95th Percentile Research Articles

Nanoparticle-Binding Immunoglobulins Predict Variable Complement Responses in Healthy and Diseased Cohorts.

Systemic administration of nanomedicines results in the activation of the complement cascade, promoting phagocytic uptake and triggering proinflammatory responses. Identifying the biomarkers that can predict the "risk" of abnormally high complement responders can improve the safety and efficacy of nanomedicines. Polyethylene glycol (PEG) and dextran are two types of clinically approved polymer coatings that trigger complement activation. We performed a multifaceted analysis of the factors affecting the complement activation by PEGylated liposomal doxorubicin (PLD) and dextran-coated superparamagnetic iron oxide nanoworms (SPIO NWs) in plasma from patients with different inflammatory disease conditions and healthy donors. The complement activation (measured as deposition of the complement protein C3) varied greatly, with 29-fold and 26-fold differences for PLD and SPIO NWs, respectively. Chronic inflammation, acute infection, use of steroids, and sex had minor effects on the variable complement activation, whereas age inversely correlated with the complement activation. C-reactive protein level was not predictive of high (top 20th percentile) complement responses. Plasma concentrations of the main complement factors, as well as total IgG and IgM, showed no correlation with the activation by either nanoparticle. On the other hand, plasma concentrations of anti-PEG IgG and IgM showed a strong positive correlation with the activation by PLD. Particularly, titers of anti-PEG IgM showed the best predictive value for the "risk" of high complement activation by PLD. Titers of antidextran IgG and IgM showed a lower correlation with the activation by SPIO NWs and poor predictive value of the top 20% complement responses. Nanoparticle-bound immunoglobulins showed the best correlation with complement activation and a strong predictive value, supporting the critical role of immunoglobulins in inciting complement. The opsonization of PLD with C3 in plasma with high anti-PEG antibodies was predominantly via the alternative pathway. Characterizing the nature of nanoparticle-binding antibodies has important implications in mitigating and stratifying nanomedicine safety.

Baseline Diameter Does Not Predict Growth Rate in a Presurgical Ascending Thoracic Aortic Aneurysm Population.

Patients with ascending thoracic aortic aneurysm are recommended to undergo routine imaging surveillance. Although maximal diameter is the primary metric of disease severity, recent American College of Cardiology/American Heart Association guidelines emphasize the importance of aortic growth in determining surgical candidacy and risk. As diameter increases, it is assumed that aortic growth rate accelerates because of increased wall tension; however, this relationship is poorly studied. We aim to investigate the relationship between ascending thoracic aortic aneurysm diameter and growth rate using vascular deformation mapping, a validated technique for 3-dimensional growth mapping with submillimeter accuracy. We retrospectively identified adult patients with ascending aortic dilation (≥4.0 cm) and serial gated computed tomography angiograms separated by ≥2 years, excluding confirmed heritable thoracic aortic disease. Ascending growth rate was defined as 90th percentile radial wall deformation by vascular deformation mapping. Maximal diameter measurements were derived from the baseline computed tomography angiogram, and aortic length and body size-adjusted indexes were calculated. Among 258 included patients (63.2% men; age of 63 years [interquartile range, 55-69 years]), mean±SD baseline diameter was 46.3±3.6 mm and median growth rate was 0.21 mm/year (interquartile range, 0.13-0.38 mm/year). No correlation was noted between growth rate and baseline diameter (r=0.02, P=0.74) or other aortic size metrics. On multivariate analysis, age was independently predictive of growth rate (β=-0.007, P=0.021), alongside weight (β=0.003, P=0.016) and the presence of moderate or severe aortic valve insufficiency (β=0.146, P=0.049). Maximal aortic diameter is not predictive of aortic growth rate, in this contemporary cohort of patients with sizes under current surgical thresholds (<55 mm).

Trends in Acute Kidney Injury Related Deaths in the US from 1999 to 2020

Background Acute kidney injury requiring dialysis is linked to long-term care demands, higher hospital mortality, and increased healthcare expenses. We aim to assess nationwide trends and regional variations in acute kidney injury-related mortality in the US. Materials and Methods We used death certificates from the CDC WONDER database (1999-2020) to calculate age-adjusted mortality rates (AAMRs) and annual percent change (APC). The data were stratified by year, gender, race/ethnicity, and geographic region. Results From 1999 to 2020, there were a total of 4,599,652 deaths attributed to acute kidney injury. The AAMR for acute kidney injury-related deaths surged from 11.4 in 1999 to 20.1 in 2020. Men consistently exhibited higher AAMRs than women throughout the study period (overall AAMR in men: 20.1; women: 13.2). When examining average AAMRs by race/ethnicity, Black/African Americans recorded the highest rates at 21.9, followed by American Indian or Alaskan Native (16.4), Whites (15.6), Hispanics (14.5), and Asian/Pacific Islander (10.7). Significant regional disparities were observed, with the southern region reporting the highest AAMR (17.2) and non-metropolitan areas having higher AAMRs than metropolitan areas (18.3 vs. 15.6). States in the top 90th percentile for acute kidney injury deaths included Indiana, Kentucky and South Carolina, which had nearly double the AAMR compared to states like New York, Utah, and Vermont. Conclusion In the last two decades, the United States has experienced a troubling increase in acute kidney injury-related deaths, emphasizing the urgent need for targeted and equitable healthcare interventions to address persistent disparities in gender, race, geography, and urbanization.

Clinical associations of complement-activating collectins, collectin-10, collectin-11 and mannose-binding lectin in preterm neonates

IntroductionPremature and low-birthweight infants are at especially high risk of perinatal complications, including impaired thermoregulation, infections and respiratory distress. Such adverse effects and the need for invasive procedures are associated with high mortality among preterms. This study focused on the influence of the innate immune system and tested the levels of collectins, collectin-10 (CL-10), collectin-11 (CL-11) and mannose-binding lectin (MBL) in preterm neonates.MethodsCord blood was collected from 535 preterms (born at gestational age ≤37 weeks). COLEC10 and COLEC11 polymorphisms were analyzed by real-time PCR and those of MBL2 by PCR/PCR-RFLP. The concentrations of collectins in sera from cord blood were determined with ELISA.FindingsLow concentrations of CL-10 in cord sera (&amp;lt;462 ng/ml corresponding to the 10th percentile) were significantly associated with births at GA ≤32 weeks. Median levels of both CL-10 and CL-11 were significantly lower in preterms with very low birthweight (&amp;lt;1500 g), low Apgar 1’ score and those who needed prolonged hospitalisation. Lower median CL-10 was also observed in fetal growth restriction cases. An important finding was the decreased concentrations of CL-10, CL-11 and MBL in respiratory distress syndrome (RDS). For CL-10 and CL-11, that relationship was confined to infants born at GA ≥33 weeks and/or with body mass at birth ≥1500 g. Only CL-10 was found to influence susceptibility to early-onset infections. COLEC11 heterozygosity for the activity-decreasing polymorphism (rs7567833, +39618 A&amp;gt;G, His219Arg) was more common in preterm premature rupture of membranes (pPROM) cases, compared with corresponding reference groups. Furthermore, C/T or T/T genotypes at COLEC11 at rs3820897 (-9570 C&amp;gt;T) as well as MBL deficiency-associated MBL2 gene variants were more common in preterms diagnosed with RDS than among unaffected newborns.ConclusionThe complement-activating collectins investigated here could be important for maintaining homeostasis in preterm neonates. Despite similar structure and specificity, MBL, CL-10 and CL-11 manifest a different spectrum of clinical associations.

Respiratory Intervals and Swimming Speed as Remotely Sensed Health Metrics in Free-Ranging Killer Whales (Orcinus orca).

Respiratory rate (mean number of breaths per minute) and respiratory interval (mean time between breaths) can offer insight into a diving mammal's activity state, metabolic rate, behavior, and synchronization due to social cohesion. Also, respiratory rate can reflect an individual animal's health and has the potential to be an informative remotely assessed health metric for monitoring individual animal health in endangered whale species and populations such as southern resident killer whales (Orcinus orca). Using data collected from noninvasive, land-based theodolite tracking, we analyzed swimming speed and surfacing intervals (i.e., mean dive time or mean time between breaths) from 20,613 surfacings of 98 individuals from two populations of the fish-eating, resident killer whale ecotype, namely, one growing (northern resident) and one declining and endangered (southern resident) population. Focal animal sampling was used to measure behavior of individuals of known age and sex in various activity states. Our objective was to evaluate variability and generate normal ranges for respiratory intervals and swimming speeds for killer whales of the Northeast Pacific Ocean resident, fish-eating ecotype to identify baseline respiratory intervals. We found that median respiratory intervals for fish-eating killer whales were between 26 and 29 s for all activity states and that swimming speeds varied by activity state. Median swimming speeds were similar for foraging and traveling (1.6 and 1.7 m/s, respectively), but were significantly slower during resting (1.1 m/s) and social activity (1.3 m/s) states. Three southern resident killer whales in poor body condition (had body condition scores in the lowest 20th percentile of the population) swam at reduced speeds and had shorter median respiratory intervals than outwardly healthy whales of similar age and sex. Respiratory rates, respiratory intervals, and swimming speeds are valuable remotely sensed metrics of health for free-swimming killer whales, especially when combined with other metrics as is the standard in veterinary examinations.

Risks Associated with Prolonged Latent Phase of Labor.

We sought to assess the impact of a prolonged latent phase (PLP) on maternal and neonatal morbidity. This is a secondary analysis of a prospective cohort study conducted 2010 to 2015 that included all term gravidas who reached active labor (6 cm). Primary outcomes were composite maternal morbidity (maternal fever, postpartum hemorrhage, transfusion, endometritis, and severe perineal lacerations) and composite neonatal morbidity (respiratory distress syndrome, mechanical ventilation, birth injury, seizures, hypoxic ischemic encephalopathy, therapeutic hypothermia, or umbilical artery pH ≤ 7.1). Outcomes were compared between patients with and without PLP, defined as ≥90th percentile of labor duration between admission and active phase. Results were stratified by induction of labor (IOL) versus spontaneous labor. A stratified analysis was performed by mode of delivery. Multivariable logistic regression was used to adjust for confounders. In this cohort of 6,509 patients, 51% underwent IOL. A total of 650 patients had a PLP with a median length of 8.5 hours in spontaneous labor and 18.8 hours in IOL. Among patients with PLP, there was a significant increase in composite maternal morbidity with both IOL (adjusted odds ratio [aOR]: 1.36, 95% confidence interval [CI]: 1.01, 1.84) and spontaneous labor (aOR: 1.49, 95% CI: 1.09, 2.04) and an increase in composite neonatal morbidity with spontaneous labor only (aOR: 1.57, 95% CI: 1.01, 2.45). Cesarean delivery occurred more often in PLP group (14.0 vs. 25.1%). Among patients who underwent cesarean delivery, PLP remained associated with increased odds of maternal morbidity compared with those with normal latent phase. PLP at or above the 90th percentile in patients who reach active labor is associated with increased risk of maternal morbidity that is not mediated by cesarean delivery. PLP in spontaneous labor is associated with increased neonatal morbidity. These data suggest that further research is needed to establish latent phase cutoffs that may be incorporated into labor management guidelines. · Latent labor ≥90th percentile is associated with increased maternal morbidity in induced and spontaneous labor.. · Latent labor ≥90th percentile in spontaneous but not induced labor is associated with increased neonatal morbidity.. · Cesarean delivery alone does not explain this increased maternal morbidity..

Pancreatitis polygenic risk score is independently associated with all-cause acute pancreatitis risk in the UK Biobank.

Acute pancreatitis (AP) is a complex disease most commonly caused by gallstones, alcohol intake, or hypertriglyceridemia. Even in subjects with hypertriglyceridemia, the risk of AP is heterogeneous. Identifying individuals with a high genetic susceptibility to AP could contribute to a better risk stratification in the clinic. This study aimed to determine if a weighted polygenic risk score (PRS) of common variants in pancreatitis susceptibility genes can independently predict all-cause AP incidence in the general population. A weighted PRS was calculated for 484932 individuals from the UK Biobank, including 3346 individuals who developed AP during follow-up. The PRS included eight single nucleotide polymorphisms in known pancreatitis susceptibility genes. Individuals with a pancreatitis PRS above the 90th percentile had a 1.21-fold (1.03-1.43; P=0.02) increased risk of AP compared with those with a pancreatitis PRS below the 90th percentile. When comparing individuals in the third tertile versus the first tertile, the risk of AP was 1.13-fold (1.00-1.28; P=0.06) higher. Individuals with both a high triglyceride (TG) level and a high pancreatitis PRS (third tertile) had a 2.31-fold (1.83-2.93; P=3.4×10-12) increased risk of AP compared with those with a low pancreatitis PRS and a low TG level (first tertile). Overall, the association between pancreatitis PRS and incident AP was independent of baseline TG level. Results of this study suggest that the accumulation of common variants in pancreatitis susceptibility genes is associated with all-cause AP incidence. Pancreatitis PRS could help clinicians identify patients who may be at higher risk of AP and who may benefit from more aggressive treatment.

Normative data for the lateralization task in the assessment of intranasal trigeminal function

To provide normative data for the lateralization task in the assessment of intranasal trigeminal function, as well as to investigate potential effects of age, sex and olfactory function. The lateralization task using eucalyptus as target stimulus was performed to assess intranasal trigeminal function. Data were collected from: 360 healthy adult participants (mean age 37.5±17.4) for the 40-trial version; 284 participants (mean age 32.6±14.1) for the 20-trial version; and 418 participants (mean age 42.6±15.6) for the 10-trial version. The "Sniffin' Sticks" test was used to measure olfactory function. The mean scores were 35.46±4.50 for the 40-trial version, 15.64±3.65 for the 20-trial version, and 8.14±2.16 for the 10-trial version. In the reference group aged 18-25 years, the 10th percentiles were 33 for the 40-trial version, 11 for the 20-trial version, and 6 for the 10-trial version. Significant effects of age and odor discrimination score were observed on lateralization performance. We provide reference scores for the lateralization task, in large sample of healthy participants. Among the three examined tasks (40, 20 and 10), the 40-trial task yielded the most reliable information. For the 40-trial version, scores equal or higher to 33 points indicate a normal lateralization ability, whereas scores between 27 and 32 may warrant further assessment. Scores below 27 possibly point towards a decreased trigeminal function. The lateralization task serves as surrogate marker of intranasal trigeminal functions and further studies with pathological cases are needed to explore its clinical usefulness.

Spatiotemporal patterns and drivers of extreme fire severity in Spain for the period 1985–2018

Extreme fire severity patterns driven by climate change have deep consequences on vegetation, subsequent fire regimes and have consequences on the effectiveness of extinction. In this work, we aimed to determine if extreme fire severity defined as the 90th percentile of RdNBR has changed in Spain in the last 3 decades, if extreme fire severity patterns have differed among the different vegetation types and what drivers have influenced extreme fire severity in both summer and non-summer fires. We have used perimeters of large wildfires (≥100 ha, n = 1719) from 1985 to 2018 in four pyroregions and the main dominant vegetation types. We have analyzed time series for each pyroregion and vegetation type to determine if there were significant trends and breakpoints in extreme fire severity. We have also analyzed the effects of drought, weather, topography and vegetation on extreme fire severity in seasonal wildfires.Extreme fire severity increased in summer fires from 1985 to 2018, especially in the East and North pyroregions, while the Southwest pyroregion reached highest values in summer. There has been an increase of severity in shrubland, mosaic vegetation and conifer forests in summer. Broadleaved forests had the lowest values of fire severity and did not show any trend in the period considered. The most important drivers of extreme fire severity are, in order of importance, pyroregion, elevation, slope, vapor pressure deficit (VPD) and vegetation type for summer fires, and VPD, vegetation types, pyroregion, windspeed and drought for non-summer fires. Global change is increasing climate-related events. Our results indicate that extreme fire severity in summer has been on the rise in recent decades in Spain, suggesting that, in a climate warming context, without strategic management of these increasingly flammable landscapes, further increases may be likely.

Associations between Dietary Patterns, Fluoride Intake and Excretion in Women Exposed to Fluoridated Salt: A Preliminary Study

Abundant information exists on fluoride intake and excretion in populations exposed to fluoridated water, but not fluoridated salt, where fluoride is eaten through a combination of foods and beverages. This study assessed associations between dietary patterns, fluoride intake and excretion in Mexican women exposed to fluoridated salt. We estimated dietary fluoride intake and excretion (mg/day) from 31 women using 24-h recalls (ASA24) and 24-h urine collections (HDMS diffusion method) and assessed agreement among both estimates of exposure with a Bland-Altman plot. Dietary patterns among the sample were explored by Principal Component Analysis and associations between these patterns and both fluoride intake and excretion were estimated. using Quantile Regressions. Median dietary fluoride intake and excretion were 0.95 and 0.90 mg/day, respectively, with better agreement at values below 1.5 mg/day. We identified three dietary patterns: “Urban Convenience”, “Plant-based” and “Egg-based”. The “Urban Convenience” pattern, characterized by dairy and convenience foods was associated with an increase of 0.25 mg and 0.34 mg of F in the 25th and 50th percentiles of intake respectively, (p &lt; 0.01), and a marginal 0.22 mg decrease in urinary fluoride (p = 0.06). In conclusion, in this sample of Mexican women, a dietary pattern rich in dairy and convenience foods, was associated with both fluoride intake and excretion.

Midlife baseline prostate-specific antigen, velocity, and doubling time association with lethal prostate cancer and mortality.

Midlife baseline prostate-specific antigen (MB PSA), defined as a single PSA value measured between 40-59 years of age, has been proposed as a tool that can limit potential harms of PSA screening. This study aimed to examine the ability of MB PSA versus PSA doubling time (PSADT) and PSA velocity (PSAV) in assessing the likelihood of developing of lethal prostate cancer (PCa) in a diverse and contemporary North American population. Men 40-59 years old, who received their first PSA between the years 1995 and 2019, were included. For MB PSA values, the first PSA test result was included. For PSADT, the first two PSA test results were included. For PSAV, the first three PSA test results within 30 months were included. Selection criteria resulted in a total of 77,594 patients with at least two PSA test results and 11,634 patients with at least three PSA test results. Multivariable Fine-Gray regression was used to examine the impact of the value of the PSA testing methods on the development of lethal PCa (defined as death from PCa or development of metastatic disease either at diagnosis or during follow-up). Time-dependent receiver operating characteristic/area under the curve (AUC) at 5, 10, and 15 years were plotted. In the main cohort, patients were most frequently in the 50-54 age category (32.8%), had a Charlson comorbidity index of 0 (70.5%), and were White (63.2%). Of these, 9.3% had the midlife baseline PSA in the top 10th percentile, and 0.4% had a PSADT 0-6 months. Lethal PCa was diagnosed in 593 (0.8%) patients. The median (interquartile range) time to lethal PCa was 8.6 (3.2-14.9) years. In the main cohort, MB PSA and PSADT showed significant associations with the occurrence of lethal PCa, with a hazard ratio (HR) of 6.10 (95% confidence interval [CI], 4.85-7.68) and HR of 2.20 (95% CI, 1.07-4.54) for patients in the top 10th percentile MB PSA group and in the PSADT between 0 to <6 months group, respectively. In patients with three PSA results available, MB PSA and PSAV showed significant associations with the occurrence of lethal PCa, with a HR of 3.95 (95% CI, 2.29-6.79) and 3.57 (95% CI, 2.17-5.86) for patients in the top 10th percentile MB PSA group and in the in the PSAV >0.4 ng/mL/year group, respectively. PSADT and PSAV did not exhibit higher AUCs than MB PSA in assessing the likelihood of lethal PCa. Specifically, they were 0.818 and 0.708 at 10 and 15 years, respectively, for the PSADT; 0.862 and 0.756 at 10 and 15 years, respectively, for the PSAV; and 0.868 and 0.762 at 10 and 15 years, respectively, for the MB PSA (all p>.05). The study findings are that PSAV or PSADT were not superior to midlife baseline in assessing the likelihood of developing lethal PCa. This suggests that these variables may not have practical use in enhancing PSA screening strategies in a clinical setting.

Quantitative MRI biomarker for classification of clinically significant prostate cancer: Calibration for reproducibility across echo times.

The purpose of the present study is to develop a calibration method to account for differences in echo times (TE) and facilitate the use of restriction spectrum imaging restriction score (RSIrs) as a quantitative biomarker for the detection of clinically significant prostate cancer (csPCa). This study included 197 consecutive patients who underwent MRI and biopsy examination; 97 were diagnosed with csPCa (grade group ≥ 2). RSI data were acquired three times during the same session: twice at minimum TE ~75ms and once at TE=90ms (TEmin1, TEmin2, and TE90, respectively). A linear regression model was determined to match the C-maps of TE90 to the reference C-maps of TEmin1 within the interval ranging from 95th to 99th percentile of signal intensity within the prostate. RSIrs comparisons were made at the 98th percentile within each patient's prostate. We compared RSIrs from calibrated TE90 (RSIrsTE90corr) and uncorrected TE90 (RSIrsTE90) to RSIrs from reference TEmin1 (RSIrsTEmin1) and repeated TEmin2 (RSIrsTEmin2). Calibration performance was evaluated with sensitivity, specificity and area under the ROC curve (AUC). Scaling factors for C1, C2, C3, and C4 were estimated as 1.68, 1.33, 1.02, and 1.13, respectively. In non-csPCa cases, the 98th percentile of RSIrsTEmin2 and RSIrsTEmin1 differed by 0.27±0.86SI (mean±standard deviation), whereas RSIrsTE90 differed from RSIrsTEmin1 by 1.82±1.20SI. After calibration, this bias was reduced to -0.51±1.21SI, representing a 72% reduction in absolute error. For patients with csPCa, the difference was 0.54±1.98SI between RSIrsTEmin2 and RSIrsTEmin1 and 2.28±2.06SI between RSIrsTE90 and RSIrsTEmin1. After calibration, the mean difference decreased to -1.03SI, a 55% reduction in absolute error. At the Youden index for patient-level classification of csPCa (8.94SI), RSIrsTEmin1 has a sensitivity of 66% and a specificity of 72%. The proposed linear calibration method produces similar quantitative biomarker values for acquisitions with different TE, reducing TE-induced error by 72% and 55% for non-csPCa and csPCa, respectively.

Changing windstorm characteristics over the US Northeast in a single model large ensemble

Abstract Extreme windstorms pose a significant hazard to infrastructure and public safety, particularly in the highly populated US Northeast (NE). However, the influence climate change and changing land use will have on these events remains unclear. A large ensemble generated using the Max-Planck Institute (MPI) Earth system model is used to generate projections of NE windstorms under different shared socioeconomic pathways (SSPs) and to attribute changes to projected land use land cover (LULC) change, externally forced changes and internal climate variability. To reduce the influence of coarse grid cell resolution and uncertainties in surface roughness lengths, windstorms are identified using simultaneous widespread exceedance of local 99th percentile 10 m wind speeds (U99). Projected declines in forest cover in the NE and the resulting reductions in surface roughness length under SSP3-7.0 lead to projections of large increases in U99 and derived windstorm intensity and scale. However, these projected changes in regional LULC under SSP3-7.0 are unprecedented in a historical context and may not be realistic. After corrections are applied to remove the influence of LULC on wind speeds, regionally averaged U99 exhibit declines for most of the single model initial-condition large ensemble (SMILE) members which are broadly proportional to the radiative forcing and global air temperature increase in the SSPs, with a median value of −0.15 ms−1 °C−1. While weak cyclones are projected to decline in frequency in the NE, intense cyclones and the resulting windstorms and indices of socioeconomic loss do not. Where present, significant trends in these loss indices are positive, and some MPI SMILE members generate future windstorms that are unprecedented in the historical period.

Association of chronic kidney disease with cognitive impairment risk in middle-aged and older adults: the first longitudinal evidence from CHARLS

Previous studies have yielded inconsistent results regarding the association between chronic kidney disease (CKD) and the risk of cognitive impairment (CI). This study aimed to investigate the longitudinal association of CKD with CI risk in the Chinese middle-aged and older population. A total of 16,515 CI-free participants 45 years of age or older including 15,595 without CKD and 920 with CKD were followed from 2011 until 2018 (median [interquartile range]: 7 [5.5-7]) to detect incident CI. Over the follow-up, 648 participants developed CI. Data were analyzed using multi-adjusted Cox proportional hazard regression and Laplace regression. The incidence rate (IR) of CI was significantly higher in individuals with CKD at 11.46 per 1,000 person-years (95% confidence interval [CI], 8.90 to 14.76) than in those without CKD at 6.38 per 1,000 person-years (95% CI, 5.89 to 6.92). Compared to those without CKD, the hazard ratios of those with CKD was 1.56 (95% CI, 1.19 to 2.04) for CI. Participants with CKD in the middle-aged group (45–54 years) exhibited a heightened risk of CI in age-stratified analyses. CKD accelerated the onset of CI by 1.24 years (10th percentile difference [PD]; 95% CI, -2.03 to -0.43, p < 0.01). The findings from this study revealed a significantly increased risk of CI in individuals with CKD, especially in middle-aged population, where the risk appeared to be more pronounced. This observation underscores the importance of early detection and intervention strategies to alleviate the potential cognitive decline associated with CKD.

Adapting to Competition: Solar PV Innovation in Europe and the Impact of the ‘China Shock’

AbstractLow cost solar energy is key to enabling the transition away from fossil fuels. Despite this, the European Union followed the United States’ example in imposing anti-dumping tariffs on solar panel imports from China in 2013, arguing that Chinese panels were unfairly subsidised and harmed its domestic industry. This paper examines the effects of Chinese import competition on firm-level innovation in solar photovoltaic technology by European firms using a sample of 10,137 firms in 15 EU countries over the period 1999–2020. I show that firms which were exposed to higher import competition innovated more if they had a relatively small existing stock of innovation, but less if their historical knowledge stock fell within the top 10th percentile of firms in the sample. This suggests that newer firms were more able to respond to increased competition by innovating, while firms with a large historical stock of innovation may have been locked into old technological paradigms. As firms with a smaller knowledge stock tended to innovate more overall, trade with China appears to have been beneficial in encouraging innovation among the most innovative firms. However, I also find evidence that import competition increased the probability of exit among firms in the sample.

7726 Central Adrenal Insufficiency From Inhaled Mometasone Manifesting As Growth Deceleration

Abstract Disclosure: S. Gurnurkar: None. F.I. Cooper: None. Introduction: While long courses and/or high-doses of oral steroids have been found to cause adrenal suppression and resultant insufficiency, inhaled corticosteroids from asthma management typically do not affect cortisol production. However, in this case, we describe a patient who presented with 3 years of growth deceleration and was found to have adrenal suppression from her inhaled corticosteroid/long-acting beta agonist, Dulera (mometasone furoate and formoterol fumarate). Case Presentation: An 11-year-old female with history of moderate persistent asthma presented to our endocrinology department with growth deceleration and resultant short stature. The parent noted that the child started to decelerate in height percentiles from the 50th percentile at age 8 to the 6th percentile at age 11. BMI gradually rose from the 85th to 95th percentiles. The parent noted that the child started having worsening asthma symptoms around the start of the growth deceleration, requiring a handful of oral steroid courses and the addition of daily inhaled corticosteroid, Dulera. She had remained on the Dulera for the previous three years, with her asthma under good control. She also took cetirizine daily and albuterol as needed. The last course of oral steroids was three months prior to her first endocrinology visit. The patient’s mid-parental target height was at the 50th percentile and she denied fatigue, headache, or abdominal pain. Family history was negative for endocrine conditions and short stature. Puberty began at age 10. Further workup was recommended. A bone age was concordant with chronologic age. Initial labs including a TSH, free T4, IGF-1, IGFBP-3, CBC, ESR, and CMP were within normal limits. A growth hormone stimulation test with arginine and clonidine was performed. Growth hormone peak was 11 ng/mL, but, interestingly, cortisol resulted as &amp;lt;1.0 ug/dl throughout the test. Due to concerns of adrenal insufficiency, she underwent a high dose ACTH stimulation test. Initial ACTH was 6.3 pg/mL (ref 6-48 pg/mL) and cortisol remained at &amp;lt;1.0 ug/dl at 0, 30, and 60 mins. She was diagnosed with central adrenal insufficiency and prescribed 11 mg/m2 BSA/day of hydrocortisone divided three times daily, with stress dosing and emergency hydrocortisone injection instructions. Conclusion: The existing literature suggests that Dulera (mometasone furoate and formoterol fumarate) does not significantly influence adrenal function nor growth velocity. However, we present the case of a child with 3 years of inhaled Dulera use and significant central adrenal insufficiency. This case report is the first of its kind to detail decreased adrenal function with Dulera in particular. Presentation: 6/2/2024

12441 Factors Affecting The Evaluation Of Adrenal Incidentalomas

Abstract Disclosure: A. Poloju: None. S.K. Pabich: None. S. Syed: None. A. Krueger: None. A. Chiu: None. Introduction: Adrenal incidentalomas are increasingly being detected, owing to the increasing number of high-resolution radiologic studies performed. While most of the nodules are non-functional, 10-15% are hormonally active and hence merit workup. We assessed the rates of, and factors associated with appropriate workup of these nodules. Methods: A retrospective analysis of CT chest and abdominal scans between Jan 1, 2021, and June 1, 2022, in adults ≥18 years at a single tertiary care center was performed. Reports were screened with key phrases to identify adrenal nodules. A chart review was conducted to confirm the reported nodule, obtain demographic data, obtain data on co-morbid conditions, and evaluate for biochemical and radiologic workup. Exclusion criteria included: patients deceased at the time of our review, previously diagnosed nodules, sub-centimeter lesions, and adrenal hemorrhage. Patients were categorized as being from high or low disadvantaged neighborhoods based on their Area Deprivation Index (ADI) score. ADI above the 50th percentile was categorized as more disadvantaged. Charleston Comorbidity Index (CCI), a 10-year survival predictor based on the presence of common diseases was abstracted. Patients with any biochemical workup were compared to patients with no workup. Bivariate analysis was performed using chi-squared and Student’s t-test analysis. A multivariate logistic regression was performed to evaluate factors associated with biochemical workup. Results: A total of 533 records were reviewed. After applying the above exclusion criteria, a total of 245 patients were included in our analysis. Baseline characteristics included: 58.7% female and 41.2% male. 67.3% had hypertension diagnosis, 22% had sleep apnea diagnosis, and 30.6% had diabetes diagnosis. 86% were White, 5.7% Black, 3.2% Hispanic, 3.2% Asian, and 1.6% Other. 71% of the patients had no biochemical workup, 18% had partial workup, and 11% had full workup. Factors associated with having either partial or full workup compared to no workup included female sex (OR 2.33, CI 1.23-4.41), internal medicine/family medicine provider ordering the scan compared to Emergency Department providers (OR 3.84, CI 1.61-9.14), and ADI scores below the 50th percentile (OR 1.98, CI 1.04-3.78). There was no statistically significant difference based on age, race, ethnicity, and CCI. There was no significant difference in the workup for hypercortisolism based on the presence of co-morbid conditions like diabetes, sleep apnea, and overweight/obesity. Conclusions: In our study population, the rates of guideline-based biochemical workup of adrenal incidentalomas were very low at 11%. Factors associated with having at least partial biochemical workup included less socioeconomic disadvantage, female sex, and studies ordered by primary care providers. Presentation: 6/3/2024

6369 Weiss-Kruszka Syndrome and Growth Hormone Deficiency, Adrenal Insufficiency, and Morbid Obesity

Abstract Disclosure: T. Falcon-Rodriguez: None. N. Solano: None. A. Diaz: None. Background: Weiss-Kruszka syndrome (WKSA) is a rare autosomal dominant genetic disorder caused by heterozygous loss-of-function variants in the ZNF462 gene. Individuals affected by this condition exhibit distinctive craniofacial features, ptosis, dysgenesis of the corpus callosum, hearing loss, intellectual disability, and hypotonia. There is one other case report that described a boy with empty sella syndrome with growth hormone deficiency and delayed puberty. Case Presentation: We present the case of a 15-year-old boy who initially came under the care of endocrinology at age 9 due to severe obesity and short stature. Past medical history included ADHD (for which he was on stimulants since age 5), microcephaly, VUR, asthma, and developmental delay. He grew along the 2nd percentile for height from the ages of 6 and 13, after which his growth velocity notably decelerated. His initial bone age at 9 years old was advanced by 3 years. His BMI had exceeded the 99th percentile since age 3. His family history was relevant for maternal type 1 diabetes mellitus, paternal height of 165 cm, and maternal height of 160 cm. Upon physical examination, notable findings included short stature, severe obesity, a low anterior hairline, arched eyebrows, upslanted palpebral fissures, low-set ears, a tubular and short nasal bridge, and an exaggerated cupid's bow. At age 9, the patient was diagnosed with growth hormone (GH) deficiency following a clonidine and glucagon stimulation test, with a GH peak of 1.9 ng/mL (normal &amp;gt;7 ng/mL). Additionally, he was diagnosed with adrenal insufficiency (cortisol peak of 5 ug/dL, after 250 mcg of cosyntropin). A brain/sella MRI revealed a hypoplastic pituitary gland. Subsequently, hydrocortisone replacement was initiated at a dose of 6 mg/m2/day, and GH treatment at a weekly dose of 0.3 mg/kg. Despite treatment with growth hormone and IGF-1 levels on the upper side of the normal range, his growth velocity did not improve significantly. He reached his peak adult height of 150 cm at age 15. His BMI had consistently been at the 99th percentile. According to his mother, he did not have issues with satiety, and his portion sizes were considered normal. He did not consume fast foods or sugary drinks, and his level of physical activity was suboptimal. Whole Exome Sequencing identified a heterozygous de novo pathogenic variant in the ZNF462 gene, specificallyc.2664 C&amp;gt;A, p.(C888*) (NM_021224.4), consistent with the diagnosis of Weiss-Kruszka syndrome (OMIM # 618619). Conclusion: We present, to our knowledge, the first report of morbid obesity and central adrenal insufficiency in a child with WSKA. GH deficiency had been previously reported in 1 patient with WSKA. The finding of a hypoplastic pituitary gland supports the diagnosis of GH deficiency and central adrenal insufficiency. Presentation: 6/3/2024

6715 Short Adult Height in Childhood Cancer Survivors: Prevalence, Risk Factors, and Genetic Contribution

Abstract Disclosure: T. Yoshida: None. J. Baedke: None. F. Wang: None. W. Moon: None. Y. Sapkota: None. J. Miguel Martínez: None. T.E. Merchant: None. C.L. Wilson: None. K.K. Ness: None. M.M. Hudson: None. Y. Yasui: None. A. Delaney: None. Background: Survivors of childhood cancer are at elevated risk for short adult height (SAH) due to cancer and/or its treatment. In the general population, height is a highly polygenic trait; heritability is estimated to be 70-80%. However, the contribution of genetic factors to SAH among childhood cancer survivors is unknown. In addition, the contribution of chemotherapy agents to risk of SAH among survivors has not been established. We assessed: 1) prevalence of SAH; 2) contribution of genetic factors; and 3) impact of cancer therapy including chemotherapy, on SAH in a large cohort of childhood cancer survivors. Methods: Participants included 4461 childhood cancer survivors aged ≥18 years (female 47.5%, mean age 33.2 years old) with measured height information. SAH was defined as height &amp;lt;3rd percentile for age and sex based on the Centers for Disease Control growth charts. Cancer and treatment history were extracted from medical records. We calculated multi-ancestry height polygenic score (PGS) using the latest methodology developed from 5.4 million individuals of diverse ancestries with more than 1 million variants, where lower score associates with shorter height. With a random sample of 75% of survivors, we fit a multivariable logistic regression model for SAH with the PGS, chemotherapy exposures/doses, corticosteroid exposures/doses, and established risk factors for SAH (e.g., age at cancer diagnosis, radiotherapy exposure) as covariates (main model). The remaining 25% of survivors served for validation of the main model and for the calculation of the population attributable fractions (PAF) of the PGS and cancer treatments. Results: The prevalence of SAH was 8.9% among all survivors (9.3% in males; 8.5% in females) and differed widely by primary cancer diagnosis. SAH was associated with lower PGS [odds ratio (OR) 0.47, 95% confidence interval (CI) 0.40-0.55 for a one standard deviation increase], alkylating agent exposure of &amp;gt;12000 mg/m2 (OR 2.19, 95% CI 1.41-3.38, vs. non-exposure), and spinal radiotherapy (OR 3.65, 95% CI 2.23-6.00, vs. non-exposure). Radiotherapy exposure to the hypothalamic-pituitary region and younger age at cancer diagnosis was also associated with SAH in a dose-response manner. The area under the ROC curve of the main model in the validation dataset was 0.80 (95% CI 0.74-0.87), suggesting good predictive ability for SAH by the model. The PAF of SAH calculated from the multiplicative logistic regression model of SAH was 85.7% for cancer treatments and 30.2% and 60.2% for having PGS below the median and the 90th percentile, respectively. Conclusions: Cancer treatments are the primary contributor to SAH risk among survivors with a PAF of 85.7%. Exposure to high-dose alkylating agents contributes to this along with radiotherapy. Inherited genetic factors also affect SAH among survivors but to a much lesser degree than cancer treatments. Presentation: 6/3/2024

7669 Higher Serum Uric Acid Levels Are Associated With a Deleterious Metabolic and Inflammatory Profile in Brazilian Adolescents: An Exploratory Cross-Sectional Analysis

Abstract Disclosure: F.Q. Iorra: None. M.P. Guahnon: None. P.G. Rodrigues: None. A.T. Barcelos: None. F.V. Cureau: None. M. Drehmer: None. B.D. Schaan: None. Introduction: The association of high serum uric acid (sUA) with metabolic syndrome (MetS) and its components have been widely studied, but there are still gaps in how this breakdown product of purine metabolism might refine cardiovascular risk assessment and correlate with other cardiovascular disease biomarkers, especially in children and adolescents. Objective: To evaluate if sUA is associated with metabolic syndrome components and inflammatory markers in Brazilian adolescents. Methods: For this cross-sectional study, 786 individuals aged 12 to 17 years old, previously enrolled in the Study of Cardiovascular Risk in Adolescents (ERICA) - a Brazilian nationwide school based study, and who were from the city of Porto Alegre, had their sUA measured from blood samples that were stored in a biorepository. Anthropometric, biochemical and blood pressure data were collected. MetS diagnosis was based on the International Diabetes Federation age-specific criteria (2005), and insulin resistance was assessed by the HOMA-IR. In accordance with a non-parametric distribution, sUA was divided into quartiles (3.7 mg/dL, 4.4 mg/dL, 5.3 mg/dL for the 25th, 50th, and 75th percentiles, respectively) for the analysis. A linear regression model and a Poisson regression model with robust error variance were used, both adjusted for age, sex and skin color. Results: Participants were 14.8 ± 1.5 years-old, predominantly women (61.7%), self-identified as white skin color (72%) and eutrophic (66.9%). Through the linear regression model, significant positive associations were found between high sUA levels and body mass index Z-score, waist circumference, systolic and diastolic blood pressure, total cholesterol, triglycerides, HOMA-IR and C-reactive protein, and significant negative associations were observed for HDL cholesterol and adiponectin. No association was found between sUA and glucose or HbA1c. We also computed a metabolic risk score as the mean Z score of waist circumference, systolic blood pressure, HDL cholesterol (negative Z score), triglycerides and glucose, which was positive related to sUA (β ± SE = 0.13 ± 0.02; p &amp;lt; 0.001). Finally, the Poisson regression model was applied to estimate the prevalence ratios (PR) for MetS and its components, between adolescents with sUA in the 4th quartile to those in the 1st quartile. An association was observed for MetS (PR 6.37, 95% CI 1.39 - 29.21, p 0.017), high waist circumference (PR 4.61, 95% CI 2.55 - 8.36, p &amp;lt; 0.001) and increased triglycerides (PR 4.76, 95% CI 1.47 - 15.44, p 0.009). Conclusion: High sUA levels were associated with a worse metabolic and inflammatory profile, as well as a greater prevalence of MetS and some of its components in adolescents. Therefore, uric acid should be considered as a potential additional marker of cardiovascular risk in this population. Support: CNPq, CAPES, FIPE, FAPERGS. Presentation: 6/1/2024