Isotype switching in human memory B cells sets intrinsic antigen-affinity thresholds that dictate antigen-driven fates.

Memory B cells (MBCs) play a critical role in protection against homologous and variant pathogen challenge by either differentiating to plasma cells (PCs) or to germinal center (GC) B cells. The human MBC compartment contains both switched IgG+ and unswitched IgM+ MBCs; however, whether these MBC subpopulations are equivalent in their response to B cell receptor cross-linking and their resulting fates is incompletely understood. Here, we show that IgG+ and IgM+ MBCs can be distinguished based on their response to κ-specific monoclonal antibodies of differing affinities. IgG+ MBCs responded only to high-affinity anti-κ and differentiated almost exclusively toward PC fates. In contrast, IgM+ MBCs were eliminated by apoptosis by high-affinity anti-κ but responded to low-affinity anti-κ by differentiating toward GC B cell fates. These results suggest that IgG+ and IgM+ MBCs may play distinct yet complementary roles in response to pathogen challenge ensuring the immediate production of high-affinity antibodies to homologous and closely related challenges and the generation of variant-specific MBCs through GC reactions.

Quantifying the environmental limits to fire spread in grassy ecosystems.

Modeling fire spread as an infection process is intuitive: An ignition lights a patch of fuel, which infects its neighbor, and so on. Infection models produce nonlinear thresholds, whereby fire spreads only when fuel connectivity and infection probability are sufficiently high. These thresholds are fundamental both to managing fire and to theoretical models of fire spread, whereas applied fire models more often apply quasi-empirical approaches. Here, we resolve this tension by quantifying thresholds in fire spread locally, using field data from individual fires (n = 1,131) in grassy ecosystems across a precipitation gradient (496 to 1,442 mm mean annual precipitation) and evaluating how these scaled regionally (across 533 sites) and across time (1989 to 2012 and 2016 to 2018) using data from Kruger National Park in South Africa. An infection model captured observed patterns in individual fire spread better than competing models. The proportion of the landscape that burned was well described by measurements of grass biomass, fuel moisture, and vapor pressure deficit. Regionally, averaging across variability resulted in quasi-linear patterns. Altogether, results suggest that models aiming to capture fire responses to global change should incorporate nonlinear fire spread thresholds but that linear approximations may sufficiently capture medium-term trends under a stationary climate.

Frequency dependence of human thresholds: both perceptual and vestibuloocular reflex thresholds.

Although perceptual thresholds have been widely studied, vestibuloocular reflex (VOR) thresholds have received less attention, so the relationship between VOR and perceptual thresholds remains unclear. We compared the frequency dependence of human VOR thresholds to human perceptual thresholds for yaw head rotation in both upright ("yaw rotation") and supine ("yaw tilt") positions, using the same human subjects and motion device. VOR thresholds were generally a little smaller than perceptual thresholds. We also found that horizontal VOR thresholds for both yaw rotation about an Earth-vertical axis and yaw tilt (yaw rotation about an Earth-horizontal axis) were relatively constant across four frequencies (0.2, 0.5, 1, and 2 Hz), with little difference between yaw rotation and yaw tilt VOR thresholds. For yaw tilt stimuli, perceptual thresholds were slightly lower at the lowest frequency and nearly constant at all other (higher) frequencies. However, for yaw rotation, perceptual thresholds increased significantly at the lowest frequency (0.2 Hz). We conclude 1) that VOR thresholds were relatively constant across frequency for both yaw rotation and yaw tilt, 2) that the known contributions of velocity storage to the VOR likely yielded these VOR thresholds that were similar for yaw rotation and yaw tilt for all frequencies tested, and 3) that the integration of otolith and horizontal canal signals during yaw tilt when supine contributes to stable perceptual thresholds, especially relative to the low-frequency perceptual thresholds recorded during yaw rotation.NEW & NOTEWORTHY We describe for the first time that human VOR thresholds differ from human forced-choice perceptual thresholds, with the difference especially evident at frequencies below 0.5 Hz. We also report that VOR thresholds are relatively constant across frequency for both yaw rotation and yaw tilt. These findings are consistent with the idea that high-pass filtering in cortical pathways impacts cognitive decision-making.

Dynamic patterning by morphogens illuminated by cis-regulatory studies.

Morphogen concentration changes in space as well as over time during development. However, how these dynamics are interpreted by cells to specify fate is not well understood. Here, we focus on two morphogens: the maternal transcription factors Bicoid and Dorsal, which directly regulate target genes to pattern Drosophila embryos. The actions of these factors at enhancers has been thoroughly dissected and provides a rich platform for understanding direct input by morphogens and their changing roles over time. Importantly, Bicoid and Dorsal do not work alone; we also discuss additional inputs that work with morphogens to control spatiotemporal gene expression in embryos.

Characterizing cancer-related cognitive impairments and impact on quality of life in women with metastatic breast cancer.

PURPOSE: Little is known about cancer-related cognitive impairments (CRCI) in women with metastatic breast cancer (MBC). The purpose of this study is to (1) comprehensively describe CRCI and any associated psychosocial and behavioral symptoms, (2) determine observable sociodemographic and clinical risk factors for CRCI, and (3) explore cognitive and psychosocial predictors of quality of life and social functioning in women living with MBC. METHODS: Using a cross-sectional design, women with MBC completed assessments (objective and subjective measures of CRCI including 3 open-ended questions, measures of psychosocial and behavioral factors, and assessments of quality of life and social function), and data were analyzed using descriptive statistics, qualitative content analysis, correlation analyses, t tests, analysis of variance, and linear regression models. RESULTS: Data from 52 women were analyzed. 69.2% of the sample reported clinically significant CRCI and 46% of the sample scored < 1 standard deviation below the standardized mean on one or more cognitive tests. Those with triple-negative MBC (compared to HER2+), recurrent MBC (compared to de novo), and no history of chemotherapy had worse subjective CRCI, and those without history of surgery and older age had worse objective CRCI. Subjective CRCI, but not objective CRCI, was significantly associated with quality of life and social functioning. CONCLUSION: Subjective and objective CRCI are likely a common problem for those with MBC. Subjective CRCI is associated with poorer quality of life and lower social functioning. Healthcare providers should acknowledge cognitive symptoms, continually assess cognitive function, and address associated unmet needs across the MBC trajectory.

Ethnicity-specific blood pressure thresholds based on cardiovascular and renal complications: a prospective study in the UK Biobank.

BACKGROUND: The appropriateness of hypertension thresholds for triggering action to prevent cardiovascular and renal complications among non-White populations in the UK is subject to question. Our objective was to establish ethnicity-specific systolic blood pressure (SBP) cutoffs for ethnic minority populations and assess the efficacy of these ethnicity-specific cutoffs in predicting adverse outcomes. METHODS: We analyzed data from UK Biobank, which included 444,418 participants from White, South Asian, Black Caribbean, and Black African populations with no history of cardiorenal complications. We fitted Poisson regression models with continuous SBP and ethnic groups, using Whites as the referent category, for the composite outcome of atherosclerotic cardiovascular disease, heart failure, and chronic kidney disease. We determined ethnicity-specific thresholds equivalent to the risks observed in Whites at SBP levels of 120, 130, and 140 mm Hg. We adjusted models for clinical characteristics, sociodemographic factors, and behavioral factors. The performance of ethnicity-specific thresholds for predicting adverse outcomes and associated population-attributable fraction (PAF) was assessed in ethnic minority groups. RESULTS: After a median follow-up of 12.5 years (interquartile range, 11.7-13.2), 32,662 (7.4%) participants had incident composite outcomes. At any given SBP, the predicted incidence rate of the composite outcome was the highest for South Asians, followed by White, Black Caribbean, and Black African. For an equivalent risk of outcomes observed in the White population at an SBP level of 140 mm Hg, the SBP threshold was lower for South Asians (123 mm Hg) and higher for Black Caribbean (156 mm Hg) and Black African (165 mm Hg). Furthermore, hypertension defined by ethnicity-specific thresholds was a stronger predictor and resulted in a larger PAF for composite outcomes in South Asians (21.5% [95% CI, 2.4,36.9] vs. 11.3% [95% CI, 2.6,19.1]) and Black Africans (7.1% [95% CI, 0.2,14.0] vs. 5.7 [95% CI, -16.2,23.5]) compared to hypertension defined by guideline-recommended thresholds. CONCLUSIONS: Guideline-recommended blood pressure thresholds may overestimate risks for the Black population and underestimate risks for South Asians. Using ethnicity-specific SBP thresholds may improve risk estimation and optimize hypertension management toward the goal of eliminating ethnic disparities in cardiorenal complications.

Experimental validation of a PNS-optimized whole-body gradient coil.

PURPOSE: Peripheral nerve stimulation (PNS) limits the usability of state-of-the-art whole-body and head-only MRI gradient coils. We used detailed electromagnetic and neurodynamic modeling to set an explicit PNS constraint during the design of a whole-body gradient coil and constructed it to compare the predicted and experimentally measured PNS thresholds to those of a matched design without PNS constraints. METHODS: We designed, constructed, and tested two actively shielded whole-body Y-axis gradient coil winding patterns: YG1 is a conventional symmetric design without PNS-optimization, whereas YG2's design used an additional constraint on the allowable PNS threshold in the head-imaging landmark, yielding an asymmetric winding pattern. We measured PNS thresholds in 18 healthy subjects at five landmark positions (head, cardiac, abdominal, pelvic, and knee). RESULTS: The PNS-optimized design YG2 achieved 46% higher average experimental thresholds for a head-imaging landmark than YG1 while incurring a 15% inductance penalty. For cardiac, pelvic, and knee imaging landmarks, the PNS thresholds increased between +22% and +35%. For abdominal imaging, PNS thresholds did not change significantly between YG1 and YG2 (-3.6%). The agreement between predicted and experimental PNS thresholds was within 11.4% normalized root mean square error for both coils and all landmarks. The PNS model also produced plausible predictions of the stimulation sites when compared to the sites of perception reported by the subjects. CONCLUSION: The PNS-optimization improved the PNS thresholds for the target scan landmark as well as most other studied landmarks, potentially yielding a significant improvement in image encoding performance that can be safely used in humans.

30 years with the Knee injury and Osteoarthritis Outcome Score (KOOS).

This narrative review describes the development and use of patient-reported outcomes over 30 years, focusing on the Knee injury and Osteoarthritis Outcome Score (KOOS). KOOS is a five-subscale patient-reported instrument intended for use from the time of knee injury to the development of osteoarthritis. Numerous studies have confirmed that the psychometric properties of the KOOS and its short-form KOOS-12 are acceptable. More recent research has focused on the use and interpretation of KOOS scores in clinical trials using thresholds, such as minimal important differences, patient-acceptable symptom states, and treatment failure. As an indication of KOOS's popularity, the total 3854 PubMed results for KOOS have increased exponentially since the first KOOS paper was published 25 years ago and now seem to have plateaued at around 650 annually. The selected articles are not based on a systematic search, but on the author's own publications, reading, and literature search that grew organically from that.

The incremental risk of fragility fractures in aging men.

INTRODUCTION: While the United States Preventative Services Task Force recommends osteoporosis screening for women 65 years and older, there is no definitive recommendation for routine osteoporosis screening in men. The purpose of this study was to determine the age at which the odds of fragility fractures (FFx) increase in men to help guide future policy discussions evaluating an optimal screening strategy in this population. METHODS: Men older than 49 years were identified in the PearlDiver Patient Records Database. Patients were excluded if they had a prior fragility fracture, if they were at high risk for osteoporosis due to comorbidities, or if they carried a diagnosis of and/or were on treatment for osteoporosis. The prevalence of FFx was trended for each age group. A stratum-specific likelihood ratio (SSLR) analysis was conducted to identify data-driven strata that maximize the incremental FFx risk by age for men. Logistic regression analyses controlling for potential confounders were conducted to test these identified strata. RESULTS: The incidence of FFx started to increase after the age of 64 years for men. Further, the identified data-driven age strata associated with a significant and incremental difference in fragility fractures were the following: 50-64, 65-69, 70-72, 73-75, 76-78, 79-80, and 81+. When compared to the youngest age stratum (50-64 years), multivariable regression showed the risk of fragility fracture incrementally increased starting in those aged 70-72 (RR, 1.31; 95% CI. 1.21-1.46; p < 0.001) with the highest risk in those aged 81+ (RR, 5.35; 95% CI, 5.10-5.62; p < 0.001). CONCLUSION: In men without a pre-existing history of osteoporosis, the risk of fragility fractures starts to increase after the age of 70. Further work building upon these data may help to identify a specific age at which routine bone health screening in males can help to minimize fractures and their associated morbidity and mortality.

Unearthing the soil-borne microbiome of land plants.

Plant-soil biodiversity interactions are fundamental for the functioning of terrestrial ecosystems. Yet, the existence of a set of globally distributed topsoil microbial and small invertebrate organisms consistently associated with land plants (i.e., their consistent soil-borne microbiome), together with the environmental preferences and functional capabilities of these organisms, remains unknown. We conducted a standardized field survey under 150 species of land plants, including 58 species of bryophytes and 92 of vascular plants, across 124 locations from all continents. We found that, despite the immense biodiversity of soil organisms, the land plants evaluated only shared a small fraction (less than 1%) of all microbial and invertebrate taxa that were present across contrasting climatic and soil conditions and vegetation types. These consistent taxa were dominated by generalist decomposers and phagotrophs and their presence was positively correlated with the abundance of functional genes linked to mineralization. Finally, we showed that crossing environmental thresholds in aridity (aridity index of 0.65, i.e., the transition from mesic to dry ecosystems), soil pH (5.5; i.e., the transition from acidic to strongly acidic soils), and carbon (less than 2%, the lower limit of fertile soils) can result in drastic disruptions in the associations between land plants and soil organisms, with potential implications for the delivery of soil ecosystem processes under ongoing global environmental change.

Increased crossing of thermal stress thresholds of vegetation under global warming.

Temperature extremes exert a significant influence on terrestrial ecosystems, but the precise levels at which these extremes trigger adverse shifts in vegetation productivity have remained elusive. In this study, we have derived two critical thresholds, using standard deviations (SDs) of growing-season temperature and satellite-based vegetation productivity as key indicators. Our findings reveal that, on average, vegetation productivity experiences rapid suppression when confronted with temperature anomalies exceeding 1.45 SD above the mean temperature during 2001-2018. Furthermore, at temperatures exceeding 2.98 SD above the mean, we observe the maximum level of suppression, particularly in response to the most extreme high-temperature events. When Earth System Models are driven by a future medium emission scenario, they project that mean temperatures will routinely surpass both of these critical thresholds by approximately the years 2050 and 2070, respectively. However, it is important to note that the timing of these threshold crossings exhibits spatial variation and will appear much earlier in tropical regions. Our finding highlights that restricting global warming to just 1.5°C can increase safe areas for vegetation growth by 13% compared to allowing warming to reach 2°C above preindustrial levels. This mitigation strategy helps avoid exposure to detrimental extreme temperatures that breach these thresholds. Our study underscores the pivotal role of climate mitigation policies in fostering the sustainable development of terrestrial ecosystems in a warming world.

Comparing environmental impacts of deep-seabed and land-based mining: A defensible framework.

The crises of climate change and biodiversity loss are interlinked and must be addressed jointly. A proposed solution for reducing reliance on fossil fuels, and thus mitigating climate change, is the transition from conventional combustion-engine to electric vehicles. This transition currently requires additional mineral resources, such as nickel and cobalt used in car batteries, presently obtained from land-based mines. Most options to meet this demand are associated with some biodiversity loss. One proposal is to mine the deep seabed, a vast, relatively pristine and mostly unexplored region of our planet. Few comparisons of environmental impacts of solely expanding land-based mining versus extending mining to the deep seabed for the additional resources exist and for biodiversity only qualitative. Here, we present a framework that facilitates a holistic comparison of relative ecosystem impacts by mining, using empirical data from relevant environmental metrics. This framework (Environmental Impact Wheel) includes a suite of physicochemical and biological components, rather than a few selected metrics, surrogates, or proxies. It is modified from the "recovery wheel" presented in the International Standards for the Practice of Ecological Restoration to address impacts rather than recovery. The wheel includes six attributes (physical condition, community composition, structural diversity, ecosystem function, external exchanges and absence of threats). Each has 3-5 sub attributes, in turn measured with several indicators. The framework includes five steps: (1) identifying geographic scope; (2) identifying relevant spatiotemporal scales; (3) selecting relevant indicators for each sub-attribute; (4) aggregating changes in indicators to scores; and (5) generating Environmental Impact Wheels for targeted comparisons. To move forward comparisons of land-based with deep seabed mining, thresholds of the indicators that reflect the range in severity of environmental impacts are needed. Indicators should be based on clearly articulated environmental goals, with objectives and targets that are specific, measurable, achievable, relevant, and time bound.

Structural alterations and pain perception at the ankle joint in patients with haemophilia.

BACKGROUND: Patients with haemophilia (PwH) suffer from chronic pain due to joint alterations induced by recurring haemorrhage. OBJECTIVES: This study aimed to investigate the relationship between structural alterations and pain perception at the ankle joint in PwH. PATIENTS/METHODS: Ankle joints of 79 PwH and 57 healthy controls (Con) underwent ultrasound examination (US) and assessment of pain sensitivity via pressure pain thresholds (PPT). US discriminated between joint activity (synovitis) and joint damage (cartilage and/or bone degeneration) applying the HEAD-US protocol. Based on US-findings, five subgroups were built: PwH with activity/damage, PwH with activity/no damage, PwH with no activity/no damage, controls with activity/no damage and controls with no activity/no damage. RESULTS: Joint activity and joint damage were significantly increased in ankles of PwH compared to Con (p ≤.001). Subgroup analysis revealed that structural alterations negatively impact pain perception. This is particularly evident when comparing PwH with both activity/damage to PwH with no activity/no damage at the tibiotalar joint (p = .001). At the fibulotalar joint, no significant differences were observed between PwH subgroups. Further analysis showed that both joint activity and joint damage result in an increase in pain sensitivity (p ≤.001). CONCLUSION: The data suggest a relation between joint activity, joint damage and pain perception in PwH. Even minor changes due to synovitis appear to affect pain perception, with the effect not intensifying at higher levels of inflammation. In terms of joint damage, severe degeneration leads to a sensitised pain state most robustly, whereas initial changes do not seem to significantly affect pain perception.

Evaluation of malaria outbreak detection methods, Uganda, 2022.

BACKGROUND: Malaria outbreaks are detected by applying the World Health Organization (WHO)-recommended thresholds (the less sensitive 75th percentile or mean + 2 standard deviations [2SD] for medium-to high-transmission areas, and the more sensitive cumulative sum [C-SUM] method for low and very low-transmission areas). During 2022, > 50% of districts in Uganda were in an epidemic mode according to the 75th percentile method used, resulting in a need to restrict national response to districts with the highest rates of complicated malaria. The three threshold approaches were evaluated to compare their outbreak-signaling outputs and help identify prioritization approaches and method appropriateness across Uganda. METHODS: The three methods were applied as well as adjusted approaches (85th percentile and C-SUM + 2SD) for all weeks in 2022 for 16 districts with good reporting rates ( ≥ 80%). Districts were selected from regions originally categorized as very low, low, medium, and high transmission; district thresholds were calculated based on 2017-2021 data and re-categorized them for this analysis. RESULTS: Using district-level data to categorize transmission levels resulted in re-categorization of 8/16 districts from their original transmission level categories. In all districts, more outbreak weeks were detected by the 75th percentile than the mean + 2SD method (p < 0.001). For all 9 very low or low-transmission districts, the number of outbreak weeks detected by C-SUM were similar to those detected by the 75th percentile. On adjustment of the 75th percentile method to the 85th percentile, there was no significant difference in the number of outbreak weeks detected for medium and low transmission districts. The number of outbreak weeks detected by C-SUM + 2SD was similar to those detected by the mean + 2SD method for all districts across all transmission intensities. CONCLUSION: District data may be more appropriate than regional data to categorize malaria transmission and choose epidemic threshold approaches. The 75th percentile method, meant for medium- to high-transmission areas, was as sensitive as C-SUM for low- and very low-transmission areas. For medium and high-transmission areas, more outbreak weeks were detected with the 75th percentile than the mean + 2SD method. Using the 75th percentile method for outbreak detection in all areas and the mean + 2SD for prioritization of medium- and high-transmission areas in response may be helpful.

A Review of Meaningful Change Thresholds for EORTC QLQ-C30 and FACT-G Within Oncology.

OBJECTIVES: This literature review provides an overview of meaningful change thresholds for the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (QLQ-C30) and the Functional Assessment of Cancer Therapy - General (FACT-G) used across hematological cancers and solid tumors (melanoma, lung, bladder, and prostate). METHODS: Embase, MEDLINE, and PubMed were searched to identify relevant oncology publications from 2016 to 2021. Label claims from the US Food and Drug Administration and the European Medicines Agency for 7 recently approved drugs (pembrolizumab, atezolizumab, glasdegib, gilteritinib, tisagenlecleucel, axicabtagene ciloleucel, and daratumumab plus hyaluronidase-fihj) were reviewed. RESULTS: Publications providing guidance on meaningful change thresholds for the QLQ-C30 displayed a growing trend away from broad "legacy" thresholds of 10 points for all QLQ-C30 scales), toward deriving "contemporary" thresholds (eg, subscale specific, population specific). Contemporary publications generally provide guidance on selecting thresholds for specific scales that account for improved or worsening thresholds (eg, QLQ-C30 subscales). This trend was not clear for FACT-G, with less new guidance available. Most clinical trials used in regulatory label submissions have used thresholds of 10 points for the QLQ-C30 subscales and 3 to 7 points for the FACT-G total score. Despite the availability of more recent guidelines, contemporary meaningful change thresholds seem slow to emerge in the published literature and regulatory labels. CONCLUSIONS: Trialists should consider using contemporary thresholds, rather than legacy thresholds, for QLQ-C30 endpoints. Thresholds derived for a similar patient-population should be used where available. Further work is required to provide these across a broader range of cancer sites.

Accuracy of second and third molar maturity indices, Olze, Haavikko, and Demirjian methods for 14- and 16-year-old age thresholds assessment in Croatian children and adolescents.

This study explores the reliability of four established legal age threshold estimation approaches in a Croatian sample. We applied Haavikko stages, Demirjian stages, Olze's third molar eruption stages, and second and third molar maturity indices measurement in 593 orthopantomograms of Croatian children and adolescents aged 11.00-20.99 years old. The left mandibular second and third molar were assessed. Logistic regression analysis was conducted to test the significance of predictive variables. Logistic Receiver operating characteristic (ROC) curves were performed to evaluate the classification ability of variables for estimating 14- and 16-year-old thresholds. The areas under the ROC curve (AUC), accuracy (Acc), sensitivity (Se), specificity (Sp), Positive Likelihood Ratio (LR +), Negative Likelihood Ratio (LR-), and Bayes post-test probability (Bayes PTP) were calculated to evaluate classification performance. Results suggest that the combination of I2M&I3M is the best classifier for the 14-year-old threshold (AUC = 0.879); for males alone, I2M is an even better classifier (AUC = 0.881). The highest Acc 80.1% (95%CI, 75.9%-83.9%), Bayes PTP 86.5% (95%CI, 82.8%-89.7%) and Sp 88.9% (95%CI, 83.0%-93.3%) were by I3M < 0.81 & I2M < 0.03 in total samples; the highest Acc 86.1% (80.6%- 90.6%), Bayes PTP 87.2% (95%CI, 81.7%- 91.4%) and Sp 87.8% (95%CI, 78.2%- 94.3%) were by I2M < 0.01 in males, Acc of Haavikko Ac and Demirjian H stage in second molar is very close with slightly lower Bayes PTP and Sp. I3M is a good classifier for 16-year-old threshold (AUC = 0.889). The cut-off value I3M < 0.34 can be used to classify the 16-year-old threshold with Acc of 80.6% (95%CI, 77.2%-83.7%), Sp of 83.4% (95%CI, 79.0%-87.3%), and 81.7% (95%CI, 78.4%-84.8%) Bayes PTP. In conclusion, to classify the 14-year-old threshold, a pair of cut-off values I3M < 0.81 & I2M < 0.03 can be used in Croatian females; I2M < 0.01, Demirjian H stage, Haavikko Ac stage in second molar, and the pair I3M < 0.81 & I2M < 0.03 can all be used in Croatian males. I3M < 0.34 can classify the 16-year-old threshold in Croatian populations.

Chronological age estimation based on dental mineralization for Syrian population.

Dental age assessment based on evaluating dental mineralization status is one of the most common methods used in forensic practice. The aim of this study is to enhance the accuracy of age diagnostics and provide reference data from the Syrian population for forensic application. After several selection steps, a total of 280 orthopantomograms (OPGs) from 140 males and 140 females from the Syrian population divided into 14 age groups between 12 and 25 years were analysed. Based on Demirjian's classification system, the mineralization stages of third molars (18, 28, 38 and 48) as well as lower second molars (37 and 47) were evaluated. Statistical investigations and evaluations were carried out to estimate the marginal probabilities of the subjects having attained ages 14 and 18 by generalized estimating equation models. Our results show that no significant differences can be revealed in the mineralization status with respect to jaw side and sex. In the Syrian population, third molars showing mineralization stage G provide evidence of reaching the age of 14 years with the highest standard of proof ("beyond reasonable doubt"). A completed mineralization in lower second molars (stage H) provides very high marginal probabilities (more than 90%) of the subjects having attained age 14 years. Nevertheless, this cannot exclude an age under 14 years. For the age threshold of 18 years, third molars showing incomplete root development (G dental stage or lower) are associated with a low probability (less than 40%) of the subject having reached 18 years of age. A person's probability of having attained 18 years of age is very high (82- 95%) when the roots of third molars are fully developed (stage H). Nevertheless, third molars at stage H do not conclusively exclude an age under 18 years.

Vestibular contributions to linear motion perception.

Vestibular contributions to linear motion (i.e., translation) perception mediated by the otoliths have yet to be fully characterized. To quantify the maximal extent that non-vestibular cues can contribute to translation perception, we assessed vestibular perceptual thresholds in two patients with complete bilateral vestibular ablation to compare to our data in 12 young (< 40 years), healthy controls. Vestibular thresholds were assessed for naso-occipital ("x-translation"), inter-aural ("y-translation"), and superior-inferior ("z-translation") translations in three body orientations (upright, supine, side-lying). Overall, in our patients with bilateral complete vestibular loss, thresholds were elevated ~ 2-45 times relative to healthy controls. No systematic differences in vestibular perceptual thresholds were noted between motions that differed only with respect to their orientation relative to the head (i.e., otoliths) in patients with bilateral vestibular loss. In addition, bilateral loss patients tended to show a larger impairment in the perception of earth-vertical translations (i.e., motion parallel to gravity) relative to earth-horizontal translations, which suggests increased contribution of the vestibular system for earth-vertical motions. However, differences were also noted between the two patients. Finally, with the exception of side-lying x-translations, no consistent effects of body orientation in our bilateral loss patients were seen independent from those resulting from changes in the plane of translation relative to gravity. Overall, our data confirm predominant vestibular contributions to whole-body direction-recognition translation tasks and provide fundamental insights into vestibular contributions to translation motion perception.

Magnitude of Urine Albumin and KIM-1 Changes Can be Used to Differentiate Glomerular Injury From Tubular Injury in Rats.

Emerging urinary kidney safety biomarkers have been evaluated in recent years and have been shown to be superior to the serum parameters blood urea nitrogen (BUN) and creatinine (sCr) for monitoring kidney injury in the proximal tubule. However, their potential application in differentiating the location of the initial kidney injury (eg, glomerulus vs tubule) has not been fully explored. Here, we assessed the performance of two algorithms that were constructed using either an empirical or a mathematical model to predict the site of kidney injury using a data set consisting of 22 rat kidney toxicity studies with known urine biomarker and histopathologic outcomes. Two kidney safety biomarkers used in both models, kidney injury molecule 1 (KIM-1) and albumin (ALB), were the best performers to differentiate glomerular injury from tubular injury. The performance of algorithms using these two biomarkers against the gold standard of kidney histopathologic examination showed high sensitivity in differentiating the location of the kidney damage to either the glomerulus or the proximal tubules. These data support the exploration of such an approach for use in clinical settings, leveraging urinary biomarker data to aid in the diagnosis of either glomerular or tubular injury where histopathologic assessments are not conducted.

Alternatives Exert Higher Health Risks than Bisphenol A on Indo-Pacific Humpback Dolphins.

The detrimental effects of bisphenol (BP) exposure are a concern for vulnerable species, Indo-Pacific humpback dolphins (Sousa chinensis). To investigate the characteristics of BP profiles and their adverse impact on humpback dolphins, we assessed the concentrations of six BPs, including bisphenol A (BPA), bisphenol S (BPS), bisphenol F (BPF), bisphenol AF (BPAF), bisphenol B (BPB), and bisphenol P (BPP) in blubber (n = 26) and kidney (n = 12) of humpback dolphins stranded in the Pearl River Estuary, China. BPS accounted for the largest proportion of the total bisphenols (∑BPs) in blubber (55%) and kidney (69%). The concentration of ∑BP in blubber was significantly higher than that in the kidney and liver. The EC50 values of five BPA alternatives were lower than those of BPA in humpback dolphin skin fibroblasts (ScSF) and human skin fibroblasts (HSF). ScSF was more sensitive to BPS, BPAF, BPB, and BPP than HSF. The enrichment pathway of BPA was found to be associated with inflammation and immune dysregulation, while BPP and BPS demonstrated a preference for genotoxicity. BPA, BPP, and BPS, which had risk quotients (RQs) > 1, were found to contribute to subhealth and chronic disease in humpback dolphins. According to the EC50-based risk assessment, BPS poses a higher health risk than BPA for humpback dolphins. This study successfully evaluated the risks of bisphenols in rare and endangered cetacean cell lines using a noninvasive method. More in vivo and in field observations are necessary to know whether the BPA alternatives are likely to be regrettable substitutions.