Population Averages Research Articles

Patient-Reported Outcomes (PROs) from the Phase 2 TRANSCEND FL Study of Lisocabtagene Maraleucel (liso-cel) in Patients (pts) with Relapsed or Refractory Follicular Lymphoma (FL)

Background: In TRANSCEND FL (NCT04245839), a global, phase 2, open-label, single-arm, multicohort, pivotal study, the CAR T cell therapy liso-cel showed promising efficacy and safety in pts with R/R FL (Morschhauser F, et al. Hematol Oncol 2023;41[S2]:877-880). Here, we present corresponding data for PROs. Methods: Adults with R/R FL after ≥ 1 prior (2L+) line of therapy (LOT) were enrolled in cohorts with 1 (2L), 2 (3L), or ≥ 3 (4L+) prior LOTs. After leukapheresis and lymphodepleting chemotherapy (LDC), pts received 1 infusion of liso-cel (100 × 10 6 CAR + T cells). Pts completed the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-30 items (EORTC QLQ-C30), Functional Assessment of Cancer Therapy-Lymphoma “Additional Concerns” Scale (FACT-LymS), and the EQ-5D-5L on the following schedule: pretreatment (≤ 7 days before LDC; baseline); before infusion on the day of liso-cel infusion (Day 1); on Days 15, 29, 60, 90, 180, 270, 365, 545, and 730 after infusion; and at the end of study assessment. PROs were evaluated using 6 EORTC QLQ-C30 primary domains of interest preselected for relevance to FL, including global health status/quality of life, physical functioning, role functioning, cognitive functioning, fatigue, and pain, and the FACT-LymS subscale assessing lymphoma-specific symptoms. EORTC QLQ-C30 remaining domains, EQ-5D-5L utility index, and EQ-VAS were examined in exploratory analyses. Unless otherwise stated, analyses were performed in all liso-cel-treated pts with assessments at baseline and ≥ 1 postbaseline visit. Separate analyses were done for pts receiving liso-cel as 2L and 3L+ therapy. Linear mixed-effects models for repeated measures were used to calculate least squares (LS) mean change from baseline for visits with ≥ 10 pts. In individual-level analyses, proportions of pts with clinically meaningful changes over time were calculated using published responder definitions. Time to confirmed deterioration or improvement in PROs was assessed in all PRO-evaluable liso-cel-treated pts by the Kaplan-Meier method. Results: Of 130 liso-cel-treated pts with 2L+ R/R FL, 116 were included in the EORTC QLQ-C30 analysis (median age, 60 years; 63% male; 55% White). Among them, 19 (16%) had received 1 prior line of systemic therapy and 97 (84%) had received ≥ 2 prior LOTs (3L, 44 [38%]; 4L+, 53 [46%]). Assessment completion rates were > 80% across visits. For EORTC QLQ-C30, mean baseline scores in study pts were comparable to EU and US population averages, with a few domains slightly worse than the EU general population. After liso-cel infusion, transient deterioration was observed in physical and role functioning and fatigue up to Day 15. Thereafter, PROs were maintained or showed meaningful improvements relative to baseline that approached or exceeded minimally important difference thresholds at some visits. Overall LS mean changes from baseline showed statistically significant improvements in most primary and some secondary domains of interest (Table 1). In individual-level analyses, from Day 29 onward, most pts (65%‒100% across domains and visits) experienced improvements or no changes in primary domains of interest. For all domains, median time to confirmed deterioration was longer than median time to confirmed improvement, indicating that liso-cel-treated pts had a greater chance of achieving improvement in PROs than of experiencing deterioration. More than half of pts achieved meaningful improvements in fatigue, pain, and FACT-LymS at 26, 5, and 15 weeks post infusion, respectively (Table 2). Across PROs, results were comparable between pts receiving liso-cel as 2L or 3L+ therapy, although those receiving liso-cel as 2L therapy generally demonstrated greater/faster meaningful improvements in most primary domains, including role and cognitive functioning, fatigue, pain, and FACT-LymS scores. Conclusions:In TRANSCEND FL, most pts with 2L or 3L+ R/R FL experienced statistically and clinically significant improvements in PROs after liso-cel treatment, including in quality of life, disease symptoms, and functioning. These data, which include the first report of PROs in pts with 2L FL treated with CAR T cell therapy, represent the direct patient experience with liso-cel treatment and complement liso-cel treatment outcomes demonstrating clinical benefit and manageable safety in pts with R/R FL.

Polygenic Modifiers of Expressivity in Telomere Biology Disorders

Telomere biology disorders (TBDs) are caused by pathogenic germline variants in genes involved in telomere maintenance resulting in very short telomeres for age and high risks of bone marrow failure, certain cancers, as well as pulmonary and liver disease. Interestingly, some pathogenic TBD mutations have variable expressivity and incomplete penetrance, even within families. Variant carriers can present with early manifestations such as the mucocutaneous triad and bone marrow failure or may not manifest until later in life with adult-onset idiopathic pulmonary fibrosis or liver disease, or have no associated clinical phenotype. The underlying causes of this heterogeneity are poorly understood. We hypothesized that common genetic variants contributing to inter-individual variation in telomere length in the general population may combine with the effects of monogenic TBD-causing variants to underlie variable clinical manifestations in TBDs. To examine this, we developed polygenic scores (PGS) to predict telomere length using genome-wide SNPs from the UK Biobank. We then applied the most predictive polygenic score to the out-of-sample All of Us cohort, as well as the National Cancer Institute's longitudinal cohort of individuals with inherited bone marrow failure syndromes, including those with TBDs (ClinicalTrials.gov Identifier: NCT00027274). If monogenic mutations and polygenic predisposition to short telomeres both contribute to the clinical severity of TBDs and likelihood of early-onset manifestations, the distribution of genetically predicted telomere length in this ascertained cohort would be shifted towards shorter telomeres compared with the population average. Consistent with this, individuals with TBDs enriched for early-onset bone marrow failure phenotypes (n = 92) have a median polygenic score 0.32 standard deviations (SDs) shorter than the UK Biobank (p=0.002), and 0.31 SDs shorter than the external All of Us cohort (p=0.003) ( Figure). Individuals with TBDs also have shorter genetically predicted telomeres compared to individuals with Fanconi anemia (n = 45) and Diamond Blackfan anemia (n = 49) (p=0.008), indicating that this phenomenon is specific to TBDs. We binned the PGS into quintiles and show that the lowest quintile is associated with an odds ratio of TBD of 1.89 [1.19,2.86], while being in the highest quintile is associated with an odds ratio of 0.54 [0.29,1.02]. Interestingly, TBD cases with no identified mutation have a median PGS 0.1 SDs towards shorter telomeres than patients with a known mutation. Collectively, these results indicate that common, genome-wide determinants of telomere length are significant modifiers of the early-onset manifestations of TBDs. We hypothesized that the converse should also be true: TBD causal variants should be present in adult population cohorts, and adult individuals with a pathogenic variant who avoided the severe childhood-onset manifestations of TBDs, should not have polygenically predicted short telomere length. To test this hypothesis, we filtered the UK Biobank for TBD causal variants annotated in ClinVar, and identified 71 putative pathogenic cases. Importantly, among these cases there were no individuals with bone marrow failure, but these individuals did have shorter telomeres compared with the UK Biobank. Interestingly, these 71 putative cases had a population-normal telomere length PGS, and significantly longer PGS predicted telomere length than the NCI cohort (p=0.025). We also find that being classified as among these pathogenic cases is associated with an odds ratio for developing pulmonary fibrosis of 10.79 [4.34,26.8]. In summary, despite normal PGS and absence of bone marrow failure, these putative cases have short telomeres and increased risk of adult manifestations of TBDs, consistent with the idea that the pathogenic mutations and common genetic variation affecting telomere length combine to impact expressivity. Collectively, these findings indicate that polygenic effects on telomere length can modify the impacts of monogenic mutations in TBD-associated genes. These results have implications not only for clinical risk assessment in patients with TBDs, but also for our general understanding and interpretation of variable penetrance/expressivity in presumed monogenic disorders.

Heuristical Approach for Optimizing Population Mean Using Ratio Estimator in Stratified Random Sampling

In this study, we have developed a Ratio type estimator in Stratified sampling to estimate the population average of study variable by using the information of a concomitant variable. By utilizing Taylor’s series, we have derived the expressions for Bias and MSE upto first degree of approximation. In numerical illustration, employing a real data set, we have demonstrated that the proposed estimator has highest Percentage relative efficiency when compared to the considered existing estimatrs. Furthermore, we have demonstrated that Separate ratio type estimators have the highest relative efficiency when contrasted with the Combined ratio type estimators.

Paid Sick Leave and Self-Reported Depression and Anxiety: Evidence From a Nationally Representative Longitudinal Survey

The objective of this study was to explore the association between access to paid sick leave (AtPSL) and self-reported feelings of depression and anxiety in a nationally representative U.S. working population. In 2023, this study examined data from the 2019-2020 Longitudinal National Health Interview Survey. A Generalized Linear Latent and Mixed Model (GLLAMM) was used to analyze the longitudinal data. The descriptive analysis of population averages showed that fewer workers with AtPSL reported daily feelings of depression (45%), anxiety (24%), and both depression and anxiety (52%) than workers without AtPSL. According to the GLLAMM analysis, the odds of workers with AtPSL self-reporting feelings of daily depression, anxiety, and both were 48%, 27%, and 51% lower, respectively, than workers without AtPSL. This analysis controlled for different demographic and socioeconomic variables. Robustness analysis demonstrated that these associations persisted when the outcome variables were measured in terms of self-reported feelings of weekly depression and anxiety. The role of mental health in improving overall well-being and the recognition of AtPSL as a social justice issue have reinforced the importance of providing paid sick leave to help protect the mental health status of workers. This study, using a unique longitudinal data set, found that AtPSL was associated with a lower prevalence of self-reported daily or weekly feelings of depression and anxiety.

Genetic diversity, variation, and structure of two populations of bigfin reef squid (Sepioteuthis lessoniana d’Orbigny) in Con Dao and Phu Quoc islands, Vietnam

BackgroundBigfin squid is one of the economically important seafood resources in Vietnam’s fisheries and the waters around Con Dao and Phu Quoc islands are two major fishing grounds where this species has been actively exploited. The start codon targeted polymorphism (SCoT) and CAAT box–derived polymorphism (CBDP) techniques were used to generate DNA fingerprinting data to analyze the genetic diversity, variation, and structure of the two populations in the waters surrounding Phu Quoc and Con Dao islands together with mitochondrial cytochrome C oxidase subunit I (COI) gene sequence data. ResultsCon Dao population possessed a higher diversity [expected heterozygosity (He) = 0.2254, Shannon index (I) = 0.3459, percentage of polymorphic bands (PPB) = 80.14%, nucleotide diversity (π) = 0.0336, haplotype diversity (h) = 0.910 with 16 haplotypes] than Phu Quoc population (He = 0.1854, I = 0.2873, PPB = 70.38%, π = 0.0246, h = 0.838 with 14 haplotypes). The genetic diversity at species level in the investigated region was at level of He = 0.2169, I = 0.3399, PPB = 86.41, π = 0.0289, and h = 0.892 with 24 haplotypes. Based on DNA fingerprinting data, the pairwise genetic similarity coefficients among individuals of the Con Dao population were lower (average of 0.7977) than the Phu Quoc population (average of 0.8316). Based on mitochondrial COI data, the pairwise genetic distances among individuals of the Con Dao population were higher (average of 0.0361) than the Phu Quoc population (average of 0.0263). Gene differentiation (GST) between two investigated populations was 0.0316 and 0.0310 leading to the genetic distance was 0.0573 and 0.0213 and the gene flow between them was Nm = 8.2209 and 11.4700 migrants per generation among populations based on DNA fingerprinting and based on COI gene sequence data, respectively. Genetic variation within individuals of both populations (WP) played the key role in total genetic variation at species level in surveyed region. ConclusionsFor the bigfin reef squid species in the surveyed region, the Con Dao population had the higher genetic diversity than the Phu Quoc population, between them existed a low to moderate genetic differentiation and a genetic exchange via gene flow. The DNA fingerprinting data better revealed the genetic differentiation between the two surveyed populations while the mitochondrial COI gene sequence data could show the phylogenetic relationship among the surveyed individuals and the other from the sea regions in Southeast Asia. Based on the results obtained, fisheries management strategies are suggested toward the conservation and sustainable exploitation of this species.

The Impact of the COVID-19 Pandemic in The Netherlands on Primary Healthcare Use and Clinical Outcomes in Persons with Type 2 Diabetes

The COVID-19 pandemic has had a significant impact on healthcare systems worldwide, including the postponing or canceling of appointments and procedures for type 2 diabetes (T2D) care by general practitioners (GPs) in the Netherlands. The aim of this study was to investigate the impact of the COVID-19 pandemic on primary healthcare use and clinical measurements for people with T2D. Additionally, we aimed to determine if changes were observed among specific risk groups: (1) persons 70 years or older, or below 70 years, (2) patients who were meeting their HbA1c targets and those who were not, and (3) patients with high-risk and non-high-risk T2D. This retrospective cohort study among persons with T2D was conducted using data from the DIAbetes MANagement and Treatment (DIAMANT) data infrastructure, deriving data from electronic medical records of Dutch GPs. The study assessed GP visit counts, and counts and values of clinical measurements, including hemoglobin A1c (HbA1c), body mass index (BMI), low-density lipoprotein (LDL) cholesterol, and systolic blood pressure (SBP). Adjusted negative binomial (NB) regression and generalized estimating equations (GEE) models were used to estimate GP visit counts and population averages of clinical measurements, respectively, comparing 2019 (pre-pandemic) with 2020 (during the pandemic). Changes in specific groups were examined by stratifying outcomes for the aforementioned subgroups. The cohort consisted of 182,048 patients with T2D (47% female, mean age 69 ± 13 years) on 1 March 2019, of which 168,097 persons (92%) still contributed follow-up data in 2020. We observed an increase in total GP visits in 2020, with an adjusted rate ratio (RR) of 1.09 (95% CI 1.08–1.09). The frequency increased for office visits (RR 1.06; 1.06–1.07) and phone calls (RR 1.33; 1.31–1.35) but remained stable for home visits (RR 1.02; 0.99–1.04). On both population and individual levels, HbA1c values increased in 2020 by 1.65 (1.59–1.70) mmol/mol compared to 2019. Observed changes in 2020 for BMI, LDL, and SBP values were also statistically significant but small. Subgroup stratifications showed higher scores of all clinical measurements in younger persons (<70 years), those who met their HbA1c target, and non-high-risk T2D patients than their respective high-risk subgroups. During the first year of the COVID-19 pandemic in the Netherlands, changes in primary healthcare use were observed among persons with T2D, with an increase in GP office visits and phone calls and a decreased number of clinical measurements and GP home visits. HbA1c levels increased among patients with T2D in 2020. Further research is necessary to determine the impact of the COVID-19 pandemic on long-term clinical outcomes and (long-term) T2D complications.

Hubungan Riwayat Pemberian ASI Eksklusif terhadap Kejadian Stunting Balita 25-59 Bulan di Wilayah Kerja Puskesmas Dolok Masihul Kabupaten Serdang Bedagai

Stunting is an outcome of nutritional status that occurs when a child has a height or length of less than -2.0 standard deviation (SD) compared to the population average. The nutritional status of stunting is calculated by comparing the height or length according to the age of the toddler, according to the World Health Organization (WHO) z-score chart (WHO, 2018). One of the causes of stunting in toddlers is not being given exclusive breastfeeding during the first 0-6 months of age because breast milk is needed during the baby's growth period so that their nutritional needs are fulfilled. The purpose of this study was to find out the relationship between the history of exclusive breastfeeding and the incidence of stunting in toddlers in the working area of the Dolok Masihul Health Center, Serdang Bedagai Regency. The type of research used is an observational research design with a cross-sectional study approach, where the dependent and independent variable data are observed and measured at the same time. There were 31 respondents who were parents and also stunted and non-stunted toddlers. The results of the study were obtained using chi-square tests between the variable history of exclusive breastfeeding on the incidence of stunting and the variable the first time a child was given food/drink other than breast milk on the incidence of stunting, the p value = 0.00 was then compared with the value a = 0.05 so that p value <a (0.00 <0.05) meaning that there is a relationship between history of exclusive breastfeeding and the incidence of stunting and there is a relationship the first time a child is given food/drink other than breast milk to the incidence of stunting in the working area of the Dolok Masihul Health Center, Serdang Bedagai Regency .

Quantifying and correcting bias in transcriptional parameter inference from single-cell data

The snapshot distribution of mRNA counts per cell can be measured using single-molecule fluorescence in situ hybridization or single-cell RNA sequencing. These distributions are often fit to the steady-state distribution of the two-state telegraph model to estimate the three transcriptional parameters for a gene of interest: mRNA synthesis rate, the switching on rate (the on state being the active transcriptional state), and the switching off rate. This model assumes no extrinsic noise, i.e., parameters do not vary between cells, and thus estimated parameters are to be understood as approximating the average values in a population. The accuracy of this approximation is currently unclear. Here, we develop a theory that explains the size and sign of estimation bias when inferring parameters from single-cell data using the standard telegraph model. We find specific bias signatures depending on the source of extrinsic noise (which parameter is most variable across cells) and the mode of transcriptional activity. If gene expression is not bursty then the population averages of all three parameters are overestimated if extrinsic noise is in the synthesis rate; underestimation occurs if extrinsic noise is in the switching on rate; both underestimation and overestimation can occur if extrinsic noise is in the switching off rate. We find that some estimated parameters tend to infinity as the size of extrinsic noise approaches a critical threshold. In contrast when gene expression is bursty, we find that in all cases the mean burst size (ratio of the synthesis rate to the switching off rate) is overestimated while the mean burst frequency (the switching on rate) is underestimated. We estimate the size of extrinsic noise from the covariance matrix of sequencing data and use this together with our theory to correct published estimates of transcriptional parameters for mammalian genes.

OR15-04 Accelerated Longitudinal Weight Gain Among Infants With In Utero COVID-19 Exposure

Abstract Disclosure: M.W. Ockene: None. S.C. Russo: None. H. Lee: None. C. Monthé-Drèze: None. T.L. Stanley: Consulting Fee; Self; RosVivo Therapeutics. Grant Recipient; Self; Pfizer, Inc. I.L. Ma: None. M. Toribio: None. L.L. Shook: None. S.K. Grinspoon: Consulting Fee; Self; Theratechnologies. A.G. Edlow: Consulting Fee; Self; Mirvie, Inc. Grant Recipient; Self; Merck. L.T. Fourman: Consulting Fee; Self; Amryt Pharmaceuticals. Grant Recipient; Self; Amryt Pharmaceuticals. Background: Since its initial outbreak in 2019, coronavirus disease 2019 (COVID-19) has led to unprecedented morbidity and mortality worldwide. Due to a high burden of infection among pregnant women, a novel population of children with in utero exposure to maternal COVID-19 has emerged for which health outcomes are largely unknown. Given the role of the intrauterine environment in shaping chronic disease risk over the life course through effects on fetal programming, there is a pressing need to delineate longitudinal growth patterns among infants born to mothers with COVID-19 during pregnancy. Methods: We conducted a longitudinal cohort study leveraging a prospectively-enrolled perinatal biorepository among 149 infants with in utero exposure to maternal COVID-19 and 127 unexposed controls. Weight, length, and BMI were abstracted from health records at 0, 2 (±0.5), 6 (±1), and 12 (±1) months and standardized using World Health Organization (WHO) growth charts. Linear mixed effect and linear regression models were used to examine differences in anthropometric z-score trajectories over the first year of life between groups. Analyses were adjusted for maternal age, ethnicity, parity, insurance type, and BMI as well as infant sex, birthdate, and breastfeeding. Our pre-specified primary endpoint was change in BMI z-score from birth to 12 months. Results: Infants with in utero COVID-19 exposure versus controls exhibited differential trajectories of weight and BMI, but not length, z-scores over the first year of life (study group x time interaction, P < 0.0001 for weight and BMI z-scores). Infants born to mothers with prenatal COVID-19 had lower BMI z-score at birth (effect size: -0.35, 95% CI, -0.66 to -0.03) and greater increase in BMI z-score from birth to 12 months (effect size: 0.53, 95% CI, 0.06 to 0.99). Change in BMI z-score was greater than the WHO population average of 0 within the exposed (P < 0.0001) but not the unexposed group. Birth weight z-score was found to mediate a significant proportion of the relationship between COVID-19 exposure and postnatal growth (estimate ± standard error, 32 ± 14%, P = 0.02). Conclusions: Infants with in utero exposure to maternal COVID-19 were found to exhibit lower birth weight and accelerated weight gain over the first year of life compared to their unexposed peers. The exaggerated growth trajectory observed in these children may be a catch-up response to a prenatal growth deficit. Lower birth weight and accelerated postnatal weight gain are established risk factors for obesity, abdominal adiposity, and cardiovascular disease later in life. Thus, children born to mothers with prenatal COVID-19 may be at heightened risk of long-term cardiometabolic complications and require close monitoring over the life course. Further studies are now needed to delineate cardiometabolic sequelae of in utero COVID-19 exposure among this emerging global population. Presentation: Friday, June 16, 2023

More spice, less salt: How capsaicin affects liking for and perceived saltiness of foods in people with smell loss

People who lose their sense of smell self-report consuming more salt to compensate for a lack of flavor and enhance eating enjoyment. However, this may contribute to excess sodium intake. Capsaicin may help increase salt taste intensity and eating enjoyment in people with smell loss, but this has not been studied in this population. The purpose of this study was to determine 1) whether salt intake in those with smell loss differs from population averages, 2) whether capsaicin increases flavor and salt taste intensity, and 3) if adding spice to foods increases liking in individuals with smell loss. Thirty-three participants 18–65 years old with confirmed smell loss for at least 12 weeks completed two sets of replicate test sessions (four total). In two sessions participants rated overall flavor intensity, taste qualities' intensities, spicy intensity, and liking for model tomato soups with low or regular sodium content and three levels of capsaicin (none, low, or moderate). In the other two sessions, participants rated the same sensory attributes for model food samples with three levels of added spice (none, low, or moderate). 24-hour urine samples were collected to determine sodium intake. Results indicate that although sodium intake is higher than recommended (<2300 mg/day) in those with smell loss (2893 ± 258 mg/day), they do not consume more sodium than population averages (3039 ± 100 mg/day; p = 0.3). Adding low and moderate amounts of capsaicin to a model tomato soup increased the intensity of overall flavor (p < 0.001) and saltiness (p = 0.004) compared to a model tomato soup without capsaicin. However, capsaicin's effect on liking differed by food type. Thus, capsaicin can improve flavor, salt taste intensity, and eating enjoyment in people with smell loss.

Poster Session: Peripheral blur may provide the eye with a cue for the sign of defocus.

The sign of defocus is used by the retina to guide emmetropization. However, the means by which the eye determines whether light is focused in front of, or behind the retina, remains elusive. In the current study, we propose a new cue for the sign of defocus: the orientation of the anisotropic peripheral blur. Previously published [1] population averages of wavefront aberrations across the horizontal visual field in hyperopes, emmetropes and myopes were used to assess peripheral optical quality and blur orientation. Due to the large magnitudes of off-axis astigmatism and coma, the peripheral retinal image quality was dominated by anisotropic blur, whose direction was also correlated with refractive error (vertically elongated peripheral blur in myopic eyes and horizontally elongated peripheral blur in emmetropic and hyperopic eyes). The differences in groups may be due to the interaction between peripheral wavefront aberrations and globe shape (i.e. peripheral axial length). We also found an interaction between longitudinal chromatic aberration and off-axis astigmatism, wherein peripheral blur orientation is wavelength dependent, raising additional questions pertaining to the nature of chromatic cues. The orientation of peripheral blur may provide the retina with an optical cue for the sign of defocus, potentially playing an important role in emmetropization. [1] Romashchenko et al., "Peripheral refraction and higher order aberrations." Clin Exp Optom 103.1 (2020): 86-94.

Functional magnetic particle imaging (fMPI) of cerebrovascular changes in the rat brain during hypercapnia

Objective. Non-invasive functional brain imaging modalities are limited in number, each with its own complex trade-offs between sensitivity, spatial and temporal resolution, and the directness with which the measured signals reflect neuronal activation. Magnetic particle imaging (MPI) directly maps the cerebral blood volume (CBV), and its high sensitivity derives from the nonlinear magnetization of the superparamagnetic iron oxide nanoparticle (SPION) tracer confined to the blood pool. Our work evaluates functional MPI (fMPI) as a new hemodynamic functional imaging modality by mapping the CBV response in a rodent model where CBV is modulated by hypercapnic breathing manipulation. Approach. The rodent fMPI time-series data were acquired with a mechanically rotating field-free line MPI scanner capable of 5 s temporal resolution and 3 mm spatial resolution. The rat’s CBV was modulated for 30 min with alternating 5 min hyper-/hypocapnic states, and processed using conventional fMRI tools. We compare our results to fMRI responses undergoing similar hypercapnia protocols found in the literature, and reinforce this comparison in a study of one rat with 9.4T BOLD fMRI using the identical protocol. Main results. The initial image in the time-series showed mean resting brain voxel SNR values, averaged across rats, of 99.9 following the first 10 mg kg−1 SPION injection and 134 following the second. The time-series fit a conventional General Linear Model with a 15%–40% CBV change and a peak pixel CNR between 12 and 29, 2–6× higher than found in fMRI. Significance. This work introduces a functional modality with high sensitivity, although currently limited spatial and temporal resolution. With future clinical-scale development, a large increase in sensitivity could supplement other modalities and help transition functional brain imaging from a neuroscience tool focusing on population averages to a clinically relevant modality capable of detecting differences in individual patients.

MA'AT Analysis: Probability Distributions of Molecular Torsion Angles in Solution from NMR Spectroscopy.

ConspectusMonosaccharides adopt multiple conformations in solution, and this structural complexity increases significantly when they are assembled into oligosaccharides and polysaccharides. Characterization of the conformational properties of saccharides in solution by NMR spectroscopy has been hampered by several complicating factors, including difficulty interpreting spectra because of significant signal overlap, population averaging of NMR parameters, and unique properties of the spectra that make accurate measurements of NMR parameters prone to error (e.g., non-first-order effects on J-couplings). Current conformational assignments rely heavily on theoretical calculations, especially molecular dynamics (MD) simulations, to interpret the experimental NMR parameters. While these studies assert that the available experimental data fit the calculated models well, a lack of independent experimental validation of the force fields from which MD models are derived and an inability to test all possible models that might be compatible with the experimental data in an unbiased manner make the approach less than ideal.NMR spin couplings or J-couplings have been used as structure constraints in organic and other types of molecules for more than six decades. The dihedral angle dependence of vicinal (three-bond) 1H-1H spin couplings (3JHH) first described by Karplus led to an explosion of applications for a wide range of conformational problems. Other vicinal J-couplings (e.g., 3JCCOP, 3JHCOP, and 3JCOCH) have been found to exhibit similar dihedral angle dependencies. 3J values have been used to assign the preferred conformation in molecules that are conformationally homogeneous. However, many molecules, particularly those in biological systems, are conformationally flexible, which complicates structural interpretations of J values in solution. Three-state staggered models are often assumed in order to deconvolute the conformationally averaged J values into conformer populations. While widely applied, this approach assumes highly idealized models of molecular torsion angles that are likely to be poor representations of those found in solution. In addition, this treatment often gives negative populations and neglects the presence of librational averaging of molecular torsion angles.Recent work in this research group has focused on the development of a hybrid experimental-computational method, MA'AT analysis, that provides probability distributions of molecular torsion angles in solution that can be superimposed on those obtained by MD. Ensembles of redundant NMR spin couplings, including 3J (vicinal), 2J (geminal), and sometimes 1J (direct) values, are used in conjunction with circular statistics to provide single- and multistate models of these angles. MA'AT analysis provides accurate mean torsion angles and circular standard deviations (CSDs) of each mean angle that describe the librational motion about the angle. Both conformational equilibria and dynamics are revealed by the method. In this Account, the salient features of MA'AT analysis are discussed, including some applications to conformational problems involving saccharides and peptides.

Continuous, long-term crawling behavior characterized by a robotic transport system.

Detailed descriptions of behavior provide critical insight into the structure and function of nervous systems. In Drosophila larvae and many other systems, short behavioral experiments have been successful in characterizing rapid responses to a range of stimuli at the population level. However, the lack of long-term continuous observation makes it difficult to dissect comprehensive behavioral dynamics of individual animals and how behavior (and therefore the nervous system) develops over time. To allow for long-term continuous observations in individual fly larvae, we have engineered a robotic instrument that automatically tracks and transports larvae throughout an arena. The flexibility and reliability of its design enables controlled stimulus delivery and continuous measurement over developmental time scales, yielding an unprecedented level of detailed locomotion data. We utilize the new system's capabilities to perform continuous observation of exploratory search behavior over a duration of 6 hr with and without a thermal gradient present, and in a single larva for over 30 hr. Long-term free-roaming behavior and analogous short-term experiments show similar dynamics that take place at the beginning of each experiment. Finally, characterization of larval thermotaxis in individuals reveals a bimodal distribution in navigation efficiency, identifying distinct phenotypes that are obfuscated when only analyzing population averages.

The Duration of Menstrual Blood Loss: Historical to Current Understanding

Most published research focuses on the amount of menstrual blood loss and, to a lesser extent, on cyclicity. Little attention has been paid to the duration of bleeding, the factors that enable its cessation within a ‘normal’ timeframe, or to patterns that entail interruption and resumption of blood loss. The definition of what constitutes normal remains arbitrary and there is no therapy specifically designed to shorten the duration of bleeding. Here, we critically review the literature that addresses the duration of bleeding and the factors that trigger endometrial breakdown and repair. Available reports used population averages which mask inter- and intra-individual variations. The duration of bleeding is not necessarily linked to the amount of loss but may be influenced by age, ethnicity, habitus, region and altitude of residence, dieting and stress. The onset of bleeding has been linked to declining steroid production by the corpus luteum. There remains considerable controversy around the extent of endometrial shedding at menstruation. This is likely to vary within and between women. The significance of a change from previous patterns, very short or prolonged bleeding, days of light loss or spotting before or after days of bleeding, or of bleed-free days that punctuate flow, remain poorly understood.

Profitability of rural practice

There is a crisis in rural veterinary medicine as rural practitio­ners face challenges in different business environments. Rural veterinary practices are complex organizational systems with economic and demographic challenges directly associated with various causal conditions which affect practice profitability and efficiency. Supported by a grant from the U.S. Department of Agriculture, data was collected from 16 mixed rural veteri­nary practices in the southeastern United States over 4 years. A 3-year financial analysis found profits and owners’ compen­sation of 20.3% of gross revenues, cost of goods sold (COGS) of 37.8% of gross revenues, practice and doctor averages cli­ent transactions of $102 and $117, respectively. Population and income averages within 40 miles of the practice were 452,939 people with household incomes of $67,780. Compared to the averaged Well-Managed Practice Benchmarks 2019, American Animal Hospital Association 2019, and American Veterinary Medical Association 2017 data, potential causal conditions chal­lenges for rural practices limiting profitability are COGS, clini­cal revenue production, and clinical work efficiency.

Applying a data-driven population segmentation approach in German claims data

BackgroundSegmenting the population into homogenous groups according to their healthcare needs may help to understand the population’s demand for healthcare services and thus support health systems to properly allocate healthcare resources and plan interventions. It may also help to reduce the fragmented provision of healthcare services. The aim of this study was to apply a data-driven utilisation-based cluster analysis to segment a defined population in the south of Germany.MethodsBased on claims data of one big German health insurance a two-stage clustering approach was applied to group the population into segments. A hierarchical method (Ward's linkage) was performed to determine the optimal number of clusters, followed by a k-means cluster analysis using age and healthcare utilisation data in 2019. The resulting segments were described in terms of their morbidity, costs and demographic characteristics.ResultsThe 126,046 patients were divided into six distinct population segments. Healthcare utilisation, morbidity and demographic characteristics differed significantly across the segments. The segment “High overall care use” comprised the smallest share of patients (2.03%) but accounted for 24.04% of total cost. The overall utilisation of services was higher than the population average. In contrast, the segment “Low overall care use” included 42.89% of the study population, accounting for 9.94% of total cost. Utilisation of services by patients in this segment was lower than population average.ConclusionPopulation segmentation offers the opportunity to identify patient groups with similar healthcare utilisation patterns, patient demographics and morbidity. Thereby, healthcare services could be tailored for groups of patients with similar healthcare needs.

First observations of Weddell seals foraging in sponges in Erebus Bay, Antarctica

Attaching cameras to marine mammals allows for first-hand observation of underwater behaviours that may otherwise go unseen. While studying the foraging behaviour of 26 lactating Weddell seals (Leptonychotes weddellii) in Erebus Bay during the austral spring of 2018 and 2019, we witnessed three adults and one pup investigating the cavities of Rossellidae glass sponges, with one seal visibly chewing when she removed her head from the sponge. To our knowledge, this is the first report of such behaviour. While the prey item was not identifiable, some Trematomus fish (a known Weddell seal prey) use glass sponges for shelter and in which to lay their eggs. Three of the four sponge foraging observations occurred around 13:00 (NZDT). Two of the three sponge foraging adults had higher-than-average reproductive rates, and the greatest number of previous pups of any seal in our study population, each having ten pups in 12 years. This is far higher than the study population average of three previous pups (± 2.6 SD). This novel foraging strategy may have evolved in response to changes in prey availability, and could offer an evolutionary advantage to some individuals that exploit prey resources that others may not. Our observations offer new insight into the foraging behaviours of one of the world’s most studied marine mammals. Further research on the social aspects of Weddell seal behaviour may increase our understanding of the extent and mechanisms of behavioural transfer between conspecifics. Research into the specific foraging behaviour of especially successful or experienced breeders is also warranted.

Growth Mindset in Veterinary Educators: An International Survey.

Carol Dweck's mindset theory describes whether an individual believes that attributes, like intelligence or morality, can be honed (growth mindset) or are innate (fixed mindset). An educator's mindset impacts their approach to teaching, students' learning, participation in faculty development, and well-being. Mindset can affect faculty members' openness to curricular change, making the study of veterinary educator mindset timely and salient, as competency-based education is spurring curricular change worldwide. The purpose of this study was to examine the mindsets of veterinary educators internationally. A survey, consisting of demographic questions and mindset items (based on previously published scales), was distributed electronically to veterinary educators internationally, at universities where English is the primary instruction medium. Mindset was evaluated for the following traits: intelligence, clinical reasoning, compassion, and morality. Scale validation, descriptive statistics, and associations to demographic variables were evaluated. A total of 446 complete surveys were received. Overall, the study population demonstrated predominantly growth mindsets for all traits, higher than population averages, with some variation by trait. There was a small effect on years teaching toward growth mindset. No other associations were found. Veterinary educators internationally who participated in this study demonstrated higher rates of growth mindset than the general population. In other fields, a growth mindset in educators has had implications for faculty well-being, teaching and assessment practices, participation in faculty development, and openness to curricular change. Further research is needed in veterinary education to evaluate the implications of these high rates of growth mindset.

36. Cephalometric Imaging Sheds Light on the Effects of Mandibular Distraction on Infants with Robin Sequence

PURPOSE: Upper airway obstruction (UAO) in infants with Robin Sequence (RS) is secondary to micrognathia and resultant posterior displacement of the tongue. Mandibular distraction osteogenesis (MDO) is a safe and effective treatment for significant UAO, but there is a paucity of data examining associated cephalometric changes. This study carefully examines mandibular cephalometric changes of infants with RS who underwent MDO using internal devices to more deeply understand both immediate and longer-term effects of distraction on mandibular shape. METHODS: Consecutive infant MDO cases (n=53) performed by the same surgeon were analyzed using preoperative and postoperative lateral cephalograms and CT scans of the mandible. Population averages for preoperative and postoperative time points were assessed using a two-sample t-test with equal variance. RESULTS: Significant post-operative morphologic changes were seen in 19 of 21 cephalometric parameters. Length, height, width, and airway parameters improved on average by 20.3 mm (60.7%), 9.8 mm (49.7%), 12.6 mm (36.1%), and 211%, respectively. The majority of cephalometric measurements displayed substantial percent change from the preoperative timepoint to device removal and a much less dramatic percent change from device removal to 6-12 months postoperatively. In fact, none of the parameters measuring mandibular length and angular cephalometrics were significant from device removal to 6-12 months after MDO. CONCLUSION: Cephalometric measurement is a powerful tool that provides a concrete metric to understand how MDO affects not just the immediate but also long-term growth of the mandible. Understanding the more quantifiable effects of mandibular distraction will allow for fine-tuning of surgical practice and optimization of outcomes.