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[1.1.1]Propellane, a compound whose structure includes two saturated carbons in which all four bonds are directed into a single hemisphere, is of theoretical interest, but has also seen recent practical applications. Mono-, di-, and trisubstituted derivatives of this propellane (by substitution of its CH2 bridges with O, S, NH, CF2, CO, SO, and SO2) remain unknown despite several computational studies that have suggested some may be stable. In this study, we show that, in several cases, substituted propellanes are spontaneously formed upon the attempted computational optimization of the geometries of anionic bridgehead bromide precursors using the ωB97X-D/aug-cc-pVDZ DFT method. Spontaneous formation suggests that these propellanes are at lower energy relative to the precursors and, therefore, are promising synthetic targets. The success or failure to spontaneously form the propellane is considered in relation to the length and strain energy of the central bridgehead-bridgehead bond, as well as the total strain energy of each propellane.

Low back pain (LBP) is often associated with the degeneration of human intervertebral discs (IVDs). However, the pain-inducing mechanism in degenerating discs remains to be elucidated. Here, we identified a subtype of locally residing nucleus pulposus cells (NPCs), generated by the environmental stress in degenerating discs, that triggered the onset of discogenic LBP. Single-cell transcriptomic analysis of human tissues showed a strong correlation between this specific pain-triggering subtype and the pain conditions in human degenerated discs. Next, we recreated this pain-triggering subtype by applying known exogenous stressors to healthy NPCsin vitro. The recreated pain phenotype activated functional sensory neurons responsein vitroand induced local inflammatory responses, hyperalgesia, and mechanical sensitivity in a healthy rat IVDin vivo. Our findings provide strong evidence of a previously unknown pain-inducing mechanism mediated by NPCs in degenerating IVDs. This newly defined pathway will aid in the development of NPC-targeted therapeutic strategies for clinically unmet need to attenuate discogenic LBP.One Sentence SummaryDiscogenic low back pain can be initiated by a stress-induced subtype of nucleus pulposus cells present in human degenerating intervertebral discs

Objective Poorly controlled salt-wasting (SW) congenital adrenal hyperplasia (CAH) patients often require high 9α-fluorocortisol doses as they show high levels of 17-hydroxyprogesterone (17OHP), which is a mineralocorticoid (MC)-receptor antagonist. Design We investigated the renin–angiotensin–aldosterone system in patients with SW-CAH receiving twice daily modified-release hydrocortisone (MR-HC, Efmody) compared with standard glucocorticoid (GC) therapy. Methods Data were analyzed from the 6-month, phase 3 study of MR-HC (n = 42) versus standard GC therapy (n = 41). MC replacement therapy remained unchanged throughout the study. Blood pressure, serum potassium, serum sodium, plasma renin activity (PRA), and serum 17OHP and androstenedione concentrations were analyzed at baseline, 4, 12, and 24 weeks. Results The median serum 17OHP in the morning was significantly lower on MR-HC compared with standard GC at 24 weeks (2.5 nmol L–1 (IQR 8.3) versus 10.5 nmol L–1 (IQR 55.2), P = .001). PRA decreased significantly from baseline to 24 weeks in patients on MR-HC (0.83 ng L–1 s–1 (IQR 1.0) to 0.48 ng L–1 s–1 (IQR 0.61), P = .012) but not in patients on standard GC (0.53 ng L–1 s–1 (IQR 0.66) to 0.52 ng L–1 s–1 (IQR 0.78), P = .613). Serum sodium concentrations increased from baseline to 24 weeks in patients on MR-HC (138.8 ± 1.9 mmol L–1 to 139.3 ± 1.8 mmol L–1, P = .047), but remained unchanged on standard GC (139.8 ± 1.6 mmol L–1 to 139.3 ± 1.9 mmol L–1, P = .135). No significant changes were seen in systolic and diastolic blood pressure and serum potassium levels. Conclusion 6 months of MR-HC therapy decreased PRA and increased sodium levels indicating a greater agonist action of the 9α-fluorocortisol dose, which may be due to the decreased levels of the MC-receptor antagonist 17OHP.

Background: Despite advances in surgery and pharmacotherapy, there remains significant residual ischemic risk after coronary artery bypass grafting surgery. Methods: In REDUCE-IT (Reduction of Cardiovascular Events With Icosapent Ethyl–Intervention Trial), a multicenter, placebo-controlled, double-blind trial, statin-treated patients with controlled low-density lipoprotein cholesterol and mild to moderate hypertriglyceridemia were randomized to 4 g daily of icosapent ethyl or placebo. They experienced a 25% reduction in risk of a primary efficacy end point (composite of cardiovascular death, myocardial infarction, stroke, coronary revascularization, or hospitalization for unstable angina) and a 26% reduction in risk of a key secondary efficacy end point (composite of cardiovascular death, myocardial infarction, or stroke) when compared with placebo. The current analysis reports on the subgroup of patients from the trial with a history of coronary artery bypass grafting. Results: Of the 8179 patients randomized in REDUCE-IT, a total of 1837 (22.5%) had a history of coronary artery bypass grafting, with 897 patients randomized to icosapent ethyl and 940 to placebo. Baseline characteristics were similar between treatment groups. Randomization to icosapent ethyl was associated with a significant reduction in the primary end point (hazard ratio [HR], 0.76 [95% CI, 0.63–0.92]; P =0.004), in the key secondary end point (HR, 0.69 [95% CI, 0.56–0.87]; P =0.001), and in total (first plus subsequent or recurrent) ischemic events (rate ratio, 0.64 [95% CI, 0.50–0.81]; P =0.0002) compared with placebo. This yielded an absolute risk reduction of 6.2% (95% CI, 2.3%–10.2%) in first events, with a number needed to treat of 16 (95% CI, 10–44) during a median follow-up time of 4.8 years. Safety findings were similar to the overall study: beyond an increased rate of atrial fibrillation/flutter requiring hospitalization for at least 24 hours (5.0% vs 3.1%; P =0.03) and a nonsignificant increase in bleeding, occurrences of adverse events were comparable between groups. Conclusions: In REDUCE-IT patients with a history of coronary artery bypass grafting, treatment with icosapent ethyl was associated with significant reductions in first and recurrent ischemic events. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01492361.

MR defecating proctography (MRDP) is a noninvasive examination that can be used for evaluating posterior compartment disorders. MRDP has several advantages over conventional fluoroscopic defecography. These benefits include high-contrast resolution evaluation of the deep pelvic organs, simultaneous multicompartmental assessment that is performed statically and dynamically during defecation, and lack of ionizing radiation. MRDP also provides a highly detailed anatomic evaluation of the pelvic floor supportive structures, including direct assessment of the pelvic floor musculature and indirect assessment of the endopelvic fascia. As the breadth of knowledge regarding anatomic and functional posterior compartment disorders expands, so too does the advancement of noninvasive and surgical treatment options for these conditions. High-quality MRDP examinations, with key anatomic and functional features reported, guide treatment planning. Reporting of MRDP examination findings with use of standardized terminology that emphasizes objective measurements rather than subjective grading aids consistent communication among radiologists, clinicians, and surgeons. Familiarity with commonly encountered posterior compartment pelvic floor pathologic entities that contribute to posterior compartment disorders and awareness of the essential information needed by surgeons are key to providing an optimal multidisciplinary discussion for planning pelvic floor dysfunction treatment. The authors provide an overview of the basic concepts of the MRDP acquisition technique, the anatomic abnormalities of posterior compartment pelvic floor pathologic entities associated with defecatory disorders, and recently developed interdisciplinary MRDP reporting templates and lexicons. In addition, the associated imaging findings that are key for surgical treatment guidance are highlighted.

Introduction: Cancer cachexia, characterized by the progressive loss of muscle mass (i.e., atrophy), has a significant impact on patient prognosis and quality of life. While skeletal muscle atrophy and weakness are well characterized in cancer patients, the progression of cancer-induced cardiac atrophy has received little attention. Preliminary work from our lab has shown that cardiac dysfunction, measured by invasive hemodynamic assessment, precedes the development of metastatic disease in a mouse model of epithelial ovarian cancer (EOC). Yet, the time course of changes in cardiac structure and function throughout the progression of ovarian cancer remain unknown. Thus, we non-invasively assessed changes in cardiac structure and function through the progression of EOC. Methods: To investigate the impact of advanced ovarian cancer on cardiac structure and function, we used an orthotopic, syngeneic mouse model of EOC. This model was generated by injecting transformed murine ovarian surface epithelial cells (ID8; 1.0 × 106) or saline (surgical sham) directly under the ovarian bursa of syngeneic mice. Echocardiography was used to assess changes in cardiac structure and function throughout the progression of EOC at days 45, 60, 75, and 90 post-tumor induction (PTI). Morphometric assessments at each timepoint were used to determine the presence of cardiac atrophy. Results: Echocardiography showed that EOC mice had preserved left ventricular (LV) function (i.e., ejection fraction) with no change in structural dimensions at days 45, 60 and 75 PTI. By day 90 PTI, LV wall thickness and end-systolic dimension decreased, suggesting evidence of cardiac atrophy. Consistent with echocardiographic data, morphometric assessment showed profound atrophy at 90 days PTI, but preserved cardiac mass at all other timepoints compared to shams. Conclusion: Together, this work demonstrates that when non-invasive techniques are used to measure changes in cardiac structure, atrophy is not evident until advanced stage ovarian cancer (i.e., 90 days PTI). Despite this, preliminary work from our lab has shown that cardiac dysfunction is present in EOC mice by 45 days PTI when assessed by invasive hemodynamics. Although echocardiography is a widely used technique for measuring indices of cardiac structure and function, our work demonstrates it lacks sensitivity to detect cardiac deficits until the overt stages of disease that accompany cancer cachexia. Thus, it is important to consider that subclinical cardiac dysfunction may exist in the early stages of cancer progression, however, these changes may go undetected unless more sensitive hemodynamic assessments are employed. Citation Format: Bridget Coyle-Asbil, Leslie M. Ogilvie, Madison Pereira, Kathy Matuszewska, Luca J. Delfinis, Shivam Gandhi, Keith R. Brunt, Christopher G. Perry, Jim Petrik, Jeremy A. Simpson. The progression of changes in cardiac structure and function in mice with epithelial ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 354.

Introduction: The intersections between cancer and cardiovascular disease (CVD) have become increasingly relevant in the care of both patient populations. To date, the cardio-oncology field has largely focused on how cancer treatment influences long-term cardiac health. Indeed, many cancer therapeutics show various toxic effects to the cardiovascular system. However, studies have also shown cardiac deficits in therapy-naïve cancer patients. This suggests that these two disease states interact through similar signaling pathways, yet the mechanisms underlying cancer-induced cardiac dysfunction remain unknown. Thus, we investigated cardiac structure and function throughout the progression of epithelial ovarian cancer (EOC). Methods: We used an orthotopic, syngeneic mouse model of ovarian cancer. Briefly, transformed murine ovarian surface epithelial cells from C57BL/6 mice (ID8; 1.0 × 106), or saline for surgical controls, were injected under the ovarian bursa of syngeneic mice. In this model, 60 days after tumor induction, mice form large ovarian masses, numerous peritoneal lesions, and develop abdominal ascites - consistent with the clinical features of stage III (advanced) EOC. To determine whether cardiac abnormalities precede the presence of advanced disease, at 45 days post-tumor induction, mice were anesthetized, and left ventricular (LV) structure and function were assessed by echocardiography and invasive hemodynamics, respectively. Myofilament activity was measured with an actomyosin MgATPase assay and protein phosphorylation was determined by SDS-PAGE with Pro-Q Diamond phosphoprotein staining. Results: EOC mice showed systolic (i.e., reduced contraction rate) and diastolic dysfunction (i.e., reduced relaxation rate, elevated diastolic filling pressure), with no evidence of hypertrophy or atrophy (i.e., no change in LV wall thickness or dimension). While there were no observed differences in myofilament ATPase activity, phosphorylation of regulatory myosin light chain 2 (MYL2) and cardiac myosin binding protein C (cMyBP-C) decreased, and tropomyosin (Tpm) phosphorylation increased in EOC mice. Conclusion: Together, these data demonstrate that ovarian cancer impairs cardiac function and alters the regulation of myofilament proteins critical for contraction and relaxation. Interestingly, the observed dephosphorylation of MYL2 and cMyBP-C and hyperphosphorylation of Tpm are consistent with features of heart failure. The findings build upon our current understanding of the interactions between cancer and CVD and show that deficits in the heart precede the development of advanced malignancy. Future work further will investigate the tumor-heart axis to identify how tumor development disrupts normal cardiac physiology. Citation Format: Leslie M. Ogilvie, Madison Pereira, Kathy Matuszewska, Bridget Coyle-Asbil, Luca J. Delfinis, Shivam Gandhi, Keith R. Brunt, Christopher G. Perry, W. Glen Pyle, Jim Petrik, Jeremy A. Simpson. Epithelial ovarian cancer causes cardiac dysfunction and myofilament dysregulation. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4248.

This paper presents an analysis of data from a wind tunnel study conducted to examine the dispersion of emissions at the edges of near-road noise barriers. The study is motivated by the concern that a barrier positioned downwind of a roadway may guide highly polluted plumes along the barrier leading to heightened concentrations as the plume spills around and downwind of the barrier end. The wind tunnel database consists of measurements of dispersion around a simulated roadway segment with various noise barrier configurations. Each roadway segment simulated in the wind tunnel had full-scale equivalent dimensions of 135 m long. Barrier segments, 135 m long with a height (H) of 6 m, were located on the downwind side of the source at a distance of 18 m from it (measured perpendicularly from the line source). Examination of the concentration patterns associated with the cases indicates that 1) vertical mixing induced by barriers persists at crosswind distances up to the edge (lateral end) of the barrier and downwind distances of x/H = 10, 2) concentration levels at all heights below z/H = 1 increase towards the edge of the barrier at downwind distances less than x/H = 7, and 3) concentration is well mixed in the vertical at the edge of the barrier, and the levels can be higher than in the middle of the barrier even when the source ends at the edge of the barrier. We have formulated a parameterization that captures the major features of these observations and can be incorporated in models such as RLINE.

Background Prednisolone and prednisone have a longer plasma elimination half-life after oral administration than hydrocortisone: 2.1 to 3.5 vs ∼1.5hrs1,2. For this reason, prednis(ol)one has been used in Congenital Adrenal Hyperplasia (CAH) by giving a dose in the evening to try to prevent the overnight rise in adrenal androgens. Modified-release hydrocortisone (MRHC) capsules, (Efmody, Diurnal Ltd, Cardiff UK), replicate the cortisol diurnal rhythm and improve the control of CAH compared to standard glucocorticoid therapy3. This post-hoc sub-analysis examines CAH control in MRHC treated patients switched from prednis(ol)one. Methods We reviewed the data of all patients taking prednis(ol)one in the randomised study of standard treatment versus MRHC3: 39 classic CAH patients on prednis(ol)one (alone or combined with hydrocortisone) (36 prednisolone; 3 prednisone) were randomised either to continue prednis(ol)one or switched to MRHC at the same hydrocortisone dose equivalent (HDE=prednisolone dose x5). Patients were assessed after 4 weeks following which blinded dose titration according to 17OHP and A4 control was performed to bring 17OHP into the optimal range ( Results Median baseline dose (HDE) was 30mg (n=39), androgen control was 56%. In patients randomised to MRHC (n=18), 39% were controlled at baseline and 94% at 4 weeks without dose adjustment. At 24 weeks, after androgen-control guided titration, the HDE dose in the prednis(ol)one group was 34mg, and in the MRHC group 27.5mg, with control being 71% and 94%, respectively. Percentage inhibition of 9am 17OHP from the levels at baseline to that at 24 weeks in the prednis(ol)one group was 32% and in the MRHC group 91%. In this study period there were no adrenal crises in the MRHC group and one in the prednis(ol)one group. MRHC-treated patients in the extension study were further titrated according to clinician assessment, at interim analysis the median MRHC dose was 20mg (median reduction 10mg) and 82% of patients were controlled at 18 months (n=28). In the ongoing extension study of all patients on MRHC (221 patient years), there were 12 adrenal crises in 5 patients (5.4/100 patient years). Conclusions Control of CAH is better on MRHC than prednisolone: 94% vs 39%; and the dose of MRHC can be down titrated to an adrenal replacement dose whilst maintaining control in the majority (82%) of patients. References 1. Pickup ME. Clin Pharmacokinet 1979 4 111-128; 2. Toothaker RD. J Pharm Sci 1982 71 573-576; 3. Merke DP. JCEM 2021 106 e2063-e2077. Presentation: Saturday, June 11, 2022 1:00 p.m. - 1:05 p.m., Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

There is emerging evidence that ovarian hormones play a significant role in the lower stroke incidence observed in pre-menopausal women compared with men. However, the role of ovarian hormones in cerebrovascular regulation remains to be elucidated. We examined the blood pressure-cerebral blood flow relationship (cerebral autoregulation) across the menstrual cycle in eumenorrheic women (n = 12; mean ± SD: age, 31 ± 7 years). Participants completed sit-to-stand and Valsalva maneuvers (VM, mouth pressure of 40 mmHg for 15 s) during the early follicular (EF), late follicular (LF), and mid-luteal (ML) menstrual cycle phases, confirmed by serum measurement of progesterone and 17β-estradiol. Middle cerebral artery blood velocity (MCAv), arterial blood pressure and partial pressure of end-tidal carbon dioxide were measured. Cerebral autoregulation was assessed by transfer function analysis during spontaneous blood pressure oscillations, rate of regulation (RoR) during sit-to-stand maneuvers, and Tieck's autoregulatory index during VM phases II and IV (AI-II and AI-IV, respectively). Resting mean MCAv (MCAv

The spectraplakin family of proteins includes ACF7/MACF1 and BPAG1/dystonin in mammals, VAB-10 in

BACKGROUND CONTEXT Nonphysiological mechanical loading and inflammation are both critically involved in intervertebral disc (IVD) degeneration, which is characterized by an increase in cytokines and matrix metalloproteases (MMPs) in the nucleus pulposus (NP). This process is known to be mediated by the NF-κB pathway. CLINICAL SIGNIFICANCE Current clinical treatments for IVD degeneration focus on the alleviation of symptoms rather than targeting the underlying mechanism. Injection of an NF-κB inhibitor may attenuate the progression of IVD degeneration. PURPOSE To investigate the ability of the NF-κB inhibitor, NEMO binding domain peptide (NBD), to alter IVD degeneration processes by reducing IL-1β- and mechanically-induced cytokine and MMP levels in human nucleus pulposus cells in vitro, and by attenuating IVD degeneration in an in vivo rat model for disc degeneration. STUDY DESIGN Experimental in vitro and animal model. PATIENT SAMPLE Discarded specimens of lumbar disc from 21 patients, and 12 Sprague Dawley rats. OUTCOME MEASURES Gene and protein expression, cell viability, µMRI and histology. METHODS IL-1β-prestimulated human nucleus pulposus cells embedded into fibrin constructs were loaded in the Flexcell FX-5000 compression system at 5 kPa and 1 Hz for 48 hours in the presence and absence of NBD. Unloaded hNPC/fibrin constructs served as controls. Cell viability in loaded and unloaded constructs was quantified, and gene and protein expression levels determined. For in vivo testing, a rat needle disc puncture model was employed. Experimental groups included injured discs with and without NBD injection and uninjured controls. Levels of disc degeneration were determined via µMRI, qPCR and histology. Funding sources include $48,874 NASS Young Investigator Research Grant and $119,174 NIH 5K01AR071512-02. There were no applicable financial relationships or conflicts of interest. RESULTS Mechanical compression of hNPC/fibrin constructs resulted in upregulation of MMP-3 and IL-8. Supplementation of media with 10 μM NBD during loading increased cell viability, and decreased MMP-3 gene and protein levels. IVD injury in rat resulted in an increase in MMP-3, IL-1β and IL-6 gene expression. Injections of 250 µg of NBD during disc injury resulted in decreased IL-6 gene expression. µMRI analysis demonstrated a reduction of disc hydration in response to disc needle injury, which was attenuated in NBD-treated IVDs. Histological evaluation showed NP and AF lesion in injured discs, which was attenuated by NBD injection. CONCLUSIONS The results of this study show NBD peptide's capacity to reduce IL-1β- and loading-induced MMP-3 levels in hNPC/fibrin constructs while increasing the cells’ viability, and to attenuate IVD degeneration in rat, involving downregulation of IL-6. Therefore, NBD may be a potential therapeutic agent to treat IVD degeneration.

Surgical care is an integral part of any healthcare system, yet there is a paucity of data on the burden of surgical disease, surgical capacity and access to surgical services in the Pacific region. This study aimed to evaluate access to surgical care through a pilot household survey in the Vanuatu island of Efate and five of its surrounding islands. The 2009 Vanuatu census’ GPS coordinates were used to randomly select 150 rural and 150 urban households from Efate and its surrounding islands. A total of 143 urban households and 142 rural households were available for inclusion in this study. A household questionnaire was developed to evaluate access to surgical care and included information regarding household demographics, socio-economic indicators and perceived and realised barriers to accessing care. The questionnaire was administered by local health workers, and data were collected electronically. Questionnaires were completed by 285 households. Two hundred and forty-one out of 254 (94.8%) households reported being able to access Port Vila Hospital, if required. The most commonly cited potential barriers to accessing surgical care were financial constraints (42.4%) and transport (26.4%). Our results provide important insights into the geographic, sociocultural and economic barriers to seeking, reaching and receiving surgical care in this region of Vanuatu. Identifying specific areas and communities with poor access to care, alongside the determinants of access, will help in designing both clinical and policy interventions to improve access to surgical care.

Axion Dark Matter eXperiment (ADMX) ultra low noise haloscope technology has enabled the successful completion of two science runs (1A and 1B) that looked for dark matter axions in the $2.66$ to $3.1$ $\mu$eV mass range with Dine-Fischler-Srednicki-Zhitnisky (DFSZ) sensitivity Ref. [1,2]. Therefore, it is the most sensitive axion search experiment to date in this mass range. We discuss the technological advances made in the last several years to achieve this sensitivity, which includes the implementation of components, such as state-of-the-art quantum limited amplifiers and a dilution refrigerator. Furthermore, we demonstrate the use of a frequency tunable Microstrip Superconducting Quantum Interference Device (SQUID) Amplifier (MSA), in Run 1A, and a Josephson Parametric Amplifier (JPA), in Run 1B, along with novel analysis tools that characterize the system noise temperature., Comment: 23 pages, 28 figures

Study Design Retrospective cohort study Objectives To describe the common types of complications and their risk factors during spine surgery in patients with achondroplasia. Methods A retrospective review was performed of medical records of adult achondroplasia patients who underwent spine surgery at our institution between 2007 and 2021. Inclusion criteria were achondroplasia and age >16 years. Surgical encounters were evaluated for durotomy, postoperative neurologic deficit, wound compromise, medical complications, and return to the operating room. Statistical analysis included evaluation of relationships across complications and fisher exact test applied to bivariate/categorical variables and t-test/ANOVA for continuous variables. Multivariable analysis using logistic regression was performed to account for patient characteristics Results Fifty-five patients with achondroplasia underwent 95 surgeries. Forty-nine percent of the surgeries involved a complication. These included durotomy (33.7%), neurologic deficit (11.6%), wound compromise (6.3%), and other medical complications (6.3%). Thirteen percent of surgeries required return to the operating room. The greatest number of complications occurred in thoracolumbar region (60.0%) compared to cervicothoracic (18.2%) and craniocervical junction (33.3%). Chronologically later surgical encounters had decreased complications and durotomies only occurred in thoracolumbar surgeries (45.7%). Conclusions Adult patients with achondroplasia undergoing surgery chronologically later in this set of consecutive patients were at a decreased risk for complications. Thoracolumbar surgeries were at the greatest risk for durotomies. Male sex was a risk factor for durotomy, while age was a risk factor for neurologic deficit. The potential for adverse surgical events should be considered when evaluating patients with achondroplasia for spine surgery.

Computational approaches in drug discovery and development hold great promise, with artificial intelligence methods undergoing widespread contemporary use, but the experimental validation of these new approaches is frequently inadequate. We are initiating Critical Assessment of Computational Hit-finding Experiments (CACHE) as a public benchmarking project that aims to accelerate the development of small molecule hit-finding algorithms by competitive assessment. Compounds will be identified by participants using a wide range of computational methods for dozens of protein targets selected for different types of prediction scenarios, as well as for their potential biological or pharmaceutical relevance. Community-generated predictions will be tested centrally and rigorously in an experimental hub(s), and all data, including the chemical structures of experimentally tested compounds, will be made publicly available without restrictions. The ability of a range of computational approaches to find novel compounds will be evaluated, compared, and published. The overarching goal of CACHE is to accelerate the development of computational chemistry methods by providing rapid and unbiased feedback to those developing methods, with an ancillary and valuable benefit of identifying new compound-protein binding pairs for biologically interesting targets. The initiative builds on the power of crowd sourcing and expands the open science paradigm for drug discovery.

Computational approaches in drug discovery and development hold great promise, with artificial intelligence methods undergoing widespread contemporary use, but the experimental validation of these new approaches is frequently inadequate. We are initiating Critical Assessment of Computational Hit-finding Experiments (CACHE) as a public benchmarking project that aims to accelerate the development of small molecule hit-finding algorithms by competitive assessment. Compounds will be identified by participants using a wide range of computational methods for dozens of protein targets selected for different types of prediction scenarios, as well as for their potential biological or pharmaceutical relevance. Community-generated predictions will be tested centrally and rigorously in an experimental hub(s), and all data, including the chemical structures of experimentally tested compounds, will be made publicly available without restrictions. The ability of a range of computational approaches to find novel compounds will be evaluated, compared, and published. The overarching goal of CACHE is to accelerate the development of computational chemistry methods by providing rapid and unbiased feedback to those developing methods, with an ancillary and valuable benefit of identifying new compound-protein binding pairs for biologically interesting targets. The initiative builds on the power of crowd sourcing and expands the open science paradigm for drug discovery., ACKNOWLEDGEMENTS The Structural Genomics Consortium is a registered charity (no: 1097737) that receives funds from Bayer AG, Boehringer Ingelheim, Bristol Myers Squibb, Genentech, Genome Canada through Ontario Genomics Institute [OGI-196], Janssen, Merck KGaA (aka EMD in Canada and US), Pfizer, Takeda and the Innovative Medicines Initiative 2 Joint Undertaking (JU) under grant agreement No 875510. The JU receives support from the European Union's Horizon 2020 research and innovation programme and EFPIA and Ontario Institute for Cancer Research, Royal Institution for the Advancement of Learning McGill University, Kungliga Tekniska Hoegskolan, Diamond Light Source Limited. This communication reflects the views of the authors and the JU is not liable for any use that may be made of the information contained herein. M. K. Gilson acknowledges funding from National Institute of General Medical Sciences (GM061300). J. J. Irwin acknowledges funding from National Institute of General Medical Sciences (GM133836). These findings are solely of the authors and do not necessarily represent the views of the NIH. The Lee laboratory at the University of Cambridge receives funding from multiple sources, including Pfizer, AstraZeneca, the Engineering and Physical Sciences Research Council and the Winton Programme for the Physics of Sustainability. T.I. Oprea and C. G. Bologa acknowledge funding from the National Institutes of Health Common Fund program, Illuminating the Druggable Genome (CA224370 and TR002278). COMPETING INTERESTS M. K. Gilson has an equity interest in and is a cofounder and scientific advisor of VeraChem LLC. J. J. Irwin is a co-founder of Blue Dolphin LLC, which undertakes fee-for-service ligand discovery. A.A. Lee is the chief scientific officer and a shareholder of PostEra Inc. T. I. Oprea has received honoraria from or consulted for Abbott, AstraZeneca, Chiron, Genentech, Infinity Pharmaceuticals, Merz Pharmaceuticals, Merck Darmstadt, Mitsubishi Tanabe, Novartis, Ono Pharmaceuticals, Pfizer, Roche, Sanofi and Wyeth, and is on the Scientific Advisory Board of ChemDiv and InSilico Medicine.

What is the central question of this study? Does habitual exercise modality affect the directionality of the cerebral pressure-flow relationship? What is the main finding and its importance? These data suggest the hysteresis-like pattern of dynamic cerebral autoregulation appears present in long-term sedentary and endurance-trained individuals, but absent in resistance-trained individuals. This is the first study to expand knowledge on the directional sensitivity of the cerebral pressure-flow relationship to trained populations.Evidence suggests the cerebrovasculature may be more efficient at dampening cerebral blood flow (CBF) variations when mean arterial pressure (MAP) transiently increases, compared to when it decreases. Despite divergent MAP and CBF responses to acute endurance and resistance training, the long-term impact of habitual exercise modality on the directionality of dynamic cerebral autoregulation (dCA) is currently unknown. Thirty-six young healthy participants (sedentary (n = 12), endurance-trained (n = 12), and resistance-trained (n = 12)) undertook a 5-min repeated squat-stand protocol at two forced MAP oscillation frequencies (0.05 and 0.10 Hz). Middle cerebral artery mean blood velocity (MCAv) and MAP were continuously monitored. We calculated absolute (ΔMCAv

Following the release of a harmful substance within an urban environment, buildings and street canyons create complex flow regimes that affect dispersion and localized effluent concentrations. While some fast-response dispersion models can capture the effects caused by individual buildings, further research is required to refine urban characterizations such as plume channeling and spreading, and initial dispersion, especially within the presence of a nonhomogeneous array of structures. Field, laboratory, and modeling experiments that simulate urban or industrial releases are critical in advancing current dispersion models. This project leverages the configuration of buildings used in a full-scale, mock urban field study to examine the concentrations of a neutrally buoyant tracer in a series of wind tunnel and Embedded Large Eddy Simulation (ELES) experiments. The behavior, propagation, and magnitude of the plumes were examined and compared to identify microscale effects. After demonstrating excellent quantitative and qualitative comparisons between the wind tunnel and ELES via lateral and vertical concentration profiles, we show that a nonlinear least squares fit of the Gaussian plume equation well represents these profiles, even within the array of buildings and network of street canyons. The initial plume dispersion depended strongly on the structures immediately adjacent to the release, and consequently, the near-surface plume spread very rapidly in the first few street canyons downwind of the source. The ELES modeling showed that under slightly oblique incoming wind directions of 5° and 15°, an additional 5° and 14° off-axis channeling of the plume occurred at ground level, respectively. This indicates how building structures can cause considerable plume drift from the otherwise expected centerline axis, especially with greater wind obliquity. Additionally, AERMOD was used to represent the class of fast-running, Gaussian dispersion models to inform where these types of models may be usefully applied within urban areas or groups of buildings. Using an urban wind speed profile and other parameters that may be locally available after a release, AERMOD was shown to qualitatively represent the ground-level plume while somewhat underestimating peak concentrations. It also overestimated the lateral plume spread and was challenged in the very near-field to the source. Adding a turbulence profile from the ELES data into AERMOD's meteorological input improved model estimates of lateral plume spread and centerline concentrations, although peak concentration values were still underestimated in the far field. Finally, we offer some observations and suggestions for Gaussian dispersion modeling based on this mock urban modeling exercise.

BACKGROUND Patients who survive traumatic atlanto-occipital dissociation (AOD) may present with normal neurological examinations and near-normal-appearing diagnostic images, such as cervical radiographs and computed tomography (CT) scans. OBSERVATIONS The authors described a neurologically intact 64-year-old female patient with a degenerative autofusion of her right C4–5 facet joints who presented to their center after a motor vehicle collision. Prevertebral soft tissue swelling and craniocervical subarachnoid hemorrhage prompted awareness and consideration for traumatic AOD. An abnormal occipital condyle–C1 interval (4.67 mm) on CT and craniocervical junction ligamentous injury on magnetic resonance imaging (MRI) confirmed the diagnosis of AOD. Her autofused right C4–5 facet joints were incorporated into the occipitocervical fusion construct. LESSONS Traumatic AOD can be easily overlooked in patients with a normal neurological examination and no associated upper cervical spine fractures. A high index of suspicion is needed when evaluating CT scans because normal values for craniocervical parameters are significantly different from the accepted ranges of normal on radiographs in the adult population. MRI of the cervical spine is helpful to evaluate for atlanto-occipital ligamentous injury and confirm the diagnosis. Occipitocervical fusion construct may need to be extended to incorporate spinal levels with degenerative autofusion to prevent adjacent level degeneration.

Objective: Alcohol consumption is considered a crime and a taboo in Iran. There is very limited information regarding the prevalence of alcohol consumption and associated risky behaviors in Iran. H...

NEW FINDINGS What is the central question of this study? Does habitual resistance and endurance exercise modify dynamic cerebral autoregulation? What is the main finding and its importance? To the authors' knowledge, this is the first study to directly assess dynamic cerebral autoregulation in resistance-trained individuals, and potential differences between exercise training modalities. Forced oscillations in blood pressure were induced by repeated squat-stands, from which dynamic cerebral autoregulation was assessed using transfer function analysis. These data indicate that dynamic cerebral autoregulatory function is largely unaffected by habitual exercise type, and further document the systemic circulatory effects of regular exercise. ABSTRACT Regular endurance and resistance exercise produce differential but desirable physiological adaptations in both healthy and clinical populations. The chronic effect of these different exercise modalities on cerebral vessels' ability to respond to rapid changes in blood pressure (BP) had not been examined. We examined dynamic cerebral autoregulation (dCA) in 12 resistance-trained (mean ± SD, 25 ± 6 years), 12 endurance-trained (28 ± 9 years) and 12 sedentary (26 ± 6 years) volunteers. The dCA was assessed using transfer function analysis of forced oscillations in BP vs. middle cerebral artery blood velocity (MCAv), induced via repeated squat-stands at 0.05 and 0.10 Hz. Resting BP and MCAv were similar between groups (interaction: both P ≥ 0.544). The partial pressure of end-tidal carbon dioxide ( PETCO2 ) was unchanged (P = 0.561) across squat-stand manoeuvres (grouped mean for absolute change +0.6 ± 2.3 mmHg). Gain and normalized gain were similar between groups across all frequencies (both P ≥ 0.261). Phase showed a frequency-specific effect between groups (P = 0.043), tending to be lower in resistance-trained (0.63 ± 0.21 radians) than in endurance-trained (0.90 ± 0.41, P = 0.052) and -untrained (0.85 ± 0.38, P = 0.081) groups at slower frequency (0.05 Hz) oscillations. Squat-stands induced mean arterial pressure perturbations differed between groups (interaction: P = 0.031), with greater changes in the resistance (P

Background Subependymomas are rare in the spinal cord. They are typically expansile, intramedullary spinal cord masses, eccentrically located with minimal gadolinium enhancement. Case Description We present a case of subependymoma originating from the cervical cord with an unusual exophytic appearance. Hallmarks of subependymoma and treatment are reviewed. Conclusions This is the first case, to our knowledge, where imaging revealed a mass appearing to be completely extramedullary with a primary exophytic component. Therefore, subependymomas should remain on the differential for masses in the spinal cord that appear extramedullary and exophytic.

We review theory and research on the assessment, development, and consequences of individual differences in gender identity, as studied among ordinary school children. Gender identity encompasses children’s appraisals of compatibility with, and motivation to fit in with, gender collectives; it is a multidimensional construct. Five dimensions of gender identity are considered in depth: felt same-gender typicality, felt other-gender typicality, gender contentedness, felt pressure for gender conformity, and intergroup bias. A host of cognitive, affective, social, and defensive processes contribute to these forms of gender identity, all of which in turn affect children’s psychosocial adjustment. Felt same-gender typicality promotes self-esteem and protects children from harmful effects of stressors, but it is associated with negative attitudes toward other-gender peers and activities unless children feel at least somewhat similar to the other gender as well. Felt other-gender typicality distresses children who do not also feel same-gender–typical. The other three gender identity variables encourage self-serving behavior (e.g., dominance) if children view it as appropriate for their gender. Children who feel gender-atypical or discontent with their gender suffer considerable distress if they feel pressure for gender conformity. Gender contentedness may be a particularly powerful contributor to children’s adoption of gender-typed behavior.

Objective (a) To establish baseline lateral craniofacial morphology and soft tissue profile outcomes for New Zealand children with complete unilateral and complete bilateral cleft lip and palate (CUCLP/CBCLP) and determine differences in relation to demographic characteristics including cleft type, sex and ethnicity and (b) To compare these outcomes to similar international studies. Settings and sample population Nation-wide prospective and retrospective cephalometric analysis of 76 patients with CUCLP and 23 patients with CBCLP pre-secondary alveolar bone graft. Materials and methods Assessment was undertaken by three experienced orthodontists blinded to patient identity. A total of 13 hard tissue and 8 soft tissue landmarks were identified allowing for an assessment of 16 angular, three linear and one ratio variables. Inter-assessor reliability was determined by pre-defined measurement error thresholds. Results Inter-assessor reliability of cephalometric landmarks restricted reporting to 10 hard tissue, four soft tissue and one ratio variables. CUCLP had greater midface and mandibular retrusion than CBCLP. Females had greater midface and mandibular prominence and smaller nasal projections. The Pacific and Māori groups had more retrusive midfacial profiles, and the Pacific group had more prominent mandibles. A sub-analysis of New Zealand European CUCLP results found they were closely aligned to Eurocleft and Americleft study centres with less favourable outcomes. Conclusions The reliability of a number of cephalometric measurements was poor. Lateral craniofacial morphology and soft tissue profile outcomes varied between CUCLP/CBCLP, sex and ethnicity. The New Zealand European outcomes are similar to or less favourable to other studies.

Resistance exercise (RE) is a popular modality for the general population and athletes alike, due to the numerous benefits of regular participation. The acute response to dynamic RE is characterised by temporary and bidirectional physiological extremes, not typically seen in continuous aerobic exercise (e.g. cycling) and headlined by phasic perturbations in blood pressure that challenge cerebral blood flow (CBF) regulation. Cerebral autoregulation has been heavily scrutinised over the last decade with new data challenging the effectiveness of this intrinsic flow regulating mechanism, particularly to abrupt changes in blood pressure over the course of seconds (i.e. dynamic cerebral autoregulation), like those observed during RE. Acutely, RE can challenge CBF regulation, resulting in adverse responses (e.g. syncope). Compared with aerobic exercise, RE is relatively understudied, particularly high-intensity dynamic RE with a concurrent Valsalva manoeuvre (VM). However, the VM alone challenges CBF regulation and generates additional complexity when trying to dissociate the mechanisms underpinning the circulatory response to RE. Given the disparate circulatory response between aerobic and RE, primarily the blood pressure profiles, regulation of CBF is ostensibly different. In this review, we summarise current literature and highlight the acute physiological responses to RE, with a focus on the cerebral circulation.

BACKGROUND Cervical spine surgery sometimes necessitates complex ventral/dorsal approaches or osteotomies that place the vertebral artery (VA) at risk of inadvertent injury. Tortuosity of the VA poses increased risk of vessel injury during anterior decompression or placement of posterior instrumentation. OBSERVATIONS In this report, the authors describe a patient with degenerative cervical spondylotic myelopathy and focal kyphotic deformity requiring corrective surgery via a combined ventral/dorsal approach. Computed tomography (CT) and CT angiography (CTA) of the spine identified a left medially enlarged C4 transverse foramen and tortuous VA V2 segment forming a potentially dangerous medial loop into the vertebral body, respectively. The patient’s presentation and management are described. LESSONS The course of the VA is variable, and a tortuous VA with significant medial or lateral displacement may be dangerous during ventral and dorsal approaches to the cervical spine. CTA of the cervical spine is warranted in cases in which atlantoaxial fixation is needed or suspicious transverse foramen morphology is identified to understand the course of the VA and identify anatomical variations that would put the VA at risk during cervical spine surgery.

The first known primate fossil from the Atlantic Coastal Plain, a mandibular fragment representing the family Omomyidae, is described from the early Eocene Fisher/Sullivan Site in northeastern Virginia. The jaw, containing m1–m2, was found near the base of the Potapaco Member, Bed B, of the Nanjemoy Formation, indicating an early Ypresian age, ca. 54.5 Ma. As the specimen lacks diagnostic antemolar dentition, its precise identity cannot be confidently determined. However, its diminutive size and plesiomorphic molar morphology suggest that it represents a primitive omomyid. Comparison with a diversity of omomyids finds that nearly all omomyid genera are larger and/or derived in various features compared to the Nanjemoy specimen. Closest resemblances are to the primitive omomyids Steinius, Anemorhysis, Loveina, Melaneremia, and especially Teilhardina.

New results are presented from wind tunnel studies performed at the United States Environmental Protection Agency (U.S. EPA), which include cases with solid roadside barriers of varying heights and cases with varying distances between the line source (roadway) and a 6-m-tall barrier. The Source-to-Barrier Distance cases include seven lanes of traffic with each lane acting as an independent source of continuous emissions along a line (i.e., line source). A mixed-wake algorithm that accounts for barrier effects within a steady-state air dispersion model was updated based on the recent wind tunnel studies. To study the effects of a solid roadside barrier, varying barrier heights and varying distances between the line source and barrier were modeled with the U.S. EPA regulatory air dispersion model AERMOD (v. 21112) using the line-source option that includes an experimental barrier option (RLINEXT). The mixed-wake algorithm reproduced the shape of the vertical concentration profiles observed in the wind tunnel data, including the uniform concentration profile from the ground vertically to a height somewhat greater than the height of the barrier. The algorithm responded appropriately to changes in barrier height and source-to-barrier distance, producing greater reductions in ground-level concentrations for taller barriers and for shorter source-to-barrier distances. Additionally, a rule of thumb that approximates the effect of a downwind barrier was formulated by converting an estimated vertical dispersion into an additional travel distance. The wind tunnel results, the update to the mixed-wake algorithm, and a comparison of the two data sets are described in this paper.

Sports-related concussions pose a significant public health concern, and preventative measures are needed to help reduce risk in sport. Vision training could be a suitable prevention strategy for sports-related concussion to help improve athletes’ abilities to scan the visual field for oncoming objects or opponents and thus anticipate head impacts. By accurately anticipating impacts, athletes can prepare for impact or attempt to avoid the collision altogether. The purpose of this review is to explore the relationships between anticipation, visual and sensorimotor performance and head accelerations, as well as to examine the efficacy of vision training programmes in reducing concussion risk in sport. Anticipation of head impacts has been shown to help reduce linear and rotational head accelerations, particularly for mild-to-moderate severity head impacts, but less so for severe head impacts. There is conflicting evidence regarding the influences visual and sensorimotor performance and oculomotor behaviour have on concussion risk. However, preliminary research indicates vision training may help reduce concussion rates in collegiate American Football players. Therefore, this promising area of research warrants further investigation, particularly the role of anticipation and visual and sensory performance on reducing concussion risk in non-helmeted contact sports.

The Jack Rabbit II Special Sonic Anemometer Study (JRII-S), a field project designed to examine the flow and turbulence within a systematically arranged mock-urban environment constructed from CONEX shipping containers, is described in detail. The study involved the deployment of 35 sonic anemometers at multiple heights and locations, including a 32 m tall, unobstructed tower located about 115 m outside the building array to document the approach wind flow characteristics. The purpose of this work was to describe the experimental design, analyze the sonic data, and report observed wind flow patterns within the urban canopy in comparison to the approaching boundary layer flow. We show that the flow within the building array follows a tendency towards one of three generalized flow regimes displaying channeling over a wide range of wind speeds, directions, and stabilities. Two or more sonic anemometers positioned only a few meters apart can have vastly different flow patterns that are dictated by the building structures. Within the building array, turbulence values represented by normalized vertical velocity variance ([Formula: see text]) are at least two to three times greater than that in the approach flow. There is also little evidence that [Formula: see text] measured at various heights or locations within the JRII array is a strong function of stability type in contrast to the approach flow. The results reinforce how urban areas create complicated wind patterns, channeling effects, and localized turbulence that can impact the dispersion of an effluent release. These findings can be used to inform the development of improved wind flow algorithms to better characterize pollutant dispersion in fast-response models.

We describe non-operative management a rare traumatic clival fracture extending through the bilateral occipital condyles. Clinical History: A 26-year-old female who was involved in a high-speed motor vehicle crash presented to an outside facility with difficulty speaking. Subsequent CT of the cervical spine demonstrated a fracture of the clivus with extension through the bilateral occipital condyles. She was then transferred to our hospital for further management where complete trauma survey noted multiple other injuries including traumatic subarachnoid hemorrhage, spinal epidural hematoma, bilateral pneumothoraces, liver laceration, bilateral upper extremity injuries, and lumbosacral fractures. Additional spinal imaging was negative for any associated vascular or spinal cord injury. Given her young age, there was a strong interest to preserve craniocervical motion and the decision was made to treat her with non-operatively with halo placement. After 18 weeks of rigid fixation, follow up imaging demonstrated completely healed fractures and at twenty-one weeks post fixation she demonstrated preserved motion of the craniocervical junction. This is a review of the literature and case report regarding this rare entity and its management.

Hyperthermia produces profound redistribution of blood and circulatory reflex function. We investigated the potential for lower body positive pressure (LBPP) to maintain or restore haemodynamics during graded hyperthermia. Eight healthy adults rested supine in a custom-made LBPP box, sealed distal to the iliac crest. Following 5 min of normothermic rest, 20 mmHg of LBPP was applied and repeated when core temperature (Tcore ) had increased passively by +0.5 and +1°C. Primary dependent variables included mean middle cerebral artery blood velocity (MCAvmean , transcranial Doppler), mean arterial blood pressure (MAP, finger photoplethysmography), heart rate (HR) and partial pressure of end-tidal carbon dioxide (PET CO2 ). The absolute increase in MAP during LBPP was lower at Tcore +1°C (2 ± 3 mmHg), compared with normothermia (7 ± 3 p = .01). The modest increase in MCAvmean was unchanged by Tcore (normothermia, 2 ± 3 cm/s; +0.5°C, 3 ± 3 cm/s and +1°C, 3 ± 4 cm/s, p = .74). By design, PET CO2 was unchanged in all conditions from normothermic baseline (42 ± 1, p = .81). LBPP-induced changes in HR were greater at +0.5°C (-13 ± 4 b/min) and +1°C (-12 ± 6 b/min) compared with normothermia (-3 ± 3 b/min, p = .01 and p = .01, respectively). These data indicate that despite a significant attenuation in MAP to LBPP with moderate hyperthermia, MCAvmean dynamics were unchanged among the thermal manipulations.