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The high levels of biodiversity supported by mountains suggest a possible link between geologic processes and biological evolution. Freshwater biodiversity is high not only in tectonically active settings but also in tectonically quiescent montane regions such as the Appalachian Mountains. We show that erosion through different rock types drove allopatric divergence between lineages of the Greenfin Darter ( Nothonotus chlorobranchius ), a fish species endemic to rivers draining metamorphic rocks in the Tennessee River basin in the United States. In the past, metamorphic rock preferred by N. chlorobranchius was more widespread, but as erosion exposed other rock types, lineages of this species were progressively isolated in tributaries farther upstream, where metamorphic rock remained. Our results suggest a geologic mechanism for initiating allopatric diversification in mountains long after tectonic activity ceases.

Objectives. Primary cilia are conserved organelles found in polarized mammalian cells that regulate neuronal growth, migration, and differentiation. Proper cilia formation is essential during eye development. Our previous reports found that both amacrine and retinal ganglion cells (RGCs) contain primary cilia in primate and rodent retinas. However, whether primary cilia are present in the inner retina of human retinal organoids remains unknown. The purpose of this study is to characterize the primary cilia distribution in human embryonic stem cell (hESC-derived retinal organoid development. Materials and Methods. Retinal organoids were differentiated from a hESC line, harvested at various developmental timepoints (day 44-day 266), and immunostained with antibodies for primary cilia, including Arl13b (for the axoneme), AC3, and Centrin3 (for the basal body). AP2α, Prox1, GAD67, Calretinin, GFAP, PKCα, and Chx10 antibodies as well as Brn3b-promoted tdTomato expression were used to visualize retinal cell types. Results. A group of ciliated cells were present in the inner aspects of retinal organoids from day 44 to day 266 in culture. Ciliated Chx10-positive retinal progenitor cells, GFAP-positive astrocytes, and PKCα-positive rod-bipolar cells were detected later during development (day 176 to day 266). Ciliation persisted during all stages of retinal developmental in AP2α-positive amacrine cells, but it was decreased in Brn3b-positive retinal ganglion cells (RGCs) at later time points. Additionally, AC3-positive astrocytes significantly decreased during the later stages of organoid formation. Conclusions. Amacrine cells in retinal organoids retain cilia throughout development, whereas RGC ciliation gradually and progressively decreases with organoid maturation.

Surgical decompression is standard care in the treatment of degenerative spondylolisthesis in patients with symptomatic lumbar spinal stenosis, but there remains controversy over the benefits of adding fusion. The persistent lack of consensus on this matter and the availability of new data warrants a contemporary systematic review and meta-analysis of the literature.Multiple online databases were systematically searched up to October 2022 for randomized controlled trials (RCTs) and prospective studies comparing outcomes of decompression alone versus decompression with fusion for lumbar spinal stenosis in patients with degenerative spondylolisthesis. Primary outcome was the Oswestry Disability Index. Secondary outcomes included leg and back pain, surgical outcomes, and radiological outcomes. Pooled effect estimates were calculated and presented as mean differences (MD) with their 95% confidence intervals (CI) at two-year follow-up.Of the identified 2403 studies, eventually five RCTs and two prospective studies were included. Overall, most studies had a low or unclear risk of selection bias and most studies were focused on low grade degenerative spondylolisthesis. All patient-reported outcomes showed low statistical heterogeneity. Overall, there was high-quality evidence suggesting no difference in functionality at two years of follow-up (MD - 0.31, 95% CI - 3.81 to 3.19). Furthermore, there was high-quality evidence of no difference in leg pain (MD - 1.79, 95% CI - 5.08 to 1.50) or back pain (MD - 2.54, 95% CI - 6.76 to 1.67) between patients undergoing decompression vs. decompression with fusion. Pooled surgical outcomes showed less blood loss after decompression only, shorter length of hospital stay, and a similar reoperation rate compared to decompression with fusion.Based on the current literature, there is high-quality evidence of no difference in functionality after decompression alone compared to decompression with fusion in patients with degenerative lumbar spondylolisthesis at 2 years of follow-up. Further studies should focus on long-term comparative outcomes, health economic evaluations, and identifying those patients that may benefit more from decompression with fusion instead of decompression alone. This review was registered at Prospero (CRD42021291603).

OBJECTIVE Carotid body tumors (CBTs) are rare, slow-growing neoplasms derived from the parasympathetic paraganglia of the carotid bodies. Although inherently vascular lesions, the role of preoperative embolization prior to resection remains controversial. In this report, the authors describe an institutional series of patients with CBT successfully treated via resection following preoperative embolization and compare the results in this series to previously reported outcomes in the treatment of CBT. METHODS All CBTs resected between 2013 and 2019 at a single institution were retrospectively identified. All patients had undergone preoperative embolization performed by interventional neuroradiologists, and all had been operated on by a combined team of cerebrovascular neurosurgeons and otolaryngology–head and neck surgeons. The clinical, radiographic, endovascular, and perioperative data were collected. All procedural complications were recorded. RESULTS Among 22 patients with CBT, 63.6% were female and the median age was 55.5 years at the time of surgery. The most common presenting symptoms included a palpable neck mass (59.1%) and voice changes (22.7%). The average tumor volume was 15.01 ± 14.41 cm3. Most of the CBTs were Shamblin group 2 (95.5%). Blood was predominantly supplied from branches of the ascending pharyngeal artery, with an average of 2 vascular pedicles (range 1–4). Fifty percent of the tumors were embolized with more than one material: polyvinyl alcohol, 95.5%; Onyx, 50.0%; and N-butyl cyanoacrylate glue, 9.1%. The average reduction in tumor blush following embolization was 83% (range 40%–95%). No embolization procedural complications occurred. All resections were performed within 30 hours of embolization. The average operative time was 173.9 minutes, average estimated blood loss was 151.8 ml, and median length of hospital stay was 4 days. The rate of permanent postoperative complications was 0%; 2 patients experienced transient hoarseness, and 1 patient had medical complications related to alcohol withdrawal. CONCLUSIONS This series reveals that endovascular embolization of CBT is a safe and effective technique for tumor devascularization, making preoperative angiography and embolization an important consideration in the management of CBT. Moreover, the successful management of CBT at the authors’ institution rests on a multidisciplinary approach whereby endovascular surgeons, neurosurgeons, and ear, nose, and throat–head and neck surgeons work together to optimally manage each patient with CBT.

A high mild traumatic brain injury (mTBI) incidence rate exists in military and sport. Hypopituitarism is an mTBI sequela; however, few studies have examined this phenomenon in those with an mTBI history. This cross-sectional study of Special Operations Forces combat soldiers aimed 1) to relate anterior pituitary gland volumes (actual and normalized) to insulin-like growth factor 1 (IGF-1) concentrations, 2) to examine the effect of mTBI history on anterior pituitary gland volumes (actual and normalized) and IGF-1 concentrations, and 3) to measure the odds of demonstrating lower anterior pituitary gland volumes (actual and normalized) or IGF-1 concentrations if self-reporting mTBI history.Anterior pituitary gland volumes were manually segmented from T1-weighted 3D brain MRI sequences; IGF-1 serum concentrations were quantified using commercial enzyme-linked immunosorbent assays. Correlations and linear regression were used to determine the association between IGF-1 serum concentration and anterior pituitary gland volume (n = 74). Independent samples t-tests were used to compare outcomes between mTBI groups and logistic regression models were fit to test the odds of demonstrating IGF-1 concentration or anterior pituitary volume less than sample median based on mTBI group (n = 54).A significant linear relationship between the subjects' anterior pituitary gland volumes and IGF-1 concentrations (r72 = 0.35, P = 0.002) was observed. Soldiers with mTBI history had lower IGF-1 concentrations (P0.001) and lower anterior pituitary gland volumes (P = 0.037) and were at greater odds for IGF-1 serum concentrations less than the sample median (odds ratio = 5.73; 95% confidence interval = 1.77-18.55).Anterior pituitary gland volume was associated with IGF-1 serum concentrations. Mild TBI history may be adversely associated with anterior pituitary gland volumes and IGF-1 concentrations. Longitudinal IGF-1 and anterior pituitary gland monitoring may be indicated in those who report one or more mTBI.

Single-stage lateral lumbar interbody fusion is a safe and effective procedure that relies on indirect decompression and fusion to treat various lumbar pathologies. This technique, however, has an overall 9% rate of indirect decompression failure, which may require additional surgery to achieve adequate direct decompression. To address this concern, we modified this technique by adding a minimally invasive, direct tubular decompression in lateral position when indicated. No study has described the technical nuances of incorporating a microtubular decompression into the single-stage lateral lumbar interbody fusion workflow (SSLLIF+).To report on the procedural steps and clinical outcomes of the SSLLIF+.In this retrospective case series of prospectively collected data, we present the detailed surgical approach of the SSLLIF+ with a single-center case series over a 5-year period. Surgical and clinical outcomes are presented.A total of 7 patients underwent a SSLLIF+ with a total of 18 levels fused and 7 levels decompressed. The SSLLIF+ was successfully performed in all cases without the occurrence of intraoperative complications in this case series. There was 1 revision after 20 months of follow-up because of adjacent segment disease. There was no need for further direct decompression in a delayed fashion.SSLLIF with direct microtubular decompression in lateral position is a safe and effective procedure in patients where indirect decompression alone may not achieve the surgical goal. Adherence to minimally invasive spine surgery principles and thoughtful patient selection facilitate the successful management of these patients while demonstrating short hospital stay and low-risk of perioperative complications.

The safety and efficacy of minimally invasive spine surgical (MISS) approaches have stimulated interest in adapting MISS principles for more complex pathology including intradural extramedullary (IDEM) tumors. No study has characterized a repeatable approach integrating the MISS surgical technique and 3-dimensional intraoperative navigated localization for the treatment of IDEM tumors.To describe a safe and reproducible technical guide for the navigated MISS technique for the treatment of benign intradural and extradural spinal tumors.Retrospective review of prospectively collected data on 20 patients who underwent navigated microsurgical tubular resection of intradural extramedullary tumors over a 5-year period. We review our approach to patient selection and report demographic and outcomes data for the cohort.Our experience demonstrates technical feasibility and safety with a 100% rate of gross total resection with no patients demonstrating recurrence during an average follow-up of 20.2 months and no instances of perioperative complications. We demonstrate favorable outcomes regarding blood loss, operative duration, and hospital length of stay.Navigated localization and microsurgical tubular resection of IDEM tumors is safe and effective. Adherence to MISS principles and thoughtful patient selection facilitate successful management of these patients.

Symptomatic lumbar spinal stenosis (LSS) is a common indication for surgery in the elderly. Preoperative radiographic evaluation of patients with LSS often reveals redundant nerve roots (RNRs). The clinical significance of RNRs is uncertain. RNRs have not been studied in the setting of minimally invasive surgery. This study investigates the relationship between RNRs and clinical outcomes after minimally invasive tubular decompression.Chart review was performed for patients with degenerative LSS who underwent minimally invasive decompression. Preoperative magnetic resonance imaging parameters were assessed, and patient-reported outcomes were analyzed.Fifty-four patients underwent surgery performed at an average of 1.8 ± 0.8 spinal levels. Thirty-one patients (57%) had RNRs. Patients with RNRs were older (median = 72 years vs. 66 years, P = 0.050), had longer median symptom duration (32 months vs. 15 months, P 0.01), and had more levels operated on (2.1 vs. 1.4; P 0.01). The median follow-up after surgery was 2 months (range = 1.3-12 months). Preoperative and postoperative patient-reported outcomes were similar based on RNR presence. Patients without RNRs had larger lumbar cross-sectional areas (CSAs) (median = 121 mmPreoperative RNRs are associated with increased age, symptom duration, and lumbar stenosis severity. Patients improved after minimally invasive decompression regardless of RNR presence. RNR presence had no effect on short-term clinical outcomes. Further study is required to assess their long-term significance.

Spinal surgery is undergoing a major transformation toward a minimally invasive paradigm. This shift is being driven by multiple factors, including the need to address spinal problems in an older and sicker population, as well as changes in patient preferences and reimbursement patterns. Increasingly, minimally invasive surgical techniques are being used in place of traditional open approaches due to significant advancements and implementation of intraoperative imaging and navigation technologies. However, in some patients, due to specific anatomic or pathologic factors, minimally invasive techniques are not always possible. Numerous algorithms have been described, and additional efforts are underway to better optimize patient selection for minimally invasive spinal surgery (MISS) procedures in order to achieve optimal outcomes. Numerous unique MISS approaches and techniques have been described, and several have become fundamental. Investigators are evaluating combinations of MISS techniques to further enhance the surgical workflow, patient safety, and efficiency.

To determine the feasibility of intravenous indocyanine green (ICG) dye use in patients with adnexal torsion to intraoperatively evaluate ovarian perfusion after detorsion.A prospective multicenter single-arm feasibility study.A teaching hospital.A total of 12 nonpregnant patients, 18 to 45 years old with surgically confirmed adnexal torsion.Torsion was surgically confirmed, the involved adnexa were untwisted laparoscopically, and ICG dye was injected intravenously. The absence or presence of ICG perfusion was documented, and the clinical decision for ovarian conservation or removal was determined by the surgeon.The primary outcome was feasibility of using ICG dye including measures such as time to visualized perfusion and operative time. Secondary outcomes included presence or absence of ovarian preservation and postoperative follow-up measures. Intraoperative visualization of ICG perfusion to the detorsed adnexa was achieved in 10 patients (83%) in a median time of 1 minute (0, 2), resulting in entire (n = 9) or partial (n = 1) ovarian conservation. Perfusion was absent in 2 cases, and postoophorectomy histologic necrosis was confirmed in one case. Median operative time was 74 minutes (48, 94). There were no adverse events related to ICG dye use.Intraoperative ICG dye use in this study was logistically feasible and conservation of the entire or partial ovary was observed in 83% of patients, including one case where preoperative Doppler flow was absent.

Flies are implicated in carrying and mechanically transmitting many primate pathogens. We investigated how fly associations vary across six monkey species (Cercopithecus ascanius, Cercopithecus mitis, Colobus guereza, Lophocebus albigena, Papio anubis, and Piliocolobus tephrosceles) and whether monkey group size impacts fly densities. Fly densities were generally higher inside groups than outside them, and considering data from these primate species together revealed that larger groups harbored more flies. Within species, this pattern was strongest for colobine monkeys, and we speculate this might be due to their smaller home ranges, suggesting that movement patterns may influence fly–primate associations. Fly associations increase with group sizes and may thus represent a cost to sociality.

There is increasing overlap in the urogynecologic and gynecologic oncologic patient populations. To improve patient advocacy and access to care, a collaborative surgical approach may benefit this cohort.The aim of the study was to evaluate surgeon attitudes toward performing concurrent urogynecologic and gynecologic oncology procedures. We hypothesized that most surgeons are amenable to collaboration.We conducted a cross-sectional questionnaire of members of the Society of Gynecologic Oncology and the American Urogynecologic Society from August to November 2020. A 23-item online survey was created to assess surgeon demographics, practice and screening patterns, and attitudes toward surgical collaboration. We also evaluated obstacles to performing joint procedures and assessed whether attitudes could be influenced by new information.A total of 338 surveys were included in the analysis, including 158 urogynecologists and 226 gynecologic oncologists (GOs). Most surgeons (77.8%) will recommend concurrent procedures with another specialty, and 97.8% of urogynecologists and 95.7% of oncologists currently perform joint surgical procedures. Male surgeons, regardless of specialty, were more likely to recommend staged procedures (44% vs 31%, P0.001), as were GOs (28% vs 10.1%, P0.001). However, oncologists were more likely than urogynecologists to initiate referrals for surgical collaboration (33.3% vs 14.4%, P0.001).A total of 22.2% of urogynecologists and oncologists prefer staging surgical procedures. The most common barrier to a combined procedure was logistics. Urogynecologists were more concerned about the effects of cancer treatments on healing, the use of mesh implants, and financial reimbursements as compared with GOs. Treatment delay was a significantly greater concern for the oncologists.

We hypothesize that artificial intelligence (AI) applied to relevant clinical testing in glaucoma has the potential to enhance the ability to detect glaucoma. This premise was discussed at the recent Collaborative Community on Ophthalmic Imaging meeting, "The Future of Artificial Intelligence-Enabled Ophthalmic Image Interpretation: Accelerating Innovation and Implementation Pathways," held virtually September 3-4, 2020. The Collaborative Community on Ophthalmic Imaging (CCOI) is an independent self-governing consortium of stakeholders with broad international representation from academic institutions, government agencies, and the private sector whose mission is to act as a forum for the purpose of helping speed innovation in healthcare technology. It was 1 of the first 2 such organizations officially designated by the Food and Drug Administration in September 2019 in response to their announcement of the collaborative community program as a strategic priority for 2018-2020. Further information on the CCOI can be found online at their website (https://www.cc-oi.org/about). Artificial intelligence for glaucoma diagnosis would have high utility globally, because access to care is limited in many parts of the world and half of all people with glaucoma are unaware of their illness. The application of AI technology to glaucoma diagnosis has the potential to broadly increase access to care worldwide, in essence flattening the Earth by providing expert-level evaluation to individuals even in the most remote regions of the planet.

Viruses in the family Rhabdoviridae infect a variety of hosts, including vertebrates, invertebrates, plants and fungi, with important consequences for health and agriculture. This study describes two newly discovered viruses of freshwater mussels from the United States.

Professor Dieter H. Wolf, a scientist of vision and depth, a role model for his students and colleagues, and a long-standing member of the Editorial Advisory Board of The EMBO Journal, sadly passed away on February 16th, 2023, in Stuttgart-Vaihingen, Germany.

As part of the central nervous system (CNS), retinal ganglion cells (RGCs) and their axons are the only neurons in the retina that transmit visual signals from the eye to the brain via the optic nerve (ON). Unfortunately, they do not regenerate upon injury in mammals. In ON trauma, retinal microglia (RMG) become activated, inducing inflammatory responses and resulting in axon degeneration and RGC loss. Since aldose reductase (AR) is an inflammatory response mediator highly expressed in RMG, we investigated if pharmacological inhibition of AR can attenuate ocular inflammation and thereby promote RGC survival and axon regeneration after ON crush (ONC). In vitro, we discovered that Sorbinil, an AR inhibitor, attenuates BV2 microglia activation and migration in the lipopolysaccharide (LPS) and monocyte chemoattractant protein-1 (MCP-1) treatments. In vivo, Sorbinil suppressed ONC-induced Iba1 + microglia/macrophage infiltration in the retina and ON and promoted RGC survival. Moreover, Sorbinil restored RGC function and delayed axon degeneration one week after ONC. RNA sequencing data revealed that Sorbinil protects the retina from ONC-induced degeneration by suppressing inflammatory signaling. In summary, we report the first study demonstrating that AR inhibition transiently protects RGC and axon from degeneration, providing a potential therapeutic strategy for optic neuropathies.

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Ovarian cancer is the most lethal gynecologic malignancy with a five-year survival rate below 25% for patients with stages III and IV disease. Identifying key mediators of ovarian cancer invasion and metastasis is critical to the development of more effective therapeutic interventions. We previously identified Filamin A interacting protein 1-like (FILIP1L) as an important mediator of cell proliferation and migration. In addition, targeted expression of FILIP1L in tumors inhibited tumor growth in vivo. In our present study, we confirmed that both mRNA and protein expression of FILIP1L were downregulated in ovarian cancer cells compared with normal ovarian epithelial cells. FILIP1L expression was inversely correlated with the invasive potential of ovarian cancer cell lines and clinical ovarian cancer specimens. We also provide evidence that DNA methylation is a mechanism by which FILIP1L is downregulated in ovarian cancer. The CpG island in the FILIP1L promoter was heavily methylated in ovarian cancer cells. Methylation status of the FILIP1L promoter was inversely correlated with FILIP1L expression in ovarian cell lines and clinical ovarian specimens. Reduced methylation in the FILIP1L promoter following treatment with a DNA demethylating agent was associated with restoration of FILIP1L expression in ovarian cancer cells. A transcription activator, cAMP-responsive element binding protein (CREB) was shown to bind to the CREB/ATF site in the CpG island of the FILIP1L promoter. Overall, these findings suggest that downregulation of FILIP1L associated with DNA methylation is related with the invasive phenotype in ovarian cancer and that modulation of FILIP1L expression has the potential to be a target for ovarian cancer therapy. Mol Cancer Res; 9(8); 1126–38. ©2011 AACR.

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Pathological changes in the atlantoaxial joint often lead to instability, pain, and neurological deterioration. One treatment option is the surgical stabilization of the atlantoaxial joint. In other areas of the spine, fusion rates have been improved by the introduction of an interbody cage. Our aim was to use cervical interbody spacers, originally designed to augment fusion across subaxial posterior cervical facets, to optimize the conditions for atlantoaxial fusion.To evaluate the safety and efficacy of implanting cervical cages in the atlantoaxial joint for C1/2 stabilization.Our retrospective study evaluated patients who had undergone C1/2 cervical fusions by the Harms/Goel technique. This technique was modified by implanting a titanium cervical interbody spacer into the joint space. Mean overall pain, as measured by a 0 to 10 visual analog scale (VAS) and neurological outcomes were measured preoperatively and postoperatively. In addition, radiological outcomes were collected using follow-up imaging.Nine patients were included in this case series. The mean preoperative VAS for overall pain was 5.0 ± 4.0, which changed to a mean VAS of 2.0 ± 3.0 after an average follow-up period of 41.4 ± 20.4 (P = .043). All patients showed a bony fusion in our case series. None of the radiological imaging during follow-up showed screw loosening, hardware breakage, implant migration, or nonunion.The implantation of cervical titanium cages into the atlantoaxial joint in combination with posterior fixation appears to be a safe and effective method for achieving C1/2 fusion.

Purpose No approved therapies directly target retinal ganglion cells (RGCs) for neuroprotection or neuroenhancement in glaucoma. Recombinant human nerve growth factor (rhNGF) has been shown to promote RGC survival and function in animal models of optic neuropathy. Here we evaluate safety, tolerability, and efficacy of short-term, high-dose rhNGF eye drops versus placebo in a cohort of glaucoma patients. Methods This study is a single-center, randomized, double-masked, vehicle-controlled, parallel group study designed to assess safety and tolerability as well as short-term neuroenhancement of structure and function (Clinicaltrials.gov NCT02855450). Sixty open-angle glaucoma patients were randomized 40:20 to receive either 180 μg/ml rhNGF or vehicle control eye drops in both eyes, three times daily for 8 weeks, with a 24-week post-treatment follow-up. One eye was officially selected as the study eye, although both eyes were studied and dosed. Primary endpoints were safety, as assessed through adverse events, and tolerability, as assessed through patient reported outcomes. Secondary outcome measures included best corrected visual acuity (BCVA), Humphrey visual field (HVF), electroretinogram (ERG), and optical coherence tomography (OCT) of retinal nerve fiber layer (RNFL) thickness at baseline, after 8 weeks of treatment, and at 4 and 24 weeks after treatment (12- and 32-weeks total). Results Of the 60 randomized subjects, 23 were female (38%) and the average age was 66.1 years. Through week 32, there were no treatment-related serious adverse events, including no unexpectedly severe progression of optic neuropathy, no adverse events affecting ocular function or pressure, and no drug-related systemic toxicity. Topical high-dose rhNGF was tolerated well, with low level of symptom burden mainly eliciting periocular ache (in 52% of treated, 5% of placebo) and only 3 patients (7.5%) discontinuing treatment due to discomfort, out of whom 1 patient (2.5%) prematurely withdrawing from the study. There were no statistically significant differences in global indices of HVF, and no meaningful differences in total, quadrant, or clock-hour mean RNFL thickness between the groups, although both of these function and structure measures showed non-significant trends towards significance in favor of rhNGF. Real-world participant data was used to generate an estimate of cohort size needed to power subsequent studies. Conclusions rhNGF is safe and tolerable in a topical 180 μg/ml formulation. Although no statistically significant short-term neuroenhancement was detected in this trial, given the strong effects of NGF in preclinical models and trends detected in this study, analysis for efficacy in a neuroprotection trial is warranted.

Summary: Background: Combustion-related nitrogen dioxide (NO2) air pollution is associated with paediatric asthma incidence. We aimed to estimate global surface NO2 concentrations consistent with the Global Burden of Disease study for 1990–2019 at a 1 km resolution, and the concentrations and attributable paediatric asthma incidence trends in 13 189 cities from 2000 to 2019. Methods: We scaled an existing annual average NO2 concentration dataset for 2010–12 from a land use regression model (based on 5220 NO2 monitors in 58 countries and land use variables) to other years using NO2 column densities from satellite and reanalysis datasets. We applied these concentrations in an epidemiologically derived concentration–response function with population and baseline asthma rates to estimate NO2-attributable paediatric asthma incidence. Findings: We estimated that 1·85 million (95% uncertainty interval [UI] 0·93–2·80 million) new paediatric asthma cases were attributable to NO2 globally in 2019, two thirds of which occurred in urban areas (1·22 million cases; 95% UI 0·60–1·8 million). The proportion of paediatric asthma incidence that is attributable to NO2 in urban areas declined from 19·8% (1·22 million attributable cases of 6·14 million total cases) in 2000 to 16·0% (1·24 million attributable cases of 7·73 million total cases) in 2019. Urban attributable fractions dropped in high-income countries (–41%), Latin America and the Caribbean (–16%), central Europe, eastern Europe, and central Asia (–13%), and southeast Asia, east Asia, and Oceania (–6%), and rose in south Asia (+23%), sub-Saharan Africa (+11%), and north Africa and the Middle East (+5%). The contribution of NO2 concentrations, paediatric population size, and asthma incidence rates to the change in NO2-attributable paediatric asthma incidence differed regionally. Interpretation: Despite improvements in some regions, combustion-related NO2 pollution continues to be an important contributor to paediatric asthma incidence globally, particularly in cities. Mitigating air pollution should be a crucial element of public health strategies for children. Funding: Health Effects Institute, NASA.

Low back pain is the leading cause of work absences and years lived with disability, and it is often associated with degenerative disc disease. In recent years, biological treatment approaches such as the use of growth factors, cell injections, annulus fibrosus (AF) repair, nucleus pulposus replacement, and tissue-engineered discs have been explored as means for preventing or reversing degenerative disc disease. Both animal and clinical studies have shown promising results for cell-based therapy on the grounds of its regenerative potential. Clinical data also indicate that stem cell injection is safe when appropriately performed, albeit its long-term safety and efficacy are yet to be explored. Numerous challenges also remain to be overcome, such as isolating, differentiating, and preconditioning the disc cells, as well as managing the nutrient-deficient and oxygen-deficient micromilieu of the intervertebral disc (IVD). AF repair methods including devices used in clinical trials have shown success in decreasing reherniation rates and improving overall clinical outcomes. In addition, recent studies that combined AF repair and nucleus pulposus replacement have shown improved biomechanical stability in IVDs after the combined treatment. Tissue-engineered IVDs for total disc replacement are still being developed, and future studies are necessary to overcome the challenges in their delivery, efficacy, and safety.

Lumbar disc degeneration is one of the leading causes of chronic low back pain. The degenerative cascade is often initiated by an imbalance between catabolic and anabolic processes in the intervertebral discs. As a consequence of extracellular matrix degradation, neoinnervation and neovascularization take place. Ultimately, this degenerative process results in disc bulging and loss of nucleus pulposus and water content and subsequent loss of disc height. Most patients respond to conservative management and surgical interventions well initially, yet a significant number of patients continue to suffer from chronic low back pain. Because of the high prevalence of long-term discogenic pain, regenerative biological therapies, including gene therapies, growth factors, cellular-based injections, and tissue-engineered constructs, have attracted significant attention in light of their potential to directly address the degenerative process. Understanding the pathophysiology of degenerative disc disease is important in both refining existing technologies and developing innovative techniques to reverse the degenerative processes in the discs. In this review, we aimed to cover the underlying pathophysiology of degenerative disc disease as well as its associated risk factors and give a comprehensive summary about the developmental, structural, radiological, and biomechanical properties of human intervertebral discs.

Purpose: This study was undertaken to examine the role of the insulin-like growth factor (IGF) signaling pathway in the response of ovarian cancer cells to Taxol and to evaluate the significance of this pathway in human epithelial ovarian tumors.Experimental Design: The effect of Taxol treatment on AKT activation in A2780 ovarian carcinoma cells was evaluated using antibodies specific for phospho-AKT. To study the drug-resistant phenotype, we developed a Taxol-resistant cell line, HEY-T30, derived from HEY ovarian carcinoma cells. IGF2 expression was measured by real-time PCR. A type 1 IGF receptor (IGF1R) inhibitor, NVP-AEW541, and IGF2 small interfering RNA were used to evaluate the effect of IGF pathway inhibition on proliferation and Taxol sensitivity. IGF2 protein expression was evaluated by immunohistochemistry in 115 epithelial ovarian tumors and analyzed in relation to clinical/pathologic factors using the χ2 or Fisher's exact tests. The influence of IGF2 expression on survival was studied with Cox regression.Results: Taxol-induced AKT phosphorylation required IGF1R tyrosine kinase activity and was associated with upregulation of IGF2. Resistant cells had higher IGF2 expression compared with sensitive cells, and IGF pathway inhibition restored sensitivity to Taxol. High IGF2 tumor expression correlated with advanced stage (P < 0.001) and tumor grade (P < 0.01) and reduced disease-free survival (P < 0.05).Conclusions: IGF2 modulates Taxol resistance, and tumor IGF2 expression is a candidate prognostic biomarker in epithelial ovarian tumors. IGF pathway inhibition sensitizes drug-resistant ovarian carcinoma cells to Taxol. Such novel findings suggest that IGF2 represents a therapeutic target in ovarian cancer, particularly in the setting of Taxol resistance. Clin Cancer Res; 16(11); 2999–3010. ©2010 AACR.

Figure S1. Correlation of RACGAP1 Immunohistochemical Staining and mRNA Expression; Figure S2. Survivin Expression in CS99 Treated With YM155

Effective cancer immunotherapy depends on the robust activation of tumor-specific antigen-presenting cells (APC). Immune agonists encapsulated within nanoparticles (NP) can be delivered to tumor sites to generate powerful antitumor immune responses with minimal off-target dissemination. Systemic delivery enables widespread access to the microvasculature and draining to the APC-rich perivasculature. We developed an immuno-nanoparticle (immuno-NP) coloaded with cyclic diguanylate monophosphate, an agonist of the stimulator of interferon genes pathway, and monophosphoryl lipid A, and a Toll-like receptor 4 agonist, which synergize to produce high levels of type I IFNβ. Using a murine model of metastatic triple-negative breast cancer, systemic delivery of these immuno-NPs resulted in significant therapeutic outcomes due to extensive upregulation of APCs and natural killer cells in the blood and tumor compared with control treatments. These results indicate that NPs can facilitate systemic delivery of multiple immune-potentiating cargoes for effective APC-driven local and systemic antitumor immunity.Significance:Systemic administration of an immuno-nanoparticle in a murine breast tumor model drives a robust tumor site–specific APC response by delivering two synergistic immune-potentiating molecules, highlighting the potential of nanoparticles for immunotherapy.

SF1: IFNβ production from macrophages by ELISA analysis; SF2: FMT imaging of mammary tumors ex vivo for spatial localization of nanoparticle; SF3: Confocal micrographs of DiI-nanoparticle fluorescence in mammary tumor tissue; SF4: Representative images of tumor masses 4 days post-treatment; SF5: Primary tumor bioluminescence and change in weight in 4T1 tumor-bearing mice; SF6: Confocal microscopy of a representative healthy lung section; SF7: Change in weight in B16F10 tumor-bearing mice

Table S4. Short Tandem Repeat Profiling of Primary Cell Line DNA and Patient Tumor Tissue DNA.

Purpose: To evaluate the drug combination of discodermolide and Taxol in human ovarian cancer cells and in an in vivo model of ovarian carcinoma.Experimental Design: The combination index method was used to evaluate the interaction of Taxol and discodermolide in human ovarian SKOV-3 carcinoma cells. Data were correlated with alterations in cell cycle distribution and caspase activation. In addition, SKOV-3 xenograft-bearing mice were treated with either Taxol, discodermolide, or a combination of both drugs given concurrently to evaluate the antitumor efficacy and toxicity of this combination. The Matrigel plug assay and CD31 immunohistochemistry were done to assess antiangiogenic effects.Results: Taxol and discodermolide interact synergistically over a range of concentrations and molar ratios that cause drug-induced aneuploidy in ovarian carcinoma cells. In SKOV-3 xenograft-bearing mice, the combination is significantly superior to either single agent, and induces tumor regressions without notable toxicities. Immunohistochemical analysis of CD31 and Matrigel plug analysis show decreased vessel formation in mice treated with the combination relative to either drug alone.Conclusions: The synergistic activity of Taxol and discodermolide in cells is most potent at drug concentrations that result in drug-induced aneuploidy rather than mitotic arrest. Moreover, in an animal model of ovarian carcinoma, this is a well-tolerated combination that induces tumor regressions and suppresses angiogenesis. These data confirm the potency of this combination and support the use of concurrent low doses of Taxol and discodermolide for potential use in cancer therapeutics.

Supplemental Figures 1-6

Supplementary Figure S1 from Potentiation of Taxol Efficacy by Discodermolide in Ovarian Carcinoma Xenograft-Bearing Mice

Supplementary Data from Insulin-like Growth Factor 2 Expression Modulates Taxol Resistance and Is a Candidate Biomarker for Reduced Disease-Free Survival in Ovarian Cancer

Supplemental Figure and Table Legends

Purpose: Uterine carcinosarcoma is a rare aggressive malignancy frequently presenting at advanced stage of disease with extrauterine metastases. Median survival is less than 2 years due to high relapse rates after surgery and poor response to chemotherapy or radiotherapy. The goal of this study was to identify novel therapeutic targets.Experimental Design: We applied RNA-seq analysis to prospectively collected uterine carcinosarcoma tumor samples from patients undergoing primary surgical resection and for comparison, normal endometrial tissues from postmenopausal women undergoing hysterectomy for benign indications. Functional assays were done in primary carcinosarcoma cell lines developed from patients and in established cell lines, as well as a cell line–derived xenograft model. Validation was done by analysis of an independent cohort of patients with uterine carcinosarcoma from The Cancer Genome Atlas (TCGA).Results: Rac GTPase–activating protein 1 (RACGAP1) was identified to be highly upregulated in uterine carcinosarcoma. Functional assays showed that RACGAP1 mediates motility and invasion via regulation of STAT3 phosphorylation and survivin expression. RACGAP1 depletion or survivin inhibition abrogated motility and invasiveness of carcinosarcoma cells, while RACGAP1 overexpression conferred invasiveness to endometrial adenocarcinoma cells. In the TCGA cohort, RACGAP1 expression correlated with survivin expression and extrauterine spread of disease.Conclusions: The RACGAP1–STAT3–survivin signaling pathway is required for the invasive phenotype of uterine carcinosarcoma and is a newly identified therapeutic target in this lethal disease. Clin Cancer Res; 22(18); 4676–86. ©2016 AACR.

Table S3. Gene Ontology Terms Enriched among Differentially Expressed Genes as identified by the DAVID Bioinformatics.

Table S1. RNA-seq Data Summary.

Supplementary Figure S2 from Potentiation of Taxol Efficacy by Discodermolide in Ovarian Carcinoma Xenograft-Bearing Mice

Introduction Treatment of non‐acute subdural hematoma (NASDH) remains challenging due to recurrence ranging from 2–37%. Middle meningeal artery embolization (MMAe) has emerged as a minimally invasive procedure uniquely poised to improve outcomes in NASDH. The goal of this study is to evaluate the clinical and radiographic characteristics of patients undergoing MMAe for NASDH, and how outcomes for MMAe differ when utilized upfront, prophylactically, or as a salvage modality after surgical evacuation. Furthermore, we investigated how independent patient risk factors, such as oncologic history and anticoagulant/antiplatelet (ACAP) medication use, may impact MMAe and NASDH outcomes. Methods This prospective study followed patients undergoing MMAe for NASDH from 2016–2021. All patients were diagnosed with a NASDH on non‐contrast CT imaging and underwent MMAe by the lead neurosurgeon. The primary outcome was NASDH recurrence post‐MMAe requiring surgical evacuation, repeat MMAe, or both within the one‐year follow up period. Additional radiographic outcomes included reduction of hematoma width and midline shift at longest follow‐up. Subgroup analyses stratified outcomes by MMAe indication: upfront (previously untreated and nonoperative NASDH), prophylactic (MMAe 1–5 days after surgical evacuation), or salvage (individuals with radiographic and clinical NASDH recurrence). Outcomes among oncologic, coagulopathic, and ACAP patients were also assessed. The modified Rankin scale (mRS) quantified post‐MMAe clinical outcomes. Results A total of 236 NASDH patients underwent 294 MMAe. Of these, 115 (48.7%), 92 (39.0%), and 29 (12.3%) patients received upfront, prophylactic, and salvage MMAe, respectively. Upfront MMAe was performed more frequently than prophylactic and salvage for patients with co‐existing malignancy (29.6%, 12.0%, 20.7%; P < 0.01) and coagulopathy (17.4%, 4.3%, 10.3%; P = 0.01). Prophylactic MMAe was more commonly performed for subacute SDH compared with upfront or salvage (15.2%, 2.6%, 0%; P < 0.001); no differences in utilization were seen for chronic or acute on chronic SDH. Sixteen (5.4%) patients presented with hematoma recurrence after MMAe requiring repeat intervention, of which 5 (1.7%) received a craniotomy, 7 (2.4%) received repeat MMAe, and 4 (1.3%) underwent both MMAe and surgical evacuation. Risk of overall NASDH recurrence requiring re‐intervention did not differ among prophylactic, upfront, and salvage groups (6.5%, 7.0%, 6.9%; P > 0.99). Clinical outcomes did not differ between MMAe indications at longest follow‐up. Within the prophylactic group, radiographic and clinical outcomes were similar between MMAe paired with twist‐drill craniostomy or with craniotomy. Subgroup analysis revealed MMAe also effectively decreased NASDH recurrence in ACAP, oncologic, and coagulopathic patients. However, patients with both an oncologic history and concurrent ACAP use less frequently achieved improved clinical status at follow‐up compared with those harboring ACAP/coagulopathic history alone, oncologic history alone, or neither (31.4%, 45.9%, 50.0%, 57.3%; P = 0.049). Conclusions MMAe is emerging as a viable treatment for curtailing recurrence and improving NASDH outcomes, with similar clinical outcomes when performed prophylactically, upfront, or as salvage treatment. NASDH patients presenting with an oncologic history and concurrent ACAP use may be less likely to achieve improved clinical status after MMAe.

As the world becomes increasingly urbanized, growing populations are exposed to poor ambient air quality and at risk of the associated health outcomes. Urban air quality is affected both by local sources of air pollution and sources outside city borders. Policy-makers who develop air quality policies need to know whether it is most effective to focus on local policies or to spend resources fostering larger regional air quality management cooperation. Identifying the fraction of air pollution exposure from emissions as a function of distance from the city is a critical element of air quality management design. We estimate the health burden associated with exposure to fine particulate matter (PM2.5), ozone (O3), and nitrogen dioxide (NO2) from county-level anthropogenic sources in and around 14 US cities; this analysis is a test-bed to conduct future global analyses. We use adjoint sensitivities calculated from the chemical transport model GEOS-Chem, high resolution satellite-derived surface concentrations of PM2.5 and NO2, and health impact assessment methods. For the 70.2 million people living in these cities, we estimate that 27,740 PM2.5- and O3-related premature deaths and 126,600 NO2-related new asthma cases were attributable to air pollution exposure in 2011. Development within the GEOS-Chem adjoint framework enables sectoral attribution and policy analysis in addition to the rote assessment of impact. We find that 70% of deaths and nearly 100% of these asthma cases were attributable to anthropogenic emissions. There is great variability in the sources of the anthropogenically-related health impacts; within-urban emissions make up 5% in Austin to 56% in Los Angeles and Phoenix (median: 31%) of urban premature deaths and 18% in Austin to 82% in Los Angeles (median: 59.5%) of new asthma cases, with the remaining portions attributable to emissions from outside the urban area. For each city, we estimate the air quality related health benefits associated with the adoption of a vehicle-miles-traveled fee in that city and in multiple spatial regions surrounding the city. The findings suggest that the proportion of urban air pollution that is regional is greater for premature deaths than new asthma cases and for the eastern US than the western US.