FIB-4 Reliability in Patients With Severe Obesity: Lower Cutoffs Needed?

BACKGROUND: Liver biopsy is the gold standard to evaluate hepatic fibrosis; however, it has many drawbacks, especially in patients with severe obesity. Noninvasive testing such as the FIB-4 score is increasingly being used as the initial screening tool to identify patients at risk for advanced fibrosis. The broader applicability of FIB-4 and the precision of its cutoff values remain uncertain in metabolic dysfunction-associated steatotic liver disease and patients with severe obesity. Our study explored the correlation between FIB-4 scores and intraoperative liver biopsy in patients with severe obesity undergoing bariatric surgery. METHODS: A total of 632 patients with severe obesity underwent preoperative vibration-controlled transient elastography and intraoperative liver biopsy during bariatric surgery from January 2020 to August 2021. Variables collected included patient demographics, laboratory values, abdominal ultrasound, vibration-controlled transient elastography, and liver biopsy results. ANOVA 1-way test, χ2 tests, and Fisher exact tests were used for quantitative and qualitative variables, respectively. The 95% CIs for the mean FIB-4 scores were used to generate surrogate cutoff values. The proposed FIB-4 cutoffs for F0-1, F2, F3, and F4 were 0.62 (CI: 0.59, 0.64), 0.88 (0.74, 1.01), 1.24 (0.94, 1.54), and 1.53 (0.82, 2.24), respectively. Area under the curve (AUC) methods were used to compare traditional to proposed cutoff values. RESULTS: Applying the traditional FIB-4 cutoffs to approximate advanced fibrosis yielded an AUC of 0.5748. Use of the proposed FIB-4 cutoffs increased the AUC to 0.6899. The proposed FIB-4 cutoffs correctly identified 40 patients with biopsy-proven advanced fibrosis (F3-F4), all of which would have been missed using traditional cutoffs. CONCLUSION: Our study revealed that the use of the currently accepted FIB-4 cutoffs as the screening modality for identifying patients with advanced fibrosis due to metabolic dysfunction-associated steatotic liver disease is insufficient and will result in missing patients with histologically confirmed advanced fibrosis. Use of the revised FIB-4 scores should be considered to diagnose patients with severe obesity at high risk of liver disease progression.

Head and Neck Squamous Cell Carcinoma Biopsies Maintained Ex Vivo on a Perfusion Device Show Gene Changes with Time and Clinically Relevant Doses of Irradiation.

Advancements in 3-Dimensional (3D) culture models for studying disease have increased significantly over the last two decades, but fully understanding how these models represent in vivo still requires further investigation. The current study investigated differences in gene expression between a baseline sample and that maintained on a tissue-on-chip perfusion device for up to 96 h, with and without clinically-relevant doses of irradiation, to allow differentiation of model and treatment effects. Tumour tissue samples from 7 Head and Neck Squamous Cell Carcinomas (HNSCC) patients were sub-divided and either fixed immediately upon excision or maintained in a tissue-on-chip device for 48 and 96 h, with or without 2 Gray (Gy) or 10 Gy irradiation. Gene expression was measured using an nCounter® PanCancer Progression Panel. Differentially expressed genes between pre- and post-ex vivo culture, and control and irradiated samples were identified using nSolver software (version 4.0). The secretome from the tumour-on-chip was analysed for the presence of cytokines using a Proteome Profiler™ platform. Significant numbers of genes both increased (n = 6 and 64) and decreased (n = 18 and 58) in expression in the tissue maintained on-chip for 48 and 96 h, respectively, compared to fresh tissue; however, the irradiation schedule chosen did not induce significant changes in gene expression or cytokine secretion. Although HNSCC tissue maintained ex vivo shows a decrease in a large proportion of altered genes, 25% and 53% (48 and 96 h) do show increased expression, suggesting that the tissue remains functional. Irradiation of tumour tissue-on-chip needs to be conducted for longer time periods for specific gene changes to be observed, but we have shown, for the first time, the feasibility of using this perfusion platform for studying the genomic response of HNSCC tissue biopsies.

An Unusual Case of Primary Gastric Balloon Cell Melanoma.

Most cases of melanoma found in the gastrointestinal tract are the result of metastasis. Although uncommon and only described in isolated case reports, primary gastric melanoma should be considered when patients present with vague gastrointestinal symptoms and a mass is identified on esophagogastroduodenoscopy or imaging. We describe a case of primary gastric balloon cell melanoma in a 73-year-old man who presented with melena. Given the high morbidity and mortality of gastric mucosal melanoma, early diagnosis and initiation of treatment can lead to improved outcomes and survival.

The Use of Tissue-on-Chip Technology to Focus the Search for Extracellular Vesicle miRNA Biomarkers in Thyroid Disease.

Small extracellular vesicles (sEVs) contain microRNAs (miRNAs) which have potential to act as disease-specific biomarkers. The current study uses an established method to maintain human thyroid tissue ex vivo on a tissue-on-chip device, allowing the collection, isolation and interrogation of the sEVs released directly from thyroid tissue. sEVs were analysed for differences in miRNA levels released from benign thyroid tissue, Graves' disease tissue and papillary thyroid cancer (PTC), using miRNA sequencing and quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) to identify potential biomarkers of disease. Thyroid biopsies from patients with benign tissue (n = 5), Graves' disease (n = 5) and PTC (n = 5) were perfused with medium containing sEV-depleted serum for 6 days on the tissue-on-chip device. During incubation, the effluents were collected and ultracentrifuged to isolate sEVs; miRNA was extracted and sequenced (miRNASeq). Out of the 15 samples, 14 passed the quality control and miRNASeq analysis detected significantly higher expression of miR-375-3p, miR-7-5p, miR-382-5p and miR-127-3p in the sEVs isolated from Graves' tissue compared to those from benign tissue (false discovery rate; FDR p < 0.05). Similarly, miR-375-3p and miR-7-5p were also detected at a higher level in the Graves' tissue sEVs compared to the PTC tissue sEVs (FDR p < 0.05). No significant differences were observed between miRNA in sEVs from PTC vs. those from benign tissue. These results were supported by Quantitative Reverse Transcriptase Polymerase Chain Reaction (qRT-PCR). The novel findings demonstrate that the tissue-on-chip technology is a robust method for isolating sEVs directly from the tissue of interest, which has permitted the identification of four miRNAs, with which further investigation could be used as biomarkers or therapeutic targets within thyroid disease.

Breast Cancer Risk Assessment and Management of the High-Risk Patient.

Breast cancer is the most commonly diagnosed nonskin cancer in women. To decrease the breast cancer burden, conserve resources, and decrease unnecessary treatments, guidelines suggest interventions be reserved for those women at greatest risk for disease. Risk assessment incorporating breast cancer risk factors and risk assessment models is of paramount importance in identifying women who have the greatest benefit from risk reduction strategies. Principles of shared decision-making should guide practitioners to incorporate patients' values, goals, and objectives in decisions around genetic testing, pharmacologic intervention, enhanced surveillance, and other risk reduction strategies.

Identification of soluble tissue-derived biomarkers from human thyroid tissue explants maintained on a microfluidic device.

Although a large cohort of potential biomarkers for thyroid cancer aggressiveness have been tested in various formats in recent years, to the best of our knowledge, thyroglobulin and calcitonin remain the only two established biomarkers associated with thyroid cancer management. Our group has recently validated a novel means of maintaining live, human ex vivo thyroid tissue within a tissue-on-chip format. The present pilot study aimed to interrogate the tissue effluent, containing all the soluble markers released by the tissue samples maintained within the devices' tissue chamber, for the presence of markers potentially associated with thyroid cancer aggressiveness. Culture effluent from tissue samples harvested from 19 individual patients who had undergone thyroidectomy for the treatment of suspected thyroid cancer was assessed, first using a proteome profiler™ angiogenesis array kit. Patients were subcategorised as 'aggressive' if they possessed a minimum of N1b level metastases, whilst 'non-aggressive' samples were T3 or lower without evidence of multifocality; and contralateral healthy thyroid tissue was harvested for comparative studies. Levels of Serpin-F1, vascular endothelial growth factor, Thrombospondin-1 and chemokine (C-C motif) ligand were significantly altered and, thus, were further investigated using ELISA to allow for quantitative analysis. The concentration of serpin-F1 was significantly increased in the effluent of aggressive thyroid cancer tissue when compared with levels released by both non-aggressive and benign samples. The present study demonstrated the usability of microfluidic technology for the analysis of the ex vivo tissue secretome in order to identify novel biomarkers.

Current understanding of nonsurgical interventions for refractory differentiated thyroid cancer: a systematic review.

Thyroid cancer incidence and related mortality is increasing year-on-year, and although treatment for early disease with surgery and radioiodine results in a 98% 5-year survival rate, recurrence and treatment refractory disease is evident in an unacceptable number of patients. Alternative treatment regimens have therefore been sought in the form of tyrosine kinase inhibitors, immunotherapy, vaccines, chimeric antigen receptor T-cell therapy and oncolytic viruses. The current review aims to consolidate knowledge and highlight the latest clinical trials using secondary therapies in thyroid cancer treatment, focusing on both in vitro and in vivo studies, which have investigated therapies other than radioiodine.

Chronic Stress and Preconception Health Among Latina Women in Metro Atlanta.

BACKGROUND: Underserved subgroups are less likely to have optimal health prior to pregnancy. We describe preconception health indicators (behavior, pregnancy intention, and obesity) among pregnant Latina women with and without chronic stress in metro Atlanta. DESIGN: We surveyed 110 pregnant Latina women enrolled in prenatal care at three clinics in Atlanta. The survey assessed chronic stress, pregnancy intention, preconception behavior changes (taking folic acid or prenatal vitamins, seeking healthcare advice, any reduction in smoking or drinking), and previous trauma. RESULTS: Specific behaviors to improve health prior to pregnancy were uncommon (e.g., taking vitamins (25.5%) or improving nutrition (20.9%)). Just under half of women were experiencing a chronic stressor at the time of conception (49.5%). Chronically stressed women were more likely to be obese (aOR: 3.0 (1.2, 7.4)), less likely to intend their pregnancy (aOR: 0.3 (0.1, 0.7)), and possibly less likely to report any PHB (45.5% vs. 57.4%; aOR: 0.5 (0.2-1.1)). CONCLUSIONS: Chronically stress women were less likely to enter prenatal care with optimal health. However, preconception behaviors were uncommon overall.

The Historical, Psychosocial, and Cultural Context of Breastfeeding in the African American Community.

Breastfeeding provides a range of benefits for the infant's growth, immunity, and development. It also has health benefits for the mother, including a reduced risk of premenopausal breast cancer, earlier return to prepregnancy weight, reduction of postpartum bleeding, and reduced risk of osteoporosis. There are a number of complex factors that influence the decision to initiate and continue breastfeeding, including those "external" to women, such as cultural beliefs. The cultural context and environment of decision making are illuminated through the prism of traditions and historical and cultural events. The ideology and sentiment of breastfeeding have changed during the course of history and have evolved within the African American community. Throughout the evolution of infant feeding practices, historical aftermaths have contributed to the legacy and emotional context of infant feeding trends. The tradition of wet nursing for African American women is inherently linked to white supremacy, slavery, medical racism and the physical, emotional, and mental abuse that enslaved African American women endured. Thus, the decision to breastfeed and the act of breastfeeding may remain deeply affected by the generational trauma of wet nursing during slavery. The associated negative connotation of wet nursing, slavery, and medical exploitation is one of the many nuanced cultural barriers that denies Black women and infants the many health benefits of breastfeeding.

The Changing Face of in vitro Culture Models for Thyroid Cancer Research: A Systematic Literature Review.

Background: Thyroid cancer is the most common endocrine malignancy worldwide. Primary treatment with surgery and radioactive iodine is usually successful, however, there remains a small proportion of thyroid cancers that are resistant to these treatments, and often represent aggressive forms of the disease. Since the 1950s, in vitro thyroid culture systems have been used in thyroid cancer research. In vitro culture models have evolved from 2-dimensional thyrocyte monolayers into physiologically functional 3-dimensional organoids. Recently, research groups have utilized in vitro thyroid cancer models to identify numerous genetic and epigenetic factors that are involved with tumorigenesis as well as test the efficacy of cytotoxic drugs on thyroid cancer cells and identify cancer stem cells within thyroid tumors. Objective of Review: The objective of this literature review is to summarize how thyroid in vitro culture models have evolved and highlight how in vitro models have been fundamental to thyroid cancer research. Type of Review: Systematic literature review. Search Strategy: The National Institute for Health and Care Excellence (NICE) Healthcare and Databases Advanced Search (HDAS) tool was used to search EMBASE, Medline and PubMed databases. The following terms were included in the search: "in vitro" AND "thyroid cancer". The search period was confined from January 2008 until June 2019. A manual search of the references of review articles and other key articles was also performed using Google Scholar. Evaluation Method: All experimental studies and review articles that explicitly mentioned the use of in vitro models for thyroid cancer research in the title and/or abstract were considered. Full-text versions of all selected articles were evaluated. Experimental studies were reviewed and grouped according to topic: genetics/epigenetics, drug testing/cancer treatment, and side populations (SP)/tumor microenvironment (TME). Results: Three thousand three hundred and seventy three articles were identified through database and manual searches. One thousand two hundred and sixteen articles remained after duplicates were removed. Five hundred and eighty nine articles were excluded based on title and/or abstract. Of the remaining 627 full-text articles: 24 were review articles, 332 related to genetic/epigenetics, 240 related to drug testing/treatments, and 31 related to SP/TME. Conclusion: In vitro cell culture models have been fundamental in thyroid cancer research. There have been many advances in culture techniques- developing complex cellular architecture that more closely resemble tumors in vivo. Genetic and epigenetic factors that have been identified using in vitro culture models can be used as targets for novel drug therapies. In the future, in vitro systems will facilitate personalized medicine, offering bespoke treatments to patients.

Comparison of Opioid Medication Use after Conventional Chemoembolization versus Drug-Eluting Embolic Chemoembolization.

PURPOSE: To assess the use of opioid analgesics and/or antiemetic drugs for pain and nausea following selective chemoembolization with doxorubicin-based conventional (c)-transarterial chemoembolization versus drug-eluting embolic (DEE)-transarterial chemoembolization for hepatocellular carcinoma (HCC). MATERIALS AND METHODS: From October 2014 to 2016, 283 patients underwent 393 selective chemoembolization procedures including 188 patients (48%) who underwent c-transarterial chemoembolization and 205 (52%) who underwent DEE-transarterial chemoembolization. Medical records for all patients were retrospectively reviewed. Administration of postprocedural opioid and/or antiemetic agents were collated. Time of administration was stratified as phase 1 recovery (0-6 hours) and observation (6-24 hours). Logistic regression model was used to investigate the relationship of transarterial chemoembolization type and use of intravenous and/or oral analgesic and antiemetic medications while controlling for other clinical variables. RESULTS: More patients treated with DEE-transarterial chemoembolization required intravenous analgesia in the observation (6-24 hours) phase (18.5%) than those treated with c-transarterial chemoembolization (10.6%; P = .033). Similar results were noted for oral analgesic agents (50.2% vs. 31.4%, respectively; P < .001) and antiemetics (17.1% vs. 7.5%, respectively; P = .006) during the observation period. Multivariate regression models identified DEE-transarterial chemoembolization as an independent predictor for oral analgesia (odds ratio [OR], 1.84; P = .011), for intravenous and oral analgesia in opioid-naïve patients (OR, 2.46; P = .029) and for antiemetics (OR, 2.56; P = .011). CONCLUSIONS: Compared to c-transarterial chemoembolization, DEE-transarterial chemoembolization required greater amounts of opioid analgesic and antiemetic agents 6-24 hours after the procedure. Surgical data indicate that a persistent opioid habit can develop even after minor surgeries, therefore, caution should be exercised, and a regimen of nonopiate pain medications should be considered to reduce postprocedural pain after transarterial chemoembolization.

Predictive validity of the adult tobacco dependence index: Findings from waves 1 and 2 of the Population Assessment of Tobacco and Health (PATH) study.

BACKGROUND AND AIMS: Building on published work1 establishing concurrent validity of a self-report tobacco dependence (TD) index among users of different tobacco products in Wave 1 (W1) of the Population Assessment of Tobacco and Health (PATH) Study, the current study examines prospective relationships with tobacco use behaviors to establish predictive validity of the TD index. Hypotheses suggested high levels of W1 TD would be associated with persistent tobacco use at Wave 2 (W2). PARTICIPANTS: A U.S. nationally representative sample of 32,320 adult W1 and W2 interviews focused on 11,615 W1 adults who were current established tobacco users and completed the W2 interview. FINDINGS: Higher TD scores and greater changes in TD scores were associated with greater quantity and frequency of tobacco use at the W2 interview for Cigarette Only (n = 7068), Smokeless (smokeless or snus pouches) Only (n = 772), Cigarette plus E-Cigarette (n = 592), and Multiple Products (n = 1866) users, although not significantly so for E-Cigarette Only (n = 367), Cigar Only (traditional, cigarillo, or filtered) (n = 584), or Hookah Only (n = 366) users. Higher TD was associated with decreased odds of successful quitting for Cigarette and Multiple Product users. Higher TD was associated with increased odds of a quit attempt for those in the Hookah and Multiple Products user groups and was not associated with quit attempts or deceased odds of quit success among exclusive E-Cigarette, Cigar, Smokeless and Cigarette plus E-Cigarette users. CONCLUSION: Support for the predictive validity of the PATH Study measures of adult TD will enable regulatory investigations of TD across several tobacco products.

The influence of lack of reference conditions on dosimetry in pre-clinical radiotherapy with medium energy x-ray beams.

Despite well-established dosimetry in clinical radiotherapy, dose measurements in pre-clinical and radiobiology studies are frequently inadequate, thus undermining the reliability and reproducibility of published findings. The lack of suitable dosimetry protocols, coupled with the increasing complexity of pre-clinical irradiation platforms, undermines confidence in preclinical studies and represents a serious obstacle in the translation to clinical practice. To accurately measure output of a pre-clinical radiotherapy unit, appropriate Codes of Practice (CoP) for medium energy x-rays needs to be employed. However, determination of absorbed dose to water (Dw) relies on application of backscatter factor (Bw) employing in-air method or carrying out in-phantom measurement at the reference depth of 2 cm in a full backscatter (i.e. 30 × 30 × 30 cm3) condition. Both of these methods require thickness of at least 30 cm of underlying material, which are never fulfilled in typical pre-clinical irradiations. This work is focused on evaluation the effects of the lack of recommended reference conditions in dosimetry measurements for pre-clinical settings and is aimed at extending the recommendations of the current CoP to practical experimental conditions and highlighting the potential impact of the lack of correct backscatter considerations on radiobiological studies.

Flavour types used by youth and adult tobacco users in wave 2 of the Population Assessment of Tobacco and Health (PATH) Study 2014-2015.

BACKGROUND: Most youth and young adult (YA) tobacco users use flavoured products; however, little is known about specific flavours used. METHODS: We report flavour types among US tobacco users from the Population Assessment of Tobacco and Health Study, wave 2, 2014-2015. At wave 2, we examined (1) flavour use and type at past 30-day use; (2) new flavoured tobacco product use and type; (3) product-specific flavour patterns across youth (ages 12-17) (n=920), YA (18-24) (n=3726) and adult (25+) (n=10 346) past 30-day and new tobacco users and (4) concordance between self-coded and expert-coded brand flavour type among all adults (18+). RESULTS: Prevalence of flavoured tobacco product use was highest among youth, followed by YA and adult 25+ any tobacco users. Within each age group, flavoured use was greatest among hookah, e-cigarette and snus users. Overall, menthol/mint, fruit and candy/sweet were the most prevalent flavour types at first and past 30-day use across age groups. For past 30-day use, all flavour types except menthol/mint exhibited an inverse age gradient, with more prevalent use among youth and YAs, followed by adults 25+. Prevalence of menthol/mint use was high (over 50% youth, YAs; 76% adults 25+) and exhibited a positive age gradient overall, though the reverse for cigarettes. Brand-categorised and self-reported flavour use measures among adults 18+ were moderately to substantially concordant across most products. CONCLUSIONS: Common flavours like menthol/mint, fruit and candy/sweet enhance appeal to young tobacco users. Information on flavour types used by product and age can inform tobacco flavour regulations to addess flavour appeal especially among youth.

Association of Flavored Tobacco Use With Tobacco Initiation and Subsequent Use Among US Youth and Adults, 2013-2015.

Importance: Flavors in tobacco products may appeal to young and inexperienced users. Objective: To examine among youth (aged 12-17 years), young adults (aged 18-24 years), and adults (aged ≥25 years) the prevalence of first use of flavored tobacco products among new tobacco users and the association between first flavored use of a given tobacco product and tobacco use 1 year later, including progression of tobacco use. Design, Setting, and Participants: This cohort study represents a longitudinal analysis of data from the Population Assessment of Tobacco and Health (PATH) Study, a nationally representative study with data collected in 2013 to 2014 (wave 1) and 2014 to 2015 (wave 2). Participants were noninstitutionalized individuals, including 11 996 youth and 26 447 adults, in selected households who participated in both waves of the PATH Study. Data analysis was conducted from July 2016 to June 2019. Main Outcomes and Measures: Prevalence of tobacco product use at wave 2. Results: The mean (SE) age of the participants was 14.5 (0.0) years for youth, 21.1 (0.0) years for young adults, and 50.3 (0.0) for adults. Most youth (71.9%; 95% CI, 69.7%-74.0%) and young adults (57.6%; 95% CI, 54.9%-60.3%) who were new users of tobacco products over the 10- to 13-month follow-up period used flavored products. First use of a menthol or mint or other flavored cigarette documented at wave 1 was positively associated with past 12-month and past 30-day cigarette use in all age groups at wave 2 compared with first use of a nonflavored cigarette (youth, flavored cigarette, past 12-month use adjusted prevalence ratio [aPR], 1.14 [95% CI, 1.05-1.25] and past 30-day use aPR, 1.15 [95% CI, 1.00-1.31]; youth, menthol or mint cigarette, past 12-month use aPR, 1.18 [95% CI, 1.08-1.29] and past 30-day use aPR, 1.19 [95% CI, 1.04-1.37]; young adult, flavored cigarette, past 12-month use aPR, 1.09 [95% CI, 1.04-1.15] and past 30-day use aPR, 1.13 [95% CI, 1.06-1.21]; young adult menthol or mint cigarette, past 12-month use aPR, 1.10 [95% CI, 1.05-1.16] and past 30-day use aPR, 1.15 [95% CI, 1.07-1.23]; adult flavored cigarette, past 12-month use aPR, 1.10 [95% CI, 1.05-1.15] and past 30-day use aPR, 1.09 [95% CI, 1.04-1.14]; adult menthol or mint cigarette, past 12-month use aPR, 1.13 [95% CI, 1.08-1.18] and past 30-day use aPR, 1.12 [95% CI, 1.07-1.17]). Among young adults, first use of flavored e-cigarettes (aPR, 2.05; 95% CI, 1.61-2.61), any cigars (aPR, 1.60; 95% CI, 1.26-2.02), cigarillos (aPR, 1.49; 95% CI, 1.08-2.05), filtered cigars (aPR, 3.69; 95% CI, 2.08-6.57), hookah (aPR, 1.91; 95% CI, 1.23-2.98), and any smokeless tobacco (aPR, 1.54; 95% CI, 1.08-2.20) was prospectively associated with current regular use of those products at wave 2 compared with first nonflavored use. Among adults aged 25 years and older, first use of flavored e-cigarettes (aPR, 1.60; 95% CI, 1.41-1.82), any cigars (aPR, 1.56; 95% CI, 1.29-1.87), cigarillos (aPR, 1.29; 95% CI, 1.01-1.64), filtered cigars (aPR, 1.79; 95% CI, 1.25-2.54), hookah (aPR, 5.66; 95% CI, 2.04-15.71), and any smokeless tobacco (aPR, 1.55; 95% CI, 1.32-1.82) was prospectively associated with current regular use of those products at wave 2 compared with first nonflavored use. Conclusions and Relevance: In this longitudinal cohort study, flavors in tobacco products were associated with youth and young adult tobacco experimentation. First use of a flavored tobacco product may place youth, young adults, and adults at risk of subsequent tobacco use.

The effect of radioiodine treatment on the diseased thyroid gland.

Purpose: Radioiodine (I131) therapy is the treatment mainstay for several benign and malignant thyroid disorders, however I131 is known to cause DNA damage and liberation of thyroidal self-antigens inducing secondary immunoreactivity. The exact mechanisms underpinning cellular death and subsequent induction of autoimmune thyroid disease following I131 treatment have not yet been fully elucidated. This manuscript aims to review the literature concerning the effects of I131 on the thyroid gland.Conclusion: The effects of I131 on malignant thyroid cells appears to depend on absorbed dose with the literature demonstrating a clear initial delay in the triggering of apoptosis in response to I131-mediated cellular damage. Some studies also observed necrotic cellular death following high-dose I131 treatment. Liberation of thyroidal self-antigen following I131 treatment helps to explain phenomena such as the subsequent induction of autoimmune thyroid disease. The clinical utility of cytokines and autoantibodies for prognostication of hypothyroidism and treatment failure following I131 remains uncertain and further appropriately-powered studies are required to clarify their role. The potential role of other cell death mechanisms activated after treatment with I131 should also be explored in order to fully delineate the thyroidal response.

Development of an anatomically correct mouse phantom for dosimetry measurement in small animal radiotherapy research.

Significant improvements in radiotherapy are likely to come from biological rather than technical optimization, for example increasing tumour radiosensitivity via combination with targeted therapies. Such paradigms must first be evaluated in preclinical models for efficacy, and recent advances in small animal radiotherapy research platforms allow advanced irradiation protocols, similar to those used clinically, to be carried out in orthotopic models. Dose assessment in such systems is complex however, and a lack of established tools and methodologies for traceable and accurate dosimetry is currently limiting the capabilities of such platforms and slowing the clinical uptake of new approaches. Here we report the creation of an anatomically correct phantom, fabricated from materials with tissue-equivalent electron density, into which dosimetry detectors can be incorporated for measurement as part of quality control (QC). The phantom also allows training in preclinical radiotherapy planning and cross-institution validation of dose delivery protocols for small animal radiotherapy platforms without the need to sacrifice animals, with high reproducibility. Mouse CT data was acquired and segmented into soft tissue, bone and lung. The skeleton was fabricated using 3D printing, whilst lung was created using computer numerical control (CNC) milling. Skeleton and lung were then set into a surface-rendered mould and soft tissue material added to create a whole-body phantom. Materials for fabrication were characterized for atomic composition and attenuation for x-ray energies typically found in small animal irradiators. Finally cores were CNC milled to allow intracranial incorporation of bespoke detectors (alanine pellets) for dosimetry measurement.

A novel microfluidic device capable of maintaining functional thyroid carcinoma specimens ex vivo provides a new drug screening platform.

BACKGROUND: Though the management of malignancies has improved vastly in recent years, many treatment options lack the desired efficacy and fail to adequately augment patient morbidity and mortality. It is increasingly clear that patient response to therapy is unique to each individual, necessitating personalised, or 'precision' medical care. This demand extends to thyroid cancer; ~ 10% patients fail to respond to radioiodine treatment due to loss of phenotypic differentiation, exposing the patient to unnecessary ionising radiation, as well as delaying treatment with alternative therapies. METHODS: Human thyroid tissue (n = 23, malignant and benign) was live-sliced (5 mm diameter × 350-500 µm thickness) then analysed or incorporated into a microfluidic culture device for 96 h (37 °C). Successful maintenance of tissue was verified by histological (H&E), flow cytometric propidium iodide or trypan blue uptake, immunohistochemical (Ki67 detection/ BrdU incorporation) and functional analysis (thyroxine [T4] output) in addition to analysis of culture effluent for the cell death markers lactate dehydrogenase (LDH) and dead-cell protease (DCP). Apoptosis was investigated by Terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL). Differentiation was assessed by evaluation of thyroid transcription factor (TTF1) and sodium iodide symporter (NIS) expression (western blotting). RESULTS: Maintenance of gross tissue architecture was observed. Analysis of dissociated primary thyroid cells using flow cytometry both prior to and post culture demonstrated no significant change in the proportion of viable cells. LDH and DCP release from on-chip thyroid tissue indicated that after an initial raised level of release, signifying cellular damage, detectable levels dropped markedly. A significant increase in apoptosis (p < 0.01) was observed after tissue was perfused with etoposide and JNK inhibitor, but not in control tissue incubated for the same time period. No significant difference in Ki-67 positivity or TTF1/NIS expression was detected between fresh and post-culture thyroid tissue samples, moreover BrdU positive nuclei indicated on-chip cellular proliferation. Cultured thyroid explants were functionally viable as determined by production of T4 throughout the culture period. CONCLUSIONS: The described microfluidic platform can maintain the viability of thyroid tissue slices ex vivo for a minimum of four days, providing a platform for the assessment of thyroid tissue radioiodine sensitivity/adjuvant therapies in real time.

Patterns and correlates of polysubstance use among US youth aged 15-17 years: wave 1 of the Population Assessment of Tobacco and Health (PATH) Study.

BACKGROUND AND AIMS: Youth aged 15-17 years are at high risk of tobacco, alcohol and drug use. Given the changing landscape with respect to availability, use of emerging products and regulatory environments, we examined patterns and correlates of polysubstance use among US youth aged 15-17 years. DESIGN: Cross-sectional self-reported data. SETTING: United States. PARTICIPANTS: A total of 6127 US youth aged 15-17 years from wave 1 (2013-14) of the nationally representative Population Assessment of Tobacco and Health (PATH) Study. MEASUREMENTS: Latent class analysis was used to identify subgroups of polysubstance use, including 12 tobacco products, alcohol, marijuana, prescription drugs and other drugs. Socio-demographic characteristics, residence in urban area, sensation-seeking, sexual orientation and internalizing and externalizing problems were examined as correlates. FINDINGS: Approximately 43.5% of 15-17-year-olds had used at least one substance in the past 12 months. A 5-class model was identified: class 1 'abstainers' (67.3%), class 2 'alcohol users' (19.2%), class 3 'alcohol, marijuana and tobacco (AMTpredominant AM ) users' (8.2%), class 4 'alcohol, marijuana and tobacco (AMTpredominant T ) users' (3.9%) and class 5 'alcohol, marijuana, tobacco and other drug (AMTOD) users' (1.4%). Abstainers were considered the reference class. Higher sensation-seeking scores, higher age and lower academic grades were each associated with greater likelihood of membership in all user classes. Gender, race/ethnicity, parents/guardians' education, residence in non-urban areas and sexual minority groups were associated with membership in some, but not all, user classes. Compared with no/low/moderate severity, high severity internalizing problems were associated with membership in classes 2, 3 and 5, whereas high severity externalizing problems were associated with membership in classes 3 and 5 only. CONCLUSIONS: There appear to be three heterogeneous polysubstance use classes among US youth aged 15-17 years. Correlates of substance use among US youth include higher sensation-seeking, poor academic performance, non-urban residence, minority sexual orientation and mental health problems.

Primary versus secondary prevention messages: College students' perceptions of effectiveness by marijuana user status.

Objective: With medical and recreational marijuana legislation expanding throughout the country, the need to educate high-risk populations is evident. The purpose of this study was to assess college students' perceptions of health communication messages comparing primary and secondary prevention messages concerning marijuana. Participants: Participants (n = 487) included college students, ages 18-25, enrolled in a Midwestern University. Methods: Participants assessed messages based on likeability, creativity, believability, persuasiveness, relevance, and usefulness using an online questionnaire that also included open-end comments. Results: Rasch analyses indicate that nonmarijuana users rated primary prevention messages higher than secondary prevention messages, whereas marijuana users ranked secondary prevention messages more favorably than primary prevention messages. Conclusion: Interventions designed to address marijuana use among college students may be more effective if tailored toward user status. Specifically, primary prevention materials should be designed for abstainers, while secondary prevention messages that focus on harm reduction strategies should be used with marijuana users.