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Abstract Background Abnormal remodeling of distal pulmonary arteries in patients with pulmonary arterial hypertension (PAH) leads to progressively increased pulmonary vascular resistance, followed by right ventricular hypertrophy and failure. Despite considerable advancements in PAH treatment prognosis remains poor. We aim to evaluate the potential for using the cytokine resistin as a genetic and biological marker for disease severity and survival in a large cohort of patients with PAH. Methods Biospecimens, clinical, and genetic data for 1121 adults with PAH, including 808 with idiopathic PAH (IPAH) and 313 with scleroderma-associated PAH (SSc-PAH), were obtained from a national repository. Serum resistin levels were measured by ELISA, and associations between resistin levels, clinical variables, and single nucleotide polymorphism genotypes were examined with multivariable regression models. Machine-learning (ML) algorithms were applied to develop and compare risk models for mortality prediction. Results Resistin levels were significantly higher in all PAH samples and PAH subtype (IPAH and SSc-PAH) samples than in controls (P

Abstract In this two-center prospective cohort study of children on ECMO, we assessed a panel of plasma brain injury biomarkers using exploratory factor analysis (EFA) to evaluate their interplay and association with outcomes. Biomarker concentrations were measured daily for the first 3 days of ECMO support in 95 participants. Unfavorable composite outcome was defined as in-hospital mortality or discharge Pediatric Cerebral Performance Category > 2 with decline ≥ 1 point from baseline. EFA grouped 11 biomarkers into three factors. Factor 1 comprised markers of cellular brain injury (NSE, BDNF, GFAP, S100β, MCP1, VILIP-1, neurogranin); Factor 2 comprised markers related to vascular processes (vWF, PDGFRβ, NPTX1); and Factor 3 comprised the BDNF/MMP-9 cellular pathway. Multivariable logistic models demonstrated that higher Factor 1 and 2 scores were associated with higher odds of unfavorable outcome (adjusted OR 2.88 [1.61, 5.66] and 1.89 [1.12, 3.43], respectively). Conversely, higher Factor 3 scores were associated with lower odds of unfavorable outcome (adjusted OR 0.54 [0.31, 0.88]), which is biologically plausible given the role of BDNF in neuroplasticity. Application of EFA on plasma brain injury biomarkers in children on ECMO yielded grouping of biomarkers into three factors that were significantly associated with unfavorable outcome, suggesting future potential as prognostic instruments.

Aim: We sought to determine if higher plasma levels of brain injury biomarkers neurofilament light (NfL), phosphorylated tau 181 (pT181), tau, and ubiquitin C-terminal hydrolase L1 (UCHL1) were associated with unfavorable outcomes in children supported on extracorporeal membrane oxygenation (ECMO) with and without preceding cardiac arrest. Methods: We conducted a secondary analysis of a two-center prospective observational study of ECMO patients 0-2 with decline from baseline PCPC among survivors. Results: Among 88 children on ECMO, mean tau levels were significantly higher on each of the first three ECMO days in children who underwent extracorporeal cardiopulmonary resuscitation (ECPR) compared to those with non-ECPR cardiac arrest or with no cardiac arrest preceding ECMO. Higher ECMO day 1 tau levels were significantly associated with increased hazard of unfavorable outcome in unadjusted (HR, 1.35, 95% CI 1.09–1.66) and adjusted (HR, 1.42; 95% CI 1.13–1.79) models. Higher levels of NfL or pT181 were not associated with increased hazard for unfavorable outcome in multivariable models. UCHL1 values were outside of detectable limits and thus deferred from analysis. Conclusions: Levels of tau were significantly associated with increased hazard of death or unfavorable neurologic outcome in unadjusted and adjusted models. Biomarkers of brain injury, particularly tau, may aid in detection of neurologic injury and neuroprognostication in patients on ECMO with and without preceding cardiac arrest.

Background: The purpose of this study is to characterize National Institutes of Health (NIH) funding for rotator cuff research and evaluate the impact of orthopedic surgeons on this portfolio. Methods: The NIH’s Research Portfolio Online Reporting Tools Expenditures and Results database was queried for “rotator cuff repair” or “rotator cuff tear” from the 2011 to 2021 fiscal years. Compound annual growth rates were calculated and grants were categorized by basic, clinical, or translational research. Funding totals were compared by Principal Investigator (PI) and grant characteristics. Results: A total of 52 grants were awarded to 38 PIs between 2011 and 2021, totaling $40,156,859. Annual NIH funding for rotator cuff tear and rotator cuff repair increased by a Compound annual growth rate of 11.0% from 2011 to 2021, compared to 3.4% for the total NIH budget. Orthopedic surgeon-scientists received $9,208,212 (22.9%), most commonly through R01 (80.5%) and K08 (7.1%) mechanisms. No significant difference in funding was found by PI sex (P = .332), degree (P = .460), academic rank (P = .118), or researcher type (P = .227). Professors had a higher h-index than associate and assistant professors (P = .001). Orthopedic surgeon-scientists had a higher h-index (mean 36.3 ± 9.4) compared to clinician-scientists (mean 8.0 ± 1.4) and research-scientists (35.5 ± 40.7) (P = .044). Clinical topics receiving the highest funding were rehabilitation (23.9%), diagnosis, (22.3%) and surgical technique (14.8%). Orthopedic surgeon-scientists acquired funding for diagnosis (57.1%), rehabilitation (17.0%), and surgical technique (14.5%). Discussion: While NIH funding for rotator cuff research is growing, orthopedic surgeon representation is low. Future studies should evaluate barriers to obtaining funding for orthopedic surgeon-scientists.

Background:. Previous reports found that 40% of randomized controlled trials (RCTs) published in The Journal of Bone & Joint Surgery (JBJS) from 1988 to 2000 and 47% of those published from 2001 to 2013 were of high quality. The purpose of this study was to assess the quality of RCTs published from 2014 to 2022 in JBJS and to compare these findings with those of prior analyses in order to identify trends over time and areas for continued improvement. Methods:. PubMed was searched for the term “randomized controlled trial” to identify studies published in JBJS from 2014 to 2022. Each included RCT was evaluated with use of the Detsky score and a risk-of-bias assessment modified from the Cochrane tool. These evaluations were then compared with previous evaluations of RCTs from the 1988 to 2000 and 2001 to 2013 periods with use of independent-sample t tests. A transformed Detsky score of >75% and a modified risk-of-bias score of ≥8 were defined as being indicative of high quality. Results:. A total of 218 RCTs were published in JBJS from 2014 to 2022. An a priori sample size was calculated in 183 studies (83.9%). A total of 152 (83.1%) of the 183 studies enrolled the calculated number of patients, of which 126 (82.9%) maintained an adequate number at the time of final follow-up. Most RCTs were conducted at a single center (146 of 218; 67%), evaluated a surgical intervention (162 of 218; 74%), and reported positive results (142 of 218; 65%). The mean transformed Detsky score was 85% ± 10% (95% confidence interval, 83.7% to 86.3%), with 82% of trials (179 of 218) scored as high quality. The mean transformed Detsky score from 2014 to 2022 was higher than that from 1988 to 2000 and that from 2001 to 2013 (85% versus 76% and 68%, respectively; p < 0.001). The mean modified risk-of-bias score was 7 ± 1, with 42% of trials (92 of 218) scored as high quality. RCTs published from 2014 to 2022 had a higher mean modified risk-of-bias score than those published from 2001 to 2013 (7 ± 1 versus 6 ± 1; p < 0.001). Compared with the 2001 to 2013 and 2014 to 2022 periods, the 1988 to 2000 period had a greater proportion of trials that reported positive results (51% and 65% versus 82%, respectively; p < 0.001) and that included data from multiple centers (31% and 33% versus 67%; p < 0.001). Conclusions:. The quality of RCTs published in JBJS from 2014 to 2022 has improved from that reported previously, as demonstrated by the increases in the modified risk-of-bias score and transformed Detsky score from prior periods. This may be the result of journal policies such as the requirements of CONSORT adherence and prospective trial registration. Investigators should focus on improving the clarity of reporting, limiting attrition bias, and making efforts to blind support staff in order to increase the quality of future RCTs. Clinical Relevance:. Improving the quality of RCTs is crucial given their potential to influence current clinical practice.

Massive irreparable rotator cuff tears (RCTs) are a commonly encountered orthopedic condition that can be difficult to treat. Several techniques have been described to manage these tears, with the implantable subacromial balloon spacer being one of the most recent. The device, which has only been approved for clinical use in the United States since 2021, functions by resisting the superior humeral head migration seen in the setting of massive RCTs and restoring normal shoulder biomechanics, as corroborated by cadaveric studies. However, results regarding clinical outcomes have been mixed to date, and further high-quality studies are needed to define the optimal use of the subacromial balloon spacer in the treatment of massive irreparable RCTs.

Background: Despite the rising incidence of anatomic total shoulder arthroplasty (ATSA) and reverse total shoulder arthroplasty (RTSA) among surgeons, little is known about the learning curve associated with these procedures. The purpose of this systematic review was to (1) identify the learning curves associated with ATSA and RTSA, (2) evaluate the effect of the learning curves on clinical outcomes, and (3) determine the number of cases needed to achieve proficiency. Methods: Four online databases [PubMed (NLM), MEDLINE (OVID), Cochrane Library (Wiley), and Scopus (Elsevier)] were systematically searched and screened according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. The search included results from the inception of each database to May 18, 2022. Data regarding study characteristics, patient demographics, learning curve analyses, patient reported outcome measures, range of motion, complication rates, and reoperation rates were collected. A quality assessment for each article was performed according to the Methodological Index for Nonrandomized Studies criteria. Results: A total of 13 studies of fair to good quality were included for analysis (one of level II evidence, five of level III, and seven of level IV) with the majority originating from the United States [n = 8, 61.5%]. Overall, there were a total of 3381 cases (1861 RTSA and 1520 ATSA), with a mean patient age of 72.6 years [range: 45-92 years]. From the studies analyzed in this systematic review, for RTSA, the approximate average number of cases surgeons need to perform to move to an acceptable position on the RTSA learning curve is 25 cases. For ATSA, a wider range of 16-86 cases was derived as only two studies reported on ATSA. Conclusion: Progression along the learning curve for RTSA and ATSA results in decreased operative times, improved patient-reported outcomes, and fewer complications. However, a true learning curve is difficult to quantify given the heterogeneity of reported outcome measures, individual surgeon experience at the time of data collection, and statistical analyses used across studies.

Abstract Pulmonary hypertension (PH) is a significant health problem that contributes to high morbidity and mortality in diverse cardiac, pulmonary, and systemic diseases in children. Evidence‐based advances in PH care have been challenged by a paucity of quality endpoints for assessing clinical course and the lack of robust clinical trial data to guide pharmacologic therapies in children. While the landmark adult AMBITION trial demonstrated the benefit of up‐front combination PH therapy with ambrisentan and tadalafil, it remains unknown whether upfront combination therapy leads to more rapid and sustained clinical benefits in children with various categories of PH. In this article, we describe the inception of the Kids Mod PAH Trial, a multicenter Phase III trial, to address whether upfront combination therapy (sildenafil and bosentan vs. sildenafil alone) improves PH outcomes in children, recognizing that marked differences between the etiology and therapeutic response between adults and children exist. The primary endpoint of this study is WHO functional class (FC) 12 months after initiation of study drug therapy. In addition to the primary outcome, secondary endpoints are being assessed, including a composite measure of time to clinical worsening, WHO FC at 24 months, echocardiographic assessment of PH and quantitative assessment of right ventricular function, 6‐min walk distance, and NT‐proBNP levels. Exploratory endpoints include selected biomarkers, actigraphy, and assessments of quality of life. This study is designed to pave the way for additional clinical trials by establishing a robust infrastructure through the development of a PPHNet Clinical Trials Network.

The pathogenesis of primary glenohumeral arthritis (GHOA) is mediated by a complex interaction between osseous anatomy and the surrounding soft tissues. Recently, there has been growing interest in characterizing the association between the anterior shoulder joint capsule and primary GHOA because of the potential for targeted treatment interventions. Emerging evidence has shown substantial synovitis, fibrosis, and mixed inflammatory cell infiltrate in the anterior capsule of osteoarthritic shoulders. In addition, increased thickening of the anterior shoulder joint capsule has been associated with greater posterior glenoid wear and humeral head subluxation. While these findings suggest that anterior capsular disease may play a causative role in the etiology and progression of eccentric GHOA, further studies are needed to support this association. The purpose of this article is to review the pathogenesis of primary GHOA, contextualize current hypotheses regarding the role of the anterior capsule in the disease process, and provide directions for future research.

Quantitative global phosphotyrosine proteomics of two mouse models of hypertrophic cardiomyopathy reveals that tyrosine kinase inhibitors may be a future therapeutic approach for treating hypertrophic cardiomyopathy.

Abstract Insulin‐like growth factor (IGF) binding proteins (IGFBPs) are a family of growth factor modifiers, some of which are known to be independently associated with pulmonary arterial hypertension (PAH) survival. IGF factor binding protein 7 (IGFBP7) is a unique low‐affinity IGFBP that, independent of IGF, stimulates prostacyclin production. This study proposed to establish associations between IGFBP7 and PAH severity and survival, using enrollment and longitudinal samples. Serum IGFBP7 levels were significantly elevated in patients with PAH compared to controls. After adjusting for age and sex, logarithmic increases in IGFBP7 were associated with a 20 m shorter six‐minute walk distance (6MWD; p

Background:. Orthopaedic surgery remains one of the most competitive residency specialties, with the number of applicants outpacing the availability of residency positions each year. The purpose of this study was to analyze present-day orthopaedic surgery match data, identify differences between matched and unmatched applicants, and compare our findings to previous trends. Methods:. Applicant data from the National Resident Matching Program from 2016 to 2022 were analyzed. The number of matched and unmatched US allopathic senior orthopaedic applicants relative to the number of available positions was used to determine respective match rates. Performance metrics and applicant characteristics were compared by match status. Trends were compared with those of previous analysis from 2006 to 2014. Results:. The number of applicants increased from 863 in 2016 to 1,068 in 2022. The match rate decreased from 75% in 2016 to 66% in 2022 (p < 0.0001). Matched applicants had a higher number of contiguous ranks (12.3 vs. 6.5; p < 0.001), United States Medical Licensing Examination (USMLE) Step-1 score (248 vs. 240; p < 0.001), USMLE Step-2 score (255 vs. 247; p < 0.001), Alpha Omega Alpha (AOA) membership (38% vs. 13%; p < 0.001), and enrollment at a top 40 National Institutes of Health (NIH)-funded medical school (34% vs. 24%, p < 0.001). Compared with 2006 to 2014 data, a smaller percentage of matched applicants were enrolled in a top 40 NIH-funded medical school (34% vs. 37%, p = 0.013). The mean differences in USMLE Step-1 score (16 vs. 8.25 points, p < 0.001) and USMLE Step-2 score (16 vs. 8.25 points, p = 0.002) in favor of matched applicants nearly halved compared with that in 2006 to 2014. In addition, there was no longer a significant difference in the number of research products (abstracts, presentations, posters, and publications) between matched and unmatched applicants (p = 0.309). Conclusions:. Differences in the academic attributes of matched and unmatched orthopaedic surgery applicants have become less profound over time, making it increasingly difficult to predict a successful match based on USMLE Step scores, AOA membership, research productivity, and medical school research reputation. Future studies should evaluate differences in subjective metrics (e.g., away rotation and interview performance and letters of recommendation) by match status.

Background: It is critical for orthopedic surgery residents and residency programs to have a current understanding of the content and resources utilized by the Orthopedic In-Training Examination (OITE) to continuously guide study and educational efforts. This study presents an updated analysis of the shoulder and elbow section of the OITE. Methods: All OITE questions, answers, and references from 2013 to 2019 were reviewed. The number of shoulder and elbow questions per year was recorded, and questions were analyzed for topic, imaging modalities, cognitive taxonomy, and references. We compared our data to the results of a previous study that analyzed shoulder and elbow OITE questions from 2002 to 2007 to examine trends and changes in this domain overtime. Results: There were 177 shoulder and elbow questions (126 shoulder, 71.2%; 51 elbow, 28.8%) of 1863 OITE questions (9.5%) over a 7-year period. The most commonly tested topics included degenerative joint disease/stiffness/arthroplasty (31.6%), anatomy/biomechanics (16.9%), instability/athletic injury (15.3%), trauma (14.7%), and rotator cuff (13.6%). Half of all questions involved clinical management decisions (49.7%). A total of 417 references were cited from 56 different sources, the most common of which were the Journal of Shoulder and Elbow Surgery (23.3%), Journal of the American Academy of Orthopaedic Surgeons (20.4%), and Journal of Bone and Joint Surgery (American Volume) (16%). The average time lag from article publication to OITE reference was 7.7 years. Compared with a prior analysis from 2002 to 2007, there was a significant increase in the number of shoulder and elbow questions on the OITE (5.5% to 9.5%; P < .001). Recent exams incorporated more complex multistep treatment questions (4.4% vs. 49.7%; P < .001) and fewer recall questions (42.2% vs. 22%; P < .001). There was a significant increase in the use of imaging modalities (53.3% vs. 79.1%; P < .001). No significant differences in the distribution of question topics were found. Conclusions: The percentage of shoulder and elbow questions on the OITE has nearly doubled over the past decade with greater emphasis on critical thinking (eg, clinical management decisions) over recall of facts. These findings should prompt educators to direct didactic efforts (eg, morning conferences and journal club) toward case-based learning to foster critical thinking and clinical reasoning skills.

Abstract Proteomic analysis of patients with pulmonary arterial hypertension (PAH) has demonstrated significant abnormalities in the insulin‐like growth factor axis (IGF). This study proposed to establish associations between a specific binding protein, insulin‐like growth factor binding protein 4 (IGFBP4), and PAH severity as well as survival across varying study cohorts. In all cohorts studied, serum IGFBP4 levels were significantly elevated in PAH compared to controls (p

Purpose: The purpose of this review was to systematically evaluate the literature on pediatric shoulder arthroscopy and outline its indications, outcomes, and complications. Methods: This systematic review was carried out in accordance with PRISMA guidelines. PubMed, Cochrane Library, ScienceDirect, and OVID Medline were searched for studies reporting the indications, outcomes, or complications in patients undergoing shoulder arthroscopy under the age of 18 years. Reviews, case reports, and letters to the editor were excluded. Data extracted included surgical techniques, indications, preoperative and postoperative functional and radiographic outcomes, and complications. The methodological quality of included studies was evaluated using the Methodological Index for Non-Randomized Studies (MINORS) tool. Results: Eighteen studies, with a mean MINORS score of 11.4/16, were identified, including a total of 761 shoulders (754 patients). Weighted average age was 13.6 years (range, 0.83-18.8 years) with a mean follow-up time of 34.6 months (range, 6-115). As part of their inclusion criteria, 6 studies (230 patients) recruited patients with anterior shoulder instability and 3 studies recruited patients with posterior shoulder instability (80 patients). Other indications for shoulder arthroscopy included obstetric brachial plexus palsy (157 patients) and rotator cuff tears (30 patients). Studies reported a significant improvement in functional outcomes for arthroscopy indicated for shoulder instability and obstetric brachial plexus palsy. A significant improvement was also noted in radiographic outcomes and range of motion for obstetric brachial plexus palsy patients. The overall rate of complication ranged from 0% to 25%, with 2 studies reporting no complications. The most common complication was recurrent instability (38 patients of 228 [16.7%]). Fourteen of the 38 patients (36.8%) underwent reoperation. Conclusion: Among pediatric patients, shoulder arthroscopy was indicated most commonly for instability, followed by brachial plexus birth palsy, and partial rotator cuff tears. Its use resulted in good clinical and radiographic outcomes with limited complications. Level of Evidence: Systematic review of Level II to IV studies.

Resistant starches (RS) are fermented in the cecum and colon to produce short-chain fatty acids and other microbial metabolites that can alter host physiology and the composition of the microbiome. We previously showed that mice fed a Total Western Diet (TWD) based on NHANES data that mimics the composition of a typical American diet, containing resistant potato starch (RPS), produced concentration dependent changes to the cecal short-chain fatty acids, the microbiome composition as well as gene expression changes in the cecum and colon that were most prevalent in mice fed the 10% RPS diet. We were then interested in whether feeding TWD/RPS would alter the resistance to bacterial-induced colitis caused by Citrobacter rodentium (Cr), a mouse pathogen that shares 66.7% of encoded genes with Enteropathogenic Escherichia coli. Mice were fed the TWD for 6 weeks followed by a 3-weeks on the RPS diets before infecting with Cr. Fecal Cr excretion was monitored over time and fecal samples were collected for 16S sequencing. Mice were euthanized on day 12 post-infection and cecal contents collected for 16S sequencing. Cecum and colon tissues were obtained for gene expression analysis, histology and to determine the level of mucosa-associated Cr. Feeding RPS increased the percentage of mice productively infected by Cr and fecal Cr excretion on day 4 post-infection. Mice fed the TWD/10% RPS diet also had greater colonization of colonic tissue at day 12 post-infection and colonic pathology. Both diet and infection altered the fecal and cecal microbiome composition with increased levels of RPS resulting in decreased α-diversity that was partially reversed by Cr infection. RNASeq analysis identified several mechanistic pathways that could be associated with the increased colonization of Cr-infected mice fed 10% RPS. In the distal colon we found a decrease in enrichment for genes associated with T cells, B cells, genes associated with the synthesis of DHA-derived SPMs and VA metabolism/retinoic acid signaling. We also found an increase in the expression of the potentially immunosuppressive gene, Ido1. These results suggest that high-level consumption of RPS in the context of a typical American diet, may alter susceptibility to gastrointestinal bacterial infections.

Abstract A pathogen inactivation step during collection or processing of clinical samples has the potential to reduce infectious risks associated with diagnostic procedures. It is essential that these inactivation methods are demonstrated to be effective, particularly for non-traditional inactivation reagents or for commercial products where the chemical composition is undisclosed. This study assessed inactivation effectiveness of twenty-four next-generation (guanidine-free) nucleic acid extraction lysis buffers and twelve rapid antigen test buffers against SARS-CoV-2, the causative agent of COVID-19. These data have significant safety implications for SARS-CoV-2 diagnostic testing and support the design and evidence-based risk assessment of these procedures.

Hypoxic–ischemic encephalopathy (HIE) is the most common cause of neonatal acquired brain injury. Although conventional MRI may predict neurodevelopmental outcomes, accurate prognostication remains difficult. As diffusion tensor imaging (DTI) may provide an additional diagnostic and prognostic value over conventional MRI, we aimed to develop a composite DTI (cDTI) score to relate to short-term neurological function. Sixty prospective neonates treated with therapeutic hypothermia (TH) for HIE were evaluated with DTI, with a voxel size of 1 × 1 × 2 mm. Fractional anisotropy (FA) and mean diffusivity (MD) from 100 neuroanatomical regions (FA/MD *100 = 200 DTI parameters in total) were quantified using an atlas-based image parcellation technique. A least absolute shrinkage and selection operator (LASSO) regression was applied to the DTI parameters to generate the cDTI score. Time to full oral nutrition [short-term oral feeding (STO) score] was used as a measure of short-term neurological function and was correlated with extracted DTI features. Seventeen DTI parameters were selected with LASSO and built into the final unbiased regression model. The selected factors included FA or MD values of the limbic structures, the corticospinal tract, and the frontotemporal cortices. While the cDTI score strongly correlated with the STO score (rho = 0.83, p = 2.8 × 10−16), it only weakly correlated with the Sarnat score (rho = 0.27, p = 0.035) and moderately with the NICHD-NRN neuroimaging score (rho = 0.43, p = 6.6 × 10−04). In contrast to the cDTI score, the NICHD-NRN score only moderately correlated with the STO score (rho = 0.37, p = 0.0037). Using a mixed-model analysis, interleukin-10 at admission to the NICU (p = 1.5 × 10−13) and tau protein at the end of TH/rewarming (p = 0.036) and after rewarming (p = 0.0015) were significantly associated with higher cDTI scores, suggesting that high cDTI scores were related to the intensity of the early inflammatory response and the severity of neuronal impairment after TH. In conclusion, a data-driven unbiased approach was applied to identify anatomical structures associated with some aspects of neurological function of HIE neonates after cooling and to build a cDTI score, which was correlated with the severity of short-term neurological functions.

Background Clinical risk factors in neonatal cardiac surgery do not fully capture discrepancies in outcomes. Targeted metabolomic analysis of plasma from neonates undergoing heart surgery with cardiopulmonary bypass was performed to determine associations with clinical outcomes. Methods and Result Samples and clinical variables from 149 neonates enrolled in the Corticosteroid Therapy in Neonates Undergoing Cardiopulmonary Bypass trial with surgical treatment for congenital heart disease between 2012 and 2016 were included. Blood samples were collected before skin incision, immediately after cardiopulmonary bypass, and 12 hours after surgery. Outcomes include composite morbidity/mortality (death, extracorporeal membrane oxygenation, cardiac arrest, acute kidney injury, and/or hepatic injury) and a cardiac composite (extracorporeal membrane oxygenation, cardiac arrest, or increase in lactate level), hepatic injury, and acute kidney injury. Targeted metabolite levels were determined by high‐resolution tandem liquid chromatography and mass spectrometry. Principal component and regression analyses were used to assess associations between metabolic profiles and outcomes, with 2 models created: a base clinical model and a base model+metabolites. Of the 193 metabolites examined, 40 were detected and quantified. The first principal component, principal component 1, was composed mostly of preoperative metabolites and was significantly associated with the composite morbidity/mortality, cardiac composite, and hepatic injury outcomes. In regression models, individual metabolites also improved model performance for the composite morbidity/mortality, cardiac composite, and hepatic injury outcomes. Significant disease pathways included myocardial injury (false discovery rate, 0.00091) and heart failure (false discovery rate, 0.041). Conclusions In neonatal cardiac surgery, perioperative metabolites were associated with postoperative outcomes and improved clinical model outcome associations. Preoperative metabolite levels alone may improve risk models and provide a basis for optimizing perioperative care.

Abstract Pulmonary arterial hypertension (PAH) is a progressive disease characterized by sustained elevations of pulmonary artery pressure. To date, we lack circulating, diagnostic, and prognostic markers that correlate to clinical and functional parameters. In this study, we performed mass spectrometry‐based proteomics analysis to identify circulating biomarkers of PAH. Plasma samples from patients with idiopathic pulmonary arterial hypertension (IPAH, N = 9) and matched normal controls (N = 9) were digested with trypsin and analyzed using data‐dependent acquisition on an Orbitrap mass spectrometer. A total of 826 (false discovery rate [FDR] 0.047) and 461 (FDR 0.087) proteins were identified across all plasma samples obtained from IPAH and control subjects, respectively. Of these, 153 proteins showed >2 folds change (p

Several studies indicate that the four major types of resistant starch (RS1-4) are fermented in the cecum and colon to produce short-chain fatty acids (SCFAs) and can alter the microbiome and host physiology. However, nearly all these studies were conducted in rodents fed with a diet that does not approximate what is typically consumed by humans. To address this, mice were fed a Total Western Diet (TWD) based on National Health and Nutrition Examination Survey (NHANES) data that mimics the macro and micronutrient composition of a typical American diet for 6 weeks and then supplemented with 0, 2, 5, or 10% of the RS2, resistant potato starch (RPS), for an additional 3 weeks. The cecal microbiome was analyzed by 16S sequencing. The alpha-diversity of the microbiome decreased with increasing consumption of RPS while a beta-diversity plot showed four discreet groupings based on the RPS level in the diet. The relative abundance of various genera was altered by feeding increasing levels of RPS. In particular, the genus Lachnospiraceae NK4A136 group was markedly increased. Cecal, proximal, and distal colon tissue mRNA abundance was analyzed by RNASeq. The cecal mRNA abundance principal component analysis showed clear segregation of the four dietary groups whose separation decreased in the proximal and distal colon. Differential expression of the genes was highest in the cecum, but substantially decreased in the proximal colon (PC) and distal colon (DC). Most differentially expressed genes were unique to each tissue with little overlap in between. The pattern of the observed gene expression suggests that RPS, likely through metabolic changes secondary to differences in microbial composition, appears to prime the host to respond to a range of pathogens, including viruses, bacteria, and parasites. In summary, consumption of dietary RPS led to significant changes to the microbiome and gene expression in the cecum and to a lesser extent in the proximal and distal colon.

Abstract Background Pulmonary arterial hypertension (PAH) is a fatal disease that results from cardio-pulmonary dysfunction with the pathology largely unknown. Insulin-like growth factor binding protein 2 (IGFBP2) is an important member of the insulin-like growth factor family, with evidence suggesting elevation in PAH patients. We investigated the diagnostic and prognostic value of serum IGFBP2 in PAH to determine if it could discriminate PAH from healthy controls and if it was associated with disease severity and survival. Methods Serum IGFBP2 levels, as well as IGF1/2 levels, were measured in two independent PAH cohorts, the Johns Hopkins Pulmonary Hypertension program (JHPH, N = 127), NHLBI PAHBiobank (PAHB, N = 203), and a healthy control cohort (N = 128). The protein levels in lung tissues were determined by western blot. The IGFBP2 mRNA expression levels in pulmonary artery smooth muscle cells (PASMC) and endothelial cells (PAEC) were assessed by RNA-seq, secreted protein levels by ELISA. Association of biomarkers with clinical variables was evaluated using adjusted linear or logistic regression and Kaplan-Meier analysis. Results In both PAH cohorts, serum IGFBP2 levels were significantly elevated (p

Abstract Background The anti-inflammatory property of ω-3 polyunsaturated fatty acids (PUFA) has been exploited in the management of inflammatory bowel disease (IBD) with promising results. However, it remains unclear if PUFA play a significant role in the resolution of inflammation and promotion of mucosal healing. Krill oil (KO) is a natural product rich in PUFA and the potent antioxidant, astaxanthin. In this study, we attempted to understand the mechanisms through which KO modulates the gut microbiome and metabolome using in vitro and in vivo colitis models and a multi-omics based approach. Results KO significantly decreased LPS-induced IL1β and TNFα expression in human macrophages in vitro in a dose-dependent manner by regulating a broad spectrum of signaling pathways, including NF-κB and NOD-like receptor signaling, and displayed a synergistic effect with COX2 and IKK2 inhibitors in attenuating inflammatory pathways. Moreover, KO was involved in the resolution of inflammation by promoting M2 polarization and enhancing macrophage-mediated intracellular bacterial killing. Parasite-dependent intestinal mucosal damage and microbial dysbiosis induced by Trichuris suis infection in pigs were partially restored by feeding KO. KO supplementation reduced the abundance of Rickettsiales and several species of Lactobacillus, which were among the important features identified by random forests analysis contributing to classification accuracy for KO supplementation. Several microbial signatures with strong predictive power for the status of both infection and supplementation were identified. The inhibitory effect of KO on histidine metabolism was identified using untargeted metabolomics. KO supplementation reduced several key metabolites related to histamine metabolism by suppressing the expression of a gene encoding l-histidine decarboxylase in the colon mucosa and reducing histamine biosynthesis of microbial origin. Moreover, the pro-resolving properties of KO were validated using a Citrobacter rodentium-induced Th1-dependent colitis murine model. Further, microbial signatures with high prediction accuracy for colitis-related pathophysiological traits were identified in mice. Conclusion The findings from this study provided a mechanistic basis for optimizing microbiome-inspired alternative therapeutics in the management of IBD. The microbial signatures identified, particularly those with strong predictive accuracy for colitis phenotypes, will facilitate the development of biomarkers associated with appropriate dietary intervention to manage intestinal inflammation. Video abstract.

Simon Read,1 James Morgan,2 David Gillespie,3 Claire Nollett,3 Marjorie Weiss,4 Davina Allen,1 Pippa Anderson,5 Heather Waterman1 1School of Healthcare Sciences, Cardiff University, Cardiff, Wales, UK; 2Cardiff and Vale University Health Board, Cardiff, Wales, UK; 3Centre for Trials Research, Cardiff University, Cardiff, Wales, UK; 4School of Pharmaceutical Sciences, Cardiff University, Cardiff, Wales, UK; 5Swansea Centre for Health Economics, Swansea University, Swansea, Wales, UKCorrespondence: Simon ReadCardiff University, Room 12.14, Eastgate House, 35-43 Newport Road, Cardiff CF24 0AB, Wales, UKTel +44 2920 688930Email readsm@cardiff.ac.ukAbstract: Patient adherence to medication is an ongoing concern for clinicians, obfuscating treatment efficacy and resulting in wastage of medicine, reduced clinical benefit, and increased mortality. Despite this, procedural guidance on how clinicians should best engage patients regarding their medicine-taking is limited in the United Kingdom. Adherence for chronic conditions is notably complex, requiring clear education, communication, and behavioural shifts to initiate and sustain daily regimens successfully. This article explores current clinician guidance on assuring patient adherence to medication within the National Health Service, comparing it to that provided for healthcare workers in the field of behavioural change. Outlining the inertia of the former and the progress of the latter, we consider what steps should be taken to address this deficit, including greater focus on patient concerns, as well as knowledge translation for healthcare professionals in future adherence research. Current United Kingdom clinical guidance for assuring patient adherence is largely outdated based on inconclusive evidence for best practice. However, efforts to encourage behavioural change in the public health setting demonstrate evidence-based success. Integrating knowledge generated around adherence behaviour and the practical application of adherence and behavioural change research, as well as funding for longer-term studies with a focus on clinical outcomes, may help to solidify the NICE guidance on adherence and further progress the field. This would require close involvement from patient groups and networks informing ethical aspects of study design and clinical implementation.Keywords: adherence, chronic conditions, behavioural change, clinical guidance, knowledge translation

Abstract Hepatoma‐derived growth factor (HDGF) was previously shown to be associated with increased mortality in a small study of idiopathic and connective tissue disease‐associated pulmonary arterial hypertension (PAH). In this study, we measured serum HDGF levels in a large multicenter cohort (total 2017 adult PAH‐Biobank enrollees), we analyzed the associations between HDGF levels and various clinical measures using linear or logistic regression models. Higher HDGF levels were found to be significantly associated with worse pulmonary hemodynamics, prostacyclin treatment; among PAH subtypes, higher HDGF levels were most associated with portopulmonary hypertension (beta = 0.469, p

This study was an endeavor to compare crowdsourced-based and geostatistical modeled projected temperature within the City of Atlanta during a September 2019 snapshot tied to a heat event. This study also ventured to decipher how spatially-variable discrepancies of prediction may be correlated to economic status via zip code and land cover/land use (LC/LU). Results suggests that satellite-correlated crowdsourced and geostatistical simulated temperature in the City of Atlanta during this snapshot to decipher differences in the spatial variations of forecasts may be correlated to economic status and LC/LU and can be implemented to potentially help with urban heat management strategies.

Objective: To determine the changes due to therapeutic hypothermia (TH) exposure in the strength of association between traditional clinical and biochemical indicators of severity of neonatal hypoxic-ischemic encephalopathy (HIE) and serum biomarkers. We hypothesized that culmination of TH changes the strength of the relationships between traditional indicators of severity of HIE and serum biomarkers.Methods: This was a single-center observational cohort study of 178 neonates with HIE treated with TH and followed with serum biomarkers: (i) brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF) (neurotrophins); (ii) tau and glial fibrillary acidic protein (GFAP) (neural cell injury); and (iii) interleukin 6 (IL-6), IL-8, and IL-10 (cytokines), during their first week of life. Adjusted mixed-effect models tested associations with HIE indicators in relation to TH exposure.Results: At admission, lower Apgar scores and base excess (BE) and higher lactate and nucleated red blood cell (NRBC) count correlated with higher Sarnat scores. These indicators of worse HIE severity, including higher Sarnat score, correlated with lower VEGF and higher tau, GFAP, and IL-10 levels at different time points. Within the first 24 h of life, patients with a Sarnat score >2 had lower VEGF levels, whereas only those with score of 3 also had higher GFAP and IL-10 levels. Tau levels increased during TH in patients with Sarnat score of 3, whereas tau and GFAP increased after TH in those with scores of 2. After adjustments, lower VEGF levels during TH and higher tau, GFAP, and IL-10 levels during and after TH were associated with worse Sarnat scores. Tau and GFAP relationship with Sarnat score became stronger after TH.Conclusion: Therapeutic hypothermia exerts an independent modulatory effect in the relationships between traditional indicators of severity of HIE and serum biomarkers after adjustments. Thus, the timing of biomarker testing in relation to TH exposure must be carefully considered if biomarkers are proposed for patient stratification in novel clinical trials.

Objectives: To evaluate the impact of a Community Health Worker (CHW)-led influenza campaign on knowledge and attitudes about vaccination in Latinx migrant and refugee populations. Methods: Twelve online workshops were conducted with 183 participants and 24 CHWs between January 12 and May 12, 2021. Participants were Latinx families living in underserved communities throughout Washington state. The initiative also included radio, animated videos, advertisements, social media, and educational materials. Results: Analysis of pre and post workshop surveys from 155 participants showed statistically significant improvements in all questions about the definition of influenza, symptoms, and risks: and in 7 of 9 questions about treatments and vaccines. Analysis of 2 open-ended questions showed increases in words key to understanding influenza, such as “virus,” “illness,” “death,” and “contagious.” There were significant increases in rates of participants identifying vaccination and antibiotics as cures for influenza. Conclusions: CHW-led workshops can be an effective way to increase knowledge about influenza and influenza vaccine. Future curriculum should emphasize the difference between viruses and bacteria, and the use of vaccination for prevention as opposed to treatment for illness.

Currently available noninvasive markers for assessing disease severity and mortality risk in pulmonary arterial hypertension (PAH) are unrelated to fundamental disease biology. Endostatin, an angiostatic peptide known to inhibit pulmonary artery endothelial cell migration, proliferation and survival in vitro, has been linked to adverse haemodynamics and shortened survival in small PAH cohorts. This observational cohort study sought to assess: 1) the prognostic performance of circulating endostatin levels in a large, multicentre PAH cohort; and 2) the added value gained by incorporating endostatin into existing PAH risk prediction models. Endostatin ELISAs were performed on enrolment samples collected from 2017 PAH subjects with detailed clinical data, including survival times. Endostatin associations with clinical variables, including survival, were examined using multivariable regression and Cox proportional hazards models. Extended survival models including endostatin were compared to null models based on the REVEAL risk prediction tool and European Society of Cardiology/European Respiratory Society (ESC/ERS) low-risk criteria using likelihood ratio tests, Akaike and Bayesian information criteria and C-statistics. Higher endostatin was associated with higher right atrial pressure, mean pulmonary arterial pressure and pulmonary vascular resistance, and with shorter 6-min walk distance (p

Introduction An important question for oral health education is whether knowledge gained during lay-led workshops is retained and applied in daily practice. This study assessed the knowledge retention and changes in oral health practices several months after oral health education workshops were held for migrant farmworkers by Community Health Workers (CHWs). Methods and Results Follow-up surveys were conducted with 32 participants 1 to 43 months post participation (60% between 6 and 21 months). The results showed a high degree of retention, in such areas as general oral health knowledge, and brushing/flossing frequency and technique among this sample. There was no relationship between length of time since the educational workshop and knowledge retained or behaviors changed. Conclusions and Recommendations An interactive, lay-led oral health education program run by CHWs can be an effective way to deliver sustained improvements in oral health knowledge and changes in oral health practice in migrant populations.

Introduction: Consensus is limited regarding optimal transcranial approaches (TCAs) for the surgical resection of olfactory groove meningiomas (OGMs). This systematic review and meta-analysis aims to examine operative and peri-operative outcomes of unilateral compared to bilateral TCAs for OGMs.Methods: Electronic databases were searched from inception until December 2019 for studies delineating TCAs for OGM patients. Patient demographics, pre-operative symptoms, surgical outcomes, and complications were evaluated and analyzed with a meta-analysis of proportions.Results: A total of 27 observational case series comparing 554 unilateral vs. 451 bilateral TCA patients were eligible for review. The weighted pooled incidence of gross total resection is 94.6% (95% CI, 90.7–97.5%; I2 = 59.0%; p = 0.001) for unilateral and 90.9% (95% CI, 85.6–95.4%; I2 = 58.1%; p = 0.003) for bilateral cohorts. Similarly, the incidence of OGM recurrence is 2.6% (95% CI, 0.4–6.0%; I2 = 53.1%; p = 0.012) and 4.7% (95% CI, 1.4–9.2%; I2 = 55.3%; p = 0.006), respectively. Differences in oncologic outcomes were not found to be statistically significant (p = 0.21 and 0.35, respectively). Statistically significant differences in complication rates in bilateral vs. unilateral TCA cohorts include meningitis (1.0 vs. 0.0%; p = 0.022) and mortality (3.2 vs. 0.2%; p = 0.007).Conclusions: While both cohorts have similar oncologic outcomes, bilateral TCA patients exhibit higher post-operative complication rates. This may be explained by underlying tumor characteristics necessitating more radical resection but may also indicate increased morbidity with bilateral approaches. However, evidence from more controlled, comparative studies is warranted to further support these findings.

We previously demonstrated that IL4, IL13, CLCA1, and CCL26 mRNA were significantly upregulated in the lungs of pigs given a low dose of all trans-retinoic acid (ATRA) and infected with Ascaris suum. We also demonstrated that in vitro ATRA induced a state of partial alternative activation in porcine macrophages (Mφs) and amplified certain aspects of M2a activation induced by IL-4. Given these results, we tested the effect of ATRA on IL-4 responses in two porcine intestinal epithelial cell lines, IPEC1 and IPEC-J2 and observed that ATRA increased mRNA for the IL-4 receptor alpha chain. ATRA also increased IL-4 induced phosphorylation of signal transducer and activator of transcription 6 (STAT6) and mRNA expression of the chloride channel, calcium activated, family member 1 (CLCA1), important for mucus formation, and chemokine (C-C motif) ligand 26 (CCL26), a potent eosinophil chemoattractant. We extended these findings to human Mφ THP-1 cells and showed that ATRA synergistically increased IL-4–induced CCL2, CCL13, and CCL26 mRNA and protein levels. Transglutaminase 2 mRNA, protein, and enzyme activity were synergistically induced in THP-1 cells pretreated with ATRA and then treated with IL-4, thus, ATRA increased signaling in response to IL-4 in porcine epithelial cells and porcine and human Mφs. Given the prevalence of allergic and parasitic diseases worldwide and the close similarities in the porcine and human immune responses, these findings have important implications for the nutritional regulation of allergic inflammation at mucosal surfaces.

Recently emerging evidence indicates accelerated age-related changes in the structure and function of the brain in schizophrenia, raising a question about its potential consequences on cognitive function. Using a large sample of schizophrenia patients and controls and a battery of tasks across multiple cognitive domains, we examined whether patients show accelerated age-related decline in cognition and whether an age-related effect differ between females and males. We utilized data of 1,415 schizophrenia patients and 1,062 healthy community collected by the second phase of the Consortium on the Genetics of Schizophrenia (COGS-2). A battery of cognitive tasks included the Letter-Number Span Task, two forms of the Continuous Performance Test, the California Verbal Learning Test, Second Edition, the Penn Emotion Identification Test and the Penn Facial Memory Test. The effect of age and gender on cognitive performance was examined with a general linear model. We observed age-related changes on most cognitive measures, which was similar between males and females. Compared to controls, patients showed greater deterioration in performance on attention/vigilance and greater slowness of processing social information with increasing age. However, controls showed greater age-related changes in working memory and verbal memory compared to patients. Age-related changes (η2p of 0.001 to .008) were much smaller than between-group differences (η2p of 0.005 to .037). This study found that patients showed continued decline of cognition on some domains but stable impairment or even less decline on other domains with increasing age. These findings indicate that age-related changes in cognition in schizophrenia are subtle and not uniform across multiple cognitive domains.

Abstract Background Symptoms of acquired tracheobronchomalacia (TBM) include wheezing, shortness of breath, and chronic cough, and can negatively affect quality of life. Successful treatment of TBM requires identification of the disorder and of contributing factors. Acquired TBM is generally associated with a number of conditions, including asthma, chronic obstructive pulmonary disease (COPD), and gastroesophageal reflux. Although a possible relationship with obstructive sleep apnea (OSA) has been observed, data illuminating such an interaction are sparse. Methods In the present study, we analyzed the percent tracheal collapse (as measured on dynamic chest CT) and detailed sleep reports of 200 patients that had been seen at National Jewish Health, half of which had been diagnosed with OSA and half which did not have OSA. Results Tracheal collapse ranged from 0 to 99% closure in the population examined, with most subjects experiencing at least 75% collapse. OSA did not relate significantly to the presence or severity of tracheobronchomalacia in this population. Sleep disordered breathing (SDB) did show a strong association with TBM (p

Abstract Background Autoinflammatory disorders are distinguished by seemingly random episodes of systemic hyperinflammation, driven in particular by IL-1. Recent pre-clinical work has shown a key role for IL-1 in epilepsy in animal models, and therapies for autoinflammation including IL-1 blockade are proposed for refractory epilepsy. Case presentation Here, we report an adolescent female with signs of persistent systemic inflammation and epilepsy unresponsive to multiple anti-epileptic drugs (AED). She was diagnosed with generalized epilepsy with a normal brain MRI and an electroencephalogram (EEG) showing occasional generalized spike and slow wave discharges. Her diagnostic evaluation showed no signs of autoimmunity or genetic causes of epilepsy or periodic fever syndromes but persistently elevated serum inflammatory markers including S100 alarmin proteins. She experienced prompt clinical response to IL-1 blockade with first anakinra and then canakinumab, with near complete resolution of clinical seizures. Additionally, she displayed marked improvements in quality of life and social/academic functioning. Baseline gene expression studies on peripheral blood mononuclear cells (PBMC) from this patient showed significantly activated gene pathways suggesting systemic immune activation, including focal adhesion, platelet activation, and Rap1 signaling, which is an upstream regulator of IL-1β production by the NLRP3 inflammasome. It also showed activation of genes that characterize inflammasome-mediated autoinflammatory disorders and no signs of interferon activation. This gene expression signature was largely extinguished after anakinra treatment. Conclusions Together, these findings suggest that patients with epilepsy responsive to immune modulation may have distinct autoinflammatory features supporting IL-1 blockade. As such, IL-1 blockade may be highly efficacious adjunctive medication for certain refractory epilepsy syndromes.

Background: Stroke is a devastating perioperative complication without effective methods for prevention or diagnosis. The objective of this study was to analyze evidence-based strategies for detecting cerebrovascular vulnerability and injury in a high-risk cohort of non-cardiac surgery patients.Methods: This was a single-center, prospective cohort study. Fifty patients undergoing non-cardiac surgery were recruited −25 with known cerebrovascular disease and 25 matched controls. Neurologic vulnerability was measured with intraoperative cerebral oximetry as the primary outcome. Perioperative neurocognitive testing and serum biomarker analysis (S-100β, neuron specific enolase, glial fibrillary acid protein, and matrix metalloproteinase-9) were measured as secondary outcomes.Results: Cerebral desaturation events (an oximetry decrease ≥20% from baseline or

Study region: This study investigated impacts of current landscape configuration on streamflow within selected small watersheds of the Atlanta, Georgia metropolitan region (AMR). Study focus: To determine effects of current landscape arrangement on watershed-wide Hydrologic Unit Code (HUC)-12 land cover/land use (LC/LU), the configurational metric of contagion was chosen. Contagion-adjusted curve numbers (CNs) were calculated for all 405 HUC-12 watersheds in the AMR. 6 watersheds were chosen for Thornthwaite Water Balance (TWB) model evaluation based upon having a stream gage record of the 5 year (60 month) period most closely associated with contagion and CN values derived from the 2011 National Land Cover Dataset (NLCD). 4 watersheds out-performed their original CN watershed simulations based upon: Nash–Sutcliffe efficiency (NSE); room mean square error (RMSE)-standard deviation ratio (RSR); and Akaike Information Criteria (AIC) analysis. New hydrological insights: Configurational metrics related to contagion of the aggregation index (AI) and clumpiness index (CI) indicated possible reasoning to explain differences found between the 4-watershed and 2-watershed categories. The AI of agricultural LC/LU within the 2-watershed category suggested greater landscape heterogeneity due to agricultural patch disaggregation, whereas the CI suggested greater overall disaggregation and landscape dispersion for all non-water LC/LU patches within the 2-watershed category and pointed towards greater landscape heterogeneity driven by higher dispersal of non-water patches. Both may lead to complex flow patterns not easily estimated within streamflow simulations. Keywords: Atlanta, Curve number, Landscape configuration, Streamflow, Thornthwaite water balance

Patients have been known to regain consciousness during surgery while still paralyzed by the anesthesia and unable to communicate their distress. Recently, electronic engineers have helped resolve this problem by improving the real-time monitoring of depth of anesthesia. Electronic measurements of the brain's activity are used for many clinical and research purposes. This is possible because the brain uses electrochemical phenomena in order to process data. Many researchers have taken this to mean that advances in computer science will eventually result in sentient computers. Some conflate artificial consciousness with artificial intelligence even though consciousness and intelligence are not positively correlated. Those not trained in neurology, or at least medicine, understandably fail to comprehend what the rich, complex word “consciousness” actually means as a term of art. Human consciousness can only be evaluated with surrogate markers and is a broad and complex spectrum that ranges from minimally conscious to waking consciousness (what the reader is experiencing right now). The necessary conditions for waking consciousness include a brain in just the right electrical, chemical, and thermal states with sufficient blood pressure. These conditions, in turn, require the brain to have a body that is maintained in the right environment. Hence, waking consciousness is a proper subset of spectrum consciousness and cannot be considered an independent phenomenon capable of being disembodied or sliced off of the spectrum. The Theory of Mind (TOM) from developmental psychology infers that a brain similar to that of humans is a sufficient condition for spectrum consciousness. But this theory is precluded for computers because a child would not recognize a computer as being a living organism that is just like the child. Although TOM could be applied to an ideal android, there is a classic mathematical theorem from systems science that makes such an android seem infeasible.

Purpose: This study rigorously explores the intersectional challenges faced by black fat males, emphasizing the amalgamation of anti-fat bias, gender and sexuality and racial discrimination within educational contexts. The purpose of this study is to dissect the complex dynamics of this intersection, shedding light on the nuanced experiences of black men. Central to this exploration is the advocacy for creating inclusive educational sanctuaries, providing a safe space for these individuals to thrive, learn and engage in holistic personal development. Design/methodology/approach: To accomplish our objectives, this paper reviewed existing literature on anti-fatness, intersecting with issues of race, gender and sexuality. Drawing upon qualitative data, this study incorporated personal narratives and experiences to offer a comprehensive perspective. Our research methodology also involved an analysis of metrics like body mass index (BMI) and its impact on health-care practices and policies, particularly concerning the black community. Findings: The research discerns that black fat males encounter multifaceted challenges in educational settings, often rooted in societal prejudices and systemic biases. It highlights the inadequacy of conventional metrics like BMI in capturing the complexity of these experiences. The study identifies the urgent need for safe school spaces, emphasizing the importance of inclusive language, varied seating arrangements and tailored educational content. These findings underscore the imperative for proactive measures in dismantling anti-fatness within academic institutions. Originality/value: This research contributes significantly to the academic discourse by pioneering an in-depth exploration of the intersectional challenges black fat males face in education. This study offers a novel perspective by focusing on the unique amalgamation of anti-fat bias and racial discrimination. The proposal for educational sanctuaries tailored to the needs of this demographic represents an innovative solution, bridging gaps in the existing literature. Through its nuanced approach and advocacy for inclusivity, this study stands as an original and pioneering contribution to the field, urging educators and policymakers to reevaluate their practices and create equitable learning environments.

Men with hypogonadism (HG) who choose testosterone replacement therapy (TRT) may have distinct characteristics that provide insight as to why they may/may not initiate therapy. The aim of the current study was to identify trends in patient characteristics and attitudes in men diagnosed with HG who initiated TRT (TRT+) compared with men who were diagnosed with HG but did not initiate TRT (TRT−). The market research-based online survey conducted between 2012 and 2013 included patients from a Federated Sample, a commercially available panel of patients with diverse medical conditions. The current analysis was composed of two groups: TRT+ ( n = 155) and TRT− ( n = 157). Patient demographics, clinical characteristics, and attitudes toward HG and TRT were examined as potential predictors of primary adherence in men with HG; cohorts were compared by using Fisher’s exact test. Significant associations among sexual orientation, relationship status, educational level, presence of comorbid erectile dysfunction, area of residence, and TRT initiation were present ( p ≤ .05). College-educated, heterosexual, married men with comorbid erectile dysfunction living in suburban and urban areas were more likely to initiate treatment. The most bothersome symptoms reported were lack of energy (90% vs. 81%, p = .075), decreased strength and endurance (86% vs. 76%, p = .077), and deterioration in work performance (52% vs. 31%, p = .004); lack of energy prompted men to seek help. Patients (48%) in the TRT+ group were more knowledgeable regarding HG as compared with TRT− respondents (14%, p < .001), and most men obtained their information from a health care professional (89% vs. 82%, p = .074). The current analysis identified distinct demographic and clinical characteristics and attitudes among TRT users compared with men who were diagnosed with HG yet remained untreated.

This study evaluated the effect of axillary administration of a 2% testosterone solution (Axiron ® ) in hypogonadal (HGN) men who had had a suboptimal response to treatment with a commercially available topical testosterone gel. HGN men averaging 57 years old, with a mean body mass index of 31.9 kg/m 2 and median baseline testosterone level (T-level) of 185.2 ng/dL, who had failed to reach normal T-levels with a topical testosterone gel (Androgel 1.62%, Androgel, Testim, or Fortesta) were treated with a 2% testosterone solution until T-levels reached a normal range (from ≥300 to ≤1,050 ng/dL) or for up to 9 weeks. Outcomes included the cumulative percentage of men with a serum T-level in the normal range during treatment with Axiron and improvement in symptoms of low energy level and low sexual drive. During the study, 95% of HGN men (72/78) attained a T-level in the normal range. The median T-level at endpoint was 495.7 ng/dL, a threefold increase over baseline, p < .001, 70% achieving normal T-levels within the first 2 weeks of treatment. In a post hoc analysis, all subjects with baseline body mass indexes >35 kg/m 2 ( n = 19) achieved T-levels in the normal range. Prior to treatment, over 61% of subjects (48/78) reported impairment in either energy level or sexual drive. After treatment (or testosterone normalization), energy level improved in 75% of subjects and sexual drive improved in 70%. Topical 2% testosterone solution is a safe and effective treatment for HGN men who have had a suboptimal response to previous treatment with topical testosterone gels.

The Aharonov-Vaidman gauge additively transforms the mean energy of a quantum mechanical system into a weak valued system energy. In this paper, the equation of motion of this weak valued energy is used to provide a mathematical statement of an extended 1st Law of Thermodynamics that is applicable to the mean energy of a closed quantum system when the mean energy is expressed in the Aharonov-Vaidman gauge, i.e., when the system’s energy is weak valued. This is achieved by identifying the generalized heat and work exchange terms that appear in the equation of motion for weak valued energy. The complex valued contributions of the additive gauge term to these generalized exchange terms are discussed and this extended 1st Law is shown to subsume the usual 1st Law that is applicable for the mean energy of a closed quantum system. It is found that the gauge transformation introduces an additional energy uncertainty exchange term that—while it is neither a heat nor a work exchange term—is necessary for the conservation of weak valued energy. A spin-1/2 particle in a uniform magnetic field is used to illustrate aspects of the theory. It is demonstrated for this case that the extended 1st Law implies the existence of a gauge potential ω and that it generates a non-vanishing gauge field F. It is also shown for this case that the energy uncertainty exchange accumulated during the evolution of the system along a closed evolutionary cycle C in an associated parameter space is a geometric phase. This phase is equal to both the path integral of ω along C and the integral of the flux of F through the area enclosed by C.