Key points Sound information is transmitted by different subtypes of spiral ganglion neurons (SGN) from the ear to the brain. Selective damage of SGN peripheral synapses (cochlear synaptopathy) is widely recognized as one of the primary mechanisms of hearing loss, whereas the mechanisms at the SGN central synapses remain unclear. We report that different subtypes of SGN central synapses converge at different ratios onto individual target cochlear nucleus neurons with distinct physiological properties, and show biased morphological and physiological changes during age‐related hearing loss (ARHL). The results reveal a new dimension in cochlear nucleus neural circuitry that systematically reassembles and processes auditory information from different SGN subtypes, which is altered during ageing and probably contributes to the development of ARHL. In addition to known cochlear synaptopathy, the present study shows that SGN central synapses are also pathologically changed during ageing, which collectively helps us better understand the structure and function of SGNs during ARHL. Abstract Sound information is transmitted from the cochlea to the brain by different subtypes of spiral ganglion neurons (SGN), which show varying degrees of vulnerability under pathological conditions. Selective cochlear synaptopathy, the preferential damage of certain subtypes of SGN peripheral synapses, has been recognized as one of the main mechanisms of hearing loss. The organization and function of the auditory nerve (AN) central synapses from different subtypes of SGNs remain unclear, including how different AN synapses reassemble onto individual neurons in the cochlear nucleus, as well as how they differentially change during hearing loss. Combining immunohistochemistry with electrophysiology, we investigated the convergence pattern and subtype‐specific synaptopathy of AN synapses at the endbulb of Held, as well as the response properties of their postsynaptic bushy neurons in CBA/CaJ mice of either sex under normal hearing and age‐related hearing loss (ARHL). We found that calretinin‐expressing (type Ia) and non‐calretinin‐expressing (type Ib/Ic) endbulbs converged along a continuum of different ratios onto individual bushy neurons with varying physiological properties. Endbulbs degenerated during ageing in parallel with ARHL. Furthermore, the degeneration was more severe in non‐calretinin‐expressing synapses, which correlated with a gradual decrease in bushy neuron subpopulation predominantly innervated by these inputs. These synaptic and cellular changes were profound in middle‐aged mice when their hearing thresholds were still relatively normal and prior to severe ARHL. Our findings suggest that biased AN central synaptopathy and the correlated shift in cochlear nucleus neuronal composition play significant roles in weakened auditory input and altered central auditory processing during ARHL.

Background: Hypertrophic cardiomyopathy (HCM)-related mortality has been decreasing within the United States; however, persistent disparities in demographic subsets may exist. In this study, we assessed nationwide trends in mortality related to HCM among people ≥15 years of age in the United States from 1999 to 2019. Methods: Trends in mortality related to HCM were assessed through a cross-sectional analysis of the Centers for Disease Control and Prevention Wide-Ranging Online Data for Epidemiological Research database. Age-adjusted mortality rates per 1 000 000 people and associated annual percent changes with 95% CIs were determined. Joinpoint regression was used to assess the trends in the overall, demographic (sex, race and ethnicity, age), and regional groups. Results: Between 1999 and 2019, 39 200 HCM-related deaths occurred. In the overall population, age-adjusted mortality rate decreased from 11.2 in 1999 to 5.4 in 2019. Higher mortality rates were observed for males, Black patients, and patients ≥75 years of age. Large metropolitan counties experienced pronounced declines in age-adjusted mortality rate over the study period. In addition, California had the highest overall age-adjusted mortality rate. Conclusions: Over the past 2 decades, HCM-related mortality has decreased overall in the United States. However, demographic and geographic disparities in HCM-related mortality have persisted over time and require further investigation.

Sound information is transmitted from the cochlea to the brain by different subtypes of spiral 22 ganglion neurons (SGN), which show varying degrees of vulnerbility under pathological conditions. 23It remains unclear how information from these SGNs reassemble among target neurons in the 24 cochlear nucleus (CN) at the auditory nerve (AN) central synapses, and how different synapses 25 change during hearing loss. Combining immunohistochemistry with electrophysiology, we 26 investigated the giant endbulb of Held synapses and their postsynaptic bushy neurons in mice 27 under normal hearing and age-related hearing loss (ARHL). We found that calretinin-expressing 28 and non-calretinin-expressing endbulbs converge at continuously different ratios onto bushy 29 neurons with varying physiological properties. Endbulbs degenerate during ARHL, and the 30 degeneration is more severe in non-calretinin-expressing synapses, which correlates with a 31 gradual decrease in neuronal subpopulation predominantly innervated by these inputs. Our 32 findings suggest that biased AN central synaptopathy and shifted CN neuronal composition 33 underlie reduced auditory input and altered central auditory processing during ARHL. 34 35 36 37 38 Key Words 39 Auditory nerve central synapse, synaptopathy, age-related hearing loss, spiral ganglion neuron, 40 calretinin, VGluT1, endbulb of Held, bushy neuron, cochlear nucleus, synaptic convergence 41 42 43 4476 Wright et al., 2014;Xie and Manis, 2017b;Zhuang et al., 2017), which degrades the firing of 77 postsynaptic bushy neurons (Xie, 2016). Despite decades of research on the endbulbs of Held, 78 4 little is known about the convergence of-as well as how synaptopathy occurs among-different 79 subtypes of endbulb of Held synapses during hearing loss. Furthermore, the impacts of subtype-80 specific synaptopathy on the response properties of postsynaptic bushy neurons remain unclear. 82To investigate these questions, we combined immunohistochemistry with electrophysiology using 83 acute brain slices from CBA/CaJ mice at three age groups: young mice (1.5-4.5 months) with 84 normal hearing, middle-aged mice (17-19 months) with moderate ARHL that mimics hidden 85 hearing loss (Sergeyenko et al., 2013), and old mice (28-32 months) with prominent ARHL. 86Endbulb synapses from type Ia SGNs (high spontaneous rate/low threshold) were differentiated 87 from the other subtypes (type Ib or Ic SGNs with medium/low spontaneous rate and medium/high 88 threshold) based on immunostaining for calretinin (Petitpre et al., 2018; Shrestha et al., 2018; Sun 89 et al., 2018). We report the innervation patterns of type Ia and non-type Ia endbulbs on individual 90 bushy neurons and their intrinsic and AN-evoked response properties, as well as subtype-specific 91 AN central synaptopathy during ARHL. 92 93 RESULTS 94 Multiple subtypes of AN central synapses converge onto individual CN neurons 95We performed current clamp recording from bushy neurons in parasagittal CN slices and filled 96 the target neurons with Alexa Fluor 5...

Socioeconomic status is an overlooked risk factor for cardiovascular disease (CVD). Low family income is a measure of socioeconomic status and may portend greater CVD risk. Therefore, we assessed the association of family income with cardiovascular risk factor and disease burden in American adults. This retrospective analysis included data from participants aged ≥ 20 years from the National Health and Nutrition Examination Survey (NHANES) cycles between 2005 and 2018. Family income to poverty ratio (PIR) was calculated by dividing family (or individual) income by poverty guidelines specific to the survey year and used as a measure of socioeconomic status. The association of PIR with the presence of cardiovascular risk factors and CVD as well as cardiac mortality and all-cause mortality was examined. We included 35,932 unweighted participants corresponding to 207,073,472 weighted, nationally representative participants. Participants with lower PIR were often female and more likely to belong to race/ethnic minorities (non-Hispanic Black, Mexican American, other Hispanic). In addition, they were less likely to be married/living with a partner, to attain college graduation or higher, or to have health insurance. In adjusted analyses, the prevalence odds of diabetes mellitus, hypertension, coronary artery disease (CAD), congestive heart failure (CHF), and stroke largely decreased in a step-wise manner from highest (≥ 5) to lowest PIR (< 1). In adjusted analysis, we also noted a mostly dose-dependent association of PIR with the risk of all-cause and cardiac mortality during a mean 5.7 and 5.8 years of follow up, respectively. Our study demonstrates a largely dose-dependent association of PIR with hypertension, diabetes mellitus, CHF, CAD and stroke prevalence as well as incident all-cause mortality and cardiac mortality in a nationally representative sample of American adults. Public policy efforts should be directed to alleviate these disparities to help improve cardiovascular outcomes in vulnerable groups with low family income.

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