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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.

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.

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.

Although the cell cycle normally progresses from G

The mobilization of subspecialty departments in reaction to the unique demands of the onset of the coronavirus disease 2019 (COVID-19) pandemic in New York City was swift and left little time for reflection and commemoration. The early days of the pandemic brought unprecedented stressors on the medical system that necessitated a restructuring of hospitals, reallocation of health care workers, and a shift in care and education paradigms to meet patient care demands and public health needs. As the number of cases, intensive care unit patients, and deaths skyrocketed in New York City, many struggled with a somewhat paradoxical difficulty in perceiving the human value of what these numbers mean. Easily lost in the statistics are the stories and experiences of the physicians and trainees who were counted on to halt their own clinical practices and adapt their skillsets to tackle the pandemic. In this article, we present 10 brief narratives from the student members of the Neurosurgery Publication Group at Weill Cornell Medical College and members of the Weill Cornell Medicine Neurological Surgery Residency Program and Department of Neurological Surgery faculty. Reflecting on these individual experiences gives us an opportunity to simultaneously contribute to a history of New York City's reaction to COVID-19 and commemorate the individuals who were impacted by or succumbed to this disease.

Neuronal repopulation achieved through transplantation or transdifferentiation from endogenous sources holds tremendous potential for restoring function in chronic neurodegenerative disease or acute injury. Key to the evaluation of neuronal engraftment is the definitive discrimination of new or donor neurons from preexisting cells within the host tissue. Recent work has identified mechanisms by which genetically encoded donor cell reporters can be transferred to host neurons through intercellular material transfer. In addition, labeling transplanted and endogenously transdifferentiated neurons through viral vector transduction can yield misexpression in host cells in some circumstances. These issues can confound the tracking and evaluation of repopulated neurons in regenerative experimental paradigms. Using the retina as an example, we discuss common reasons for artifactual labeling of endogenous host neurons with donor cell reporters and suggest strategies to prevent erroneous conclusions based on misidentification of cell origin.

A 24-year-old woman presented with a seizure-like episode of left hemibody sensory loss. Magnetic resonance imaging and magnetic resonance angiography revealed multiple distal fusiform cerebral aneurysms requiring angiographic evaluation and possible endovascular treatment. On preoperative workup, transthoracic echocardiography revealed a large, 4.1 × 2.1 cm, mobile left atrial mass prolapsing into the left ventricle during diastole. Multidisciplinary discussion among representatives from neurosurgery, cardiology, and cardiothoracic surgery determined the plan to proceed with diagnostic cerebral angiogram and aneurysm embolization before moving forward with heart surgery. Cerebral angiogram revealed several right distal middle cerebral artery fusiform aneurysms and a right distal posterior inferior cerebellar artery fusiform aneurysm. Subsequently, the patient underwent endovascular coil embolization of the largest distal M4 fusiform aneurysm, measuring 3.3 × 3.2 mm in maximal diameter. The patient recovered to baseline in the surgical intensive care unit and was discharged home on postoperative day 7 with close neurosurgical and cardiology follow-up.

An otherwise healthy 57-year-old man presented with intermittent low back pain and was incidentally found to have a left-sided paraspinal mass invading the spinal canal and causing spinal cord compression. He underwent a T11-12 hemilaminectomy, facetectomy, and instrumented fusion for a gross total resection with a good clinical outcome. Pathology revealed the lesion to be a ganglioneuroma. Ganglioneuroma is a rare and interesting pathology. These tumors are benign peripheral neuroblastic tumors derived from the neural crest and found along the entire neuroaxis. Tumors come to clinical attention if they cause symptomatic compression of neural structures or are found incidentally on imaging. Additionally, as these tumors share a common lineage with pheochromocytomas, systemic symptoms can be observed resulting from secretion of vasoactive peptides. The pathologic diagnosis of ganglioneuroma is predominantly based on morphology.

Purpose This study examined whether short-term use of topical nonsteroidal anti-inflammatory drug (NSAID) or steroid therapy affected the efficacy of selective laser trabeculoplasty (SLT). Design Double-masked, randomized, placebo-controlled, dual-center, multisurgeon trial. Participants Patients older than 18 years with intraocular pressure (IOP) of more than 18 mmHg for whom the clinician decided SLT was the appropriately indicated therapy were randomized to 1 of 3 groups in a ratio of 1:1:1 as follows: ketorolac 0.5%, prednisolone 1%, or saline tears. Methods After SLT, patients randomized into each group were instructed to use an unmarked drop 4 times daily starting the day of SLT and continuing for 4 additional days. The Kruskal-Wallis test and Wilcoxon rank-sum test were used for continuous variables when comparing 2 or 3 treatment groups, respectively. The Fisher exact test was used for categorical variables. Main Outcome Measures The primary outcome of this study was IOP at 12 weeks. Secondary outcome measures included IOP at 1 and 6 weeks, patient-reported pain, and detectable anterior chamber inflammation. Results Ninety-six eyes of 85 patients fit inclusion criteria and were enrolled between the 2 sites. The NSAID, steroid, and placebo groups were similar in baseline demographics and baseline IOP (mean, 23.3±3.9 mmHg; P = 0.57). There was no statistically significant difference in IOP decrease among groups at week 6. Both the NSAID and steroid groups showed a statistically significantly greater decrease in IOP at week 12 compared with the placebo group (mean, –6.2±3.1 mmHg, –5.2±2.7 mmHg, and –3±4.3 mmHg, respectively; P = 0.02 [analysis of variance] and P = 0.002 [t test] for NSAID vs. placebo groups; P = 0.02 for steroid vs. placebo groups). Conclusions Significantly better IOP reduction at 12 weeks was measured in eyes treated with steroid or NSAID drops after SLT. Short-term postoperative use of NSAID or steroid drops may improve IOP reduction after SLT. Longer-term follow-up studies are indicated.

Objectives: This study sought to evaluate the effects of the Carillon device on mitral regurgitation severity and left ventricular remodeling.Background: Functional mitral regurgitation (FM...

Simian arteriviruses are endemic in some African primates and can cause fatal hemorrhagic fevers when they cross into primate hosts of new species. We find that CD163 acts as an intracellular receptor for simian hemorrhagic fever virus (SHFV; a simian arterivirus), a rare mode of virus entry that is shared with other hemorrhagic fever-causing viruses (e.g., Ebola and Lassa viruses). Further, SHFV enters and replicates in human monocytes, indicating full functionality of all of the human cellular proteins required for viral replication. Thus, simian arteriviruses in nature may not require major adaptations to the human host. Given that at least three distinct simian arteriviruses have caused fatal infections in captive macaques after host-switching, and that humans are immunologically naive to this family of viruses, development of serology tests for human surveillance should be a priority.

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 the safety, tolerability, and efficacy of short-term, high-dose rhNGF eye drops versus placebo in a cohort of glaucoma patients.This was a prospective, phase 1b, single-center, randomized, double-masked, vehicle-controlled, parallel-group study.This study was designed to assess safety and tolerability as well as short-term neuroenhancement of structure and function (clinicaltrials.gov NCT02855450). A total of 60 open-angle glaucoma patients were randomized 40:20 to receive either 180 μg/mL rhNGF or vehicle control eye drops in both eyes, 3 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 by adverse events, and tolerability, as assessed by patient-reported outcomes. Secondary outcome measures included best corrected visual acuity (BCVA), Humphrey visual field, electroretinograpy (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).Of the 60 randomized patients, 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 a low level of symptom burden mainly eliciting periocular ache (in 52% of treated group and 5% of placebo group) and only 3 patients (7.5%) discontinuing treatment because of discomfort, of whom 1 patient (2.5%) prematurely withdrew from the study. There were no statistically significant differences in global indices of Humphrey visual field 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 nonsignificant trends toward significance in favor of rhNGF. Real-world participant data was used to generate an estimate of cohort size needed to power subsequent studies.Use of 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 the trends detected in this study, analysis for efficacy in a neuroprotection trial is warranted. NOTE: Publication of this article is sponsored by the American Ophthalmological Society.

A 67-year-old male with chronic lymphocytic leukemia was admitted with headaches and ring-enhancing lesions on magnetic resonance imaging of the brain. His current regimen included rituximab and ibrutinib with trimethoprim-sulfamethoxazole for secondary Pneumocystis jirovecii pneumonia prevention. All other elements of his history were noncontributory. The diagnosis of an invasive fungal infection was made via light microscopy of a stereotactic brain biopsy specimen.

Summary Background Tocilizumab, a monoclonal antibody directed against the interleukin-6 receptor, has been proposed to mitigate the cytokine storm syndrome associated with severe COVID-19. We aimed to investigate the association between tocilizumab exposure and hospital-related mortality among patients requiring intensive care unit (ICU) support for COVID-19. Methods We did a retrospective observational cohort study at 13 hospitals within the Hackensack Meridian Health network (NJ, USA). We included patients (aged ≥18 years) with laboratory-confirmed COVID-19 who needed support in the ICU. We obtained data from a prospective observational database and compared outcomes in patients who received tocilizumab with those who did not. We applied a multivariable Cox model with propensity score matching to reduce confounding effects. The primary endpoint was hospital-related mortality. The prospective observational database is registered on ClinicalTrials.gov , NCT04347993 . Findings Between March 1 and April 22, 2020, 764 patients with COVID-19 required support in the ICU, of whom 210 (27%) received tocilizumab. Factors associated with receiving tocilizumab were patients' age, gender, renal function, and treatment location. 630 patients were included in the propensity score-matched population, of whom 210 received tocilizumab and 420 did not receive tocilizumab. 358 (57%) of 630 patients died, 102 (49%) who received tocilizumab and 256 (61%) who did not receive tocilizumab. Overall median survival from time of admission was not reached (95% CI 23 days–not reached) among patients receiving tocilizumab and was 19 days (16–26) for those who did not receive tocilizumab (hazard ratio [HR] 0·71, 95% CI 0·56–0·89; p=0·0027). In the primary multivariable Cox regression analysis with propensity matching, an association was noted between receiving tocilizumab and decreased hospital-related mortality (HR 0·64, 95% CI 0·47–0·87; p=0·0040). Similar associations with tocilizumab were noted among subgroups requiring mechanical ventilatory support and with baseline C-reactive protein of 15 mg/dL or higher. Interpretation In this observational study, patients with COVID-19 requiring ICU support who received tocilizumab had reduced mortality. Results of ongoing randomised controlled trials are awaited. Funding None.

In almost all animals studied to date, the crucial process of egg activation, by which an arrested mature oocyte transitions into an actively developing embryo, initiates with an increase in Ca2+ in the oocyte's cytoplasm. This Ca2+ rise sets off a series of downstream events, including the completion of meiosis and the dynamic remodeling of the oocyte transcriptome and proteome, which prepares the oocyte for embryogenesis. Calcineurin is a highly conserved phosphatase that is activated by Ca2+ upon egg activation and that is required for the resumption of meiosis in Xenopus, ascidians, and Drosophila. The molecular mechanisms by which calcineurin transduces the calcium signal to regulate meiosis and other downstream events are still unclear. In this study, we investigate the regulatory role of calcineurin during egg activation in Drosophila melanogaster,. Using mass spectrometry, we quantify the phosphoproteomic and proteomic changes that occur during egg activation, and we examine how these events are affected when calcineurin function is perturbed in female germ cells. Our results show that calcineurin regulates hundreds of phosphosites and also influences the abundance of numerous proteins during egg activation. We find calcineurin-dependent changes in cell cycle regulators including Fizzy (Fzy), Greatwall (Gwl) and Endosulfine (Endos); in protein translation modulators including PNG, NAT, eIF4G, and eIF4B; and in important components of signaling pathways including GSK3β and Akt1. Our results help elucidate the events that occur during the transition from oocyte to embryo.

To link short-term exposures of air pollutants to health outcomes, scientists must use high temporal and spatial resolution estimates of PM2.5 concentrations. In this work, we develop a daily PM2.5 product at 1 × 1 km2 spatial resolution across the eastern United States (east of 90° W) with the aid of 1 × 1 km2 MAIAC aerosol optical depth (AOD) data, 36 × 36 km2 WRF-Chem output, 1 × 1 km2 land-use type from the National Land Cover Database, and 0.125° × 0.125° ERA-Interim re-analysis meteorology. A gap-filling technique is applied to MAIAC AOD data to construct robust daily estimates of AOD when the satellite data are missing (e.g., areas obstructed by clouds or snow cover). The input data are incorporated into a multiple-linear regression model trained to surface observations of PM2.5 from the EPA Air Quality System (AQS) monitoring network. The model generates a high-fidelity estimate (r2 = 0.75 using a 10-fold random cross-validation) of daily PM2.5 throughout the eastern United States. Of the inputs to the statistical model, WRF-Chem output (r2 = 0.66) is the most important contributor to the skill of the model. MAIAC AOD is also a strong contributor (r2 = 0.52). Daily PM2.5 output from our statistical model can be easily integrated into county-level epidemiological studies. The novelty of this project is that we are able to simulate PM2.5 in a computationally efficient manner that is constrained to ground monitors, satellite data, and chemical transport model output at high spatial resolution (1 × 1 km2) without sacrificing the temporal resolution (daily) or spatial coverage (>2,000,000 km2).

Although several proteasome subunits have been shown to bind ubiquitin (Ub) chains, many ubiquitylated substrates also associate with 26S proteasomes via "shuttling factors." Unlike the well-studied yeast shuttling factors Rad23 and Dsk2, vertebrate homologs Ddi2 and Ddi1 lack a Ub-associated domain; therefore, it is unclear how they bind Ub. Here, we show that deletion of Ddi2 leads to the accumulation of Ub conjugates with K11/K48 branched chains. We found using affinity copurifications that Ddi2 binds Ub conjugates through its Ub-like domain, which is also required for Ddi2 binding to proteasomes. Furthermore, in cell extracts, adding Ub conjugates increased the amount of Ddi2 associated with proteasomes, and adding Ddi2 increased the binding of Ub conjugates to purified proteasomes. In addition, Ddi2 also contains a retroviral protease domain with undefined cellular roles. We show that blocking the endoprotease activity of Ddi2 either genetically or with the HIV protease inhibitor nelfinavir increased its binding to Ub conjugates but decreased its binding to proteasomes and reduced subsequent protein degradation by proteasomes leading to further accumulation of Ub conjugates. Finally, nelfinavir treatment required Ddi2 to induce the unfolded protein response. Thus, Ddi2 appears to function as a shuttling factor in endoplasmic reticulum-associated protein degradation and delivers K11/K48-ubiquitylated proteins to the proteasome. We conclude that the protease activity of Ddi2 influences this shuttling factor activity, promotes protein turnover, and helps prevent endoplasmic reticulum stress, which may explain nelfinavir's ability to enhance cell killing by proteasome inhibitors.

Summary A new study reports the ability to generate cells caught in a ‘no-man’s land’ between interphase and M phase by simultaneously disrupting feedback loops controlling the activities of the main mitotic driver Cdk1–cyclin B and its counteracting phosphatase PP2A-B55.

Gyroviruses are small, single stranded DNA viruses in the family Anelloviridae. In chickens, the type virus (chicken anemia virus; CAV) causes epidemic disease in poultry flocks worldwide. In 2007 and 2008, young crested screamers (Chauna torquata) at a zoo in Wisconsin, USA, died of neurologic disease with clinical and pathological features resembling CAV infection. Conventional diagnostics were negative, but molecular analyses revealed coinfection of an affected bird with three variants of a novel Gyrovirus lineage, GyV10. Analysis of ten additional screamers from this and another zoo revealed infection in all but one bird, with co-infections and persistent infections common. The association between GyV10 ("screamer anemia virus," provisionally) and the disease remains unproven, but certain immunological and neurologic features of the syndrome would expand the known pathologic consequences of Gyrovirus infection. To control the virus, autogenous vaccines, environmental decontamination, and management strategies to limit vertical and horizontal transmission might prove effective.

An integrated immunometabolic response during negative energy balance is required for host survival. Three new papers by Jordan et al. (2019), Nagai et al. (2019), and Collins et al. (2019) report that monocytes, naive B cells, and memory CD8 T cells use bone marrow as a haven to tide off periods of metabolic adversity to maintain immune-responsiveness.

BACKGROUND CONTEXT Disc herniations that obstruct the spinal canal by more than 50% are considered “Giant Disc Herniations” (GDHs). GDHs are less common than disc herniations of smaller volume, but they more frequently cause severe pain, cauda equina syndrome and neurological deficits. GDHs are challenging to treat from a surgical perspective due to their size. As a result of their surgical challenges, it is debated if minimally invasive tubular approaches are an effective and safe treatment for lumbar GDHs. PURPOSE In order to evaluate the efficacy and safety of the surgical treatment of lumbar GDHs using tubular minimally invasive surgery (MIS), we investigated the viability of the procedure. STUDY DESIGN/SETTING We conducted a retrospective study evaluating patients who had undergone tubular MIS at our clinic by our senior surgeon in the period from 01/2015 to 03/2020 due to a lumbar disc herniation. PATIENT SAMPLE A total number of 227 cases were identified. OUTCOME MEASURES Age, gender and BMI were recorded and assessed. In addition to these parameters, the presence of neurological deficits such as cauda equina syndrome were evaluated. Furthermore, the surgical time, complications, estimated intraoperative blood loss and number of surgical revisions were recorded. METHODS All procedures were performed using tubular microsurgical techniques with the assistance of a microscope. The surgical procedure was performed through an 18 mm tubular retractor. Modification of technique compared to regular tubular discectomy was that we first performed an over-the-top bilateral decompression in order to create room for the safe performance of the discectomy. RESULTS A total of 22 patients were included in the study. The patients had a mean age of 49.8 (+/-18) years. In the included cases, 59% (n=13) of the patients were male and 41% (n=9) were female. The mean BMI was 26.6 (+/- 5.4) m2/kg. The average surgery time was 109 (+/- 46) min with an average estimated blood loss of CONCLUSIONS Tubular MIS is suitable for the surgical treatment of GDHs. The rate of revision surgery was low in our cohort and the number of complications was also low. We conclude that minimally invasive “over the top” decompression for GDH is a safe and effective way of treating this pathology. FDA DEVICE/DRUG STATUS This abstract does not discuss or include any applicable devices or drugs.

Objectives: Treating elderly women with ovarian cancer presents the clinician with difficult management decisions due to potential increased morbidity and mortality during treatment. We evaluated all women with ovarian cancer diagnosed at age ≥80. We sought to identify the rationale of the treatment decisions made in this elderly cohort. We hypothesized that women diagnosed with ovarian cancer at ≥80 years are less likely to receive standard of care treatment (SOC). Methods: After institutional review board (IRB) approval, all women diagnosed with ovarian cancer at ≥80 years of age, who received treatment at our institution from January 2011 to September 2018 were eligible for inclusion. Data collected included functional status, initial presentation, stage, treatment course, and demographics. Attention was paid to the rationale behind treatment decisions which deviated from SOC. These deviations were as follows: Patient goals of care; patient comorbidities; a combination of goals of care and comorbidities; or other. Deviation from SOC was classified as one of the following: Treatment declined, surgery related (inadequate, not recommended, or declined), adjuvant therapy not completed, other, and two or more. Statistical analysis was performed utilizing Wilcoxon rank sum test, Chi-square, and Kruskal-Wallis tests. Results: 61 patients met criteria for inclusion. 52% were age 80-84, 38% were age 85-89, and 10% were 90 years or older. Only 9.8% of all the patients (n=6) received SOC. Patients age 80-84 were more likely to receive SOC than patients age 85-89 and 90+ (p=0.049). 16% of our elderly cohort received NACT, compared to 18% of women with ovarian cancer at all ages who are treated at our institution. There were no women above the age of 85 (n=29) who received SOC for their pathologic diagnosis and stage of disease. The way in which treatment deviated from SOC did not vary by age group. However, the justification underlying treatment decisions deviating from SOC did vary significantly by age group: Individuals ≥90 were likely to receive alternate treatment due to co-existing comorbidities, while the goals of care were a significant factor in decisions made by women 85-89 (p=0.01). Overall survival did not differ significantly between the age groups (p=0.25). Conclusions: Women diagnosed with ovarian cancer at or above the age of 85 did not receive SOC compared with younger women. 16% of all elderly women chose NACT. Co-existing patient comorbidities were the primary reasons for deviation from SOC in patients 90 and above. The patients’ own management decisions played a significant role in women age 85-89.

We investigate the representation of emissions from the largest (Class 3) commercial marine vessels (c3 Marine) within the Community Multiscale Air Quality (CMAQ) model. In present emissions inventories developed by the United States Environmental Protection Agency (EPA), c3 Marine emissions are divided into off-shore and near-shore files. Off-shore c3 Marine emissions are vertically distributed within the atmospheric column, reflecting stack-height and plume rise. Near-shore c3 Marine emissions, located close to the US shoreline, are erroneously assumed to occur only at the surface. We adjust the near-shore c3 Marine emissions inventory by vertically distributing these emissions to be consistent with the off-shore c3 Marine inventory. Additionally, we remove near-shore c3 Marine emissions that overlap with off-shore c3 Marine emissions within the EPA files. The CMAQ model generally overestimates surface ozone (O3) compared to Air Quality System (AQS) site observations, with the largest discrepancies occurring near coastal waterways. We compare modeled O3 from two CMAQ simulations for June, July, and August (JJA) 2011 to surface O3 observations from AQS sites to examine the efficacy of the c3 Marine emissions improvements. Model results at AQS sites show average maximum 8-hr surface O3 decreases up to ∼6.5 ppb along the Chesapeake Bay, and increases ∼3–4 ppb around Long Island Sound, when the adjusted c3 Marine emissions are used. Along with the c3 Marine emissions adjustments, we reduce on-road mobile NOX emissions by 50%, motivated by work from Anderson et al. 2014, and reduce the lifetime of the alkyl nitrate species group from ∼10 days to ∼1 day based on work by Canty et al. 2015, to develop the “c3 Science” model scenario. Simulations with these adjustments further improve model representation of the atmosphere. We calculate the ratio of column formaldehyde (HCHO) and tropospheric column nitrogen dioxide (NO2) using observations from the Ozone Monitoring Instrument and CMAQ model output to investigate the photochemical O3 production regime (VOC or NOX-limited) of the observed and modeled atmosphere. Compared to the baseline, the c3 Science model scenario more closely simulates the HCHO/NO2 ratio calculated from OMI data. Model simulations for JJA 2018 using the c3 Science scenario show a reduction of surface O3 by as much as ∼13 ppb for areas around the Chesapeake Bay and ∼2–3 ppb at locations in NY and CT downwind of New York City. These reductions are larger in 2018 than in 2011 due to a change in the photochemical O3 production regime in the Long Island Sound region and the projected decline of other (non-c3 Marine) sources of O3 precursors, highlighting the importance of proper representation of c3 Marine emissions in future modeling scenarios.

National guidelines have advocated broad molecular profiling as a part of the standard diagnostic evaluation for advanced non-small cell lung cancer (NSCLC), with the goal of identifying driver mutations for which effective therapies or clinical trials are available. However, adherence to genomic testing guidelines could present challenges to community oncologists.We performed a retrospective review of genomic testing patterns in patients with nonsquamous NSCLC treated by 89 oncologists at 15 sites throughout New Jersey and Maryland from January 2013 to December 2015.A total of 814 patients (89% with stage IV; 11% with stage IIIB) were identified in the COTA Inc database. Of the 814 patients, 479 (59%) met the guideline recommendations for EGFR (epidermal growth factor receptor) and ALK (anaplastic lymphoma kinase) biomarker testing; 63 (8%) underwent comprehensive genomic profiling for all 4 major types of alterations (point mutations, indels, fusions, and copy number amplifications). Gender, age, race, site of care (referral vs. community center), and practice size did not influence comprehensive genomic profiling frequency. Active smokers and patients who died within 30 days were tested less frequently (P .05). Among those not tested for EGFR and ALK, 52% received chemotherapy without documented reasons for no testing, 32% did not receive antineoplastic therapy, and 13% had insufficient tissue for genotyping.Genomic testing presents multiple logistical challenges for the community-based oncologist, including coordination of sample handling, long turnaround times, test reimbursement, access to targeted therapies, insufficient tissue, and patient harm from the repeat biopsies necessary if the tissue sample is insufficient. Opportunities exist for improvement in guideline adherence, possibly through new technologies such as "liquid biopsies," which obviates the need tissue biopsy samples in select settings.

Summary Background Internal tandem duplication mutations in FLT3 are common in acute myeloid leukaemia and are associated with rapid relapse and short overall survival. The clinical benefit of FLT3 inhibitors in patients with acute myeloid leukaemia has been limited by rapid generation of resistance mutations, particularly in codon Asp835 (D835). We aimed to assess the highly selective oral FLT3 inhibitor gilteritinib in patients with relapsed or refractory acute myeloid leukaemia. Methods In this phase 1–2 trial, we enrolled patients aged 18 years or older with acute myeloid leukaemia who either were refractory to induction therapy or had relapsed after achieving remission with previous treatment. Patients were enrolled into one of seven dose-escalation or dose-expansion cohorts assigned to receive once-daily doses of oral gilteritinib (20 mg, 40 mg, 80 mg, 120 mg, 200 mg, 300 mg, or 450 mg). Cohort expansion was based on safety and tolerability, FLT3 inhibition in correlative assays, and antileukaemic activity. Although the presence of an FLT3 mutation was not an inclusion criterion, we required ten or more patients with locally confirmed FLT3 mutations ( FLT3 mut+ ) to be enrolled in expansion cohorts at each dose level. On the basis of emerging findings, we further expanded the 120 mg and 200 mg dose cohorts to include FLT3 mut+ patients only. The primary endpoints were the safety, tolerability, and pharmacokinetics of gilteritinib. Safety and tolerability were assessed in the safety analysis set (all patients who received at least one dose of gilteritinib). Responses were assessed in the full analysis set (all patients who received at least one dose of study drug and who had at least one datapoint post-treatment). Pharmacokinetics were assessed in a subset of the safety analysis set for which sufficient data for concentrations of gilteritinib in plasma were available to enable derivation of one or more pharmacokinetic variables. This study is registered with ClinicalTrials.gov, number NCT02014558, and is ongoing. Findings Between Oct 15, 2013, and Aug 27, 2015, 252 adults with relapsed or refractory acute myeloid leukaemia received oral gilteritinib once daily in one of seven dose-escalation (n=23) or dose-expansion (n=229) cohorts. Gilteritinib was well tolerated; the maximum tolerated dose was established as 300 mg/day when two of three patients enrolled in the 450 mg dose-escalation cohort had two dose-limiting toxicities (grade 3 diarrhoea and grade 3 elevated aspartate aminotransferase). The most common grade 3–4 adverse events irrespective of relation to treatment were febrile neutropenia (97 [39%] of 252), anaemia (61 [24%]), thrombocytopenia (33 [13%]), sepsis (28 [11%]), and pneumonia (27 [11%]). Commonly reported treatment-related adverse events were diarrhoea (41 [16%] of 252]), fatigue (37 [15%]), elevated aspartate aminotransferase (33 [13%]), and elevated alanine aminotransferase (24 [10%]). Serious adverse events occurring in 5% or more of patients were febrile neutropenia (78 [31%] of 252; five related to treatment), progressive disease (43 [17%]), sepsis (36 [14%]; two related to treatment), pneumonia (27 [11%]), acute renal failure (25 [10%]; five related to treatment), pyrexia (21 [8%]; three related to treatment), bacteraemia (14 [6%]; one related to treatment), and respiratory failure (14 [6%]). 95 people died in the safety analysis set, of which seven deaths were judged possibly or probably related to treatment (pulmonary embolism [200 mg/day], respiratory failure [120 mg/day], haemoptysis [80 mg/day], intracranial haemorrhage [20 mg/day], ventricular fibrillation [120 mg/day], septic shock [80 mg/day], and neutropenia [120 mg/day]). An exposure-related increase in inhibition of FLT3 phosphorylation was noted with increasing concentrations in plasma of gilteritinib. In-vivo inhibition of FLT3 phosphorylation occurred at all dose levels. At least 90% of FLT3 phosphorylation inhibition was seen by day 8 in most patients receiving a daily dose of 80 mg or higher. 100 (40%) of 249 patients in the full analysis set achieved a response, with 19 (8%) achieving complete remission, ten (4%) complete remission with incomplete platelet recovery, 46 (18%) complete remission with incomplete haematological recovery, and 25 (10%) partial remission. Interpretation Gilteritinib had a favourable safety profile and showed consistent FLT3 inhibition in patients with relapsed or refractory acute myeloid leukaemia. These findings confirm that FLT3 is a high-value target for treatment of relapsed or refractory acute myeloid leukaemia; based on activity data, gilteritinib at 120 mg/day is being tested in phase 3 trials. Funding Astellas Pharma, National Cancer Institute (Leukemia Specialized Program of Research Excellence grant), Associazione Italiana Ricerca sul Cancro.

The proteasome-associated deubiquitinating enzyme Usp14/Ubp6 inhibits protein degradation by catalyzing substrate deubiquitination and by poorly understood allosteric actions. However, upon binding a ubiquitin chain, Usp14 enhances proteasomal degradation by stimulating ATP and peptide degradation. These studies were undertaken to clarify these seemingly opposite regulatory roles of Usp14 and their importance. To learn how the presence of Usp14 on 26S proteasomes influences its different activities, we compared enzymatic and regulatory properties of 26S proteasomes purified from wild-type mouse embryonic fibroblast cells and those lacking Usp14. The proteasomes lacking Usp14 had higher basal peptidase activity than WT 26S, and this activity was stimulated to a greater extent by adenosine 5′-O-(thiotriphosphate) (ATPγS) than with WT particles. These differences were clear even though Usp14 is present on only a minor fraction (30–40%) of the 26S in WT mouse embryonic fibroblast cells. Addition of purified Usp14 to the WT and Usp14-defficient proteasomes reduced both their basal peptidase activity and the stimulation by ATPγS. Usp14 inhibits these processes allosterically because a catalytically inactive Usp14 mutant also inhibited them. Proteasomes lacking Usp14 also exhibited greater deubiquitinating activity by Rpn11 and greater basal ATPase activity than WT particles. ATP hydrolysis by WT proteasomes is activated if they bind a ubiquitinated protein, which is loosely folded. Surprisingly, proteasomes lacking Usp14 could be activated by such proteins even without a ubiquitin chain present. Furthermore, proteasomes lacking Usp14 are much more active in degrading non-ubiquitinated proteins (e.g. Sic1) than WT particles. Thus, without a ubiquitinated substrate present, Usp14 suppresses multiple proteasomal activities, especially basal ATP consumption and degradation of non-ubiquitinated proteins. These allosteric effects thus reduce ATP hydrolysis by inactive proteasomes and nonspecific proteolysis and enhance proteasomal specificity for ubiquitinated proteins.

Animal serum is an essential supplement for cell culture media. Contamination of animal serum with adventitious viruses has led to major regulatory action and product recalls. We used metagenomic methods to detect and characterize viral contaminants in 26 bovine serum samples from 12 manufacturers. Across samples, we detected sequences with homology to 20 viruses at depths of up to 50,000 viral reads per million. The viruses detected represented nine viral families plus four taxonomically unassigned viruses and had both RNA genomes and DNA genomes. Sequences ranged from 28% to 96% similar at the amino acid level to viruses in the GenBank database. The number of viruses varied from zero to 11 among samples and from one to 11 among suppliers, with only one product from one supplier being entirely "clean." For one common adventitious virus, bovine viral diarrhea virus (BVDV), abundance estimates calculated from metagenomic data (viral reads per million) closely corresponded to Ct values from quantitative real-time reverse transcription polymerase chain reaction (rtq-PCR), with metagenomics being approximately as sensitive as rtq-PCR. Metagenomics is useful for detecting taxonomically and genetically diverse adventitious viruses in commercial serum products, and it provides sensitive and quantitative information.

Intraocular pressure (IOP)-lowering ophthalmic solutions that inhibit Rho-associated protein kinases (Rock) and norepinephrine transporters (Net) are currently under clinical evaluation. Here we evaluate topical application of one such drug for its effects on retinal ganglion cell (RGC) survival and axon regeneration after optic nerve crush injury. We performed unilateral optic nerve crush on young rats (P18) and topically applied Rock/Net inhibitor AR-13324 or placebo 3 times a day for 14 days. IOP was measured starting 3 days before and up to 9 days after injury. On day 12, cholera toxin B (CTB) was injected intravitreally to trace optic nerve regeneration. On day 14, retinas and optic nerves were collected. The retinas were flat-mounted and stained with RBPMS to quantify RGC survival and the optic nerves were sectioned for optic nerve axon quantification using fluorescent and confocal microscopy. Rock phosphorylation targets implicated in axon growth including cofilin and LIMK were examined by fluorescence microscopy and quantitative western blotting. AR-13324 lowered IOP as expected. RGC survival and optic nerve axon regeneration were significantly higher with Rock/Net inhibitor treatment compared with placebo. Furthermore, topical therapy decreased Rock target protein phosphorylation in the retinas and proximal optic nerves. These data suggest that topical administration of a Rock/Net inhibitor promotes RGC survival and regeneration after optic nerve injury, with associated molecular changes indicative of posterior drug activity. Coordinated IOP lowering and neuroprotective or regenerative effects may be advantageous in the treatment of patients with glaucoma.