95th Percentile Research Articles

Mortality Risk of Low BMI in Life Insurance Applicants.

-This study seeks to quantify the mortality effect of low levels of body mass index (BMI) on life insurance applicants who, based on their laboratory profile and other information, appear to be suitable for life insurance coverage. -It has been demonstrated that low BMI is associated with higher mortality risk than normal or near-normal BMI. -Data were collected from over 4.7 million life insurance applicants with available BMI tested between 1995 and 2021, and vital status was assessed via the Social Security Death Master File. Cox models treating BMI as continuous and as a categorical variable were constructed, controlling for age, and split by sex after excluding those with laboratory or biometric test results, which were far enough outside the normal range to imply elevated mortality. -Models treating BMI as a continuous variable and allowing an interaction term for age showed that low BMI was strongly associated with mortality at ages 50 and above in both sexes. In the categorical models, only the lowest category of BMI (below the 1st percentile) in men aged 40-60, the lowest 2 categories (below the 5th percentile) in women aged 40-60, and the lowest 3 categories (below the 10th percentile) in those aged 60-80 years, were significantly associated with elevated mortality. No elevated mortality was detected in those under age 40 with low BMI. -Based on this study, low BMI is associated with elevated mortality in otherwise healthy applicants, but this association is dependent on age.

Axial length elongation profiles from 3 to 6 years in an Asian paediatric population: the Growing Up in Singapore Towards Healthy Outcomes birth cohort study (GUSTO)

AimsTo determine axial length (AL) elongation profiles in children aged 3–6 years in an Asian population.MethodsEligible subjects were recruited from the Growing Up in Singapore Towards Healthy Outcomes birth cohort....

Intuitive eating, diet quality, and nutritional status of vulnerable children living separated from their families: A pilot study

AbstractNutritional problems can be seen in children living separated from their families. This cross-sectional pilot study aimed to evaluate intuitive eating, diet quality, and nutritional status of children living separated from their families. A total of 55 adolescent girls aged 12–18 years participated in the study. Anthropometric measurements, biochemical data, and 24-h dietary recall data were collected. The Intuitive Eating Scale-2 (IES-2) and the Turkish version of the Healthy Lifestyle-Diet (HLD-TR) index were used. Participants were divided into two groups according to their scores on the diet quality index using the 50th percentile. Group 1 consisted of participants with a score of 25 points or less, and Group 2 consisted of participants with a score above 25 points. Waist circumference (72.0 (66–83), 65.0 (60–77)) was significantly higher in Group 1 (P < 0.05). IES–2 score (3.05 (2.85–3.40), 3.30 (3.12–3.90)) and two sub–factors; reliance in hunger and satiety cues (2.80 (1.80–3.40), 4.00 (2.60–4.60)) and body–food choice congruence (2.50 (2.00–3.50), 3.50 (3.00–4.50)) were higher in Group 2 (P < 0.05). After adjustment for body mass index, age, and energy intake, there was a significant positive correlation between IES-2 and HLD-TR scores (P = 0.029). In conclusion, it may be advantageous to resort to strategies that promote intuitive eating to reduce obesity and associated problems in this vulnerable group.

German adult population norm values of the short Warwick Edinburgh mental well-being scale (SWEMWBS).

The Warwick-Edinburgh Mental Well-Being Scale represents an internationally established inventory to assess population mental well-being. Particularly the short form (SWEMWBS) is recommended for use in Mental Health Surveillance. In the present study, we present normative data of the SWEMWBS for the German adult population. Data from the telephone survey German Health Update (GEDA) in 2022 representative of the German adult population (48.9% women, 18-98 years) was processed to estimate SWEMWBS percentile norm values, T-values, z-values and internationally comparable logit-transformed raw scores for the total sample (N = 5,606) as well as stratified by sex, age group and sex with age group combinations. The average mental well-being was comparable to that of other European countries at M = 27.3 (SD = 4.0; logit-transformed: M = 24.79, SD = 3.73). To provide a benchmark, the cut off for low well-being was set at the 15th percentile (raw score: 23; logit-transformed: 20.73), for high well-being at the 85th percentile (raw score: 32; logit-transformed: 29.31). The present study provides SWEMWBS norm values for the German adult population. The normative data can be used for national and international comparisons on a population level to initiate, plan and evaluate mental well-being promotion and prevention measures.

Resolving spatial response heterogeneity in glioblastoma.

Spatial intratumoral heterogeneity poses a significant challenge for accurate response assessment in glioblastoma. Multimodal imaging coupled with advanced image analysis has the potential to unravel this response heterogeneity. Based on automated tumor segmentation and longitudinal registration with follow-up imaging, we categorized contrast-enhancing voxels of 61 patients with suspected recurrence of glioblastoma into either true tumor progression (TP) or pseudoprogression (PsP). To allow the unbiased analysis of semantically related image regions, adjacent voxels with similar values of cerebral blood volume (CBV), FET-PET, and contrast-enhanced T1w were automatically grouped into supervoxels. We then extracted first-order statistics as well as texture features from each supervoxel. With these features, a Random Forest classifier was trained and validated employing a 10-fold cross-validation scheme. For model evaluation, the area under the receiver operating curve, as well as classification performance metrics were calculated. Our image analysis pipeline enabled reliable spatial assessment of tumor response. The predictive model reached an accuracy of 80.0% and a macro-weighted AUC of 0.875, which takes class imbalance into account, in the hold-out samples from cross-validation on supervoxel level. Analysis of feature importances confirmed the significant role of FET-PET-derived features. Accordingly, TP- and PsP-labeled supervoxels differed significantly in their 10th and 90th percentile, as well as the median of tumor-to-background normalized FET-PET. However, CBV- and T1c-related features also relevantly contributed to the model's performance. Disentangling the intratumoral heterogeneity in glioblastoma holds immense promise for advancing precise local response evaluation and thereby also informing more personalized and localized treatment strategies in the future.

DSC-PWI presurgical differentiation of grade 4 astrocytoma and glioblastoma in young adults: rCBV percentile analysis across enhancing and non-enhancing regions.

The presurgical discrimination of IDH-mutant astrocytoma grade 4 from IDH-wildtype glioblastoma is crucial for patient management, especially in younger adults, aiding in prognostic assessment, guiding molecular diagnostics and surgical planning, and identifying candidates for IDH-targeted trials. Despite its potential, the full capabilities of DSC-PWI remain underexplored. This research evaluates the differentiation ability of relative-cerebral-blood-volume (rCBV) percentile values for the enhancing and non-enhancing tumor regions compared to the more commonly used mean or maximum preselected rCBV values. This retrospective study, spanning 2016-2023, included patients under 55 years (age threshold based on World Health Organization recommendations) with grade 4 astrocytic tumors and known IDH status, who underwent presurgical MR with DSC-PWI. Enhancing and non-enhancing regions were 3D-segmented to calculate voxel-level rCBV, deriving mean, maximum, and percentile values. Statistical analyses were conducted using the Mann-Whitney U test and AUC-ROC. The cohort consisted of 59 patients (mean age 46; 34 male): 11 astrocytoma-4 and 48 glioblastoma. While glioblastoma showed higher rCBV in enhancing regions, the differences were not significant. However, non-enhancing astrocytoma-4 regions displayed notably higher rCBV, particularly in lower percentiles. The 30th rCBV percentile for non-enhancing regions was 0.705 in astrocytoma-4, compared to 0.458 in glioblastoma (p = 0.001, AUC-ROC = 0.811), outperforming standard mean and maximum values. Employing an automated percentile-based approach for rCBV selection enhances differentiation capabilities, with non-enhancing regions providing more insightful data. Elevated rCBV in lower percentiles of non-enhancing astrocytoma-4 is the most distinguishable characteristic and may indicate lowly vascularized infiltrated edema, contrasting with glioblastoma's pure edema.

Trypanosoma cruzi Infection in Pregnancies without Congenital Transmission Is Associated with Reduced Fetal Growth: A Cross-Sectional Study in Argentina, Honduras, and Mexico.

We aimed to measure the association between Trypanosoma cruzi infection in pregnancy and reduced fetal growth in the absence of T. cruzi congenital transmission. We conducted a cross-sectional study of secondary data of all singleton live births between 2011 and 2013 in five hospitals from Argentina, Honduras, and Mexico. We excluded newborns with T. cruzi infection. Noninfected pregnant people were those without any positive rapid tests. The main study outcomes were birth weight, head circumference, and length for gestational age and sex. Logistic regression models were adjusted for country, age, education level, and obstetric history. Of the 26,544 deliveries, 459 (1.7%) pregnant people were found by rapid tests to be positive for T. cruzi. Of these, 320 were positive by enzyme-linked immunosorbent assay and 231 had a positive polymerase chain reaction (PCR) test. Uninfected newborns from T. cruzi-infected pregnant people were more likely to have birth weights below the 5th and 10th percentiles and head circumferences below the 3rd and 10th percentiles. Among T. cruzi-infected pregnant people diagnosed by PCR, the odds ratios were 1.58 for birth weight below the 10th percentile (95% CI, 1.12-2.23) and 1.57 for birth weight below the 5th percentile (95% CI, 1.02-2.42). Higher T. cruzi parasitic loads in pregnancy had a stronger association with reduced fetal growth (both in birth weight and head circumference), with an odds ratio of 2.31 (95% CI, 1.36-3.91) for a birth weight below the 5th percentile. The association shows, irrespective of causality, that newborns of pregnancies with T. cruzi have an increased risk of reduced fetal growth. We recommend further studies to assess other potential confounders and the causality of these associations.

Temporal trend of age at menarche in Korean females born between 1927 and 2004: a population-based study.

The age at menarche has decreased worldwide. Previous studies on Korean adolescents have reported a downward trend in age at menarche. This study aimed to investigate the current trends in age at menarche among Korean adolescents using nationally representative data. The study used data from the Korea National Health and Nutrition Examination Survey 2007-2021. A total of 50,730 females born between 1927 and 2004 with information on age at menarche were included. The trend in age at menarche was analyzed according to 15 birth-year groups (with 5-year intervals) using quantile regression analysis. The mean age at menarche decreased from 16.92 ± 0.06 years for females born before 1935 to 12.45 ± 0.04 years for females born between 2000 and 2004 (p <.001). According to the percentile group of age at menarche, mean menarche age decreased by -0.071 years per year (95% confidence interval [CI], -0.072 to -0.070) in total, -0.050 years per year (95% CI, -0.052 to -0.048) in the 3rd percentile group, -0.088 years per year (95% CI, -0.091 to -0.085) in the 97th percentile group (p <.001 for all). A decreasing trend of age at menarche was more prominent in the obesity group (-0.080 years per year, 95% CI, -0.082 to -0.078) compared to the non-obesity group (-0.069 years per year, 95% CI, -0.071 to -0.068) (p <.001 for both). Ongoing downward trend in age at menarche was observed in Korean females born until 2004, decreasing by 0.71 years per decade. The downward trend was faster in individuals with a higher percentile of age at menarche and in those with obesity.

Association of Postarrest Hypotension Burden With Unfavorable Neurologic Outcome After Pediatric Cardiac Arrest.

Quantify hypotension burden using high-resolution continuous arterial blood pressure (ABP) data and determine its association with outcome after pediatric cardiac arrest. Retrospective observational study. Academic PICU. Children 18 years old or younger admitted with in-of-hospital or out-of-hospital cardiac arrest who had invasive ABP monitoring during postcardiac arrest care. None. High-resolution continuous ABP was analyzed up to 24 hours after the return of circulation (ROC). Hypotension burden was the time-normalized integral area between mean arterial pressure (MAP) and fifth percentile MAP for age. The primary outcome was unfavorable neurologic status (pediatric cerebral performance category ≥ 3 with change from baseline) at hospital discharge. Mann-Whitney U tests compared hypotension burden, duration, and magnitude between favorable and unfavorable patients. Multivariable logistic regression determined the association of unfavorable outcomes with hypotension burden, duration, and magnitude at various percentile thresholds from the 5th through 50th percentile for age. Of 140 patients (median age 53 [interquartile range 11-146] mo, 61% male); 63% had unfavorable outcomes. Monitoring duration was 21 (7-24) hours. Using a MAP threshold at the fifth percentile for age, the median hypotension burden was 0.01 (0-0.11) mm Hg-hours per hour, greater for patients with unfavorable compared with favorable outcomes (0 [0-0.02] vs. 0.02 [0-0.27] mm Hg-hr per hour, p < 0.001). Hypotension duration and magnitude were greater for unfavorable compared with favorable patients (0.03 [0-0.77] vs. 0.71 [0-5.01]%, p = 0.003; and 0.16 [0-1.99] vs. 2 [0-4.02] mm Hg, p = 0.001). On logistic regression, a 1-point increase in hypotension burden below the fifth percentile for age (equivalent to 1 mm Hg-hr of burden per hour of recording) was associated with increased odds of unfavorable outcome (adjusted odds ratio [aOR] 14.8; 95% CI, 1.1-200; p = 0.040). At MAP thresholds of 10th-50th percentiles for age, MAP burden below the threshold was greater in unfavorable compared with favorable patients in a dose-dependent manner. High-resolution continuous ABP data can be used to quantify hypotension burden after pediatric cardiac arrest. The burden, duration, and magnitude of hypotension are associated with unfavorable neurologic outcomes.

Mercury stocks in discontinuous permafrost and their mobilization by river migration in the Yukon River Basin

Abstract Rapid warming in the Arctic threatens to destabilize mercury (Hg) deposits contained within soils in permafrost regions. Yet current estimates of the amount of Hg in permafrost vary by ~4 times. Moreover, how Hg will be released to the environment as permafrost thaws remains poorly known, despite threats to water quality, human health, and the environment. Here we present new measurements of total mercury (THg) contents in discontinuous permafrost in the Yukon River Basin in Alaska. We collected riverbank and floodplain sediments from exposed banks and bars near the villages of Huslia and Beaver. Median THg contents were 49+13/-21 ng THg g sediment−1 and 39 +16 /-18 ng THg g sediment−1 for Huslia and Beaver, respectively (uncertainties as 15th and 85th percentiles). Corresponding THg:organic carbon ratios were 5.4+2 /-2.4 Gg THg Pg C-1 and 4.2+2.4 /-2.9 Gg THg Pg C-1. To constrain floodplain THg stocks, we combined measured THg contents with floodplain stratigraphy. Trends of THg increasing with smaller sediment size and calculated stocks in the upper 1 m and 3 m are similar to those suggested for this region by prior pan-Arctic studies. We combined THg stocks and river migration rates derived from remote sensing to estimate particulate THg erosional and depositional fluxes as river channels migrate across the floodplain. Results show similar fluxes within uncertainty into the river from erosion at both sites (95 +12 /-47 kg THg yr-1 and 26 +154/-13 kg THg yr-1 at Huslia and Beaver, respectively), but very different fluxes out of the river via deposition in aggrading bars (60 +40/-29 kg THg yr-1 and 10+5.3/-1.7 kg THg yr-1). Thus, a significant amount of THg is liberated from permafrost during bank erosion, while a variable but generally lesser portion is subsequently redeposited by migrating rivers.

Investigating the relationship between extreme weather and cryptosporidiosis and giardiasis in Colorado: A multi-decade study using distributed-lag nonlinear models

Environmentally-mediated protozoan diseases like cryptosporidiosis and giardiasis are likely to be highly impacted by extreme weather, as climate-related conditions like temperature and precipitation have been linked to their survival, distribution, and overall transmission success. Our aim was to investigate the relationship between extreme temperature and precipitation and cryptosporidiosis and giardiasis infection using monthly weather data and case reports from Colorado counties over a twenty-one year period. Data on reportable diseases and weather among Colorado counties were collected using the Colorado Electronic Disease Reporting System (CEDRS) and the Daily Surface Weather and Climatological Summaries (Daymet) Version 3 dataset, respectively. We used a conditional Poisson distributed-lag nonlinear modeling approach to estimate the lagged association (between 0 and 12-months) between relative temperature and precipitation extremes and the risk of cryptosporidiosis and giardiasis infection in Colorado counties between 1997 and 2017, relative to the risk found at average values of temperature and precipitation for a given county and month. We found distinctly different patterns in the associations between temperature extremes and cryptosporidiosis, versus temperature extremes and giardiasis. When maximum or minimum temperatures were high (90th percentile) or very high (95th percentile), we found a significant increase in cryptosporidiosis risk, but a significant decrease in giardiasis risk, relative to risk at the county and calendar-month mean. Conversely, we found very similar relationships between precipitation extremes and both cryptosporidiosis and giardiasis, which highlighted the prominent role of long-term (>8 months) lags. Our study presents novel insights on the influence that extreme temperature and precipitation can have on parasitic disease transmission in real-world settings. Additionally, we present preliminary evidence that the standard lag periods that are typically used in epidemiological studies to assess the impacts of extreme weather on cryptosporidiosis and giardiasis may not be capturing the entire relevant period.

A Comprehensive Analysis of Leadership Attributes, Discrepancies, and Implications for Gender Equity in Vascular Surgery

Well-developed leadership skills have been associated with a better understanding of healthcare context, increased team performance, and improved patient outcomes. Surgeons, in particular, stand to benefit from leadership development. While studies have focused on investigating knowledge gaps and needs of surgeons in leadership roles, there is a noticeable gap in the literature concerning leadership in Vascular Surgery. The goal of this study was to characterize current leadership attributes of vascular surgeons and understand demographic influences on leadership patterns. This retrospective cohort study was a descriptive analysis of vascular surgeons and their observers who took the leadership practice inventory (LPI) from 2020 to 2023. The LPI is a 30 question inventory that measures the frequency of specific leadership behaviors across five practices of leadership. A total of 110 vascular surgeons completed the LPI. The majority of participants were white (56%) and identified as male (60%). Vascular surgeons most frequently observed the "enabling others to act" leadership practice style (8.90 ± 0.74) by all evaluators. Vascular surgeons were most frequently above the 70th percentile in the "challenge the process" leadership practice style (49%) compared to the average of other leaders world-wide. Observers rated vascular surgeons as displaying significantly more frequent leadership behaviors than vascular surgeons rated themselves in every leadership practice style (P-value < 0.01). The only demographic variable associated with a significantly increased occurrence of achieving 70th percentile across all five leadership practice styles was the male gender: a multivariable model adjusting for objective experience showed men were at least 3.5 times more likely to be rated above the 70th percentile than women. Vascular surgeons under report the frequency at which they practice leadership skills across all five leadership practice styles and should recognize their strengths of enabling others to act and challenging the process. Men are recognized as exhibiting all five leadership practices more frequently than women, regardless of current position or experience level. This observation may reflect the limited leadership positions available for women, thereby restricting their opportunities to demonstrate leadership practices as frequently or recognizably as their male counterparts.

Respiratory morbidity among offspring misclassified as growth restricted.

An ultrasound-based diagnosis implies that some fetuses suspected to be growth-restricted (FGR) are discovered at birth to be appropriately grown (appropriate for gestational age [AGA] birth weight, between the 10th and 90th percentile). These fetuses may thus be exposed to unnecessary medical interventions, including early labor induction. In this study, we have evaluated the long-term respiratory health of offspring misclassified as FGR. A population-based cohort analysis was conducted, including deliveries of AGA singletons between 1991 and 2021 at a tertiary referral hospital. Incidence of morbidity due to various respiratory conditions was compared between AGA offspring with prenatal diagnosis of FGR, and those without a false diagnosis of FGR. The Kaplan-Meier approach was used to estimate cumulative morbidity incidence. The stratified Cox proportional-hazards model was used to control for confounders. A total of 324,620 deliveries of AGA newborns were included in the analyses; 3249 of them (1.0%) were misclassified prenatally as FGR. The FGR subgroup delivered at an earlier gestational age (36.7 vs. 39.1 weeks, p < .001) and had more than 25% higher incidence of respiratory-related morbidity during childhood (33.2% vs. 26.5%), specifically related to asthma and obstructive sleep apnea (p < .001 for all). A higher cumulative morbidity rate due to respiratory conditions was observed in the Kaplan-Meier survival curve (log-rank p value < .001). This association between FGR and respiratory morbidity was independent of preterm delivery, maternal age, cesarean delivery, and child's birth year (adjusted hazard ratio = 1.14, 95% confidence interval: 1.07-1.21, p < .001), using a Cox proportional hazards model. AGA newborns misclassified as FGR, are at an increased risk for long-term respiratory morbidity during childhood and adolescence.

Independent validation of 30-day emergency department visit after initial chemotherapy A-PROACCT model.

e23243 Background: This study assessed model performance and, more importantly, the clinical usefulness of the PROACCT model created by Grant et al. (JAMA, 2019), refined as A-PROACCT by Stein et al. (JOP, 2023) with data from Orlando Health. The predictive performance of models anticipating acute care events within thirty days (ACE30) of initial chemotherapy administration (ICA) were evaluated. Methods: Stein et al. models classified high-risk patients as those whose model output risk score was at or above the 90th percentile. They studied 5153 ICAs between July and November of 2021, of which 559 (10.8%) had an ACE30. Their first model used drug category, age group, ED visits and hospitalizations in the prior year, and cancer type, and had sensitivity (Sen), specificity, (Spec), C-Statistic (C-Stat), and positive predictive value (PPV) of 0.28, 0.93, 0.79 and 0.18 respectively. Their second model added insurance category, number of anti-cancer agents, race, and BMI category and reported Sen, Spec, C-Stat, and PPV of 0.30, 0.94, 0.80 and 0.23 respectively. Of the high-risk patients, 33.6% and 34.1% had an ACE30 respectively. Of the low-risk patients, 8.3% and 8.1% had an ACE30 respectively. Our data were propagated through the two models. Results: Between February of 2012 and April 2021, Orlando Health had 15,483 distinct patient visits with ICAs. Overall, 2046 (13.2%) had an ACE30. Model one had Sen, Spec, C-Stat, and PPV of 0.19, 0.92, 0.65 and 0.27 respectively. Model two had Sen, Spec, C-Stat, and PPV of 0.19, 0.91, 0.65 and 0.25 respectively. Both models had an accuracy of 0.82. This demonstrated our data fit the Stein model. Of the 1460 ICAs identified as high-risk by model one, 387 (26.5%) had an ACE30, and of the 14,023 ICAs identified as low-risk, 1659 (11.8%) had an ACE30. Of the 1549 ICAs identified as high-risk by model two, 393 (25.4%) had an ACE30, and of the 13,934 ICAs identified as low-risk, 1653 (11.9%) had an ACE30. The difference of ACE30 rates between high risk and low risk groups were statistically significant (p &lt; 0.0001) in both models. This demonstrated both models were clinically useful in identifying chemotherapy patients at high risk of acute care events. Conclusions: These models allowed for clinically relevant stratification of patients into meaningful high-risk and low-risk groups (26.5% vs 11.8% with our data) for risk of acute care events within 30 days of initial chemotherapy administration. Nevertheless, only 26.5% of these high-risk patients actually had an acute care event within thirty days of initial chemotherapy administration. Further research is needed to improve the precision of identifying high-risk patients, by potentially adding more clinical variables, using alternative sampling methods, and employing nonlinear and more complex machine learning methodologies.

Development of novel MUC1-C targeting antibody-drug conjugate for pancreatic cancer treatment.

e15025 Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive forms of cancers, which is usually diagnosed in advanced stages and presents an abysmal 5-year survival rate of 3-10%. With late detection of metastasized/advanced disease, curative surgery is not an option for most patients. Accordingly, there is an urgent unmet need for development of therapeutics targeting the pancreatic cancer cells. MUC1 is one such cell surface antigen that is aberrantly overexpressed in most solid tumors including pancreatic cancer. In this study we report preclinical efficacy of pharmacological inhibition of MUC1 signaling by GO-203 and targeted delivery of toxin conjugated to novel MUC1-C antibodies (7B8 and 3D1) binding to the extra cellular domain (ECD) to the PDAC xenografts. Methods: Subjects from TCGA-PAAD were stratified into high (75th percentile) and low (25th percentile) MUC1-expressing cohorts. Differential expression was performed using DESeq2, followed by GSEA, and signaling network analysis using partial correlation networks, ARACNE, and BC3NET. Anti-MUC1 antibody-drug conjugates (ADCs) were generated by coupling monomethyl auristatin E (3D1-MMAE, 7B8-MMAE) via V-C-PAB linker and characterized for anti-tumor activity against pancreatic cancer cells including MIA PaCa-1, CAPAN2 and HAPF-II. Paired-end RNA-seq (50bp) was aligned and quantified to the Human Ensembl GRC38 reference using STAR aligner. Subcutaneous xenografts were obtained in nude mice by injecting 5X106 HPAF-II tumor cells. Results: Differential expression, pathway, and network analyses revealed consistent dysregulation of cancer survival-related processes, and P53-related pathways in the cohort with increased MUC1 expression. The ADCs (DAR of ~3.5) exhibited efficient internalization in cancer cells and associated apoptotic cell death (Kds = 2 - 5nM). Pharmacological inhibition of MUC1 signaling by GO-203 demonstrated reduction in canonical pathways including P53 and EMT. Treatment with 3D1-MMAE compared to both vehicle and GO-203 showed dysregulation of cellular metabolism pathways (cholesterol homeostasis, glycolysis) and exhibited several strong indicators of cellular stress including activation of unfolded protein response processes and mTorc1 signaling. Excellent tumor-suppressive effects of ADCs were observed in HPAF-II xenografts in nude mice. The 7.5 mg/kg (i.v., q7dx3), treatment showed complete tumor regression from 14th day (end of treatment) till the date of termination (Day 50). Doses up to 40 mg/kg were well tolerated by the mice and this anti-tumor efficacy was observed without any appreciable loss in body weight or adverse effects on tissues. Conclusions: Targeted delivery of MMAE toxin to the pancreatic cancer cells presents an exciting opportunity for a novel therapeutic intervention for the treatment of pancreatic cancer patients with MUC1 over expression in tumors.

Long-term exposure to ambient fine particulate matter (PM2.5) and attributable pulmonary tuberculosis notifications in Ningxia Hui Autonomous Region, China: a health impact assessment

IntroductionLong-term exposure to fine particulate matter (≤2.5 µm (PM2.5)) has been associated with pulmonary tuberculosis (TB) notifications or incidence in recent publications. Studies quantifying the relative contribution of long-term PM2.5...

Esophageal cancer in the United States: A 21-year mortality analysis (1999-2020).

e23258 Background: Esophageal cancer (EC) is the sixth leading cause of cancer-related deaths in the United States, with a mere 20% survival rate in the first five years, making it a significant public health concern. Considering the lack of comprehensive evaluations of mortality trends that are undergoing substantial transformations on a global scale, this study aims to provide an update on the mortality rates of esophageal cancer and its trends in the United States. Methods: The mortality trends among adults with EC were analyzed using data from the Centers for Disease Control and Prevention Wide-Ranging Online Data for Epidemiological Research (CDC WONDER) database, where EC was presented as a contributing or the underlying cause of death. Code C15 “Malignant Neoplasms of Esophagus” in the International Classification of Disease, tenth revision (ICD-10) was used to identify the data. Crude and age-adjusted mortality rates (AAMRs) per 100,000 people were extracted. Annual percent changes (APCs) in AAMRs with 95% CI were obtained using joint point regression analysis across different demographic (sex, race/ethnicity, and age) and geographic (state, urban-rural, and regional) subgroups. Results: Between 1999 and 2020, 309,725 documented deaths were attributed to esophageal cancer. The overall AAMR decreased from 1999-2020 (6.69 to 5.68). Males had higher consistently higher AAMRs than females (10.96 vs. 2.24). NH White had the highest overall AAMR (6.88), followed by NH Black (6.46), NH American Indian (4.95), Hispanic or Latino (3.31), and NH Asian or Pacific Islander (2.57). CMRs also increased with advancing age and were greatest in individuals over the age of 85 years. AAMR also varied by region (overall AAMR: Midwest: 7.18; Northeast: 6.75; South: 6.07; West: 5.76), and non-metropolitan areas had higher AAMR (non-core areas: 7.09; micropolitan areas: 7.19) than metropolitan areas (large central metropolitan areas: 5.75; large fringe areas: 6.33). The states in the upper 90th percentile of esophageal cancer-related AAMR were Vermont, District of Columbia, West Virginia, Ohio, New Hampshire, and Maine, and exhibited an approximately two-fold increase in AAMRs, compared to states falling in the lower 10th percentile. Conclusions: Over the last two decades, there has been an overall decline in mortality related to EC in the United States. However, demographic and geographic discrepancies in EC-related mortality persist, necessitating additional exploration and development of specifically directed treatments.

Subseasonal Potential Predictability of Horizontal Water Vapor Transport and Precipitation Extremes in the North Pacific

Abstract Accurate forecasts of weather conditions have the potential to mitigate the social and economic damages they cause. To make informed decisions based on forecasts, it is important to determine the extent to which they could be skillful. This study focuses on subseasonal forecasts out to a lead time of four weeks. We examine the differences between the potential predictability, which is computed under the assumption of a “perfect model,” of integrated vapor transport (IVT) and precipitation under extreme conditions in subseasonal forecasts across the northeast Pacific. Our results demonstrate significant forecast skill of extreme IVT and precipitation events (exceeding the 90th percentile) into week 4 for specific areas, particularly when anomalously wet conditions are observed in the true model state. This forecast skill during weeks 3 and 4 is closely associated with a zonal extension of the North Pacific jet. These findings of the source of skillful subseasonal forecasts over the U.S. West Coast could have implications for water management in these regions susceptible to drought and flooding extremes. Additionally, they may offer valuable insights for governments and industries on the U.S. West Coast seeking to make informed decisions based on extended weather prediction. Significance Statement The purpose of this study is to understand the differences between the ability to predict high amounts of the transport of water vapor and precipitation over the North Pacific 3 and 4 weeks into the future. The results indicate that differences do exist in a region that is relevant to precipitation on the U.S. West Coast. To physically explain why differences in predictability exist, the relationship between weekly extremes of the extension of the jet stream, IVT, and precipitation over the North Pacific is explored. These findings may impact decisions relevant to water management on the U.S. West Coast susceptible to drought and flooding extremes.

Association of germline polygenic risk for thyroid autoimmunity with overall survival in the I-SPY2 Trial.

10600 Background: Germline genetic variation influences immune activity and risk of autoimmunity, and has been hypothesized to play a role in response to cancer therapeutics and survival. Prior studies of breast cancer have reported associations between genetic variation in thyroid autoimmunity and overall survival (OS). Here, we aim to investigate the association between a polygenic risk score for hypothyroidism (PRS-H) and response to therapy in women with early-stage breast cancer, and hypothesize that high PRS-H will be associated with better treatment response and survival. Methods: This study includes 1,368 women aged 18 years and above with stage II-III breast cancer of size &gt; 2.5cm by clinical exam, with germline data available. It is an approved biomarker analysis of the I-SPY 2 trial, which is a phase II, adaptive, randomized platform trial across multiple sites studying novel cancer therapeutics across multiple arms for use as neoadjuvant chemotherapy for early-stage breast cancer. The outcome of survival is defined as alive at the most recent follow-up. Using the Cox proportional hazards model, we evaluate the association between a previously published PRS-H and overall survival. Models are adjusted for age at screening, immunotherapy status, and five principal components. Results: Among 1,368 early-stage breast cancer women, 33% (n=447) had pCR, and 85% (n=1,157) were alive at the last follow-up. Additionally, 16% (n=219) of women received immunotherapy. We observe a significant association between PRS-H and OS (HR = 0.78, 95% CI 0.66-0.92, p=0.004). Individuals in the top 10th percentile of the PRS-H (highest genetic risk) have improved survival (log rank p=0.04). Conclusions: Germline genetic variation in thyroid autoimmunity proclivity is associated with improved overall survival in our cohort of women with early-stage breast cancer receiving neoadjuvant chemotherapy. Our findings suggest that the genetic risk for autoimmunity may be important for long-term survival. We will expand this analysis to include the entire I SPY 2 population when all patients have completed genotyping. We plan to further characterize the role of germline autoimmunity profiles and survival. Clinical trial information: NCT01042379 .

Unmet need for mental health care among adolescents in Asia and Europe.

The unmet need for mental health care is a global concern. There is a lack of cross-cultural studies examining adolescent help-seeking behavior from both formal and informal sources, including both high-and lower-income countries. This study investigates mental health help-seeking behavior in eight Asian and European countries. Data from 13,184 adolescents aged 13-15 (51% girls) was analysed using mixed-effects logistic regression with school-wise random intercepts to compare countries and genders. Although a significant proportion of adolescents considered getting or sought informal help, formal help-seeking remained exceptionally low, especially in middle-income countries (< 1%), while it ranged from 2 to 7% in high-income countries. Among adolescents with high emotional and behavioral problems (scoring above the 90th percentile on the Strengths and Difficulties Questionnaire), 1-2% of those in middle-income countries and 6-25% of those in high-income countries sought formal help. Girls generally seek more help than boys. The study shows the most adolescents do not receive formal help for mental health problems. The unmet need gap is enormous, especially in lower-income countries. Informal sources of support, including relatives, peers, and teachers, play a crucial role, especially in lower-income countries.