Urine Biomarkers of Kidney Tubule Health and Risk of Incident CKD in Persons Without Diabetes: The ARIC, MESA, and REGARDS Studies.

Rationale & Objective: Tubulointerstitial damage is a feature of early chronic kidney disease (CKD), but current clinical tests capture it poorly. Urine biomarkers of tubulointerstitial health may identify risk of CKD. Study Design: Prospective cohort (Atherosclerosis Risk in Communities [ARIC]) and case-cohort (Multi-Ethnic Study of Atherosclerosis [MESA] and Reasons for Geographic and Racial Differences in Stroke [REGARDS]). Setting & Participants: Adults with estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m2 and without diabetes in the ARIC, REGARDS, and MESA studies. Exposures: Baseline urine monocyte chemoattractant protein-1 (MCP-1), alpha-1-microglobulin (α1m), kidney injury molecule-1, epidermal growth factor, and chitinase-3-like protein 1. Outcome: Incident CKD or end-stage kidney disease. Analytical Approach: Multivariable Cox proportional hazards regression for each cohort; meta-analysis of results from all 3 cohorts. Results: 872 ARIC participants (444 cases of incident CKD), 636 MESA participants (158 cases), and 924 REGARDS participants (488 cases) were sampled. Across cohorts, mean age ranged from 60 ± 10 to 63 ± 8 years, and baseline eGFR ranged from 88 ± 13 to 91 ± 14 mL/min/1.73 m2. In ARIC, higher concentrations of urine MCP-1, α1m, and kidney injury molecule-1 were associated with incident CKD. In MESA, higher concentration of urine MCP-1 and lower concentration of epidermal growth factor were each associated with incident CKD. In REGARDS, none of the biomarkers were associated with incident CKD. In meta-analysis of all 3 cohorts, each 2-fold increase α1m concentration was associated with incident CKD (HR, 1.19; 95% CI, 1.08-1.31). Limitations: Observational design susceptible to confounding; competing risks during long follow-up period; meta-analysis limited to 3 cohorts. Conclusions: In 3 combined cohorts of adults without prevalent CKD or diabetes, higher urine α1m concentration was independently associated with incident CKD. 4 biomarkers were associated with incident CKD in at least 1 of the cohorts when analyzed individually. Kidney tubule health markers might inform CKD risk independent of eGFR and albuminuria.

This study analyzed 3 cohorts (ARIC, MESA, and REGARDS) of adults without diabetes or prevalent chronic kidney disease (CKD) to determine the associations of 5 urinary biomarkers of kidney tubulointerstitial health with incident CKD, independent of traditional measures of kidney health. Meta-analysis of results from all 3 cohorts suggested that higher baseline levels of urine alpha-1-microglobulin were associated with incident CKD at follow-up. Results from individual cohorts suggested that in addition to alpha-1-microglobulin, monocyte chemoattractant protein-1, kidney injury molecule-1, and epidermal growth factor may also be associated with the development of CKD. These findings underscore the importance of kidney tubule interstitial health in defining risk of CKD independent of creatinine and urine albumin.

How do beliefs about different human papillomavirus-related diseases vary among young gay, bisexual, and other men who have sex with men in the United States?

Purpose: To determine how beliefs about various disease outcomes caused by human papillomavirus (HPV) infection differ among young gay, bisexual, and other men who have sex with men (YGBMSM). Methods: From 2019 to 2021, we recruited cisgender YGBMSM ages 18-25 in the United States who were unvaccinated against HPV (n = 1,227). Survey items examined three disease outcomes (genital warts, anal cancer, and oropharyngeal cancer) for each of three different beliefs (perceived vulnerability, perceived severity, and worry). Results: Participants reported lower perceived vulnerability to and worry about anal cancer and oropharyngeal cancer compared to genital warts (all p < 0.001). Participants also reported greater perceived severity of anal cancer and oropharyngeal cancer compared to genital warts (all p < 0.001). Some patterns of beliefs differed by participant characteristics. Conclusions: The beliefs of YGBMSM varied by HPV-related disease outcome. Findings can guide future HPV vaccination communication efforts for YGBMSM by informing how to better frame messages and increase relevance.

Consistency of metabolite associations with measured glomerular filtration rate in children and adults.

Background: There is interest in identifying novel filtration markers that lead to more accurate GFR estimates than current markers (creatinine and cystatin C) and are more consistent across demographic groups. We hypothesize that large-scale metabolomics can identify serum metabolites that are strongly influenced by glomerular filtration rate (GFR) and are more consistent across demographic variables than creatinine, which would be promising filtration markers for future investigation. Methods: We evaluated the consistency of associations between measured GFR (mGFR) and 887 common, known metabolites quantified by an untargeted chromatography- and spectroscopy-based metabolomics platform (Metabolon) performed on frozen blood samples from 580 participants in Chronic Kidney Disease in Children (CKiD), 674 participants in Modification of Diet in Renal Disease (MDRD) Study and 962 participants in African American Study of Kidney Disease and Hypertension (AASK). We evaluated metabolite-mGFR correlation association with metabolite class, molecular weight, assay platform and measurement coefficient of variation (CV). Among metabolites with strong negative correlations with mGFR (r < -0.5), we assessed additional variation by age (height in children), sex, race and body mass index (BMI). Results: A total of 561 metabolites (63%) were negatively correlated with mGFR. Correlations with mGFR were highly consistent across study, sex, race and BMI categories (correlation of metabolite-mGFR correlations between 0.88 and 0.95). Amino acids, carbohydrates and nucleotides were more often negatively correlated with mGFR compared with lipids, but there was no association with metabolite molecular weight, liquid chromatography/mass spectrometry platform and measurement CV. Among 114 metabolites with strong negative associations with mGFR (r < -0.5), 27 were consistently not associated with age (height in children), sex or race. Conclusions: The majority of metabolite-mGFR correlations were negative and consistent across sex, race, BMI and study. Metabolites with consistent strong negative correlations with mGFR and non-association with demographic variables may represent candidate markers to improve estimation of GFR.

Zipime-Weka-Schista study protocol: a longitudinal cohort study and economic evaluation of an integrated home-based approach for genital multipathogen screening in women, including female genital schistosomiasis, human papillomavirus, Trichomonas and HIV in Zambia.

INTRODUCTION: Multiplathogen home-based self-sampling offers an opportunity to increase access to screening and treatment in endemic settings with high coinfection prevalence of sexually transmitted (HIV, Trichomonas vaginalis (Tv), human papillomavirus (HPV)) and non-sexually transmitted pathogens (Schistosoma haematobium (Sh)). Chronic coinfections may lead to disability (female genital schistosomiasis) and death (cervical cancer). The Zipime-Weka-Schista (Do self-testing sister!) study aims to evaluate the validity, acceptability, uptake, impact and cost-effectiveness of multipathogen self-sampling for genital infections among women in Zambia. METHODS AND ANALYSIS: This is a longitudinal cohort study aiming to enrol 2500 non-pregnant, sexually active and non-menstruating women aged 15-50 years from two districts in Zambia with 2-year follow-up. During home visits, community health workers offer HIV and Tv self-testing and cervicovaginal self-swabs for (1) HPV by GeneXpert and, (2) Sh DNA detection by conventional (PCR)and isothermal (recombinase polymerase assay) molecular methods. Schistosoma ova and circulating anodic antigen are detected in urine. At a clinic follow-up, midwives perform the same procedures and obtain hand-held colposcopic images. High-risk HPV positive women are referred for a two-quadrant cervical biopsy according to age and HIV status. A cost-effectiveness analysis is conducted in parallel. ETHICS AND DISSEMINATION: The University of Zambia Biomedical Research Ethics Committee (UNZABREC) (reference: 1858-2021), the London School of Hygiene and Tropical Medicine (reference: 25258), Ministry of Health and local superintendents approved the study in September 2021.Written informed consent was obtained from all participants prior to enrolment. Identifiable data collected are stored securely and their confidentiality is protected in accordance with the Data Protection Act 1998.

Serum and Urine Metabolites and Kidney Function.

BACKGROUND: Metabolites represent a read-out of cellular processes underlying states of health and disease. METHODS: We evaluated cross-sectional and longitudinal associations between 1255 serum and 1398 urine known and unknown (denoted with "X" in name) metabolites (Metabolon HD4, 721 detected in both biofluids) and kidney function in 1612 participants of the Atherosclerosis Risk in Communities (ARIC) Study. All analyses were adjusted for clinical and demographic covariates, including for baseline eGFR and UACR in longitudinal analyses. RESULTS: At visit 5 of the ARIC study, the mean age of participants was 76 years (SD 6), 56% were women, mean eGFR was 62 ml/min/1.73m2 (SD 20), and median urine albumin-to-creatinine level (UACR) was 13 mg/g (IQR 25). In cross-sectional analysis, 675 serum and 542 urine metabolites were associated with eGFR (Bonferroni-corrected p < 4.0E-5 for serum analyses and p < 3.6E-5 for urine analyses), including 248 metabolites shared across biofluids. Fewer metabolites (75 serum and 91 urine metabolites, including 7 shared across biofluids) were cross-sectionally associated with albuminuria. Guanidinosuccinate, N2,N2-dimethylguanosine, hydroxy-N6,N6,N6-trimethyllysine, X-13844, and X-25422 were significantly associated with both eGFR and albuminuria. Over a mean follow-up of 6.6 years, serum mannose (HR 2.3 [1.6,3.2], p = 2.7E-5) and urine X-12117 (HR 1.7 [1.3,2.2], p = 1.9E-5) were risk factors for UACR doubling, whereas urine sebacate (HR 0.86 [0.80,0.92], p = 1.9E-5) was inversely associated. Compared to clinical characteristics alone, including the top 5 endogenous metabolites in serum and urine associated with longitudinal outcomes improved the outcome prediction (AUCs for eGFR decline: clinical model = 0.79, clinical + metabolites model = 0.87, p = 8.1E-6; for UACR doubling: clinical model = 0.66, clinical + metabolites model = 0.73, p = 2.9E-5). CONCLUSIONS: Metabolomic profiling in different biofluids provided distinct and potentially complementary insights into the biology and prognosis of kidney diseases.

Patients' and professionals' experiences with remote care during COVID-19: a qualitative study in general practices in low-income neighborhoods.

AIM: To explore how patients and general practice professionals in low-income neighborhoods experienced the increase of remote care during COVID-19. BACKGROUND: As the GP (general practitioner) is the first point of contact in Dutch health care, there are concerns about access to remote care for patients from low-income neighborhoods. Now that general practice professionals have returned to the pre-pandemic ways of healthcare delivery, this paper looks back at experiences with remote care during COVID-19. It investigates experiences of both patients and general practice professionals with the approachability and appropriateness of remote care and their satisfaction. METHODS: In this qualitative study, 78 patients and 18 GPs, 7 nurse practitioners and 6 mental health professionals were interviewed. Interviews were held on the phone and face-to-face in the native language of the participants. FINDINGS: Remote care, especially telephone consultation, was generally well-approachable for patients from low-income neighborhoods. Contrarily, video calling was rarely used. This was partly because patients did not know how to use it. The majority of patients thought remote care was possible for minor ailments but would also still like to see the doctor face-to-face regularly. Patients were generally satisfied with remote care at the time, but this did not necessarily reflect their willingness to continue using it in the future. Moreover, there was lack in consensus among general practice professionals on the appropriateness of remote care for certain physical and mental complaints. Nurse practitioners and mental health professionals had a negative attitude toward remote care. In conclusion, it is important to take the opinions and barriers of patients and care providers into account and to increase patient-centered care elements and care provider satisfaction in remote care. Integrating remote care is not only important in times of crisis but also for future care that is becoming increasingly digitalized.

Strontium isotopes track female dispersal in Taï chimpanzees.

OBJECTIVES: Chimpanzees (Pan troglodytes) are patrilocal, with males remaining in their natal community and females dispersing when they reach sexual maturity. However, the details of female chimpanzee dispersal, such as their possible origin, are difficult to assess, even in habituated communities. This study investigates the utility of 87Sr/86Sr analysis for (1) assessing Sr baseline differences between chimpanzee territories and (2) identifying the status (immigrant or natal) of females of unknown origin within the territories of five neighboring communities in Taï National Park (Côte d'Ivoire). MATERIALS AND METHODS: To create a local Sr isoscape for the Taï Chimpanzee Project (TCP) study area, we sampled environmental samples from TCP-established territories (n = 35). To assess dispersal patterns, 34 tooth enamel samples (one per individual) were selected from the Taï chimpanzee skeletal collection. 87Sr/86Sr analysis was performed on all 69 samples at the W.M. Keck Lab. The theoretical density and overlap of chimpanzee communities as well as generalized linear mixed models (GLMMs) were used to test each question. RESULTS: 87Sr/86Sr ratios for natal male chimpanzees ranged from 0.71662 to 0.72187, which is well within the corresponding environmental baseline range of 0.70774-0.73460. The local Sr isoscapes fit was estimated with the root-mean-square error value, which was 0.0048 (22% of the whole 87Sr/86Sr data range). GLMMs identified significant differences in 87Sr/86Sr ratios between natal and unknown North community origin groups, suggesting that after 1980, females of unknown origin could be immigrants to North community (n = 7, z-ratio = -4.08, p = 0.0001, power = 0.94). DISCUSSION: This study indicates that 87Sr/86This study indicates that 87Sr/86Sr analysis can successfully identify immigrant females in skeletal collections obtained from wild chimpanzee communities, enabling the tracking of female dispersal patterns historically. There are, however, significant limitations within the scope of this study, such as (1) the absence of reliable maps for the TCP study area, (2) limited capacity for environmental sampling, (3) small sample sizes, and (4) tooth formation in wild chimpanzees.

Dietary supplementation with grape seed extract from Vitus vinifera prevents suppression of GABAergic protein expression in female Sprague Dawley trigeminal ganglion in a model of chronic temporomandibular joint disorder.

OBJECTIVE: To investigate cellular changes in protein expression in the trigeminal ganglion in an established preclinical chronic model of temporomandibular joint disorder (TMD) in response to grape seed extract (GSE) supplementation based on its beneficial use in preclinical chronic orofacial pain models. DESIGN: Three experimental conditions included female Sprague-Dawley rats as naïve controls, and animals subjected to neck muscle inflammation and prolonged jaw opening with and without daily supplementation of GSE in the drinking water prior to inflammation. Changes were evaluated in mechanical sensitivity to von Frey filaments and protein expression in the trigeminal ganglion of animals 14 days post jaw opening. RESULTS: Calcitonin-gene related peptide and protein kinase A, proteins positively associated with peripheral sensitization and enhanced nociception, did not show elevated expression at day 14 in the model compared to naïve or GSE supplemented animals. However, neuronal levels of glutamate decarboxylase (GAD) 65/67, which are enzymes responsible for the synthesis of the inhibitory neurotransmitter GABA that functions to suppress neuronal excitability, were significantly decreased on day 14 post jaw opening. Similarly, a significant decrease in neuronal expression of the GABA receptor subunits GABAB1 and GABAB2, but not GABAA, was observed in the TMD model. Importantly, GSE prevented suppression of GAD 65/67 and GABAB subunits, maintaining levels similar to naïve animals. CONCLUSION: Results from our study provide evidence of the downregulation of inhibitory GABAergic proteins in trigeminal ganglion neurons in a preclinical chronic TMD model and the benefits of GSE supplementation in preventing their suppression and maintaining normal levels.

Insulin resistance during androgen deprivation therapy in men with prostate cancer.

BACKGROUND: Androgen deprivation therapy (ADT) in prostate cancer (PCa) has been associated with development of insulin resistance. However, the predominant site of insulin resistance remains unclear. METHODS: The ADT & Metabolism Study was a single-center, 24-week, prospective observational study that enrolled ADT-naive men without diabetes who were starting ADT for at least 24 weeks (ADT group, n = 42). The control group comprised men without diabetes with prior history of PCa who were in remission after prostatectomy (non-ADT group, n = 23). Prevalent diabetes mellitus was excluded in both groups using all three laboratory criteria defined in the American Diabetes Association guidelines. All participants were eugonadal at enrollment. The primary outcome was to elucidate the predominant site of insulin resistance (liver or skeletal muscle). Secondary outcomes included assessments of body composition, and hepatic and intramyocellular fat. Outcomes were assessed at baseline, 12, and 24 weeks. RESULTS: At 24 weeks, there was no change in hepatic (1.2; 95% confidence interval [CI], -2.10 to 4.43; p = .47) or skeletal muscle (-3.2; 95% CI, -7.07 to 0.66; p = .10) insulin resistance in the ADT group. No increase in hepatic or intramyocellular fat deposition or worsening of glucose was seen. These changes were mirrored by those observed in the non-ADT group. Men undergoing ADT gained 3.7 kg of fat mass. CONCLUSIONS: In men with PCa and no diabetes, 24 weeks of ADT did not change insulin resistance despite adverse body composition changes. These findings should be reassuring for treating physicians and for patients who are being considered for short-term ADT.

Cell surface CD55 traffics to the nucleus leading to cisplatin resistance and stemness by inducing PRC2 and H3K27 trimethylation on chromatin in ovarian cancer.

BACKGROUND: Platinum resistance is the primary cause of poor survival in ovarian cancer (OC) patients. Targeted therapies and biomarkers of chemoresistance are critical for the treatment of OC patients. Our previous studies identified cell surface CD55, a member of the complement regulatory proteins, drives chemoresistance and maintenance of cancer stem cells (CSCs). CSCs are implicated in tumor recurrence and metastasis in multiple cancers. METHODS: Protein localization assays including immunofluorescence and subcellular fractionation were used to identify CD55 at the cell surface and nucleus of cancer cells. Protein half-life determinations were used to compare cell surface and nuclear CD55 stability. CD55 deletion mutants were generated and introduced into cancer cells to identify the nuclear trafficking code, cisplatin sensitivity, and stem cell frequency that were assayed using in vitro and in vivo models. Detection of CD55 binding proteins was analyzed by immunoprecipitation followed by mass spectrometry. Target pathways activated by CD55 were identified by RNA sequencing. RESULTS: CD55 localizes to the nucleus of a subset of OC specimens, ascites from chemoresistant patients, and enriched in chemoresistant OC cells. We determined that nuclear CD55 is glycosylated and derived from the cell surface pool of CD55. Nuclear localization is driven by a trafficking code containing the serine/threonine (S/T) domain of CD55. Nuclear CD55 is necessary for cisplatin resistance, stemness, and cell proliferation in OC cells. CD55 S/T domain is necessary for nuclear entry and inducing chemoresistance to cisplatin in both in vitro and in vivo models. Deletion of the CD55 S/T domain is sufficient to sensitize chemoresistant OC cells to cisplatin. In the nucleus, CD55 binds and attenuates the epigenetic regulator and tumor suppressor ZMYND8 with a parallel increase in H3K27 trimethylation and members of the Polycomb Repressive Complex 2. CONCLUSIONS: For the first time, we show CD55 localizes to the nucleus in OC and promotes CSC and chemoresistance. Our studies identify a therapeutic mechanism for treating platinum resistant ovarian cancer by blocking CD55 nuclear entry.

SCINE-Software for chemical interaction networks.

The software for chemical interaction networks (SCINE) project aims at pushing the frontier of quantum chemical calculations on molecular structures to a new level. While calculations on individual structures as well as on simple relations between them have become routine in chemistry, new developments have pushed the frontier in the field to high-throughput calculations. Chemical relations may be created by a search for specific molecular properties in a molecular design attempt, or they can be defined by a set of elementary reaction steps that form a chemical reaction network. The software modules of SCINE have been designed to facilitate such studies. The features of the modules are (i) general applicability of the applied methodologies ranging from electronic structure (no restriction to specific elements of the periodic table) to microkinetic modeling (with little restrictions on molecularity), full modularity so that SCINE modules can also be applied as stand-alone programs or be exchanged for external software packages that fulfill a similar purpose (to increase options for computational campaigns and to provide alternatives in case of tasks that are hard or impossible to accomplish with certain programs), (ii) high stability and autonomous operations so that control and steering by an operator are as easy as possible, and (iii) easy embedding into complex heterogeneous environments for molecular structures taken individually or in the context of a reaction network. A graphical user interface unites all modules and ensures interoperability. All components of the software have been made available as open source and free of charge.

EndoPRS: Incorporating Endophenotype Information to Improve Polygenic Risk Scores for Clinical Endpoints.

Polygenic risk score (PRS) prediction of complex diseases can be improved by leveraging related phenotypes. This has motivated the development of several multi-trait PRS methods that jointly model information from genetically correlated traits. However, these methods do not account for vertical pleiotropy between traits, in which one trait acts as a mediator for another. Here, we introduce endoPRS, a weighted lasso model that incorporates information from relevant endophenotypes to improve disease risk prediction without making assumptions about the genetic architecture underlying the endophenotype-disease relationship. Through extensive simulation analysis, we demonstrate the robustness of endoPRS in a variety of complex genetic frameworks. We also apply endoPRS to predict the risk of childhood onset asthma in UK Biobank by leveraging a paired GWAS of eosinophil count, a relevant endophenotype. We find that endoPRS significantly improves prediction compared to many existing PRS methods, including multi-trait PRS methods, MTAG and wMT-BLUP, which suggests advantages of endoPRS in real-life clinical settings.

Epigenetic and proteomic signatures associate with clonal hematopoiesis expansion rate.

Clonal hematopoiesis of indeterminate potential (CHIP), whereby somatic mutations in hematopoietic stem cells confer a selective advantage and drive clonal expansion, not only correlates with age but also confers increased risk of morbidity and mortality. Here, we leverage genetically predicted traits to identify factors that determine CHIP clonal expansion rate. We used the passenger-approximated clonal expansion rate method to quantify the clonal expansion rate for 4,370 individuals in the National Heart, Lung, and Blood Institute (NHLBI) Trans-Omics for Precision Medicine (TOPMed) cohort and calculated polygenic risk scores for DNA methylation aging, inflammation-related measures and circulating protein levels. Clonal expansion rate was significantly associated with both genetically predicted and measured epigenetic clocks. No associations were identified with inflammation-related lab values or diseases and CHIP expansion rate overall. A proteome-wide search identified predicted circulating levels of myeloid zinc finger 1 and anti-Müllerian hormone as associated with an increased CHIP clonal expansion rate and tissue inhibitor of metalloproteinase 1 and glycine N-methyltransferase as associated with decreased CHIP clonal expansion rate. Together, our findings identify epigenetic and proteomic patterns associated with the rate of hematopoietic clonal expansion.

Sex and Sexual Orientation Differences in Dark Triad Traits, Sexual Excitation/Inhibition, and Sociosexuality.

The present study sought to investigate sex and sexual orientation differences in several traits related to sexuality and sexual behavior. Examining sexual orientation differences alongside basic sex differences to help identify correlates of sexual orientation diversity, and whether individuals with varying degrees of same-sex attraction show concurrent sex-atypical shifts in other domains. Males tend to score higher than females in the Dark Triad (DT) traits of sub-clinical narcissism, psychopathy, and Machiavellianism. Similarly, females tend to be more cautious than males in their attitudes and desires toward casual sex activity (i.e., sociosexuality). These sex differences may be related to the propensity for individuals to become easily sexually excited, which is higher in males, or to instead inhibit sexual arousal, which is higher in females. In a large undergraduate sample (N = 2047), we replicated expected sex differences in DT traits, sociosexuality, and sexual excitation/inhibition. We found that non-heterosexual females were "male-shifted" in some of these traits, but these shifts tended to be strongest among mostly heterosexual and bisexual individuals. Furthermore, we found that within-sex variation in sociosexuality, sexual excitation, and sexual inhibition was not related to sexual orientation in a linear fashion. Instead, sociosexuality and sexual excitation were related to sexual orientation in a curvilinear (inverted-U) fashion, especially among females. The fact that traits correlated with bisexuality and homosexuality were somewhat distinct is consistent with the idea that different developmental pathways may lead to these discrete sexual attraction patterns.

Spatiotemporal patterns of Lyme disease in North Carolina: 2010-2020.

Background: Lyme disease is the most common vector-borne disease in the United States with the majority of cases occurring in the Northeast, upper Midwest, and mid-Atlantic regions. While historically considered a low incidence state, North Carolina (NC) has reported an increasing number of cases over the past decade. Therefore, the aim of this study was to characterise the spatiotemporal evolution of Lyme disease in NC from 2010 to 2020. Methods: Confirmed and probable cases reported to the NC Division of Public Health without associated travel to high-transmission state were included in the analysis. The study period was divided into four sub-periods and data were aggregated by zip code of residence. The absolute change in incidence was mapped and spatial autocorrelation analyses were performed within each sub-period. Findings: We identified the largest absolute changes in incidence in zip codes located in northwestern NC along the Appalachian Mountains. The spatial distribution of cases became increasingly clustered over the study period (Moran's I of 0.012, p = 0.127 in 2010-2012 vs. 0.403, p < 0.0001 in 2019-2020). Identified clusters included 22 high-incidence zip codes in the 2019-2020 sub-period, largely overlapping with the same areas experiencing the greatest absolute changes in disease incidence. Interpretation: Lyme disease has rapidly emerged in northwestern NC with some zip codes reporting incidence rates similar to historically high incidence regions across the US Northeast, mid-Atlantic, and upper Midwest. Efforts are urgently needed to raise awareness among medical providers to prevent excess morbidity. Funding: Funding was provided by a "Creativity Hub" award from the UNC Office of the Vice Chancellor for Research. Additional support was provided by Southeastern Center of Excellence in Vector Borne Diseases (U01CK000662).

Scientific and religious beliefs are primarily shaped by testimony.

Understanding why individuals are more confident of the existence of invisible scientific phenomena (e.g., oxygen) than invisible religious phenomena (e.g., God) remains a puzzle. Departing from conventional explanations linking ontological beliefs to direct experience, we introduce a model positing that testimony predominantly shapes beliefs in both scientific and religious domains. Distinguishing direct experience (personal observation) from cultural input (testimony-based evidence), we argue that even apparently direct experiences often stem from others' testimony. Our analysis indicates that variability in direct experience cannot explain belief disparities between science and religion, within each domain, or across cultures. Instead, variability in testimony is the primary driver of ontological beliefs. We present developmental evidence for testimony-based beliefs and elucidate the mechanisms underlying their impact.