Clinical characteristics and outcomes of adrenal hemorrhage.

BACKGROUND: Although uncommon, adrenal hemorrhage has multiple etiologies. Because clinical characteristics, management, and outcomes of patients with adrenal hemorrhage are inadequately described, we examined the underlying etiology, need for intervention, evolution of imaging characteristics, and adequacy of subsequent evaluation. METHODS: We performed a retrospective review of patients diagnosed with adrenal hemorrhage (radiologist-confirmed density consistent with hemorrhage on computed tomography) from 2005 to 2021 at a university-based institution. Demographic characteristics, hemorrhage etiology, and subsequent follow-up were analyzed. RESULTS: Of 193 adrenal hemorrhage patients, the mean age was 49.2 ± 18.3 years, and 35% were female. Clinical presentations included trauma (47%), abdominal or flank pain (28%), incidental findings on imaging acquired for other reasons (12%), postoperative complication (8%), or shock (3%). Hemorrhage outside of the gland was present in 62% of patients. Unilateral hemorrhage was more frequent (93%) than bilateral (7%). A total of 12% of patients had nodules, but only 70% of these were identified on initial imaging, and only 43% had hormonal evaluation. Of 7 patients who had adrenalectomy or biopsy, pathology was either benign (57%) or nonadrenal malignancy (43%). No adrenocortical carcinomas were identified. Follow-up imaging was performed in 56% of patients and revealed decreased, stable, resolved, or increased adrenal hemorrhage size in 39%, 19%, 30%, and 12% of patients, respectively. CONCLUSION: Adrenal hemorrhage is secondary to multiple etiologies, most commonly trauma. In the setting of adrenal hemorrhage, many adrenal nodules were not identified on initial imaging. Only a minority of patients with nodules underwent "complete" biochemical evaluation. Follow-up imaging may improve the identification of underlying nodules needing hormonal evaluation.

Effect of family cohesion on oral health predictors in children and adolescents: A systematic review.

OBJECTIVE: The family environment influences oral health conditions and the utilization of dental services. The emotional link between the family members and the degree to which they are resilient and close to each other is represented as family cohesion and adaptability. This systematic review critically appraises and synthesizes existing evidence on the effect of family cohesion on oral health predictors in children and adolescents. METHODS: The protocol was registered in PROSPERO (CRD42023453608). Databases such as PubMed, Embase, and Scopus were electronically searched in September 2023. No restriction of time frame was allowed. Risk of bias was assessed using the Agency for Healthcare Research and Quality tool. RESULTS: Initially, 272 records were identified from PubMed (133), Embase (122) and Scopus (10) databases and other sources, finally leading to 12 cross-sectional studies to be included. Eleven studies were carried out in Brazil and one in USA. Only one study reported moderate risk, whereas the others all reported low risk of bias. The studies were carried out from 2013-2023. The frequency of dental visits, oral health literacy, and self-perceived need for dental treatment were reported to be higher in families with the better cohesive ties. An inconsistent direct association was reported between dental caries and family cohesion. CONCLUSIONS: Family dynamics are important in shaping oral health behaviors and outcomes during a pivotal phase of development. Further exploration through longitudinal studies in this field can elucidate causal pathways and potential moderators.

Pleuroparenchymal fibroelastosis as a late complication of childhood cancer therapy: A case series.

Pleuroparenchymal fibroelastosis (PPFE) is a rare interstitial pneumonia with distinct clinicopathologic features. It has been associated with exposure to hematopoietic stem cell transplantation (HSCT) and classical alkylating agents. Here, we highlight PPFE as a late complication of childhood cancer therapy by describing the cases of four survivors of childhood cancer with a diagnosis of treatment-related PPFE. All patients received high-dose alkylating agents. PPFE should be considered in the differential diagnosis of restrictive lung disease in patients with history of exposure to alkylating agents or HSCT. Development of PPFE-specific, noninvasive diagnostic tools and disease-modifying therapies will clinically benefit these patients.

Clozapine-laden carbon dots delivered to the brain via an intranasal pathway: Synthesis, characterization, ex vivo, and in vivo studies.

Clozapine, which is widely used to treat schizophrenia, shows low bioavailability due to poor solubility and high first-pass metabolism. The study aimed to design clozapine-loaded carbon dots (CDs) to enhance availability of the clozapine to the brain via intranasal pathway. The CDs were synthesized by pyrolysis of citric acid and urea at 200 °C by hydrothermal technique and characterized by photoluminescence, transmission electron microscopy (TEM), X-ray Photoelectron Spectrometer (XPS), and Fourier transform infrared spectrum (FTIR). The optimized clozapine-loaded CDs (CLZ-CDs-1:3-200) showed a quasi-spherical shape (9-12 nm) with stable blue fluorescence. The CDs showed high drug solubilization capacity (1.5 mg drug in 1 mg/ml CDs) with strong electrostatic interaction with clozapine (drug loading efficiency = 94.74%). The ex vivo release study performed using nasal goat mucosa showed sustained release of clozapine (43.89%) from CLZ-CDs-1:3-200 for 30 h. The ciliotoxicity study (histopathology) confirmed no toxicity to the nasal mucosal tissues using CDs. In the rat model (in vivo pharmacokinetic study), when CDs were administrated by the intranasal route, a significantly higher concentration of clozapine in the brain tissue (Cmax = 58.07 ± 5.36 µg/g and AUCt (µg/h*g) = 105.76 ± 12.31) was noted within a short time (tmax = 1 h) compared to clozapine suspension administered by intravenous route (Cmax = 20.99 ± 3.91 µg/g, AUC t (µg/h*g) = 56.89 ± 12.31, and tmax = 4 h). The high value of drug targeting efficiency (DTE, 486%) index and direct transport percentage (DTP, 58%) indicates the direct entry of clozapine-CDs in the brain via the olfactory route. In conclusion, designed CDs demonstrated a promising dosage form for targeted nose-to-brain delivery of clozapine for the effective treatment of schizophrenia.

Bioengineered in vitro three-dimensional tumor models in endocrine cancers.

Abstract: Endocrine tumors are a heterogeneous cluster of malignancies that originate from cells that can secrete hormones. Examples include, but are not limited to, thyroid cancer, adrenocortical carcinoma, and neuroendocrine tumors. Many endocrine tumors are relatively slow to proliferate, and as such, they often do not respond well to common antiproliferative chemotherapies. Therefore, increasing attention has been given to targeted therapies and immunotherapies in these diseases. However, in contrast to other cancers, many endocrine tumors are relatively rare, and as a result, less is understood about their biology, including specific targets for intervention. Our limited understanding of such tumors is in part due to a limitation in model systems that accurately recapitulate and enable mechanistic exploration of these tumors. While mouse models and 2D cell cultures exist for some endocrine tumors, these models often may not accurately model nuances of human endocrine tumors. Mice differ from human endocrine physiology and 2D cell cultures fail to recapitulate the heterogeneity and 3D architectures of in vivo tumors. To complement these traditional cancer models, bioengineered 3D tumor models, such as organoids and tumor-on-a-chip systems, have advanced rapidly in the past decade. However, these technologies have only recently been applied to most endocrine tumors. In this review we provide descriptions of these platforms, focusing on thyroid, adrenal, and neuroendocrine tumors and how they have been and are being applied in the context of endocrine tumors.

Sign language based educational interventions vs. other educational interventions to improve the oral health of hearing-impaired individuals: A systematic review and meta-analysis.

OBJECTIVE: Individuals with special needs requiring special care are more vulnerable to oral health problems. Sign language is a communication medium and language of instruction for individuals with hearing impairments. The purpose of this systematic review and meta-analysis was to assess the effectiveness of sign language-based educational interventions compared to other educational interventions in improving the oral health of hearing-impaired individuals. METHODS: PubMed, Scopus, Embase, and Cochrane Central Register of Controlled Trials databases were searched without any restriction on the publication date. Analytical and experimental studies that evaluated and compared the effectiveness of sign language with other educational intervention groups such as videos, posters etc were included. RESULTS: Initially, 5568 records were identified. Three relevant publications from India were eligible and included in the systematic review and meta-analysis. Differences were reported in favour of sign language over other interventions concerning plaque status, gingival health, and oral hygiene status. CONCLUSION: Sign language-based interventions were found to be effective. However, further studies in different locations and populations are required to support their effectiveness.

Heterogeneous parathyroid near-infrared autofluorescence patterns are associated with single adenomas in primary hyperparathyroidism.

BACKGROUND: Primary adenoma (PA) and multi-gland hyperplasia (MGH) account for 85% and 15% of primary hyperparathyroidism (PHPT) cases, respectively. Near-infrared autofluorescence (NIRAF) enhances intraoperative parathyroid identification. We hypothesized that PA would display a more heterogeneous NIRAF pattern compared to MGH. METHODS: Patients undergoing surgery for sporadic PHPT were categorized based on the presence of PA or MGH. To quantify heterogeneity, we utilized ratios of (1) mean parathyroid gland (PG) NIRAF over background NIRAF (mean ratio), (2) minimum and (3) maximum PG NIRAF over mean PG NIRAF (minimum and maximum ratios). Additionally, a heterogeneity score was quantified using mean ratio (mean PG NIRAF over background NIRAF), and overall NIRAF (mean NIRAF of eight random 15 × 15 pixel areas). A point was assigned to ratios <0.8 or >1.2. Images were quantified by ImageJ software. Mann-Whitney test was performed for all comparisons. RESULTS: Of 78 patients, 63 had a single PA and 15 had MGH, totaling 102 PGs. There was no difference between their mean ratios. PA had a lower minimum ratio compared to that of MGH (0.86 ± 0.01 vs. 0.93 ± 0.01, p = 0.001) and a brighter maximum ratio (1.21 ± 0.02 vs. 1.12 ± 0.01, p = 0.0008). PA also scored higher on their heterogeneity scores compared to MGH (1.27 ± 0.23 vs. 0.33 ± 0.15, p = 0.001). CONCLUSION: Single parathyroid adenomas display a more heterogeneous autofluorescence pattern compared to that of multi-gland hyperplasia. Intraoperative characterization of PGs by real-time NIR imaging patterns may be a beneficial adjunct during parathyroid surgery.

Texture analysis using Horadam polynomial coefficient estimate for the class of Sakaguchi kind function.

This present work provides the initial co-efficient bounds of the function f(z) which is defined in open unit disk [Formula: see text]. We introduced bi-univalent class [Formula: see text]. Making use of Horadam polynomials [Formula: see text] and the generating function [Formula: see text], we estimated the bounds of [Formula: see text] and [Formula: see text] for the given function to be in the defined class. Moreover Fekete-Szego inequalities are calculated. In addition to all the results obtained mathematically, we provide application for Horadam polynomial in computer vision.

A 3D adrenocortical carcinoma tumor platform for preclinical modeling of drug response and matrix metalloproteinase activity.

Adrenocortical carcinoma (ACC) has a poor prognosis, and no new drugs have been identified in decades. The absence of drug development can partly be attributed to a lack of preclinical models. Both animal models and 2D cell cultures of ACC fail to accurately mimic the disease, as animal physiology is inherently different than humans, and 2D cultures fail to represent the crucial 3D architecture. Organoids and other small 3D in vitro models of tissues or tumors can model certain complexities of human in vivo biology; however, this technology has largely yet to be applied to ACC. In this study, we describe the generation of 3D tumor constructs from an established ACC cell line, NCI-H295R. NCI-H295R cells were encapsulated to generate 3D ACC constructs. Tumor constructs were assessed for biomarker expression, viability, proliferation, and cortisol production. In addition, matrix metalloproteinase (MMP) functionality was assessed directly using fluorogenic MMP-sensitive biosensors and through infusion of NCI-H295R cells into a metastasis-on-a-chip microfluidic device platform. ACC tumor constructs showed expression of biomarkers associated with ACC, including SF-1, Melan A, and inhibin α. Treatment of ACC tumor constructs with chemotherapeutics demonstrated decreased drug sensitivity compared to 2D cell culture. Since most tumor cells migrate through tissue using MMPs to break down extracellular matrix, we validated the utility of ACC tumor constructs by integrating fluorogenic MMP-sensitive peptide biosensors within the tumor constructs. Lastly, in our metastasis-on-a-chip device, NCI-H295R cells successfully engrafted in a downstream lung cell line-based construct, but invasion distance into the lung construct was decreased by MMP inhibition. These studies, which would not be possible using 2D cell cultures, demonstrated that NCI-H295R cells secreted active MMPs that are used for invasion in 3D. This work represents the first evidence of a 3D tumor constructs platform for ACC that can be deployed for future mechanistic studies as well as development of new targets for intervention and therapies.

Metabolic engineering of E. coli for ß-alanine production using a multi-biosensor enabled approach.

ß-alanine is an important biomolecule used in nutraceuticals, pharmaceuticals, and chemical synthesis. The relatively eco-friendly bioproduction of ß-alanine has recently attracted more interest than petroleum-based chemical synthesis. In this work, we developed two types of in vivo high-throughput screening platforms, wherein one was utilized to identify a novel target ribonuclease E (encoded by rne) as well as a redox-cofactor balancing module that can enhance de novo ß-alanine biosynthesis from glucose, and the other was employed for screening fermentation conditions. When combining these approaches with rational upstream and downstream module engineering, an engineered E. coli producer was developed that exhibited 3.4- and 6.6-fold improvement in ß-alanine yield (0.85 mol ß-alanine/mole glucose) and specific ß-alanine production (0.74 g/L/OD600), respectively, compared to the parental strain in a minimal medium. Across all of the strains constructed, the best yielding strain exhibited 1.08 mol ß-alanine/mole glucose (equivalent to 81.2% of theoretic yield). The final engineered strain produced 6.98 g/L ß-alanine in a batch-mode bioreactor and 34.8 g/L through a whole-cell catalysis. This approach demonstrates the utility of biosensor-enabled high-throughput screening for the production of ß-alanine.

Adrenal Near-Infrared Autofluorescence.

Context: Parathyroid tissue is one of the few tissues to have strong near-infrared (NIR) autofluorescence, which has been exploited to improve intraoperative parathyroid identification. The US Food and Drug Administration has approved 2 devices for this purpose. Adrenal glands can be difficult to distinguish from surrounding fat, an issue during total adrenalectomy. Objective: We hypothesized adrenal tissue may also possess considerable NIR autofluorescence. Methods: Resected patient adrenal specimens were examined after robotic adrenalectomy with an NIR camera intraoperatively. Patients did not receive fluorescent dye. Images were taken of both gross and sectioned specimens. Post hoc image analysis was performed with ImageJ software. Confocal microscopy was performed on selected tissues using immunofluorescence and hematoxylin-eosin staining. Results: Resected tissue was examined from 22 patients undergoing surgery for pheochromocytomas (6), primary aldosteronism (3), adrenocorticotropin-independent hypercortisolism (10), and a growing or suspicious mass (3). Normal adrenal tissue demonstrated strong NIR autofluorescence. The intensity ratio compared to background (set as 1) for gross images was 2.03 ±â€…0.51 (P < .0001) compared to adjacent adipose of 1.24 ±â€…0.18. Autofluorescence from adrenal tumors was also detected at variable levels of intensity. Cortisol-producing tumors had the highest fluorescence ratio of 3.01 ±â€…0.41. Confocal imaging localized autofluorescence to the cytosol, with the highest intensity in the zona reticularis followed by the zona fasciculata. Conclusion: Normal and abnormal adrenal tissues possess natural NIR autofluorescence. Highest autofluorescence levels were associated with cortisol-producing tumors. Confocal imaging demonstrated the highest intensity in the zona reticularis. NIR cameras may have the potential to improve identification of adrenal tissue during surgery.

Smaller parathyroids have higher near-infrared autofluorescence intensity in hyperparathyroidism.

BACKGROUND: Intraoperative parathyroid gland identification can be challenging. Parathyroid glands have an intrinsic autofluorescence when excited by wavelengths in the near-infrared region. Studies using near-infrared cameras to detect parathyroid gland near-infrared autofluorescence have suggested improved identification. The pathologic parathyroid glands in primary hyperparathyroidism have variable near-infrared autofluorescence intensity, but how this correlates with different characteristics of hyperparathyroidism is unknown. Our objective was to correlate the fluorescent intensity of excited glands with clinical variables to enhance a surgeon's ability to identify parathyroid glands. METHODS: The data on patients undergoing surgery for primary hyperparathyroidism were collected. The images were collected intraoperatively with a handheld near-infrared device and analyzed. The data consisted of the ratio of mean parathyroid gland near-infrared autofluorescence over background (white gauze) near-infrared autofluorescence. The variables assessed for correlation with autofluorescence intensity were gland volume and weight, preoperative serum calcium and parathyroid hormone, age, body mass index, and sex. The images were quantified by Image J software (National Institutes of Health, Bethesda, MD). The lasso regression was analyzed by R version 4.1.3 to calculate adjusted P values (R Foundation for Statistical Computing, Vienna, Austria). RESULTS: From 2017 to 2021, 131 patients with primary hyperparathyroidism underwent parathyroidectomies of 151 parathyroid glands. The mean near-infrared autofluorescence intensity of parathyroid glands had a negative correlation with weight with lighter glands fluorescing more (P = .019) and a positive correlation with age with glands from older patients fluorescing more (P = .013). There were no significant correlations with preoperative serum calcium and parathyroid hormone, body mass index, and sex (P > .05). CONCLUSION: In patients with primary hyperparathyroidism, we found that autofluorescence intensity correlated with parathyroid gland weight and patient age. This suggested that near-infrared camera use may be particularly helpful in identifying smaller adenomas and in older patients.

Near-infrared Autofluorescence Features of Parathyroid Carcinoma.

Introduction: Parathyroid carcinoma is very rare, and intraoperative definitive diagnosis can be elusive with currently available diagnostics. Near-infrared (NIR) autofluorescence is an emerging tool that identifies parathyroid glands in real time. It is not known whether NIR autofluorescence can detect parathyroid carcinoma intraoperatively. Methods: Patients with preoperative suspicion for parathyroid carcinoma were identified from ongoing studies examining parathyroid autofluorescence with a NIR camera and probe. Specimens from these patients were examined intraoperatively to determine their autofluorescence patterns. Results: Three patients with suspected parathyroid carcinoma were identified preoperatively. Intraoperative NIR autofluorescence imaging showed a relative lack of autofluorescence for all cases, in contrast to parathyroid adenomas and normal parathyroid glands, which typically exhibit significant autofluorescence. Final pathology confirmed parathyroid carcinoma in all cases. Conclusion: Parathyroid carcinoma can be difficult to confirm prior to final pathology review. Our 3 cases suggest that absence of NIR autofluorescence may suggest the likelihood of parathyroid carcinoma, but more studies are needed to investigate this experience.

Ethics Consultation Requests After Implementation of an Electronic Health Record Order.

PURPOSE: As the role of clinical ethics consultation in health care advances, there are calls to standardize the process of consultation. The Ethics Committee at Memorial Sloan Kettering Cancer Center (MSK) hypothesized that the process of requesting an ethics consultation could be improved by instituting an electronic health record (EHR) order for consultation requests. This report summarizes the impact of adopting an EHR order for ethics consultation requests at MSK. METHODS: This retrospective review of all clinical ethics consultations requested at a tertiary cancer center from May 2017 to February 2020 spans 17 months before and after implementation of an electronic order for consultation requests. Summary statistics are presented using Pearson chi-square analyses with a significance level of 0.05. RESULTS: There was a significant increase in the total number of consultation requests placed after implementation of the EHR order (n = 165, 0.08% of total patients) compared with before (n = 108, 0.05% of total patients; P = .007). The number of consults requested by providers from inpatient (P = .02) and outpatient (P = .04) settings significantly increased. The proportion of consults placed by medical versus nonmedical providers remained unchanged (P = .32). CONCLUSION: In this large single-institution retrospective study, implementation of an EHR order for ethics consultation requests was associated with a significant increase in the number of consultation requests. Implementation of an electronic order may decrease barriers to ethics consultation in diverse practice settings. Further longitudinal, multicenter studies are needed to assess strategies to improve access to clinical ethics consultation for oncology patients.

Vertical sleeve gastrectomy induces enteroendocrine cell differentiation of intestinal stem cells through bile acid signaling.

Vertical sleeve gastrectomy (VSG) results in an increase in the number of hormone-secreting enteroendocrine cells (EECs) in the intestinal epithelium; however, the mechanism remains unclear. Notably, the beneficial effects of VSG are lost in a mouse model lacking the nuclear bile acid receptor farnesoid X receptor (FXR). FXR is a nuclear transcription factor that has been shown to regulate intestinal stem cell (ISC) function in cancer models. Therefore, we hypothesized that the VSG-induced increase in EECs is due to changes in intestinal differentiation driven by an increase in bile acid signaling through FXR. To test this, we performed VSG in mice that express EGFP in ISC/progenitor cells and performed RNA-Seq on GFP-positive cells sorted from the intestinal epithelia. We also assessed changes in EEC number (marked by glucagon-like peptide-1, GLP-1) in mouse intestinal organoids following treatment with bile acids, an FXR agonist, and an FXR antagonist. RNA-Seq of ISCs revealed that bile acid receptors are expressed in ISCs and that VSG explicitly alters expression of several genes that regulate EEC differentiation. Mouse intestinal organoids treated with bile acids and 2 different FXR agonists increased GLP-1-positive cell numbers, and administration of an FXR antagonist blocked these effects. Taken together, these data indicate that VSG drives ISC fate toward EEC differentiation through bile acid signaling.

Opioid and Sucrose Craving Are Accompanied by Unique Behavioral and Affective Profiles after Extended Abstinence in Male and Female Rats.

Incubation of craving refers to the intensification of drug-seeking behavior in response to reward-paired cues over the course of abstinence. In rodents, craving and drug-seeking behaviors have been measured by an increase in lever pressing in the absence of reinforcer availability in response to cue presentations. However, craving in rodents is difficult to define and little is known about the behavioral signatures that accompany increased drug-seeking behavior measured by lever pressing. The affective components of relapse are also important, but understudied in rodents. Hormonal fluctuations influence craving for psychostimulants, but little is known about the impact of the estrous cycle on opioid-seeking behavior. This study sought to delineate the behavioral and affective signatures associated with craving, and to examine the influence of the female estrous cycle on craving. Male and female rats underwent 10 d of intravenous opioid self-administration. Separate cohorts of control rats self-administered oral sucrose, a natural nondrug reward. Cue-induced seeking tests were conducted after 1 or 30d of forced abstinence. These sessions were recorded and scored for overall locomotion, instances of sniffing, grooming, or hyperactivity. Ultrasonic vocalizations (USVs) were also recorded to determine affective profiles that accompany opioid seeking. Although active lever presses and overall locomotion increased unanimously over extended abstinence from heroin and sucrose, a sex- and reinforcer-specific behavioral and affective signature of craving emerged. Furthermore, although the female estrous cycle did not affect taking or seeking, it appears to influence more granular behaviors.

Ambiguous and Incomplete: Natural Language Processing Reveals Problematic Reporting Styles in Thyroid Ultrasound Reports.

OBJECTIVE: Natural language processing (NLP) systems convert unstructured text into analyzable data. Here, we describe the performance measures of NLP to capture granular details on nodules from thyroid ultrasound (US) reports and reveal critical issues with reporting language. METHODS: We iteratively developed NLP tools using clinical Text Analysis and Knowledge Extraction System (cTAKES) and thyroid US reports from 2007 to 2013. We incorporated nine nodule features for NLP extraction. Next, we evaluated the precision, recall, and accuracy of our NLP tools using a separate set of US reports from an academic medical center (A) and a regional health care system (B) during the same period. Two physicians manually annotated each test-set report. A third physician then adjudicated discrepancies. The adjudicated "gold standard" was then used to evaluate NLP performance on the test-set. RESULTS: A total of 243 thyroid US reports contained 6,405 data elements. Inter-annotator agreement for all elements was 91.3%. Compared with the gold standard, overall recall of the NLP tool was 90%. NLP recall for thyroid lobe or isthmus characteristics was: laterality 96% and size 95%. NLP accuracy for nodule characteristics was: laterality 92%, size 92%, calcifications 76%, vascularity 65%, echogenicity 62%, contents 76%, and borders 40%. NLP recall for presence or absence of lymphadenopathy was 61%. Reporting style accounted for 18% errors. For example, the word "heterogeneous" interchangeably referred to nodule contents or echogenicity. While nodule dimensions and laterality were often described, US reports only described contents, echogenicity, vascularity, calcifications, borders, and lymphadenopathy, 46, 41, 17, 15, 9, and 41% of the time, respectively. Most nodule characteristics were equally likely to be described at hospital A compared with hospital B. CONCLUSIONS: NLP can automate extraction of critical information from thyroid US reports. However, ambiguous and incomplete reporting language hinders performance of NLP systems regardless of institutional setting. Standardized or synoptic thyroid US reports could improve NLP performance.