Exo84c-regulated degradation is involved in the normal self-incompatible response in Brassicaceae.

The self-incompatibility system evolves in angiosperms to promote cross-pollination by rejecting self-pollination. Here, we show the involvement of Exo84c in the SI response of both Brassica napus and Arabidopsis. The expression of Exo84c is specifically elevated in stigma during the SI response. Knocking out Exo84c in B. napus and SI Arabidopsis partially breaks down the SI response. The SI response inhibits both the protein secretion in papillae and the recruitment of the exocyst complex to the pollen-pistil contact sites. Interestingly, these processes can be partially restored in exo84c SI Arabidopsis. After incompatible pollination, the turnover of the exocyst-labeled compartment is enhanced in papillae. However, this process is perturbed in exo84c SI Arabidopsis. Taken together, our results suggest that Exo84c regulates the exocyst complex vacuolar degradation during the SI response. This process is likely independent of the known SI pathway in Brassicaceae to secure the SI response.

Bioenergetic signatures of neurodevelopmental regression.

Background: Studies have linked autism spectrum disorder (ASD) to physiological abnormalities including mitochondrial dysfunction. Mitochondrial dysfunction may be linked to a subset of children with ASD who have neurodevelopmental regression (NDR). We have developed a cell model of ASD which demonstrates a unique mitochondrial profile with mitochondrial respiration higher than normal and sensitive to physiological stress. We have previously shown similar mitochondrial profiles in individuals with ASD and NDR. Methods: Twenty-six ASD individuals without a history of NDR (ASD-NoNDR) and 15 ASD individuals with a history of NDR (ASD-NDR) were recruited from 34 families. From these families, 30 mothers, 17 fathers and 5 typically developing (TD) siblings participated. Mitochondrial respiration was measured in peripheral blood mononuclear cells (PBMCs) with the Seahorse 96 XF Analyzer. PBMCs were exposed to various levels of physiological stress for 1 h prior to the assay using 2,3-dimethoxy-1,4-napthoquinone. Results: ASD-NDR children were found to have higher respiratory rates with mitochondria that were more sensitive to physiological stress as compared to ASD-NoNDR children, similar to our cellular model of NDR. Differences in mitochondrial respiration between ASD-NDR and TD siblings were similar to the differences between ASD-NDR and ASD-NoNDR children. Interesting, parents of children with ASD and NDR demonstrated patterns of mitochondrial respiration similar to their children such that parents of children with ASD and NDR demonstrated elevated respiratory rates with mitochondria that were more sensitive to physiological stress. In addition, sex differences were seen in ASD children and parents. Age effects in parents suggested that mitochondria of older parents were more sensitive to physiological stress. Conclusion: This study provides further evidence that children with ASD and NDR may have a unique type of mitochondrial physiology that may make them susceptible to physiological stressors. Identifying these children early in life before NDR occurs and providing treatment to protect mitochondrial physiology may protect children from experiencing NDR. The fact that parents also demonstrate mitochondrial respiration patterns similar to their children implies that this unique change in mitochondrial physiology may be a heritable factor (genetic or epigenetic), a result of shared environment, or both.

Imaging plant metabolism in situ.

Mass spectrometry imaging (MSI) has emerged as an invaluable analytical technique for investigating the spatial distribution of molecules within biological systems. In the realm of plant science, MSI is increasingly employed to explore metabolic processes across a wide array of plant tissues, including those in leaves, fruits, stems, roots, and seeds, spanning various plant systems such as model species, staple and energy crops, and medicinal plants. By generating spatial maps of metabolites, MSI has elucidated the distribution patterns of diverse metabolites and phytochemicals, encompassing lipids, carbohydrates, amino acids, organic acids, phenolics, terpenes, alkaloids, vitamins, pigments, and others, thereby providing insights into their metabolic pathways and functional roles. In this review, we present recent MSI studies that demonstrate the advances made in visualizing the plant spatial metabolome. Moreover, we emphasize the technical progress that enhances the identification and interpretation of spatial metabolite maps. Within a mere decade since the inception of plant MSI studies, this robust technology is poised to continue as a vital tool for tackling complex challenges in plant metabolism.

Hypoglossal Nerve Stimulation and Cardiovascular Outcomes for Patients With Obstructive Sleep Apnea: A Randomized Clinical Trial.

Importance: Sham-controlled trials are needed to characterize the effect of hypoglossal nerve stimulation (HGNS) therapy on cardiovascular end points in patients with moderate-severe obstructive sleep apnea (OSA). Objective: To determine the effect of therapeutic levels of HGNS, compared to sham levels, on blood pressure, sympathetic activity, and vascular function. Design, Setting, and Participants: This double-blind, sham-controlled, randomized crossover therapy trial was conducted from 2018 to 2022 at 3 separate academic medical centers. Adult patients with OSA who already had an HGNS device implanted and were adherent and clinically optimized to HGNS therapy were included. Participants who had fallen asleep while driving within 1 year prior to HGNS implantation were excluded from the trial. Data analysis was performed from January to September 2022. Interventions: Participants underwent a 4-week period of active HGNS therapy and a 4-week period of sham HGNS therapy in a randomized order. Each 4-week period concluded with collection of 24-hour ambulatory blood pressure monitoring (ABPM), pre-ejection period (PEP), and flow-mediated dilation (FMD) values. Main Outcomes and Measures: The change in mean 24-hour systolic blood pressure was the primary outcome, with other ABPM end points exploratory, and PEP and FMD were cosecondary end points. Results: Participants (n = 60) were older (mean [SD] age, 67.3 [9.9] years), overweight (mean [SD] body mass index, calculated as weight in kilograms divided by height in meters squared, 28.7 [4.6]), predominantly male (38 [63%]), and had severe OSA at baseline (mean [SD] apnea-hypopnea index, 33.1 [14.9] events/h). There were no differences observed between active and sham therapy in 24-hour systolic blood pressure (mean change on active therapy, -0.18 [95% CI, -2.21 to 1.84] mm Hg), PEP (mean change on active therapy, 0.11 [95% CI, -5.43 to 5.66] milliseconds), or FMD (mean change on active therapy, -0.17% [95% CI, -1.88% to 1.54%]). Larger differences between active and sham therapy were observed in a per-protocol analysis set (n = 20) defined as experiencing at least a 50% reduction in apnea-hypopnea index between sham and active treatment. Conclusions and Relevance: In this sham-controlled HGNS randomized clinical trial, mean 24-hour systolic blood pressure and other cardiovascular measures were not significantly different between sham and active HGNS therapy. Several methodologic lessons can be gleaned to inform future HGNS randomized clinical trials. Trial Registration: ClinicalTrials.gov Identifier: NCT03359096.

Candidemia in Adult Patients in the ICU: A Reappraisal of Susceptibility Testing and Antifungal Therapy.

OBJECTIVE: To provide updates on the epidemiology and recommendations for management of candidemia in patients with critical illness. DATA SOURCES: A literature search using the PubMed database (inception to March 2023) was conducted using the search terms "invasive candidiasis," "candidemia," "critically ill," "azoles," "echinocandin," "antifungal agents," "rapid diagnostics," "antifungal susceptibility testing," "therapeutic drug monitoring," "antifungal dosing," "persistent candidemia," and "Candida biofilm." STUDY SELECTION/DATA EXTRACTION: Clinical data were limited to those published in the English language. Ongoing trials were identified through ClinicalTrials.gov. DATA SYNTHESIS: A total of 109 articles were reviewed including 25 pharmacokinetic/pharmacodynamic studies and 30 studies including patient data, 13 of which were randomized controlled clinical trials. The remaining 54 articles included fungal surveillance data, in vitro studies, review articles, and survey data. The current 2016 Infectious Diseases Society of America (IDSA) Clinical Practice Guideline for the Management of Candidiasis provides recommendations for selecting empiric and definitive antifungal therapies for candidemia, but data are limited regarding optimized dosing strategies in critically ill patients with dynamic pharmacokinetic changes or persistent candidemia complicated. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: Outcomes due to candidemia remain poor despite improved diagnostic platforms, antifungal susceptibility testing, and antifungal therapy selection for candidemia in critically ill patients. Earlier detection and identification of the species causing candidemia combined with recognition of patient-specific factors leading to dosing discrepancies are crucial to improving outcomes in critically ill patients with candidemia. CONCLUSIONS: Treatment of candidemia in critically ill patients must account for the incidence of non-albicans Candida species and trends in antifungal resistance as well as overcome the complex pathophysiologic changes to avoid suboptimal antifungal exposure.

Extranodal extension in head and neck squamous cell carcinoma: need for accurate pretherapeutic staging to select optimum treatment and minimize toxicity.

PURPOSE OF REVIEW: In 2017, the American Joint Committee on Cancer (AJCC) introduced the inclusion of extracapsular nodal extension (ENE) into the N staging of nonviral head and neck squamous cell carcinoma (HNSCC), while retaining the traditional N classification based on the number and sizes of metastatic nodes. The extent of ENE was further defined as microscopic ENE (ENEmi) and major ENE (ENEma) based on extent of disease beyond the nodal capsule (≤ or > 2 mm). This article reviews the evidence and progress made since these changes were introduced. RECENT FINDINGS: The 'gold standard' for evaluation ENE is histopathologic examination, the current preferred primary treatment of patients with HNSCC is by radiation-based therapy ±â€Šchemotherapy or biotherapy. The current pretreatment staging is by imaging, which needs improved reliability of radiologic rENE assessment with reporting needs to consider both sensitivity and specificity (currently computed tomography images have high-specificity but low-sensitivity). Adjuvant chemotherapy is indicated for patients with ENEma to enhance disease control, whereas for patients with ENEmi, there is a need to assess the benefit of adjuvant chemotherapy. Evidence that the presence of pENE in HPV-positive oropharyngeal carcinoma is an independent prognostic factor and should be considered for inclusion in future AJCC editions has recently emerged. SUMMARY: There remains a paucity of data on the reliability of imaging in the staging of rENE, more so the for the accurate assessment of ENEmi. Optimistic early results from use of artificial intelligence/deep learning demonstrate progress and may pave the way for better capabilities in tumor staging, treatment outcome prediction, resulting in improved survival outcomes.

The Role of En Bloc Resection in the Modern Era for Primary Spine Tumors.

STUDY DESIGN: A literature review. OBJECTIVE: The aim of this review is to provide an overview of benign and malignant primary spine tumors and a balanced analysis of the benefits and limitations of (and alternatives to) surgical treatment with en bloc resection. SUMMARY OF BACKGROUND DATA: Primary spine tumors are rare but have the potential to cause severe morbidity, either from the disease itself or as a result of treatment. The prognosis, goals, and treatment options vary significantly with the specific disease entity. Appropriate initial management is critical; inappropriate surgery before definitive treatment can lead to recurrence and may render the patient incurable, as salvage options are often inferior. METHODS: We performed a comprehensive search of the PubMed database for articles relevant to primary spine neoplasms and en bloc spine surgery. Institutional review board approval was not needed. RESULTS: Although Enneking-appropriate en bloc surgery can be highly morbid, it often provides the greatest chance for local control and/or patient survival. However, there is growing data to support modern radiotherapy as a feasible and less morbid approach to certain primary neoplasms that historically were considered radioresistant. CONCLUSIONS: Choosing the optimal approach to primary spine tumors is complex. A comprehensive and up-to-date assessment of the evidence is required to guide patient care and to balance the often-competing goals of prolonging life and preserving quality of life.

Can scuba diving transform the lives of people with physical impairments? A mixed methods study.

PURPOSE: This study aimed to: (1) test and explain the type of experience scuba diving is among people with physical impairments based on the experience-type framework; (2) assess and describe their personality based on the Big Five domains; and (3) identify if personality, years diving, and diving level predict experience-type. METHODS: An explanatory sequential mixed methods design was employed. The quantitative phase used a cross-sectional survey (n = 103). The qualitative phase used follow-up interviews with 15 participants divided into 3 case study groups. Joint displays with meta-inferences integrated the data. RESULTS: Quantitative and qualitative findings concurred on scuba being a transformative experience. 82.52% of survey participants reported scuba as a transformative experience, with no significant differences on experience impact based on impairment category (p = 0.56), impairment onset (p = 0.66), gender (p = 0.08), race/ethnicity (p = 0.51), or age (p = 0.07). Big Five personality domains, years diving, or diving level did not predict experience impact (R2 = 0.14, F(12,90) = 1.304, p = 0.2305). Data strand results differed on salient personality domains. Seven qualitative themes emerged, five on experience-type and two on personality. CONCLUSIONS: We recommend the exploration of scuba diving as a prospective rehabilitation intervention.

Innovative rehabilitation interventions that provide positive experiences and long-term health benefits to people with physical impairments are needed.Participants reported that scuba diving had a positive transformative impact in their lives through positive emotions, peace/relaxation, personal growth, development of skills, social connections, physical and mental healing, and lasting behavioral changes.Reporting scuba diving as a transformative experience was not influenced by the scuba divers' personality domains, diving level, demographic characteristics, or the number of years they had been diving.Authors recommend the consideration and further exploration of scuba diving as a prospective physical and psychosocial rehabilitation intervention.

Using Machine Learning to Leverage Biomarker Change and Predict Colorectal Cancer Recurrence.

PURPOSE: The risk of colorectal cancer (CRC) recurrence after primary treatment varies across individuals and over time. Using patients' most up-to-date information, including carcinoembryonic antigen (CEA) biomarker profiles, to predict risk could improve personalized decision making. METHODS: We used electronic health record data from an integrated health system on a cohort of patients diagnosed with American Joint Committee on Cancer stage I-III CRC between 2008 and 2013 (N = 3,970) and monitored until recurrence or end of follow-up. We addressed missingness in recurrence outcomes and longitudinal CEA measures, and engineered CEA features using current and past biomarker values for inclusion in a risk prediction model. We used a discrete time Superlearner model to evaluate various algorithms for predicting recurrence. We evaluated the time-varying discrimination and calibration of the algorithms and assessed the role of individual predictors. RESULTS: Recurrence was documented in 448 (11.3%) patients. XGBoost with depth = 1 (XGB-D1) predicted recurrence substantially better than all other algorithms at all time points, with AUC ranging from 0.87 (95% CI, 0.86 to 0.88) at 6 months to 0.94 (95% CI, 0.92 to 0.96) at 54 months. The only variable used by XGB-D1 was 6-month change in log CEA. Predicted 1-year risk of recurrence was nearly zero for patients whose log CEA did not increase in the last 6 months, between 12.2% and 34.1% for patients whose log CEA increased between 0.10 and 0.40, and 43.6% for those with a log CEA increase >0.40. Compared with XGB, penalized regression approaches (lasso, ridge, and elastic net) performed poorly, with AUCs ranging from 0.58 to 0.69. CONCLUSION: A flexible, machine learning approach that incorporated longitudinal CEA information yielded a simple and high-performing model for predicting recurrence on the basis of 6-month change in log CEA.

Comparison of quartz and sapphire optical chambers for infrared laser sealing of vascular tissues using a reciprocating, side-firing optical fiber: Simulations and experiments.

INTRODUCTION: Infrared (IR) lasers are being tested as an alternative to radiofrequency (RF) and ultrasonic (US) surgical devices for hemostatic sealing of vascular tissues. In previous studies, a side-firing optical fiber with elliptical IR beam output was reciprocated, producing a linear IR laser beam pattern for uniform sealing of blood vessels. Technical challenges include limited field-of-view of vessel position within the metallic device jaws, and matching fiber scan length to variable vessel sizes. A transparent jaw may improve visibility and enable custom treatment. METHODS: Quartz and sapphire square optical chambers (2.7 × 2.7 × 25 [mm3 ] outer dimensions) were tested, capable of fitting into a 5-mm-OD laparoscopic device. A 1470 nm laser was used for optical transmission studies. Razor blade scans and an IR beam profiler acquired fiber (550-µm-core/0.22NA) output beam profiles. Thermocouples recorded peak temperatures and cooling times on internal and external chamber surfaces. Optical fibers with angle polished distal tips delivered 94% of light at a 90° angle. Porcine renal arteries with diameters of 3.4 ± 0.7 mm (n = 13) for quartz and 3.2 ± 0.7 mm (n = 14) for sapphire chambers (p > 0.05), were sealed using 30 W for 5 s. RESULTS: Reflection losses at material/air interfaces were 3.3% and 7.4% for quartz and sapphire. Peak temperatures on the external chamber surface averaged 74 ± 8°C and 73 ± 10°C (p > 0.05). Times to cool down to 37°C measured 13 ± 4 s and 27 ± 7 s (p < 0.05). Vessel burst pressures (BP) averaged 883 ± 393 mmHg and 412 ± 330 mmHg (p < 0.05). For quartz, 13/13 (100%) vessels were sealed (BP > 360 mmHg), versus 9/14 (64%) for sapphire. Computer simulations for the quartz chamber yielded peak temperatures (78°C) and cooling times (16 s) similar to experiments. CONCLUSIONS: Quartz is an inexpensive material for use in a laparoscopic device jaw, providing more consistent vessel seals and faster cooling times than sapphire and current RF and US devices.

Clinical application of physical therapy in facial paralysis treatment: A review.

This review aims to summarize recent studies regarding the specific modalities of physical therapy as a form of treatment for patients with facial paralysis, analyze the different components of physical therapy, and provide healthcare providers with guidance for their best practice in treating patients with facial paralysis. This paper will discuss the mechanism, indications, and impact factors for facial retraining, evaluate the standards for facial retraining, the creation of a treatment plan, and analyze the combined use of facial retraining with botulinum toxin injections and the application of facial retraining in post facial reanimation patients. Other modes of physical therapy, including electrical stimulation, dry needling, and acupuncture, will be addressed. Lastly, the application of new digital technology will be discussed.

Healthcare Costs and Healthcare Utilization Outcomes of Vitamin D3 Supplementation at 5000 IU Daily during a 10.9 Month Observation Period within a Pragmatic Randomized Clinical Trial.

Vitamin D insufficiency has been linked to multiple conditions including bone disease, respiratory disease, cardiovascular disease, diabetes, and cancer. Observational studies indicate lower healthcare costs and healthcare utilization with sufficient vitamin D levels. The secondary aims of our previously published pragmatic clinical trial of vitamin D3 supplementation were comparisons of healthcare costs and healthcare utilization. Comparisons were made between the vitamin D3 at 5000 IU supplementation group and a non-supplemented control group. Costs of care between the groups differed but were not statistically significant. Vitamin D3 supplementation reduced healthcare utilization in four major categories: hospitalizations for any reason (rate difference: -0.19 per 1000 person-days, 95%-CI: -0.21 to -0.17 per 1000 person-days, p < 0.0001); ICU admissions for any reason (rate difference: -0.06 per 1000 person-days, 95%-CI: -0.08 to -0.04 per 1000 person-days, p < 0.0001); emergency room visits for any reason (rate difference: -0.26 per 1000 person-days, 95%-CI: -0.46 to -0.05 per 1000 person-days, p = 0.0131; and hospitalizations due to COVID-19 (rate difference: -8.47 × 10-3 per 1000 person-days, 95%-CI: -0.02 to -1.05 × 10-3 per 1000 person-days, p = 0.0253). Appropriately powered studies of longer duration are recommended for replication of these utilization findings and analysis of cost differences.

Optimising a computational model of human auditory cortex with an evolutionary algorithm.

We demonstrate how the structure of auditory cortex can be investigated by combining computational modelling with advanced optimisation methods. We optimise a well-established auditory cortex model by means of an evolutionary algorithm. The model describes auditory cortex in terms of multiple core, belt, and parabelt fields. The optimisation process finds the optimum connections between individual fields of auditory cortex so that the model is able to reproduce experimental magnetoencephalographic (MEG) data. In the current study, this data comprised the auditory event-related fields (ERFs) recorded from a human subject in an MEG experiment where the stimulus-onset interval between consecutive tones was varied. The quality of the match between synthesised and experimental waveforms was 98%. The results suggest that neural activity caused by feedback connections plays a particularly important role in shaping ERF morphology. Further, ERFs reflect activity of the entire auditory cortex, and response adaptation due to stimulus repetition emerges from a complete reorganisation of AC dynamics rather than a reduction of activity in discrete sources. Our findings constitute the first stage in establishing a new non-invasive method for uncovering the organisation of the human auditory cortex.

An Effective Sanitizer for Fresh Produce Production: In Situ Plasma-Activated Water Treatment Inactivates Pathogenic Bacteria and Maintains the Quality of Cucurbit Fruit.

The effect of plasma-activated water (PAW) generated with a dielectric barrier discharge diffusor (DBDD) system on microbial load and organoleptic quality of cucamelons was investigated and compared to the established sanitizer, sodium hypochlorite (NaOCl). Pathogenic serotypes of Escherichia coli, Salmonella enterica, and Listeria monocytogenes were inoculated onto the surface of cucamelons (6.5 log CFU g-1) and into the wash water (6 log CFU mL-1). PAW treatment involved 2 min in situ with water activated at 1,500 Hz and 120 V and air as the feed gas; NaOCl treatment was a wash with 100 ppm total chlorine; control treatment was a wash with tap water. PAW treatment produced a 3-log CFU g-1 reduction of pathogens on the cucamelon surface without negatively impacting quality or shelf life. NaOCl treatment reduced the pathogenic bacteria on the cucamelon surface by 3 to 4 log CFU g-1; however, this treatment also reduced fruit shelf life and quality. Both systems reduced 6-log CFU mL-1 pathogens in the wash water to below detectable limits. The critical role of superoxide anion radical (·O2-) in the antimicrobial power of DBDD-PAW was demonstrated through a Tiron scavenger assay, and chemistry modeling confirmed that ·O2- generation readily occurs in DBDD-PAW generated with the employed settings. Modeling of the physical forces produced during plasma treatment showed that bacteria likely experience strong local electric fields and polarization. We hypothesize that these physical effects synergize with reactive chemical species to produce the acute antimicrobial activity seen with the in situ PAW system. IMPORTANCE Plasma-activated water (PAW) is an emerging sanitizer in the fresh food industry, where food safety must be achieved without a thermal kill step. Here, we demonstrate PAW generated in situ to be a competitive sanitizer technology, providing a significant reduction of pathogenic and spoilage microorganisms while maintaining the quality and shelf life of the produce item. Our experimental results are supported by modeling of the plasma chemistry and applied physical forces, which show that the system can generate highly reactive ·O2- and strong electric fields that combine to produce potent antimicrobial power. In situ PAW has promise in industrial applications as it requires only low power (12 W), tap water, and air. Moreover, it does not produce toxic by-products or hazardous effluent waste, making it a sustainable solution for fresh food safety.

Patient perspectives on post-bariatric surgery nutritional supplementation.

BACKGROUND: Bariatric procedures increase patient risk of long-term metabolic complications primarily due to nutrient deficiencies. The mainstay of prevention includes routine vitamin and mineral supplementation; however, patient-reported barriers to daily compliance are poorly understood. METHODS: Post-bariatric surgery patients electively participated in an 11-point outpatient survey at a single academic institution. Surgical procedures included either laparoscopic sleeve gastrectomy (SG) or gastric bypass (GB). At the time of survey, patients ranged from 1-month to 15 years from surgery. Survey items consisted of dichotomous (yes/no), multiple choice, and open-ended free response questions. Descriptive statistics were evaluated. RESULTS: Two hundred and fourteen responses were collected, 116 (54%) underwent SG and 98 (46%) underwent GB. Of these, 49% of samples were during short-term postoperative follow-up visits (0-3 months), 34% intermediate follow-up (4-12 months), and 17% long-term follow-up (> 1 year). A total of 98% of patients reported that insurance did not cover their supplement cost. Most patients reported current vitamin use (95%), with 87% reporting daily compliance. Daily compliance was observed in 94%, 79%, and 73% of SG patients at short-, intermediate-, and long-term follow-up visits, respectively. While GB patients reported daily compliance in 84%, 100%, and 92% of short, intermediate, and long-term responses. Of those who were unable to take vitamins daily, non-compliance was attributed most to forgetting (54%), and less often to side effects (11%), or taste (11%). Patient-reported strategies for remembering to take vitamins included tying into daily routine (55%), use of a pill box (7%), and alarm reminders (7%). CONCLUSIONS: Daily compliance with post-bariatric surgery vitamin supplementation does not appear to vary based on postoperative time-period or surgical procedure. While a minority of patients struggle with daily compliance, factors associated with non-compliance include patient forgetting, side effects, and taste. Widespread utilization of patient-reported daily reminder strategies may lead to improved overall compliance and reduce incidence of nutritional deficiencies.

MYB-bHLH-TTG1 in a Multi-tiered Pathway Regulates Arabidopsis Seed Coat Mucilage Biosynthesis Genes Including PECTIN METHYLESTERASE INHIBITOR14 Required for Homogalacturonan Demethylesterification.

MYB-bHLH-TTG1 (MBW) transcription factor (TF) complexes regulate Arabidopsis seed coat biosynthesis pathways via a multi-tiered regulatory mechanism. The MYB genes include MYB5, MYB23 and TRANSPARENT TESTA2 (TT2), which regulate GLABRA2 (GL2), HOMEODOMAIN GLABROUS2 (HDG2) and TRANSPARENT TESTA GLABRA2 (TTG2). Here, we examine the role of PECTIN METHYLESTERASE INHIBITOR14 (PMEI14) in seed coat mucilage pectin methylesterification and provide evidence in support of multi-tiered regulation of seed coat mucilage biosynthesis genes including PMEI14. The PMEI14 promoter was active in the seed coat and developing embryo. A pmei14 mutant exhibited stronger attachment of the outer layer of seed coat mucilage, increased mucilage homogalacturonan demethylesterification and reduced seed coat radial cell wall thickness, results consistent with decreased PMEI activity giving rise to increased PME activity. Reduced mucilage release from the seeds of myb5, myb23, tt2 and gl2, hdg2, ttg2 triple mutants indicated that HDG2 and MYB23 play minor roles in seed coat mucilage deposition. Chromatin immunoprecipitation analysis found that MYB5, TT8 and seven mucilage pathway structural genes are directly regulated by MYB5. Expression levels of GL2, HDG2, TTG2 and nine mucilage biosynthesis genes including PMEI14 in the combinatorial mutant seeds indicated that these genes are positively regulated by at least two of those six TFs and that TTG1 and TTG2 are major regulators of PMEI14 expression. Our results show that MYB-bHLH-TTG1 complexes regulate mucilage biosynthesis genes, including PMEI14, both directly and indirectly via a three-tiered mechanism involving GL2, HDG2 and TTG2.

Racial Disparities in the Ascertainment of Cancer Recurrence in Electronic Health Records.

PURPOSE: There is growing interest in using computable phenotypes or proxies to identify important clinical outcomes, such as cancer recurrence, in rich electronic health records data. However, the race/ethnicity-specific accuracies of these proxies remain unclear. We examined whether the accuracy of a proxy for colorectal cancer (CRC) recurrence differed by race/ethnicity and the possible mechanisms that drove the differences. METHODS: Using data from a large integrated health care system, we identified a stratified random sample of 282 Black/African American (AA), Hispanic, and non-Hispanic White (NHW) patients with CRC who received primary treatment. Patient 5-year recurrence status was estimated using a utilization-based proxy and evaluated against the true recurrence status obtained using detailed chart review and by race/ethnicity. We used covariate-adjusted probit regression models to estimate the associations between race/ethnicity and misclassification. RESULTS: The recurrence proxy had excellent overall accuracy (positive predictive value [PPV] 89.4%; negative predictive value 96.5%; mean difference in timing 1.96 months); however, accuracy varied by race/ethnicity. Compared with NHW patients, PPV was 14.9% lower (95% CI, 2.53 to 28.6) among Hispanic patients and 4.3% lower (95% CI, -4.8 to 14.8) among Black/AA patients. The proxy disproportionately inflated the 5-year recurrence incidence for Hispanic patients by 10.6% (95% CI, 4.2 to 18.2). Compared with NHW patients, proxy recurrences for Hispanic patients were almost three times as likely to have been misclassified as positive (adjusted risk ratio 2.91 [95% CI, 1.21 to 8.31]). Higher false positives among racial/ethnic minorities may be related to higher prevalence of noncancerous lung-related problems and substantial delays in primary treatment because of insufficient patient-provider communication and abnormal treatment patterns. CONCLUSION: Using a proxy with worse accuracy among racial/ethnic minority patients to estimate population health may misdirect resources and support erroneous conclusions around treatment benefit for these patients.

Normal 24-hour urine calcium concentrations after long-term daily oral intake of vitamin D in doses ranging from 5000 to 50,000 international units in 14 adult hospitalized psychiatric patients.

Many controversies exist regarding vitamin D3 supplementation. These include not only diseases that are responsive to vitamin D supplementation, but also the long-term safety of prolonged daily oral vitamin D3 intake above 4000-10,000 International Units (IU). In particular, supplementation levels that do not result in adverse events, and the upper limits of safe serum 25-hydroxyvitamin D (25OHD) concentrations. Adverse reactions reported to occur with excessive vitamin D intake include hypercalcemia, renal failure, calcium crystal formation, undetectable parathyroid hormone concentrations, and hypercalciuria, all of which are reported to be reversible. To address the long-term safety of vitamin D supplementation, we previously reported data from patients in our hospital who have been voluntarily supplemented with vitamin D3 ranging from 5,000 to 10,000 IU/day since July 2011 as a standard of care for the prevention and treatment of vitamin D deficiency. Historically 90% of patients have agreed to daily supplementation, with most taking 10,000 IU/day. These data indicate no evidence for hypercalcemia, renal failure, calcium crystal formation, nephrolithiasis. or undetectable parathyroid hormone concentrations in patients taking 5000 or 10,000 IU/day for extended periods of time. As another measure for potential vitamin D toxicity, we retrospectively assessed 24-hour urine calcium excretion in 14 individuals on long-term daily oral vitamin D intake ranging from 5000 to 50,000 IU/day to further assess the safety of supplementation using these doses. This included patients taking either 5000 (4), 10,000 (9), or 50,000 (1) IU/day. Time on supplementation ranged from 10 to 102 months. A patient taking 400 IU/day and getting frequent sun exposure was also included. All fifteen 24-hour urine calcium measurements were normal. The current findings complement our experience with over 7000 patients in the past 13 years, indicating that prolonged daily oral intake of vitamin D3 ranging from 5000 to 10,000 IU/day is safe.

A narrative review of social determinants of health education in health professional programs and potential pathways for integration into Doctor of Chiropractic programs.

Objectives: To conduct a narrative review of the literature pertaining to strategies employed by health professional programs to teach social determinants of health (SDOH) and use the results to describe pathways for integrating SDOH education into Doctor of Chiropractic programs (DCPs). Methods: A narrative review of peer-reviewed literature describing SDOH education in health professional programs within the United States was performed. The results were used to inform potential pathways of integrating SDOH education into all aspects of DCPs. Results: Twenty-eight papers demonstrated health professional programs' incorporation of SDOH education and assessment into didactic and experiential learning opportunities. Educational interventions resulted in positive changes in knowledge and attitudes toward SDOH. Conclusion: This review demonstrates existing methods for integrating SDOH in health professional programs. Methods may be adopted and assimilated into an existing DCP. Further research is needed to understand barriers and facilitators to the implementation of SDOH education into DCPs.

Objectifs: Réaliser une analyse narrative de la littérature relative aux stratégies employées par les programmes de professionnels de la santé pour enseigner les déterminants sociaux de la santé (DSS) et utiliser les résultats pour décrire les voies d'intégration de l'enseignement des DSS dans les programmes de doctorat en chiropratique (PDC). Méthodes: Une analyse narrative de la documentation évaluée par les pairs décrivant l'enseignement des déterminants sociaux de la santé dans les programmes de formation des professionnels de la santé aux États-Unis a été réalisée. Les résultats ont été utilisés pour éclairer les voies potentielles d'intégration de l'enseignement des DSS dans tous les aspects des PDC. Résultats: Vingt-huit articles ont fait état de l'intégration, par les programmes de professionnels de la santé, de l'enseignement et de l'évaluation des DSS dans les possibilités d'apprentissage didactique et expérientiel. Les interventions éducatives ont entraîné des changements positifs dans les connaissances et les attitudes à l'égard des DSS. Conclusion: Cette étude présente les méthodes existantes d'intégration des DSS dans les programmes de formation des professionnels de la santé. Ces méthodes peuvent être adoptées et assimilées dans un PDC existant. D'autres recherches sont nécessaires pour comprendre les obstacles et les facilitateurs de la mise en oeuvre de l'enseignement des DSS dans les PDC.