Search

ImportanceThyroid cancer is the most common pediatric endocrine malignant neoplasm. Disparities in the workup of thyroid nodules may be significantly associated with thyroid cancer outcomes.ObjectiveTo determine the association of sociodemographic factors with the odds of receiving a biopsy, timeliness of the procedure, and risk of nodule malignancy.Design, Setting, and ParticipantsThis was a retrospective cross-sectional study using insurance claims data from the Optum Clinformatics Data Mart database. The study cohort comprised pediatric patients diagnosed with single thyroid nodules between 2003 and 2020. Data analysis was performed from January 1, 2003, to June 30, 2020.Main Outcomes and MeasuresMultivariable logistic regression models were used to identify demographic variables associated with biopsy and nodule malignant neoplasm. A multivariable linear regression model was used to assess the time between thyroid nodule diagnosis and biopsy.ResultsOf 11 643 children (median [IQR] age at diagnosis or procedure, 15 [12-17] years; 8549 [73.2%] were female and 3126 [26.8%] were male) diagnosed with single thyroid nodules, 2117 (18.2%) received a biopsy. Among the patients who received a biopsy, 304 (14.4%) were found to have a malignant nodule. Greater parental education was associated with a shorter diagnosis-to-biopsy interval (mean difference, −7.24 days; 95% CI, −13.75 to −0.73). Older age at nodule diagnosis (odds ratio [OR], 1.11; 95% CI, 1.09-1.13) and female gender (OR, 1.25; 95% CI, 1.11-1.40) were associated with increased odds of receiving a biopsy, while Black/African American (OR, 0.80; 95% CI, 0.65-0.99) and Hispanic (OR, 0.84; 95% CI, 0.72-0.99) patients had lower odds of receiving a biopsy compared with White patients. Finally, female gender (OR, 1.08; 95% CI, 0.80-1.47) was not associated with lower odds of nodule malignant neoplasm.Conclusions and RelevanceFindings of this cross-sectional study highlight disparities in the diagnostic management of pediatric thyroid nodules. These results call for future work to ensure equitable access to thyroid care for all children.

To assess the incidence, clinical presentation, and survival in Native Hawaiian and other Pacific Islander (NHPI) patients with well-differentiated thyroid cancer.This population-based incidence analysis and retrospective cohort study utilized data from the Surveillance, Epidemiology, and End Results database.Incidence analysis included patients diagnosed between 1990 and 2014, while the cohort to study clinical presentation and survival comprised patients diagnosed between 2004 and 2015.Incidence rates and trends were compared among NHPI, Asian, and non-Hispanic White (NHW) populations. Clinical presentation was assessed via multivariable logistic regression. Survival was assessed per Cox regression.Recent incidence trends (2009-2014) show that the rate of increase remained consistent among NHPI patients (annual percentage change, 3.67%; 95% CI, 2.66%-4.69%), while it slowed in the NHW population and plateaued among Asians as compared with previous years. NHPI patients were more likely to present with distant metastasis than NHW patients (odds ratio, 3.37; 95% CI, 1.97-5.36) and Asian patients (odds ratio, 1.82; 95% CI, 1.05-2.97). NHPI race was also associated with advanced T stage and nodal metastasis as compared with the NHW race. Survival outcomes were similar among NHPI, NHW, and Asian patients.Well-differentiated thyroid cancer incidence has increased at a higher rate for the NHPI population as opposed to the NHW and Asian populations in recent years. NHPI patients are more likely to present with advanced disease when compared with NHW and Asian patients. These results highlight the importance of disaggregating the often-combined Asian/Pacific Islander group in epidemiologic studies.

Objectives: This study assesses the impact of adverse histologic risk factors including worst pattern of invasion (WPOI), predominant pattern of invasion (PPOI), tumor budding, and tumor infiltrating lymphocytes (TILS), on risk of recurrence in patients with early-stage Oral Cavity Squamous Cell Carcinoma (OCSCC). Methods: Retrospective chart review was performed at a single institution to identify patients with OCSCC who underwent surgical excision. Inclusion criteria included T1-T2 stage disease based on AJCC seventh edition guidelines, no cervical lymph node involvement, no perineural invasion (PNI), no lymphovascular invasion (LVI), no post-operative adjuvant radiation therapy, and cancer involving only the oral tongue or floor of mouth. Patients were excluded if they had positive final margins. A subset of 35 patients were selected for additional histologic review to determine WPOI, PPOI, TB, and TILS. Bivariable and multivariable cox analysis were performed to determine variables associated with recurrence. Results: One hundred and sixty-one patients met criteria and were included in the analysis. Variables that were significantly associated with recurrence on bivariable analysis included tumors with high risk PPOI (groups 4 and 5; P = .021), TB with 10 or more buds ( P = .021), T-stage ( P = .001), neck dissection ( P = .03), and depth of invasion (DOI) >4 mm ( P = .044). Multivariable cox proportional hazards found T-stage (HR: 6.40; 95% CI 1.67, 24.50; P = .007), neck dissection (HR: 0.23; 95% CI 0.07, 0.82; P = .023), and TBs (HR: 1.17; 95% CI 1.05, 1.30; P = .006) to be most predictive of recurrence. Conclusions: TB is a strong predictor of recurrence. WPOI, PPOI, and TILS were not statistically significant risk factors for recurrence.

ImportanceHuman papillomavirus (HPV) is strongly associated with head and neck cancer, and HPV status is considered a prognostic factor. Being a sexually transmitted infection, HPV-related cancers may have greater risk of stigma and psychological distress; however, the potential association of HPV-positive status with psychosocial outcomes, such as suicide, is understudied in head and neck cancer.ObjectiveTo investigate the association between HPV tumor status and suicide risk among patients with head and neck cancer.Design, Setting, and ParticipantsThis population-based retrospective cohort study included adult patients with clinically confirmed cases of head and neck cancer based on HPV tumor status from the Surveillance, Epidemiology, and End Results database from January 1, 2000, to December 31, 2018. Data analysis was conducted from February 1 to July 22, 2022.Main Outcomes and MeasuresThe outcome of interest was death by suicide. Primary measure was HPV status of tumor site, dichotomized as positive or negative. Covariates included age, race, ethnicity, marital status, cancer stage at presentation, treatment modality, and type of residence. Cumulative risk of suicide among patients with HPV-positive and HPV-negative head and neck cancer was assessed using Fine and Gray competing risk models.ResultsOf 60 361 participants, the mean (SD) age was 61.2 (13.65) years, and 17 036 (28.2%) were women; there were 347 (0.6%) American Indian, 4369 (7.2%) Asian, 5226 (8.7%) Black, 414 (0.7%) Native Hawaiian or Other Pacific Islander, and 49 187 (81.5%) White individuals. A competing risk analysis showed a significant difference in the cumulative incidence of suicide between HPV-positive cancers (5-year suicide-specific mortality, 0.43%; 95% CI, 0.33%-0.55%) and HPV-negative cancers (5-year suicide-specific mortality, 0.24%; 95% CI, 0.19%-0.29%). Tumor status that was HPV positive was associated with increased suicide risk in the unadjusted model (hazard ratio [HR], 1.76; 95% CI, 1.28-2.40), but not the fully adjusted model (adjusted HR, 1.18; 95% CI, 0.79-1.79). Among people with oropharyngeal cancer only, HPV status was associated with increased suicide risk, but the width of the confidence interval prevented definitive conclusion (adjusted HR, 1.61; 95% CI 0.88-2.94).Conclusions and RelevanceThe results of this cohort study suggest that patients with HPV-positive head and neck cancer have similar risk of suicide as patients with HPV-negative cancer, despite differences in overall prognosis. Early mental health interventions may be associated with reduced suicide risk in all patients with head and neck cancer and should be assessed in future work.

Ageing is characterized by the development of persistent pro-inflammatory responses that contribute to atherosclerosis, metabolic syndrome, cancer and frailty1-3. The ageing brain is also vulnerable to inflammation, as demonstrated by the high prevalence of age-associated cognitive decline and Alzheimer's disease4-6. Systemically, circulating pro-inflammatory factors can promote cognitive decline7,8, and in the brain, microglia lose the ability to clear misfolded proteins that are associated with neurodegeneration9,10. However, the underlying mechanisms that initiate and sustain maladaptive inflammation with ageing are not well defined. Here we show that in ageing mice myeloid cell bioenergetics are suppressed in response to increased signalling by the lipid messenger prostaglandin E2 (PGE2), a major modulator of inflammation11. In ageing macrophages and microglia, PGE2 signalling through its EP2 receptor promotes the sequestration of glucose into glycogen, reducing glucose flux and mitochondrial respiration. This energy-deficient state, which drives maladaptive pro-inflammatory responses, is further augmented by a dependence of aged myeloid cells on glucose as a principal fuel source. In aged mice, inhibition of myeloid EP2 signalling rejuvenates cellular bioenergetics, systemic and brain inflammatory states, hippocampal synaptic plasticity and spatial memory. Moreover, blockade of peripheral myeloid EP2 signalling is sufficient to restore cognition in aged mice. Our study suggests that cognitive ageing is not a static or irrevocable condition but can be reversed by reprogramming myeloid glucose metabolism to restore youthful immune functions.

To describe the natural history, detail the treatment patterns, and identify the risk factors for cochlear implant (CI) infections in a large US cohort.Retrospective study based on insurance claims.Optum Data Mart database: 6101 patients who received CIs from 2003 to 2019.Infections, treatments patterns, and timelines were described. A multivariable logistic regression model was used to assess the association between postoperative oral antibiotics and CI infection.The cohort includes 4736 (77.6%) adults and 1365 (22.4%) children. Between adult and pediatric patients, rates of CI infection (5.1% vs 4.5%,Postoperative oral antibiotics were not associated with lower risk of infection or interventions. Otitis media episodes and lower income were associated with increased risk of infection among adults as well as intervention overall. Infection typically presented within the first 6 months after surgery, with children presenting earlier than adults. Overall, our findings serve as a resource for providers to consider in their care of patients with CIs.

Parotid gland incidentaloma (PGI) management has not been well characterized in the literature. This study assesses clinicopathologic features, initial evaluation, management, and outcomes of PGIs discovered on various imaging modalities.This is a retrospective case series from a single academic institution. The study cohort included 34 patients with parotid gland incidentalomas discovered between January 2009 and December 2019.Parotid gland incidentalomas were most frequently identified on magnetic resonance imaging (16 patients, 47.1%). Most patients (26 patients, 76.5%) underwent further evaluation with subsequent imaging, most often magnetic resonance imaging (18 patients, 69.2%), and fine needle aspiration biopsy (33 patients, 97.1%). Most tumors were benign on fine needle aspiration biopsy (19 patients, 57.6%). Most cases (21 patients, 61.8%) were managed with observation without parotidectomy. Malignant findings on fine needle aspiration cytology were associated with increased likelihood of undergoing parotidectomy (25% vs 0%; p = 0.04). Among the patients who received a parotidectomy, most (8 patients, 61.5%) had benign findings on final histopathology.Parotid gland incidentalomas were discovered across a diverse set of imaging modalities in our institution. Magnetic resonance imaging and fine needle aspiration were often performed for further evaluation. Most cases were found to be benign on fine needle aspiration and were managed with observation. These findings highlight the necessity of appropriate work-up for these tumors, and the need for shared decision making between the patient and the physician in selecting the appropriate treatment strategy.

Objectives To evaluate the rate of lymph node metastasis in parotid gland acinar cell carcinoma, to identified factors associated with increased risk of metastasis, and to evaluate the effect of nodal metastasis on survival. Methods This is a retrospective cohort study utilizing data from a large population-based cancer database. Data were extracted from the Surveillance, Epidemiology, and End Results (SEER) 18 database. The study cohort included patients with parotid gland acinar cell carcinoma diagnosed between 2000 and 2015. Results The overall rate of lymph node metastasis was 6.8%. T3/T4 (OR 6.17, 95% CI, 3.03 to 13.16) disease along with High Grade (OR 15.95) disease were associated with increased risk of nodal metastasis. Non-white, non-Black race was associated with decreased risk. Age and sex were not associated with nodal metastasis. Nodal metastasis was associated with worse OS (HR 6.27, 95% CI, 3.85 to 10.20) and DSS (HR 6.96, 95% CI, 3.81 to 12.73) after adjusting for covariates. Conclusion Parotid gland acinar cell carcinoma carries a low risk of nodal metastasis. Both advanced T stage and high grade are associated with increased risk of nodal metastasis. Nodal metastasis is associated with decreased overall survival. Level of evidence 3 Laryngoscope, 131:E1125-E1129, 2021.

This case-control study investigates whether diffusion-weighted imaging shows microstructural abnormalities across the brain regions of children with pediatric acute-onset neuropsychiatric syndrome., Key Points Question How does diffusion-weighted magnetic resonance imaging differ between patients with pediatric acute-onset neuropsychiatric syndrome and pediatric control participants? Findings In this case-control study of 34 consecutive patients with pediatric acute-onset neuropsychiatric syndrome who had 3 Tesla magnetic resonance imaging, all assessed brain regions, particularly the deep gray matter (eg, the thalamus, basal ganglia, and amygdala), had statistically significantly increased mean diffusivity compared with 64 control participants. These diffusion abnormalities are consistent with the cardinal clinical symptoms of these patients, including obsessions, compulsions, emotional dysregulation, and sleep disturbances. Meaning Diffusion-weighted magnetic resonance imaging may offer valuable quantitative information to assist with the diagnostic workup of pediatric acute-onset neuropsychiatric syndrome., Importance Epidemiological studies indicate a link between obsessive-compulsive disorder and infections, particularly streptococcal pharyngitis. Pediatric acute-onset neuropsychiatric syndrome (PANS) manifests suddenly with obsessions, compulsions, and other behavioral disturbances, often after an infectious trigger. The current working model suggests a unifying inflammatory process involving the central nervous system, particularly the basal ganglia. Objective To investigate whether diffusion-weighted magnetic resonance imaging (DWI) detects microstructural abnormalities across the brain regions of children with PANS. Design, Setting, and Participants Case-control study performed at a single-center, multidisciplinary clinic in the United States focusing on the evaluation and treatment of children with PANS. Sixty consecutive patients who underwent 3 Tesla (T) magnetic resonance imaging (MRI) before immunomodulation from September 3, 2012, to March 30, 2018, were retrospectively reviewed for study inclusion. Six patients were excluded by blinded investigators because of imaging or motion artifacts, 3 patients for major pathologies, and 17 patients for suboptimal atlas image registration. In total, 34 patients with PANS before initiation of treatment were compared with 64 pediatric control participants. Main Outcomes and Measures Using atlas-based MRI analysis, regional brain volume, diffusion, and cerebral blood flow were measured in the cerebral white matter, cerebral cortex, thalamus, caudate, putamen, pallidum, hippocampus, amygdala, nucleus accumbens, and brainstem. An age and sex–controlled multivariable analysis of covariance was used to compare patients with control participants. Results This study compared 34 patients with PANS (median age, 154 months; age range, 55-251 months; 17 girls and 17 boys) and 64 pediatric control participants (median age, 139 months; age range, 48-213 months); 41 girls and 23 boys). Multivariable analysis demonstrated a statistically significant difference in MRI parameters between patients with PANS and control participants (F21,74 = 6.91; P

Highlights • Microstructural and macrostructural changes in sensorineural hearing loss. • Magnetic resonance imaging as tool to assess cerebral volume and diffusion. • Greater diffusion in cortex, thalamus, caudate, brainstem with hearing loss. • Smaller brainstem volume with hearing loss. • Connexin 26, Pendrin mutations show diffusion changes in brainstem and thalamus., Purpose Sensorineural hearing loss (SNHL) is the most prevalent congenital sensory deficit in children. Information regarding underlying brain microstructure could offer insight into neural development in deaf children and potentially guide therapies that optimize language development. We sought to quantitatively evaluate MRI-based cerebral volume and gray matter microstructure children with SNHL. Methods & Materials We conducted a retrospective study of children with SNHL who obtained brain MRI at 3 T. The study cohort comprised 63 children with congenital SNHL without known focal brain lesion or structural abnormality (33 males; mean age 5.3 years; age range 1 to 11.8 years) and 64 age-matched controls without neurological, developmental, or MRI-based brain macrostructure abnormality. An atlas-based analysis was used to extract quantitative volume and median diffusivity (ADC) in the following brain regions: cerebral cortex, thalamus, caudate, putamen, globus pallidus, hippocampus, amygdala, nucleus accumbens, brain stem, and cerebral white matter. SNHL patients were further stratified by severity scores and hearing loss etiology. Results Children with SNHL showed higher median ADC of the cortex (p = .019), thalamus (p

Recent advances highlight a pivotal role for cellular metabolism in programming immune responses. Here, we demonstrate that cell-autonomous generation of nicotinamide adenine dinucleotide (NAD(+)) via the kynurenine pathway (KP) regulates macrophage immune function in aging and inflammation. Isotope tracer studies revealed that macrophage NAD(+) derives substantially from KP metabolism of tryptophan. Genetic or pharmacological blockade of de novo NAD(+) synthesis depleted NAD(+), suppressed mitochondrial NAD(+)-dependent signaling and respiration, and impaired phagocytosis and resolution of inflammation. Innate immune challenge triggered upstream KP activation but paradoxically suppressed cell-autonomous NAD(+) synthesis by limiting the conversion of downstream quinolinate to NAD(+), a profile recapitulated in aging macrophages. Increasing de novo NAD(+) generation in immune-challenged or aged macrophages restored oxidative phosphorylation and homeostatic immune responses. Thus, KP-derived NAD(+) operates as a metabolic switch to specify macrophage effector responses. Breakdown of de novo NAD(+) synthesis may underlie declining NAD(+) levels and rising innate immune dysfunction in aging and age-associated diseases.

Botticelli et al. proposed the activity of indoleamine-2,3-dioxygenase 1 (IDO) as a potential mechanism and predictive marker for primary resistance against anti-PD-1 treatment in the context of non-small cell lung cancer. However, there are a few points for the authors to address in order to strengthen their claims. First, there are many enzymes that modulate the kynurenine to tryptophan ratio, thereby calling into question their use of the ratio as a proxy for IDO activity. Second, the authors could compare IDO to other proposed markers in the literature, providing a better understanding of its predictive value.

BACKGROUND Neurofibromatosis Type 1 (NF1) is a multisystem disorder with wide ranging clinical implications. Patients may present with macrocephaly, stroke, and cognitive deficits, all of which may impede normal neural development. We applied atlas-based, multi-parametric MRI analysis of regional brain to evaluate diffusion, arterial spin-labeled (ASL) perfusion, and volumetric changes in children with NF1. METHODS Children evaluated for NF1 from 2009 to 2018 at Stanford University (n=78) were retrospectively reviewed and compared to healthy controls (n=100). All patients underwent diffusion-weighted (DWI) magnetic resonance imaging at 3T, and children with brain tumors were excluded. Using atlas-based DWI analyses, we assessed volume, median apparent diffusion coefficient (ADC), and cerebral blood flow in the cerebral cortex, thalamus, caudate, putamen, globus pallidus, hippocampus, amygdala, nucleus accumbens, brain stem, and cerebral white matter. We also measured volume of the lateral ventricles. Multivariate analysis of covariance was used to test for differences between controls and NF1 patients, controlling for gender and age at time of imaging. RESULTS Comparing NF1 to controls, we detected increased volume and decreased ASL cerebral blood flow in white matter and all subcortical and cortical structures except for brainstem volume. Median ADC was also increased in the thalamus, pallidum, hippocampus, and brainstem. CONCLUSIONS Using a multi-parametric approach, we demonstrate quantitative measures of microstructural and physiologic changes of the NF1 brain. Atlas-based, quantitative MRI brain signatures may serve as biomarkers of neural development and further provide insight into associated cognitive dysfunction or risks for vasculopathy-related strokes in children with NF1.

High volume manufacturing (HVM) for silicon devices poses numerous challenges beyond simply designing and demonstrating a useful product. This paper describes several of those challenges using examples from Intel's HVM experience fabricating on-die interconnects for high performance logic products at the 45nm process node.

Copper interconnects require two types of barrier layers: a liner on the sides and bottoms of the damascene features and a cap on top of the damascene features. The key functions of the barrier layers are to prevent copper and oxygen diffusion and promote adhesion with both the interlayer dielectric (ILD) and the copper. The cap layer must also protect the copper from corrosion during subsequent patterning steps and act as an etchstop for partially landed vias. Most copper damascene processes use a PVD Ta and/or Ta(N) alloy liner and PECVD SiN or SiCN dielectric cap. However, as copper interconnects continue to scale to finer dimensions these metal barrier technologies become problematic due to wiring resistance and current density issues. This paper describes some of the alternative liner and cap technologies that are being developed to address these issues.

A leading edge 130 nm technology with 6 layers of Cu interconnects and 1.3 V operation has previously been presented (Tyagi et al., 2000). In this work, we enhance the previous technology with the following: transistor improvements which support a 60 nm gate dimension and increased drive current, improved 6-T SRAM device matching to allow low power and high performance operation from 0.7 to 1.4 V, and a 5% linear shrink to reduce the 6-T SRAM cell to 2.00 /spl mu/m/sup 2/ while still using 248 nm lithography. Saturation drive currents of 1.30 mA//spl mu/m for N-channel and 0.66 mA//spl mu/m for P-channel low VT devices are the highest reported to date. Excellent device short channel effects are obtained for the 60 nm gate length devices as measured by the 270 mV threshold voltage and

A leading edge 130 nm generation logic technology with 6 layers of dual damascene Cu interconnects is reported. Dual Vt transistors are employed with 1.5 nm thick gate oxide and operating at 1.3 V. High Vt transistors have drive currents of 1.03 mA//spl mu/m and 0.5 mA//spl mu/m for NMOS and PMOS respectively, while low Vt transistors have currents of 1.17 mA//spl mu/m and 0.6 mA//spl mu/m respectively. Technology design rules allow a 6-T SRAM cell with an area of 2.45 /spl mu/m/sup 2/, while array specific design rule give the densest SRAM reported to date, the 6-T cell has an area of only 2.09 /spl mu/m/sup 2/. Excellent yield and performance is demonstrated on a 18 Mbit CMOS SRAM.

The characteristics of various fast ion conductors (FICs) are reviewed with an emphasis on correlating their structural and transport properties. This approach leads toward an improved understanding of the cause of fast ion conduction in solids and suggests avenues for future research and applications. All three categories of fast ion conductors—extrinsic, intrinsic and amorphous—are briefly reviewed. Special attention is focused on (a) some of the newer, intrinsically disordered oxygen conductors such as α-Ta 2 O 5 and the pyrochlore system Gd 2 (Zr x Ti 1−x ) 2 O 7 , (b) amorphous cation conductors both organic and inorganic and (c) two-phase composite systems. Some of the more promising new FICs are discussed in relation to applications which will probably become increasingly important before the end of the century including fuel cells, batteries, sensors, electrochemical pumps and smart windows.