Well-being grants in an academic medical center: A case example.

Academic medical centers (AMCs) rely on engaged and motivated faculty for their success. Significant burnout among clinical and research faculty has resulted in career disengagement and turnover. As such, AMCs must be vested in cultivating faculty engagement and well-being through novel initiatives that support faculty. The Well-Being Education Grants program was established by the Office for Well-Being within the Center for Faculty Development at Massachusetts General Hospital to provide the impetus many faculty needed to dedicate time to their well-being, demonstrating that investments in multi-component interventions around faculty well-being require resources and funding.

Erratum: 210 Preliminary Validation of the Arabic Global Neuropsychological Assessment (GNA) - ERRATUM.

[This corrects the article DOI: 10.1017/cts.2023.283.].

Selective inhibition of integrin αvß6 leads to rapid induction of urinary bladder tumors in cynomolgus macaques.

Administration of a novel and selective small molecule integrin αvß6 inhibitor, MORF-627, to young cynomolgus monkeys for 28 days resulted in the rapid induction of epithelial proliferative changes in the urinary bladder of 2 animals, in the absence of test agent genotoxicity. Microscopic findings included suburothelial infiltration by irregular nests and/or trabeculae of epithelial cells, variable cytologic atypia, and high mitotic rate, without invasion into the tunica muscularis. Morphologic features and patterns of tumor growth were consistent with a diagnosis of early-stage invasive urothelial carcinoma. Ki67 immunohistochemistry demonstrated diffusely increased epithelial proliferation in the urinary bladder of several monkeys, including those with tumors, and αvß6 was expressed in some epithelial tissues, including urinary bladder, in monkeys and humans. Spontaneous urothelial carcinomas are extremely unusual in young healthy monkeys, suggesting a direct link of the finding to the test agent. Inhibition of integrin αvß6 is intended to locally and selectively block transforming growth factor beta (TGF-ß) signaling, which is implicated in epithelial proliferative disorders. Subsequent in vitro studies using a panel of integrin αvß6 inhibitors in human bladder epithelial cells replicated the increased urothelial proliferation observed in monkeys and was reversed through exogenous application of TGF-ß. Moreover, analysis of in vivo models of liver and lung fibrosis revealed evidence of epithelial hyperplasia and cell cycle dysregulation in mice treated with integrin αvß6 or TGF-ß receptor I inhibitors. The cumulative evidence suggests a direct link between integrin αvß6 inhibition and decreased TGF-ß signaling in the local bladder environment, with implications for epithelial proliferation and carcinogenesis.

Effects of Repeated Administration and Comparability of Alternate Forms for the Global Neuropsychological Assessment (GNA).

The Global Neuropsychological Assessment (GNA) is an extremely brief battery of cognitive tasks assessing episodic memory, processing speed, working memory, verbal fluency, executive function, and mood. It can be given in under 15 minutes, has five alternate forms, and does not require an examinee to be literate. The purpose of this study was to quantify practice effects over repeated administrations and assess comparability of the GNA's five alternate forms, preparing the battery for repeated administration in research and clinical settings. Forty participants each completed all five GNA forms at weekly intervals following a Latin square design (i.e., each form was administered at every position in the sequence an equal number of times). In a cognitively intact population, practice effects of 0.56 to 1.06 SD were observed across GNA measures when comparing the first and fifth administration. Most GNA tests showed nonsignificant interform differences with cross-form means differing by 0.35 SD or less, with the exception of modest but statistically significant interform differences for the GNA Story Memory subtest across all five forms. However, post hoc analysis identified clusters of two and three Story Memory alternate forms that were equivalent.

Integration and expression: The complementary functions of self-reflection.

No construct is more central to personality than the person's self-concept. Higher-order domains of self-assessment, including self-perceived skills, traits, and values, are expressed in action and provide frames of reference for deciding whether to accept or reject personally relevant social feedback. To perform these functions in a consistent manner, the domains of self-concept need to achieve coherence, with the components of each domain sufficiently integrated to provide an unequivocal platform for decision making and behavior. This depiction implies two functions of self-reflection-one focused on forging coherence in self-concept and the other focusing on the expression of domains that have achieved coherence. We refer to these two modes of self-reflection, respectively, as integration and expression. Both modes can be understood in terms of a spotlight of attention that focuses on different regions of the self-structure. In the integration mode, the spotlight converges on incoherent regions of self-concept to eliminate inconsistencies among the lower-level components. In the expression mode, the spotlight converges on coherent regions of self-concept that can provide an unequivocal platform for decision making and effective action. Using agent-based modeling, we illustrate the operation of both modes, discuss the conditions that differentially activate them, and develop their implications for personality dynamics.

Preliminary Validation of the Global Neuropsychological Assessment in Alzheimer's Disease and Healthy Volunteers.

METHODS: We administered the Global Neuropsychological Assessment (GNA), an abbreviated cognitive battery, to 105 adults aged 73.0 ± 7.1 years, including 28 with probable Alzheimer's disease, 9 with amnestic mild cognitive impairment, and 68 healthy controls. We examined group differences in baseline performance, test-retest reliability, and correlations with other conventional tests. RESULTS: Healthy adults outperformed patients on all five GNA subtests. Test-retest intraclass correlation coefficients were significant for all GNA subtests. Among patients with healthy controls, GNA Story Memory correlated best with Wechsler Memory Scale-Revised (WMS-R) Logical Memory for learning and delayed recall, GNA Digit Span correlated most highly with the Wechsler Adult Intelligence Scale-Third Edition (WAIS-III) Digit Span, GNA Perceptual Comparison correlated most highly with the Trail Making Test, and GNA Animal Naming correlated most highly with Supermarket Item Naming. CONCLUSIONS: Preliminary findings suggest that the GNA shows good test-retest validity, clear convergent and discriminant construct validity, and excellent diagnostic criterion validity for dementia and mild cognitive impairment in an American sample.

Per- and polyfluoroalkyl substances and their alternatives in paper food packaging.

Per- and polyfluoroalkyl substances (PFAS) have been used in food contact paper and paperboard for decades due to their unique ability to provide both moisture and oil/grease resistance. Once thought to be innocuous, it is now clear that long chain PFAS bioaccumulate and are linked to reproductive and developmental abnormalities, suppressed immune response, and tumor formation. Second-generation PFAS have shorter biological half-lives but concerns about health risks from chronic exposure underscore the need for safe substitutes. Waxes and polymer film laminates of polyethylene, poly(ethylene-co-vinyl alcohol), and polyethylene terephthalate are commonly used alternatives. However, such laminates are neither compostable nor recyclable. Lamination with biodegradable polymers, including polyesters, such as polylactic acid (PLA), polybutylene adipate terephthalate, polybutylene succinate, and polyhydroxyalkanoates, are of growing research and commercial interest. PLA films are perhaps the most viable alternative, but performance and compostability are suboptimal. Surface sizings and coatings of starches, chitosan, alginates, micro- and nanofibrilated cellulose, and gelatins provide adequate oil barrier properties but have poor moisture resistance without chemical modification. Plant proteins, including soy, wheat gluten, and corn zein, have been tested as paper coatings with soy being the most commercially important. Internal sizing agents, such as alkyl ketene dimers, alkenyl succinic anhydride, and rosin, improve moisture resistance but are poor oil/grease barriers. The difficulty in finding a viable replacement for PFAS chemicals that is cost-effective, fully biodegradable, and environmentally sound underscores the need for more research to improve barrier properties and process economics in food packaging products.

Persistence of Inflammatory Phenotype in Residual Psoriatic Plaques in Patients on Effective Biologic Therapy.

Many psoriasis patients treated with biologics do not achieve total skin clearance. These patients possess residual plaques despite ongoing biologic treatment. To elucidate mechanisms of plaque persistence despite overall good drug response, we studied 50 subjects: psoriasis patients with residual plaques treated with one of three different biologics, untreated patients, and healthy controls. Skin biopsies from all subjects were characterized using three methods: mRNA expression, histology, and FACS of hematopoietic skin cells. Although all three methods provided evidence of drug effect, gene expression analysis revealed the persistence of key psoriasis pathways in treated plaques, including granulocyte adhesion and diapedesis, T helper type17 activation pathway, and interferon signaling with no novel pathways emerging. Focal decreases in parakeratosis and keratinocyte proliferation and differential reduction in IL-17 producing CD103- T cells, but no change in CD103+ tissue-resident memory T cells were observed. Of note, antitumor necrosis factor increased the interferon signaling pathway already present. Interestingly mast cells were the dominant source of IL-22 in all psoriasis subjects. These data suggest that while subtle differences can be observed in drug-treated plaques, underlying biologic mechanisms are similar to those present in untreated psoriatic lesions.

Mechanistic and pharmacological assessment of murine IL-23 mediated psoriasiform dermatitis; implications for drug discovery.

BACKGROUND: Animal models of Psoriasis (PsO) are important for our understanding of the pathophysiology of human disease but rarely manifest all features of the disease. In order to facilitate greater understanding of the underlying biology of PsO it is key that we understand the strengths and limitations of models used. OBJECTIVE: While humanized mouse models are available for PsO they remain technically challenging, expensive, require prolonged timelines and require a continued source of human tissue. Another approach is to focus on developing mechanistic models which recapitulate key features of human PsO. The role of the IL-23/IL-17 pathway as a key driver of human PsO is both well characterized and clinically validated. The goal of this manuscript is to provide a comprehensive disease and pharmacological assessment of IL-23 driven skin inflammation and its similarity to human psoriatic skin. METHODS: Intradermal injection of IL-23 has been used to study the IL-23 pathway in rodents, and this current study further characterizes pathology, cellular infiltrate, and gene signature kinetics, as well as the modulation of disease features by clinically relevant agents. RESULTS: Our results indicate that IL-23 triggers an early and robust activation of the immune system resulting in accumulation of T cell and monocyte/macrophage populations. It also supports changes in gene expression that parallel those observed in human PsO samples and is responsive to biologics commonly used to treat PsO in the clinic. CONCLUSIONS: Collectively, our studies indicate that a 5 day model of IL-23 psoriasiform dermatitis can be used to assess the pharmacology of novel small molecules/biologics in the treatment of PsO.

Targeting Anti-TGF-ß Therapy to Fibrotic Kidneys with a Dual Specificity Antibody Approach.

Targeted delivery of a therapeutic agent to a site of pathology to ameliorate disease while limiting exposure at undesired tissues is an aspirational treatment scenario. Targeting diseased kidneys for pharmacologic treatment has had limited success. We designed an approach to target an extracellular matrix protein, the fibronectin extra domain A isoform (FnEDA), which is relatively restricted in distribution to sites of tissue injury. In a mouse unilateral ureteral obstruction (UUO) model of renal fibrosis, injury induced significant upregulation of FnEDA in the obstructed kidney. Using dual variable domain Ig (DVD-Ig) technology, we constructed a molecule with a moiety to target FnEDA and a second moiety to neutralize TGF-ß After systemic injection of the bispecific TGF-ß + FnEDA DVD-Ig or an FnEDA mAb, chemiluminescent detection and imaging with whole-body single-photon emission computed tomography (SPECT) revealed significantly higher levels of each molecule in the obstructed kidney than in the nonobstructed kidney, the ipsilateral kidney of sham animals, and other tissues. In comparison, a systemically administered TGF-ß mAb accumulated at lower concentrations in the obstructed kidney and exhibited a more diffuse whole-body distribution. Systemic administration of the bispecific DVD-Ig or the TGF-ß mAb (1-10 mg/kg) but not the FnEDA mAb attenuated the injury-induced collagen deposition detected by immunohistochemistry and elevation in Col1a1, FnEDA, and TIMP1 mRNA expression in the obstructed kidney. Overall, systemic delivery of a bispecific molecule targeting an extracellular matrix protein and delivering a TGF-ß mAb resulted in a relatively focal uptake in the fibrotic kidney and reduced renal fibrosis.

Longitudinal Changes in Measured Glomerular Filtration Rate, Renal Fibrosis and Biomarkers in a Rat Model of Type 2 Diabetic Nephropathy.

BACKGROUND: Obese ZSF-1 rats display many features of human type II diabetes including nephropathy (DN). The study aimed to further understand the relevance of this model to DN, for which glomerular filtration rate (GFR), renal fibrosis and several urinary/tissue biomarkers was followed over 24 weeks in ZSF-1 rats. METHODS: Intact/sham or uninephrectomized male and female ZSF-1 rats were studied. GFR was measured by transdermal clearance of fluorescein isothiocyanate-sinistrin. Urine was collected every 2-4 weeks for biomarker analysis. Renal tissue was examined histologically for fibrosis and for levels of inflammatory and fibrotic genes. RESULTS: Male obese ZSF-1 rats demonstrated metabolic syndrome and proteinuria. Female counterparts were hyperlipidemic with delayed proteinuria, but were not hyperglycemic. Kidney hyperfiltration was observed in male obese rats in weeks 2-4 after surgery, and subsequently declined to levels significantly lower than controls. Tubulointerstitial/glomerular fibrosis in male obese rats was significantly elevated by week 12 post surgery and continued to expand in the ensuing weeks, particularly in uninephrectomized rats. Female rats had less severe fibrosis. Except for epidermal growth factor which decreased, the levels of several key inflammatory, injury and fibrotic factors were elevated in both tissue (mRNA) and urine (protein) of male obese rats. CONCLUSION: Male obese ZSF-1 rats represent an important DN model, manifesting key pathophysiological features including metabolic syndrome, proteinuria, progressive tubular and glomerular fibrosis, and transient hyperfiltration followed by progressive decline in renal function. Uninephrectomy significantly accelerated disease progression. Females were less severe in disease manifestation. Several urinary and tissue biomarkers were identified in the male obese rats that tracked with disease progression.

A-306989, an inhibitor of adenosine kinase, is renoprotective in rodent models of podocyte, basement membrane, and obstructive injury.

Adenosine (ADO) is an important regulatory purine nucleoside that accumulates at sites of inflammation and tissue injury including in diseases associated with renal pathology. Endogenous levels of ADO may be increased by inhibiting the ADO-metabolizing enzyme, ADO kinase (AK). AK inhibitors have demonstrated protection in rodent models of diabetic nephropathy. To further investigate AK inhibition as a potential mechanism for renal protection, A-306989, a potent non-nucleoside AK inhibitor, was examined in both in vitro and in vivo assays of renal injury. A-306989 prevented podocyte damage (disruption of actin cytoskeleton) and increased podocyte survival following puromycin aminonucleoside (PAN) application in both mouse and human conditionally immortalized podocytes. Prophylactic oral administration of A-306989 (1.5, 5 and 15mg/kg) reduced proteinuria in a dose-dependent manner and repressed pro-inflammatory/fibrotic gene up-regulation; A-306989 was also efficacious when administered two days following the PAN-insult. A-306989 (10 and 30mg/kg) also significantly reduced proteinuria and macrophage infiltration in a rat model of glomerulonephritis. Finally, A-306989 (15 and 50mg/kg) reduced the expression levels of pro-inflammatory/fibrotic genes, and reduced macrophage infiltration (50mg/kg), but did not affect the deposition of interstitial collagen in fibrotic kidneys from mice with unilateral ureter obstruction. A-306989 also had beneficial actions on "quality of life" measures including improving body weight loss. Thus, these data indicate that enhancement of endogenous ADO levels by A-306989 can positively modulate renal pathology and mimic some of the previously reported beneficial actions of ADO A2A receptor agonists.

Validation of the Face Name Associative Memory Exam in cognitively normal older individuals.

The recently developed Face Name Associative Memory Exam (FNAME), a challenging paired associative learning task, shows promise in detecting the subtle cognitive changes characteristic of preclinical Alzheimer's disease. In this study, we evaluated the validity and reliability of the FNAME in 210 cognitively normal older individuals (58-90 years of age). Construct validity of the measure was assessed by principal components analysis, which revealed two independent factors. Correlations between the FNAME subtests and another episodic memory test were significant. The results indicated strong test-retest reliability in a subsample (n = 41). Normative data stratified by age were also generated.

Kohler's Disease.

We present a pediatric case report of foot pain due to Kohler's disease.

Soluble epoxide hydrolase contamination of specific catalase preparations inhibits epoxyeicosatrienoic acid vasodilation of rat renal arterioles.

Cytochrome P-450 metabolites of arachidonic acid, the epoxyeicosatrienoic acids (EETs) and hydrogen peroxide (H(2)O(2)), are important signaling molecules in the kidney. In renal arteries, EETs cause vasodilation whereas H(2)O(2) causes vasoconstriction. To determine the physiological contribution of H(2)O(2), catalase is used to inactivate H(2)O(2). However, the consequence of catalase action on EET vascular activity has not been determined. In rat renal afferent arterioles, 14,15-EET caused concentration-related dilations that were inhibited by Sigma bovine liver (SBL) catalase (1,000 U/ml) but not Calbiochem bovine liver (CBL) catalase (1,000 U/ml). SBL catalase inhibition was reversed by the soluble epoxide hydrolase (sEH) inhibitor tAUCB (1 µM). In 14,15-EET incubations, SBL catalase caused a concentration-related increase in a polar metabolite. Using mass spectrometry, the metabolite was identified as 14,15-dihydroxyeicosatrienoic acid (14,15-DHET), the inactive sEH metabolite. 14,15-EET hydrolysis was not altered by the catalase inhibitor 3-amino-1,2,4-triazole (3-ATZ; 10-50 mM), but was abolished by the sEH inhibitor BIRD-0826 (1-10 µM). SBL catalase EET hydrolysis showed a regioisomer preference with greatest hydrolysis of 14,15-EET followed by 11,12-, 8,9- and 5,6-EET (V(max) = 0.54 ± 0.07, 0.23 ± 0.06, 0.18 ± 0.01 and 0.08 ± 0.02 ng DHET·U catalase(-1)·min(-1), respectively). Of five different catalase preparations assayed, EET hydrolysis was observed with two Sigma liver catalases. These preparations had low specific catalase activity and positive sEH expression. Mass spectrometric analysis of the SBL catalase identified peptide fragments matching bovine sEH. Collectively, these data indicate that catalase does not affect EET-mediated dilation of renal arterioles. However, some commercial catalase preparations are contaminated with sEH, and these contaminated preparations diminish the biological activity of H(2)O(2) and EETs.

Instrumental activities of daily living impairment is associated with increased amyloid burden.

BACKGROUND/AIMS: Instrumental activities of daily living (IADL) impairment in Alzheimer's disease has been associated with global amyloid deposition in postmortem studies. We sought to determine whether IADL impairment is associated with increased cortical Pittsburgh Compound B (PiB) retention. METHODS: Fifty-five subjects (19 normal older controls, NC, and 36 with mild cognitive impairment, MCI) underwent clinical assessments and dynamic PiB positron emission tomography imaging. RESULTS: A linear multiple regression model showed that greater IADL impairment was associated with greater global PiB retention in all subjects (R(2) = 0.40; unstandardized partial regression coefficient, ß = 5.8; p = 0.0002) and in MCI subjects only (R(2) = 0.28; ß = 6.1; p = 0.003), but not in NC subjects only. CONCLUSION: These results suggest that daily functional impairment is related to greater amyloid burden in MCI.

Face-name associative memory performance is related to amyloid burden in normal elderly.

Cerebral amyloid beta (Aß) deposition occurs in a substantial fraction of cognitively normal (CN) older individuals. However, it has been difficult to reliably detect evidence of amyloid-related cognitive alterations in CN using standard neuropsychological measures. We sought to determine whether a highly demanding face-name associative memory exam (FNAME) could detect evidence of Aß-related memory impairment in CN. We studied 45 CN subjects (mean age=71.7 ± 8.8) with Clinical Dementia Rating (CDR) scores=0 and MMSE ≥ 28, using Positron Emission Tomography with Pittsburgh Compound B (PiB PET). Memory factor scores were derived from a principal components analysis for FNAME name retrieval (FN-N), FNAME occupation retrieval (FN-O) and the 6-Trial Selective Reminding Test (SRT). Using multiple linear and logistic regression analyses, we related the memory factor scores to PiB distribution volume ratios (DVR, cerebellar reference) as either a continuous or a dichotomous variable in frontal cortex and a posterior cortical region representing the precuneus, posterior cingulate and lateral parietal cortices (PPCLP), co-varying for age and AMNART IQ (a proxy of cognitive reserve (CR)). A significant inverse relationship for FN-N was found with Aß deposition in frontal (R(2)=0.29, ß=-2.2, p=0.02) and PPCLP cortices (R(2)=0.26, ß=-2.4, p=0.05). In contrast, neither FN-O nor the SRT were significantly related to Aß deposition. Performance on a demanding test of face-name associative memory was related to Aß burden in brain regions associated with memory systems. Associative memory for faces and names, a common complaint among older adults, may be a sensitive marker of early Aß-related impairment.

Tracheal intubation practice and maintaining skill competency: survey of pediatric emergency department medical directors.

PURPOSE: One of the most critical resuscitation skills in pediatric emergency medicine is establishing and maintaining a patent airway. This often requires tracheal intubation (TI). The purpose of this survey study was to determine the practice of TI in pediatric emergency departments (PEDs) and the methods used by PED medical directors to maintain TI competency among PED physicians. METHODS: This is an observational survey study. Medical directors of PEDs were surveyed through e-mail (http://web-online-surveys.com). There were 20 survey questions: 4 yes/no and 16 multiple choice. RESULTS: Of the 108 PED medical directors who were surveyed, 61 (57%) completed the questionnaire. The mean number of TI per PED for 1 year was 63.7; SD, 79.3; median, 37; range, 3 to 400. The mean percentage of TI that were rapid sequence intubations was 76%; SD, 19.8%; median, 83%; range, 30% to 100%. The physician types most commonly performing TI on nontrauma versus trauma patients were as follows: pediatric emergency medicine, 50 (82%) versus 43 (70%); emergency medicine, 4 (7%) versus 4 (7%); and anesthesiology, 1 (2%) versus 4 (7%). The physician types most commonly consulted for difficult airway patients were: anesthesiology, 40 (66%); and pediatric critical care, 14 (23%). Alternative or rescue airway equipment/procedures available to PED were as follows: laryngeal mask airway (LMA), 50 (90%); needle cricothyroidotomy, 47 (77%); fiberoptic scope, 34 (56%); and tracheal tube introducer, 22 (36%). There were 38 (62%) PED medical directors who judged the number of TI opportunities to be inadequate to maintain TI competency among their physicians. The following activities reported as required for remedial training or to maintain TI competency were: pediatric advanced life support/advanced pediatric life support courses, 42 (69%); simulation training, 29 (48%); perform TI under the supervision of an anesthesiologist, 23 (38%); advance airway course, 21 (34%); and/or none, 1 (2%). CONCLUSIONS: Most PED TI for both nontrauma and trauma patients were performed by PED physicians. Most of these were rapid sequence intubations. The number of TI per PED had a large range. Most PED medical directors judged this number to be inadequate to maintain TI competency. Didactic activities to maintain TI skills were most common, but many other activities were used.