The people behind the papers - Julia Grzymkowski and Nanette Nascone-Yoder.

As the digestive system develops, the gut tube lengthens and convolutes to correctly package the intestine. Intestinal malrotation is a prevalent birth anomaly, but its underlying causes are not well understood. In this new study, Nanette Nascone-Yoder and colleagues show that exposure of Xenopus embryos to atrazine, a widely-used herbicide, can disrupt cellular metabolism in the developing gut tube and lead to intestinal malrotation. We caught up with first author Julia Grzymkowski and corresponding author Nanette Nascone-Yoder, Professor at North Carolina State University, to hear more about the story.

Effectiveness of Covid-19 Vaccines over a 9-Month Period in North Carolina.

BACKGROUND: The duration of protection afforded by coronavirus disease 2019 (Covid-19) vaccines in the United States is unclear. Whether the increase in postvaccination infections during the summer of 2021 was caused by declining immunity over time, the emergence of the B.1.617.2 (delta) variant, or both is unknown. METHODS: We extracted data regarding Covid-19-related vaccination and outcomes during a 9-month period (December 11, 2020, to September 8, 2021) for approximately 10.6 million North Carolina residents by linking data from the North Carolina Covid-19 Surveillance System and the Covid-19 Vaccine Management System. We used a Cox regression model to estimate the effectiveness of the BNT162b2 (Pfizer-BioNTech), mRNA-1273 (Moderna), and Ad26.COV2.S (Johnson & Johnson-Janssen) vaccines in reducing the current risks of Covid-19, hospitalization, and death, as a function of time elapsed since vaccination. RESULTS: For the two-dose regimens of messenger RNA (mRNA) vaccines BNT162b2 (30 µg per dose) and mRNA-1273 (100 µg per dose), vaccine effectiveness against Covid-19 was 94.5% (95% confidence interval [CI], 94.1 to 94.9) and 95.9% (95% CI, 95.5 to 96.2), respectively, at 2 months after the first dose and decreased to 66.6% (95% CI, 65.2 to 67.8) and 80.3% (95% CI, 79.3 to 81.2), respectively, at 7 months. Among early recipients of BNT162b2 and mRNA-1273, effectiveness decreased by approximately 15 and 10 percentage points, respectively, from mid-June to mid-July, when the delta variant became dominant. For the one-dose regimen of Ad26.COV2.S (5 × 1010 viral particles), effectiveness against Covid-19 was 74.8% (95% CI, 72.5 to 76.9) at 1 month and decreased to 59.4% (95% CI, 57.2 to 61.5) at 5 months. All three vaccines maintained better effectiveness in preventing hospitalization and death than in preventing infection over time, although the two mRNA vaccines provided higher levels of protection than Ad26.COV2.S. CONCLUSIONS: All three Covid-19 vaccines had durable effectiveness in reducing the risks of hospitalization and death. Waning protection against infection over time was due to both declining immunity and the emergence of the delta variant. (Funded by a Dennis Gillings Distinguished Professorship and the National Institutes of Health.).

An interview with Debby Silver.

Debby Silver is an Associate Professor at Duke University Medical Center and the Duke Institute for Brain Sciences, in Durham, North Carolina. Debby's research focusses on mammalian cortical neurogenesis, and on how RNA metabolism controls cell behaviors in the developing brain. Earlier this year, Debby became an Academic Editor at Development, and we met over Zoom to discuss her career path and research interests, as well as her motivation for joining the Development team.

Delayed Diagnosis of Locally Acquired Lyme Disease, Central North Carolina, USA.

Healthcare providers in North Carolina, USA, have limited experience diagnosing and managing Lyme disease because few cases occur annually statewide. We outline the prolonged diagnostic course for a patient with locally acquired Lyme disease in North Carolina. This case highlights the need for greater awareness and professional education.

Rickettsia parkeri Rickettsiosis in Kidney Transplant Recipient, North Carolina, USA, 2023.

Spotted fever rickettsiosis is rarely observed in solid organ transplant recipients, and all previously reported cases have been associated with tick bite months to years after transplantation. We describe a kidney transplant recipient in North Carolina, USA, who had a moderately severe Rickettsia parkeri infection develop during the immediate posttransplant period.

Suicide Mortality Among Formerly Incarcerated People Compared With the General Population in North Carolina, 2000-2020.

We aimed to compare rates and characteristics of suicide mortality in formerly incarcerated people with those of the general population in North Carolina. We conducted a retrospective cohort study of 266,400 people released from North Carolina state prisons between January 1, 2000, and March 1, 2020. Using direct and indirect standardization by age, sex, and calendar year, we calculated standardized suicide mortality rates and standardized mortality ratios comparing formerly incarcerated people with the North Carolina general population. We evaluated effect modification by race/ethnicity, sex, age, and firearm involvement. Formerly incarcerated people had approximately twice the overall suicide mortality of the general population for 3 years after release, with the highest rate of suicide mortality being observed in the 2-week period after release. In contrast to patterns in the general population, formerly incarcerated people had higher rates of non-firearm-involved suicide mortality than firearm-involved suicide mortality. Formerly incarcerated female, White and Hispanic/Latino, and emerging adult people had a greater elevation of suicide mortality than their general-population peers compared with other groups. These findings suggest a need for long-term support for formerly incarcerated people as they return to community living and a need to identify opportunities for interventions that reduce the harms of incarceration for especially vulnerable groups. This article is part of a Special Collection on Mental Health.

Commercial Versus Medicaid Insurance and Use of High-Priced Anticancer Treatments.

BACKGROUND: Because the markups on cancer drugs vary by payor, providers' financial incentive to use high-price drugs is differential according to each patient's insurance type. We evaluated the association between patient insurer (commercial vs Medicaid) and the use of high-priced cancer treatments. MATERIALS AND METHODS: We linked cancer registry, administrative claims, and demographic data for individuals diagnosed with cancer in North Carolina from 2004 to 2011, with either commercial or Medicaid insurance. We selected cancers with multiple FDA-approved, guideline-recommended chemotherapy options and large price differences between treatment options: advanced colorectal, lung, and head and neck cancer. The outcome was a receipt of a higher-priced option, and the exposure was insurer: commercial versus Medicaid. We estimated risk ratios (RRs) for the association between insurer and higher-priced treatment using log-binomial models with inverse probability of exposure weights. RESULTS: Of 812 patients, 209 (26%) had Medicaid. The unadjusted risk of receiving higher-priced treatment was 36% (215/603) for commercially insured and 27% (57/209) for Medicaid insured (RR: 1.31, 95% CI: 1.02-1.67). After adjustment for confounders the association was attenuated (RR: 1.15, 95% CI: 0.81-1.65). Exploratory subgroup analysis suggested that commercial insurance was associated with increased receipt of higher-priced treatment among patients treated by non-NCI-designated providers (RR: 1.53, 95% CI: 1.14-2.04). CONCLUSIONS: Individuals with Medicaid and commercial insurance received high-priced treatments in similar proportion, after accounting for differences in case mix. However, modification by provider characteristics suggests that insurance type may influence treatment selection for some patient groups. Further work is needed to determine the relationship between insurance status and newer, high-price drugs such as immune-oncology agents.

COVID-19 hospitalization risk after outpatient nirmatrelvir/ritonavir use, January to August 2022, North Carolina.

BACKGROUND: In the USA, nirmatrelvir/ritonavir is authorized for the treatment of mild-to-moderate COVID-19 in patients at least 12 years of age, at high risk for progression to severe COVID-19. OBJECTIVES: To estimate the impact of outpatient nirmatrelvir/ritonavir on COVID-19 hospitalization risk in a US healthcare system. METHODS: We conducted a cohort study using electronic health records among outpatients with a positive SARS-CoV-2 PCR test between January and August 2022. We evaluated the association of nirmatrelvir/ritonavir therapy with time to hospitalization by estimating adjusted HRs and assessed the impact of nirmatrelvir/ritonavir on predicted COVID-19 hospitalizations using machine-learning methods. RESULTS: Among 44 671 patients, 4948 (11%) received nirmatrelvir/ritonavir, and 201 (0.4%) were hospitalized within 28 days of COVID-19 diagnosis. Nirmatrelvir/ritonavir recipients were more likely to be older, white, vaccinated, have comorbidities and reside in areas with higher average socioeconomic status. The 28 day cumulative incidence of hospitalization was 0.06% (95% CI: 0.02%-0.17%) among nirmatrelvir/ritonavir recipients and 0.52% (95% CI: 0.46%-0.60%) among non-recipients. For nirmatrelvir/ritonavir versus no therapy, the age-adjusted HR was 0.08 (95% CI: 0.03-0.26); the fully adjusted HR was 0.16 (95% CI: 0.05-0.50). In the machine-learning model, the primary features reducing predicted hospitalization risk were nirmatrelvir/ritonavir, younger age, vaccination, female gender and residence in a higher socioeconomic status area. CONCLUSIONS: COVID-19 hospitalization risk was reduced by 84% among nirmatrelvir/ritonavir recipients in a large, diverse healthcare system during the Omicron wave. These results suggest that nirmatrelvir/ritonavir remained highly effective in a setting substantially different than the original clinical trials.

Understanding mechanisms of racial disparities in breast cancer: an assessment of screening and regular care in the Carolina Breast Cancer Study.

PURPOSE: Screening history influences stage at detection, but regular preventive care may also influence breast tumor diagnostic characteristics. Few studies have evaluated healthcare utilization (both screening and primary care) in racially diverse screening-eligible populations. METHODS: This analysis included 2,058 women age 45-74 (49% Black) from the Carolina Breast Cancer Study, a population-based cohort of women diagnosed with invasive breast cancer between 2008 and 2013. Screening history (threshold 0.5 mammograms per year) and pre-diagnostic healthcare utilization (i.e. regular care, based on responses to "During the past ten years, who did you usually see when you were sick or needed advice about your health?") were assessed as binary exposures. The relationship between healthcare utilization and tumor characteristics were evaluated overall and race-stratified. RESULTS: Among those lacking screening, Black participants had larger tumors (5 + cm) (frequency 19.6% vs 11.5%, relative frequency difference (RFD) = 8.1%, 95% CI 2.8-13.5), but race differences were attenuated among screening-adherent participants (10.2% vs 7.0%, RFD = 3.2%, 0.2-6.2). Similar trends were observed for tumor stage and mode of detection (mammogram vs lump). Among all participants, those lacking both screening and regular care had larger tumors (21% vs 8%, RR = 2.51, 1.76-3.56) and advanced (3B +) stage (19% vs 6%, RR = 3.15, 2.15-4.63) compared to the referent category (screening-adherent and regular care). Under-use of regular care and screening was more prevalent in socioeconomically disadvantaged areas of North Carolina. CONCLUSIONS: Access to regular care is an important safeguard for earlier detection. Our data suggest that health equity interventions should prioritize both primary care and screening.

Two years of newborn screening for Duchenne muscular dystrophy as a part of the statewide Early Check research program in North Carolina.

PURPOSE: Current and emerging treatments for Duchenne muscular dystrophy (DMD) position DMD as a candidate condition for newborn screening (NBS). In anticipation of the nomination of DMD for universal NBS, we conducted a prospective study under the Early Check voluntary NBS research program in North Carolina, United States. METHODS: We performed screening for creatine kinase-MM (CK-MM), a biomarker of muscle damage, on residual routine newborn dried blood spots (DBS) from participating newborns. Total creatine kinase testing and next generation sequencing of an 86-neuromuscular gene panel that included DMD were offered to parents of newborns who screened positive. Bivariate and multivariable analyses were performed to assess effects of biological and demographic predictors on CK-MM levels in DBS. RESULTS: We screened 13,354 newborns and identified 2 males with DMD. The provisional 1626 ng/mL cutoff was raised to 2032 ng/mL to improve specificity, and additional cutoffs (900 and 360 ng/mL) were implemented to improve sensitivity for older and low-birthweight newborns. CONCLUSION: Population-scale screening for elevated CK-MM in DBS is a feasible approach to identify newborns with DMD. Inclusion of birthweight- and age-specific cutoffs, repeat creatine kinase testing after 72 hours of age, and DMD sequencing improve sensitivity and specificity of screening.

Multiple joint osteoarthritis (MJOA): What's in a name?

OBJECTIVE: To summarize the current state of the literature regarding multi-joint osteoarthritis (MJOA) and discuss important future directions. DESIGN: A narrative review of the author's work and other key references on this topic with a focus on the Johnston County studies, definitions of MJOA and their impact, multi-site pain in osteoarthritis (OA), genetics and biomarkers in MJOA, and perspectives on future work. RESULTS: MJOA is variably defined and lacks a clear consensus definition, making comprehensive study challenging. Involvement of both symptoms and structural changes of OA in multiple joints in an individual is common, but patterns vary by sex, race/ethnicity, and other factors. Outcomes (e.g., general health, function, falls, mortality) are negatively impacted by a greater whole-body OA burden. Recent genetic and biomarker studies including whole-body OA assessments have begun to shed some light on potentially unique factors in the MJOA population. CONCLUSIONS: Consideration of MJOA is essential for ongoing study of OA phenotypes, epidemiology, risk factors, genetics, biomarkers, and outcomes, to fully understand and eventually limit the negative impact of OA burden on health.

Bee species richness through time in an urbanizing landscape of the southeastern United States.

Compared to non-urban environments, cities host ecological communities with altered taxonomic diversity and functional trait composition. However, we know little about how these urban changes take shape over time. Using historical bee (Apoidea: Anthophila) museum specimens supplemented with online repositories and researcher collections, we investigated whether bee species richness tracked urban and human population growth over the past 118 years. We also determined which species were no longer collected, whether those species shared certain traits, and if collector behavior changed over time. We focused on Wake County, North Carolina, United States where human population size has increased over 16 times over the last century along with the urban area within its largest city, Raleigh, which has increased over four times. We estimated bee species richness with occupancy models, and rarefaction and extrapolation curves to account for imperfect detection and sample coverage. To determine if bee traits correlated with when species were collected, we compiled information on native status, nesting habits, diet breadth, and sociality. We used non-metric multidimensional scaling to determine if individual collectors contributed different bee assemblages over time. In total, there were 328 species collected in Wake County. We found that although bee species richness varied, there was no clear trend in bee species richness over time. However, recent collections (since 2003) were missing 195 species, and there was a shift in trait composition, particularly lost species were below-ground nesters. The top collectors in the dataset differed in how often they collected bee species, but this was not consistent between historic and contemporary time periods; some contemporary collectors grouped closer together than others, potentially due to focusing on urban habitats. Use of historical collections and complimentary analyses can fill knowledge gaps to help understand temporal patterns of species richness in taxonomic groups that may not have planned long-term data.

STI self-testing: ensuring representation and outreach to teens and adolescents in expanded approaches.

In our correspondence, we describe the results from a quality improvement survey in a sexual health clinic in North Carolina regarding attitudes and perceptions among adolescents and providers regarding specimen self-collection. We find that adolescents have high levels of acceptability for self-collection and confidence in their ability to self-collection; however, providers expressed hesitation regarding the ability of adolescents to self-collection. Our study shows that while self-collection may provide a way to expand testing access to difficult-to-reach populations, we must ensure that providers are confident in the corresponding results.

Are the diagnostic rates of autistic females increasing? An examination of state-wide trends.

BACKGROUND: Autism has been considered a 'male-dominant' condition. However, recent research suggests that autistic females are underdiagnosed, misdiagnosed, and later diagnosed. Females may also have different and more nuanced behavioral profiles. To examine diagnosis rates of females, we used 20 years of state-wide data to characterize historical trends in the diagnosis of autism in females to determine whether the proportion of females diagnosed with autism has changed over time. METHODS: Data were drawn from 10,247 participants (males = 8,319, females = 1928) who received an autism diagnosis between 2000 and 2021 from state-wide autism centers associated with the University of North Carolina TEACCH Autism Program. RESULTS: The rates of females diagnosed with autism increased at a greater rate compared with males. Age of diagnosis remained consistently higher for females. Late diagnosis (defined as 13+) increased over time across both males and females, however, was more commonly associated with females, particularly those with co-occurring intellectual disability. CONCLUSIONS: Our results indicate that the proportion of females diagnosed with autism has increased steadily over a 20-year period, which likely reflects greater societal knowledge of how autism may manifest differentially in females.

A Novel Approach to Analyze Disparities in Colorectal Cancer Screening and Mortality.

INTRODUCTION: Reducing disparities in colorectal cancer (CRC) screening rates and mortality remains a priority. Mitigation strategies to reduce these disparities have largely been unsuccessful. The primary aim is to determine variables in models of healthcare utilization and their association with CRC screening and mortality in North Carolina. METHODS: A cross-sectional analysis of publicly available data across North Carolina using variable reduction techniques with clustering to evaluate association of CRC screening rates and mortality was performed. RESULTS: Three million sixty-five thousand five hundred thirty-seven residents (32.1%) were aged 50 y or more. More than two-thirds (68.8%) were White, while 20.5% were Black. Approximately 61% aged 50 y or more underwent CRC screening (range: 44.0%-80.5%) and had a CRC mortality of 44.8 per 100,000 (range 22.8 to 76.6 per 100,000). Cluster analysis identified two factors, designated social economic education index (factor 1) and rural provider index (factor 2) for inclusion in the multivariate analysis. CRC screening rates were associated with factor 1, consisting of socioeconomic and education variables, and factor 2, comprised of the number of providers per 10,000 individuals aged 50 y or more and rurality. An increase in both factors 1 and 2 by one point would result in an increase in CRC screening rated by 6.8%. CRC mortality was associated with factor 2. An increase in one point in factor 1 results in a decrease in mortality risk by 10.9%. CONCLUSIONS: In North Carolina, using variable reduction with clustering, CRC screening rates were associated with the inter-relationship of the number of providers and rurality, while CRC mortality was associated with the inter-relationship of social, economic, and education variables.

Support for the size-mediated sensitivity hypothesis within a diverse carnivore community.

Carnivore community dynamics are governed by a complex set of often interacting biotic, abiotic and anthropogenic factors that are increasingly volatile as a result of global change. Understanding how these changing conditions influence carnivore communities is urgent because of the important role carnivores play within ecosystems at multiple trophic levels, and the conservation threats that many carnivores face globally. While a great deal of research attention has historically been focused on large carnivores within ecosystems, the size-mediated sensitivity hypothesis has recently been proposed where the smallest carnivore in a system is likely to be the most responsive to the diverse suite of ongoing environmental and anthropogenic changes within ecological communities. We deployed camera traps at 197 sites over 4 years to monitor a diverse suite of mammalian carnivores within the Blue Ridge Mountains of western North Carolina and then used a two-step occupancy modelling-structural equation modelling framework to investigate the relative support for four primary hypothesized drivers (interspecific competition/predation, habitat complexity, food availability and anthropogenic disturbance) on carnivore occurrence. We found that each of the 10 carnivores in our system responded differently to conditions associated with each of these four hypothesized drivers, but that small and medium-sized carnivores had a greater number of significant (p < 0.05) pathways by which these conditions were influencing occupancy relative to large carnivores. In particular, the smallest carnivore observed in our study was the only species for which we found support for each of the four hypothesized drivers influencing occupancy. Collectively, our study supports the size-mediated sensitivity hypothesis and suggests that small carnivores are ideal sentinel species for global change. We echo recent calls for adopting a middle-out approach to investigations into carnivore community dynamics by refocusing sustained monitoring and research efforts on smaller carnivores within systems.

Intrinsic risk factors for alpha-gal syndrome in a case-control study, 2019 to 2020.

BACKGROUND: Alpha-gal syndrome (AGS) is an allergy to galactose-α-1,3-galactose (alpha-gal), a carbohydrate found in most mammals. Evidence indicates that AGS develops after a tick bite, and in the United States, AGS is most associated with bites from Amblyomma americanum (lone star tick); however, not all persons bitten by ticks develop clinical AGS. OBJECTIVE: To investigate intrinsic risk factors associated with the development of AGS. METHODS: We performed a case-control study among adults presenting for diagnosis or management of AGS at an allergy clinic in North Carolina during 2019 to 2020 and compared them with controls enrolled from 2 nearby internal medicine clinics. A questionnaire gathered epidemiologic and tick exposure data, and blood was obtained for alpha-gal-specific IgE and other testing. RESULTS: The 82 enrolled case patients and 191 controls did not differ significantly by age or sex. Case patients were more likely than controls to have A or O blood types (non B-antigen), have experienced childhood allergies, and have a family history of AGS and other food allergies. Case patients were also more likely to report experiencing long healing times for insect bites or stings and a family history of allergy to stinging or biting insects. CONCLUSION: This study suggested that intrinsic factors contribute to risk of developing AGS. Some traits are genetic, but common behaviors among households and family units likely also contribute. Identification of these risk factors can inform personal risk, aid health care providers in understanding susceptible populations, and contribute to ongoing understanding of AGS epidemiology.

Association of hydroxyurea adherence with transcranial Doppler screenings in children with sickle cell disease.

BACKGROUND: National sickle cell disease (SCD) guidelines recommend oral hydroxyurea (HU) starting at 9 months of age, and annual transcranial Doppler (TCD) screenings to identify stroke risk in children aged 2-16 years. We examined prevalence and proportion of TCD screenings in North Carolina Medicaid enrollees to identify associations with sociodemographic factors and HU adherence over 3 years. STUDY DESIGN: We conducted a longitudinal study with children ages 2-16 years with SCD enrolled in NC Medicaid from years 2016-2019. Prevalence of TCD screening claims was calculated for 3 years, and proportion was calculated for 12, 24, and 36 months of Medicaid enrollment. Enrollee HU adherence was categorized using HU proportion of days covered. Multivariable Poisson regression assessed for TCD screening rates by HU adherence, controlling for age, sex, and rurality. RESULTS: The prevalence of annual TCD screening was between 39.5% and 40.1%. Of those with 12-month enrollment, 77.8% had no TCD claims, compared to 22.2% who had one or higher TCD claims. Inversely, in children with 36 months of enrollment, 36.7% had no TCD claims compared to 63.3% who had one or higher TCD claims. The proportion of children with two or higher TCD claims increased with longer enrollment (10.5% at 12 months, 33.7% at 24 months, and 52.6% at 36 months). Children with good HU adherence were 2.48 (p < .0001) times more likely to have TCD claims than children with poor HU adherence. CONCLUSION: While overall TCD screening prevalence was low, children with better HU adherence and longer Medicaid enrollment had more TCD screenings. Multilevel interventions are needed to engage healthcare providers and families to improve both evidence-based care and annual TCD screenings in children with SCD.

Opioid Use Among Children and Adults With Sickle Cell Disease in North Carolina Medicaid Enrollees in the Era of Opioid Harm Reduction.

Adults and children with sickle cell disease (SCD) are predominantly African American, with pain-related health disparities. We examined opioid prescription fill patterns in adults and children with SCD and compared factors associated with fills in North Carolina Medicaid enrollees. Our retrospective cohort study included 955 enrollees diagnosed with SCD having at least one opioid fill. Associations were measured between two cohorts (12 and 24 mo of continuous enrollment) for the following characteristics: sex, age, enrollee residence, hydroxyurea adherence, comanagement, enrollment in Community Care North Carolina, prescription for short versus short and long-acting opioids, and emergency department reliance. The majority of individuals did not have an opioid claim over a 12 or 24-month period. Claims increased at ages 10 to 17, peaking at ages 18 to 30. The increased number of claims was associated with the following factors: increasing age, male, short versus long-acting opioids, and Medicaid enrollment for 24 versus 12 months. Community Care North Carolina enrollees in the 12-month cohort had higher opioid days of supply per month; the inverse was true of the 24-month cohort.