more work is needed to further understand this complex interaction across populations and environments. The main objectives of this study were to: 1) assess GEI in maize grain yield based on reaction norm models and predict hybrid performance across a gradient of environmental (EG) conditions and 2) perform a genome-wide association study (GWAS) and post-GWAS analyses for maize grain yield using data from 2014 to 2017 of the Genomes to Fields initiative hybrid trial. After quality control, 2,126 hybrids with genotypic and phenotypic data were assessed across 86 environments representing combinations of locations and years, although not all hybrids were evaluated in all environments. Heritability was greater in higher-yielding environments due to an increase in genetic variability in these environments in comparison to the low-yielding environments. GWAS was carried out for yield and five single nucleotide polymorphisms (SNPs) with the highest magnitude of effect were selected in each environment for follow-up analyses. Many candidate genes in proximity of selected SNPs have been previously reported with roles in stress response. Genomic prediction was performed to assess prediction accuracy of previously tested or untested hybrids in environments from a new growing season. Prediction accuracy was 0.34 for cross validation across years (CV0-Predicted EG) and 0.21 for cross validation across years with only untested hybrids (CV00-Predicted EG) when compared to Best Linear Unbiased Prediction (BLUPs) that did not utilize genotypic or environmental relationships. Prediction accuracy improved to 0.80 (CV0-Predicted EG) and 0.60 (CV00-Predicted EG) when compared to the whole-dataset model that used the genomic relationships and the environmental gradient of all environments in the study. These results identify regions of the genome for future selection to improve yield and a methodology to increase the number of hybrids evaluated across locations of a multi-environment trial through genomic prediction.

Summary: Background: Systemic sclerosis is a heterogenous disease in which little is known about patterns of patient-reported symptom clusters. We aimed to identify classes of individuals with similar anxiety, depression, fatigue, sleep disturbance, and pain symptoms and to evaluate associated sociodemographic and disease-related characteristics. Methods: This multi-centre cross-sectional study used baseline data from Scleroderma Patient-centered Intervention Network Cohort participants enrolled from 2014 to 2020. Eligible participants completed the PROMIS-29 v2.0 measure. Latent profile analysis was used to identify homogeneous classes of participants based on patterns of anxiety, depression, fatigue, sleep disturbance, and pain scores. Sociodemographic and disease-related characteristics were compared across classes. Findings: Among 2212 participants, we identified five classes, including four classes with “Low” (565 participants, 26%), “Normal” (651 participants, 29%), “High” (569 participants, 26%), or “Very High” (193 participants, 9%) symptom levels across all symptoms. Participants in a fifth class, “High Fatigue/Sleep/Pain and Low Anxiety/Depression” (234 participants, 11%) had similar levels of fatigue, sleep disturbance, and pain as in the “High” class but low anxiety and depression symptoms. There were significant and substantive trends in sociodemographic characteristics (age, education, race or ethnicity, marital or partner status) and increasing disease severity (diffuse disease, tendon friction rubs, joint contractures, gastrointestinal symptoms) across severity-based classes. Disease severity and sociodemographic characteristics of “High Fatigue/Sleep/Pain and Low Anxiety/Depression” class participants were similar to the “High” severity class. Interpretation: Most people with systemic sclerosis can be classified by levels of patient-reported symptoms, which are consistent across symptoms and highly associated with sociodemographic and disease-related variables, except for one group which reports low mental health symptoms despite high levels of other symptoms and substantial disease burden. Studies are needed to better understand resilience in systemic sclerosis and to identify and facilitate implementation of cognitive and behavioural strategies to improve coping and overall quality of life. Funding: National Institute of Nursing Research (F31NR019007), Canadian Institutes of Health Research, Arthritis Society Canada, the Lady Davis Institute for Medical Research, the Jewish General Hospital Foundation, McGill University, Scleroderma Society of Ontario, Scleroderma Canada, Sclérodermie Québec, Scleroderma Manitoba, Scleroderma Atlantic, Scleroderma Association of BC, Scleroderma SASK, Scleroderma Australia, Scleroderma New South Wales, Scleroderma Victoria, and Scleroderma Queensland.

Remote sensing enables the rapid assessment of many traits that provide valuable information to plant breeders throughout the growing season to improve genetic gain. These traits are often extracted from remote sensing data on a row segment (rows within a plot) basis enabling the quantitative assessment of any row-wise subset of plants in a plot, rather than a few individual representative plants, as is commonly done in field-based phenotyping. Nevertheless, which rows to include in analysis is still a matter of debate. The objective of this experiment was to evaluate row selection and plot trimming in field trials conducted using four-row plots with remote sensing traits extracted from RGB (red-green-blue), LiDAR (light detection and ranging), and VNIR (visible near infrared) hyperspectral data. Uncrewed aerial vehicle flights were conducted throughout the growing seasons of 2018 to 2021 with data collected on three years of a sorghum experiment and two years of a maize experiment. Traits were extracted from each plot based on all four row segments (RS) (RS1234), inner rows (RS23), outer rows (RS14), and individual rows (RS1, RS2, RS3, and RS4). Plot end trimming of 40 cm was an additional factor tested. Repeatability and predictive modeling of end-season yield were used to evaluate performance of these methodologies. Plot trimming was never shown to result in significantly different outcomes from non-trimmed plots. Significant differences were often observed based on differences in row selection. Plots with more row segments were often favorable for increasing repeatability, and excluding outer rows improved predictive modeling. These results support long-standing principles of experimental design in agronomy and should be considered in breeding programs that incorporate remote sensing.

Single-cell RNA sequencing (scRNA-seq) technologies are instrumental to improving our understanding of virus–host interactions in cell culture infection studies and complex biological systems because they allow separating the transcriptional signatures of infected versus non-infected bystander cells. A drawback of using biosafety level (BSL) 4 pathogens is that protocols are typically developed without consideration of virus inactivation during the procedure. To ensure complete inactivation of virus-containing samples for downstream analyses, an adaptation of the workflow is needed. Focusing on a commercially available microfluidic partitioning scRNA-seq platform to prepare samples for scRNA-seq, we tested various chemical and physical components of the platform for their ability to inactivate Nipah virus (NiV), a BSL-4 pathogen that belongs to the group of nonsegmented negative-sense RNA viruses. The only step of the standard protocol that led to NiV inactivation was a 5 min incubation at 85 °C. To comply with the more stringent biosafety requirements for BSL-4-derived samples, we included an additional heat step after cDNA synthesis. This step alone was sufficient to inactivate NiV-containing samples, adding to the necessary inactivation redundancy. Importantly, the additional heat step did not affect sample quality or downstream scRNA-seq results.

Plain English Summary Gender-expansive describes gender identities that do not fit within the binary gender identity system, such as man or woman. We asked gender-expansive participants in The PRIDE Study to fill out a widely used survey about muscle dysmorphia (when someone is worried about not being muscular enough). We found that this issue about muscularity has three parts for gender-expansive people: (1) a desire to be bigger and more muscular, (2) dissatisfaction with the way their body looks, and (3) problems with normal life functions. We find that this survey is appropriate for use in gender-expansive people. These results can help providers and researchers understand the muscle-related problems that gender-expansive people face.

IntroductionResting heart rate (HR) and heart rate variability (HRV) have been linked with cognition in the general population and in older individuals. The knowledge of this aspect of heart-brain relationship is relatively absent in older individuals with early Alzheimer's disease (AD) pathology. This study explores relationships of the HR, HRV, and cognition in cognitively healthy individuals with pathological amyloid/tau ratio (CH-PATs) in cerebral spinal fluid (CSF) compared to those with normal ratio (CH-NATs).MethodsWe examined the relationships between 1) resting HR and Mini‐Mental State Examination (MMSE); 2) resting HR and brain processing during Stroop interference; and 3) resting vagally mediated HRV (vmHRV) and task switching performance.ResultsOur studies showed that compared to CH-NATs, those CH-PATs with higher resting HR presented with lower MMSE, and less brain activation during interference processing. In addition, resting vmHRV was significantly correlated with task switching accuracy in CH-NATs, but not in CH-PATs.DiscussionThese three different tests indicate dysfunctional heart-brain connections in CH-PATs, suggesting a potential cardio-cerebral dysfunctional integration.

Yield for biofuel crops is measured in terms of biomass, so measurements throughout the growing season are crucial in breeding programs, yet traditionally time- and labor-consuming since they involve destructive sampling. Modern remote sensing platforms, such as unmanned aerial vehicles (UAVs), can carry multiple sensors and collect numerous phenotypic traits with efficient, non-invasive field surveys. However, modeling the complex relationships between the observed phenotypic traits and biomass remains a challenging task, as the ground reference data are very limited for each genotype in the breeding experiment. In this study, a Long Short-Term Memory (LSTM) based Recurrent Neural Network (RNN) model is proposed for sorghum biomass prediction. The architecture is designed to exploit the time series remote sensing and weather data, as well as static genotypic information. As a large number of features have been derived from the remote sensing data, feature importance analysis is conducted to identify and remove redundant features. A strategy to extract representative information from high-dimensional genetic markers is proposed. To enhance generalization and minimize the need for ground reference data, transfer learning strategies are proposed for selecting the most informative training samples from the target domain. Consequently, a pre-trained model can be refined with limited training samples. Field experiments were conducted over a sorghum breeding trial planted in multiple years with more than 600 testcross hybrids. The results show that the proposed LSTM-based RNN model can achieve high accuracies for single year prediction. Further, with the proposed transfer learning strategies, a pre-trained model can be refined with limited training samples from the target domain and predict biomass with an accuracy comparable to that from a trained-from-scratch model for both multiple experiments within a given year and across multiple years.

Background: People with sickle cell disease frequently use complementary and integrative therapies to cope with their pain, yet few studies have evaluated their effectiveness. The 3-arm, 3-site pragmatic Hybrid Effectiveness-implementation Trial of Guided Relaxation and Acupuncture for Chronic Sickle Cell Disease Pain (GRACE) has 3 priorities: (1) evaluate guided relaxation and acupuncture to improve pain control; (2) determine the most appropriate and effective treatment sequence for any given patient based on their unique characteristics; and (3) describe the processes and structures required to implement guided relaxation and acupuncture within health care systems. Methods: Participants (N = 366) are being recruited and randomized 1:1:1 to one of 2 intervention groups or usual care. The acupuncture intervention group receives 10 sessions over approximately 5 weeks. The guided relaxation intervention group receives access to video sessions ranging from 2 to 20 min each viewed daily over 5 weeks. The usual care group receives the standard of clinical care for sickle cell disease. Participants are re-randomized at 6 weeks depending on their pain impact score. Assessments occur at 6 weeks, 12 weeks, and 24 weeks. The primary outcome is the change in pain impact score and secondary measures include opioid use, anxiety, depression, sleep, pain catastrophizing, substance use, global impression of change, constipation, and hospitalizations. The GRACE study uses the Consolidated Framework for Implementation Research to plan, execute, and evaluate the associated implementation processes. Conclusion: The results from GRACE will represent a critical step toward improving management of pain affecting patients with sickle cell disease.ClinicalTrials.gov Identifier: NCT04906447.

Abstract Regional‐scale estimations of sorghum biomass production allow identification of optimum genotype×environment×management (G×E×M) combinations for bioenergy generation. The objective of this study was to determine the degree of contributions of G, E, and M toward variability in sorghum biomass in the United States. Using the Agricultural Production Systems sIMulator in a grid computing platform, biomass was simulated for irrigated and rainfed conditions for 30 years across the United States for four sorghum varietal types (grain—GS, sudangrass—SS, photosensitive—PS, and photo‐insensitive—PI). Simulated biomass was assessed by environments clustered using the sum of intercepted solar radiation (ir), mean of temperature stress factor (tp) and water stress factor (sw). Simulated biomass ranged from 5.8 t ha−1 (GS‐rainfed) to 27.5 t ha−1 (PI‐irrigated). Under high‐temperature environments (mean annual temperature = 25°C), rainfed biomass between 40 and 80 days after planting (DAP) was strongly correlated with sw (r = 0.64–0.86) and irrigated biomass with ir (r = 0.68–0.81). Under low‐temperature environments (mean annual temperature = 18°C) after 40 DAP, tp and ir had greater effects than sw (r = 0.55–0.82). Biomass variance was mainly explained by varietal type (50%–76%) in all environments×irrigation combinations, except in the high‐ and mid‐temperature environments under rainfed conditions where rainfall had the major effect (25%–45%). However, when mean temperature during the growing season decreased from 25°C (high environments) to 18°C (low environments), the contribution of mean temperature to biomass variance increased from 7% to 34% (rainfed) and from 4% to 36% (irrigated). Varietal type had the larger interactions with other factors independently of the environment and irrigation. We demonstrated a need to quantify (i) the main G×E×M drivers of biomass variability based on environmental stress factors and (ii) the variance contribution of these drivers on sorghum biomass. Our regional‐scale estimations are key inputs for future robust biomass projections of energy sorghum genotypes integrating G×E×M under climate change scenarios.

Cardiovascular complications are major clinical hallmarks of acute and post-acute coronavirus disease 2019 (COVID-19). However, the mechanistic details of SARS-CoV-2 infectivity of endothelial cells remain largely unknown. Here, we demonstrate that the receptor binding domain (RBD) of the SARS-CoV-2 spike (S) protein shares a similarity with the proline-rich binding ena/VASP homology (EVH1) domain and identified the endoplasmic reticulum (ER) resident calreticulin (CALR) as an S-RBD interacting protein. Our biochemical analysis showed that CALR, via its proline-rich (P) domain, interacts with S-RBD and modulates proteostasis of the S protein. Treatment of cells with the proteasomal inhibitor bortezomib increased the expression of the S protein independent of CALR, whereas the lysosomal/autophagy inhibitor bafilomycin 1A, which interferes with the acidification of lysosome, selectively augmented the S protein levels in a CALR-dependent manner. More importantly, the shRNA-mediated knockdown of CALR increased SARS-CoV-2 infection and impaired calcium homeostasis of human endothelial cells. This study provides new insight into the infectivity of SARS-CoV-2, calcium hemostasis, and the role of CALR in the ER-lysosome-dependent proteolysis of the spike protein, which could be associated with cardiovascular complications in COVID-19 patients.

Current guidelines recommend restricting acetaminophen (APAP) use in patients with cirrhosis, but evidence to support that recommendation is lacking. Prior studies focused on pharmacokinetics (PK) of APAP in cirrhosis but did not rigorously examine clinical outcomes, sensitive biomarkers of liver damage, or serum APAP‐protein adducts, which are a specific marker of toxic bioactivation. Hence, the goal of this pilot study was to test the effects of regularly scheduled APAP dosing in a well‐defined compensated cirrhosis group compared to control subjects without cirrhosis, using the abovementioned outcomes. After a 2‐week washout, 12 subjects with and 12 subjects without cirrhosis received 650 mg APAP twice per day (1.3 g/day) for 4 days, followed by 650 mg on the morning of day 5. Patients were assessed in‐person at study initiation (day 1) and on days 3 and 5. APAP‐protein adducts and both conventional (alanine aminotransferase) and sensitive (glutamate dehydrogenase [GLDH], full‐length keratin 18 [K18], and total high‐mobility group box 1 protein) biomarkers of liver injury were measured in serum on the mornings of days 1, 3, and 5, with detailed PK analysis of APAP, metabolites, and APAP‐protein adducts throughout day 5. No subject experienced adverse clinical outcomes. GLDH and K18 were significantly different at baseline but did not change in either group during APAP administration. In contrast, clearance of APAP‐protein adducts was dramatically delayed in the cirrhosis group. Minor differences for other APAP metabolites were also detected. Conclusion: Short‐term administration of low‐dose APAP (650 mg twice per day,

It remains unclear whether improvements in one cognitive task transfer to other tasks. Here, the authors show that changes in prefrontal neuronal activation, firing rate, and local field potentials induced during active learning of a working memory task are also evident in a control task.

PurposeAthletes regularly perform resistance training, yet it is unknown how best to monitor its intensity. This study compared different resistance exercise intensity metrics to determine their sensitivity to manipulating work rate (via altering inter-set rest and load).MethodsFollowing baseline testing for 10- and 3-repetition maximum (RM; squat and bench press), fourteen trained participants completed four volume-matched protocols in a randomised order: 3x10 with 85% 10RM, 60 s rest (3x1060s); 3x10 with 85% 10RM, 180 s (3x10180s); 8x3 with 85% 3RM, 120 s (8x3120s); 8x3 with 85% 3RM, 300 s (8x3300s). Internal intensity was quantified via rate of oxygen consumption ([Formula: see text]), heart rate, blood lactate concentration, and rating of perceived exertion (RPE). External intensity was assessed via previously developed "Training-Intensity" (TI) and "Intensity-Index" (II) metrics, and from exercise work rate (expressed as kg∙min-1 and joules∙min-1).ResultsInternal intensity and work-rate metrics were highest for 3x1060s, followed by 3x10180s, 8x3120s and 8x3300s (p≤0.027). TI and II were higher for 8x3 than 3x10 protocols (pConclusionsWork rate corroborated objective internal intensity metrics during resistance exercise, with the highest work rate session (3x1060s) also eliciting greater RPE scores than other protocols. In contrast, the TI and II did not agree with other intensity measures, likely because they do not consider rest periods. Practitioners can plan for the physiological and perceptual demands of resistance training by estimating work rate.

Abstract A novel localized surface plasmon resonance (LSPR) system based on the coupling of gold nanomushrooms (AuNMs) and gold nanoparticles (AuNPs) is developed to enable a significant plasmonic resonant shift. The AuNP size, surface chemistry, and concentration are characterized to maximize the LSPR effect. A 31 nm redshift is achieved when the AuNMs are saturated by the AuNPs. This giant redshift also increases the full width of the spectrum and is explained by the 3D finite‐difference time‐domain (FDTD) calculation. In addition, this LSPR substrate is packaged in a microfluidic cell and integrated with a CRISPR‐Cas13a RNA detection assay for the detection of the SARS‐CoV‐2 RNA targets. Once activated by the target, the AuNPs are cleaved from linker probes and randomly deposited on the AuNM substrate, demonstrating a large redshift. The novel LSPR chip using AuNP as an indicator is simple, specific, isothermal, and label‐free; and thus, provides a new opportunity to achieve the next generation multiplexing and sensitive molecular diagnostic system.

Quantifying the digestibility of proteins in cereal grain is important for assessing and improving the nutritional quality of the grain after ingestion. This trait is particularly important for sorghum since the grain protein is known to be less digestible after wet cooking compared to other cereals. The reduced digestibility contributes to malnutrition in regions where sorghum is consumed as a staple food. We describe here a modified, high-throughput protocol to quantify pepsin-digestible proteins in sorghum grain before and after cooking. The protocol includes three basic steps: • grinding and cooking the sorghum into a small porridge for 20 min, • digesting the porridge with pepsin for at least 2 h, • extracting and assaying the protein extract.This method closely resembles the reality of sorghum usage as food and feed, can be scaled to process large numbers of samples and can be adapted for use with other cereal crops. This protocol requires only basic lab equipment and expertise, and one person can easily process 280 samples (140 accessions) in 7-8 h.

IntroductionSexual and gender minority (SGM) communities, including lesbian, gay, bisexual, transgender, queer, intersex, asexual, and Two-Spirit people, have historically been researched from a deficits-based approach that fails to highlight the ways communities survive and thrive in the face of adversity. This study endeavored to create a model of resources that promote SGM resilience using a sample that amplified traditionally underrepresented perspectives, including individuals from racial and/or ethnic minority groups, trans and/or gender diverse individuals, individuals on the asexual spectrum, and older adults.MethodsParticipant responses to three open-ended questions from The PRIDE Study's (an online national longitudinal cohort study of SGM people) 2018 Annual Questionnaire were analyzed using constructivist grounded theory. These questions examined what brings people joy and what they appreciate most about their SGM identity. Participants (n = 315) were randomly selected from a larger sample of people who had responded to demographic questions and at least one open-ended question (N = 4,030) in a manner to ensure diverse representation across race/ethnicity, gender identity, sexual orientation, age, and region of residence.ResultsThe proposed model includes social resources (Connecting with Others, Cultivating Family, Helping Others, Participating in Culture and Spirituality), affective generative resources (Engaging in Enriching Pursuits, Accessing Economic Resources), and introspective resources (Exploring One's Authentic Self, Persevering through Hardship) that are theorized to contribute to SGM resilience across the life course.ConclusionsSGM communities may tap into various resources to promote resilience. As public health practitioners, we can help to foster this resilience by resourcing and supporting initiatives that foster social connection, create spaces for community members to engage with various types of enrichment, facilitate access to economic resources, and provide support and inclusion for all SGM community members.

Abstract Purpose/Objectives Holmium laser enucleation of the prostate (HoLEP) is commonly performed in patients with significant bladder outlet obstruction. However, there are few reports on the toxicity of external beam irradiation (RT) for prostate cancer in patients after prior HoLEP. In this study, we evaluate the side effects and treatment outcomes of RT after HoLEP. Materials/Methods Eighteen patients who had HoLEP and subsequently received RT for prostate cancer were included. Data collected included patient and disease characteristics, urinary function, and radiation dose. Acute and late urinary (GU) and gastrointestinal (GI) side effects were evaluated. Disease control and survival rates were calculated using Kaplan–Meier method. Results Median follow‐up was 18 months (range: 4–46 months). Median prostate volume was 107 ml before HoLEP and 24 ml after HoLEP. Median International Prostate Symptom Score (IPSS) was 17 (range: 5–32) before HoLEP. Median decline in IPSS score after HoLEP was 7 (range: −2–21). On uroflow study, peak flow rate, and post‐void residual were significantly improved after HoLEP. After radiation, peak flow rate and average flow rate showed a decline but remained significantly improved compared to pre‐HoLEP measurements. Maximum acute Common Terminology Criteria for Adverse Events (CTCAE) adverse events were 12 grade 1 and 3 grade 2 for GU, and 3 grade 1 for GI, respectively. Maximum late adverse events were 13 grade 1 and 2 grade 2 for GU, and all grade 0 for GI, respectively. At last follow‐up, there were 8 grade 1 and 1 grade 2 late GU, and 3 grade 1 late GI adverse events, respectively. There was no significant increase in urinary incontinence after RT compared to before RT. The 18‐month biochemical control, local control, distant control rates were 78%, 94%, and 80%, respectively. Conclusions Patients who received RT as definitive treatment for prostate cancer after prior HoLEP had low risk of serious acute and late side effects. HoLEP can be safely performed and should be considered in patients with significant bladder outlet obstruction and large prostate volume before RT.

Abstract Background Breakthrough imaging technologies may challenge the plant phenotyping bottleneck regarding marker-assisted breeding and genetic mapping. In this context, X-Ray CT (computed tomography) technology can accurately obtain the digital twin of root system architecture (RSA) but computational methods to quantify RSA traits and analyze their changes over time are limited. RSA traits extremely affect agricultural productivity. We develop a spatial–temporal root architectural modeling method based on 4D data from X-ray CT. This novel approach is optimized for high-throughput phenotyping considering the cost-effective time to process the data and the accuracy and robustness of the results. Significant root architectural traits, including root elongation rate, number, length, growth angle, height, diameter, branching map, and volume of axial and lateral roots are extracted from the model based on the digital twin. Our pipeline is divided into two major steps: (i) first, we compute the curve-skeleton based on a constrained Laplacian smoothing algorithm. This skeletal structure determines the registration of the roots over time; (ii) subsequently, the RSA is robustly modeled by a cylindrical fitting to spatially quantify several traits. The experiment was carried out at the Ag Alumni Seed Phenotyping Facility (AAPF) from Purdue University in West Lafayette (IN, USA). Results Roots from three samples of tomato plants at two different times and three samples of corn plants at three different times were scanned. Regarding the first step, the PCA analysis of the skeleton is able to accurately and robustly register temporal roots. From the second step, several traits were computed. Two of them were accurately validated using the root digital twin as a ground truth against the cylindrical model: number of branches (RRMSE better than 9%) and volume, reaching a coefficient of determination (R2) of 0.84 and a P

Circulating biomarkers of drug-induced liver injury (DILI) have been a focus of research in hepatology over the last decade, and several novel DILI biomarkers that hold promise for certain applications have been identified. For example, glutamate dehydrogenase holds promise as a specific biomarker of liver injury in patients with concomitant muscle damage. It may also be a specific indicator of mitochondrial damage. In addition, microRNA-122 is sensitive for early detection of liver injury in acetaminophen overdose patients. However, recent events in the field of DILI biomarker research have provided us with an opportunity to step back, consider how biomarker discovery has been done thus far, and determine how to move forward in a way that will optimize the discovery process. This is important because major challenges remain in the DILI field and related areas that could be overcome in part by new biomarkers. In this short review, we briefly describe recent progress in DILI biomarker discovery and development, identify current needs, and suggest a general approach to move forward.