Proxy Marker Research Articles

Feline Papillomatosis.

Different types of feline papillomaviruses (PVs) are associated with a variety of skin lesions and neoplasia, such as papillomas and cell carcinomas, but the virus can also be found in healthy skin. In this review, the European Advisory Board on Cat Diseases (ABCD), a scientifically independent board of veterinary experts on feline infectious diseases from 11 European Countries, discusses the current knowledge of feline PV infections. Cats most likely become infected through lesions or abrasions of the skin. Most PV infections remain asymptomatic. Besides cat-specific PVs, DNA sequences most closely related to human and bovine PVs have been detected in feline skin lesions. Diagnosis is supported by the histological detection of PV-induced cell changes and intralesional detection of viral antigen (immunostaining) or viral DNA (in situ hybridization). Immunostaining of p16CDKN2A protein (p16) can be performed as a proxy marker for PV-induced neoplasms. There is no specific treatment for PV-induced skin lesions. Spontaneous regression commonly occurs. In the case of invasive squamous cell carcinoma (ISCC), complete excision should be considered, if possible.

Differential effects of left DLPFC anodal and cathodal tDCS interventions on the brain in children with autism: A randomized controlled trial.

Autism spectrum disorder (ASD) is a complex and heterogeneous neurodevelopmental disorder with few effective treatment options. In recent years, transcranial direct current stimulation (tDCS) has been applied in interventions for ASD, often targeting the left dorsolateral prefrontal cortex (DLPFC). However, studies investigating anodal and cathodal tDCS interventions have reported differing outcomes. Therefore, this study aimed to compare and analyze the effects of these two stimulations through a randomized controlled trial, utilizing both behavioral assessments and EEG proxy markers capable of characterizing the brain's excitatory-inhibitory balance. This study recruited a total of 24 children with ASD (20 males and 4 females; mean age ± SD: 5.5 ± 1.2 years), who were randomly divided into two groups receiving either anodal or cathodal tDCS targeting the DLPFC. The stimulation intensity was set at 1 mA, administered five times per week for a total of 20 sessions. Behavioral intervention outcomes were assessed using the Social Responsiveness Scale (SRS) and the Autism Behavior Checklist (ABC). Additionally, the study evaluated the effects of tDCS on the brain's excitatory-inhibitory balance by analyzing corrected periodic alpha oscillation power and bandwidth, as well as non-periodic exponent and offset derived from EEG data. Following anodal tDCS intervention, results from the SRS scale indicated a decrease in overall scores, with significant differences observed in social communication and social motivation among children. On the ABC scale, overall scores also decreased, with significant differences noted in sensory behavior, social relating, body and object use, and language and communication skills. Non-periodic exponent and offsets increased following anodal tDCS stimulation, whereas they decreased after cathodal tDCS stimulation. Regarding alpha oscillation power, there was a significant increase following anodal tDCS and a significant decrease following cathodal tDCS. In terms of alpha oscillation bandwidth, there was a reduction following anodal tDCS and an increase following cathodal tDCS. Further correlation analysis revealed that in children who received anodal tDCS intervention, non-periodic exponent showed correlations with behaviors such as social communication. Our study results demonstrated that anodal and cathodal tDCS targeting the left DLPFC had distinct effects on the behavior and excitatory-inhibitory balance of children with ASD. Anodal tDCS intervention appeared to have a more positive impact compared to cathodal intervention. However, the sample size was small, and we focused solely on the effects of tDCS, with our experimental design perhaps not being able to generalize to all external manipulations of excitability in our study. In future research, we will continue to improve the experiments to address these limitations.

The density histograms-derived computerized integrated index (CII) predicts mortality in idiopathic pulmonary fibrosis

Quantitative assessment of the extent of radiological alterations in interstitial lung diseases is a promising field of application that goes beyond the limitations of qualitative scoring. Analysis of density histograms, i.e., skewness, kurtosis, and mean lung attenuation, is among the most studied approaches. We recently proposed their integration in a single parameter, the computerized integrated index (CII), to reduce their redundancy. The CII has proven effective in detecting subclinical lung involvement, correlates with lung function/disease activity, and predicts mortality in systemic sclerosis patients. Seventy-three newly diagnosed and therapy-naive IPF patients (M = 50; median age: 70.2 years) were prospectively enrolled from January 2014 to December 2022, and followed till December 2023. At baseline, all underwent lung function testing and volumetric high resolution chest CT. Density histograms were analyzed with an open-source automatic platform (Slicer 3D) and CII derived by means of Principal Component Analysis, as previously described. During a median follow-up of 5.8 years, 39 (53.4%) subjects died. Median overall survival (OS) was 4.9 years (95% CI 3.7 years-not estimable). The CII was significantly associated with OS (HR 0.49; 95% CI 0.35–0.68; P < 0.001) and correlated with lung function (r = 0.41; 95% CI 0.19 to 0.60; P < 0.001 for FVC, and r = 0.62; 95% CI 0.44 to 0.75; P < 0.001 for DLCOsb). Patients stratification according to CII tertile, showed a consistent reduction in the hazard of death. After adjusting for body mass index, smoking, GAP stage, and anti-fibrotic therapy, the CII preserved a significant association with the hazard of death (HR 0.35; 95% CI 0.2–0.63; P < 0.001). CII is a proxy marker of IPF severity worthy of use for prognostication purposes in daily practice.

Individual muscle hypertrophy in high-load resistance training with and without blood flow restriction: A near-infrared spectroscopy approach

ABSTRACT We aimed to compare individual hypertrophic responses to high-load resistance training (HL-RT) or high-load with blood flow restriction (HL-BFR). Furthermore, we investigated whether greater responsiveness to one of the protocols could be explained by acute changes in blood deoxyhemoglobin concentration (HHb) and total hemoglobin concentration (tHb) (proxy markers of metabolic stress). Ten untrained participants had their legs randomized into both HL-RT and HL-BFR and underwent 10 weeks of training. Muscle cross-sectional area (mCSA) was measured at baseline and post training, while HHb and tHb during the final session. Using a threshold of 2 × typical errors (3.24%) to compare protocols, five participants showed greater mCSA increases after HL-RT (16.44 ± 7.90%) compared to HL-BFR (10.74 ± 7.12%, p = 0.0054) and five did not respond better to HL-RT (8.95 ± 10.83%) compared to HL-BFR (13.33 ± 8.59%) (p = 0.3105). Additionally, HL-RT induced lower HHb (5855.78 ± 12905.99; p = 0.0101) and tHb (−43169.70 ± 37793.17; p = 0.0030) AUC values compared to HL-BFR (HHb: 39254.80 ± 27020.15; tHb: 46309.40 ± 31613.97). In conclusion, despite the higher levels of metabolic stress markers, most participants did not present greater muscle hypertrophy by combining blood flow restriction with HL-RT.

Inequalities in the Quality and Safety of Post-Diagnostic Primary Care for People With Dementia: A Scoping Review.

International guidelines make recommendations for the delivery of safe, high-quality primary care for people with dementia including prescribing, personalised care planning and regular holistic reviews. It is unclear how the quality and safety of this healthcare varies with socio-economic factors. This scoping review aimed to understand the depth and breadth of existing evidence exploring socio-economic variation in the quality and safety of primary care for people with dementia. Prescribing and care planning indicators of high-quality, safe primary care were defined from guidance. Composite and proxy markers of socio-economic status (SES) were defined. EMBASE, MEDLINE, PsychInfo, The Cochrane Database of Systematic Reviews, worldcat.org and clinicaltrial.gov databases were searched. Studies in English, on human participants from 2006 onwards were eligible. Narrative synthesis was conducted. Studies explored how one or more selected indicators (anti-dementia medication and anti-psychotic prescribing, potentially inappropriate prescribing (PIP), medication review, dementia review or care planning) varied with a recognised marker of SES in people with dementia. Searches identified 1980 studies after removing duplicates. 385 full texts were reviewed, with 53 eligible for inclusion (51 quantitative, 2 reviews). Most identified studies explored prescribing processes (50 quantitative, 2 reviews), with 2 exploring annual review. There was evidence of substantial disparity in quality and safety indicators in studies exploring prescribing; 20/29 (69%) of studies exploring anti-dementia medication prescribing found those with markers of lower SES were significantly less likely to receive these. 16/28 studies exploring PIP/Anti-psychotics found significant disparities in safe prescribing for those with markers of lower SES. Neither study exploring annual reviews found any significant differences across SES. We found evidence of disparity in the quality and safety of post-diagnostic primary care for people with dementia based on SES, particularly for a range of prescribing indicators. Further work exploring inequalities in care planning and reviews for people with dementia is needed to understand existing inequalities in the quality and safety of primary care for people with dementia.

PATH-59. HISTOLOGIC CORRELATES FOR MOLECULAR FEATURES IN MENINGIOMAS

Abstract Histologic findings are the primary determinant of meningioma prognosis and post-operative management. However, the association of specific pathologic features with molecular alterations has not yet been comprehensively investigated. Here we utilized a large dataset of well-characterized meningiomas to identify correlates between clinically relevant histological and molecular features. Detailed histologic information was collected for 809 resected meningiomas, including cases with DNA methylation (n=380), copy number array (n=252), next-generation sequencing (n=52), RNA risk score (n=394), and/or TERT promoter profiling (n=238). Analyses were conducted on prognostic pathologic features, including WHO Grade, Ki-67, mitotic index (MI), brain invasion, and atypical histologic findings (necrosis, hypercellularity, prominent nucleoli, sheeting, and small cells). Correlation with molecular variables was performed using Fisher’s Exact Tests, including DNA methylation subgroup, RNA risk score, CNV profiles, and TERT promoter mutations. All statistics were corrected for multiple hypothesis testing. Nearly 65% of meningiomas exhibited at least one atypical histologic feature. Among said features, Ki-67/MI, WHO Grade, sheeting, and necrosis were associated with recurrent lesions and known clinical features of aggressive meningiomas. Several histologic features, including hypercellularity, elevated Ki-67/mitotic index, and WHO grade, also correlated with DNA methylation and RNA risk groups. Several chromosomal arm events were related to specific pathologic features (prominent nucleoli, Ki-67, MI, and grade), including chromosomes 1, 4, 10, 14, and 18. Our analysis highlights the continued value in screening for histologic markers of aggressive behavior in meningiomas, as they correlate with the presence of high-risk molecular features and may serve as proxy markers when advanced molecular testing is not available.

Normalization of short-chain fatty acid concentration by bacterial count of stool samples improves discrimination between eubiotic and dysbiotic gut microbiota caused by Clostridioides difficile infection-

ABSTRACT Short-chain fatty acids (SCFAs) represent a cornerstone of gut health, serving as critical mediators of immune modulation and overall host homeostasis. Patients with dysbiosis caused by Clostridioides difficile infection (CDI) typically exhibit lower SCFAs levels compared to healthy stool donors and, thus, the concentration of SCFAs has been proposed as a proxy marker of a healthy microbiota. However, there is no consistency in the methods used to quantify SCFAs in stool samples and usually, the results are normalized by the weight of the stool samples, which does not address differences in water and fiber content and ignores bacterial counts in the sample (the main component of stool that contributes to the composition of these metabolites in the sample). Here, we show that normalized SCFAs concentrations by the bacterial count improve discrimination between healthy and dysbiotic samples (patients with CDI), particularly when using acetate and propionate levels. After normalization, butyrate is the metabolite that best discriminates eubiotic and dysbiotic samples according to the area under the receiver operating characteristic (ROC) curve (AUC-ROC = 0.860, [95% CI: 0.786–0.934], p < .0001).

Acute Changes in Hamstring Injury Risk Factors After a Session of High-Volume Maximal Sprinting Speed Efforts in Soccer Players.

Maximal sprinting speed (MSS) overexposure is associated with increased risk of injury. This study aimed to describe changes in sprint performance-related factors and hamstring strain injury (HSI) risk factors after a high-volume sprinting session in soccer players. A high-volume sprinting session can induce acute changes in several sprint performance-related factors (sprint time and mechanical properties) and HSI risk factors (posterior chain muscle strength, hamstring range of motion, and dynamic lumbo-pelvic control [LPC], measured as changes in anterior pelvic tilt [APT] during maximal speed sprinting). Prospective observational case series. Level 4. Fifteen active male amateur soccer players participated. Changes in sprint performance-related factors and HSI risk factors were examined for 72 hours after high-volume MSS efforts (H-VMSSE) using a soccer-contextualized multifactorial approach. Muscle damage proxy markers (hamstring perceived soreness and creatine kinase) were also examined. H-VMSSE induced decrements in sprint performance-related factors. Significant reductions in theoretical maximal horizontal velocity (P < 0.01; effect size [ES], -0.71) and performance (P = 0.02; ES, -0.59) were observed for 48 and 72 hours after H-VMSSE. Small but significant reductions in posterior chain muscle force-generating capacity were detected for 48 and 72 hours after H-VMSSE for the nondominant (P < 0.03; ES, -0.60) and dominant (P < 0.04; ES, -0.40) leg. Finally, players exhibited persistent small, albeit nonsignificant (P = 0.06; ES, 0.53), decreases in dynamic LPC (APT increases) for 72 hours after H-VMSSE. H-VMSSE induced declines in both sprint performance-related factors and HSI risk factors. Sprinting can alter a player's anatomic structure by increasing APT during the maximum speed phase of the sprint. A soccer-contextualized multifactorial approach might allow for the regulation of MSS dosage depending on individual HSI risk factor status, thereby serving as a tailored "vaccine" for sprinting needs.

Fecal and Serum Granulocyte Protein Levels in Inflammatory Bowel Disease and Irritable Bowel Syndrome and Their Relation to Disease Activity.

Neutrophilic calprotectin (CP) and myeloperoxidase (MPO), neutrophil gelatinase-associated lipocalin (NGAL), and eosinophil-derived neurotoxin (EDN) are suggested proxy markers for gut inflammation. However, there are insufficient supporting data for MPO, NGAL, and EDN. In a cross-sectional investigation including adult patients, we studied the ability of CP, MPO, NGAL, and EDN, measured in fecal and serum samples, to differentiate between inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS), and to predict disease activity. Fifty-nine patients had ulcerative colitis (UC), 38 had Crohn's disease, and 100 patients had IBS. The protein concentrations were higher in patients with IBD in the fecal samples ( P < 0.001) and the serum samples ( P < 0.01), and they correlated weakly (r s ≤0.38) between the sample sources. Fecal EDN was higher in patients with Crohn's disease compared with UC (1.79 vs 0.50 mg/kg, P = 0.016). The neutrophilic proteins were superior to EDN in the fecal samples for differentiating between patients with IBD and IBS. Fecal MPO (cutoff: 0.86 mg/kg) had the highest sensitivity (74.7%) and specificity (84.6%). Combining fecal CP and MPO increased the sensitivity to 82.3% (specificity: 73.6%). NGAL (cutoff: 196.9 μg/L) showed the best discriminating performance in serum (sensitivity: 62.9%; specificity: 68.0%). Serum NGAL (cutoff: 272.4 μg/L) predicted active disease in UC (Partial Mayo Score ≥2) with a sensitivity and specificity of 57.1% and 83.3%, respectively. Fecal MPO and serum NGAL are promising novel biomarkers, in addition to fecal CP, for differentiating between IBD and IBS. Serum NGAL may also predict disease activity in patients with UC.

Quantifying and Adjusting for Confounding From Health-Seeking Behavior and Health Care Access in Observational Research.

Health-seeking behavior and health care access (HSB/HCA) are recognized confounders in many observational studies but are not directly measurable in electronic health records. We used proxy markers of HSB/HCA to quantify and adjust for confounding in observational studies of influenza and COVID-19 vaccine effectiveness (VE). This cohort study used primary care data prelinked to secondary care and death data in England. We included individuals aged ≥66 years on 1 September 2019 and assessed influenza VE in the 2019-2020 season and early COVID-19 VE (December 2020-March 2021). VE was estimated with sequential adjustment for demographics, comorbidities, and 14 markers of HSB/HCA. Influenza vaccination in the 2019-2020 season was also considered a negative control exposure against COVID-19 before COVID-19 vaccine rollout. We included 1 991 284, 1 796 667, and 1 946 943 individuals in the influenza, COVID-19, and negative control exposure populations, respectively. Markers of HSB/HCA were positively correlated with influenza and COVID-19 vaccine uptake. For influenza, adjusting for HSB/HCA markers in addition to demographics and comorbidities increased VE against influenza-like illness from -1.5% (95% CI, -3.2% to .1%) to 7.1% (95% CI, 5.4%-8.7%) with a less apparent trend for more severe outcomes. For COVID-19, adjusting for HSB/HCA markers did not change VE estimates against infection or severe disease (eg, 2 doses of BNT162b2 against infection: 82.8% [95% CI, 78.4%-86.3%] to 83.1% [95% CI, 78.7%-86.5%]). Adjusting for HSB/HCA markers removed bias in the negative control exposure analysis (-7.5% [95% CI, -10.6% to -4.5%] vs -2.1% [95% CI, -6.0% to 1.7%] before vs after adjusting for HSB/HCA markers). Markers of HSB/HCA can be used to quantify and account for confounding in observational vaccine studies.

No signs of mast cell involvement in long-COVID: Acase-control study.

Long-COVID caused by SARS-CoV-2 infection has significant and increasing effects on human health worldwide. Although a unifying molecular or biological explanation is lacking, several pathophysiological mechanisms have been proposed. Involvement of mast cells-evolutionary old "multipurpose" innate immune cells-was reported recently in studies of acute infection and post-acute-COVID-19 syndrome. Mast cell activity has been suggested in long-COVID. In this case-control study, we compared data from 24 individuals with long-COVID (according to the NICE criteria) and 24 age- and sex-matched healthy individuals with a history of SARS-CoV-2 infection without developing sequelae. Serum levels of the proteases beta-tryptase (TPSB2) and carboxypeptidase (CPA3), which are mast cell specific, were measured using immunoassays. The values were compared between the two groups and correlated to measures of physical exertional intolerance. TPSB2 and CPA3 levels were median (range) 26.9 (2.0-1000) and 5.8 (1.5-14.0) ng/mL, respectively, in the long-COVID group. The corresponding values in the control group were 10.9 (2.0-1000) (p = 0.93) and 5.3 (3.5-12.9) ng/mL (p = 0.82). No significant correlations between TPSB2 or CPA3 levels and scores on the ten physical subscales of SF-36, 3.1-3.10 were revealed. We found no significant differences in the levels of mast cell activation markers TPSB2 and CPA3 between the long-COVID and control groups and no correlations with proxy markers of exercise intolerance. Mast cell activation does not appear to be part of long-term pathogenesis of long-COVID, at least in the majority of patients.

Ethnic and region-specific genetic risk variants of stroke and its comorbid conditions can define the variations in the burden of stroke and its phenotypic traits.

Burden of stroke differs by region, which could be attributed to differences in comorbid conditions and ethnicity. Genomewide variation acts as a proxy marker for ethnicity, and comorbid conditions. We present an integrated approach to understand this variation by considering prevalence and mortality rates of stroke and its comorbid risk for 204 countries from 2009 to 2019, and Genome-wide association studies (GWAS) risk variant for all these conditions. Global and regional trend analysis of rates using linear regression, correlation, and proportion analysis, signifies ethnogeographic differences. Interestingly, the comorbid conditions that act as risk drivers for stroke differed by regions, with more of metabolic risk in America and Europe, in contrast to high systolic blood pressure in Asian and African regions. GWAS risk loci of stroke and its comorbid conditions indicate distinct population stratification for each of these conditions, signifying for population-specific risk. Unique and shared genetic risk variants for stroke, and its comorbid and followed up with ethnic-specific variation can help in determining regional risk drivers for stroke. Unique ethnic-specific risk variants and their distinct patterns of linkage disequilibrium further uncover the drivers for phenotypic variation. Therefore, identifying population- and comorbidity-specific risk variants might help in defining the threshold for risk, and aid in developing population-specific prevention strategies for stroke.

Dual clumped isotopes (Δ47 and Δ48) reveal non-equilibrium formation of freshwater cements

Low-Mg calcite, precipitating from meteoric fluids, is a common mineral that forms in a variety of near-surface diagenetic environments. However, recent studies, based on a combination of analyses of δ18O and Δ47 values, have suggested that this mineral might form in disequilibrium and consequently yield kinetic bias in Δ47-derived temperatures and fluid δ18O values. Here, we use dual clumped isotope proxies (Δ47 and Δ48) to investigate the influence of kinetic isotope effects within different meteoric diagenetic zones of Holocene and Pleistocene carbonates from the southern Florida and the Dominican Republic. In the Miami Oolite, the primary aragonite ooids and secondary low-Mg calcite cements in the bulk sample were separated from each other and their isotopic compositions (δ13C, δ18O, Δ47 and Δ48 values) were measured. The Δ47 and Δ48 values of the separated aragonite are consistent with the modern ooid sediments and in approximate equilibrium with the surface seawater. In contrast, the low-Mg calcite cement shows the higher Δ48 and lower Δ47 values, than expected, with the disequilibrium arising as a result of CO2 degassing in the vadose zone. Such deviations of Δ47 and Δ48 values are also observed in low-Mg calcite vadose cements in the Dominican Republic. While low-Mg calcites formed in the lower freshwater phreatic zone in the Dominican Republic have the Δ47- and Δ48-derived temperatures close to expected, the same mineral forming near the water-table and upper phreatic zone shows much higher Δ48-derived temperatures (up to ∼ 90 °C). The possible origin of such elevated temperatures can be attributed to non-equilibrium processes caused by changes in pH and pCO2, mediated by microbial sulfate reduction. Such differential kinetic behavior of Δ48 values between vadose and phreatic zones could be used as a proxy marker for the presence and the location of a water-table. This study demonstrates the great potential of dual clumped isotopes in the investigation of meteoric diagenesis and will help understand the alteration of ancient sequences and the interpretation of stable C isotope trends that they contain.

The association of circulating bioenergetic metabolites with healthy human aging

Aging is an inevitable and gradual decline in several biological functions. Mitochondrial dysfunction is one of the most important hallmarks of aging. In this context, alterations in metabolites associated with mitochondrial dysfunction may serve as a significant biomarker. This study aimed to investigate the existence of a relationship between the key metabolites involved in bioenergetics metabolism and aging. 53 volunteers ranged 20–85 years participated in the study. We tested the association between different tricarboxylic acid (TCA) cycle metabolites, fatty acid metabolism, and amino acid metabolism with age, sex, body composition, and proxy markers of aging such as walking speed, grip strength and chair test. We found that lactic acid negatively correlated with age while several fatty acid metabolites, such as azelaic, sebacic, and linoleic acids, showed positive correlations with age (p < 0.05). Sex-specific trends, such as glycerol, and dodecanoic acid, were also observed for certain metabolites. Furthermore, citric acid levels were found to have a significant association with physical function and body composition measures. Participants with higher citric acid levels displayed improved performance in physical tests and favorable body composition indices. Additionally, fumaric acid and adipic acid showed positive correlations with fat-free body mass, while sebacic acid was negatively associated with measures of fat mass. These findings underscore the importance of understanding the role of circulating bioenergetics metabolites with age, sex variations, and their potential implications in body composition and physical performance.

Evaluating the Sputum Bacteriological Profile of Lower Respiratory Tract Infections With Bartlett Score Analysis in a Tertiary Care Hospital in Southern Karnataka.

Lower respiratory tract infections (LRTIs) are one of the most commonly encountered infections with significant mortality and morbidity. Sputum is the most frequently obtained sample for LRTI diagnosis. However, sputum samples carry the risk of being non-representative due to the risk of contamination with oral colonizers. To overcome the dilemma with respect to representative sampling, the use of a scoring system such as the Bartlett scoring system is emphasized.This study probes the bacterial profile of sputum samples among patients presenting with LRTIs and their antibiotic susceptibility profile in relation to the Bartlett scoring system. Retrospective data for a period of three years, comprising 4960 sputum samples from patients presenting with LRTI, were collected to study the bacterial profile and antibiogram in comparison with the sputum quality analyzed by the Bartlett scoring system. Out of the 4960 sputum samples analyzed from patients with LRTI, 31.18% yielded the growth of bacterial pathogens, and 98.64% of the sputum samples yielding pathogenic growth had a significant Bartlett score. Sputum samples are non-invasive representative samples of lower airway infective pathologies. Sputum quality assessment by Bartlett scoring serves as a proxy marker to rule out respiratory colonization and aid culture-based diagnosis.

Serum Prestin Level May Increase Following Music Exposure That Induces Temporary Threshold Shifts: A Pilot Study.

To determine if blood prestin level changes after exposure to music at high sound pressure levels, and if this change is associated with temporary threshold shift (TTS) and/or changes in distortion product (DP) amplitude. Participants were exposed to pop-rock music at 100 dBA for 15 min monaurally through headphones. Pure-tone audiometry, DP amplitude, and blood prestin level were measured before and after exposure. Fourteen adults (9 women; age range: 20 to 54 years, median age = 31 [Interquartile ratio = 6.75]) with normal hearing were included in the study. Mean prestin level increased shortly after exposure to music, then returned to baseline within 1 week, although this trend was not observed in all participants. All participants presented TTS or a decrease in DP amplitude in at least one frequency after music exposure. There was a statistically significant average threshold elevation at 4 min postexposure. Statistically significant DP amplitude shifts were observed at 4 and 6 kHz, 2 min following exposure. Mean baseline serum prestin level (mean: 140.00 pg/mL, 95% confidence interval (CI): 125.92 to 154.07) progressively increased following music exposure, reaching a maximum at 2 hr (mean: 158.29 pg/mL, 95% CI: 130.42 to 186.66) and returned to preexposure level at 1 week (mean: 139.18 pg/mL, 95% CI: 114.69 to 163.68). However, after correction for multiple comparisons, mean prestin level showed no statistically significant increase from baseline at any timepoint. No correlation between maximum blood prestin level change and average TTS or distortion product otoacoustic emission amplitude shift was found. However, in an exploratory analysis, TTS at 6 kHz (the frequency at which maximum TTS occurred) decreased significantly as baseline blood prestin level increased. The results suggest that blood prestin level may change after exposure to music at high sound pressure levels, although statistical significance was not reached in this relatively small sample after correction. Baseline serum prestin level may also predict the degree of TTS. These findings thus suggest that the role of baseline serum prestin level as a proxy marker of cochlear susceptibility to intense music exposure should be further explored.

Oxytocin-receptor-expressing neurons in the lateral parabrachial nucleus activate widespread brain regions predominantly involved in fluid satiation

Fluid satiation is an important signal and aspect of body fluid homeostasis. Oxytocin-receptor-expressing neurons (OxtrPBN) in the dorsolateral subdivision of the lateral parabrachial nucleus (dl LPBN) are key neurons which regulate fluid satiation. In the present study, we investigated brain regions activated by stimulation of OxtrPBN neurons in order to better characterise the fluid satiation neurocircuitry in mice. Chemogenetic activation of OxtrPBN neurons increased Fos expression (a proxy marker for neuronal activation) in known fluid-regulating brain nuclei, as well as other regions that have unclear links to fluid regulation and which are likely involved in regulating other functions such as arousal and stress relief. In addition, we analysed and compared Fos expression patterns between chemogenetically-activated fluid satiation and physiological-induced fluid satiation. Both models of fluid satiation activated similar brain regions, suggesting that the chemogenetic model of stimulating OxtrPBN neurons is a relevant model of physiological fluid satiation. A deeper understanding of this neural circuit may lead to novel molecular targets and creation of therapeutic agents to treat fluid-related disorders.

Exploring genetic polymorphisms and transcript levels of antioxidant and metabolic markers for prediction and monitoring diarrhea in Holstein dairy calves

ABSTRACT The objective of this study was to investigate the genetic polymorphisms and transcript levels of antioxidant and metabolic markers for diarrhea monitoring in Holstein dairy calves. For DNA and RNA extraction, blood samples were taken from 100 female calves (50 with diarrhea and 50 appearing healthy). DNA sequencing and real time PCR for and metabolic genes were performed to identify genetic variants linked to diarrhea susceptibility. Results revealed that there were nucleotide sequence variations in the investigated genes between healthy and diarrheal calves. Keap1, HMOX1, CMPK2, ASPG, FPGT, TNNI3 K, and LPCAT1 were considerably more highly expressed in diarrheic calves than resistant ones. The Nrf2, PRDX2, and PRDX6 genes, however, produced a different pattern. This study provides a practical control strategy to lessen newborn diarrhea in Holstein dairy calves and emphasizes the significance of nucleotide variations along with antioxidant and metabolic gene expression patterns as proxy markers of diarrhea susceptibility/resistance.

Socioeconomic status in adulthood of children with and without a history of seizures: A retrospective cohort study

ObjectiveCompare adulthood socioeconomic status for children with and without a history of seizures. MethodsRetrospective cohort study using Aberdeen Children of the Nineteen Fifties (ACONF) data comprising children born 1950–1956 attending primary school 1962–1964, with follow-up data collected in 2001. Adulthood socioeconomic status was based on registrar general measure of occupational social class and categorised as high or low. We adjusted for potentially confounding variables including childhood socioeconomic status, behavioural issues (Rutter A/B scores), biological sex, school test scores, educational attainment, parental engagement with education, peer-status in school, and alcohol use in adulthood. A multivariate binary logistic regression was performed to estimate the adjusted association between children with a history of seizures of any type (for example febrile seizures, or provoked seizures of any other etiology or seizures in the context of epilepsy) or severity and adult socioeconomic status. Multiple imputation using the Monte-Carlo-Markov-Chain method accounted for missing data. ResultsPooled estimates (N = 2,208) comparing children with a history of seizures (n = 81) and children without a history of seizures (n = 2,127) found no differences between these cohorts in terms of adulthood socioeconomic status in both unadjusted (Odds Ratio (OR) 1.45 [95 % CI 0.71–2.96], p = 0.31) and adjusted (1.02 [0.46, 2.24], p = 0.96) analyses. Compared to males, females were at increased odds of having a lower socioeconomic status in adulthood (1.56 [1.13–2.17], p = 0.01).Compared to those with low educational attainment, those with moderate (0.32 [0.21, 0.48], p < 0.001) and high (0.12 [0.07, 0.20], p < 0.001) educational attainment were at reduced odds of having a lower socioeconomic status in adulthood. ConclusionCognitive problems in childhood (using educational attainment and scores on primary school tests proxy markers for cognition) rather than a history of seizures per se, were associated with lower SES in a population of adults born 1950–56 in Aberdeen. This relationship may be different depending on the time in history and nation/region of study. Given the changes in health, education and social support in the management of children with seizures over time, it would be of interest to investigate outcomes in a contemporary cohort. Such studies should ideally have validated diagnoses of seizures, details on seizure characteristics such as seizure type and severity, and a large sample size using national data.

P976 Treatment with exclusive enteral nutrition (EEN) impacts the peripheral blood mononuclear cell profile of paediatric patients with Crohn’s disease

Abstract Background Background: Despite its established clinical efficacy, the immunological effects of exclusive enteral nutrition (EEN) in Crohn’s disease (CD) are yet to be elucidated. This study investigated the impact of EEN on circulating peripheral blood mononuclear cells (PBMCs) and how any effects observed varied according to clinical response to treatment. Methods Methods: Children with active CD received EEN for eight weeks as their sole induction treatment. Blood and faecal samples were collected prior to EEN and upon EEN completion. PBMCs were isolated, stained and analysed using flow cytometry. Differences in PBMCs types were compared during EEN. Faecal calprotectin was measured with ELISA. Absence of gluten immunogenic peptide (GIP) in faeces was used as a proxy marker of EEN compliance. Results Results: Nine participants were recruited (Table 1), three of whom initiated azathioprine during their course of EEN. Following treatment with EEN a decrease in the relative number and frequency of circulating effector memory CD8+ T cells re-expressing CD45RA (TEMRA) was observed with a corresponding increase in the frequency of circulating central and effector memory CD8+ T cells (Fig. 1). When we excluded participants that commenced thiopurines during their course of EEN a decrease in the relative number of circulating TEMRA CD8+ T cells persisted and a decrease in naïve CD8+ T cells in the blood was also observed. Participants who demonstrated a decrease in faecal calprotectin 50% following treatment with EEN (n= 5) also demonstrated an increase in the frequency of circulating central memory CD8+ T cells. When focussing on participants (n=7) within our cohort who demonstrated a high-level of compliance (undetected GIP in faeces) during EEN, we again observed a decrease in number of TEMRA CD8+ T cells in blood alongside an increase in the frequency of circulating central and effector memory CD8+ T cells. Conclusion Conclusion: We observed significant changes in CD8+ T cell populations in the peripheral blood of children following treatment with EEN. These changes were observed irrespective of background immunomodulator use and persisted in participants which achieved &amp;gt;50% decrease in FC or demonstrated compliance to EEN. Our observed changes in CD8+ T cell populations, particularly the consistent increases in circulating effector and memory CD8+ T cells, are likely a consequence of the actions of EEN in decreasing the diversity and composition of the gut bacteria, therefore reducing the recruitment of effector/memory cells from the blood into the intestine.