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Abstract: The San Francisco Estuary, in central California, has several long-running monitoring programs that have been used to reveal human-induced changes throughout the estuary in the last century. Here, we pair synoptic records of particulate organic matter (POM) composition from 1990–1996 and 2007–2016 with more robust long-term monitoring program records of total suspended sediment (TSS) concentrations generally starting in the mid-1970s to better understand how POM and TSS sources and transport have shifted. Specifically, POM C:N ratios and stable isotope values were used as indicators of POM source and to separate the bulk POC pool into detrital and phytoplankton components. We found that TSS and POC sources have shifted significantly across the estuary in time and space from declines in terrestrial inputs. Landward freshwater and brackish water sites, in the Delta and near Suisun Bay, witnessed long-term declines in TSS (32 to 52%), while seaward sites, near San Pablo Bay, recorded recent increases in TSS (16 to 121%) that began to trend downwards at the end of the record considered. Bulk POM C:N ratios shifted coeval with the TSS concentration changes at nearly all sites, with mean declines of 12 to 27% between 1990–1996 and 2007–2016. The widespread declines in bulk POM C:N ratios and inferred changes in POC concentrations from TSS trends, along with the substantial declines in upstream TSS supply through time (56%), suggest measurable reductions in terrestrial inputs to the system. Changes in terrestrial TSS and POM inputs have implications for biotic (e.g., food web dynamics) and abiotic organic matter cycling (e.g., burial, export) along the estuarine continuum. This work demonstrates how human-generated environmental changes can propagate spatially and temporally through a large river-estuary system. More broadly, we show how underutilized monitoring program datasets can be paired with existing (and often imperfect) synoptic records to generate new system insight in lieu of new data collection.

Objective: The aim of this study was to assess the utility of ultrasound (US) imaging for diagnosis of abnormal tracheal morphology, such as tracheal cartilaginous sleeves (TCS), in patients with syndromic craniosynostosis (SC)., Study Design: Age-matched cohort study., Setting: Tertiary pediatric hospital., Methods: Two age-matched cohorts were identified: patients with SC and known TCS based upon airway endoscopy and normal controls without tracheal pathology. Enrolled patients underwent awake US of the neck which were randomized and reviewed by blinded pediatric radiologists and rated on presence or absence of normal tracheal cartilage morphology and visualization or nonvisualization of a tracheostomy tube. Fisher's exact test was used to assess pooled data. Fleiss' Kappa (κ) was calculated to assess inter-rater reliability., Results: Ten patients were included in each cohort. Control patients were gender and age-matched to TCS patients with a mean difference of 3.7 months (±3.9 months). Across all raters, cartilage type was correctly identified in 93% (95% confidence interval [CI]: 84%-98%) and tracheostomy visualization in 97% (95% CI: 89%-99%). The sensitivity and specificity for detection of abnormal cartilage pathology was 87% and 100%, respectively. Inter-rater reliability for cartilage assessment was κ = 0.88 (95% CI: 0.67-1.00, P < .05) and 0.83 (95% CI: 0.58-1.00, P < .05) for tracheostomy presence., Conclusion: This study demonstrated that tracheal US is a feasible, accurate screening tool for TCS, and can be successfully performed non-sedated in patients up to 18 years of age, both with and without tracheostomy tubes in place., (© 2024 American Academy of Otolaryngology–Head and Neck Surgery Foundation.)

Objectives: To investigate the relationship between social determinants of health and timeliness of management, adherence to follow-up, and outcomes of treatment with interarytenoid injection augmentation (IAIA)., Methods: Retrospective cohort study of all pediatric patients treated with IAIA at a large pediatric institution's multidisciplinary aerodigestive clinic between August 2022 and February 2024. Retrieved demographic factors, dates of referral, consultation, treatment, and follow-up, as well as objective measures of dysphagia and aspiration via videofluoroscopic swallow study (VFSS) reports, using dysphagia outcome and severity scale (DOSS) scores and the greatest unsafe thickness, or 'aspiration score'. These factors were analyzed for correlation with social determinants of health determined through the Area of Deprivation Index (ADI)., Results: A total of 120 patients, median age 15 months were included. All underwent IAIA for the indication of persistent pharyngeal dysphagia. The median national ADI score was 45. Patients experienced average improvement in laryngeal penetration and aspiration from an aspiration score of slightly thick preoperatively to thin postoperatively, and improvement in dysphagia from mild-moderate to mild. No correlation was identified between ADI, race and ethnicity, or sex and measures of timeliness of treatment, loss to follow-up, receipt of feeding therapy, or outcome of treatment., Conclusion: Addressing persistent dysphagia in pediatric patients with IAIA seems to be equivalently efficacious across a wide population, and outcome did not vary significantly depending on patients' race or socioeconomic contexts. This finding may be due in part to the utilization of a well-organized multidisciplinary center to treat these complex patients., Level of Evidence: 4 Laryngoscope, 2024., (© 2024 The American Laryngological, Rhinological and Otological Society, Inc.)

Objective: The objective of this study was to assess the efficacy and complication rates of interarytenoid injection augmentation (IAIA) for the treatment of dysphagia in patients 1 year of age and under and to determine if concurrent feeding therapy (FT) affects outcome., Study Design: Retrospective case series., Setting: Tertiary pediatric hospital., Methods: Retrospective review of patients 13 months of age and younger with dysphagia treated by IAIA over a 4-year period. The efficacy of IAIA was determined by comparing perioperative videofluoroscopic swallow studies (VFSS) and Dysphagia Outcome and Severity Scale (DOSS) scores. Complication rates and utilization of concomitant FT were determined by evaluating postoperative admission and follow-up records., Results: Sixty-five patients met inclusion criteria (median age 8 months, interquartile range [IQR]: 7-11). Sixty-seven percent of patients improved on postoperative VFSS scores (median improvement in aspiration of 2 thickness levels, IQR 0-3, P < .0001), and 56% improved in DOSS scores (median increase of 1, IQR: 0-1.5, P < .0001). Ninety-two percent of patients were discharged home on the day of surgery. The 30-day relevant readmission rate was 5%. No patients had intraoperative complications or severe complications at follow-up. No statistical difference in aspiration or DOSS was noted in the concomitant FT cohort due to a lack of sample size., Conclusion: This study demonstrates that IAIA in children under 13 months old shows comparable rates of success and complications to older patients reported in the literature. No patients had long-term complications and most were discharged home on the day of surgery. More studies are needed to determine the effect of concomitant FT on IAIA., (© 2024 American Academy of Otolaryngology–Head and Neck Surgery Foundation.)

Objective: Respiratory failure secondary to multilevel airway compromise may present complex airway challenges in patients with specific skeletal dysplasia diagnoses. This study sought to identify and characterize subgroups of skeletal dysplasia diagnoses that more frequently undergo operative airway evaluations and tracheostomy placement., Methods: Retrospective electronic medical record review of pediatric patients with an ICD-10 associated skeletal dysplasia diagnosis and CPT-specified airway intervention at a tertiary pediatric hospital from 1990 to 2022. Patients without a defined skeletal dysplasia diagnosis, subjects with craniosynostosis syndromes, and those with limited clinical data were excluded. Collected variables included demographics, age at diagnosis, comorbidities, operative procedures, and airway interventions. Descriptive statistical analysis was utilized to evaluate data distribution., Results: From the initial population of 313 patients, 41 subjects were confirmed to have clinical features and/or genetic testing consistent with a skeletal dysplasia diagnosis. A tracheostomy was placed in 19/41 subjects and these patients' records were further analyzed. Skeletal dysplasia groups with more frequent tracheostomy placement included Filamins and related disorders, Sulfation disorders, and Chondrodysplasia punctata. In the patients with a tracheostomy, skeletal dysplasia was diagnosed at a median age of 0.3 years (IQR 4.8 years), and tracheostomy was initiated at a median age of 1.8 years (IQR 2.2 years). Only four of these patients were successfully decannulated, and two subjects are deceased., Conclusion: Over 32 years, nearly half of the skeletal dysplasia patients who underwent airway interventions eventually had a tracheostomy placed. Respiratory insufficiency and complex airway management challenges are common manifestations of skeletal dysplasia., Competing Interests: Declaration of competing interest The authors have no competing interests to declare that are relevant to the content of this article., (Copyright © 2024 Elsevier B.V. All rights reserved.)

This protocol describes the method for creating 3D-printed trachea models for use in high-fidelity simulation-based training and advanced surgical planning for pediatric patients undergoing slide tracheoplasty. The goal is to provide a template and methodology to allow for replicability and more widespread dissemination of these models to improve clinical training and patient care. Laryngoscope, 134:4409-4413, 2024., (© 2024 The American Laryngological, Rhinological and Otological Society, Inc.)

Objective: The objective of this study was to develop and assess multidisciplinary advanced surgical planning (ASP) sessions using three dimensional (3D) printed models for cervicothoracic slide tracheoplasty (CST). We hypothesized that these sessions would improve surgeon confidence, streamline intraoperative planning, and highlight the utility of 3D modeling., Methods: 3D-printed patient-specific trachea models were used in pre-operative ASP sessions consisting of a multidisciplinary case discussion and hands-on slide tracheoplasty simulation. Participants completed a survey rating realism, utility, impact on the final surgical plan, and pre- and post-session confidence. Statistical analysis was performed via Wilcoxon and Kruskal-Wallis tests., Results: Forty-eight surveys were collected across nine sessions and 27 different physicians. On a 5-point Likert scale, models were rated as "very realistic", "very useful" (both median of 4, IQR 3-4 and 4-5, respectively). Overall confidence increased by 1.4 points (+/- 0.7, p < 0.0001), with the largest change seen in those with minimal prior slide tracheoplasty experience (p = 0.005). Participants felt that the sessions "strongly" impacted their surgical plan or anticipated performance (median 4, IQR 4-5), regardless of training level or experience., Conclusion: 3D-printed patient-specific models were successfully implemented in ASP sessions for CST. Models were deemed very realistic and very useful by surgeons across multiple specialties and training levels. Surgical planning sessions also strongly impacted the final surgical plan and increased surgeon confidence for CST., Level of Evidence: 4 Laryngoscope, 134:3395-3401, 2024., (© 2024 The American Laryngological, Rhinological and Otological Society, Inc.)

Introduction: Clozapine is the most effective antipsychotic for treatment-resistant schizophrenia, but it is markedly underutilized, particularly in the US Black population, partly because of concern over clozapine-associated low absolute neutrophil count (ANC). People of African descent have a lower normative ANC range than the White population, which is associated with a specific "ACKR1-null" ("Duffy null") CC genotype (SNP rs2814778) on the ACKR1 gene, termed benign ethnic neutropenia (BEN). The range of ANC variability and safety of clozapine have not been established in people with BEN or examined prospectively in people of African descent., Methods: We completed a multisite, 6-month, prospective, open-label clinical trial of clozapine treatment in people of African descent with schizophrenia spectrum disorders for whom clozapine was clinically indicated, with or without the ACKR1-null genotype. We examined clozapine safety and weekly ANC during clozapine treatment and evaluated ANC variability by ACKR1-null genotype, sex, study site, and clozapine dosing using repeated measures analysis of covariance. Genotype was assayed using TaqMan® technology., Results: We enrolled 274 participants, of whom 227 (82.8 %) completed 6 months of clozapine treatment. There was one case of severe neutropenia (<500 cells/mm 3 ) (0.36 %) over 1467.6 person-months of clozapine exposure. This participant recovered without sequelae after discontinuation of clozapine. Of the 249 participants with known genotypes, 199 (79.9 %) had the ACKR1-null genotype. Neutropenia (<1500 cells/mm 3 ) occurred significantly more often in the ACKR1-null group (33 % [65/199]) than in those with the T allele (6 % (3/50); p < 0.001). Fourteen (5 %) patients discontinued due to adverse events. Rates of infection and fever were low and sialorrhea was the commonest side effect (N = 187, 68 %)., Conclusion: To our knowledge, this is the largest prospective clozapine trial in people of African descent. Severe neutropenia was rare, despite the high prevalence (80 %) of the ACKR1-null genotype. Our findings suggest that clozapine can be used safely in Black patients including those with BEN., Competing Interests: Declaration of competing interest Dr. Deanna Kelly serves on an advisory board for Alkermes, Teva, and Janssen. Dr. Richard Adebayo has served on the advisory boards of Janssen and a consultant for Invega product. Dr. Raymond Loves serves as a consultant for the Maryland Department of Health and the SMI Advisor, American Psychiatric Association. Dr. Sophie Lanzkron has served as an advisor for Bluebird bio, Novo Nordisk, Pfizer, Novartis and Magenta. She has research funding from Imana, Novartis, GBT, Takeda, CSL-Behring, HRSA, PCORI, MD CHRC. Dr. Robert Buchanan has served on the advisory board for Acadia, Merck and Neurocranial, is a consultant for Boehringer-Ingelheim, and is on DSMB for Merck, Negron, and Roche. All other authors have no conflicts to disclose., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Endoscopy is the gold standard for characterizing pediatric airway disorders, however, it is limited for quantitative analysis due to lack of three-dimensional (3D) vision and poor stereotactic depth perception. We utilize structure from motion (SfM) photogrammetry, to reconstruct 3D surfaces of pathologic and healthy pediatric larynges from monocular two-dimensional (2D) endoscopy. Models of pediatric subglottic stenosis were 3D printed and airway endoscopies were simulated. 3D surfaces were successfully reconstructed from endoscopic videos of all models using an SfM analysis toolkit. Average subglottic surface error between SfM reconstructed surfaces and 3D printed models was 0.65 mm as measured by Modified Hausdorff Distance. Average volumetric similarity between SfM surfaces and printed models was 0.82 as measured by Jaccard Index. SfM can be used to accurately reconstruct 3D surface renderings of the larynx from 2D endoscopy video. This technique has immense potential for use in quantitative analysis of airway geometry and virtual surgical planning., (© 2024 American Academy of Otolaryngology–Head and Neck Surgery Foundation.)

Reducing emissions is vital to improve sustainability, and industry leaders have set emission goals to reduce gross emissions, lower emissions intensity, or reach net zero. However, additional traits should also be measured and compared in terms of their impact on the broader definition of sustainability. In addition to environmental impact, a sustainable breeding objective must consider profit, animal welfare, farmer well-being, and social responsibility. Traits to be considered include direct emissions (e.g., nitrogen and methane), production efficiency (e.g., feed efficiency), health (e.g., calf and transition cow health), and welfare traits (e.g., polled). Many of these novel traits require labor- and cost-intensive phenotyping procedures. Consequently, this results in relatively modest data sets and estimated breeding values with limited reliability. Opportunities exist to overcome this limitation by developing cost-effective and easily quantifiable proxy traits and utilizing international collaboration to expand novel phenotype reference populations. Furthermore, noneconomic values can be estimated to quantify the impact of a trait on societal perspective (e.g., farmer preference) or environmental impact (methane emissions), and combined with economic weights to calculate aggregate weights for each trait. Although validation techniques are still uncertain, the United Nations Sustainable Development Goals may be applied to determine the improvement in sustainability due to genetic selection. This approach provides the flexibility to accommodate diverse sustainability perspectives, encompassing the disparities between developed and developing countries. Currently, the number and quality of relevant phenotypes are the main limiting factor. However, as confidence grows in the opportunity to improve sustainability through genetic selection, substantial new investment will be required in both refining phenotyping methodologies and conceptualizing novel breeding designs., (© 2024.)

Ultrasonography is gaining popularity as a diagnostic imaging modality for airway pathology. Tracheal ultrasound (US) has several nuances that are important for clinicians, including imaging artifacts, which can be mistaken for pathology. Tracheal mirror image artifacts (TMIAs) occur when the US beam is reflected back to the transducer in a nonliner direction or with multiple timesteps. It has previously been believed that the convexity of the tracheal cartilage prevents mirror image artifacts, but in reality, the air column acts as an acoustic mirror and causes TMIA. We describe a cohort of patients with both normal and pathologic tracheas, all of whom have TMIA on the tracheal US. These artifacts are important to recognize, especially as the airway US becomes more commonplace., (© 2023 American Academy of Otolaryngology-Head and Neck Surgery Foundation.)

Discrimination toward black hair is pervasive in today's society. Hair discrimination is negative bias manifested toward black natural or textured hair styles typically worn by persons of African descent. This commentary discusses the potential effects of hair discrimination on the health and well-being of persons of African descent. Specifically, it explores the mental and physical health implications of hair discrimination and situates it within the broader context of social determinants of health. The Creating a Respectful and Open World for Natural Hair Act has been recently passed in the United States House of Representatives, but more work is needed to eliminate hair discrimination and its negative effects., Competing Interests: Four of the authors are affiliated with CROWNCampaign.com, a national advocacy organization toward ending discrimination, but this is not in conflict with the content of this article., (© Manka Nkimbeng et al., 2023; Published by Mary Ann Liebert, Inc.)

Objectives: Endoscopic laryngeal cleft repair (ELCR) with endolaryngeal suturing is an advanced surgical skill. This study objective was to assess the validity of 3-dimensionally (3D) printed laryngeal suturing simulator for ELCR., Study Design: Development and validation of a simulator for ELCR., Methods: An ELCR model was developed using 3D printed and readily available materials. Participants were surveyed before and after a simulation session using five-point Likert scale questions. Performance data was assessed using blinded expert video review and rated using a novel objective structured assessment of technical skills (OSATS) for endoscopic laryngeal suturing., Results: Twenty-one participants ranging from residents to attendings completed the simulation session. Survey respondents reported on a five-point Likert scale that the model was "easy to use" and "quite realistic" (both mean of 4). Confidence improved significantly in 86% of participants (p < 0.01). Overall OSATS scores (out of a total of 55) showed a median improvement in technical skills of 11.7 points (p = 0.004). OSATS demonstrated good intra-rater (κ = 0.689 and 0.677) and moderate inter-rater (κ = 0.573) reliability. Completion times improved from the first to the last suture by a median time of 512 to 350 s (decrease of 202 s, p = 0.002). Participants with no prior ELCR experience improved more than those with in vivo experience., Conclusion: This study demonstrates the validity of a simulator utilizing 3D printed larynges for ELCR. A novel OSATS for endoscopic laryngeal suturing was successfully implemented. Confidence, technical skills, and completion times improved with the use of the model across a variety of participants. Laryngoscope, 133:785-791, 2023., (© 2022 The American Laryngological, Rhinological and Otological Society, Inc.)

In IgE-mediated food allergies, exposure to the allergen activates systemic allergic responses. Oral immunotherapy (OIT) treats food allergies through incremental increases in oral allergen exposure. However, OIT only induces sustained clinical tolerance and decreased basophil sensitivity in a subset of individuals despite increases in circulating allergen-specific IgG in all treated individuals. Therefore, we examined the allergen-specific antibodies from 2 OIT cohorts of patients with sustained and transient responses. Here, we compared antibodies from individuals with sustained or transient responses and discovered specific tolerance-associated conformational epitopes of the immunodominant allergen Ara h 2 recognized by neutralizing antibodies. First, we identified what we believe to be previously unknown conformational, intrahelical epitopes using x-ray crystallography with recombinant antibodies. We then identified epitopes only recognized in sustained tolerance. Finally, antibodies recognizing tolerance-associated epitopes effectively neutralized allergen to suppress IgE-mediated effector cell activation. Our results demonstrate the molecular basis of antibody-mediated protection in IgE-mediated food allergy, by defining how these antibodies disrupt IgE-allergen interactions to prevent allergic reactions. Our approach to studying the structural and functional basis for neutralizing antibodies demonstrates the clinical relevance of specific antibody clones in antibody-mediated tolerance. We anticipate that our findings will form the foundation for treatments of peanut allergy using neutralizing antibodies and hypoallergens.

Objectives: Patients born with bilateral head and neck lymphatic malformations (BHNLMs) often require multiple invasive treatments, including tracheostomy. We hypothesized that primary targeted medical therapy (pTMT) with diagnostic needle aspiration reduces the need for invasive therapy such as surgical resection and/or sclerotherapy., Methods: Retrospective case review was performed of infants with BHNLMs (Grade 2 or De Serres stage IV and V) treated only at our institution from 2000 to 2021. Patients were divided into two cohorts: those managed with pTMT and those managed with observation, sclerotherapy, or surgical intervention (non-pTMT). Data regarding interventions, clinical outcomes, morbidity, and mortality were analyzed with descriptive statistics., Results: Nine children with BHNLMs met inclusion criteria. Three (33%) were in the pTMT cohort and six (66%) were non-pTMT. Eight (89%) malformations were genotyped, and all demonstrated hotspot PIK3CA variants. All pTMT patients had sirolimus initiated in the first month of life and underwent needle aspiration of malformation cyst fluid for cell-free DNA samples. All pTMT patients tolerated medical therapy. For the non-pTMT cohort, primary treatment included none (deceased, n = 1, 17%), observation with needle aspiration (n = 1, 17%), surgical resection (n = 2, 33%), or combination surgery and sclerotherapy (n = 2, 33%). Intubation duration, intensive care and initial hospital length of stay were not different between cohorts. Four non-pTMT patients (67%) required tracheostomy, and two (33%) died prior to discharge. All pTMT patients survived and none required tracheostomy. Non-pTMT patients required a median of two invasive therapies prior to discharge (IQR 1-4) and a mean total of 13 over the course of their lifetime (IQR 1-16), compared to the pTMT group who did not require any lifetime invasive therapy, even after initial pTMT and discharge home., Conclusion: This study compares patients with BHNLMs (Grade 2) treated with pTMT versus those treated with observation or invasive therapy. Patients treated with pTMT required no surgical or invasive procedural treatment of their malformations, no tracheostomy placement, no unplanned readmissions after discharge, and had no mortalities. Needle aspiration was useful as a therapeutic adjunct for cell-free DNA diagnosis of PIK3CA variants, which guided TMT., Competing Interests: Declaration of competing interest Dr. Randall Bly is co-founder and holds a financial interest of ownership equity with Edus Health, Inc and EigenHealth, Inc. He is consultant and stockholder, Spiway, LLC. These are not related to this study. All other authors do not have information to disclose., (Copyright © 2022. Published by Elsevier B.V.)

Congenital tracheal stenosis is a rare but potentially life-threatening condition that is most commonly caused by complete tracheal rings. Slide tracheoplasty was initially introduced as a surgical treatment for congenital tracheal stenosis in 1989 and has significantly improved outcomes and overall survival rates for these patients. It has subsequently been adapted to treat other conditions such as laryngotracheal stenosis, tracheoesophageal fistula, and bronchial stenosis. This article reviews the history, the variety of applications, perioperative management, surgical techniques, potential complications, and new frontiers in slide tracheoplasty surgery., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objective: Enhanced Recovery After Surgery protocols are relatively new in cardiac surgery. Enhanced Recovery After Surgery addresses perioperative analgesia by implementing multimodal pain control regimens that include both opioid and nonopioid components. We investigated the effects of an Enhanced Recovery After Surgery protocol at our institution on postoperative outcomes with particular focus on analgesia., Methods: Single-center retrospective study comparing perioperative opioid use before and after implementation of an Enhanced Recovery After Surgery protocol at our institution. Subjects were divided into 2 cohorts: Enhanced Recovery After Surgery (study group from year 2020) and pre-Enhanced Recovery After Surgery (control group from year 2018). Baseline and perioperative variables including total opioid use from the day of surgery to postoperative day 5 were collected. Opioid use was calculated as morphine milligram equivalents and compared between the 2 cohorts., Results: A total of 466 patients were included: 250 in the Enhanced Recovery After Surgery group and 216 in the pre-Enhanced Recovery After Surgery group. Both groups had similar baseline characteristics, but the Enhanced Recovery After Surgery group had significantly more subjects with intravenous drug use history ( P  < .0001), endocarditis ( P  < .0001), and liver disease ( P  = .007) compared with the pre-Enhanced Recovery After Surgery group. Every day from the day of surgery to postoperative day 5, the Enhanced Recovery After Surgery group had significant reduction (57%) in opioid use compared with the pre-Enhanced Recovery After Surgery group. Total opioid use for the entire length of stay was 259 morphine milligram equivalents in the Enhanced Recovery After Surgery group versus 452 morphine milligram equivalents in the pre-Enhanced Recovery After Surgery group ( P  < .0001). Subgroup analysis of subjects with intravenous drug use history did not demonstrate a significant reduction in opioid use., Conclusions: Enhanced Recovery After Surgery protocols with an emphasis on multimodal pain management throughout perioperative care are associated with a significant reduction in the postoperative use of opioid analgesics., (© 2022 Published by Elsevier Inc. on behalf of The American Association for Thoracic Surgery.)

Objectives: Weight loss has been proposed as risk factor for patulous Eustachian tube (PET), however, it has not been well-characterized how this subpopulation responds to standard treatments. This study aimed to evaluate PET symptom improvement in the setting of and absence of rapid weight loss., Methods: This retrospective case series included patients diagnosed with PET at an academic institution. Demographic characteristics, medical comorbidities, presenting symptoms, treatment, and outcomes of symptom improvement were reviewed. Univariate analysis modeled the likelihood of symptom improvement between rapid weight loss and non-rapid weight loss patients., Results: A total of 124 patients (median age 55 years, 61 % female) were included. At diagnosis, 7 (5.6 %) patients were underweight, 40 (32.3 %) were normal weight, 32 (25.8 %) were overweight, and 45 (36/3 %) were obese. There were 39 (31.5 %) patients who had history of weight loss prior to presentation; of these, 22 (17.7 %) noted rapid weight loss and 17 (13.7 %) had non-rapid weight loss. There were 62 (50.0 %) patients who were recommended conservative treatment, and 62 (50.0 %) who underwent medical and/or surgical treatment. Symptom resolution was achieved in 49 (39.5 %) patients. On univariate analysis, patients with rapid weight loss were significantly more likely to experience improvement (p = 0.006) than non-rapid weight loss. Rapid weight loss patients had a four-fold increased likelihood of symptom improvement compared to non-rapid weight loss patients (OR = 4.8, p = 0.053)., Conclusions: While rapid weight loss and bariatric surgery are reported risk factors for the development of PET, our findings suggest that patients with rapid weight loss are significantly more likely to achieve symptom improvement than non-rapid weight loss., Competing Interests: Declaration of competing interest None of the authors have significant conflicts of interest with any companies or organizations whose products or services may be discussed in this article., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Immunoglobulin E (IgE) antibody is a critical effector molecule for adaptive allergen-induced immune responses, which affect up to 40% of the population worldwide. Allergens are usually innocuous molecules but induce IgE antibody production in allergic subjects. Allergen cross-linking of IgE bound to its high affinity receptor (FcεRI) on mast cells and basophils triggers release of histamine and other mediators that cause allergic symptoms. Little is known about the direct allergen-IgE antibody interaction due to the polyclonal nature of serum IgE and the low frequency of IgE-producing B cells in blood. Here, we report the X-ray crystal structure of a house dust mite allergen, Der p 2, in complex with Fab of a human IgE monoclonal antibody (mAb) isolated by hybridoma technology using human B cells from an allergic subject. This IgE mAb, 2F10, has the correct pairing of heavy and light chains as it occurs in vivo . Key amino acids forming the IgE epitope on Der p 2 were identified. Mutation of these residues ablated their functional ability to cross-link IgE in a mouse model of passive systemic anaphylaxis. These analyses revealed an important conformational epitope associated with the IgE antibody repertoire to a major mite allergen., (© The Author(s) 2022. Published by Oxford University Press on behalf of the National Academy of Sciences.)

This research explores possible options to reduce greenhouse gas (GHG) emissions in the Australian dairy industry by (1) including an environmental component in the national breeding program and (2) estimating the economic and environmental impacts of implementation of the subsequent indexes. A total of 12 possible selection indexes were considered. These indexes were developed to predict changes in gross per-animal methane production (using 3 scenarios depending on availability and efficacy of a direct methane trait breeding value prediction) with 4 different carbon prices, integrating them into an augmentation of the current conventional national selection index. Although some economic response is lost with inclusion of the GHG subindexes in the Balanced Performance Index, options do exist where this loss is marginal and, even in scenarios where all selection pressure is based on the environmental weighting, economic progress is still made in all cases. When including environmental traits within an index, if a relatively low percentage of economic gain or index progression is sacrificed, then approximately 40 to 50% of the maximum possible reductions in emissions may be achieved. This concurrent selection of estimated breeding values that have a correlated favorable response in emissions in addition to direct selection on a residual methane trait allows a high level of methane reduction to be achieved with a realized cost to farmers that is far lower than the economic value placed on carbon. By implementing a GHG subindex in the national breeding program, we can achieve up to a 7.9% decrease in residual methane and 9 times the reduction in gross emissions in 10 yr, compared with the current breeding program, with little to no cost to farmers. By 2050, selection based on one of the more moderate index scenarios at a carbon price of AUD$250/t (AUD$1 = US$0.71), or opportunity cost to farmers of AUD$87.22, will reduce gross emissions by 8.23% and emissions intensity by 21.25%, therefore offering a mitigation strategy that will be effective at reducing emissions with little compromise to profit., (The Authors. Published by Elsevier Inc. and Fass Inc. on behalf of the American Dairy Science Association®. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).)

Introduction: Patients with severe mental illness are falsely characterized as aggressive by the media, perpetuating stigma. While exaggerated, some patients with severe mental illness are more aggressive without treatment. Clozapine may have a unique anti-aggressive effect in patients with schizophrenia-related disorders, independent of antipsychotic or sedative effects. Limited data in forensic and involuntary committed patients is currently available., Purpose: This study evaluates clozapine's effects on hostility and aggression in court-ordered Black patients., Methods: This study analyzes a subgroup of Black patients from a larger prospective 24-week open-label clozapine study. All patients were involuntarily committed and enrolled from two participating state psychiatric hospitals. The primary outcome measured was total use of 'as needed' (PRN) or 'immediate need' (STAT) medications for aggression/hostility. Secondary outcomes included number and duration of seclusion and restraint (S/R) episodes, and changes in Brief Psychiatric Rating Scale (BPRS) hostility factor score., Results: Sixty-nine patients were included in our analysis. Significant reductions were noted in PRN/STAT medication use over time (χ 2  = 6.90; p = 0.008) and the BPRS hostility factor score was reduced by 30% over the 24 weeks (F = 4.34, df = 62, p = 0.002)., Conclusions: Treatment with clozapine effectively reduced hostility and aggression within this cohort of involuntarily committed Black patients with mental illness compared to baseline. Specifically, it helped lower the total number of PRN/STAT medication administrations and improved clinician-rated hostility factor scores on the BPRS. Our findings are pertinent as data in forensic settings is lacking and Black patients have been infrequently included in large prospective clinical trials with clozapine., Gov Identifier: NCT02404155., (Copyright © 2022. Published by Elsevier B.V.)

We developed a SARS-CoV-2 spike subunit vaccine formulation containing dual TLR ligand liposome adjuvant. The vaccine-induced robust systemic neutralizing antibodies and completely protected mice from a lethal challenge. Two immunizations protected against lung injury and cleared the virus from lungs upon challenge. The adjuvanted vaccine also elicited systemic and local anti-Spike IgA which can be an important feature for a COVID-19 vaccine., (© 2021. The Author(s).)

The dairy industry has been scrutinized for the environmental impact associated with rearing and maintaining cattle for dairy production. There are 3 possible opportunities to reduce emissions through genetic selection: (1) a direct methane trait, (2) a reduction in replacements, and (3) an increase in productivity. Our aim was to estimate the independent effects of traits in the Australian National Breeding Objective on the gross methane production and methane intensity (EI) of the Australian dairy herd of average genetic potential. Based on similar published research, the traits determined to have an effect on emissions include production, fertility, survival, health, and feed efficiency. The independent effect of each trait on the gross emissions produced per animal due to genetic improvement and change in EI due to genetic improvement (intensity value, IV) were estimated and compared. Based on an average Australian dairy herd, the gross emissions emitted per cow per year were 4,297.86 kg of carbon dioxide equivalents (CO 2 -eq). The annual product output, expressed in protein equivalents (protein-eq), and EI per cow were 339.39 kg of protein-eq and 12.67 kg of CO 2 -eq/kg of protein-eq, respectively. Of the traits included in the National Breeding Objective, genetic progress in survival and feed saved were consistently shown to result in a favorable environmental impact. Conversely, production traits had an unfavorable environmental impact when considering gross emissions, and favorable when considering EI. Fertility had minimal impact as its effects were primarily accounted for through survival. Mastitis resistance only affected IV coefficients and to a very limited extent. These coefficients may be used in selection indexes to apply emphasis on traits based on their environmental impact, as well as applied by governments and stakeholders to track trends in industry emissions. Although initiatives are underway to develop breeding values to reduce methane by combining small methane data sets internationally, alternative options to reduce emissions by utilizing selection indexes should be further explored., (© 2021, The Authors. Published by Elsevier Inc. and Fass Inc. on behalf of the American Dairy Science Association®. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).)

Selecting for lower methane (CH 4 ) emitting animals is one of the best approaches to reduce CH 4 given that genetic progress is permanent and cumulative over generations. As genetic selection requires a large number of animals with records and few countries actively record CH 4 , combining data from different countries could help to expedite accurate genetic parameters for CH 4 traits and build a future genomic reference population. Additionally, if we want to include CH 4 in the breeding goal, it is important to know the genetic correlations of CH 4 traits with other economically important traits. Therefore, the aim of this study was first to estimate genetic parameters of 7 suggested methane traits, as well as genetic correlations between methane traits and production, maintenance, and efficiency traits using a multicountry database. The second aim was to estimate genetic correlations within parities and stages of lactation for CH 4 . The third aim was to evaluate the expected response of economically important traits by including CH 4 traits in the breeding goal. A total of 15,320 methane production (MeP, g/d) records from 2,990 cows belonging to 4 countries (Canada, Australia, Switzerland, and Denmark) were analyzed. Records on dry matter intake (DMI), body weight (BW), body condition score, and milk yield (MY) were also available. Additional traits such as methane yield (MeY; g/kg DMI), methane intensity (MeI; g/kg energy-corrected milk), a genetic standardized methane production, and 3 definitions of residual methane production (g/d), residual feed intake, metabolic BW (MBW), BW change, and energy-corrected milk were calculated. The estimated heritability of MeP was 0.21, whereas heritability estimates for MeY and MeI were 0.30 and 0.38, and for the residual methane traits heritability ranged from 0.13 to 0.16. Genetic correlations between different methane traits were moderate to high (0.41 to 0.97). Genetic correlations between MeP and economically important traits ranged from 0.29 (MY) to 0.65 (BW and MBW), being 0.41 for DMI. Selection index calculations showed that residual methane had the most potential for inclusion in the breeding goal when compared with MeP, MeY, and MeI, as residual methane allows for selection of low methane emitting animals without compromising other economically important traits. Inclusion of residual feed intake in the breeding goal could further reduce methane, as the correlation with residual methane is moderate and elicits a favorable correlated response. Adding a negative economic value for methane could facilitate a substantial reduction in methane emissions while maintaining an increase in milk production., (The Authors. Published by Elsevier Inc. and Fass Inc. on behalf of the American Dairy Science Association®. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).)

A recently developed methodological approach for determining the greenhouse gas emissions impact of national breeding programs was applied to measure the effects of current and future breeding goals on the emission intensity (EI) of the Canadian dairy industry. Emission intensity is the ratio of greenhouse gas outputted in comparison to the product generated. Traits under investigation affected EI by either decreasing the direct emissions yield (i.e. increasing feed performance), changing herd structure (i.e. prolonging herd life) or through the dilution effect of increased production (i.e. increasing fat yield). The intensity value (IV) of each trait, defined as the change in emissions' intensity per unit change in each trait, was calculated for each of the investigated traits. The IV trend of these traits was compared for the current and prospective selection index, as well as for a system with and without quota (the supply management policy designed to prevent overproduction). The overall EI of the average genetic merit Canadian dairy herd per breeding female was 5.07 kg CO 2 eq/kg protein equivalent output. The annual reduction in EI due to the improvement of production traits was -0.027, -0.018 and -0.006 for fat, protein and milk other solids, respectively. The functional traits, herd life and mastitis resistance, had more modest effects (-0.008 and -0.001, respectively). These results are consistent with international studies that identified traits related to production, survival, health and fertility as having the largest impact on the environmental footprint of dairy cattle. Overall, the dairy industry is becoming more efficient by reducing its EI through selection of environmentally favorable traits, with a 1% annual reduction of EI in Canada., (Copyright © 2020. Published by Elsevier B.V.)

Methane is a greenhouse gas of high interest to the dairy industry, with 57% of Australia's dairy emissions attributed to enteric methane. Enteric methane emissions also constitute a loss of approximately 6.5% of ingested energy. Genetic selection offers a unique mitigation strategy to decrease the methane emissions of dairy cattle, while simultaneously improving their energy efficiency. Breeding objectives should focus on improving the overall sustainability of dairy cattle by reducing methane emissions without negatively affecting important economic traits. Common definitions for methane production, methane yield, and methane intensity are widely accepted, but there is not yet consensus for the most appropriate method to calculate residual methane production, as the different methods have not been compared. In this study, we examined 9 definitions of residual methane production. Records of individual cow methane, dry matter intake (DMI), and energy corrected milk (ECM) were obtained from 379 animals and measured over a 5-d period from 12 batches across 5 yr using the SF 6 tracer method and an electronic feed recording system, respectively. The 9 methods of calculating residual methane involved genetic and phenotypic regression of methane production on a combination of DMI and ECM corrected for days in milk, parity, and experimental batch using phenotypes or direct genomic values. As direct genomic values (DGV) for DMI are not routinely evaluated in Australia at this time, DGV for FeedSaved, which is derived from DGV for residual feed intake and estimated breeding value for bodyweight, were used. Heritability estimates were calculated using univariate models, and correlations were estimated using bivariate models corrected for the fixed effects of year-batch, days in milk, and lactation number, and fitted using a genomic relationship matrix. Residual methane production candidate traits had low to moderate heritability (0.10 ± 0.09 to 0.21 ± 0.10), with residual methane production corrected for ECM being the highest. All definitions of residual methane were highly correlated phenotypically (>0.87) and genetically (>0.79) with one another and moderately to highly with other methane candidate traits (>0.59), with high standard errors. The results suggest that direct selection for a residual methane production trait would result in indirect, favorable improvement in all other methane traits. The high standard errors highlight the importance of expanding data sets by measuring more animals for their methane emissions and DMI, or through exploration of proxy traits and combining data via international collaboration., (The Authors. Published by Elsevier Inc. and Fass Inc. on behalf of the American Dairy Science Association®. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).)

Introduction: Obesity continues to be a problem in the United States with greater than 35% of the adult population affected. Obesity influences fracture care as it affects impact forces, alters cellular pathways of healing, and is often associated with higher complication rates. Distal radius fractures are among the most common fracture patterns in the adult population. The purpose of this study was to evaluate the effect of BMI on the degree of intra-articular fracture comminution, operative time, and return to the OR in obese patients who underwent operation for distal radius fractures., Methods: A retrospective analysis of the American College of Surgeons National Surgical Improvement Program's (ACS-NSQIP) database was performed and logistic regressions were used to assess the relationship between BMI and open treatment of distal radius fractures. Three separate CPT codes were used to distinguish between extra-articular fractures, intra-articular split fracture, and intra-articular fracture with comminution. Percutaneous or closed treatment of distal radius fractures were excluded., Results: A total of 11,228 patients (mean age 65.1 years) with open reduction and internal fixation of distal radius fractures were identified. For every increase in BMI point, there was an increased risk of intra-articular split fracture by 1.7% (OR 1.017, 95% CI 1.010-1.023, p < 0.01) and increased risk of intra-articular comminution by 3.1% (OR 3.1, 95% CI 1.025-1.037, p < 0.01). Additionally, for every increase in BMI point, the risk of a surgical complication increased by 2.3% DISCUSSION: This nationally representative, population-based study demonstrates that elevated BMI is associated with increased risk for intra-articular involvement and higher risk for post-operative complications. Our results can be useful to patients and orthopedic surgeons as prognostic information for counseling patients on expectations following open reduction and surgical fixation of distal radius fractures., Level of Evidence: Case-control study. Level III., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020. Published by Elsevier Ltd.)

IgE Abs drive the symptoms of allergic disease upon cross-linking allergens on mast cells or basophils. If the IgE binding sites on the allergens could be identified, it may be useful for creating new forms of immunotherapy. However, direct knowledge of the human IgE (hIgE) epitopes is limited because of the very low frequency of IgE-producing B cells in blood. A new hybridoma technology using human B cells from house dust mite-allergic patients was used to identify four Der p 2-specific hIgE mAbs. Their relative binding sites were assessed and compared by immunoassays with three previously studied murine IgG mAbs. Immunoassays showed that the recognition of Der p 2 by the first three hIgE was inhibited by a single murine IgG, but the fourth hIgE recognized a different epitope from all the other mAbs. The functional ability of the hIgE that bind different epitopes to cross-link Der p 2 was demonstrated in a mouse model of passive systemic anaphylaxis. Nuclear magnetic resonance analyses of Der p 2 in complex with IgG and IgE Abs were used to identify specific residues in the epitopes. To our knowledge, the combination of immunoassays to distinguish overlapping epitopes and nuclear magnetic resonance analyses to identify specific residues involved in Ab binding provided the first epitope mapping of hIgE mAbs to an allergen. The technologies developed in this study will be useful in high-resolution mapping of human epitopes on other Ags and the design of improved therapeutics., (Copyright © 2020 by The American Association of Immunologists, Inc.)

Although plantar flexion force steadiness (FS) is reduced in persons with Parkinson's disease (PD), the underlying causes are unknown. The aim of this exploratory design study was to ascertain the influence of maximal voluntary contraction (MVC) force and gastrocnemius-Achilles muscle-tendon unit behaviour on FS in persons with PD. Nine persons with PD and nine age- and sex-matched non-PD controls (~70 years, 6 females per group) performed plantar flexion MVCs and sub-maximal tracking tasks at 5, 10, 25, 50 and 75% MVC. Achilles tendon elongation and medial gastrocnemius fascicle lengths were recorded via ultrasound during contraction. FS was quantified using the coefficient of variation (CV) of force. Contributions of MVC and tendon mechanics to FS were determined using multiple regression analyses. Persons with PD were 35% weaker during MVC ( p = 0.04) and had 97% greater CV ( p = 0.01) with 47% less fascicle shortening ( p = 0.004) and 38% less tendon elongation ( p = 0.002) than controls. Reduced strength was a direct contributor to lower FS in PD (ß = 0.631), and an indirect factor through limiting optimal muscle-tendon unit interaction. Interestingly, our findings indicate an uncoupling between fascicle shortening and tendon elongation in persons with PD. To better understand limitations in FS and muscle-tendon unit behavior, it is imperative to identify the origins of MVC decrements in persons with PD.

Feed represents a substantial proportion of production costs in the dairy industry and is a useful target for improving overall system efficiency and sustainability. The objective of this study was to develop methodology to estimate the economic value for a feed efficiency trait and the associated methane production relevant to Canada. The approach quantifies the level of economic savings achieved by selecting animals that convert consumed feed into product while minimizing the feed energy used for inefficient metabolism, maintenance and digestion. We define a selection criterion trait called Feed Performance (FP) as a 1 kg increase in more efficiently used feed in a first parity lactating cow. The impact of a change in this trait on the total lifetime value of more efficiently used feed via correlated selection responses in other life stages is then quantified. The resulting improved conversion of feed was also applied to determine the resulting reduction in output of emissions (and their relative value based on a national emissions value) under an assumption of constant methane yield, where methane yield is defined as kg methane/kg dry matter intake (DMI). Overall, increasing the FP estimated breeding value by one unit (i.e. 1 kg of more efficiently converted DMI during the cow's first lactation) translates to a total lifetime saving of 3.23 kg in DMI and 0.055 kg in methane with the economic values of CAD $0.82 and CAD $0.07, respectively. Therefore, the estimated total economic value for FP is CAD $0.89/unit. The proposed model is robust and could also be applied to determine the economic value for feed efficiency traits within a selection index in other production systems and countries.

In this study, we estimated genetic parameters and genomic prediction accuracies of serum biomarkers of health in early-lactation dairy cows. A single serum sample was taken from 1,393 cows, located on 14 farms in southeastern Australia, within 30 d after calving. Sera were analyzed for biomarkers of energy balance (β-hydroxybutyrate and fatty acids), macromineral status (Ca and Mg), protein nutritional status (urea and albumin), and immune status (globulins, albumin-to-globulin ratio, and haptoglobin). After editing, 47,162 SNP marker genotypes were used to estimate genomic heritabilities and breeding values (GEBV) for these traits in ASReml. Heritabilities were low for β-hydroxybutyrate, fatty acids, Ca, Mg, and urea (0.09 ± 0.04, 0.18 ± 0.05, 0.07 ± 0.04, 0.19 ± 0.06, and 0.18 ± 0.05, respectively), and moderate for albumin, globulins, and albumin-to-globulin ratio (0.27 ± 0.06, 0.46 ± 0.06, and 0.41 ± 0.06, respectively). The heritability of haptoglobin concentration was close to 0. The magnitude of genetic correlations between traits (estimated using bivariate models) varied considerably (0.01 to 0.96), and standard errors of these correlations were high (0.02 to 0.44). Interestingly, the direction of most genetic correlations was favorable, suggesting that selecting for more optimal concentrations of one biomarker may result in more optimal concentrations of other biomarkers. Correlations between biomarker GEBV and existing breeding values for survival, somatic cell count, and daughter fertility were small to moderate (0.07 to 0.45) and favorable, whereas correlations with breeding values for milk production traits were small (≤0.15). Accuracies of GEBV were evaluated by using 5-fold cross validation, and by calculating accuracies from prediction error variances associated with the GEBV. Accuracies of GEBV predicted using 5-fold cross validation were low (0.05 to 0.27), whereas the means of individual accuracies were greater, ranging from 0.31 to 0.51. Although increasing the size of the reference population should theoretically improve accuracies, our results suggest that genomic prediction of health biomarkers may allow identification of cows that are less susceptible to diseases in early lactation., (The Authors. Published by FASS Inc. and Elsevier Inc. on behalf of the American Dairy Science Association®. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).)

Der p 2 is one of the most important allergens from the house dust mite Dermatophagoides pteronyssinus Identification of human IgE Ab binding epitopes can be used for rational design of allergens with reduced IgE reactivity for therapy. Antigenic analysis of Der p 2 was performed by site-directed mutagenesis based on the x-ray crystal structure of the allergen in complex with a Fab from the murine IgG mAb 7A1 that binds an epitope overlapping with human IgE binding sites. Conformational changes upon Ab binding were confirmed by nuclear magnetic resonance using a 7A1-single-chain variable fragment. In addition, a human IgE Ab construct that interferes with mAb 7A1 binding was isolated from a combinatorial phage-display library constructed from a mite-allergic patient and expressed as two recombinant forms (single-chain Fab in Pichia pastoris and Fab in Escherichia coli ). These two IgE Ab constructs and the mAb 7A1 failed to recognize two Der p 2 epitope double mutants designed to abolish the allergen-Ab interaction while preserving the fold necessary to bind Abs at other sites of the allergen surface. A 10-100-fold reduction in binding of IgE from allergic subjects to the mutants additionally showed that the residues mutated were involved in IgE Ab binding. In summary, mutagenesis of a Der p 2 epitope defined by x-ray crystallography revealed an IgE Ab binding site that will be considered for the design of hypoallergens for immunotherapy., (Copyright © 2019 by The American Association of Immunologists, Inc.)

Objective: Although there is significant need for mental health care among service members, stigma surrounding these services, along with myths associated with behavioral health treatment, discourages care seeking. This study evaluated the effect of a video designed to demystify mental health treatment on barriers to seeking care among military personnel., Methods: Participants were 294 active duty U.S. Marine Corps personnel who were randomly assigned to the intervention video only, the intervention video with discussion, or an attentional control video. Participants completed questionnaires that assessed social stigma regarding mental health treatment and willingness to seek help at pretest, posttest, and 6-week follow-up; personal desire for mental health care was assessed at pretest and 6-week follow-up., Results: Participants who viewed the intervention video in either condition showed significant and similar decreases in social stigma and increases in willingness to seek help at posttest (p<.001), whereas participants in the control group showed no change at posttest in either variable. Although social stigma did not differ by intervention group at the 6-week follow-up, participants in either intervention were 2.56 times more likely than participants in the control group to report a personal desire for mental health care at the 6-week follow-up (p=.05). There were no significant differences between the two interventions on the main outcomes., Conclusions: A video in which mental health care providers explain the treatment process may be effective as an initial stand-alone social stigma reduction intervention. Additional efforts are likely needed to sustain effects and to realize increases in help-seeking behavior.

Background: Approximately one-third of people with schizophrenia have elevated levels of anti-gliadin antibodies of the immunoglobulin G type (AGA IgG) — a higher rate than seen in healthy controls. We performed the first double-blind clinical trial of gluten-free versus gluten-containing diets in a subset of patients with schizophrenia who were positive for AGA IgG., Methods: In this pilot feasibility study, 16 participants with schizophrenia or schizoaffective disorder who had elevated AGA IgG (≥ 20 U) but were negative for celiac disease were admitted to an inpatient unit for a 5-week trial. All participants received standardized gluten-free meals and were randomized in a double-blind fashion to receive a shake containing 10 g of gluten flour or 10 g of rice flour each day. Participants were rated for psychiatric, cognitive and gastrointestinal symptoms at baseline and endpoint., Results: Of the 16 participants, 14 completed the 5-week trial (2 discontinued early for administrative reasons). Compared with participants on the gluten-containing diet, participants on the gluten-free diet showed improvement on the Clinical Global Impressions scale (Cohen d = –0.75) and in negative symptoms (Cohen d = –0.53). We noted no improvement in positive or global cognitive symptoms, but did observe an improvement in attention favouring the gluten-free diet (Cohen d = 0.60). Robust improvements in gastrointestinal adverse effects occurred in the gluten-free group relative to the glutencontaining group. Adverse effects were similar between groups., Limitations: This study was limited by its small sample size; larger studies are needed., Conclusion: This feasibility study suggests that removal of gluten from the diet is associated with improvement in psychiatric and gastrointestinal symptoms in people with schizophrenia or schizoaffective disorder., Competing Interests: D. Kelly served as an advisor to Lundbeck and HLS Therapeutics. A. Fasano is the founder and a stock holder of Alba Therapeutics. R. Buchanan served on the advisory boards for Astellas Pharma, Avanir, Boehringer Ingelheim-RCV, ITI, Inc., Lundbeck and Roche. He was a consultant for Takeda and Upsher-Smith Laboratories and on the DSMB for Pfizer. W. Carpenter has served as an advisor to Boehringer Ingelheim, Allergan, Health Analytics and Teva. All other authors have nothing to disclose., (© 2019 Joule Inc. or its licensors)

Purpose/background: Prolactin-related adverse effects contribute to nonadherence and adverse health consequences, particularly in women with severe mental illness. Treating these adverse effects may improve treatment acceptability, adherence, and long-term outcomes., Methods/procedures: Premenopausal women with a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision diagnosis of schizophrenia, schizoaffective disorder, or bipolar disorder were recruited for a randomized, double-blind, placebo-controlled 16-week trial of adjunct aripiprazole (5-15 mg/d). Participants had elevated prolactin (>24 ng/mL) and were experiencing galactorrhea, amenorrhea, oligomenorrhea, or sexual dysfunction on a prolactin-elevating antipsychotic. Participants were evaluated biweekly for prolactin elevation and galactorrhea and completed a menstrual diary review. Psychiatric symptoms and adverse effects were closely monitored., Findings/results: Forty-six women were randomized (n = 25 aripiprazole, n = 21 placebo). Thirty-seven completed at least 8 weeks of the study (n = 20 [80%] aripiprazole and n = 17 [81%] placebo). Aripiprazole (mean dose, 11.7 ± 2.4 mg/d) was effective for lowering prolactin relative to placebo (P = 0.04). In addition, 45% (9/20) of the aripiprazole group had a normalized prolactin (<24 mg/mL) compared with 12% (2/17) of the placebo group (P = 0.028). Galactorrhea resolved in 77% (10/13) of the aripiprazole-treated participants compared with 33% (4/12) in the placebo group (P = 0.028). Normalization of sexual function (<16 on the Arizona Sexual Experience Scale) occurred in 50% on aripiprazole (7/14) versus 9% (1/11) on placebo (P = 0.030). No differences between groups in symptoms or adverse effects were noted. Overall, women rated a mean score of 4.6 ± 0.6 on a 5-point Likert scale for sexual function improvement, suggesting their particular satisfaction with improvement in this domain., Implications/conclusions: Building upon prior studies, this rigorous evaluation confirms the utility of adjunctive aripiprazole as a strategy for improving prolactin and managing prolactin-related adverse effects in premenopausal women with psychosis.

Achilles tendon mechanics influence plantar flexion force steadiness (FS) and balance. In the upper limb, elbow flexor FS is greater in supinated and neutral forearm orientations compared to pronated, with contributions of tendon mechanics remaining unknown in position-dependent FS. This study investigated whether distal biceps brachii (BB) tendon mechanics across supinated, neutral and pronated forearm orientations influence position-dependent FS of the elbow flexors. Eleven males (23 ± 3 years) performed submaximal isometric elbow flexion tasks at low (5, 10% maximal voluntary contraction (MVC)) and high (25, 50, 75% MVC) force levels in supinated, neutral and pronated forearm orientations. Distal BB tendon elongation and CSA were recorded on ultrasound to calculate mechanics of tendon stress, strain and stiffness. Relationships between FS, calculated as coefficient of variation (CV) of force, and tendon mechanics were evaluated with multiple regressions. Supinated and neutral were ∼50% stronger and ∼60% steadier than pronated (p < 0.05). Tendon stress was ∼52% greater in supinated and neutral compared to pronated, tendon strain was ∼36% greater in neutral than pronated (p < 0.05), while tendon stiffness (267.4 ± 78.9 N/mm) did not differ across orientations (p > 0.05). At low forces, CV of force was predicted by MVC (r 2 : 0.52) in supinated, and MVC and stress in neutral and pronated (r 2 : 0.65-0.81). At high force levels, CV of force was predicted by MVC and stress in supinated (r 2 : 0.49), and MVC in neutral (r 2 : 0.53). Absolute strength and tendon mechanics influence the ability of the BB tendon to distribute forces, and thus are key factors in position-dependent FS., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Despite a lack of robust data regarding their efficacy, oral antibiotics and steroids remain two of the most common treatments for chronic rhinosinusitis without nasal polyps (CRSsNP). We sought to objectively compare the efficacy of antibiotics and steroids, independently and in combination, for the initial treatment of CRSsNP. To that end, we conducted a retrospective chart review of 100 patients-51 men and 49 women, age 20 to 85 years (mean: 50)-who were treated for CRSsNP from January 2010 through January 2015. Of this group, 17 patients were treated with an antibiotic only, 28 with a steroid only, and 55 with both agents. All patients underwent computed tomography (CT) before and after treatment, and we compared the three groups' pre- and post-treatment Lund-Mackay CT scores, symptom scores, and rates of surgery. The average time between the pre- and post-treatment visits was 4.4 weeks. The mean Lund-Mackay CT score for the entire study population was significantly lower after treatment than at baseline (6.3 vs. 9.1; p < 0.001); however, there were no significant differences among the three groups in either pre- or post-treatment scores. Symptom scores were significantly better in the combination therapy group than in the two monotherapy groups (p < 0.001). In all, 40 of the 100 patients underwent surgery; the difference in surgery rates among the three groups was not statistically significant (p = 0.884). Surgery was performed on 9 of the 52 (17.3%) patients who either were followed for at least 1 year or who had had surgery within the first year postoperatively; again, there were no significant differences among the three groups (p = 0.578). We conclude that although the Lund-Mackay CT scores decreased significantly in the antibiotic, steroid, and combination therapy groups, no one regimen was superior to any other for treating CRSsNP in our study.

Clozapine is the sole antipsychotic agent effective for the treatment of refractory schizophrenia. Sixty percent of clozapine-treated patients, however, fail to adequately respond. Minocycline, a tetracycline antibiotic, possesses antiinflammatory and neuroprotective properties that may play a role in schizophrenia. Clozapine is mainly metabolized by CYP1A2 enzymes, and minocycline may potentially inhibit CYP1A2 as hypothesized by case report data. To date, no pharmacokinetic interaction has been reported between minocycline and clozapine. This is a secondary analysis of a 10-week controlled study of adjunctive minocycline to clozapine in treatment refractory schizophrenia. Clozapine plasma levels were collected every two weeks during the study. 28 participants assigned to receive minocycline and 22 assigned to placebo were included. No differences existed in baseline demographics, clozapine dose or plasma levels. Average changes from baseline in clozapine plasma level (p = 0.033) were significantly higher in the minocycline group despite maintenance of stable doses. No statistically significant treatment differences were found in the norclozapine (p = 0.754) or total clozapine (p = 0.053) changes in plasma levels, although possible changes in total clozapine levels require further investigation. This analysis suggests that minocycline administration may lead to increased clozapine plasma levels. Further study is needed to examine possible explanations.

Popular media often portray people with a mental illness as being aggressive, violent, and incarcerated as a result of their behavior. Despite exaggeration in the media, risks for some aggressive behaviors are in fact higher in individuals with schizophrenia. This is often the case with influence of comorbid substance use disorders. It is essential that mental health professionals are aware of treatments that may help with attenuating and treating behaviors that contribute to violence, aggression and incarceration. This paper reviews violence and incarceration in individuals with schizophrenia as well as recommendations, guidelines and benefits for the use of clozapine in this population. Clozapine remains one of the most underutilized evidence-based medications available in the psychiatric arena in the United States. It is a viable and recommended option in the forensic population and it may be helpful on the path to recovery as well as bring substantial savings to the criminal justice system.

Objective: To determine if clozapine can be safely utilized in psychiatric patients with benign neutropenia., Methods: A single-center, retrospective chart review study of records from 2001 to 2014 was conducted in an inpatient psychiatric hospital. Patients included had benign neutropenia prior to receiving clozapine and received clozapine using modified monitoring guidelines. All available laboratory values for absolute neutrophil count (ANC) before initiation and during treatment were evaluated. The primary endpoint was difference in ANC after initiation of clozapine from before clozapine., Results: A total of 26 patients were reviewed. The mean age at clozapine initiation was 34 years. The majority were African-American (73% [n = 19]), with more men than women (73% [n = 19] vs 27% [n = 7]). The mean lowest ANC value was not significantly different after clozapine initiation compared to before (1.5× 10³ cells/mm³ and 1.4 × 10³ cells/mm³, respectively; P = .22). The overall mean ANC was significantly higher after initiation than before (2.63 × 10³ cells/mm³ and 2.13 × 10³ cells/mm³, respectively; P < .001). There were no cases of severe neutropenia (ANC < 0.5 × 10³ cells/mm³), and no patient was discontinued for falling below modified guideline limits. There were fewer occurrences of mild neutropenia (ANC < 2.0 × 10³ cells/mm³) after clozapine initiation than before (16.0% and 31.4%, respectively; P < .001). There were also fewer occurrences of moderate neutropenia (ANC < 1.5 × 10³ cells/mm³), with 2.1% after clozapine and 13.3% before (P < .001)., Conclusions: Twenty-six patients with benign neutropenia were safely treated with clozapine. Pre-clozapine neutropenia did not predict increased risk for severe neutropenia with clozapine. Patients had significantly fewer episodes of mild and moderate neutropenia after receiving clozapine compared to before., (© Copyright 2016 Physicians Postgraduate Press, Inc.)

Study Objective: To determine whether extended-infusion carboplatin, initiated at approximately the eighth cumulative carboplatin cycle and prior to development of carboplatin hypersensitivity, reduces the incidence of carboplatin hypersensitivity reactions in patients with ovarian, fallopian tube, or peritoneal cancer., Design: Retrospective chart review., Setting: Large integrated health system., Patients: A total of 326 patients with ovarian, fallopian tube, or primary peritoneal cancer who received at least eight cumulative cycles of carboplatin between January 2007 and September 2014 were included. Of these, 161 patients received all doses of carboplatin infused over 30 or 60 minutes (standard-infusion group [total of 1317 carboplatin cycles]), and 165 patients received the 3-hour extended infusion of carboplatin administered at approximately the eighth cumulative cycle and prior to development of a hypersensitivity reaction (extended-infusion group [total of 1527 carboplatin cycles])., Measurements and Main Results: Baseline characteristics were similar between the groups, except significantly more patients in the extended-infusion group received triple premedication therapy prior to infusion (p<0.001). Hypersensitivity reactions occurred in 64 patients (40%) who received standard-infusion carboplatin and 40 patients (24.2%) who received extended-infusion carboplatin (p=0.0027). The median cycle of hypersensitivity reaction development did not differ significantly between the groups: 9 cycles in patients who received standard-infusion versus 11 cycles in patients who received extended-infusion carboplatin (p=0.06). Through regression analysis, the premedication regimen received prior to carboplatin infusion was the only variable significantly associated with hypersensitivity reactions (odds ratio 0.59, 95% confidence interval 0.36-0.97, p=0.038)., Conclusion: Patients who received extended-infusion carboplatin experienced a lower incidence of hypersensitivity reactions than patients who received standard-infusion carboplatin, which may be attributed to the triple premedication regimen received more frequently in patients in the extended-infusion group., (© 2016 Pharmacotherapy Publications, Inc.)

Although disclosure of stressful events can alleviate distress, self-critical perfectionism may pose an especially strong impediment to disclosure during stress, likely contributing to poorer psychological well-being. In the current study, after completing a measure of self-critical perfectionism (the Discrepancy subscale of the Almost Perfect Scale--Revised; Slaney, Rice, Mobley, Trippi, & Ashby, 2001), 396 undergraduates completed measures of stress and disclosure at the end of each day for 1 week. Consistent with hypotheses and previous research, multilevel modeling results indicated significant intraindividual coupling of daily stress and daily disclosure where disclosure was more likely when experiencing high stress than low stress. As hypothesized, Discrepancy moderated the relationship between daily stress and daily disclosure. Individuals higher in self-critical perfectionism (Discrepancy) were less likely to engage in disclosure under high stress, when disclosure is often most beneficial, than those with lower Discrepancy scores. These results have implications for understanding the role of stress and coping in the daily lives of self-critical perfectionists., ((c) 2015 APA, all rights reserved).)

Objective: Clozapine is the most effective antipsychotic for treatment refractory people with schizophrenia, yet many patients only partially respond. Accumulating preclinical and clinical data suggest benefits with minocycline. We tested adjunct minocycline to clozapine in a 10-week, double-blind, placebo-controlled trial. Primary outcomes tested were positive, and cognitive symptoms, while avolition, anxiety/depression, and negative symptoms were secondary outcomes., Methods: Schizophrenia and schizoaffective participants (n = 52) with persistent positive symptoms were randomized to receive adjunct minocycline (100 mg oral capsule twice daily; n = 29) or placebo (n = 23)., Results: Brief Psychiatric Rating Scale (BPRS) psychosis factor (P = 0.098; effect size [ES], 0.39) and BPRS total score (P = 0.075; ES, 0.55) were not significant. A change in total BPRS symptoms of more than or equal to 30% was observed in 7 (25%) of 28 among minocycline and 1 (4%) of 23 among placebo participants, respectively (P = 0.044). Global cognitive function (MATRICS Consensus Cognitive Battery) did not differ, although there was a significant variation in size of treatment effects among cognitive domains (P = 0.03), with significant improvement in working memory favoring minocycline (P = 0.023; ES, 0.41). The Scale for the Assessment of Negative Symptoms total score did not differ, but significant improvement in avolition with minocycline was noted (P = 0.012; ES, 0.34). Significant improvement in the BPRS anxiety/depression factor was observed with minocycline (P = 0.028; ES, 0.49). Minocycline was well tolerated with significantly fewer headaches and constipation compared with placebo., Conclusions: Minocycline's effect on the MATRICS Consensus Cognitive Battery composite score and positive symptoms were not statistically significant. Significant improvements with minocycline were seen in working memory, avolition, and anxiety/depressive symptoms in a chronic population with persistent symptoms. Larger studies are needed to validate these findings.

The primary goal of this study was to examine how perfectionism affects psychological symptoms during the course of treatment. We examined session-by-session symptom changes in a sample of 105 adult clients who presented for counseling at a psychology training clinic housed at a large Midwestern university in the United States. Using a recently developed measure of perfectionism (Short Almost Perfect Scale [SAPS]) that possesses good psychometric features, we were able to investigate effects of both maladaptive (high self-criticism) and adaptive (high standards with low self-criticism) perfectionistic characteristics on indicators of personal and interpersonal psychological distress across time. Multilevel modeling analyses indicated that both symptomatic distress and interpersonal problems improved over the course of therapy. Maladaptive perfectionism was associated with higher levels of interpersonal problems and distress at the outset of therapy, and related differentially to change patterns in symptom distress and interpersonal problems over the course of treatment. Maladaptive perfectionism, however, was not related to level of symptoms at the end of therapy. Adaptive perfectionistic characteristics were associated with fewer interpersonal problems at the beginning and end of therapy. Results suggest the value of assessing perfectionistic characteristics at the onset of treatment, even for clients not presenting with obvious concerns linked to such individual differences., ((c) 2015 APA, all rights reserved).)

Fragment screening is one approach to hit identification for early stage drug discovery projects. Like any screening library, diversity is needed in fragment libraries. This includes coverage of shape and electrostatic space, as well as chemotype diversity. A new, easily interpretable shape-based fingerprint is described and its utility in probing fragment library content is demonstrated using a Rule of Three library from Maybridge. This method explicitly considers size as a component of shape. It allows interrogation of shape space on both a per conformer and a per molecule level, and includes a measure of flexibility. This allows for the identification of highly flexible compounds and their exclusion from the analysis. A comparison with two literature methods, the triangle plot approach of Sauer and Schwarz and the plane of best fit method of Firth et al., is also included., (Copyright © 2015 Elsevier Ltd. All rights reserved.)