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Himerometroidea is a clade of chiefly shallow-water, tropical, feather-star crinoids that is currently divided, based on morphology, into four families comprising 119 extant species in 31 genera. Our molecular phylogenetic results, based on three mitochondrial (CO1, 16S, CytB) and two nuclear (ITS and 28S) markers for 55 accepted species in 23 of the extant genera, allow for six clades within Himerometroidea to be given family ranks. Maximum parsimony, maximum likelihood, and Bayesian inference analyses recovered largely congruent topologies with varying nodal support. A new classification revises generic placements among five families: Himerometridae, Colobometridae, and Mariametridae, all retained, and Pontiometridae and Stephanometridae both resurrected. Zygometridae is no longer accepted, since the type genus of the family, Zygometra, falls within Himerometridae. Catoptometra was recovered as a sister clade with respect to those treated herein as a new family, Catoptometridae. Two genera, Iconometra and Analcidometra, are retained within Himerometroidea but without family assignments pending further assessment of their positions. Currently published diagnostic and descriptive morphological features are noted where possible to support taxonomic names in the recovered phylogeny, although more examination of morphology is needed to identify synapomorphies and designate taxon names formally.

Swimming-induced pulmonary edema (SIPE) is a respiratory condition frequently seen among Naval Special Warfare (NSW) trainees. The incidence of positive respiratory panel (RP) findings in trainees with a diagnosis of SIPE currently is unknown.Does a significant difference exist in the incidence of respiratory pathogens in nasopharyngeal samples of NSW candidates with SIPE and a control group?Retrospective analysis of clinical information from NSW Sea, Air, and Land (SEAL) team candidates with a diagnosis of SIPE over a 12-month period. Candidates who demonstrated the common signs and symptoms of SIPE underwent a nasopharyngeal swab and RP test for common respiratory pathogens. SIPE diagnoses were supported by two-view chest radiography. RP tests were obtained for a selected control group of first-phase trainees without SIPE.Forty-five of 1,048 SEAL team candidates received a diagnosis of SIPE (4.3%). Five had superimposed pneumonia. Thirty-six of 45 showed positive results for at least one microorganism on the RP (80%). In the study group, human rhinovirus/enterovirus (RV/EV) was the most frequently detected organism (37.8%), followed by coronavirus OC43 (17.8%), and parainfluenza virus type 3 (17.8%). Sixteen of 68 candidates from the control group showed positive RP (24%) findings. Patients with SIPE and positive RP results reported dyspnea (94%), pink frothy sputum (44%), and hemoptysis (22%) more frequently than the control participants with positive RP results. Those who reported respiratory infection symptoms in both the study and control groups showed higher incidences of positive RP results (P = .046).We observed that 80% of trainees with a diagnosis of SIPE showed positive results on a point-of-care RP. This positivity rate was significantly higher than that of RP test results from the control cohort. These findings suggest an association between colonization with a respiratory pathogen and the development of SIPE in NSW candidates.

Much of our understanding of atmospheric circulation comes from relationships between aspects of the circulation and the mean state of the atmosphere. In particular, the concept of mean available potential energy (MAPE) has been used previously to relate the strength of the extratropical storm tracks to the zonal-mean temperature and humidity distributions. Here, we calculate for the first time the MAPE of the zonally varying (i.e., three-dimensional) time-mean state of the atmosphere including the effects of latent heating. We further calculate a local MAPE by restricting the domain to an assumed eddy size, and we partition this local MAPE into convective and nonconvective components. Local convective MAPE maximizes in the subtropics and midlatitudes, in many cases in regions of the world that are known to have intense convection. Local nonconvective MAPE has a spatial pattern similar to the Eady growth rate, although local nonconvective MAPE has the advantage that it takes into account latent heating. Furthermore, the maximum potential ascent associated with local nonconvective MAPE is related to the frequency of warm conveyor belts (WCBs), which are ascending airstreams in extratropical cyclones with large impacts on weather. This maximum potential ascent can be calculated based only on mean temperature and humidity, and WCBs tend to start in regions of high maximum potential ascent on a given day. These advances in the use of MAPE are expected to be helpful to connect changes in the mean state of the atmosphere, such as under global warming, to changes in important aspects of extratropical circulation.

OBJECTIVE The accurate identification and reporting of adverse events (AEs) is crucial for quality improvement. A myriad of AE systems are utilized. There is a lack of understanding of the differences between prospective versus retrospective, disease-specific versus generic, and point-of-care versus chart-abstracted systems. The objective of this study was to compare the benefits and limitations between the prospective, disease-specific, point-of-care Spine Adverse Events Severity System (SAVES) and the retrospective, generic, and chart-abstracted National Surgical Quality Improvement Program (NSQIP) for the identification and reporting of AEs in adult patients undergoing spinal surgery. METHODS The authors conducted an observational ambidirectional cohort study of adult patients undergoing spine surgery other than for trauma between 2011 and 2019 in a quaternary spine center. Patients were identified using Current Procedural Terminology codes in the NSQIP database and matched using unique medical record numbers to their corresponding record in SAVES. The incidence of AEs and per-patient AEs as recorded in NSQIP and SAVES was the primary outcome of interest. Comparable AEs were identified by matching NSQIP AEs to equivalent ones in SAVES. Chi-square tests were used to test for significant differences in the incidence of overall and comparable AEs between the databases. RESULTS There were 2198 patients identified in NSQIP, of whom 2033 also had complete records in SAVES. SAVES identified 5342 individual AEs in 1484 patients (73%) compared with 1291 individual AEs in 807 patients (39.7%) with the NSQIP database (p < 0.001). SAVES identified 250 intraoperative and 422 postoperative spine-specific AEs that NSQIP did not record. NSQIP captured a greater number of AEs beyond 30 days, including prolonged length of stay > 30 days, unplanned readmission, unplanned reoperation, and death later than 30 days after surgery compared with SAVES. CONCLUSIONS SAVES captures a greater incidence of peri- and intraoperative spine-specific AEs than NSQIP, while NSQIP identifies a greater number of AEs beyond 30 days. While a prospective, disease-specific, point-of-care AE system such as SAVES is specific for guiding quality improvement in spine surgery, it incurs greater time and financial costs. Conversely, a retrospective, generic, and chart-abstracted system such as NSQIP provides equivocal cross-institutional comparability with reduced time and financial costs. Specific contextual and aim-specific needs should guide the choice and implementation of an AE system.

Cyathostomins are the most common and highly prevalent parasites of horses worldwide. Historically, the control of cyathostomins has mainly relied on the routine use of anthelmintic products. Increasing reports on anthelmintic resistance (AR) in cyathostomins are concerning. A potential method proposed for detecting emerging AR in cyathostomins has been estimating the egg reappearance period (ERP). This paper reviews the data available for the ERP of cyathostomins against the three major classes of anthelmintics, macrocyclic lactones, tetrahydropyrimidines, and benzimidazoles. Published peer-reviewed original research articles were obtained from three databases (PubMed, CAB Direct and Web of Science) and were evaluated for their inclusion in a systematic review. Subsets of articles were then subjected to a review of ERP data. A total of 54 (of 134) studies published between 1972 and 2022 met the criteria for inclusion in the systematic review. Until the beginning of 2022, there was no agreed definition of the ERP; eight definitions of ERP were identified in the literature, complicating the comparison between studies. Additionally, potential risk factors for the shortening of the ERP, including previous anthelmintic use and climate, were frequently not described. Reports of shortened ERP for moxidectin and ivermectin are frequent: 20 studies that used comparable ERP definitions reported shortened moxidectin and ivermectin ERPs of 35 and 28 days, respectively. It is unclear whether the ERPs of these anthelmintics reduced to such levels are due to the development of AR or some biological factors related to horses, cyathostomin species, and/or the environment. The ERPs for other anthelmintics, such as fenbendazole and pyrantel, were frequently not reported due to established resistance against these drugs. Future research in horses is required to understand the mechanism(s) behind the shortening of ERP for cyathostomins. Based on this systematic review, we propose recommendations for future ERP studies.

Carissa spinarum (mũkawa in Kikuyu, lamuriak in Maasai) and Azadirachta indica (neem, mwarubaini in Kiswahili) are widely used in African communities. C. spinarum is used as food and as treatment for gonorrhoea, cancer, and abnormal pain in pregnancy. A. indica is used as a mosquito-repellent and as treatment for malaria and dental carries. Both plants have broad biological activities including anticancer, hypoglycaemic, antinociceptive, and anti-inflammatory activity. However, data on their safety for use during pregnancy is scarce. This study aimed to determine the teratogenic effects of C. spinarum and A. indica in mice. FDA guidelines for reproduction studies were used. Pregnant mice were randomly divided into 8 groups (n=5) for the assay. Plant extracts were prepared in the doses 100, 250, and 500mg/kg body weight. Phenytoin sodium 100mg/kg body weight was used as the positive control and distilled water was used as the negative control. Treatments were administered orally and began from gestation day 6 and ended on gestation day 15. On gestation day 18, the mice were weighed and euthanized and the pups were recovered. Weights of the gravid uteri, number of pups and their body measurements, and incidences of foetal resorption were also recorded. Data were expressed as means and their standard errors and analysed using one-way ANOVA/Dunnett’s post hoc test. The significance level was set at p

How abnormal neurodevelopment relates to the tumour aggressiveness of medulloblastoma (MB), the most common type of embryonal tumour, remains elusive. Here we uncover a neurodevelopmental epigenomic programme that is hijacked to induce MB metastatic dissemination. Unsupervised analyses of integrated publicly available datasets with our newly generated data reveal that SMARCD3 (also known as BAF60C) regulates Disabled 1 (DAB1)-mediated Reelin signalling in Purkinje cell migration and MB metastasis by orchestrating cis-regulatory elements at the DAB1 locus. We further identify that a core set of transcription factors, enhancer of zeste homologue 2 (EZH2) and nuclear factor I X (NFIX), coordinates with the cis-regulatory elements at the SMARCD3 locus to form a chromatin hub to control SMARCD3 expression in the developing cerebellum and in metastatic MB. Increased SMARCD3 expression activates Reelin–DAB1-mediated Src kinase signalling, which results in a MB response to Src inhibition. These data deepen our understanding of how neurodevelopmental programming influences disease progression and provide a potential therapeutic option for patients with MB.

In this paper the occurrence, distribution and abundance of cetaceans in offshore waters of Onslow Bay, North Carolina, USA is described. Between June 2007 and June 2010 monthly aerial and shipboard line-transect surveys were conducted along ten 74km transects placed perpendicular to the shelf break. In total 42,676km of aerial trackline (218 sightings) and 5,209km of vessel trackline (100 sightings) were observed. Seven species of cetaceans were observed, but the fauna was dominated strongly by common bottlenose and Atlantic spotted dolphins. Both species were present year-round in the study area. Using photo-identification techniques, five bottlenose dolphins and one spotted dolphin were resighted during the three-year period. In general, the abundance of cetaceans in Onslow Bay was low and too few sightings were made to estimate monthly abundances for species other than bottlenose and spotted dolphins. Maximum monthly abundances of bottlenose and spotted dolphins were 4,100 (95% CI: 1,300–9,400) in May 2010 and 6,000 (95% CI: 2,500–17,400) in March 2009, respectively. Bottlenose dolphins were found throughout the study area, although they were encountered most frequently just off the shelf break. In contrast, spotted dolphins exhibited a strong preference for waters over the continental shelf and were not encountered beyond the shelf break.

Childhood B-cell acute lymphoblastic leukaemia (B-ALL) is characterised by recurrent genetic abnormalities that drive risk-directed treatment strategies. Using current techniques, accurate detection of such aberrations can be challenging, due to the rapidly expanding list of key genetic abnormalities. Whole genome sequencing (WGS) has the potential to improve genetic testing, but requires comprehensive validation. We performed WGS on 210 childhood B-ALL samples annotated with clinical and genetic data. We devised a molecular classification system to subtype these patients based on identification of key genetic changes in tumour-normal and tumour-only analyses. This approach detected 294 subtype-defining genetic abnormalities in 96% (202/210) patients. Novel genetic variants, including fusions involving genes in the MAP kinase pathway, were identified. WGS results were concordant with standard-of-care methods and whole transcriptome sequencing (WTS). We expanded the catalogue of genetic profiles that reliably classify PAX5alt and ETV6::RUNX1-like subtypes. Our novel bioinformatic pipeline improved detection of DUX4 rearrangements (DUX4-r): a good-risk B-ALL subtype with high survival rates. Overall, we have validated that WGS provides a standalone, reliable genetic test to detect all subtype-defining genetic abnormalities in B-ALL, accurately classifying patients for the risk-directed treatment stratification, while simultaneously performing as a research tool to identify novel disease biomarkers.

Airway hyperresponsiveness (AHR) is commonly assessed by a methacholine challenge test (MCT), during which a provocative concentration causing a 20% reduction in forced expiratory volume in 1 second (FEVWe analysed the changes in spirometry, lung volumes and sGaw during MCT in 211 randomly selected patients being evaluated for AHR to support a clinical diagnosis of asthma.The mean (SD) age of the group was 53 (15) years, with 141 women (67%). Overall lung function was normal, with FEVChanges in sGaw during MCT indicate clinically significant AHR in support of a clinical diagnosis of asthma among patients being evaluated for asthma.

Currently in the United States, there exists a patchwork of state-level laws and regulations surrounding cannabis use. Although cannabis (excluding hemp under the Agricultural Improvement Act of 2018, Public Law 115-334) is illegal at the federal level and is not FDA (U.S. Food and Drug Administration) approved for any indication, many states allow patients with qualifying conditions to register for their medical cannabis program (MCP). To better understand the quality of cannabis found in these programs, we collected laws, regulations, and guidance documents available on public state-run websites and compared them with current good manufacturing practices (CGMPs) applicable to finished drug products. CGMPs for human drugs contain minimum requirements for the methods, facilities, and controls used in manufacturing, processing, and packaging of a drug product to assure it is safe for use. Such a comparison will aid the development of consistent quality standards that could, in turn, improve the quality of a wide range of cannabis medical products in development that may be sold in the United States. States may likewise choose to have the cannabis and cannabis-derived products that fall within their MCP to follow quality-focused guidelines, such as those listed in CGMPs, to ensure the quality of these products and promote public health. This study further solidifies the need for standardized testing protocols and methodologies to keep consumers safe.

To characterize the epidemiological trends and mortality of cutaneous lupus erythematosus (CLE) between 1976 and 2018 in Olmsted County, Minnesota.In this retrospective population-based cohort study, all incident and prevalent CLE cases among adult residents in Olmsted County, Minnesota, between January 1, 1976, and December 31, 2018, were identified and categorized by subtype through medical record review using the resources of the Rochester Epidemiology Project.The overall incidence rate of CLE between 1976 and 2018 was 3.9 (95% CI, 3.4 to 4.5) per 100,000. The incidence of CLE was relatively stable, with no major trend across sexes or age groups. The age- and sex-adjusted prevalence of CLE was 108.9 per 100,000 on January 1, 2015. Mortality in CLE patients was similar to that of the general population, with a standardized mortality ratio of 1.23 (95% CI, 0.88 to 1.66) with no observed trends in mortality over time.In the past 4 decades, the incidence of CLE remained stable. Patients with CLE have mortality comparable to that of the general population.

This study examined the influence of pectinase-producing non-Saccharomyces yeasts on the chemical and sensory attributes of red and white wines with added pectin. Merlot and Chardonnay wines were produced with or without a mixture of pectinase-producing non-Saccharomyces yeasts (Cryptococcus adeliensis, Issatchenkia orientalis, and Pichia kluyveri) added to the must prior to alcoholic fermentation conducted by a commercial strain of Saccharomyces cerevisiae. To ensure sufficient substrate was present, varying concentrations of apple pectin (up to 1.25 g/L for red wines and 1.00 g/L for white wine) were added at the start of fermentation. After bottling, trained panelists (n = 10) analyzed these wines for aroma, flavor, taste, and mouthfeel attributes. For both wines, significant interactions were noted between the presence of non-Saccharomyces yeasts and pectin addition which affected pH, titratable acidity, and concentrations of D-galacturonic acid. While no significant sensory differences were observed among the red wines, limited changes were noted for white wines. However, a strong positive correlation was found between the D-galacturonic acid and buttery aroma for Chardonnay and with flavor for Merlot. Increasing D-galacturonic acid concentrations, through utilization of non-Saccharomyces yeasts, may improve the wine quality as a buttery aroma is often associated with high-quality Chardonnay. For both red and white wines, the utilization of these particular non-Saccharomyces yeasts significantly influenced chemical properties but yielded minor sensory changes without any faults. PRACTICAL APPLICATION: With the recent trend to reduce alcohol content in commercial wines, the interest in non-Saccharomyces yeasts has grown. This study showed that the addition of non-Saccharomyces yeasts, perhaps due to their pectinase activity, influenced the chemical characteristics of red and white wines with limited sensory differences, making these yeasts a useful tool for winemakers to modify wine properties.

Of 1003 children with acute lymphoblastic leukaemia (ALL), 147 (14.7%) presented without peripheral blood blasts (PBB). While absence of PBB was not independently associated with survival outcomes when compared to those with PBB, patients without PBB had distinct genetic and clinical characteristics. Notably, we identified a novel genotype-phenotype relationship, in that the patients without PBB had a significantly higher incidence of hyperdiploid B-ALL, accounting for almost half of all patients without PBB (46.9% vs. 22.7%, p 0.001). Further, absence of PBB was associated with decreased rates of leukaemia involvement of the central nervous system (p 0.001).

Several species of Streptomyces cause common scab, a major disease of potato, primarily through the phytotoxic effects of the phytotoxin thaxtomin A. Several phytopathogenic Streptomyces species have also been implicated as the causative agents of scab diseases of taproot crops including beet, carrot, radish, parsnip, and turnip. But the molecular mechanisms employed by Streptomyces to infect these crops is unknown. In this work, we tested the hypothesis that thaxtomin A biosynthesis is also necessary for Streptomyces-caused scab of beet, carrot, radish, and turnip. Thaxtomin A induced plant stunting and cell death of all four of these species. Streptomyces mutants in which the transcriptional regulator of thaxtomin A biosynthesis is disrupted were nonvirulent on all four crops, and complementation of the transcriptional regulator rescued thaxtomin A biosynthesis and plant pathogenicity to wild-type levels. These results demonstrate that thaxtomin A is the primary virulence determinant of scab disease of these other crops.

Background Intensive chemotherapeutic regimens with craniospinal irradiation have greatly improved survival in medulloblastoma patients. However, survival markedly differs among molecular subgroups and their biomarkers are unknown. Through unbiased screening, we found Schlafen family member 11 (SLFN11), which is known to improve response to DNA damaging agents in various cancers, to be one of the top prognostic markers in medulloblastomas. Hence, we explored the expression and functions of SLFN11 in medulloblastoma. Methods SLFN11 expression for each subgroup was assessed by immunohistochemistry in 98 medulloblastoma patient samples and by analyzing transcriptomic databases. We genetically or epigenetically modulated SLFN11 expression in medulloblastoma cell lines and determined cytotoxic response to the DNA damaging agents cisplatin and topoisomerase I inhibitor SN-38 in vitro and in vivo. Results High SLFN11 expressing cases exhibited significantly longer survival than low expressing cases. SLFN11 was highly expressed in the WNT-activated subgroup and in a proportion of the SHH-activated subgroup. While WNT activation was not a direct cause of the high expression of SLFN11, a specific hypomethylation locus on the SLFN11 promoter was significantly correlated with high SLFN11 expression. Overexpression or deletion of SLFN11 made medulloblastoma cells sensitive and resistant to cisplatin and SN-38, respectively. Pharmacological upregulation of SLFN11 by the brain-penetrant histone deacetylase-inhibitor RG2833 markedly increased sensitivity to cisplatin and SN-38 in SLFN11-negative medulloblastoma cells. Intracranial xenograft studies also showed marked sensitivity to cisplatin by SLFN11-overexpression in medulloblastoma cells. Conclusions High SLFN11 expression is one factor which renders favorable outcomes in WNT-activated and a subset of SHH-activated medulloblastoma possibly through enhancing response to cisplatin.

Recent advancements in understanding the biology of glioblastomas (GBM) and increasing adoption of genomic sequencing in oncology practice have led to the discovery of several targetable mutations in these cancers. Among them, the BRAF V600E mutation can be found in approximately 3% of GBM. Despite the aggressive nature of GBM, metastatic disease is rarely observed. While there are growing data utilizing BRAF-targeting strategies in patients with GBM, data examining their efficacy in cases of metastatic GBM are lacking. We present the case of a 46-year-old female with GBM, isocitrate dehydrogenase (IDH)-wildtype and O6-methylguanine-DNA methyltransferase promoter (MGMT) unmethylated, BRAF V600E-mutant, and MYC amplified with extra-central nervous system spread to the spine and lung. Four months after completion of treatment with standard chemoradiation and temozolomide, the patient developed severe back pain, leading to the eventual discovery of her metastatic disease. Based on the presence of the BRAF V600E mutation, the patient was treated with and achieved an intracranial and systemic response to combination BRAF-MEK targeted inhibition for 9 months before evidence of progression.

Purpose: In many cancers, nivolumab in combination with ipilimumab improves response rates compared with either agent alone, but the combination has not been evaluated in childhood cancer. We conducted a phase I/II trial of nivolumab plus ipilimumab in children and young adults with recurrent/refractory solid tumors. Patients and Methods: ADVL1412, Part C assessed safety of nivolumab plus ipilimumab at two dose levels (DL): DL1 1 mg/kg of each drug and DL2 3 mg/kg nivolumab plus 1 mg/kg ipilimumab. Part D evaluated response at the recommended phase II dose (RP2D) in Ewing sarcoma, rhabdomyosarcoma, and osteosarcoma. Part E tested DL3 (1 mg/kg nivolumab plus 3 mg/kg ipilimumab) in Ewing sarcoma and rhabdomyosarcoma. Tumor response was measured using RECIST v1.1. Pharmacokinetics and PD-L1 expression on archival tissues were assessed. Results: Fifty-five eligible patients enrolled. Based on safety, tolerability, and similar drug exposure to the same doses administered in adults, DL2 was defined as the pediatric RP2D. Among 41 patients treated at the RP2D, 2 patients experienced dose-limiting toxicities during cycle 1, and 4 patients experienced toxicities beyond that period. Two patients had clinically significant sustained partial responses (1 rhabdomyosarcoma, 1 Ewing sarcoma) and 4 had stable disease. Among 8 patients treated at DL3, 3 dose-limiting toxicities (DLT) occurred, all immune-related adverse events; no objective responses were observed. Conclusions: The RP2D of nivolumab (3 mg/kg) plus ipilimumab (1 mg/kg) is well tolerated in children and young adults with solid tumors and shows some clinical activity. Increased dose of ipilimumab (3 mg/kg) plus nivolumab (1 mg/kg) was associated with increased toxicity without clinical benefit.

OBJECTIVE In multilevel posterior cervical instrumented fusion, extension of fusion across the cervicothoracic junction (CTJ) at T1 or T2 has been associated with decreased rates of reoperation and pseudarthrosis but with longer surgical time and increased blood loss. The impact on patient-reported outcomes (PROs) remains unclear. The primary objective was to determine whether extension of fusion through the CTJ influenced PROs at 3, 12, and 24 months after surgery. The secondary objective was to compare the number of patients who reached the minimal clinically important differences (MCIDs) for the PROs, modified Japanese Orthopaedic Association (mJOA) score, operative time, intraoperative blood loss, length of stay, discharge disposition, adverse events (AEs), reoperation within 24 months of surgery, and patient satisfaction. METHODS This was a retrospective observational cohort study of prospectively collected multicenter data of patients with degenerative cervical myelopathy. Patients who underwent posterior instrumented fusion of 4 levels or greater (between C2 and T2) between January 2015 and October 2020 and received 24 months of follow-up were included. PROs (scores on the Neck Disability Index [NDI], EQ-5D, physical component summary and mental component summary of SF-12, and numeric rating scale for arm and neck pain) and mJOA scores were compared using ANCOVA and adjusted for baseline differences. Patient demographic characteristics, comorbidities, and surgical details were abstracted. The proportions of patients who reached the MCIDs for these outcomes were compared with the chi-square test. Operative duration, intraoperative blood loss, AEs, reoperation, discharge disposition, length of stay, and satisfaction was compared by using the chi-square test for categorical variables and the independent-samples t-test for continuous variables. RESULTS A total of 198 patients were included in this study (101 patients with fusion not crossing the CTJ and 97 with fusion crossing the CTJ). Patients with a construct extending through the CTJ were more likely to be female and have worse baseline NDI scores (p > 0.05). When adjusted for baseline differences, there were no statistically significant differences between the two groups in terms of the PROs and mJOA scores at 3, 12, and 24 months. Surgical duration was longer (p < 0.001) and intraoperative blood loss was greater in the group with fusion extending to the upper thoracic spine (p = 0.013). There were no significant differences between groups in terms of AEs (p > 0.05). Fusion with a construct crossing the CTJ was associated with reoperation (p = 0.04). Satisfaction with surgery was not significantly different between groups. The proportions of patients who reached the MCIDs for the PROs were not statistically different at any time point. CONCLUSIONS There were no statistically significant differences in PROs between patients with a posterior construct extending to the upper thoracic spine and those without such extension for as long as 24 months after surgery. The AE profiles were not significantly different, but longer surgical time and increased blood loss were associated with constructs extending across the CTJ.

Objective To correlate the histopathologic results of conjunctival specimens with clinical findings in patients with conjunctivochalasis and report the results of the paste-pinch-cut technique for management. Design Retrospective chart review. Methods SETTING: Single tertiary ophthalmological centre (Ocular Surface Diseases and Dry Eye Clinic, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Md.). Methods Twenty-five patients (32 eyes) with clinically significant conjunctivochalasis. All patients were referred for clinically significant dry eye without previous diagnosis of chalasis. Sixteen patients had an underlying inflammatory systemic condition. Intervention or Observation Procedure(s): Patients underwent surgery with paste-pinch-cut technique. Subjective dry eye symptoms and ocular surface staining scores (corneal and conjunctival staining using fluorescein and lissamine green respectively) were assessed at every visit. Main outcome measures Change in patient symptoms and ocular surface staining scores and histopathologic findings in conjunctival specimens. Results After surgery, significant improvement was achieved in dry-eye symptoms as well as both corneal and conjunctival staining scores in 29 eyes on reduced topical therapy. Only 3 eyes had persisting conjunctival lissamine staining. Light microscopic examination disclosed mild to moderate lymphoplasmocytic inflammation of the conjunctivae with areas of epithelial goblet cell loss, squamous metaplasia, stromal edema, and fibrosis. Conclusion Conjunctivochalasis appears to be associated with significant inflammation in the setting of dry eye and underlying inflammatory systemic conditions. Although topical anti-inflammatory treatment could be attempted in the initial management, surgical excision should be considered in the absence of clinical response.

Medulloblastoma (MB) comprises a group of heterogeneous paediatric embryonal neoplasms of the hindbrain with strong links to early development of the hindbrain 1–4. Mutations that activate Sonic hedgehog signalling lead to Sonic hedgehog MB in the upper rhombic lip (RL) granule cell lineage 5–8. By contrast, mutations that activate WNT signalling lead to WNT MB in the lower RL 9,10. However, little is known about the more commonly occurring group 4 (G4) MB, which is thought to arise in the unipolar brush cell lineage 3,4. Here we demonstrate that somatic mutations that cause G4 MB converge on the core binding factor alpha (CBFA) complex and mutually exclusive alterations that affect CBFA2T2, CBFA2T3, PRDM6, UTX and OTX2. CBFA2T2 is expressed early in the progenitor cells of the cerebellar RL subventricular zone in Homo sapiens, and G4 MB transcriptionally resembles these progenitors but are stalled in developmental time. Knockdown of OTX2 in model systems relieves this differentiation blockade, which allows MB cells to spontaneously proceed along normal developmental differentiation trajectories. The specific nature of the split human RL, which is destined to generate most of the neurons in the human brain, and its high level of susceptible EOMES +KI67 + unipolar brush cell progenitor cells probably predisposes our species to the development of G4 MB.

The ancient human footprints in valley-bottom sediments in Tularosa Valley, New Mexico, are fascinating and potentially important because they suggest interactions between Pleistocene megafauna as well as great antiquity. The dating of those footprints is crucial in interpretations of when humans first came to North America from Asia, but the ages have larger uncertainties than has been reported. Some of that uncertainty is related to the possibility of a radiocarbon reservoir in the water in which the dated propagules of Ruppia cirrhosa grew. As a test of that possibility, Ruppia specimens collected in 1947 from nearby Malpais Spring returned a radiocarbon age of ca. 7400 cal yr BP. We think it would be appropriate to devise and implement independent means for dating the footprints, thus lowering the uncertainty in the proposed age of the footprints and leading to a better understanding of when humans first arrived in the Americas.

Purpose: To evaluate AZD4635, an adenosine A2A receptor antagonist, as monotherapy or in combination with durvalumab in patients with advanced solid tumors. Patients and Methods: In phase Ia (dose escalation), patients had relapsed/refractory solid tumors; in phase Ib (dose expansion), patients had checkpoint inhibitor–naïve metastatic castration-resistant prostate cancer (mCRPC) or colorectal carcinoma, non–small cell lung cancer with prior anti–PD-1/PD-L1 exposure, or other solid tumors (checkpoint-naïve or prior anti–PD-1/PD-L1 exposure). Patients received AZD4635 monotherapy (75–200 mg once daily or 125 mg twice daily) or in combination with durvalumab (AZD4635 75 or 100 mg once daily). The primary objective was safety; secondary objectives included antitumor activity and pharmacokinetics; exploratory objectives included evaluation of an adenosine gene signature in patients with mCRPC. Results: As of September 8, 2020, 250 patients were treated (AZD4635, n = 161; AZD4635+durvalumab, n = 89). In phase Ia, DLTs were observed with monotherapy (125 mg twice daily; n = 2) and with combination treatment (75 mg; n = 1) in patients receiving nanosuspension. The most common treatment-related adverse events included nausea, fatigue, vomiting, decreased appetite, dizziness, and diarrhea. The RP2D of the AZD4635 capsule formulation was 75 mg once daily, as monotherapy or in combination with durvalumab. The pharmacokinetic profile was dose-proportional, and exposure was adequate to cover target with 100 mg nanosuspension or 75 mg capsule once daily. In patients with mCRPC receiving monotherapy or combination treatment, tumor responses (2/39 and 6/37, respectively) and prostate-specific antigen responses (3/60 and 10/45, respectively) were observed. High versus low blood-based adenosine signature was associated with median progression-free survival of 21 weeks versus 8.7 weeks. Conclusions: AZD4635 monotherapy or combination therapy was well tolerated. Objective responses support additional phase II combination studies in patients with mCRPC.

Background Elevated oxidative stress (OxS), mitochondrial dysfunction, and hallmarks of aging are identified as key contributors to aging, but improving/reversing these defects in older adults (OA) is challenging. In prior studies, we identified that deficiency of the intracellular antioxidant glutathione (GSH) could play a role and reported that supplementing GlyNAC (combination of glycine and N-acetylcysteine [NAC]) in aged mice improved GSH deficiency, OxS, mitochondrial fatty-acid oxidation (MFO), and insulin resistance (IR). To test whether GlyNAC supplementation in OA could improve GSH deficiency, OxS, mitochondrial dysfunction, IR, physical function, and aging hallmarks, we conducted a placebo-controlled randomized clinical trial. Methods Twenty-four OA and 12 young adults (YA) were studied. OA was randomized to receive either GlyNAC (N = 12) or isonitrogenous alanine placebo (N = 12) for 16-weeks; YA (N = 12) received GlyNAC for 2-weeks. Participants were studied before, after 2-weeks, and after 16-weeks of supplementation to assess GSH concentrations, OxS, MFO, molecular regulators of energy metabolism, inflammation, endothelial function, IR, aging hallmarks, gait speed, muscle strength, 6-minute walk test, body composition, and blood pressure. Results Compared to YA, OA had GSH deficiency, OxS, mitochondrial dysfunction (with defective molecular regulation), inflammation, endothelial dysfunction, IR, multiple aging hallmarks, impaired physical function, increased waist circumference, and systolic blood pressure. GlyNAC (and not placebo) supplementation in OA improved/corrected these defects. Conclusion GlyNAC supplementation in OA for 16-weeks was safe and well-tolerated. By combining the benefits of glycine, NAC and GSH, GlyNAC is an effective nutritional supplement that improves and reverses multiple age-associated abnormalities to promote health in aging humans. Clinical Trials Registration Number: NCT01870193

Unidad de excelencia María de Maeztu CEX2019-000940-M Atmospheric soot loadings from nuclear weapon detonation would cause disruptions to the Earth's climate, limiting terrestrial and aquatic food production. Here, we use climate, crop and fishery models to estimate the impacts arising from six scenarios of stratospheric soot injection, predicting the total food calories available in each nation post-war after stored food is consumed. In quantifying impacts away from target areas, we demonstrate that soot injections larger than 5 Tg would lead to mass food shortages, and livestock and aquatic food production would be unable to compensate for reduced crop output, in almost all countries. Adaptation measures such as food waste reduction would have limited impact on increasing available calories. We estimate more than 2 billion people could die from nuclear war between India and Pakistan, and more than 5 billion could die from a war between the United States and Russia-underlining the importance of global cooperation in preventing nuclear war.

Access to high quality and accessible online health information (OHI) is critical for reducing disparities, overcoming barriers, and improving the health of women with disabilities. This study aimed to understand women with physical disabilities' use of the Internet to access OHI, most often searched health topics, perceived usefulness of OHI, and self-reported eHealth literacy and challenges in OHI seeking.We conducted a national online survey with 508 women with physical disabilities who used the Internet.Respondents utilized a wide variety of OHI resources. They searched a broad array of health and disability-related topics, with bowel/bladder and finding a physician the most highly searched topics. They generally had confidence in their eHealth literacy skills and ability to understand statistics in OHI. Nevertheless, although our sample consisted of a majority of highly educated internet-users, a sizeable percentage found OHI seeking difficult and frustrating, did not find the information very helpful, and had concerns about the quality of information.This study serves as a call to action to disability and rehabilitation scientists, health care providers, and other health professionals to enhance the availability and accessibility of OHI critical to empowering women with physical disabilities to make well-informed health decisions. Implications for rehabilitationAccess to high quality online health information (OHI) is critical for reducing disparities, overcoming barriers, and improving the health of women with disabilities.Many of the women with disabilities in our study found OHI seeking difficult and frustrating, did not find the information very helpful, and had concerns about the quality of the information.Disability and rehabilitation scientists, health care providers, and public health and health policy professionals need to do more to enhance the availability and accessibility of OHI and resources critical to empowering women with physical disabilities to make well-informed health decisions.Physical medicine and rehabilitation scientists are encouraged to develop and improve assistive technologies needed for accessing OHI, which in turn can promote the independent functioning of people with disabilities.

Ultrasound-based blood flow (BF) monitoring is vital in the diagnosis and treatment of a variety of cardiovascular and neurologic conditions. Finite spatial resolution of clinical color flow (CF) systems, however, has hampered measurement of vessel cross Section areas. We propose a resolution enhancement technique that allows reliable determination of BF in small vessels. We leverage sparsity in the spatial distribution of the frequency spectrum of routinely collected CF data to blindly determine the point spread function (PSF) of the imaging system in a robust manner. The CF data are then deconvolved with the PSF, and the volumetric flow is computed using the resulting velocity profiles. Data were collected from phantom blood vessels with diameters between 2 and 6 mm using a clinical ultrasound system at 2 MHz insonation frequency. The proposed method yielded a flow estimation bias of 0 mL/min, standard deviation of error (SDE) of 22 mL/min, and a root-mean-square error (RMSE) of 22 mL/min over a 150 mL/min range of mean flows. Recordings were also obtained in low signal-to-noise ratio (SNR) conditions using a skull mimicking element, resulting in an estimation bias of -13 mL/min, SDE of 23 mL/min, and an RMSE of 26 mL/min. The effect of insonation frequency was also investigated by obtaining recordings at 4.3 MHz, yielding an estimation bias of -16 mL/min, SDE of 16 mL/min, and an RMSE of 22 mL/min. The results indicate that our technique can lead to clinically acceptable flow measurements across a range of vessel diameters in high and low SNR regimes.

The new experimental measurements of beam spin asymmetry were performed for the deeply virtual exclusive $\pi^0$ production in a wide kinematic region with the photon virtualities $Q^2$ up to 8 GeV$^2$ and the Bjorken scaling variable $x_B$ in the valence regime. The data were collected by the CEBAF Large Acceptance Spectrometer (CLAS12) at Jefferson Lab with longitudinally polarized 10.6 GeV electrons scattered on an unpolarized liquid-hydrogen target. Sizable asymmetry values indicate a substantial contribution from transverse virtual photon amplitudes to the polarized structure functions.The interpretation of these measurements in terms of the Generalized Parton Distributions (GPDs) demonstrates their sensitivity to the chiral-odd GPD $\bar E_T$, which contains information on quark transverse spin densities in unpolarized and polarized nucleons and provides access to the proton's transverse anomalous magnetic moment. Additionally, the data were compared to a theoretical model based on a Regge formalism that was extended to the high photon virtualities., Comment: arXiv admin note: substantial text overlap with arXiv:2210.14557

The polarized cross-section ratio σLT′/σ0 from hard exclusive π−Δ++ electroproduction off an unpolarized hydrogen target has been extracted based on beam-spin asymmetry measurements using a 10.2 GeV/10.6 GeV incident electron beam and the CLAS12 spectrometer at Jefferson Lab. The study, which provides the first observation of this channel in the deep-inelastic regime, focuses on very forward-pion kinematics in the valence regime, and photon virtualities ranging from 1.5 GeV2 up to 7 GeV2. The reaction provides a novel access to the d-quark content of the nucleon and to p→Δ++ transition generalized parton distributions. A comparison to existing results for hard exclusive π+n and π0p electroproduction is provided, which shows a clear impact of the excitation mechanism, encoded in transition generalized parton distributions, on the asymmetry.

The study utilized IoT technology to improve parking efficiency and user convenience. The system contained a device that can accurately detect the status of parking slots. This includes when a slot is occupied, vacant, or reserved. When an unauthorized vehicle occupies a reserved slot, the equipped alarm system is triggered. The system also features a mobile application that provides real-time information on nearby parking lots and their status. The application included reservation and navigation features, supports secure payment options, and incorporates a smart redirection feature to guide users to alternative parking lots when their chosen option is full. The hardware device achieved 100% accuracy in slot status detection. In all the trials conducted, the alarm system succeeded in alerting unauthorized vehicles. The smart redirection feature successfully navigated users to nearby available parking lots when their initial choice was full. The findings demonstrate the system's working functionality. The system passed in the conducted tests suggesting that it can improve driver experience when looking for parking.

Douglas Channel is the principal shipping route between the town of Kitimat and the Pacific Ocean. Prediction of near-surface currents is crucial for safe tanker navigation and cleaning-up oil spills. Three years of current velocity data were collected at two moorings located 30 km apart. Spectral, wavelet, and harmonic analysis of measured currents throughout the upper (40-m) and lower (50–358 m) water columns indicated the predominant influence of semidiurnal (SD) tidal currents. In the upper layer, wind and density flows resulted in considerable seasonal and interannual variability of these currents. Analysis of the SD variance reveals three major components: barotropic, coherent baroclinic, and random baroclinic. The predictability of near-surface currents depends on the relative contribution and stability of the first two components. Tidal constants estimated for one year were used to predict currents for two other years; we found that at the mooring closer to the entrance of Douglas Channel, 80 to 89% of the SD energy in the upper layer and 89–93% in the lower layer can be forecasted, while closer to the two channel head, these numbers are smaller: 55–70% and 79–89%, respectively.

In-plume ozone depletion was observed for about ten days by Microwave Limb Sounder (Aura/MLS) right after the January 2022 Hunga Tonga-Hunga Ha’apai (HTHH) eruption. This work analyzes the dynamic and chemical causes of this ozone depletion. The results show that the large water injection (~150 Tg) from the HTHH eruption, with ~0.0013 Tg injection of ClO (or ~0.0009 Tg of HCl), causes ozone loss due to strongly enhanced HOx and ClOx cycles and their interactions. Aside from the gas phase chemistry, the heterogeneous reaction rate for HOCl+HCl→Cl2+H2O increases to 104 cm-3 sec-1 and is a major cause of chlorine activation, making this event unique compared with the springtime polar ozone depletion where HCl+ClONO2 is more important. The large water injection causes relative humidity over ice to increase to 70 %–100 %, decreases the H2SO4/H2O binary solution weight percent to 35 % compared with the 70 % ambient value, and decreases the plume temperature by 2–6 K. These changes lead to high heterogeneous reaction rates. Plume lofting of ozone-poor air is evident during the first two days after the eruption, but ozone concentrations quickly recover because its chemical lifetime is short at 20 hPa. With such a large seawater injection, we expect that ~5 Tg Cl was lifted into the stratosphere by the HTHH eruption in the form of NaCl, but only ~0.02 % of that remained as active chlorine in the stratosphere. lightning NOx changes are not the reason for the HTHH initial in-plume O3 loss.

The direct effects of nuclear war would be horrific, with blasts, fires, and radiation killing and injuring many people. But in 1983, United States and Soviet Union scientists showed that a nuclear war could also produce a nuclear winter, with catastrophic consequences for global food supplies for people far removed from the conflict. Smoke from fires ignited by nuclear weapons exploded on cities and industrial targets would block out sunlight, causing dark, cold, and dry surface conditions, producing a nuclear winter, with surface temperatures below freezing even in summer for years. Nuclear winter theory helped to end the nuclear arms race in the 1980s and helped to produce the Treaty on the Prohibition of Nuclear Weapons in 2017, for which the International Campaign to Abolish Nuclear Weapons received the 2017 Nobel Peace Prize. Because awareness of nuclear winter is now widespread, nuclear nations have so far not used nuclear weapons. But the mere existence of nuclear weapons means that they can be used, by unstable leaders, accidently from technical malfunctions, such as in computers and sensors, due to human error, or by terrorists. Because they cannot be used without the danger of escalation (resulting in a global humanitarian catastrophe), because of recent threats to use them by Russia, and because nuclear deterrence doctrines of all nuclear-armed states are based on the capability and readiness to use nuclear weapons, it is even more urgent for scientists to study these issues, to broadly communicate their results, and to work for the elimination of nuclear weapons.