Nonsurgical improvement of severe upper airway obstruction in infants with Robin sequence and cleft palate using Stanford Orthodontic Airway Plate treatment.

STUDY OBJECTIVES: Severe respiratory distress of neonates with Robin sequence (RS) is traditionally managed by surgery. Stanford Orthodontic Airway Plate treatment (SOAP) is a nonsurgical option. The study aimed to determine if SOAP can improve polysomnography (PSG) parameters of neonates with RS. METHODS: PSG of neonates with RS treated with SOAP at a single hospital were retrospectively analyzed. Patients without PSG at all 4 time points (pre-, start of-, mid-, and post-treatment) were excluded. Data were analyzed using a linear mixed effects model. RESULTS: Sixteen patients were included. All patients had cleft palate (CP). The median age (min, max) at the start of treatment was 1.1 months (0.5, 2.3) with the treatment duration of 4.5 months (3.5, 6.0). The mean obstructive apnea-hypopnea index (95% confidence interval) decreased from 39.3 events/hour (32.9, 45.7) to 12.2 events/hour (6.7, 17.7) (P < 0.001), obstructive apnea index decreased from 14.1 (11.2, 17.0) events/hour to 1.0 (-1.5, 3.5) events/hour (P < 0.001), and oxygen nadir increased from 79.9% (77.4, 82.5) to 88.2% (85.5, 90.8) (P < 0.001) between pre- and start of treatment. Respiratory improvements were sustained during and after the treatment. All patients avoided mandibular distraction osteogenesis or tracheostomy following SOAP. CONCLUSIONS: As being a rare diagnosis, the number of participants was, as expected, low. However, the current study demonstrates that SOAP can improve PSG parameters, demonstrating its potential utility before surgical interventions for neonates with RS and CP experiencing severe respiratory distress.

Impact of a coaching program on resident perceptions of communication confidence and feedback quality.

BACKGROUND: While communication is an essential skill for providing effective medical care, it is infrequently taught or directly assessed, limiting targeted feedback and behavior change. We sought to evaluate the impact of a multi-departmental longitudinal residency communication coaching program. We hypothesized that program implementation would result in improved confidence in residents' communication skills and higher-quality faculty feedback. METHODS: The program was implemented over a 3-year period (2019-2022) for surgery and neurology residents at a single institution. Trained faculty coaches met with assigned residents for coaching sessions. Each session included an observed clinical encounter, self-reflection, feedback, and goal setting. Eligible residents completed baseline and follow-up surveys regarding their perceptions of feedback and communication. Quantitative responses were analyzed using paired t-tests; qualitative responses were analyzed using content analysis. RESULTS: The baseline and follow-up survey response rates were 90.0% (126/140) and 50.5% (46/91), respectively. In a paired analysis of 40 respondents, residents reported greater confidence in their ability to communicate with patients (inpatient: 3.7 vs. 4.3, p < 0.001; outpatient: 3.5 vs. 4.2, p < 0.001), self-reflect (3.3 vs. 4.3, p < 0.001), and set goals (3.6 vs. 4.3, p < 0.001), as measured on a 5-point scale. Residents also reported greater usefulness of faculty feedback (3.3 vs. 4.2, p = 0.001). The content analysis revealed helpful elements of the program, challenges, and opportunities for improvement. Receiving mentorship, among others, was indicated as a core program strength, whereas solving session coordination and scheduling issues, as well as lowering the coach-resident ratio, were suggested as some of the improvement areas. CONCLUSIONS: These findings suggest that direct observation of communication in clinical encounters by trained faculty coaches can facilitate long-term trainee growth across multiple core competencies. Future studies should evaluate the impact on patient outcomes and workplace-based assessments.

Multi-institutional Analysis of Metastasis-directed Therapy with or Without Androgen Deprivation Therapy in Oligometastatic Castration-sensitive Prostate Cancer.

BACKGROUND: Metastasis-directed therapy (MDT) is increasingly being used in oligometastatic castration-sensitive prostate cancer (omCSPC). However, it is currently unclear how to optimally integrate MDT with the standard of care of systemic hormonal therapy. OBJECTIVE: To report long-term outcomes of MDT alone versus MDT and a defined course of androgen deprivation therapy (ADT) in omCSPC. DESIGN, SETTING, AND PARTICIPANTS: Here, a multicenter, international retrospective cohort of omCSPC as defined by conventional imaging was reported. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Biochemical progression-free survival (bPFS), distant progression-free survival (dPFS), and combined biochemical or distant progression-free survival (cPFS) were evaluated with Kaplan-Meier and multivariable Cox proportional hazard regression models. RESULTS AND LIMITATIONS: A total of 263 patients were included, 105 with MDT + ADT and 158 with MDT alone. The majority of patients had metachronous disease (90.5%). Five-year bPFS, dPFS, and cPFS were, respectively, 24%, 41%, and 19% in patients treated with MDT + ADT and 11% (hazard ratio [HR] 0.48, 95% confidence interval [CI] 0.36-0.64), 29% (HR 0.56, 95% CI 0.40-0.78), and 9% (HR 0.50, 95% CI 0.38-0.67) in patients treated with MDT alone. On a multivariable analysis adjusting for pretreatment variables, the use of ADT was associated with improved bPFS (HR 0.43, p < 0.001), dPFS (HR 0.45, p = 0.002), and cPFS (HR 0.44, p < 0.001). CONCLUSIONS: In this large multi-institutional report, the addition of concurrent ADT to MDT appears to improve time to prostate-specific antigen progression and distant recurrence, noting that about 10% patients had durable control with MDT alone. Ongoing phase 3 studies will help further define treatment options for omCSPC. PATIENT SUMMARY: Here, we report a large retrospective review evaluating the outcomes of metastasis-directed therapy with or without a limited course of androgen deprivation for patients with oligometastatic castration-sensitive prostate cancer. This international multi-institutional review demonstrates that the addition of androgen deprivation therapy to metastasis-directed therapy (MDT) improves progression-free survival. While a proportion of patients appear to have long-term disease control with MDT alone, further work in biomarker discovery is required to better identify which patients would be appropriate for de-escalated therapy.

Night-time sleep duration and postpartum weight retention in primiparous women.

Objectives: Approximately 75% of women weigh more at 1-year postpartum than pre-pregnancy. More than 47% retain >10 lbs at 1-year postpartum, which is associated with adverse health outcomes for mother and child. Disturbed sleep may contribute to risk of postpartum weight retention (PWR) as short sleep duration is associated with increased risk of obesity. Thus, we investigated whether night-time sleep duration is associated with risk for excessive PWR. We also explored night-time sleep duration and change in postpartum waist circumference. Methods: This is an ancillary analysis from a prospective cohort study. Participants were healthy primiparous adults with a singleton birth. Excessive PWR at 1-year postpartum was defined as ≥7% of pre-pregnancy weight. Log-binomial and linear regression assessed associations between night-time sleep duration at 6 months postpartum and PWR at 1-year postpartum. Linear regression assessed the association between night-time sleep duration and change in postpartum waist circumference. Results: Mean age of participants (N = 467) was 29.51 (SD ±â€…4.78) years. Night-time sleep duration by actigraphy or self-report was not associated with risk for excessive PWR (risk ratio 0.96, [95%CI 0.87-1.06]; risk ratio 0.95 [95%CI 0.83-1.07], respectively) or change in waist circumference. Conclusion: Night-time sleep duration at 6 months postpartum was not associated with PWR at 1-year postpartum. Mixed findings among our results and previous research could be due to our focus on night-time sleep, and differences in sleep measurement methods and timeframes across studies. More comprehensively assessing sleep, including multiple sleep dimensions, may help advance our understanding of potential links between sleep and PWR. Trial Registration: The parent study, Motherhood and Pelvic Health (MAP Study), is registered at https://clinicaltrials.gov/ct2/show/NCT02512016, NCT02512016.

Cognitive impairment in post-acute sequelae of COVID-19 and short duration myalgic encephalomyelitis patients is mediated by orthostatic hemodynamic changes.

Introduction: Cognitive impairment is experienced by people with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and post-acute sequelae of COVID-19 (PASC). Patients report difficulty remembering, concentrating, and making decisions. Our objective was to determine whether orthostatic hemodynamic changes were causally linked to cognitive impairment in these diseases. Methods: This prospective, observational cohort study enrolled PASC, ME/CFS, and healthy controls. All participants underwent clinical evaluation and assessment that included brief cognitive testing before and after an orthostatic challenge. Cognitive testing measured cognitive efficiency which is defined as the speed and accuracy of subject's total correct responses per minute. General linear mixed models were used to analyze hemodynamics and cognitive efficiency during the orthostatic challenge. Additionally, mediation analysis was used to determine if hemodynamic instability induced during the orthostatic challenge mediated the relationship between disease status and cognitive impairment. Results: Of the 276 participants enrolled, 256 were included in this study (34 PASC, 71 < 4 year duration ME/CFS, 69 > 10 year ME/CFS duration, and 82 healthy controls). Compared to healthy controls, the disease cohorts had significantly lower cognitive efficiency scores immediately following the orthostatic challenge. Cognitive efficiency remained low for the >10 year ME/CFS 2 and 7 days after orthostatic challenge. Narrow pulse pressure less than 25% of systolic pressure occurred at 4 and 5 min into the orthostatic challenge for the PASC and ME/CFS cohorts, respectively. Abnormally narrow pulse pressure was associated with slowed information processing in PASC patients compared to healthy controls (-1.5, p = 0.04). Furthermore, increased heart rate during the orthostatic challenge was associated with a decreased procedural reaction time in PASC and < 4 year ME/CFS patients who were 40 to 65 years of age. Discussion: For PASC patients, both their disease state and hemodynamic changes during orthostatic challenge were associated with slower reaction time and decreased response accuracy during cognitive testing. Reduced cognitive efficiency in <4 year ME/CFS patients was associated with higher heart rate in response to orthostatic stress. Hemodynamic changes did not correlate with cognitive impairment for >10 year ME/CFS patients, but cognitive impairment remained. These findings underscore the need for early diagnosis to mitigate direct hemodynamic and other physiological effects on symptoms of cognitive impairment.

Evaluating Emergency Medicaid Program Policy Changes During the COVID-19 Pandemic.

INTRODUCTION: Trauma patients are twice as likely to be uninsured as the general population, which can lead to limited access to postinjury resources and higher mortality. The Hospital Presumptive Eligibility (HPE) program offers emergency Medicaid for eligible patients at presentation. The HPE program underwent several changes during the COVID-19 pandemic; we quantify the program's success during this time and seek to understand features associated with HPE approval. METHODS: A mixed methods study at a Level I trauma center using explanatory sequential design, including: 1) a retrospective cohort analysis (2015-2021) comparing HPE approval before and after COVID-19 policy changes; and 2) semistructured interviews with key stakeholders. RESULTS: 589 patients listed as self-pay or Medicaid presented after March 16, 2020, when COVID-19 policies were first implemented. Of these, 409 (69%) patients were already enrolled in Medicaid at hospitalization. Among those uninsured at arrival, 160 (89%) were screened and 98 (61%) were approved for HPE. This marks a significant improvement in the prepandemic HPE approval rate (48%). In adjusted logistic regression analyses, the COVID-19 period was associated with an increased likelihood of HPE approval (versus prepandemic: aOR, 1.64; P = 0.005). Qualitative interviews suggest that mechanisms include state-based expansion in HPE eligibility and improvements in remote approval such as telephone/video conferencing. CONCLUSIONS: The HPE program experienced an overall increased approval rate and adapted to policy changes during the pandemic, enabling more patients' access to health insurance. Ensuring that these beneficial changes remain a part of our health policy is an important aspect of improving access to health insurance for our patients.

Accuracy of Wireless Pulse Oximeter on Preterm or <2.5 kg Infants.

OBJECTIVE: Monitoring heart rate (HR) and oxygen saturation (SpO2) in infants is essential in the neonatal intensive care unit. Wireless pulse oximeter technology has been advancing but with limited accuracy data on preterm infants. This observational study compared HR and SpO2 of the wireless Owlet Smart Sock 3 (OSS3) to the wired Masimo SET (Masimo) pulse oximeter in preterm or <2.5 kg infants. STUDY DESIGN: Twenty-eight eligible infants were enrolled. They weighed between 1.7 and 2.5 kg and were without anomalies or medical instability. OSS3 and Masimo simultaneously monitored HR and SpO2 for 60 minutes. The data were aligned by time epoch and filtered for poor tracings. The agreement was compared using the Pearson's correlation coefficient, the Bland-Altman method, average root mean square (ARMS), and prevalence and bias adjusted kappa (PABAK) analyses. RESULTS: Two infants' data were excluded due to motion artifacts or device failures. The corrected gestational age and current weights were 35 ± 3 weeks and 2.0 ± 0.2 kg (mean ± standard deviation), respectively. Over 21 hours of data showed that HR was strongly correlated between the two devices (r = 0.98, p < 0.001), with a difference of -1.3 beats per minute (bpm) and the limit of agreement (LOA) -6.3 to 3.4 bpm based on the Bland-Altman method. SpO2 was positively correlated between the two devices (r = 0.71, p < 0.001) with a SpO2 bias of 0.3% (LOA: -4.6 to 4.5%). The estimated ARMS of OSS3 compared with Masimo was 2.3% for SpO2 in the 70 to 100% range. The precision decreased with lower SpO2. A strong agreement (PABAK = 0.94) was between the two devices on whether SpO2 was above or below 90%. CONCLUSION: OSS3 provided comparable HR and SpO2 accuracy to Masimo in preterm or <2.5 kg infants. Motion artifacts, lack of arterial blood gas comparisons, and lack of racial and ethnic diversity are the study limitations. More OSS3 data on the Lower HR and SpO2 ranges were needed before implementing inpatient use. KEY POINTS: · Pulse oximeters are vital for monitoring preterm infants' HR and SpO2 levels.. · Limited data exist on the accuracy of the wireless OSS3 on preterm infants.. · This observational study found that the OSS3 is comparable to the Masimo SET in measuring HR and SpO2 in preterm or <2.5 kg infants..

Evaluation of Hypofractionated Radiation Therapy Use and Patient-Reported Outcomes in Men With Nonmetastatic Prostate Cancer in Australia and New Zealand.

Importance: Randomized clinical trials in prostate cancer have reported noninferior outcomes for hypofractionated radiation therapy (HRT) compared with conventional RT (CRT); however, uptake of HRT across jurisdictions is variable. Objective: To evaluate the use of HRT vs CRT in men with nonmetastatic prostate cancer and compare patient-reported outcomes (PROs) at a population level. Design, Setting, and Participants: Registry-based cohort study from the Australian and New Zealand Prostate Cancer Outcomes Registry (PCOR-ANZ). Participants were men with nonmetastatic prostate cancer treated with primary RT (excluding brachytherapy) from January 2016 to December 2019. Data were analyzed in March 2021. Exposures: HRT defined as 2.5 to 3.3 Gy and CRT defined as 1.7 to 2.3 Gy per fraction. Main Outcomes and Measures: Temporal trends and institutional, clinicopathological, and sociodemographic factors associated with use of HRT were analyzed. PROs were assessed 12 months following RT using the Expanded Prostate Cancer Index Composite (EPIC)-26 Short Form questionnaire. Differences in PROs were analyzed by adjusting for age and National Comprehensive Cancer Network risk category. Results: Of 8305 men identified as receiving primary RT, 6368 met the inclusion criteria for CRT (n = 4482) and HRT (n = 1886). The median age was 73.1 years (IQR, 68.2-77.3 years), 2.6% (168) had low risk, 45.7% (2911) had intermediate risk, 44.5% (2836) had high-/very high-risk, and 7.1% (453) had regional nodal disease. Use of HRT increased from 2.1% (9 of 435) in the first half of 2016 to 52.7% (539 of 1023) in the second half of 2019, with lower uptake in the high-/very high-risk (1.9% [4 of 215] to 42.4% [181 of 427]) compared with the intermediate-risk group (2.2% [4 of 185] to 67.6% [325 of 481]) (odds ratio, 0.26; 95% CI, 0.15-0.45). Substantial variability in the use of HRT for intermediate-risk disease remained at the institutional level (median 53.3%; range, 0%-100%) and clinician level (median 57.9%; range, 0%-100%) in the last 2 years of the study period. There were no clinically significant differences across EPIC-26 urinary and bowel functional domains or bother scores. Conclusions and Relevance: In this cohort study, use of HRT for prostate cancer increased substantially from 2016. This population-level data demonstrated clinically equivalent PROs and supports the continued implementation of HRT into routine practice. The wide variation in practice observed at the jurisdictional, institutional, and clinician level provides stakeholders with information that may be useful in targeting implementation strategies and benchmarking services.

Unexpectedly high mortality in Pacific herring embryos exposed to the 2007 Cosco Busan oil spill in San Francisco Bay.

In November 2007, the container ship Cosco Busan released 54,000 gallons of bunker fuel oil into San Francisco Bay. The accident oiled shoreline near spawning habitats for the largest population of Pacific herring on the west coast of the continental United States. We assessed the health and viability of herring embryos from oiled and unoiled locations that were either deposited by natural spawning or incubated in subtidal cages. Three months after the spill, caged embryos at oiled sites showed sublethal cardiac toxicity, as expected from exposure to oil-derived polycyclic aromatic compounds (PACs). By contrast, embryos from the adjacent and shallower intertidal zone showed unexpectedly high rates of tissue necrosis and lethality unrelated to cardiotoxicity. No toxicity was observed in embryos from unoiled sites. Patterns of PACs at oiled sites were consistent with oil exposure against a background of urban sources, although tissue concentrations were lower than expected to cause lethality. Embryos sampled 2 y later from oiled sites showed modest sublethal cardiotoxicity but no elevated necrosis or mortality. Bunker oil contains the chemically uncharacterized remains of crude oil refinement, and one or more of these unidentified chemicals likely interacted with natural sunlight in the intertidal zone to kill herring embryos. This reveals an important discrepancy between the resolving power of current forensic analytical chemistry and biological responses of keystone ecological species in oiled habitats. Nevertheless, we successfully delineated the biological impacts of an oil spill in an urbanized coastal estuary with an overlapping backdrop of atmospheric, vessel, and land-based sources of PAC pollution.

Cardiac arrhythmia is the primary response of embryonic Pacific herring (Clupea pallasi) exposed to crude oil during weathering.

Teleost embryos develop a syndrome characterized by edema when exposed to water that weathers substrates contaminated with crude oil. Previous studies using zebrafish demonstrated that crude oil exposure causes cardiogenic edema, and that the most abundant polycyclic aromatic hydrocarbons (PAHs) in weathered crude oils (tricyclic fluorenes, dibenzothiophenes, and phenanthrenes) are cardiotoxic, causing arrhythmia through a pathway that does not require activation of the aryl hydrocarbon receptor (AHR). We demonstrate here for Pacific herring, a species impacted by the Exxon Valdez oil spill, that the developing heart is the primary target of crude oil exposure. Herring embryos exposed to the effluent of oiled gravel columns developed dose-dependent edema and irregular cardiac arrhythmia soon afterthe heartbeat was established. At a dose that produced cardiac dysfunction in 100% of exposed embryos, tissue levels of tricyclic PAHs were below 1 micromol/kg, suggesting a specific, high affinity target in the heart. These findings have implications for understanding the mechanism of tricyclic PAH cardiotoxicity, the development of biomarkers for the effects of PAH exposure in fish, and understanding the long-term impacts of oil spills and other sources of PAH pollution in aquatic environments.

Hospital-treated dog bites in Minnesota, 1998-2005.

This paper is the first to describe the incidence of hospital-treated dog bites in Minnesota using hospital discharge data supplemented with medical record review. The rate of hospital-treated dog bites rose 40% during the 8-year period studied, with the largest growth being seen in the number of emergency department (ED) visits. The highest rates of both hospitalization and ED treatment occurred among children ages 1 to 4 years. In most instances (75%), the victim was familiar with the dog(s) involved. The dog bites most often occurred in the home (48%) and yard (18%). Our findings emphasize the importance of physicians, especially pediatricians and family physicians, counseling parents about the importance of supervising their children when they are around dogs and teaching them safe behaviors around animals. Finally, this study validates the value of hospital discharge data for surveillance of hospital-treated dog bites.

Sparklers, smoke bombs, and snakes, oh my! Effect of legislation on fireworks-related injuries in Minnesota, 1999-2005.

In 2002, Minnesota changed its law banning all fireworks and allowed for nonexplosive, nonaerial fireworks. This article reports that hospitals have seen a steady rise in the number of patients treated for injuries related to fireworks, including a 100% increase in the number of annual fireworks-related injuries between the years 1999 and 2005 based on hospital discharge data.

Climatic and landscape correlates for potential West Nile virus mosquito vectors in the Seattle region.

Climatic and landscape patterns have been associated with both relative mosquito abundance and transmission of mosquito-borne illnesses in many parts of the world, especially warm and tropical climes. To determine if temperature, precipitation, or degree of urbanization were similarly important in the number of potential mosquito vectors for West Nile virus in the moderately temperate climate of western Washington, mosquitoes were collected using CDC carbon-dioxide/light traps set throughout the Seattle region during the summers of 2003 and 2004. The type and abundance of recovered species were compared to ecological correlates. Temperature and mosquito abundance were positively correlated, while precipitation was not strongly correlated with numbers of mosquitoes. Potential WNV mosquito vectors were most abundant in urban and suburban sites, including sites near communal roosts of American crows (Corvus brachyrhynchos). Exurban sites had the greatest vector species diversity, and Culex pipiens was the most abundant species throughout the region.

Developmental toxicity of 4-ring polycyclic aromatic hydrocarbons in zebrafish is differentially dependent on AH receptor isoforms and hepatic cytochrome P4501A metabolism.

Polycyclic aromatic hydrocarbons (PAHs) derived from fossil fuels are ubiquitous contaminants and occur in aquatic habitats as highly variable and complex mixtures of compounds containing 2 to 6 rings. For aquatic species, PAHs are generally accepted as acting through either of two modes of action: (1) "dioxin-like" toxicity mediated by activation of the aryl hydrocarbon receptor (AHR), which controls a battery of genes involved in PAH metabolism, such as cytochrome P4501A (CYP1A) and (2) "nonpolar narcosis", in which tissue uptake is dependent solely on hydrophobicity and toxicity is mediated through non-specific partitioning into lipid bilayers. As part of a systematic analysis of mechanisms of PAH developmental toxicity in zebrafish, we show here that three tetracyclic PAHs (pyrene, chrysene, and benz[a]anthracene) activate the AHR pathway tissue-specifically to induce distinct patterns of CYP1A expression. Using morpholino knockdown of ahr1a, ahr2, and cyp1a, we show that distinct embryolarval syndromes induced by exposure to two of these compounds are differentially dependent on tissue-specific activation of AHR isoforms or metabolism by CYP1A. Exposure of embryos with and without circulation (silent heart morphants) resulted in dramatically different patterns of CYP1A induction, with circulation required to deliver some compounds to internal tissues. Therefore, biological effects of PAHs cannot be predicted simply by quantitative measures of AHR activity or a compound's hydrophobicity. These results indicate that current models of PAH toxicity in fish are greatly oversimplified and that individual PAHs are pharmacologically active compounds with distinct and specific cellular targets.

Epidemiology of emergency department-treated traumatic brain injury in Minnesota.

A number of population-based studies have been published on mortality and hospitalizations associated with traumatic brain injury (TBI). However, very little has been published on treatment of TBI in the emergency department (ED), despite the fact that most cases are seen in such settings. Minnesota is 1 of 2 states funded by the Centers for Disease Control and Prevention since 2001 to conduct surveillance of TBIs treated in EDs. A sample of medical records from 2002 and 2003 was reviewed to better understand the epidemiology of ED-treated TBI and identify risk factors for and interventions to prevent them. We found males, infants, adolescents and young adults, blacks, and residents of the 7-county Twin Cities metropolitan area were most likely to be seen in the ED for TBI. Sports and recreational activities were the leading causes of these injuries, followed by falls and motor vehicle crashes.

Interleukin 31, a cytokine produced by activated T cells, induces dermatitis in mice.

T cell-derived cytokines are important in the development of an effective immune response, but when dysregulated they can promote disease. Here we identify a four-helix bundle cytokine we have called interleukin 31 (IL-31), which is preferentially produced by T helper type 2 cells. IL-31 signals through a receptor composed of IL-31 receptor A and oncostatin M receptor. Expression of IL-31 receptor A and oncostatin M receptor mRNA was induced in activated monocytes, whereas epithelial cells expressed both mRNAs constitutively. Transgenic mice overexpressing IL-31 developed severe pruritus, alopecia and skin lesions. Furthermore, IL-31 receptor expression was increased in diseased tissues derived from an animal model of airway hypersensitivity. These data indicate that IL-31 may be involved in promoting the dermatitis and epithelial responses that characterize allergic and non-allergic diseases.

Genetic effects on age-dependent onset and islet cell autoantibody markers in type 1 diabetes.

Age-dependent associations between type 1 diabetes risk genes HLA, INS VNTR, and CTLA-4 and autoantibodies to GAD65 (GADAs), ICA512/IA-2, insulin, and islet cells were determined by logistic regression analysis in 971 incident patients with type 1 diabetes and 702 control subjects aged 0-34 years. GADAs were associated with HLA-DQ2 in young but not in older patients (P = 0.009). Autoantibodies to insulin were negatively associated with age (P < 0.0001) but positively associated with DQ8 (P = 0.03) and with INS VNTR (P = 0.04), supporting possible immune tolerance induction. ICA512/IA-2 were negatively associated with age (P < 0.0001) and with DQ2 (P < 0.0001) but positively associated with DQ8 (P = 0.04). Males were more likely than females to be negative for GADA (P < 0.0001), autoantibodies to islet cells (P = 0.04), and all four autoantibody markers (P = 0.004). The CTLA-4 3' end microsatellite marker was not associated with any of the autoantibodies. We conclude that age and genetic factors such as HLA-DQ and INS VNTR need to be combined with islet autoantibody markers when evaluating the risk for type 1 diabetes development.