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Neuroanatomists have long speculated that expanded primate brains contain an increased morphological diversity of inhibitory neurons (INs) 1 , and recent studies have identified primate-specific neuronal populations at the molecular level 2 . However, we know little about the developmental mechanisms that specify evolutionarily novel cell types in the brain. Here, we reconstruct gene expression trajectories specifying INs generated throughout the neurogenic period in macaques and mice by analysing the transcriptomes of 250,181 cells. We find that the initial classes of INs generated prenatally are largely conserved among mammals. Nonetheless, we identify two contrasting developmental mechanisms for specifying evolutionarily novel cell types during prenatal development. First, we show that recently identified primate-specific TAC3 striatal INs are specified by a unique transcriptional programme in progenitors followed by induction of a distinct suite of neuropeptides and neurotransmitter receptors in new-born neurons. Second, we find that multiple classes of transcriptionally conserved olfactory bulb (OB)-bound precursors are redirected to expanded primate white matter and striatum. These classes include a novel peristriatal class of striatum laureatum neurons that resemble dopaminergic periglomerular cells of the OB. We propose an evolutionary model in which conserved initial classes of neurons supplying the smaller primate OB are reused in the enlarged striatum and cortex. Together, our results provide a unified developmental taxonomy of initial classes of mammalian INs and reveal multiple developmental mechanisms for neural cell type evolution. Evolutionary modelling shows that an initial set of inhibitory neurons serving olfactory bulbs may have been repurposed to diversify the taxonomy of interneurons found in the expanded striata and cortices in primates.

Human pluripotent stem cells hold significant promise for regenerative medicine. However, long differentiation protocols and immature characteristics of stem cell-derived cell types remain challenges to the development of many therapeutic applications. In contrast to the slow differentiation of human stem cells in vitro that mirrors a nine-month gestation period, mouse stem cells develop according to a much faster three-week gestation timeline. Here, we tested if co-differentiation with mouse pluripotent stem cells could accelerate the differentiation speed of human embryonic stem cells. Following a six-week RNA-sequencing time course of neural differentiation, we identified 929 human genes that were upregulated earlier and 535 genes that exhibited earlier peaked expression profiles in chimeric cell cultures than in human cell cultures alone. Genes with accelerated upregulation were significantly enriched in Gene Ontology terms associated with neurogenesis, neuron differentiation and maturation, and synapse signaling. Moreover, chimeric mixed samples correlated with in utero human embryonic samples earlier than human cells alone, and acceleration was dose-dependent on human-mouse co-culture ratios. The altered gene expression patterns and developmental rates described in this report have implications for accelerating human stem cell differentiation and the use of interspecies chimeric embryos in developing human organs for transplantation.

Central estrogen signaling coordinates energy expenditure, reproduction, and in concert with peripheral estrogen impacts skeletal homeostasis in females. Here, we ablate estrogen receptor alpha (ERα) in the medial basal hypothalamus and find a robust bone phenotype only in female mice that results in exceptionally strong trabecular and cortical bones, whose density surpasses other reported mouse models. Stereotaxic guided deletion of ERα in the arcuate nucleus increases bone mass in intact and ovariectomized females, confirming the central role of estrogen signaling in this sex-dependent bone phenotype. Loss of ERα in kisspeptin ( Kiss1 )-expressing cells is sufficient to recapitulate the bone phenotype, identifying Kiss1 neurons as a critical node in this powerful neuroskeletal circuit. We propose that this newly-identified female brain-to-bone pathway exists as a homeostatic regulator diverting calcium and energy stores from bone building when energetic demands are high. Our work reveals a previously unknown target for treatment of age-related bone disease. Estrogen promotes negative energy balance and preserves skeletal physiology. Here the authors show that loss of estrogen signalling after ablating estrogen receptor alpha (ERa) in specific hypothalamic neuronal populations leads to a marked sex-dependent increase in bone mass in female mice.

Purpose Vertigo and dizziness are common complaints at emergency departments (ED), often leading to computed tomography (CT) and CT angiography (CTA) studies, which when used non-selectively, have low clinical utility. The study assesses whether two quality improvement interventions (educational rounds and clinical decision making support tool) can better align CTA ordering rates with clinical practice guidelines in the ED workup of vertigo/dizziness at a large community hospital. Methods CTA head and neck imaging rates were collected for patients presenting to the hospital’s ED with dizziness/vertigo as the chief complaint during 6-month pre- and post-intervention periods and compared rates using the Chi-Square Test. The interventions were joint ED/Diagnostic Imaging/Stroke Neurology rounds discussing CTA head/neck indications and dissemination of a clinical decision making support tool. Results The absolute reduction was 5.79% ( N  = 4,230, p  < 0.001) in CTA rates for patients presenting with dizziness/vertigo between the pre- and post-intervention periods. For vertigo, the absolute reduction was 12.27% ( N  = 402, p  < 0.005). For dizziness, the absolute reduction was 5.17% ( N  = 3828, p  < 0.001). Despite the global decrease in CTA studies, there was no statistically significant decrease in CTA rates for the patients who were diagnosed with cerebrovascular accident or transient ischemic attack in the ED, indicating that the interventions were effective in limiting to the targeted CTA studies. Conclusions This project was effective in improving patient safety and system efficiency, while providing a framework for low-burden, effective, practice-modifying quality improvement initiatives. Graphical Abstract

Pluripotent stem cells retain the developmental timing of their species of origin in vitro, an observation that suggests the existence of a cell-intrinsic developmental clock, yet the nature and machinery of the clock remain a mystery. We hypothesize that one possible component may lie in species-specific differences in the kinetics of transcriptional responses to differentiation signals. Using a liquid-handling robot, mouse and human pluripotent stem cells were exposed to identical neural differentiation conditions and sampled for RNA-sequencing at high frequency, every 4 or 10 minutes, for the first 10 hours of differentiation to test for differences in transcriptomic response rates. The majority of initial transcriptional responses occurred within a rapid window in the first minutes of differentiation for both human and mouse stem cells. Despite similarly early onsets of gene expression changes, we observed shortened and condensed gene expression patterns in mouse pluripotent stem cells compared to protracted trends in human pluripotent stem cells. Moreover, the speed at which individual genes were upregulated, as measured by the slopes of gene expression changes over time, was significantly faster in mouse compared to human cells. These results suggest that downstream transcriptomic response kinetics to signaling cues are faster in mouse versus human cells, and may offer a partial account for the vast differences in developmental rates across species.

Background: Untreated or residual developmental dysplasia of the hip may cause significant morbidity. Periacetabular osteotomy (PAO) allows for surgical reorientation of the acetabulum but requires a significant recovery period. Because of the physical demands of active military service, hip dysplasia or its treatment with PAO may cause a significant impact on the careers of affected personnel. Purpose: To measure the impact of symptomatic acetabular dysplasia and its treatment with PAO on the physical readiness of personnel in the United States Armed Forces. Study Design: Case series; Level of evidence, 4. Methods: Records from an interservice hip-preservation practice were reviewed for all patients who underwent PAO while on active duty from January 2014 through April 2017. Collected information included branch of service, military occupation, preoperative duty restrictions related to the hip, and concomitant surgical procedures. Patients were evaluated for a minimum of 24 months and assessed for their time to return to duty, continued duty restrictions, and referrals to the medical evaluation board. Results: Twenty patients (15 female, 5 male) underwent a PAO while on active duty during the period assessed. The mean patient age at surgery was 25.9 years, and the mean follow-up was 3.3 years (range, 2.3-5.4 years). In the 6 months preceding surgery, 94% of the 17 patients with available records were on duty restrictions specific to their hip (14 temporary, 2 permanent). After PAO, 35% of patients (n = 7) returned to full duty and 85% were able to remain on active duty (n = 12) or complete their military service commitments (n = 5) without noted medical disability. Three patients were medically discharged after PAO, with 1 patient referred due to hip pathology. Conclusion: Acetabular dysplasia significantly affects physical readiness in affected servicemembers, with 94% requiring duty restrictions. PAO allowed 85% of patients to return to military service, and 1 in 3 were able to return to full duty.

There are advantages to this-most notably, the spread of what Woolf's husband Leonard called a \"sense of intimacy and complete freedom of thought and speech\"-but there are also downsides. America's victory over Nazi Germany in World War II and the success of the civil rights movement in the 1960s. [...]not every place has to sound like a job site. [...]we once again build a culture of modesty and restraint, we will continue to learn of offensive statements by people who aspire to public roles.

Objectives: The role of hip instability in pre-arthritic hip disease is increasingly recognized, particularly in female patients. Generalized joint hypermobility (GJH) can be reliably assessed and quantified by the Beighton score with a score of 5 or greater is typically considered a marker of GJH. Given the female preponderance of symptomatic FAI, GJH may play a role in the pathophysiology of pre-arthritic hip pain as well as the outcomes of surgical treatment. The purpose of this study was (1) to determine the distribution of Beighton scores in a female cohort undergoing FAI surgery and (2) to determine if the Beighton score is correlated with patient-reported outcomes (PROs) in females undergoing hip arthroscopy for FAI. Methods: A prospective multicenter cohort study of 677 FAI patients undergoing primary hip arthroscopy was performed across 13 surgeons. The current study included a subgroup of 377 females from the larger cohort. Inclusion criteria were patients aged 14-45 years with idiopathic FAI. Exclusion criteria were the diagnosis of Ehlers-Danlos syndrome, previous ipsilateral hip procedures, lateral center edge angles less than 20 degrees, associated disorders, or Tönnis 2 or greater osteoarthritis. All patients underwent standardized hip arthroscopy with capsular closure/plication. The Beighton score (0-9) was self-scored by patients as has been shown to be a reliable method. Beighton scores were broken into five subgroups: 0-3 (normal), 4 (borderline GJH), 5-6 (mild GJH), and 7+ (moderate/severe GJH). PROs were measured at a minimum one-year follow-up. The modified Harris hip score (mHHS) was assessed relative to the minimal clinically important difference (MCID) of 8 and patient acceptable symptom state (PASS) of 74. Additional PROs included the HOOS domains of Pain and Sports/Recreation and the iHOT-12 score. Composite failure was defined as a reoperation for persistent symptoms or a failure to achieve either the mHHS, MCID, or PASS. Results: The mean Beighton scores in females was 4.1 with 56.9% having a Beighton score of 4 or greater. Mild GJH was present in 21.6%, while moderate/severe GJH was present in 22.2%. Overall, elevated Beighton scores were not predictive of inferior outcomes of hip arthroscopy for FAI in females and the presence of mild GJH was associated with superior outcomes relative to non-GJH and moderate/severe GJH subgroups. The rate of composite failure was lowest in the mild GJH group (6.2%) compared to the non-GJH group (9.7%), borderline (12.5%), and moderate/severe groups (13.6%), although this difference did not reach statistical significance. Females with mild GJH had significantly higher changes in iHot-12 and HOOS pain domain (p=0.012 and p=0.005, respectively). Conclusions: Over half of female patients undergoing FAI surgery have some level of underlying GJH as measured by the Beighton score. The presence of elevated Beighton scores did not appear to preclude excellent outcomes in females undergoing hip arthroscopy for FAI. Females with mild GJH actually demonstrated superior outcomes to other subgroups. Further longer-term outcomes are needed to better understand the role of GJH on the longevity outcomes of surgical treatment of FAI.

Raspail's description of a society succumbing to an invading force was informed by his childhood experience of World War II, when he cycled home from boarding school amid the chaos of Germany's invasion of France. Mette Frederiksen, the left-wing leader of Denmark, has pursued a crackdown on migrants and joined with Giorgia Meloni in criticizing the European Court of Human Rights for making it too difficult to repel and expel them. Because the migrants are presented as utterly alien, there is no point of contact between them and the novel's central characters, no subterranean sympathies or uneasy recognitions to set off the tale of conflict.

According to the unnamed source, Alex Acosta, the federal prosecutor in the case, gave this explanation to Trump administration officials while he was being vetted as secretary of labor. At one point, state prosecutors offered Epstein a plea deal that entailed five years of probation, no jail time, no sex-offender registration, and no need to pay restitution to victims- the ultimate sweetheart deal. Frustrated with state prosecutors, Palm Beach police approached Acosta, who agreed to take up the case. Because of the riskiness of a trial, he succeeded in arranging a \"non-prosecution agreement,\" under which Epstein would plead guilty to sex crimes. Throughout the tense negotiations, Acosta insisted that Epstein must serve jail time, register as a sex offender, and offer restitution to his victims.