Lower total cholesterol and triglyceride levels in ankylosing spondylitis than non-inflammatory rheumatic disease controls in a 1978-98 study: a potential effect of increased physical energetics in manual occupations in the pre-2000 chronologic era.

OBJECTIVES: No article on serum lipids in ankylosing spondylitis (AS) and control subjects has been reported from USA. The primary aim of this study was to determine if any difference occurred in serum lipid levels in AS and control rheumatic disorders in two time periods, 1978-98 and 2000-10. The secondary aim was to investigate variables associated with lipid levels and if a difference was found between AS and control disorders. METHODS: The AS patients were compared to non-inflammatory rheumatic disorders (NIRDs) in 1978-98 and 2000-10 surveys and to rheumatoid arthritis (RA) in the 2000-10 survey. Patients were matched within 5 years of age, sex, and clinic or hospital source. RESULTS: In the 1978-98 survey, entry mean (SEM) serum cholesterol level [mg/dL] was highly (p<0.001) significantly lower in 69 AS [179.0 (4.8)] than 69 matched NIRD controls [208.0 (5.6)]. In 29 pairs of AS and NIRD subjects having manual labour occupations, mean (SEM) cholesterol level was additionally lower in AS [156.7 (5.9)] and higher in 29 NIRD controls [213.3 (8.6)] (p<0.001). In manual labour workers, mean (SEM) serum triglyceride was significantly lower (p=0.004) in 15 AS [110.3 (14.1)] than 14 NIRD controls [185.2 (19.3)]. In the 2000-10 survey, no lipid difference was found between AS vs. NIRD control patients. CONCLUSIONS: In the 1978-98 survey, AS had significantly lower mean serum cholesterol and triglyceride levels than NIRD control patients. Associated manual labour occupations may have significantly contributed to results, possibly related to increased energy expenditures from physical activity in the pre-2000 era.

Conserved chromatin and repetitive patterns reveal slow genome evolution in frogs.

Frogs are an ecologically diverse and phylogenetically ancient group of anuran amphibians that include important vertebrate cell and developmental model systems, notably the genus Xenopus. Here we report a high-quality reference genome sequence for the western clawed frog, Xenopus tropicalis, along with draft chromosome-scale sequences of three distantly related emerging model frog species, Eleutherodactylus coqui, Engystomops pustulosus, and Hymenochirus boettgeri. Frog chromosomes have remained remarkably stable since the Mesozoic Era, with limited Robertsonian (i.e., arm-preserving) translocations and end-to-end fusions found among the smaller chromosomes. Conservation of synteny includes conservation of centromere locations, marked by centromeric tandem repeats associated with Cenp-a binding surrounded by pericentromeric LINE/L1 elements. This work explores the structure of chromosomes across frogs, using a dense meiotic linkage map for X. tropicalis and chromatin conformation capture (Hi-C) data for all species. Abundant satellite repeats occupy the unusually long (~20 megabase) terminal regions of each chromosome that coincide with high rates of recombination. Both embryonic and differentiated cells show reproducible associations of centromeric chromatin and of telomeres, reflecting a Rabl-like configuration. Our comparative analyses reveal 13 conserved ancestral anuran chromosomes from which contemporary frog genomes were constructed.

Female Preferences for More Elaborate Signals Are an Emergent Outcome of Male Chorusing Interactions in Túngara Frogs.

AbstractIn chorusing species, conspecific interference exerts strong selection on signal form and timing to maximize conspicuousness and attractiveness within the signaling milieu. We investigated how túngara frog calling strategies were influenced by varied social environments and male phenotypes and how calling interactions influenced female preferences. When chorusing, túngara frog calls consist of a whine typically followed by one to three chucks. In experimental choruses we saw that as chorus size increased, calls increasingly had their chucks overlapped by the high-amplitude beginning section of other callers' whines. Playback experiments revealed that such overlap reduced the attractiveness of calls to females but that appending additional chucks mitigated this effect. Thus, more elaborate calls were preferred when calls suffered overlap, although they were not preferred when overlap was absent. In response to increasing risk of overlap in larger choruses, males increased call elaboration. However, males overwhelmingly produced two-chuck calls in even the largest choruses, despite our results suggesting that additional chucks would more effectively safeguard calls. Furthermore, aspects of male phenotypes predicted to limit call elaboration had negligible or uncertain effects, suggesting that other constraints are operating. These results highlight how complex interrelations among signal form, signaling interactions, and the social environment shape the evolution of communication in social species.

Circular RNAs and acute kidney injury: a clinical science commentary on Cao et al.

Acute kidney injury (AKI) remains a significant clinical problem with a high mortality rate. Thus, the need for early recognition and treatment of AKI is an important goal. Clinical Science has a history of publishing high impact work across a breadth of scientific disciplines to improve understanding of disease mechanisms, including nephrology. This commentary spotlights a paper from more recent history that is highly cited. The work focuses on the mechanistic role of circular RNA in the pathobiology of AKI using approaches that include both in vivo experimental models and human cell culture experiments to delineate a potentially novel cellular pathway.

Cardiovascular research at the Heart of Clinical Science.

Clinical Science was originally established as the journal Heart in 1909 by Sir Thomas Lewis and Sir James Mackenzie. Heart was an influential journal publishing cardiovascular research and was renamed Clinical Science in 1933 to attract broader research interests. Nevertheless, cardiovascular research contributions remain a foundational part of the journal to this day. This editorial provides historical perspective on the journal's cardiovascular origins and includes data related to cardiovascular publications from the past decade. Clinical Science is committed to publishing leading cardiovascular research from the field and looks forward to receiving your submission.

Artificial Intelligence for Automated Implant Identification in Total Hip Arthroplasty: A Multicenter External Validation Study Exceeding Two Million Plain Radiographs.

BACKGROUND: The surgical management of complications after total hip arthroplasty (THA) necessitates accurate identification of the femoral implant manufacturer and model. Automated image processing using deep learning has been previously developed and internally validated; however, external validation is necessary prior to responsible application of artificial intelligence (AI)-based technologies. METHODS: We trained, validated, and externally tested a deep learning system to classify femoral-sided THA implants as one of the 8 models from 2 manufacturers derived from 2,954 original, deidentified, retrospectively collected anteroposterior plain radiographs across 3 academic referral centers and 13 surgeons. From these radiographs, 2,117 were used for training, 249 for validation, and 588 for external testing. Augmentation was applied to the training set (n = 2,117,000) to increase model robustness. Performance was evaluated by area under the receiver operating characteristic curve, sensitivity, specificity, and accuracy. Implant identification processing speed was calculated. RESULTS: The training and testing sets were drawn from statistically different populations of implants (P < .001). After 1,000 training epochs by the deep learning system, the system discriminated 8 implant models with a mean area under the receiver operating characteristic curve of 0.991, accuracy of 97.9%, sensitivity of 88.6%, and specificity of 98.9% in the external testing dataset of 588 anteroposterior radiographs. The software classified implants at a mean speed of 0.02 seconds per image. CONCLUSION: An AI-based software demonstrated excellent internal and external validation. Although continued surveillance is necessary with implant library expansion, this software represents responsible and meaningful clinical application of AI with immediate potential to globally scale and assist in preoperative planning prior to revision THA.

Postcranial description of Wendiceratops pinhornensis and a taphonomic analysis of the oldest monodominant ceratopsid bonebed.

The early centrosaurine ceratopsid, Wendiceratops pinhornensis, was discovered in Alberta, Canada in a medium density monodominant bonebed from the Oldman Formation (mid-Campanian, ~79 Ma). The bonebed contains abundant, well-preserved, adult-sized and some juvenile-sized postcranial material, allowing for the first description of a number of elements of the postcrania of this basal centrosaurine ceratopsid. The postcranial elements described are generally consistent with postcrania described for more derived centrosaurine taxa. However the rectangular-shaped distal terminus of the ischium previously considered to be an apomorphy of Wendiceratops. is shown to also be present in Medusaceratops, and thus may be a synapomorphy of basal centrsaurines. The bonebed represents a lag deposit within a mudstone-bearing overbank facies and contains individuals from multiple age classes. It contains over 95% ceratopsid remains, with all identifiable elements referable to Wendiceratops. The elements are completely disarticulated, but have undergone little weathering or abrasion (both Stage 0), although the ends of long bones and processes capped by cartilage in life frequently exhibit evidence of wet rot and breakage by hydrological reworking after decomposition. The taphonomy of the bonebed is consist with other monodominant centrosaurine bonebeds that have been interpreted as mass death assemblages preserving evidence of gregarious (herding) behavior. At approximately 79 million years old, the Wendiceratops bonebed is approximately two million years older than other ceratopsid bonebeds indicating that this bonebed is the oldest documented evidence of herding behavior in a ceratopsid.

Fifty years of impact on treating bone disease: a commentary on Gasser et al.

The precise control of whole-body calcium is essential for the maintenance of normal physiological function. Disruptions in calcium homeostasis can lead to pathology including osteoporosis, kidney stone formation, and cardiac arrythmias. During the 1960s and early 1970s, a full understanding of calcium metabolism was still emerging. This commentary spotlights a seminal Clinical Science paper published in 1972 that significantly advanced the field and contributed to the eventual approval of bisphosphonate drugs commonly used to treat postmenopausal osteoporosis, cancer metastases, and other calcium disorders.

Epithelial sodium channels in macrophage migration and polarization: role of proinflammatory cytokines TNFα and IFNγ.

Migration of monocytes-macrophages plays an important role in phagocytosis of pathogens and cellular debris in a variety of pathophysiological conditions. Although epithelial Na+ channels (ENaCs) are required for normal migratory responses in other cell types, their role in macrophage migration signaling is unknown. To address this possibility, we determined whether ENaC message is present in several peripheral blood monocyte cell populations and tissue-resident macrophages in healthy humans using the Human Protein Atlas database (www.proteinatlas.org) and the mouse monocyte cell line RAW 264.7 using RT-PCR. We then determined that selective ENaC inhibition with amiloride inhibited chemotactic migration (∼50%), but not phagocytosis, of the mouse monocyte-macrophage cell line RAW 264.7. Furthermore, we generated a cell line stably expressing an NH2-terminal truncated αENaC to interrupt normal channel trafficking and found it suppressed migration. Prolonged exposure (48 h) of RAW 264.7 cells to proinflammatory cytokines interferon γ (IFNγ) and/or tumor necrosis factor α (TNFα) inhibited RAW 264.7 migration and abolished the amiloride (1 µM)-sensitive component of migration, a finding consistent with ENaC downregulation. To determine if proinflammatory cytokines regulate αENaC protein expression, cells were exposed to proinflammatory cytokines IFNγ (10 ng/mL, last 48 h) and TNFα (10 ng/mL, last 24 h). By Western blot analysis, we found whole cell αENaC protein is reduced ≥50%. Immunofluorescence demonstrated heterogeneous αENaC inhibition. Finally, we found that overnight exposure to amiloride stimulated morphological changes and increased polarization marker expression. Our findings suggest that ENaC may be a critical molecule in macrophage migration and polarization.

The appendicular myology of Stegoceras validum (Ornithischia: Pachycephalosauridae) and implications for the head-butting hypothesis.

In this study, we use an exceptional skeleton of the pachycephalosaur Stegoceras validum (UALVP 2) to inform a comprehensive appendicular muscle reconstruction of the animal, with the goal of better understanding the functional morphology of the pachycephalosaur postcranial skeleton. We find that S. validum possessed a conservative forelimb musculature, particularly in comparison to early saurischian bipeds. By contrast, the pelvic and hind limb musculature are more derived, reflecting peculiarities of the underlying skeletal anatomy. The iliotibialis, ischiocaudalis, and caudofemoralis muscles have enlarged attachment sites and the caudofemoralis has greater leverage owing to the distal displacement of the fourth trochanter along the femur. These larger muscles, in combination with the wide pelvis and stout hind limbs, produced a stronger, more stable pelvic structure that would have proved advantageous during hypothesized intraspecific head-butting contests. The pelvis may have been further stabilized by enlarged sacroiliac ligaments, which stemmed from the unique medial iliac flange of the pachycephalosaurs. Although the pubis of UALVP 2 is not preserved, the pubes of other pachycephalosaurs are highly reduced. The puboischiofemoralis musculature was likely also reduced accordingly, and compensated for by the aforementioned improved pelvic musculature.

Is there a role of proinflammatory cytokines on degenerin-mediated cerebrovascular function in preeclampsia?

Preeclampsia (PE) is associated with adverse cerebrovascular effects during and following parturition including stroke, small vessel disease, and vascular dementia. A potential contributing factor to the cerebrovascular dysfunction is the loss of cerebral blood flow (CBF) autoregulation. Autoregulation is the maintenance of CBF to meet local demands with changes in perfusion pressure. When perfusion pressure rises, vasoconstriction of cerebral arteries and arterioles maintains flow and prevents the transfer of higher systemic pressure to downstream microvasculature. In the face of concurrent hypertension, loss of autoregulatory control exposes small delicate microvessels to injury from elevated systemic blood pressure. While placental ischemia is considered the initiating event in the preeclamptic cascade, the factor(s) mediating cerebrovascular dysfunction are poorly understood. Elevated plasma proinflammatory cytokines, such as tumor necrosis factor α (TNF-α) and interleukin-17 (IL-17), are potential mediators of autoregulatory loss. Impaired CBF responses to increases in systemic pressure are attributed to the impaired pressure-induced (myogenic) constriction of small cerebral arteries and arterioles in PE. Myogenic vasoconstriction is initiated by pressure-induced vascular smooth muscle cell (VSMC) stretch. Recent studies from our laboratory group indicate that proinflammatory cytokines impair the myogenic mechanism of CBF autoregulation via inhibition of vascular degenerin proteins, putative mediators of myogenic constriction in VSMCs. This brief review links studies showing the effect of proinflammatory cytokines on degenerin expression and CBF autoregulation to the pathological cerebral consequences of preeclampsia.

Cross-modal facilitation of auditory discrimination in a frog.

Stimulation in one sensory modality can affect perception in a separate modality, resulting in diverse effects including illusions in humans. This can also result in cross-modal facilitation, a process where sensory performance in one modality is improved by stimulation in another modality. For instance, a simple sound can improve performance in a visual task in both humans and cats. However, the range of contexts and underlying mechanisms that evoke such facilitation effects remain poorly understood. Here, we demonstrated cross-modal stimulation in wild-caught túngara frogs, a species with well-studied acoustic preferences in females. We first identified that a combined visual and seismic cue (vocal sac movement and water ripple) was behaviourally relevant for females choosing between two courtship calls in a phonotaxis assay. We then found that this combined cross-modal stimulus rescued a species-typical acoustic preference in the presence of background noise that otherwise abolished the preference. These results highlight how cross-modal stimulation can prime attention in receivers to improve performance during decision-making. With this, we provide the foundation for future work uncovering the processes and conditions that promote cross-modal facilitation effects.

Long-term memory in frog-eating bats.

Long-term memory has clear advantages for animals but also has neurological and behavioral costs1-3. Encoding memories is metabolically expensive1. Older memories can interfere with retrieval of more recent memories3, prolong decision-making and reduce cognitive flexibility2,3. Given these opposing selection pressures, understanding how long memories last can shed light on how memory enhances or constrains animals' abilities to exploit their niches. Although testing memory retention in wild animals is difficult, it is important because captive conditions do not reflect the complex cognitive demands of wild environments, and long-term captivity changes the brain4 (Data S1A). Here, we trained wild-caught frog-eating bats (Trachops cirrhosus) to find prey by flying to a novel acoustic cue. After they learned the rewarded sound, we released them back into the wild, and then re-captured some of them one to four years later. When re-tested, all eight 'experienced' bats that previously learned the novel prey sounds flew to those sounds within seconds, whereas 17 naïve bats tested with the same sounds showed weak responses. Experienced bats also showed behavior indicating generalization of memories between novel sounds and rewards over time. The frog-eating bat's remarkably long memory indicates that an ability to remember rarely encountered prey may be advantageous for this predator and suggests hitherto unknown cognitive abilities in bats.

Tuned in to communication sounds: Neuronal sensitivity in the túngara frog midbrain to frequency modulated signals.

For complex communication signals, it is often difficult to identify the information-bearing elements and their parameters necessary to elicit functional behavior. Consequently, it may be difficult to design stimuli that test how neurons contribute to communicative processing. For túngara frogs (Physalaemus pustulosus), however, previous behavioral testing with numerous stimuli showed that a particular frequency modulated (FM) transition in the male call is required to elicit phonotaxis and vocal responses. Modeled on such behavioral experiments, we used awake in vivo recordings of single units in the midbrain to determine if their excitation was biased to behaviorally important FM parameters. Comparisons of stimulus driven action potentials revealed greatest excitation to the behaviorally important FM transition: a downward FM sweep or step that crosses ~600 Hz. Previous studies using long-duration acoustic exposure found immediate early gene expression in many midbrain neurons to be most sensitive to similar FM. However, those data could not determine if FM coding was accomplished by the population and/or individual neurons. Our data suggest both coding schemes could operate, as 1) individual neurons are more sensitive to the behaviorally significant FM transition and 2) when single unit recordings are analytically combined across cells, the combined code can produce high stimulus discrimination (FM vs. noise driven excitation), approaching that found in behavioral discrimination of call vs. noise.

Sexual selection and the ascent of women: Mate choice research since Darwin.

Darwin's theory of sexual selection fundamentally changed how we think about sex and evolution. The struggle over mating and fertilization is a powerful driver of diversification within and among species. Contemporaries dismissed Darwin's conjecture of a "taste for the beautiful" as favoring particular mates over others, but there is now overwhelming evidence for a primary role of both male and female mate choice in sexual selection. Darwin's misogyny precluded much analysis of the "taste"; an increasing focus on mate choice mechanisms before, during, and after mating reveals that these often evolve in response to selection pressures that have little to do with sexual selection on chosen traits. Where traits and preferences do coevolve, they can do so whether fitness effects on choosers are positive, neutral, or negative. The spectrum of selection on traits and preferences, and how traits and preferences respond to social effects, determine how sexual selection and mate choice influence broader-scale processes like reproductive isolation and population responses to environmental change.

Abdominal fellowship-trained versus generalist radiologist accuracy when interpreting MR and CT for the diagnosis of appendicitis.

OBJECTIVES: To compare the diagnostic accuracy of generalist radiologists working in a community setting against abdominal radiologists working in an academic setting for the interpretation of MR when diagnosing acute appendicitis among emergency department patients. METHODS: This observational study examined MR image interpretation (non-contrast MR with diffusion-weighted imaging and intravenous contrast-enhanced MR) from a prospectively enrolled cohort at an academic hospital over 18 months. Eligible patients had an abdominopelvic CT ordered to evaluate for appendicitis and were > 11 years old. The reference standard was a combination of surgery and pathology results, phone follow-up, and chart review. Six radiologists blinded to clinical information, three each from community and academic practices, independently interpreted MR and CT images in random order. We calculated test characteristics for both individual and group (consensus) diagnostic accuracy then performed Chi-square tests to identify any differences between the subgroups. RESULTS: Analysis included 198 patients (114 women) with a mean age of 31.6 years and an appendicitis prevalence of 32.3%. For generalist radiologists, the sensitivity and specificity (95% confidence interval) were 93.8% (84.6-98.0%) and 88.8% (82.2-93.2%) for MR and 96.9% (88.7-99.8%) and 91.8% (85.8-95.5%) for CT. For fellowship-trained radiologists, the sensitivity and specificity were 96.9% (88.2-99.5%) and 89.6% (82.8-94%) for MR and 98.4% (90.5-99.9%) and 93.3% (87.3-96.7%) for CT. No statistically significant differences were detected between radiologist groups (p = 1.0, p = 0.53, respectively) or when comparing MR to CT (p = 0.21, p = 0.17, respectively). CONCLUSIONS: MR is a reliable, radiation-free imaging alternative to CT for the evaluation of appendicitis in community-based generalist radiology practices. KEY POINTS: • There was no significant difference in MR image interpretation accuracy between generalist and abdominal fellowship-trained radiologists when evaluating sensitivity (p = 1.0) and specificity (p = 0.53). • There was no significant difference in accuracy comparing MR to CT imaging for diagnosing appendicitis for either sensitivity (p = 0.21) or specificity (p = 0.17). • With experience, generalist radiologists enhanced their MR interpretation accuracy as demonstrated by improved interpretation sensitivity (OR 2.89 CI 1.44-5.77, p = 0.003) and decreased mean interpretation time (5 to 3.89 min).

Health inequities and the inappropriate use of race in nephrology.

Chronic kidney disease is an important clinical condition beset with racial and ethnic disparities that are associated with social inequities. Many medical schools and health centres across the USA have raised concerns about the use of race - a socio-political construct that mediates the effect of structural racism - as a fixed, measurable biological variable in the assessment of kidney disease. We discuss the role of race and racism in medicine and outline many of the concerns that have been raised by the medical and social justice communities regarding the use of race in estimated glomerular filtration rate equations, including its relationship with structural racism and racial inequities. Although race can be used to identify populations who experience racism and subsequent differential treatment, ignoring the biological and social heterogeneity within any racial group and inferring innate individual-level attributes is methodologically flawed. Therefore, although more accurate measures for estimating kidney function are under investigation, we support the use of biomarkers for determining estimated glomerular filtration rate without adjustments for race. Clinicians have a duty to recognize and elucidate the nuances of racism and its effects on health and disease. Otherwise, we risk perpetuating historical racist concepts in medicine that exacerbate health inequities and impact marginalized patient populations.