Update on Pediatric Thyroid Cancer Incidence and Mortality Trends in the United States, 2000-2018.

Thyroid cancer is the most common endocrine malignancy in the pediatric population. A recent study has revealed a recent decline in overall US thyroid cancer incidence rates. The aim of this study is to assess whether there has been a corresponding decline in incidence rates in the pediatric population. We used the Surveillance, Epidemiology, and End Results (SEER) database to analyze the pediatric thyroid cancer incidence rate. The results demonstrate that the incidence rate of pediatric thyroid cancer continued to increase from 2000 to 2018. Future studies are needed to understand how recent changes in guidelines are affecting incidence rates.

Thyroid Cancer Incidence Among Korean Individuals: A Comparison of South Korea and the United States.

OBJECTIVE: To compare thyroid cancer incidence rates and trends between Korean, non-Korean Asian, and non-Hispanic White populations in the United States, and between the US Korean population and the South Korean population. METHOD: Population-based analysis of cancer incidence data. Cases of thyroid cancer diagnosed during 1999-2014 from the Korean Central Cancer Registry (KCCR) and the Surveillance, Epidemiology, and End Results (SEER) 9 detailed Asian/Pacific Islander subgroup incidence and population dataset were included. Incidence rates were obtained from the datasets, and annual percent change (APC) of the incidence rates was calculated using Joinpoint regression analysis. RESULTS: Thyroid cancer incidence rate for 1999-2014 was significantly higher for South Korea (48.05 [95% CI 47.89-48.22] per 100,000 person-years) than for the US Korean population (11.12 [95% CI 10.49-11.78] per 100,000 person-years), which was slightly higher than the Non-Korean Asian population (10.23 [95% CI 10.02-10.43] per 100,000 person-years), and slightly lower than the Non-Hispanic White population (12.78 [95% CI 12.69-12.87] per 100,000 person-years). Incidence rates in South Korea increased dramatically (average APC 17.9, 95% CI 16.0-19.9), significantly higher than the US Korean population (average APC 5.0, 95% CI 3.1-6.8), which was similar to the non-Korean Asian (average APC 2.5, 95% CI 0.9-4.2) and the non-Hispanic White (average APC 5.1, 95% CI 4.7-5.6) populations. CONCLUSIONS: South Korea's high thyroid cancer incidence rates cannot be attributed to genetic factors, but are likely due to health care system factors. LEVEL OF EVIDENCE: 3 Laryngoscope, 2024.

Microstructural Changes in the Brainstem Auditory Pathway in Children With Hearing Loss.

OBJECTIVE: To assess the utility of diffusion tensor imaging of the auditory pathway in children with sensorineural hearing loss (SNHL). STUDY DESIGN: Retrospective cohort study. SETTING: A single academic tertiary children's hospital. PATIENTS: Sixteen pediatric patients with bilateral SNHL of at least moderate severity in the poorer ear (eight male; mean age, 5.3 ± 4.9 yrs). Controls consisted of age- and sex-matched children with normal hearing who were imaged for nonotologic, non-neurologic medical concerns and found to have normal magnetic resonance imaging (MRI). INTERVENTIONS: Three Tesla MRI scanners were used for diffusion tensor imaging. MAIN OUTCOME MEASURES: Quantitative diffusion tensor metrics were extracted from the superior olivary nucleus (SON), inferior colliculus (IC), and ipsilateral fiber tracts between the SON and IC delineated by tractography. RESULTS: We identified differences in fractional anisotropy of the SON between the SNHL cohort and controls (0.377 ± 0.056 vs. 0.422 ± 0.052; p = 0.009), but not in the IC. There were no differences in the mean diffusivity (MD) values in the IC and SON. Among younger children (≤5 yrs), MD was decreased in the SNHL cohort compared with controls in the IC (0.918 ± 0.051 vs. 1.120 ± 0.142; p < 0.001). However, among older children (>5 yrs), there were no differences in MD (1.124 ± 0.198 vs. 0.997 ± 0.103; p = 0.119). There were no differences in MD or fractional anisotropy in the white matter fibers of the IC-SON tract. CONCLUSIONS: Our results suggest abnormal neural tracts along the central auditory pathway among children with SNHL. Longitudinal studies should assess the prognostic value of these MRI-based findings for assessing long-term outcomes and determining intervention efficacy.

Nonopioid Versus Opioid Analgesics After Thyroid and Parathyroid Surgery: A Systematic Review.

OBJECTIVE: To determine whether nonopioid analgesic regimens, taken after discharge for thyroid and parathyroid surgery have noninferior pain outcomes in comparison to opioid analgesic regimens. Secondarily, we sought to determine if nonopioid analgesic regimens decrease the number of opioid medications taken after thyroid and parathyroid surgery, and to assess adverse events associated with opioid versus nonopioid regimens. DATA SOURCES: PubMed, Embase, Cochrane. REVIEW METHODS: A comprehensive search of the literature was performed according to the PRISMA guidelines, and identified 1299 nonduplicate articles for initial review of which 2 randomized controlled trials (RCTs) were identified as meeting all eligibility criteria. Meta-analysis was not conducted due to heterogeneity in the data and statistical analyses. RESULTS: Both RCTs included in this systematic review found no significant differences in postoperative pain scores between individuals discharged with a nonopioid only analgesic regimen compared to analgesic regimen that included oral opioid medications. One study reported significantly increased number of postoperative calls related specifically to pain in the nonopioid arm compared to the opioid arm (15.6% vs. 3.2%, P = .045). CONCLUSION: This systematic review of RCTs revealed a limited number of studies examining nonopioid versus opioid postoperative pain medications among adults who undergo thyroid and parathyroid surgery. Among the 2 RCTs on this topic, there is a shared finding that nonopioid analgesic regimens are noninferior to opioid analgesic regimens in managing postoperative pain after thyroid and parathyroid surgery, supporting the use of nonopioid pain regimens given the risk of opioid dependence associated with prescription opioid medications.

Single Versus Multigene Testing for Hereditary Hearing Loss: Use and Costs in a Commercially Insured Cohort.

OBJECTIVE: The objectives of this study were to describe trends in single-gene GJB2/6 (connexin 26/30) and multigene hearing loss panel (HLP) testing for hereditary hearing loss using real-world evidence. STUDY DESIGN: Retrospective study using insurance claims data. SETTING: Optum Data Mart database from 2015 to 2020. METHODS: Rates of overall and hearing-specific genetic testing and costs to insurers and patients were reported. Linear regression models were used to assess the proportion of single-gene GJB2/6 testing over time. Additional linear regression models were used to assess changes in costs over time. RESULTS: From 2015 to 2020, 91,986 children received genetic testing for any indication, of which 601 (0.65%) received hearing-specific tests. The proportion of single-gene GJB2/6 testing remained similar over time (mean difference [MD]: -1.3% per year; 95% confidence interval [CI]: -4.3%, 1.7%), while multigene HLP use increased over time (MD: 4.0% per year; 95% CI: 0.4%, 7.5%). The median charge for single-gene GJB2/6 testing remained constant during the study period (MD: -$34; 95% CI: -$86, $18), while the median charge for multigene HLP decreased during the study period (MD: -$145 per year; 95% CI: -$278, -$12). CONCLUSION: Compared to molecular testing for GJB2/6, HLPs are becoming more common for hereditary hearing loss. The comprehensiveness of HLP and decreasing costs provide justification for its more widespread adoption moving forward.

Association of Human Papillomavirus Status With Suicide Risk Among Patients With Head and Neck Cancer.

Importance: Human 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. Objective: To investigate the association between HPV tumor status and suicide risk among patients with head and neck cancer. Design, Setting, and Participants: This 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 Measures: The 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. Results: Of 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 Relevance: The 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.

Impact of Histologic Risk Factors on Recurrence Rates for Oral Cavity Squamous Cell Carcinoma.

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.

Thyroid Cancer Incidence, Clinical Presentation, and Survival Among Native Hawaiian and Other Pacific Islanders.

OBJECTIVE: To assess the incidence, clinical presentation, and survival in Native Hawaiian and other Pacific Islander (NHPI) patients with well-differentiated thyroid cancer. STUDY DESIGN: This population-based incidence analysis and retrospective cohort study utilized data from the Surveillance, Epidemiology, and End Results database. SETTING: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Sociodemographic Disparities in the Diagnostic Management of Pediatric Thyroid Nodules.

Importance: Thyroid cancer is the most common pediatric endocrine malignant neoplasm. Disparities in the workup of thyroid nodules may be significantly associated with thyroid cancer outcomes. Objective: To 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 Participants: This 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 Measures: Multivariable 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. Results: Of 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 Relevance: Findings 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.

Early Onset Diffusion Abnormalities in Refractory Headache Disorders.

Objective: This study sought to determine if individuals with medically refractory migraine headache have volume or diffusion abnormalities on neuroimaging compared to neurotypical individuals. Background: Neuroimaging biomarkers in headache medicine continue to be limited. Early prediction of medically refractory headache and migraine disorders could result in earlier administration of high efficacy therapeutics. Methods: A single-center, retrospective, case control study was performed. All patients were evaluated clinically between 2014 and 2018. Individuals with medically refractory migraine headache (defined by ICDH-3 criteria) without any other chronic medical diseases were enrolled. Patients had to have failed more than two therapeutics and aura was not exclusionary. The initial MRI study for each patient was reviewed. Multiple brain regions were analyzed for volume and apparent diffusion coefficient values. These were compared to 81 neurotypical control patients. Results: A total of 79 patients with medically refractory migraine headache were included and compared to 74 neurotypical controls without headache disorders. Time between clinical diagnosis and neuroimaging was a median of 24 months (IQR: 12.0-37.0). Comparison of individuals with medically refractory migraine headache to controls revealed statistically significant differences in median apparent diffusion coefficient (ADC) in multiple brain subregions (p < 0.001). Post-hoc pair-wise analysis comparing individuals with medically refractory migraine headache to control patients revealed significantly decreased median ADC values for the thalamus, caudate, putamen, pallidum, amygdala, brainstem, and cerebral white matter. No volumetric differences were observed between groups. Conclusions: In individuals with medically refractory MH, ADC changes are measurable in multiple brain structures at an early age, prior to the failure of multiple pharmacologic interventions and the diagnosis of medically refractory MH. This data supports the hypothesis that structural connectivity issues may predispose some patients toward more medically refractory pain disorders such as MH.

Infectious Complications Following Cochlear Implant: Risk Factors, Natural History, and Management Patterns.

OBJECTIVE: To describe the natural history, detail the treatment patterns, and identify the risk factors for cochlear implant (CI) infections in a large US cohort. STUDY DESIGN: Retrospective study based on insurance claims. SETTING: Optum Data Mart database: 6101 patients who received CIs from 2003 to 2019. METHODS: 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. RESULTS: 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%, P = .18) and explantation (1.2% vs 0.8%, P = .11) were not significantly different. Infections typically occurred within 5 months of surgery. Children were diagnosed with CI infection earlier than adults (median difference, -1.5 months; P = .001). Postoperative oral antibiotic supply was not associated with lower risk of CI infection in either children or adults. However, among adults, otitis media was associated with higher odds of CI infection (odds ratio, 1.41; P < .001), while higher income was associated with lower odds of CI infection (odds ratio, 0.71; P = .03). CONCLUSIONS: 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.

Thyroid Cancer Incidence and Mortality Trends in the United States: 2000-2018.

Background: Thyroid cancer incidence has significantly increased in the United States over the past few decades. Recent studies have suggested a change in thyroid cancer incidence trends following 2013. The main objective of this study was to update the data on thyroid cancer incidence and mortality trends in the United States. Methods: Thyroid cancer incidence and incidence-based mortality trends were evaluated using the Surveillance, Epidemiology, and End Results-18 cancer registry. Cases of thyroid cancer diagnosed in 2000-2018 and thyroid cancer deaths during 2000-2018 were included. Annual percent change (APC) was calculated using joinpoint regression analysis. Results: Among 197,070 patients, female (75.6%) and white (81.0%) patients comprised the majority of cases. Papillary thyroid carcinoma (PTC) was the most common histology (89.1%). Incidence rates increased during 2000-2009 (APC 6.80, 95% confidence interval [CI 6.46 to 7.13]) and 2009-2014 (APC 2.58 [CI 1.71 to 3.47]) and then decreased during 2014-2018 (APC -2.33 [CI -3.15 to -1.51]). The incidence trends for PTC overall, localized disease, and tumors ≤1.0 cm mirrored the overall thyroid cancer trends, while incidence rates for regional disease stabilized during 2015-2018 (APC -1.65 [CI -4.09 to 0.84]). The incidence of distant disease decreased during 2015-2018 (APC -17.86 [CI -26.47 to -8.25]). The incidence of tumors ≤1.0 cm decreased (APC -5.83 [CI -7.24 to -4.40]), while the incidence of tumors 1.1-2.0 cm (APC -0.10 [CI -1.16 to 0.96]), 2.1-4.0 cm (APC 1.12 [CI -0.17 to 2.43]), and >4.0 cm (APC -1.13 [CI -4.58 to 2.45]) stabilized during the most recent 4-6 years. Incidence-based mortality increased throughout 2000-2018 (average APC 1.35 [CI 0.88 to 1.82]). Conclusions: Thyroid cancer incidence rates have declined since 2014. Similar declines are noted for PTC, localized disease, and tumors ≤1.0 cm, but not for tumors >2.0 cm. Incidence-based mortality rates continue to increase. These findings suggest that changing patterns in the management of thyroid nodules may have led to a decrease in diagnosis of small indolent tumors, but not more advanced tumors.

Parotid gland incidentalomas: A single-institution experience.

PURPOSE: 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. MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Restoring metabolism of myeloid cells reverses cognitive decline in ageing.

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.

Cerebral volume and diffusion MRI changes in children with sensorineural hearing loss.

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 < .001), caudate (p = .005), and brainstem (p = .003) and smaller brainstem volumes (p = .007) compared to controls. Patients with profound bilateral SNHL did not show any significant differences compared to patients with milder bilateral SNHL, but both cohorts independently had smaller brainstem volumes compared to controls. Children with unilateral SNHL showed greater amygdala volumes compared to controls (p = .021), but no differences were found comparing unilateral SNHL to bilateral SNHL. Based on etiology for SNHL, patients with Pendrin mutations showed higher ADC values in the brainstem (p = .029, respectively); patients with Connexin 26 showed higher ADC values in both the thalamus (p < .001) and brainstem (p < .001) compared to controls. CONCLUSION: SNHL patients showed significant differences in diffusion and volume in brain subregions, with region-specific findings for patients with Connexin 26 and Pendrin mutations. Future longitudinal studies could examine macro- and microstructure changes in children with SNHL over development and potential predictive role for MRI after interventions including cochlear implant outcome.

Association of Pediatric Acute-Onset Neuropsychiatric Syndrome With Microstructural Differences in Brain Regions Detected via Diffusion-Weighted Magnetic Resonance Imaging.

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 < .001; partial η2 = 0.662). All assessed brain regions had statistically significantly increased median diffusivity compared with 64 control participants. Specifically, the deep gray matter (eg, the thalamus, basal ganglia, and amygdala) demonstrated the most profound increases in diffusivity consistent with the cardinal clinical symptoms of obsessions, compulsions, emotional dysregulation, and sleep disturbances. No statistically significant differences were found regarding volume and cerebral blood flow. Conclusions and Relevance: This study identifies cerebral microstructural differences in children with PANS in multiple brain structures, including the deep gray matter structures (eg, the thalamus, basal ganglia, and amygdala). Further study of MRI is warranted in prospective, clinical trials as a potential quantitative method for assessing patients under evaluation for PANS.

Macrophage de novo NAD+ synthesis specifies immune function in aging and inflammation.

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.