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ImportanceLarynx cancer is associated with considerable morbidity for patients and has a high mortality rate. Historical analyses showed that the incidence of larynx cancer was decreasing but the mortality was not similarly improving.ObjectiveTo assess whether incidence and mortality trends in larynx cancer in the US have improved.Design, Setting, and ParticipantsThis cohort study used population-based data from the Surveillance, Epidemiology, and End Results Program database for patients older than 18 years who were diagnosed with laryngeal cancer between January 1, 1986, and December 31, 2018. Data were analyzed from May 1, 2021, to May 31, 2022.Main Outcomes and MeasuresThe main outcomes were incidence and mortality of larynx cancer by sex, subsite, and patterns of surgical treatment.ResultsAmong 40 850 US patients with larynx cancer diagnosed from 1986 to 2018 (80.4% male), the incidence of larynx cancer decreased 55% from 5.00 per 100 000 people (95% CI, 4.70-5.32 per 100 000 people) to 2.26 per 100 000 people (95% CI, 2.11-2.42 per 100 000 people). During the same period, mortality decreased only 43% from 1.59 per 100 000 people (95% CI, 1.53-1.64 per 100 000 people) to 0.89 per 100 000 people (95% CI, 0.86-0.92 per 100 000 people). This corresponds to a 25% relative increase in case-fatality rate. Examination by stage showed a decrease in the incidence of localized disease at diagnosis of 40% from 2.65 per 100 000 people (95% CI, 2.44-2.89 per 100 000 people) to 1.60 per 100 000 people (95% CI, 1.45-1.76 per 100 000 people) from 1986 to 2002 and of 45% from 2.15 per 100 000 people (95% CI, 1.98-2.34 per 100 000 people) to 1.19 per 100 000 people (95% CI, 1.08-1.31 per 100 000 people) from 2005 to 2018. Distribution of larynx cancer by subsite remained stable, with most cases affecting the glottis. The proportion of patients receiving surgery as their first course of treatment decreased regardless of stage at presentation.Conclusions and RelevanceIn this cohort study, between 1986 and 2018, the incidence of larynx cancer decreased in the US, primarily because of the decrease in the incidence of localized disease. Mortality did not decrease similarly, resulting in an increased case-fatality rate overall. Encouraging earlier referrals for cancer concern, focusing resources where larynx cancer rates remain highest, renewing attention to research on new biologic causes of different tumor biologic characteristics, and conducting trials to directly compare treatments may help reverse this trend.

BackgroundMost analyses of excess mortality during the COVID-19 pandemic have employed aggregate data. Individual-level data from the largest integrated healthcare system in the US may enhance understanding of excess mortality.MethodsWe performed an observational cohort study following patients receiving care from the Department of Veterans Affairs (VA) between 1 March 2018 and 28 February 2022. We estimated excess mortality on an absolute scale (i.e., excess mortality rates, number of excess deaths), and a relative scale by measuring the hazard ratio (HR) for mortality comparing pandemic and pre-pandemic periods, overall, and within demographic and clinical subgroups. Comorbidity burden and frailty were measured using the Charlson Comorbidity Index and Veterans Aging Cohort Study Index, respectively.ResultsOf 5,905,747 patients, median age was 65.8 years and 91% were men. Overall, the excess mortality rate was 10.0 deaths/1000 person-years (PY), with a total of 103,164 excess deaths and pandemic HR of 1.25 (95% CI 1.25-1.26). Excess mortality rates were highest among the most frail patients (52.0/1000 PY) and those with the highest comorbidity burden (16.3/1000 PY). However, the largest relative mortality increases were observed among the least frail (HR 1.31, 95% CI 1.30-1.32) and those with the lowest comorbidity burden (HR 1.44, 95% CI 1.43-1.46).ConclusionsIndividual-level data offered crucial clinical and operational insights into US excess mortality patterns during the COVID-19 pandemic. Notable differences emerged among clinical risk groups, emphasising the need for reporting excess mortality in both absolute and relative terms to inform resource allocation in future outbreaks.KEY MESSAGESMost analyses of excess mortality during the COVID-19 pandemic have focused on evaluations of aggregate data, which may miss important individual-level drivers of excess mortality that may serve as future targets for improvement initiatives.Using individual-level data from a national integrated healthcare system, we estimated absolute and relative excess mortality and number of excess deaths overall and within demographic and clinical subgroups.Absolute rates of excess mortality were typically highest in groups where the baseline rate of mortality was higher; namely in older age groups and among those with more comorbidities and higher levels of physiologic frailty.Relative measures of excess mortality were typically greatest among younger age groups and among those with lower physiologic frailty and fewer comorbidities.Relative measures of excess mortality attenuated but remained elevated after censoring follow-up at first documented SARS-CoV-2 infection or COVID-19, suggesting that factors beyond SARS-CoV-2 infection contributed to the observed excess mortality during the pandemic.

BACKGROUND: The noninvasive subtype of encapsulated follicular variant of papillary thyroid carcinoma (eFVPTC) has been reclassified as noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) in 2016 to reflect the indolent behavior and favorable prognosis of this type of tumor. This terminology change has also de-escalated its management approach from cancer treatment to a more conservative treatment strategy befitting a benign thyroid neoplasm. OBJECTIVE: To characterize the reduced health care costs and improved quality of life (QOL) from management of NIFTP as a nonmalignant tumor compared with the previous management as eFVPTC. METHODS: A cost-effectiveness analysis was performed by creating Markov models to simulate two management strategies for NIFTP: (i) de-escalated management of the tumor as NIFTP involving lobectomy with reduced follow-up, (ii) management of the tumor as eFVPTC involving completion thyroidectomy/radioactive iodine ablation for some patients, and follow-up recommended for carcinoma. The model was simulated for 5 and 20 years following diagnosis of NIFTP. Aggregate costs and quality-life years were measured. One-way sensitivity analysis was performed for all variables. RESULTS: Over a five-year simulation period, de-escalated management of NIFTP had a total cost of $12,380.99 per patient while the more aggressive management of the tumor as eFVPTC had a total cost of $16,264.03 per patient (saving $3883.05 over five years). Management of NIFTP provided 5.00 quality-adjusted life years, whereas management as eFVPTC provided 4.97 quality-adjusted life years. Sensitivity analyses showed that management of NIFTP always resulted in lower costs and greater quality-adjusted life years (QALYs) over the sensitivity ranges for individual variables. De-escalated management for NIFTP is expected to produce ∼$6–42 million in cost savings over a five-year period for these patients, and incremental 54–370 QALYs of increased utility in the United States. CONCLUSION: The degree of cost savings and improved patient utility of de-escalated NIFTP management compared with traditional management was estimated to be $3883.05 and 0.03 QALYs per patient. We demonstrate that these findings persisted in sensitivity analysis to account for variability in recurrence rate, surveillance approaches, and other model inputs. These findings allow for greater understanding of the economic and QOL impact of the NIFTP reclassification.

Introduction Molecular testing has helped clinicians and cytopathologists to further categorize indeterminate thyroid fine needle aspiration (FNA) specimens. The purpose of the present study was to evaluate the accuracy of commercially available molecular tests, review their effects on patient treatment, and correlate the molecular alterations with the histologic findings. Materials and methods A pathology laboratory information system search identified thyroid FNAs performed at our institution between January 1, 2015 and June 30, 2020. The results of surgical follow-up and ancillary molecular testing were collected. We evaluated the accuracy of these tests and whether they could reduce the number of surgeries performed. Results Our laboratory information system search identified 510 cases reported as atypia of undetermined significance, 94 as suspicious for follicular neoplasm, and 44 as suspicious for follicular neoplasm, Hurthle cell type. Of the specimens, 343 had no ancillary molecular testing, 146 were sent for ThyGenX/ThyraMIR, and 136 were sent for ThyroSeq. Of the patients without molecular testing, 50.4% had undergone follow-up surgery compared with 30.8% after ThyGenX/ThyraMIR and 38.2% after ThyroSeq testing, resulting in 38.9% and 24.2% fewer surgeries and an odds ratio of 0.04 (95% confidence interval, 0.00-0.33) and 0.14 (95% confidence interval, 0.01-0.95), respectively. For ThyGenX/ThyraMIR testing, the risk of malignancy for high and moderate to high risk alterations was 80%, 28.6% for moderate and low to moderate risk alterations, and 23.1% for low risk alterations. For ThyroSeq, the risk of malignancy was 87.5% for high risk alterations, 36.8% for intermediate to high risk alterations, 27.3% for intermediate risk alterations, and 0% for low risk alterations. The areas under the curve for ThyGenX/ThyraMIR and ThyroSeq testing were 0.65 and 0.85, respectively. Conclusions These findings suggest that, at our institution, both ThygenX/ThyraMIR and ThyroSeq can be used to effectively stratify cytology specimens based on the risk of malignancy and reduce the number of surgeries performed at our institution.

In this study, gadolinium (Gd) doped MgAl layered double hydroxides (LDHs) were synthesized via a ‘bottom-up’ method and fully characterized by X-ray diffraction, infrared spectroscopy and relaxivity measurements. Two cytotoxic agents were then intercalated via ion-exchange. X-ray diffraction patterns exhibit expanded interlayer spacings as a result of successful drug intercalation. Infrared spectra also showed characteristic peaks of the incorporated methotrexate (MTX) or 5-fluorouracil (5-FU). The LDHs were found to be highly stable under physiological conditions, while in acidic conditions a small proportion of Gd was freed into the immersion medium. Dissolution tests revealed that both 5FU and MTX were rapidly released from the LDH carrier. The longitudinal relaxivity of Gd-LDHs remains largely stable during drug release over 24 h, and was higher in acidic environments. Overall, the drug-loaded Gd-LDH systems prepared in this study could serve as pH-sensitive theranostic platforms for MRI-guided anti-cancer therapy.

A Design of Experiments approach was used to optimise synthesis of core@shell SPION@silica nanoparticles. Multiple linear regression analyses established relationships between the applied experimental variables and resulting particle properties.

We report a novel magnetically-facilitated approach to produce 1-D ‘nano-necklace’ arrays composed of 0-D magnetic nanoparticles, which are assembled and coated with an oxide layer to produce semi-flexible core@shell type...

ImportanceCounseling prior to thyroid cancer (TC) treatment is an essential component of informed consent. An informed patient affects treatment-related expectations and patient engagement, factors that contribute significantly to patient-reported quality-of-life outcomes.ObjectiveTo describe experiences with pretreatment counseling among survivors of TC and to test factors associated with self-reported treatment meeting expectations.Design, Setting, and ParticipantsA cross-sectional survey was administered between October 18, 2019, and February 8, 2020, to members of ThyCa: Thyroid Cancer Survivors’ Association Inc, and to individuals accessing the public-facing ThyCa website. Survey respondents were asked 55 questions, including 4 free-text questions and 2 multiple-choice questions about pretreatment counseling.Main Outcomes and MeasuresRespondents self-reported (1) their unmet information needs, (2) rates of treatment meeting expectations, and (3) rates of treatment understanding. A mixed-methods analysis was performed, including qualitative content analysis of free-text responses and multivariable logistic regression of factors associated with self-reported levels of treatment meeting expectations.ResultsOf the 1412 survey respondents, 1249 were women (88.4%). The median age at diagnosis was 48 years (range, 18-85 years), and the median age at the time of survey completion was 60 years (range, 18-87 years). A total of 1259 respondents (89.2%) provided free-text responses to the question, “What would you tell someone newly diagnosed with your same condition?” Of these individuals, 526 (37.2%) reported inadequate pretreatment plan understanding and 578 (40.9%) reported that their treatment experience did not meet their expectations. Treatment met expectations for only 95 respondents (18.1%) reporting an inadequate pretreatment plan understanding. Of the 526 survivors of TC reporting a lack of understanding, 473 (90.0%) provided additional textual comments, most commonly in the categories of postoperative treatment, surveillance, and treatment effects. On multivariable logistic regression, self-reported failure to have an understanding of TC treatment was independently associated with failure of treatment to meet expectations (odds ratio, 5.1 [95% CI, 3.7-6.9]). Patients reporting a full understanding of their treatment plan were 5-fold more likely to indicate that their initial treatment experience was on par with expectations, independent of reported postoperative complications, age, sex, and other potential confounders.Conclusions and RelevanceIn this survey study, a substantial proportion of survivors of TC reported inadequate pretreatment understanding. This gap in understanding was associated with high levels of self-reported failure of treatment to meet expectations, which in turn is associated in other studies with poorer patient-reported quality-of-life outcomes. These outcomes may be improved by addressing gaps in patient understanding so expectations more closely match TC diagnosis and treatment pathways.

ImportanceThe COVID-19 pandemic had a substantial impact on the overall rate of death in the United States during the first year. It is unclear whether access to comprehensive medical care, such as through the VA healthcare system, altered death rates compared to the US population.ObjectiveQuantify the increase in death rates during the first year of the COVID-19 pandemic in the general US population and among individuals who receive comprehensive medical care through the Department of Veterans Affairs (VA).DesignAnalysis of changes in all-cause death rates by quarter, stratified by age, sex race/ethnicity, and region, based on individual-level data. Hierarchical regression models were fit in a Bayesian setting. Standardized rates were used for comparison between populations.Setting and participantsGeneral population of the United States, enrollees in the VA, and active users of VA healthcare.Exposure and main outcomeChanges in rates of death from any cause during the COVID-19 pandemic in 2020 compared to previous years.ResultsSharp increases were apparent across all of the adult age groups (25 years and older) in both the general US population and the VA populations. Across all of 2020, the relative increase in death rates was similar in the general US population (RR: 1.20 (95% CI: 1.17, 1.22)), VA enrollees (RR: 1.20 (95% CI: 1.14, 1.29)), and VA active users (RR: 1.19 (95% CI: 1.14, 1.26)). Because the pre-pandemic standardized mortality rates were higher in the VA populations prior to the pandemic, the absolute rates of excess mortality were higher in the VA populations.Conclusions and RelevanceDespite access to comprehensive medical care, active users of the VA had similar relative mortality increases from all causes compared with the general US population. Factors that influenced baseline rates of death and that mitigated viral transmission in the community are more likely to have influenced the impact of the pandemic.

BACKGROUND: The 2015 American Thyroid Association endorsed less aggressive management for low-risk papillary thyroid cancer (LR-PTC). We aimed to identify factors influencing physicians’ recommendations for LR-PTC. METHODS: We surveyed members of three professional societies and assessed respondents’ recommendations for managing LR-PTC using patient scenarios. Multivariable logistic regression models identified clinical and non-clinical factors associated with recommending total thyroidectomy (TT) and active surveillance (AS). RESULTS: The 345 respondents included 246 surgeons and 99 endocrinologists. Physicians’ preference for their own management if diagnosed with LR-PTC had the strongest association with their recommendation for TT and AS (TT: OR 12.3; AS: OR 7.5, p

Our aim is to discuss the concepts of sex and gender in the context of thyroid cancer epidemiology.It has been long-established in global epidemiologic data that thyroid cancer incidence rates are higher in women than men. However, what has been less well understood is whether this reflects sex disparities in cancer susceptibility, gender disparities in detection, or a combination. A recent meta-analysis of autopsy data from individuals who were not known to have thyroid cancer in their lifetime demonstrated no difference in the prevalence of thyroid cancer in women and men, suggesting that gender differences may be the reason for gender-based differences in thyroid cancer detection. This finding, and sex differences in auto immunity and other factors that may affect cancer susceptibility are explored.Additional research to explore gender- and sex-specific data on thyroid cancer would inform our understanding of the differences and similarities between men and women in susceptibility and detection of thyroid cancer and help to optimize disease management for all genders and both sexes.

This article is part of the themed collections: Recent Open Access Articles and Environmental Science: Nano Recent HOT Articles., Nano-sized titanium dioxide (nTiO2) represents the highest produced nanomaterial by mass worldwide and, due to its prevalent industrial and commercial use, it inevitably reaches the natural environment. Previous work has revealed a negative impact of nTiO2 upon marine phytoplankton growth, however, studies are typically carried out at concentrations far exceeding those measured and predicted to occur in the environment currently. Here, a series of experiments were carried out to assess the effects of both research-grade nTiO2 and nTiO2 extracted from consumer products upon the marine dominant cyanobacterium, Prochlorococcus, and natural marine communities at environmentally relevant and supra-environmental concentrations (i.e., 1 μg L−1 to 100 mg L−1). Cell declines observed in Prochlorococcus cultures were associated with the extensive aggregation behaviour of nTiO2 in saline media and the subsequent entrapment of microbial cells. Hence, higher concentrations of nTiO2 particles exerted a stronger decline of cyanobacterial populations. However, within natural oligotrophic seawater, cultures were able to recover over time as the nanoparticles aggregated out of solution after 72 h. Subsequent shotgun proteomic analysis of Prochlorococcus cultures exposed to environmentally relevant concentrations confirmed minimal molecular features of toxicity, suggesting that direct physical effects are responsible for short-term microbial population decline. In an additional experiment, the diversity and structure of natural marine microbial communities showed negligible variations when exposed to environmentally relevant nTiO2 concentrations (i.e., 25 μg L−1). As such, the environmental risk of nTiO2 towards marine microbial species appears low, however the potential for adverse effects in hotspots of contamination exists. In future, research must be extended to consider any effect of other components of nano-enabled product formulations upon nanomaterial fate and impact within the natural environment., C. J. D. was supported by the NERC CENTA DTP studentship NE/L002493/1. J. A. C.-O. was funded by a NERC Independent Research Fellowship NE/K009044/1, Ramón y Cajal contract RYC-2017-22452 (co-funded by the Ministerio de Ciencia, Innovación y Universidades, the Agencia Estatal de Investigación (10.13039/100014440), and the European Social Fund (10.13039/501100004895)) and project PID2019-109509RB-I00 / AEI / 10.13039/501100011033.

ImportanceDuring the first year of the COVID-19 pandemic, there was a substantial increase in the rate of death in the United States. It is unclear whether those who had access to comprehensive medical care through the Department of Veterans Affairs (VA) health care system had different death rates compared with the overall US population.ObjectiveTo quantify and compare the increase in death rates during the first year of the COVID-19 pandemic between individuals who received comprehensive medical care through the VA health care system and those in the general US population.Design, Setting, and ParticipantsThis cohort study compared 10.9 million enrollees in the VA, including 6.8 million active users of VA health care (those with a visit in the last 2 years), with the general population of the US, with deaths occurring from January 1, 2014, to December 31, 2020. Statistical analysis was conducted from May 17, 2021, to March 15, 2023.Main Outcomes and MeasuresChanges in rates of death from any cause during the COVID-19 pandemic in 2020 compared with previous years. Changes in all-cause death rates by quarter were stratified by age, sex, race and ethnicity, and region, based on individual-level data. Multilevel regression models were fit in a bayesian setting. Standardized rates were used for comparison between populations.ResultsThere were 10.9 million enrollees in the VA health care system and 6.8 million active users. The demographic characteristics of the VA populations were predominantly male (>85% in the VA health care system vs 49% in the general US population), older (mean [SD], 61.0 [18.2] years in the VA health care system vs 39.0 [23.1] years in the US population), and had a larger proportion of patients who were White (73% in the VA health care system vs 61% in the US population) or Black (17% in the VA health care system vs 13% in the US population). Increases in death rates were apparent across all of the adult age groups (≥25 years) in both the VA populations and the general US population. Across all of 2020, the relative increase in death rates compared with expected values was similar for VA enrollees (risk ratio [RR], 1.20 [95% CI, 1.14-1.29]), VA active users (RR, 1.19 [95% CI, 1.14-1.26]), and the general US population (RR, 1.20 [95% CI, 1.17-1.22]). Because the prepandemic standardized mortality rates were higher in the VA populations prior to the pandemic, the absolute rates of excess mortality were higher in the VA populations.Conclusions and RelevanceIn this cohort study, a comparison of excess deaths between populations suggests that active users of the VA health system had similar relative increases in mortality compared with the general US population during the first 10 months of the COVID-19 pandemic.

ImportanceIdentification and preservation of parathyroid glands (PGs) remain challenging despite advances in surgical techniques. Considerable morbidity and even mortality result from hypoparathyroidism caused by devascularization or inadvertent removal of PGs. Emerging imaging technologies hold promise to improve identification and preservation of PGs during thyroid surgery.ObservationThis narrative review (1) comprehensively reviews PG identification and vascular assessment using near-infrared autofluorescence (NIRAF)—both label free and in combination with indocyanine green—based on a comprehensive literature review and (2) offers a manual for possible implementation these emerging technologies in thyroid surgery.Conclusions and RelevanceEmerging technologies hold promise to improve PG identification and preservation during thyroidectomy. Future research should address variables affecting the degree of fluorescence in NIRAF, standardization of signal quantification, definitions and standardization of parameters of indocyanine green injection that correlate with postoperative PG function, the financial effect of these emerging technologies on near-term and longer-term costs, the adoption learning curve and effect on surgical training, and long-term outcomes of key quality metrics in adequately powered randomized clinical trials evaluating PG preservation.

Thermoresponsive polymers have attracted huge interest as a way of developing smart/adaptable materials for biomedicine, particularly due to changes in their solubility above the LCST. However, temperature is not always an appropriate or desirable stimulus given the variety of other cellular microenvironments that exist, including pH, redox potentials, ionic strength, and metal ion concentration. Here, we achieve a highly specific, isothermal solubility switch for poly(

The synthesis of single-core superparamagnetic iron oxide nanoparticles (SPIONs) coated with a silica shell of controlled thickness remains a challenge, due to the dependence on a multitude of experimental variables. Herein, we utilise design of experiment (DoE) to study the formation of SPION@SiO2 nanoparticles (NPs) via reverse microemulsion. Using a 33 full factorial design, the influence of reactant concentration of tetraethyl orthosilicate (TEOS) and ammonium hydroxide (NH4OH), as well as the number of fractionated additions of TEOS on the silica shell was investigated with the aim of minimising polydispersity and increasing the population of SPION@SiO2 NPs formed. This investigation facilitated a reproducible and controlled approach for the high yield synthesis of SPION@SiO2 NPs with uniform silica shell thickness. Application of a multiple linear regression analysis established a relationship between the applied experimental variables and the resulting silica shell thickness. These experimental variables were similarly found to dictate the monodispersity of the SPION@SiO2 NPs formed. The overall population of single-core@shell particles, was dependent on the interaction between the number of moles of TEOS and NH4OH, with no influence from the number of fractionated additions of TEOS. This work demonstrates the complexity of the preparative method, and produces an accessible and flexible synthetic model to achieve monodisperse SPION@SiO2 NPs with controllable shell thickness.

Efforts to improve cancer care primarily come from two fields: improvement science and implementation science. The two fields have developed independently, yet they have potential for synergy. Leveraging that synergy to enhance alignment could both reduce duplication and, more importantly, enhance the potential of both fields to improve care. To better understand potential for alignment, we examined 20 highly cited cancer-related improvement science and implementation science studies published in the past 5 years, characterizing and comparing their objectives, methods, and approaches to practice change. We categorized studies as improvement science or implementation science based on authors’ descriptions when possible; otherwise, we categorized studies as improvement science if they evaluated efforts to improve the quality, value, or safety of care, or implementation science if they evaluated efforts to promote the implementation of evidence-based interventions into practice. All implementation studies (10/10) and most improvement science studies (6/10) sought to improve uptake of evidence-based interventions. Improvement science and implementation science studies employed similar approaches to change practice. For example, training was employed in 8/10 implementation science studies and 4/10 improvement science studies. However, improvement science and implementation science studies used different terminology to describe similar concepts and emphasized different methodological aspects in reporting. Only 4/20 studies (2 from each category) described using a formal theory or conceptual framework to guide program development. Most studies were multi-site (10/10 implementation science and 6/10 improvement science) and a minority (2 from each category) used a randomized design. Based on our review, cancer-related improvement science and implementation science studies use different terminology and emphasize different methodological aspects in reporting but share similarities in purpose, scope, and methods, and are at similar levels of scientific development. The fields are well-positioned for alignment. We propose that next steps include harmonizing language and cross-fertilizing methods of program development and evaluation.

BACKGROUND: The development of systemic treatment options leveraging the molecular landscape of advanced thyroid cancer is a burgeoning field. This is a multidisciplinary evidence-based statement on the definition of advanced thyroid cancer and its targeted systemic treatment. METHODS: An expert panel was assembled, a literature review was conducted, and best practice statements were developed. The modified Delphi method was applied to assess the degree of consensus for the statements developed by the author panel. RESULTS: A review of the current understanding of thyroid oncogenesis at a molecular level is presented and characteristics of advanced thyroid cancer are defined. Twenty statements in topics including the multidisciplinary management, molecular evaluation, and targeted systemic treatment of advanced thyroid cancer are provided. CONCLUSIONS: With the growth in targeted treatment options for thyroid cancer, a consensus definition of advanced disease and statements regarding the utility of molecular testing and available targeted systemic therapy is warranted.

Context It is not known how underlying subclinical papillary thyroid cancer (PTC) differs by age. This meta-analysis of autopsy studies investigates how subclinical PTC prevalence changes over the lifetime. Methods We searched PubMed, Embase, and Web of Science databases from inception to May 2021 for studies that reported the prevalence of PTC found at autopsy. Two investigators extracted the number of subclinical PTCs detected in selected age groups and extent of examination. A quality assessment tool was used to assess bias. Logistic regression models with random intercepts were used to pool the age-specific subclinical PTC prevalence estimates. Results Of 1773 studies screened, 16 studies with age-specific data met the inclusion criteria (n = 6286 autopsies). The pooled subclinical PTC prevalence was 12.9% (95% CI 7.8-16.8) in whole gland and 4.6% (2.5- 6.6) in partial gland examination. Age-specific prevalence estimates were ≤40 years, 11.5% (6.8-16.1); 41-60 years, 12.1% (7.6-16.5); 61-80 years, 12.7% (8-17.5); and 81+ years, 13.4% (7.9-18.9). Sex did not affect age-specific prevalence and there was no difference in prevalence between men and women in any age group. In the regression model, the OR of prevalence increasing by age group was 1.06 (0.92-1.2, P = .37). Conclusion This meta-analysis shows the prevalence of subclinical PTC is stable across the lifespan. There is not a higher subclinical PTC prevalence in middle age, in contrast to higher observed incidence rates in this age group. These findings offer unique insights into the prevalence of subclinical PTC and its relationship to age.

Objectives To characterize the experiences of providers in completing the cause of death section on death certificates, with particular reference to deaths in people who have cancer. Methods Focus groups were conducted until thematic saturation was reached, resulting in four groups over three months. Participants were from a variety of specialties and levels and types of training. Focus groups were recorded and transcribed verbatim and analyzed using constant comparison analysis. Results Three types of challenges to case classification were identified. 1) Infrastructural and procedural challenges encountered when completing death certificates, including the rigid structure of the form, lack of training in its completion, and lack of real-time feedback. 2) Clinical uncertainty and the varied approaches providers take to determine the cause of death based on their perception of the purpose of the death certificate. 3) Choosing cause of death in decedents with a history of cancer. Conclusions There are specific and substantial challenges in the death certification process that lead to errors in documenting the cause of death, but many of these challenges could be addressed with structural change to the forms or mechanism of training. Using these data to inform change could improve the death certification process and reliability of this data.

Forensic mental health services in high income countries are typically high cost and low volume, providing care to people with mental illness, personality disorders, learning disability and autism deemed to pose a risk to others. Research into how forensic mental health services work as a whole system is limited. Such research is urgently needed to guide policy makers and ensure that services operate effectively.

Sustained and localized delivery of chemotherapeutics in postoperative cancer treatment leads to a radical improvement in prognosis and a much decreased risk of tumor recurrence. In this work, polydopamine (PDA)-coated superparamagnetic iron oxide nanoparticle (SPION)-loaded polycaprolactone and poly(lactic-co-glycolic acid) fibers were developed as a potential implant to ensure safe and sustained release of the chemotherapeutic drug methotrexate (MTX), as well as provide local contrast for magnetic resonance imaging (MRI). Fibres were prepared by co-axial electrospinning and loaded with MTX-layered double hydroxide (LDH) nanocomposites in the core, yielding organic-inorganic hybrids ranging from 1.23 to 1.48 µm in diameter. After surface coating with PDA, SPIONs were subsequently loaded on the fibre surface and found to be evenly distributed, providing high MRI contrast. In vitro drug release studies showed the PDA coated fibres gave sustained release of MTX over 18 days, and the release profile is responsive to conditions representative of the tumor microenvironment such as slightly acidic pH values or elevated concentrations of the reducing agent glutathione (GSH). In vitro studies with Caco-2 and A549 cells showed highly effective killing with the PDA coated formulations, which was further enhanced at higher levels of GSH. The fibres hence have the potential to act as an implantable drug-eluting platform for the sustained release of cytotoxic agents within a tumor site, providing a novel treatment option for post-operative cancer patients.

Importance: There is epidemiologic evidence that the increasing incidence of thyroid cancer is associated with subclinical disease detection. Evidence for a true increase in thyroid cancer incidence has also been identified. However, a true increase in disease would likely be heralded by an increased incidence of thyroid-referable symptoms in patients presenting with disease.Objectives: To evaluate whether modes of detection (MODs) used to identify thyroid nodules for surgical removal have changed compared with historic data and to determine if MODs vary by geographic location.Design, Setting, and Participants: This was a retrospective analysis of pathology and medical records of 1328 patients who underwent thyroid-directed surgery in 16 centers in 4 countries: 4 centers in Canada, 1 in Denmark, 1 in South Africa, and 12 in the US. The participants were the first 100 patients (or the largest number available) at each center who had thyroid surgery in 2019. The MOD of the thyroid finding that required surgery was classified using an updated version of a previously validated tool as endocrine condition, symptomatic thyroid, surveillance, or without thyroid-referable symptoms (asymptomatic). If asymptomatic, the MOD was further classified as clinician screening examination, patient-requested screening, radiologic serendipity, or diagnostic cascade.Main Outcomes and Measures: The MOD of thyroid nodules that were surgically removed, by geographic variation; and the proportion and size of thyroid cancers discovered in patients without thyroid-referable symptoms compared with symptomatic detection. Data analyses were performed from April 2021 to February 2022.Results: Of the 1328 patients (mean [SD] age, 52 [15] years; 993 [75%] women; race/ethnicity data were not collected) who underwent thyroid surgery that met inclusion criteria, 34% (448) of the surgeries were for patients with thyroid-related symptoms, 41% (542) for thyroid findings discovered without thyroid-referable symptoms, 14% (184) for endocrine conditions, and 12% (154) for nodules with original MOD unknown (under surveillance). Cancer was detected in 613 (46%) patients; of these, 30% (183 patients) were symptomatic and 51% (310 patients) had no thyroid-referable symptoms. The mean (SD) size of the cancers identified in the symptomatic group was 3.2 (2.1) cm (median [range] cm, 2.6 [0.2-10.5]; 95% CI, 2.91-3.52) and in the asymptomatic group, 2.1 (1.4) cm (median [range] cm, 1.7 [0.05-8.8]; 95% CI, 1.92-2.23). The MOD patterns were significantly different among all participating countries.Conclusions and Relevance: This retrospective analysis found that most thyroid cancers were discovered in patients who had no thyroid-referable symptoms; on average, these cancers were smaller than symptomatic thyroid cancers. Still, some asymptomatic cancers were large, consistent with historic data. The substantial difference in MOD patterns among the 4 countries suggests extensive variations in practice.

Layered rare-earth hydroxides have begun to gather increasing attention as potential theranostic platforms owing to their extensive intercalation chemistry combined with magnetic and fluorescent properties. In this work, the potential of layered terbium hydroxide (LTbH) as a platform for simultaneous drug delivery and fluorescence imaging was evaluated. LTbH-Cl ([Tb2(OH)5]Cl·yH2O) was loaded with three nonsteroidal anti-inflammatory drugs (diclofenac, ibuprofen, and naproxen) via ion-exchange. Drug release studies in phosphate buffered saline (pH = 7.4) revealed all three formulations release their drug cargo rapidly over the course of approximately 5 hours. In addition, solid state fluorescence studies indicated that fluorescence intensity is strongly dependent on the identity of the guest anion. It was postulated that this feature may be used to track the extent of drug release from the formulation, which was subsequently successfully demonstrated for the ibuprofen loaded LTbH. Overall, LTbH exhibits good biocompatibility, high drug loading, and a strong, guest-dependent fluorescence signal, all of which are desirable qualities for theranostic applications.

The inclusion of students with autism spectrum disorder (ASD) is increasing, but there have been no longitudinal studies of included students in Australia. Interview data reported in this study concern primary school children with ASD enrolled in mainstream classes in South Australia and New South Wales, Australia. In order to examine perceived facilitators and barriers to inclusion, parents, teachers, and principals were asked to comment on the facilitators and barriers to inclusion relevant to each child. Data are reported about 60 students, comprising a total of 305 parent interviews, 208 teacher interviews, and 227 principal interviews collected at 6-monthly intervals over 3.5 years. The most commonly mentioned facilitator was teacher practices. The most commonly mentioned barrier was intrinsic student factors. Other factors not directly controllable by school staff, such as resource limitations, were also commonly identified by principals and teachers. Parents were more likely to mention school- or teacher-related barriers. Many of the current findings were consistent with previous studies but some differences were noted, including limited reporting of sensory issues and bullying as barriers. There was little change in the pattern of facilitators and barriers identified by respondents over time. A number of implications for practice and directions for future research are discussed.

Background This American Head and Neck Society (AHNS) consensus statement focuses on evidence-based comprehensive pain management practices for thyroid and parathyroid surgery. Overutilization of opioids for postoperative pain management is a major contributing factor to the opioid addiction epidemic however evidence-based guidelines for pain management after routine head and neck endocrine procedures are lacking. Methods An expert panel was convened from the membership of the AHNS, its Endocrine Surgical Section, and ThyCa. An extensive literature review was performed, and recommendations addressing several pain management subtopics were constructed based on best available evidence. A modified Delphi survey was then utilized to evaluate group consensus of these statements. Conclusions This expert consensus provides evidence-based recommendations for effective postoperative pain management following head and neck endocrine procedures with a focus on limiting unnecessary use of opioid analgesics.

Background Care for patients with thyroid nodules is complex and multidisciplinary, and research demonstrates variation in care. The objective was to develop clinical guidelines and quality metrics to reduce unwarranted variation and improve quality. Methods Multidisciplinary expert consensus and modified Delphi approach. Source documents were workflow algorithms from Kaiser Permanente Northern California and Cancer Care of Ontario based on the 2015 American Thyroid Association management guidelines for adult patients with thyroid nodules and differentiated thyroid cancer. Results A consensus-based, unified preoperative, perioperative, and postoperative workflow was developed for North American use. Twenty-one panelists achieved consensus on 16 statements about workflow-embedded process and outcomes metrics addressing safety, access, appropriateness, efficiency, effectiveness, and patient centeredness of care. Conclusion A panel of Canadian and United States experts achieved consensus on workflows and quality metric statements to help reduce unwarranted variation in care, improving overall quality of care for patients diagnosed with thyroid nodules.

Cerium oxide nanoparticles (nCeO2) are used at an ever-increasing rate, however, their impact within the aquatic environment remains uncertain. Here, we expose the ecologically significant marine cyanobacterium Prochlorococcus sp. MED4 to nCeO2 at a wide range of concentrations (1 μg L–1 to 100 mg L–1) under simulated natural and nutrient rich growth conditions. Flow cytometric analysis of cyanobacterial populations displays the potential of nCeO2 (100 μg L–1) to significantly reduce Prochlorococcus cell density in the short-term (72 h) by up to 68.8% under environmentally relevant conditions. However, following longer exposure (240 h) cyanobacterial populations are observed to recover under simulated natural conditions. In contrast, cell-dense cultures grown under optimal conditions appear more sensitive to exposure during extended incubation, likely as a result of increased rate of encounter between cyanobacteria and nanoparticles at high cell densities. Exposure to supra-environmental nCeO2 concentrations (i.e., 100 mg L–1) resulted in significant declines in cell density up to 95.7 and 82.7% in natural oligotrophic seawater and nutrient enriched media, respectively. Observed cell decline is associated with extensive aggregation behaviour of nCeO2 upon entry into natural seawater, as observed by dynamic light scattering (DLS), and hetero-aggregation with cyanobacteria, confirmed by fluorescent microscopy. Hence, the reduction of planktonic cells is believed to result from physical removal due to co-aggregation and co-sedimentation with nCeO2 rather than by a toxicological and cell death effect. The observed recovery of the cyanobacterial population under simulated natural conditions, and likely reduction in nCeO2 bioavailability as nanoparticles aggregate and undergo sedimentation in saline media, means that the likely environmental risk of nCeO2 in the marine environment appears low.

SummaryCurrently the primary method for confirming acute SARS-CoV-2 infection is through the use of molecular assays that target highly conserved regions within the viral genome. Many, if not most of the diagnostic targets currently in use were produced early in the pandemic, using genomes sequenced and shared in early 2020. As viral diversity increases, mutations may arise in diagnostic target sites that have an impact on the performance of diagnostic tests. Here, we report on a local outbreak of SARS-CoV-2 which had gained an additional mutation at position 28890 of the nucleocapsid protein, on a background of pre-existing mutations at positions 28881, 28882, 28883 in one of the main circulating viral lineages in Wales at that time. The impact of this additional mutation had a statistically significant impact on the Ct value reported for the N gene target designed by the Chinese CDC and used in a number of commercial diagnostic products. Further investigation identified that, in viral genomes sequenced from Wales over the summer of 2020, the N gene had a higher rate of mutations in diagnostic target sites than other targets, with 115 issues identified affecting over 10% of all cases sequenced between February and the end of August 2020. In comparison an issue was identified for ORFab, the next most affected target, in less than 1.4% of cases over the same time period. This work emphasises the potential impact that mutations in diagnostic target sites can have on tracking local outbreaks, as well as demonstrating the value of genomics as a routine tool for identifying and explaining potential diagnostic primer issues as part of a laboratory quality management system. This work also indicates that with increasing genomic sequencing data availability, there is a need to re-evaluate the diagnostic targets that are in use for SARS-CoV-2 testing, to better target regions that are now demonstrated to be of lower variability.

Objective Thyroid and parathyroid surgery is performed by both general surgeons and otolaryngologists. We describe the proportion of surgeries performed by specialty, providing data to support decisions about when and to whom to direct research, education, and quality improvement interventions. Methods We tabulated case numbers for privately insured patients undergoing thyroid and parathyroid surgery in Marketscan: 2010–2016 and trainee case logs for residents and fellows in general surgery and otolaryngology. Summary statistics and tests for trends and differences were calculated. Results Marketscan data captured 114 500 thyroid surgeries. The proportion performed by each specialty was not significantly different. Otolaryngologists performed 58 098 and general surgeons performed 56 402. Otolaryngologists more commonly performed hemithyroidectomy (n = 25 148, 43.29% of all thyroid surgeries performed by otolaryngologists) compared to general surgeons (n = 20 353, 36.09% of all thyroid surgeries performed by general surgeons). Marketscan data captured 21 062 parathyroid surgeries: 6582 (31.25%) were performed by otolaryngologists, and 14 480 (68.75%) were performed by general surgeons. The case numbers of otolaryngology and general surgery trainees completing residency and fellowship varied 6- to 9-fold across different sites. The wide variation may reflect both the level of exposure a particular training program offers and trainee level of interest. Conclusion Thyroid surgical care is equally provided by general surgeons and otolaryngologists. Both specialties contribute significantly to parathyroid surgical care. Both specialties should provide input into and be targets of research, quality, and education interventions.

Objective Active surveillance for low-risk papillary thyroid cancer (PTC) was endorsed by the American Thyroid Association guidelines in 2015. The attitudes and beliefs of physicians treating thyroid cancer regarding the active surveillance approach are not known. Methods A national survey of endocrinologists and surgeons treating thyroid cancer was conducted from August to September 2017 via professional society emails. This mixed-methods analysis reported attitudes toward potential factors impacting decision-making regarding active surveillance, beliefs about barriers and facilitators of its use, and reasons why physicians would pick a given management strategy for themselves if they were diagnosed with a low-risk PTC. Survey items about attitudes and beliefs were derived from the Cabana model of barriers to guideline adherence and theoretical domains framework of behavior change. Results Among 345 respondents, 324 (94%) agreed that active surveillance was appropriate for at least some patients, 81% agreed that active surveillance was at least somewhat underused, and 76% said that they would choose surgery for themselves if diagnosed with a PTC of ≤1 cm. Majority of the respondents believed that the guidelines supporting active surveillance were too vague and that the current supporting evidence was too weak. Malpractice and financial concerns were identified as additional barriers to offering active surveillance. The respondents endorsed improved information resources and evidence as possible facilitators to offering active surveillance. Conclusion Although there is general support among physicians who treat low-risk PTC for the active surveillance approach, there is reluctance to offer it because of the lack of robust evidence, guidelines, and protocols.