95th Percentile Research Articles

Mixed reality-based technology to visualize and facilitate treatment planning of impacted teeth: Proof of concept.

We propose a method utilizing mixed reality (MR) goggles (HoloLens 2, Microsoft) to facilitate impacted canine alignment, as planning the traction direction and force delivery could benefit from 3D data visualization using mixed reality (MR). Cone-beam CT scans featuring isometric resolution and low noise-to-signal ratio were semi-automatically segmented in Inobitec software. The exported 3D mesh (OBJ file) was then optimized for the HoloLens 2. Using the Unreal Engine environment, we developed an application for the HoloLens 2, implementing HoloLens SDK and UX Tools. Adjustable pointers were added for planning attachment placement, traction direction, and point of force application. The visualization was presented to participants of a course on impacted teeth treatment, followed by a 10-question survey addressing potential advantages (5-point scale: 1 = totally agree, 5 = totally disagree). Out of 38 respondents, 44.7% were orthodontists, 34.2% dentists, 15.8% dental students, and 5.3% dental technicians. Most respondents (44.7%) were between 35 and 44 years old, and only 1 (2.6%) respondent was 55-64 years old. Median answers for six questions were 'totally agree' (25th percentile 1, 75th percentile 2) and for four questions 'agree' (25th percentile 1, 75th percentile 2). No correlation was found between age, profession, and responses. Our method generated substantial interest among clinicians. The initial responses affirm the potential benefits, supporting the continued exploration of MR-based techniques for the treatment of impacted teeth. However, the recommendation for widespread use awaits validation through clinical trials.

DANSPOT: A Multicenter Stepped-Wedge Cluster-Randomized Trial of the Reclassification of Acute Myocardial Infarction: Rationale and Study Design.

Cardiac troponins are the preferred biomarkers for the diagnosis of acute myocardial infarction. Although sex-specific 99th percentile thresholds of troponins are recommended in international guidelines, the clinical effect of their use is poorly investigated. The DANSPOT Study (The Danish Study of Sex- and Population-Specific 99th percentile upper reference limits of Troponin) aims to evaluate the clinical effect of a prospective implementation of population- and sex-specific diagnostic thresholds of troponins into clinical practice. This study is a nationwide, multicenter, stepped-wedge cluster-randomized trial of the implementation of population- and sex-specific thresholds of troponins in 22 of 23 clinical centers in Denmark. We established sex-specific thresholds for 5 different troponin assays based on troponin levels in a healthy Danish reference population. Centers will sequentially cross over from current uniform manufacturer-derived thresholds to the new population- and sex-specific thresholds. The primary cohort is defined as patients with symptoms suggestive of acute coronary syndrome having at least 1 troponin measurement performed within 24 hours of arrival with a peak troponin value between the current uniform threshold and the new sex-specific female and male thresholds. The study will compare the occurrence of the primary outcome, defined as a composite of nonfatal myocardial infarction, unplanned revascularization, and all-cause mortality within 1 year, separately for men and women before and after the implementation of the new sex-specific thresholds. The DANSPOT Study is expected to show the clinical effects on diagnostics, treatment, and clinical outcomes in patients with myocardial infarction of implementing sex-specific diagnostic thresholds for troponin based on a national Danish reference population. URL: https://www.clinicaltrials.gov; Unique identifier: NCT05336435.

Prospective measurement of the width of cerebrospinal fluid spaces by cranial ultrasound in neurologically healthy children aged 0–19 months

BackgroundUltrasound (US) is often the first method used to look for brain or cerebrospinal fluid (CSF) space pathologies. Knowledge of normal CSF width values is essential. Most of the available US normative values were established over 20 years ago, were obtained with older equipment, and cover only part of the age spectrum that can be examined by cranial US. This prospective study aimed to determine the normative values of the widths of the subarachnoid and internal CSF spaces (craniocortical, minimal and maximal interhemispheric, interventricular, and frontal horn) for high-resolution linear US probes in neurologically healthy infants and children aged 0–19 months and assess whether subdural fluid collections can be delineated.MethodsTwo radiologists measured the width of the CSF spaces with a conventional linear probe and an ultralight hockey-stick probe in neurologically healthy children not referred for cranial or spinal US.ResultsThis study included 359 neurologically healthy children (nboys = 178, 49.6%; ngirls = 181, 50.4%) with a median age of 46.0 days and a range of 1–599 days. We constructed prediction plots, including the 5th, 50th, and 95th percentiles, and an interactive spreadsheet to calculate normative values for individual patients. The measurements of the two probes and the left and right sides did not differ, eliminating the need for separate normative values. No subdural fluid collection was detected.ConclusionNormative values for the widths of the subarachnoid space and the internal CSF spaces are useful for evaluating intracranial pathology, especially when determining whether an increase in the subarachnoid space width is abnormal.

Interpretation of the nine-step test for Eustachian tube function should consider mastoid cavity volume.

The modified nine-step test is a classical method for evaluating Eustachian tube function. However, clinical interpretation of the increased maximal difference in middle ear pressure (mdMEP) in the modified nine-step test is unknown. We hypothesised that the different reservoir effects of the mastoid cavity can bias the results of the modified nine-step test. A total of 108 consecutive participants (216 ears) were retrospectively screened. Of these, 55 participants (82 ears) who met the inclusion/exclusion criteria were enrolled. The volumetric results of the mastoid cavity, parameters of the modified nine-step test (mdMEP, middle ear pressure, tympanic membrane compliance), and demographic data were analysed. A significant negative correlation was found between mdMEP and mastoid cavity volume (R = .467, p < .001). Ears with mdMEP >70 daPa showed poor pneumatization in the mastoid cavity, with volumes less than 3000 mm3 (10th percentile of all ears analysed). Ears with mastoid cavity volumes lower than the 25th percentile showed a significantly higher mdMEP (p < .001). Patients with mastoid cavity volumes higher than the 75th percentile were significantly younger (p < .001). Multivariate regression analysis for mdMEP showed a good fit (R = .854) using factors including middle ear pressure, admittance and, most importantly, the reciprocal of mastoid volume (Beta = 0.752, p < .001). The mdMEP, the main parameter of the modified nine-step test, was negatively correlated with the mastoid cavity volume. Therefore, the results of the modified nine-step test should be interpreted with consideration of mastoid cavity volume.

Normative values of the nociceptive blink reflex habituation

Introduction: Habituation is a physiological phenomenon, characterized by response reduction to repeated stimulus presentation. In headache disorders, habituation studies have involved different paradigms with several stimulation parameters and sensory modalities, and consistently showed impaired habituation in primary headaches in the interictal phase. The nociceptive blink reflex (nBR) and its related R2 response, modulated by a polysynaptic network in the trigeminocervical complex, is one of the most studied in the field. The lack of nBR habituation normative data hampered the possibility to draw conclusions regarding the functional status of individual patients. The present study aims to define normative values for the nBR habituation process in healthy subjects without a personal diagnosis and family history of migraine, or other headache disorders.Methods: We enrolled 40 healthy subjects (24 females, 32.7±11.6 years) for nBR recording and nBR habituation assessment. To assess the habituation of nBR, 26 consecutive stimuli were administered at three different and randomized stimulus frequencies (0.2, 0.3, 0.5 Hz). After excluding the first response, the remaining 25 area under the curve (AUC) were divided in 5 blocks, and the average values of the AUC was calculated for each block. The percentage reduction in the AUC of the fifth block, compared to the first, represents the habituation index (HI) value. We considered a one-tailed 10th percentile threshold as the lower threshold of normative values for nBR HI.Results: The habituation phenomenon was confirmed for all study frequencies. The absolute AUC of the R2 component across the five blocks of stimulation was higher in female subjects when compared to male for 0.5 Hz (p=0.021) and 0.2 Hz (p=0.007). We found a frequency-dependent habituation pattern, being lower at the 0.2 Hz stimulation when compared to 0.5 Hz (p=0.001), and 0.3 Hz (p=0.008). The average HIs were 73.1±13.6 at 0.5 Hz, 69.2±15.0 at 0.3 Hz, and 61.1±21.4 at 0.2 Hz. HIs were comparable between male and female subjects, without correlations with age, intensity of stimulation, and latency of the R2 component. The 10th percentile of the HIs was 43.5% for 0.5 Hz, 55.8% for 0.3 Hz, and 28.6% for 0.2 Hz.Conclusions: We investigated the nBR habituation in a population of healthy subjects for normative data collection. We described a frequency- dependent degree of habituation, being more pronounced at higher frequencies of stimulation. Moreover, we described gender-related features of response behaviour, which is extremely important in the migraine field. Our study further characterized the physiological habituation phenomenon in healthy controls exposed to a nociceptive stimulation. The definition of a normative habituation value will open novel possibilities in the study of migraine, as well as other headache and pain disorders.

A Rare Consanguineous Case of Alazami Syndrome in a Jordanian Family: Clinical Presentation, Genetic Analysis, and Therapeutic Approaches - A Case Report

Objective: Alazami syndrome (AS) is an infrequent genetic disorder inherited in an autosomal recessive pattern, characterized by the presence of multiple congenital abnormalities. This study explores a case of a 4-year-old girl with AS, examining symptoms, genetic factors, and treatment efficacy. Case report: A 4-year-old girl, born to consanguineous Jordanian parents, displayed dysmorphic features including low birth weight, microcephaly, hyperthyroidism, short stature, blue sclera, triangular-shaped face, deep-set eyes, narrow palpebral fissures, and a prominent forehead. Examination revealed height (92 cm) and weight (7.7 kg) below the 5th and 3rd percentiles respectively. Blood tests and renal ultrasound were normal. Whole exome sequencing (WES) identified a homozygous eight-base pair deletion within exon 5 of the LARP7 gene on chromosome 4q25, confirming the diagnosis of AS, an autosomal recessive disorder. This variant induces frameshift mutations leading to premature stop codons, suggesting a probable mechanism of illness via loss of function. Treatment involving growth monitoring and therapy led to significant improvements in height, weight, and communication skills within three months. Conclusion: We describe a rare autosomal recessive AS case due to consanguinity, with a frameshift mutation in the LARP7 gene found via WES. Our AS treatment program effectively alleviates symptoms and enhances developmental progress.

Association between exposure to ambient air pollution, meteorological factors and atopic dermatitis consultations in Singapore—a stratified nationwide time-series analysis

Atopic dermatitis (AD) is a chronic inflammatory skin disease affecting approximately 20% of children globally. While studies have been conducted elsewhere, air pollution and weather variability is not well studied in the tropics. This time-series study examines the association between air pollution and meteorological factors with the incidence of outpatient visits for AD obtained from the National Skin Centre (NSC) in Singapore. The total number of 1,440,844 consultation visits from the NSC from 2009 to 2019 was analysed. Using the distributed lag non-linear model and assuming a negative binomial distribution, the short-term temporal association between outpatient visits for AD and air quality and meteorological variability on a weekly time-scale were examined, while adjusting for long-term trends, seasonality and autocorrelation. The analysis was also stratified by gender and age to assess potential effect modification. The risk of AD consultation visits was 14% lower (RR10th percentile: 0.86, 95% CI 0.78–0.96) at the 10th percentile (11.9 µg/m3) of PM2.5 and 10% higher (RR90th percentile: 1.10, 95% CI 1.01–1.19) at the 90th percentile (24.4 µg/m3) compared to the median value (16.1 µg/m3). Similar results were observed for PM10 with lower risk at the 10th percentile and higher risk at the 90th percentile (RR10th percentile: 0.86, 95% CI 0.78–0.95, RR90th percentile: 1.10, 95% CI 1.01–1.19). For rainfall for values above the median, the risk of consultation visits was higher up to 7.4 mm in the PM2.5 model (RR74th percentile: 1.07, 95% CI 1.00–1.14) and up to 9 mm in the PM10 model (RR80th percentile: 1.12, 95% CI 1.00–1.25). This study found a close association between outpatient visits for AD with ambient particulate matter concentrations and rainfall. Seasonal variations in particulate matter and rainfall may be used to alert healthcare providers on the anticipated rise in AD cases and to time preventive measures to reduce the associated health burden.

Revisiting the Implications of a Wide or Narrow Fetal Cavum Septi Pellucidi.

To investigate short-term neonatal developmental outcomes in fetuses with an isolated wide or narrow cavum septi pellucidi (CSP) using new reference ranges. A cross-sectional study on fetuses at 16 + 0 to 36 + 6 weeks of gestation between December 2020 and January 2022. CSP width reference ranges were constructed from low-risk pregnancies. Wide and narrow CSPs were defined as measurements above the 95th percentile and below the 5th percentile, respectively. For the primary outcome fetuses with normal neurosonograms were included. Neonatal developmental outcomes were assessed using the Survey of Well-being of Young Children (SWYC). A total of 352 fetuses were included in this study, of whom 138 were healthy and had uncomplicated neonatal outcomes. These fetuses constituted the control group and were used to construct the CSP width reference ranges. Of 185 fetuses in the neurosonography group, 9.7% had wide and 7.6% had narrow CSPs, of whom 33.3% and 22.2%, respectively, scored below the SWYC threshold for expected developmental milestones, a rate similar to that reported in the general population. The presence of a prenatally isolated wide or narrow CSP does not appear to the risk of neonatal neurodevelopmental delay.

Maternal vascular indices at 36 weeks' gestation in small and growth restricted fetuses.

To compare maternal vascular indices and hemodynamic parameters at 35-37 weeks' gestation, in pregnancies complicated by small for gestational age (SGA) fetuses and those with fetal growth restriction (FGR). This was a prospective observational non-intervention study in women with singleton pregnancies attending for a routine hospital visit at 35+0 to 36+6 weeks' gestation. The visit included recording of maternal demographic characteristics and medical history, vascular indices and hemodynamic parameters obtained by a non-invasive operator independent device, including pulse wave velocity, augmention index, cardiac output, stroke volume, central systolic and diastolic blood pressure, total peripheral resistance and fetal heart rate. Hypertensive disorders of pregnancy were excluded and the values in the SGA and FGR groups were compared between them and with unaffected pregnancies. Diagnosis of SGA was based on the birth of a baby with birthweight below the 10th percentile for gestational age. In FGR, in addition to a birthweight below the 10th percentile, at the 35-37 weeks scan Doppler studies had shown that the uterine artery or umbilical artery pulsatility index (PI) was above the 95th percentile for gestational age or the fetal middle cerebral artery PI was below the 5th percentile. In the 6,413 women included in the study there were 605 (9.4%) cases of SGA, 133 (2.1%) of FGR and 5,675 (88.5%) unaffected by SGA or FGR. Women with SGA or FGR, compared to unaffected pregnancies, had increased peripheral vascular resistance and reduced cardiac output. Central systolic and diastolic blood pressure were also increased, whereas aortic stiffness assessed by pulse wave velocity and augmentation index did not differ between affected and unaffected pregnancies. In the FGR, compared to the SGA group, central systolic and diastolic blood pressure were higher, whereas, heart rate was lower. In SGA and FGR pregnancies there are deranged maternal hemodynamic responses when these are compared to normal pregnancies. Mothers with FGR babies have higher central blood pressure compared to SGA ones, but it remains unclear whether these differences are driven by the size of the fetus or pathological fetal growth. This article is protected by copyright. All rights reserved.

Detectable troponin below the 99th percentile predicts survival in patients undergoing coronary angiography

BackgroundCardiac troponin I (cTnI) above the 99th percentile is associated with an increased risk of major adverse events. Patients with detectable cTnI below the 99th percentile are a heterogeneous group with a less well-defined risk profile. The purpose of this study is to investigate the prognostic relevance of detectable cTnI below the 99th percentile in patients undergoing coronary angiography. MethodsThe study included 14,776 consecutive patients (mean age of 65.4 ± 12.7 years, 71.3 % male) from the Essen Coronary Artery Disease (ECAD) registry. Patients with cTnI levels above the 99th percentile and patients with ST-segment elevation acute myocardial infarction were excluded. All-cause mortality was defined as the primary endpoint. ResultsDetectable cTnI below the 99th percentile was present in 2811 (19.0 %) patients, while 11,965 (81.0 %) patients were below detection limit of the employed assay. The mean follow-up was 4.25 ± 3.76 years. All-cause mortality was 20.8 % for patients with detectable cTnI below the 99th percentile and 15.0 % for those without detectable cTnI. In a multivariable Cox regression analysis, detectable cTnI was independently associated with all-cause mortality with a hazard ratio of 1.60 (95 % CI 1.45–1.76; p < 0.001). There was a stepwise relationship with increasing all-cause mortality and tertiles of detectable cTnI levels with hazard ratios of 1.63 (95 % CI 1.39–1.90) for the first tertile to 2.02 (95 % CI 1.74–2.35) for the third tertile. ConclusionsDetectable cTnI below the 99th percentile is an independent predictor of mortality in patients undergoing coronary angiography with the risk of death growing progressively with increasing troponin levels.

Characterizing residential sector load curves from smart meter datasets

Understanding how and when residential electricity is used throughout the day is integral to the successful implementation of potential residential demand management strategies. Our analysis characterizes the daily hourly load profiles of approximately 160,000 residential electricity customers across the Southern California Edison (SCE) service area during the period spanning 2015 to 2016 and 2018 to 2019 across weekends, weekdays, seasons, and climate zones. We find that total daily electricity usage was highest in the hottest months of the year compared to milder months, particularly for households located in the hottest climate zones. The most energy-consumptive hours occurred during the mid-afternoon during the hottest months, in contrast to early evening high consumption in cooler months. We find that customers with average daily consumption at or above the 80th percentile cumulatively consume over 40% of electricity during the hottest months of the year residential load, while the bottom half of customers cumulatively consume <25% of the total residential load. The disparities in electricity usage across SCE households are higher in the mid-day, especially in milder months across all regions, and in mild climate zones compared to hotter climate zones since loads are not as dependent on high HVAC loads.

Abstract PO5-16-08: Breast cancer in men: 15 years of experience in an oncology reference center in northern Mexico

Abstract Background Breast cancer in men accounts for about 1% of all breast cancers. Classic risk factors include increasing age, a family history of cancer, and mutations in predisposing genes. The alteration of the estrogen-androgen ratio has been as involved in the genesis of this cancer due to its increased risk in conditions such as liver dysfunction, obesity, marijuana use, thyroid disease, Klinefelter’s syndrome, hormonal therapies, orchitis, cryptorchidism, and testicular damage. Purpose Hereby we aim to update the analysis of the published demographic, clinical and treatment-related characteristics of this disease in our center including the last 15 years, as well as newly identified relevant variables that will serve as the basis for awareness and screening programmes for our population. Methods We performed a retrospective observational analysis of the medical records of men diagnosed with breast cancer that were treated in “Centro Universitario Contra el Cáncer” between January 2007 and December 2022. A total of seventeen cases of male breast cancer were included in the analysis. The variables included are age at diagnosis, body mass index, comorbidities, cigarette and alcohol use, method of diagnosis, histological type/grade, clinical stage, estrogen, progesterone, and human epidermal growth factor receptor-2 (HER2) receptor status, and treatment received. We also looked at the dates of symptom onset, diagnosis, and treatment to determine the intervals between these events. SPSS v25 software was used for data analysis. The Shapiro-Wilk test was employed to determine the normality of the variables. Variables with a normal distribution were described with median and interquartile range for the 25th and 75th percentiles. Categorical variables were expressed as absolute numbers and percentages. Results Although we found some similarities between the characteristics of our population and those reported in the American and European series, there were many significant differences. Mean age at diagnosis was 62.9 (±11.7) years, 5.5 years earlier than the reported age of 68.4 years. In terms of risk factors, our population was twice as likely to report a family history of cancer as the American series (41% vs. 15-20%). Overweight and obesity together accounted for 76.5% followed by alcohol consumption in 70.6% and cigarette smoking in 47.1% of patients. Diabetes mellitus and systemic arterial hypertension were present in 70% of our population. These entities are known to alter the estrogen-androgen ratio. The initial symptom in 88.2% of patients was a retroareolar tumor. The mean time from symptom onset to cancer diagnosis was 14.4 months. Estrogen and/or progesterone receptor status was positive in 82.3%. HER2 overexpression was not found. 17.6% of the cancers were classified as triple negative in contrast to the 0.3% reported in other series. Regarding treatment, 88.3% underwent upfront surgery, of which 76% were modified radical mastectomies. Axillary node dissection was performed in 86.6% of the cases and sentinel node biopsy in the rest. Seventy-six percent of patients received chemotherapy and radiotherapy in the adjuvant setting. Tamoxifen was the most common drug of choice (87.5%) in the patients considered as candidates for hormonal therapy Conclusions This study updates the results previously reported from our center with additional information that enabled new important conclusions to be drawn about our population. These findings provide the basis for a better understanding of this disease, which is necessary to establish public policies and recommendations to reduce the negative impact of this type of cancer. Table. Demographic and Clinical Characteristics of the Patients Citation Format: Fernando Peña, Javier A. Martínez-Moyano, Francisco Alvarado-Villarreal, Carlos Salazar-Mejía, David Hernández-Barajas, Oscar Vidal-Gutiérrez. Breast cancer in men: 15 years of experience in an oncology reference center in northern Mexico [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-16-08.

Abstract PO2-13-03: Spatial HER2 heterogeneity on HER2-PET in HER2-low and negative disease: potential biomarker for antibody-drug conjugate effect

Abstract Background: Anti-HER2 antibody drug conjugates (ADCs) can assert an effect in part of patients with HER2-low breast cancer. In light of patient burden and financial sustainability, biomarkers to select responding patients are urgently needed, but so far, none have been identified. In the IMPACT trial (NCT01957332), patients with newly diagnosed and non-rapidly progressive metastatic breast cancer (MBC) of all subtypes (including HER2-negative, -low, and –positive disease) were included. We assessed the performance of Zirconium-89 (89Zr)-trastuzumab positron emission tomography (HER2-PET) in HER2-low and negative MBC. Methods: All patients received extensive workup, including a metastasis biopsy and HER2-PET at baseline. HER2 status was determined by immunohistochemistry (IHC) and in situ hybridization. ⁸⁹Zr-trastuzumab uptake was quantified as maximum and mean standardized uptake values (SUVmax, SUVmean) in metastases and healthy background tissue. Quantitative ⁸⁹Zr-trastuzumab uptake of all metastases and corresponding biopsied metastasis, was related to HER2 IHC status. Results: In 200 patients, ⁸⁹Zr-trastuzumab uptake was quantified in 5,163 metastases. With increasing HER2 IHC status, uptake was higher (geometric mean SUVmax 7.0, 7.6, 7.3, and 17.4 with HER2 IHC 0, 1, 2, or 3+, in respectively 71, 71, 20, and 24 biopsied metastases (P  0.001 between IHC 0 and 3+). SUVmax in lesions was heterogeneous within and between patients for all HER2 IHC groups. All HER2 IHC groups, also HER2-negative and -low, had uptake exceeding that of the healthy background (geometric mean tumor-to-background ratio SUVmax &amp;gt;1 in all groups, increasing with higher HER2 IHC). Of patients with a HER2 IHC 0 biopsy, 27.8% had at least one metastasis elsewhere in the body, with uptake exceeding the overall 90th SUVmax percentile of 14.6; in HER2 low IHC1+ and 2+, this was 31.9% and 30%. Conclusions: In this largest series with HER2-PET in patients with MBC, we show that ±30% of patients with HER2-low or -negative IHC in the biopsy, in fact, have metastases with high HER2 uptake elsewhere in the body. This spatial heterogeneity provides novel insights into HER2-negative and -low disease compared to standard HER2 IHC of a single biopsy. As HER2-PET uptake is related to ADC response in HER2 positive MBC1, HER2-PET is a potential biomarker for anti-HER2 ADC effect in HER2-low and -negative MBC as well. Reference: 1. Gebhart G, et al. Ann Oncol 2016;27(4): 619-624. Supported by the Dutch Cancer Society grant 2012-5565 Citation Format: Carolien Schroder, Jasper van Geel, Bertha Eisses, Adrienne Brouwers, Sjoerd Elias, Frederike Bensch, Evelien Kuip, Agnes Jager, Andor Glaudemans, Bert van der Vegt, Willemien Menke-van der Houven van Oordt, Elisabeth de Vries. Spatial HER2 heterogeneity on HER2-PET in HER2-low and negative disease: potential biomarker for antibody-drug conjugate effect [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-13-03.

Metal mixture exposures and serum lipid levels in childhood: the Rhea mother-child cohort in Greece.

Growing evidence suggests that cardiovascular disease develops over the lifetime, often beginning in childhood. Metal exposures have been associated with cardiovascular disease and important risk factors, including dyslipidemia, but prior studies have largely focused on adult populations and single metal exposures. To investigate the individual and joint impacts of multiple metal exposures on lipid levels during childhood. This cross-sectional study included 291 4-year-old children from the Rhea Cohort Study in Heraklion, Greece. Seven metals (manganese, cobalt, selenium, molybdenum, cadmium, mercury, and lead) were measured in whole blood using inductively coupled plasma mass spectrometry. Serum lipid levels included total cholesterol, triglycerides, high-density lipoprotein (HDL) cholesterol, and low-density lipoprotein (LDL) cholesterol. To determine the joint and individual impacts of child metal exposures (log2-transformed) on lipid levels, Bayesian kernel machine regression (BKMR) was employed as the primary multi-pollutant approach. Potential effect modification by child sex and childhood environmental tobacco smoke exposure was also evaluated. BKMR identified a positive association between the metal mixture and both total and LDL cholesterol. Of the seven metals examined, selenium (median 90.6 [IQR = 83.6, 96.5] µg/L) was assigned the highest posterior inclusion probability for both total and LDL cholesterol. A difference in LDL cholesterol of 8.22 mg/dL (95% CI = 1.85, 14.59) was observed when blood selenium was set to its 75th versus 25th percentile, holding all other metals at their median values. In stratified analyses, the positive association between selenium and LDL cholesterol was only observed among boys or among children exposed to environmental tobacco smoke during childhood. Growing evidence indicates that cardiovascular events in adulthood are the consequence of the lifelong atherosclerotic process that begins in childhood. Therefore, public health interventions targeting childhood cardiovascular risk factors may have a particularly profound impact on reducing the burden of cardiovascular disease. Although growing evidence supports that both essential and nonessential metals contribute to cardiovascular disease and risk factors, such as dyslipidemia, prior studies have mainly focused on single metal exposures in adult populations. To address this research gap, the current study investigated the joint impacts of multiple metal exposures on lipid concentrations in early childhood.

Different cardiovascular risks associated with elevated creatinine-based eGFR and cystatin C-based eGFR

To compare the association of elevated estimated glomerular filtration rate (eGFR) based on creatinine (eGFRcr) and cystatin C (eGFRcys) with the risk of cardiovascular diseases (CVD) and chronic kidney diseases (CKD). 372,060 participants free of CVD and CKD in the UK Biobank were included. Participants were categorized into low, normal and high eGFR groups according to the age- and sex-specific 5th and 95th percentiles of eGFR. The primary outcome was incident CVD, defined as a combination of ischemic heart disease, stroke, heart failure, and atrial fibrillation. Thresholds for high eGFR varied with age and sex, ranging from 96.5 to 116.0 mL/min/1.73 m2 and 100.3 to 120.1 mL/min/1.73 m2 for eGFRcr and eGFRcys, respectively. During a median follow-up of 12.4 years, 39,855 (10.7%) participants developed CVD. Compared with normal eGFR levels, high eGFRcr levels were associated with a higher risk of CVD (HR, 1.19; 95% CI: 1.14–1.25), while high eGFRcys levels were associated with a lower risk of CVD (HR, 0.90; 95% CI: 0.85–0.95). Compared to normal eGFR levels, both high eGFRcr and high eGFRcys levels were related to a lower risk of CKD. Elevated eGFRcr levels were associated with a higher risk of CVD, and elevated eGFRcys levels were associated with a lower risk of CVD.

Abstract PO5-13-09: Clinical usage of a CLIA accredited protein/phosphoprotein assay for breast cancer: Primary usage cases and significant findings in the HER2- setting

Abstract Background: A CLIA-accredited assay that measures the expression and/or activation levels of 32 clinically actionable protein and phosphoprotein analytes in clinical tissue biopsy samples was launched in January 2021. The current intended use population for the assay is for patients with late/advanced stage breast cancer wherein molecular profiling is being utilized for clinical decision making. Assessment of physician ordering practices, clinical use dynamics as well as protein/phosphoprotein actionability frequencies were determined for clinically actionable biomarkers. Methods: A total of 219 cases have been processed to date, with mean turn-around time of 16.4 days. The assay utilizes laser capture microdissection to enrich tumor epithelium from FFPE core needle biopsy and resection material coupled to reverse phase protein array. Results for each of the 32 analytes are generated by comparing each patient to a reference population and reported both as a relative quartile and as a continuous percentile compared to the reference population (0-100%). For the purposes of this analysis, significant expression/activation cutpoints were set at the 40th percentile threshold. Results: To date, clinicians have requested the test most frequently to identify potential therapeutic targets in patients with HER2-negative disease (84% of all tested patients, 36% were triple-negative). Despite the majority of cases being HER2-negative, we found that phosphorylated (p) HER2 (Y1248) was found to be activated in 17% of all HER2-negative cases and 19% of triple negative breast cancer cases (TNBC). pHER2 was concurrently activated with pHER3 (Y1289) in 15% (12/80) of TNBC cases and 13% (24/187) of all HER2-negative cases. pHER2 presented concurrently with pEGFR (Y1068 or T654) in 14% (11/80) of TNBC cases and 14% (26/187) of all HER2- cases. Expression of TROP2 was observed in 16% of HER2-negative patients including 11% of ER+/HER2- and 23% of TNBC cancers. MHCII expression, a recently described candidate predictive biomarker of anti-PDL1/PD1 response in TNBC, was found to be expressed in 29% of TNBC patients. Activation frequencies of other clinically relevant drug targets in HER2-negative disease such AKT and mTOR pathway activation was also assessed. We found that pAKT (S473 and/or T308) was activated in 7% of ER+/HER2- cases and 14% of TNBC. Concurrent with AKT activation, at least one additional member of the AKT-mTOR pathway (mTORC1 (S2448), 4E-BP1 (S65), p70S6K (T389), or S6RP (S235/S236) was co-activated in 50% and 45% of ER+/HER2- and TNBC cancers respectively. Conclusion: This initial assessment of a CLIA LDT protein/phosphoprotein assay utilized to date found that physicians most often order the test for advanced stage HER2-negative breast cancer. Activation/expression of clinically important protein drug targets with potential actionability in HER2-negative disease was observed in a significant number of cases and demonstrates the power of the assay to elucidate actionable targets for potential therapeutic intervention. Citation Format: Claudius Mueller, Brian Corgiat, Emanuel Petricoin, Kayla Sparks, Joyce O'Shaughnessy, Chelsea Gawryletz, Matthew Schwartz, Justin Davis. Clinical usage of a CLIA accredited protein/phosphoprotein assay for breast cancer: Primary usage cases and significant findings in the HER2- setting [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-13-09.

Reference values and associated factors of controlled attenuation parameter and liver stiffness in adults: A cross-sectional study

Background & aimsThe utilization of non-invasive techniques for liver fibrosis and steatosis assessment has gained acceptance as a viable substitute for liver biopsy in clinical practice. This study aimed to establish normative data for the controlled attenuation parameter (CAP) and liver stiffness measurement (LSM) by age and gender, as well as to explore the relationship between anthropometric measures, clinical status, and biochemical profile according to the 90th percentile cut-off values for CAP/LSM in a U.S. adult population. Methods and resultsIn this cross-sectional analysis, 7.522 US adults aged 20–80 years from the National Health and Nutrition Examination Survey (NHANES 2017–2020) were included. CAP and LSM were quantified using the FibroScan® 502-v2 device. A comprehensive range of data was collected, including sociodemographic, anthropometric, biochemical, lifestyle, and clinical conditions. Participants were segmented by sex and age. The median ± standard deviation (SD) for CAP was significantly lower in women (258.27 ± 61.02 dB/m) than in men (273.43 ± 63.56 dB/m), as was the median ± SD for LSM (women: 5.50 ± 4.12 kPa, men: 6.36 ± 5.63 kPa). Although median CAP and LSM values displayed an upward trend with age, statistical significance was not achieved. Notably, higher liver CAP values (above the 90th percentile) correlated with more pronounced clinical and biochemical profile differences compared to lower CAP values (below the 90th percentile) (p < 0.001). ConclusionsOur study provides age- and sex-stratified standard values for CAP and LSM in a sizeable, nationally representative cohort of adults. The evidence of sex-specific variations in TE test results from our study sets the stage for future research to further corroborate these findings.

Assessing the impact of bias correction approaches on climate extremes and the climate change signal

AbstractWe assess the impact of three bias correction approaches on present day means and extremes, and climate change signal, for six climate variables (precipitation, minimum and maximum temperature, radiation, vapour pressure and mean sea level pressure) from dynamically downscaled climate simulations over Queensland, Australia. Results show that all bias‐correction methods are effective at removing systematic model biases, however the results are variable and season‐dependent. Importantly, our results are based on fully independent cross‐validation, an advantage over similar studies. Linear scaling preserves the climate change signals for temperature, while quantile mapping and the distribution‐based transfer function modify the climate change signal and patterns of change. The Perkins score for all the values above the 95th percentile and below the 5th percentile was used to evaluate how well the climate model matches the observational data. Bias correction improved Perkins score for extremes for some variables and seasons. We rank the bias‐correction methods based on the Kling–Gupta efficiency (KGE) score calculated during the validation period. We find that linear scaling and empirical quantile mapping are the best approaches for Queensland for mean climatology. On average, bias correction led to an improvement in the KGE score of 23% annually. However, in terms of extreme values, quantile mapping and statistical distribution‐based transfer function approaches perform best, and linear scaling tends to perform worst. Our results show that, except linear scaling, all approaches impact the climate change signal.

The Impacts of Changing Winter Warm Spells on Snow Ablation Over Western North America

AbstractAn increase in winter air temperature can amplify snowmelt and sublimation in mountain regions with implications to water resources and ecological systems. Winter Warm Spells (WWS) are defined as a winter period (December to February, DJF) of at least 3 consecutive days with daily maximum temperature anomaly above the 90th percentile (using a moving‐average of 15 days between 2001 and 2013). We calculate WWS for every 4‐km grid cell within an atmospheric model over western North America to characterize WWS and analyze snow ablation and their changes in a warmer climate. We find that days with ablation during WWS represent a small fraction of winter days (0.6 days), however, 49% of total winter ablation (33.4 mm/DJF) occurs during WWS. Greater extreme ablation rates (99th percentile) occur 18% more frequently during WWS than during non‐WWS days. Ablation rates during WWS in humid regions are larger (9 mm d−1) than in dry regions (7 mm d−1) in a warmer climate, which can be explained by differences in the energy balance and the snowpack's cold content. We find that warmer (0.8°C), longer (1.8 days) and more frequent (3.7 more events) WWS increase total winter ablation (on average 109% or 18 mm/DJF) in a warmer climate. Winter melt during WWS in warm and humid places is expected to increase about 3 times more than in the cold and dry region. This study provides a comprehensive description of WWS and their impact on snowpack dynamics, which is relevant to reservoir operations and water security.

Motor unit potential recruitment reference values in common upper and lower extremity muscles

ObjectiveTo define reference values for motor unit (MU) recruitment during needle EMG of six commonly examined muscles at low to moderate contraction. MethodsNeedle examination was performed for each muscle in a total of 111 subjects without neuromuscular disorders. Fastest firing rates and recruitment ratios (RRs) were calculated in at least 5 sites within each muscle. Upper limits of normal based on 97th percentile for fastest MU firing rates and RRs were calculated for each muscle. The means of fastest firing rates were compared among muscles using the Friedman and Wilcoxon signed rank tests. ResultsThe upper limits of normal were 12–15 Hz for fastest firing rates and were slightly higher in the deltoid and triceps than the other muscles. ConclusionFiring rates >15 Hz recorded at multiple sites within a single muscle exceed the 97th percentile of normal subjects and may suggest reduced MU recruitment. In some muscles, rates >12 Hz might support mildly reduced recruitment. Recruitment ratios varied depending on number of firing MUs, whereas the fastest firing MU rate did not. SignificanceThe determination of reference values for fastest MU firing rates can help to identify mild reduction in recruitment with more accuracy.