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Drought is one of the key environmental factors affecting the growth and yield potential of rice. Grain shape, on the other hand, is an important factor determining the appearance, quality, and yield of rice grains. Here, we re-sequenced 275 Xian accessions and then conducted a genome-wide association study (GWAS) on six agronomic traits with the 404,411 single nucleotide polymorphisms (SNPs) derived by the best linear unbiased prediction (BLUP) for each trait. Under two years of drought stress (DS) and normal water (NW) treatments, a total of 16 QTLs associated with rice grain shape and grain weight were detected on chromosomes 1, 2, 3, 4, 5, 7, 8, 11, and 12. In addition, these QTLs were analyzed by haplotype analysis and functional annotation, and one clone (GSN1) and five new candidate genes were identified in the candidate interval. The findings provide important genetic information for the molecular improvement of grain shape and weight in rice.

Recent data suggest that patients with stage III melanoma are at high risk for developing central nervous system (CNS) metastases. Because a subset of patients with stage II melanoma experiences worse survival outcomes than some patients with stage III disease, the authors investigated the risk of CNS metastasis in stage II melanoma to inform surveillance guidelines for this population.The authors examined clinicopathologic data prospectively collected from 1054 patients who had cutaneous melanoma. The χPatients with stage III melanoma had a higher rate of developing brain metastases than those with stage II melanoma (100 of 468 patients [21.4%] vs. 82 of 586 patients [14.0%], respectively; p = .002). However, patients who had stage IIC melanoma had a significantly higher rate of isolated first recurrences in the CNS compared with those who had stage III disease (12.1% vs. 3.6%; p = .002). The risk of ever developing brain metastases was similarly elevated for patients who had stage IIC disease (hazard ratio [HR], 3.16; 95% CI, 1.77-5.66), stage IIIB disease (HR, 2.83; 95% CI, 1.63-4.91), and stage IIIC disease (HR, 2.93; 95% CI, 1.81-4.74), and the risk was highest in patients who had stage IIID disease (HR, 8.59; 95% CI: 4.11-17.97).Patients with stage IIC melanoma are at elevated risk for first recurrence in the CNS. Surveillance strategies that incorporate serial neuroimaging should be considered for these individuals until more accurate predictive markers can be identified.

BACKGROUND: Although most patients with cutaneous melanoma are non-Hispanic whites (NHWs), minorities consistently suffer worse melanoma-specific survival (MSS). Much of the literature comes from analyses of registries from the 1990s and 2000s. OBJECTIVE: We sought to evaluate whether and to what degree racial disparity in MSS persists since 2010. METHODS: We analyzed 381,035 patients from the Surveillance, Epidemiology, and End Results registry. Race categories included Hispanic, NHW, non-Hispanic black (NHB), non-Hispanic Asian or Pacific Islander (NHAPI), and non-Hispanic American Indian/Alaska Native (NHAIAN). We evaluated the association between MSS and race in 3 time periods: before the year 2000, 2000 to 2009, and 2010 or later. NHW was the reference group for all analyses. RESULTS: Racial disparity worsened from before the year 2000 to 2010 or later for Hispanic (P

Objectives The number of older adults on methadone maintenance treatment (MMT) for opioid use disorder is increasing, but little is known about the characteristics and healthcare needs of this aging treatment population. This population may experience accelerated aging due to comorbidities and health behaviors. The aim of this study was to compare the prevalence of geriatric conditions among adults age ≥50 on MMT to a nationally representative sample of community-dwelling older adults. Methods We performed a geriatric assessment on 47 adults age ≥50 currently on MMT enrolled in 2 opioid treatment programs, in New York City and in East Providence, Rhode Island. We collected data on self-reported geriatric conditions, healthcare utilization, chronic medical conditions, physical function, and substance use. The results were compared to 470 age, sex, and race/ethnicity-matched adults in the national Health and Retirement Study. Results The mean age of the study sample was 58.8 years and 23.4% were female. The most common chronic diseases were hypertension (59.6%) and arthritis (55.3%) with 66% reporting ≥2 diseases. For geriatric conditions, adults on MMT had a significantly higher prevalence of mobility, hearing, and visual impairments as well as falls, urinary incontinence, chronic pain, and insomnia than the Health and Retirement Study sample. Conclusions Older adults on MMT in 2 large opioid treatment programs have a high prevalence of geriatric conditions. An interdisciplinary, geriatric-based approach to care that focuses on function and addresses geriatric conditions is needed to improve the health of this growing population.

A variety of algorithms have been proposed to cope with issues associated with local refinements of numerical grids typically employed to cope with subsurface flow driven by sources acting on diverse scales (e.g., pumping wells, channels or ditches or abrupt changes in hydraulic conductivity distributions). In this context, here we focus on grid refinement associated with nonmatching grids, which still pose significant challenges in terms of accuracy. We propose a numerical modeling scheme based on a new algorithm that has an improved accuracy when compared against approaches that are typically used in conjunction with nonmatching grids. Our approach is based on the vertex-centred finite-volume method (VCFVM), the key feature of the algorithm resting on setting all unknowns on vertices of the mesh elements while the flux crossing a lateral surface of the control volume centred around a mesh vertex is expressed as a function of the hydraulic heads at the vertices of the element containing the lateral surface. A given row of the stiffness matrix of the system includes the entries associated with mass conservation formulated for the control volume associated with a corresponding grid node. Since the algorithm sets all unknowns on element vertices and a control volume can be defined for each vertex, our scheme readily embeds treatment of nonmatching grids in the presence of local grid refinement. Hydraulic heads evaluated through our algorithm are benchmarked against (a) results obtained from the widely used and tested MODFLOW and MODFLOW6 groundwater modeling suites in the presence of a variety of boundary conditions and considering high resolution matching (for MODFLOW) and nonmatching (for MODFLOW6) grids, and (b) a test analytical solution. Our results show that the average value of relative root mean square error (RRMSE) resulting from comparing our approach against the analytical solution and the MODFLOW simulations performed on the highly resolved grid (which we consider as reference) was always lower than 0.50%, thus imbuing us with confidence with respect to the accuracy of our proposed scheme. Additionally, while the requirement of CPU time associated with our algorithm is of the same order (on average) as the one associated with MODFLOW6 (benefits being noted mainly for settings involving flow in confined groundwater scenarios), our scheme is highly flexible in terms of spatial discretization and is characterized by higher accuracy for a given discretization.

Background Immune checkpoint inhibition (ICI) improves survival outcomes for patients with several types of cancer including metastatic melanoma (MM), but serious immune-related adverse events requiring intervention with immunosuppressive medications occur in a subset of patients. Skin toxicity (ST) has been reported to be associated with better response to ICI. However, understudied factors, such as ST severity and potential survivor bias, may influence the strength of these observed associations. Methods To examine the potential confounding impact of such variables, we analyzed advanced cancer patients enrolled prospectively in a clinicopathological database with protocol-driven follow up and treated with ICI. We tested the associations between developing ST, stratified as no (n = 617), mild (n = 191), and severe (n = 63), and progression-free survival (PFS) and overall survival (OS) in univariable and multivariable analyses. We defined severe ST as a skin event that required treatment with systemic corticosteroids. To account for the possibility of longer survival associating with adverse events instead of the reverse, we treated ST as a time-dependent covariate in an adjusted model. Results Both mild and severe ST were significantly associated with improved PFS and OS (all P Conclusions Our data reveal the influence of time to event and its severity as covariates in analyzing the relationship between ST and ICI outcomes. These differences in outcomes cannot be solely explained by the use of immunosuppressive medications, and thus highlight the importance of host- and disease-intrinsic factors in determining ICI response and toxicity. Trial registration: The patient data used in this manuscript come from patients who were prospectively enrolled in two institutional review board-approved databases at NYU Langone Health (institutional review board #10362 and #S16-00122).

This study investigates the influence of clogging substances on pore characteristics and permeability of geotextile envelopes that were used for 3, 7 and 15 years in irrigated farmlands in Xinjiang region, which is arid and suffers from the soil salinity problem. Results show that the macropores (above 125 μm) of envelopes are evidently clogged, whereas the smaller pores less than 100 μm are still unblocked after operation. The permeability coefficients of geotextile envelopes after serving for 3 and 15 years are smaller than the minimum required permeability coefficients after clogging. The main chemical components of clogging substances in the geotextile envelope are silicon dioxide and calcium carbonate. Calcium carbonate content of the geotextile envelope is consistent with calcium carbonate content of soil. Chemical clogging susceptibility increases with the operation time of the subsurface drainage pipes. The ratio of O90 size of envelope material over d90 of soils (O90/d90) and saturation index (SI) can be used to assess the susceptibility of physical and chemical clogging respectively. This study provides a preliminary reference for estimating the clogging susceptibility of geotextile envelopes in arid areas.

The aim of this study was to determine the prevalence of myocarditis among patients presenting with myocardial infarction with nonobstructive coronary arteries (MINOCA) in relation to the angiographic severity of nonobstructive coronary artery disease (CAD).MINOCA represents about 6% of all cases of acute myocardial infarction. Myocarditis is a diagnosis that may be identified by cardiac magnetic resonance (CMR) imaging in patients with a provisional diagnosis of MINOCA.A systematic review was performed to identify studies reporting the results of CMR findings in MINOCA patients with nonobstructive CAD or normal coronary arteries. Study-level and individual patient data meta-analyses were performed using fixed- and random-effects methods.Twenty-seven papers were included, with 2,921 patients with MINOCA; CMR findings were reported in 2,866 (98.1%). Myocarditis prevalence was 34.5% (95% confidence interval [CI]: 27.2% to 42.2%) overall and was numerically higher in studies that defined MINOCA as myocardial infarction with angiographically normal coronary arteries compared with a definition that permitted nonobstructive CAD (45.9% vs. 32.3%; p = 0.16). In a meta-analysis of individual patient data from 9 of the 27 studies, the pooled prevalence of CMR-confirmed myocarditis was greater in patients with angiographically normal coronary arteries than in those with nonobstructive CAD (51% [95% CI: 47% to 56%] vs. 23% [95% CI: 18% to 27%]; p 0.001). Men and younger patients with MINOCA were more likely to have myocarditis. Angiographically normal coronary arteries were associated with increased odds of myocarditis after adjustment for age and sex (adjusted odds ratio: 2.30; 95% CI: 1.12 to 4.71; p = 0.023).Patients with a provisional diagnosis of MINOCA are more likely to have CMR findings consistent with myocarditis if they have angiographically normal coronary arteries.

Multiple system atrophy (MSA) is a fatal neurodegenerative disease characterized by the aggregation of α-synuclein in glia and neurons. Sirolimus (rapamycin) is an mTOR inhibitor that promotes α-synuclein autophagy and reduces its associated neurotoxicity in preclinical models.To investigate the efficacy and safety of sirolimus in patients with MSA using a futility design. We also analyzed 1-year biomarker trajectories in the trial participants.Randomized, double-blind, parallel group, placebo-controlled clinical trial at the New York University of patients with probable MSA randomly assigned (3:1) to sirolimus (2-6 mg daily) for 48 weeks or placebo. Primary endpoint was change in the Unified MSA Rating Scale (UMSARS) total score from baseline to 48 weeks. (ClinicalTrials.gov NCT03589976).The trial was stopped after a pre-planned interim analysis met futility criteria. Between August 15, 2018 and November 15, 2020, 54 participants were screened, and 47 enrolled and randomly assigned (35 sirolimus, 12 placebo). Of those randomized, 34 were included in the intention-to-treat analysis. There was no difference in change from baseline to week 48 between the sirolimus and placebo in UMSARS total score (mean difference, 2.66; 95% CI, -7.35-6.91; P = 0.648). There was no difference in UMSARS-1 and UMSARS-2 scores either. UMSARS scores changes were similar to those reported in natural history studies. Neuroimaging and blood biomarker results were similar in the sirolimus and placebo groups. Adverse events were more frequent with sirolimus. Analysis of 1-year biomarker trajectories in all participants showed that increases in blood neurofilament light chain (NfL) and reductions in whole brain volume correlated best with UMSARS progression.Sirolimus for 48 weeks was futile to slow the progression of MSA and had no effect on biomarkers compared to placebo. One-year change in blood NfL and whole brain atrophy are promising biomarkers of disease progression for future clinical trials. © 2022 International Parkinson and Movement Disorder Society.

Background Early reports on cancer patients with coronavirus disease 2019 (COVID‐19) corroborated speculation that cancer patients are at increased risk for becoming infected with severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) and developing severe COVID‐19. However, cancer patients are a heterogeneous population and their corresponding risk may be different. Aim To compare COVID‐19 presentation in patients with active malignancy to those with a history of cancer to determine the impact of cancer status on COVID‐19 outcomes in the two groups. Methods and results Of the 6724 patients who were hospitalized at NYU Langone Health (3/16/20‐7/31/20) and tested positive for SARS‐CoV‐2, 580 had either active cancer (n = 221) or a history of cancer (n = 359). We compared the baseline clinicodemographic characteristics and hospital courses of the two groups. We studied the relationship between cancer status and the rate of admission to the intensive care unit (ICU), use of invasive mechanical ventilation (IMV), and all‐cause mortality. The two groups had similar laboratory results associated with COVID‐19 infection, incidence of venous thromboembolism, and incidence of severe COVID‐19. Active cancer status was not associated with the rate of ICU admission (p = .307) or use of IMV (p = .236), but was significantly associated with worse all‐cause mortality in both univariate and multivariate analysis with odds ratios of 1.48 (95% confidence interval [CI]: 1.04–2.09; p = .028) and 1.71 (95% CI: 1.12–2.63; p = .014), respectively. Conclusion Active cancer patients had worse survival outcomes compared to patients with a history of cancer despite similar COVID‐19 disease characteristics in the two groups. Our data suggest that cancer care should continue with minimal interruptions during the pandemic to bring about response and remission as soon as possible.

BACKGROUND AND OBJECTIVES: AKI is a common complication of coronavirus disease 2019 (COVID-19) and is associated with high mortality. Palliative care, a specialty that supports patients with serious illness, is valuable for these patients but is historically underutilized in AKI. The objectives of this paper are to describe the use of palliative care in patients with AKI and COVID-19 and their subsequent health care utilization. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We conducted a retrospective analysis of New York University Langone Health electronic health data of COVID-19 hospitalizations between March 2, 2020 and August 25, 2020. Regression models were used to examine characteristics associated with receiving a palliative care consult. RESULTS: Among patients with COVID-19 (n=4276; 40%), those with AKI (n=1310; 31%) were more likely than those without AKI (n=2966; 69%) to receive palliative care (AKI without KRT: adjusted odds ratio, 1.81; 95% confidence interval, 1.40 to 2.33; P

Environmental noise monitoring in New York City nursing homes before and after new restrictions to reduce spread of COVID-19 revealed increased nighttime noise, reflecting greater sleep disruption.

Background Recent preclinical data suggest that there may be therapeutic synergy between immune checkpoint blockade and inhibition of the coagulation cascade. Here, we investigate whether patients who received immune checkpoint inhibitors (ICI) and were on concomitant anticoagulation (AC) experienced better treatment outcomes than individuals not on AC.Affiliation: Kindly confirm if corresponding authors affiliation is identified correctly.The corresponding author's affiliation is correct. Methods We studied a cohort of 728 advanced cancer patients who received 948 lines of ICI at NYU (2010–2020). Patients were classified based on whether they did (n = 120) or did not (n = 828) receive therapeutic AC at any point during their treatment with ICI. We investigated the relationship between AC status and multiple clinical endpoints including best overall response (BOR), objective response rate (ORR), disease control rate (DCR), progression free survival (PFS), overall survival (OS), and the incidence of bleeding complications.Affiliations: Journal instruction requires a country for affiliations; however, this is missing in affiliations 1 to 5. Please verify if the provided country is correct and amend if necessary.The country is correct for all affiliations (1 - 5). Results Treatment with AC was not associated with significantly different BOR (P = 0.80), ORR (P =0.60), DCR (P =0.77), PFS (P = 0.59), or OS (P =0.64). Patients who received AC were significantly more likely to suffer a major or clinically relevant minor bleed (P = 0.05). Conclusion AC does not appear to impact the activity or efficacy of ICI in advanced cancer patients. On the basis of our findings, we caution that there is insufficient evidence to support prospectively evaluating the combination of AC and immunotherapy.

Additional file 1. Additional Tables.

Goals The goal of this study was to quantify the association between demographic factors and advanced colorectal cancer (CRC) in patients under age 50. Background CRC incidence in the United States has declined in older individuals but increased in those under age 50 (early-onset). More than 60% of early-onset CRC patients present with advanced disease (stage III/IV), but predictors of stage in this population are poorly defined. Study We analyzed CRC cases diagnosed between age 20 and 49 in the United States Surveillance, Epidemiology, and End Results (SEER) 18 database during 2004 to 2015. Logistic regression models were fit to assess the impact of age, sex, race, ethnicity, marital status, and cancer site on the probability of advanced disease. Results The analysis included 37,044 cases. On multivariable regression, age was inversely associated with advanced disease. Relative to 45 to 49-year-olds, 40 to 44-year-olds had 8% greater odds of having advanced CRC, and 20 to 24-year-olds had 53% greater odds. Asians, blacks, and Pacific Islanders had 10%, 12%, and 45% greater odds of advanced disease compared with whites. Compared with nonpartnered individuals, those with partners had 11% lower odds of advanced CRC. Both right-sided and left-sided colon cancer were more likely to be diagnosed at stage IV compared with rectal cancer. Conclusions Among individuals with early-onset CRC, younger age, Asian, black, or Pacific Islander race, and being nonpartnered were predictors of advanced disease at presentation. Colon cancer was more likely to be diagnosed at stage IV than rectal cancer. Patient characteristics associated with advanced CRC may indicate both differences in tumor biology and disparities in health care access.

Apolipoprotein L1 (APOL1) gene risk variants (RV) associate with renal and cardiovascular disease particularly in SLE. We hypothesized that in RV-carrying human umbilical vein endothelial cells (HUVECs) cytokine-induced APOL1 expression compromises mitochondrial respiration, lysosome integrity, and autophagic flux. HUVEC cultures of each APOL1 genotype were generated. APOL1 was expressed using IFNɣ; HUVEC mitochondrial function, lysosome integrity, and autophagic flux were measured. IFNɣ increased APOL1 expression across all genotypes 20-fold (p=0.001). Compared to the homozygous G0 (ancestral) allele (0RV), high risk (2RV) HUVECs showed both depressed baseline and maximum mitochondrial oxygen consumption (p

Background: There is a need to monitor brain resuscitation during CPR. Furthermore, 10% of CA survivors report cognitive activity and 2-3% report consciousness during CPR. Methods: Using data from a prospective study (AWARE-II) with bimodal brain monitoring during CPR (EEG, [Massimo] and regional cerebral oxygenation [rSO2 normal 60-80%]) using cerebral oximetry [Nonin]), we sought to identify EEG rhythms, their progression over time, and underlying rSO2 thresholds. Inclusion criteria: In hospital CA, ≥ 18 years. Raw EEG data were captured as images (1/second) during CPR pauses, while rSO2 was captured continuously. Results: 38 patients were recruited; mean age 69±16 with duration of CPR (10-60 mins). We captured 362 EEG images. 91 (25%) were artifacts. Among the 271 interpretable images, there were 13 EEG rhythms placed into 6 groups based on their association with normal/near normal, seizures, coma, absence of cortical activity as follows: Group 1 (Non-epileptogenic): Theta, Delta, Alpha, Group 2 (Epileptogenic/Spike and Wave): Generalized Rhythmic Delta Activity (GRDA) + Spike (S), Delta + S, Theta + S, Burst Suppression with GRDA + S, Group 3 (Flat-line): Marked Voltage Attenuation (MVA), Group 4 (Coma State): Burst Suppression (w/ GRDA, Delta, and/or Theta), Group 5: GRDA, Group 6: Generalized Periodic Discharges (GPD). MVA/absence of activity was observed throughout CPR time and across all rSO2 ranges. Normal/near normal (non-epileptogenic) including alpha rhythms (which to our knowledge is described for the first time), and epileptogenic rhythms were observed with rSO2>30% Conclusions: While unclear whether non-epileptogenic rhythms are associated with transient periods of ROSC, however real-time bimodal brain monitoring provides insights regarding brain resuscitation and its dynamic interaction with patient factors. While ischemia may cause epileptogenic activity, there are periods of normal/near-normal cortical activity despite prolonged CPR >45-60 mins. A minimal threshold of brain oxygen delivery (rSO2>30%) may be required for cortical activity. These data raise questions regarding assumptions of irreversible brain damage with prolonged CPR, as well as the possibility of consciousness and cognitive activity during CPR.

Background The use of direct-acting antivirals (DAA) has expanded transplantation from hepatitis C viremic donors (HCV-VIR). Our team has conducted an open-label, prospective trial to assess outcomes transplanting HCV viremic hearts. Glecaprevir/pibrentasvir (GLE/PIB) was our sole DAA. Methods Serial quantitative hepatitis C virus (HCV) RNA PCR was obtained to assess HCV viral titers. Between January 2018 and June 2019, a total of 50 recipients were transplanted. Of these, 22/50 (44%) were from HCV-VIR, the remaining 28 from non-viremic (HCV NON-VIR) donors. An 8-week course of GLE/PIB was initiated at 1 week post-transplant. Results There was no difference in demographic or clinical parameters between groups. All 22 recipients of HCV-VIR transplants became viremic. GLE/PIB was effective in decreasing viremia to undetectable levels by 6 weeks post-transplant in all patients. The median time to first undetectable HCV quantitative PCR was (4.3 weeks, IQR: 4-5.7 weeks). All patients demonstrated sustained undetectable viral load through 1-year follow-up. There was no difference in survival at one year between HCV NON-VIR 28/28: (100%) vs HCV-VIR 21/22 (95%) recipients. Conclusions Our center reports excellent outcomes in transplanting utilizing hearts from HCV-VIR donors. No effect on survival or co-morbidity was found. An 8-week GLE/PIB course was safe and effective when initiated approximately 1 week post-transplant.

10572 Background: Several reports have suggested that cancer patients are at increased risk for contracting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and suffering worse coronavirus disease 2019 (COVID-19) outcomes. However, little is known about the impact of cancer status on presentation and outcome. Here, we report on the association between cancer status and survival in hospitalized patients who tested positive for SARS-CoV-2 during the height of pandemic in New York City. Methods: Of the 6,724 patients who were hospitalized at NYU Langone Health (3/16/20 - 7/31/20) and tested positive for SARS-CoV-2, 580 had either active cancer (n = 221) or a history of cancer (n = 359). Patients were classified as having active malignancy if they either received treatment within six months of their COVID-19 diagnosis or they had measurable disease documented at the time of their hospitalization. Patients were categorized as having a history of cancer if there was no evidence of measurable disease or there were no treatments administered within six months of their COVID-19 diagnosis. We compared the baseline clinicodemographic characteristics and hospital courses of the two groups, and the relationship between cancer status and the rate of admission to the intensive care unit (ICU), use of invasive mechanical ventilation (IMV), and all-cause mortality. Results: There was no differences between the two groups in their baseline laboratory results associated with COVID-19 infection, incidence of venous thromboembolism, or incidence of severe COVID-19. Active cancer status was not associated with the rate of ICU admission ( P = 0.307) or use of IMV ( P = 0.236), but was significantly associated with worse all-cause mortality in both univariate and multivariate analysis with ORs of 1.48 (95% CI: 1.04-2.09; P = 0.028) and 1.71 (95% CI: 1.12-2.63; P = 0.014), respectively. Conclusions: Active cancer patients had worse survival outcomes compared to patients with a history of cancer despite similar COVID-19 disease characteristics in the two groups. Our data suggest that cancer care should continue with minimal interruptions during the pandemic to bring about response and remission as soon as possible. Additionally, these findings support the growing body of evidence that malignancy portends worse COVID-19 prognosis, and demonstrate that the risk may even apply to those without active disease.

Subsurface drainage is effective for not only controlling groundwater table depth but also alleviating soil salinization especially in arid and semi-arid agricultural areas. While substantial research efforts have been spent to determine the parameters (e.g., drain depth, drain spacing, and pipe diameter) of subsurface drainage pipe layout for water drainage, less attention has been paid to determine the parameters for salt discharge, which is important in arid and semi-arid regions. This paper presents a comprehensive study that used experimental and numerical methods to determine the pipe layout parameters for both water and salt drainage. A total of nine field experiments were conducted in Yanqi County, an arid area of Xinjiang Province, China, for a combination of different values of drain depth, drain spacing, and pipe diameter. The experimental results indicate that drain depth and spacing are significantly more important than pipe diameter for soil desalinization. Soil water content and salinity measured during the experiments were used to calibrate and validate a numerical model developed for simulating soil water flow and salt transport under drainage conditions. Two proposed indices (critical depth of soil desalinization and ratio of salt discharge and leaching), combined with two existing indices (salt discharge amount and soil desalinization rate), were used to represent the soil desalinization and salt discharge effects under different subsurface pipe layout parameters. The results suggest that drain depth has a significant influence on all indices, while the drain spacing has a significant influence on salt discharge amount and ratio of salt discharge and leaching. The relationships between layout parameters of subsurface pipes and proposed indices were quantified and used to determine appropriate layout parameters of subsurface pipes.

BackgroundRecent research suggests that baseline body mass index (BMI) is associated with response to immunotherapy. In this study, we test the hypothesis that worsening nutritional status prior to the start of immunotherapy, rather than baseline BMI, negatively impacts immunotherapy response.MethodsWe studied 629 patients with advanced cancer who received immune checkpoint blockade at New York University. Patients had melanoma (n=268), lung cancer (n=128) or other primary malignancies (n=233). We tested the association between BMI changes prior to the start of treatment, baseline prognostic nutritional index (PNI), baseline BMI category and multiple clinical end points including best overall response (BOR), objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) and overall survival (OS).ResultsDecreasing pretreatment BMI and low PNI were associated with worse BOR (p=0.04 and p=0.0004), ORR (p=0.01 and p=0.0005), DCR (p=0.01 and p<0.0001), PFS (p=0.02 and p=0.01) and OS (p<0.001 and pConclusionStandard of care measures of worsening nutritional status more accurately associate with immunotherapy outcomes than static measurements of BMI. Future studies should focus on determining whether optimizing pretreatment nutritional status, a modifiable variable, leads to improvement in immunotherapy response.

To assess the impact of allopurinol on diabetes in a retrospective cohort of Veterans' Affairs patients with gout.The New York Harbor VA computerized patient record system was searched to identify patients with an ICD-9 code for gout meeting at least 4 modified 1977 American Rheumatology Association gout diagnostic criteria. Patients were divided into subgroups based on >30 continuous days of allopurinol, versus no allopurinol. New diagnoses of diabetes, defined according to American Diabetes Association diagnostic criteria or clinical documentation explicitly stating a new diagnosis of diabetes, were identified during an observation period from January 1, 2000 through December 31, 2015.Six hundred six gout patients used allopurinol >30 continuous days, and 478 patients never used allopurinol. Over an average 7.9 ± 4.8 years of follow-up, there was no significant difference in diabetes incidence between the allopurinol and non-allopurinol groups (11.7/1000 person-years vs 10.0/1000 person-years, P = .27). A lower diabetes incidence in the longest versus shortest quartiles of allopurinol use (6.3 per 1000 person-years vs 19.4 per 1000 person-years, P

e22046 Background: Immune checkpoint inhibition (ICI) improves progression-free survival (PFS) and overall survival (OS) for patients with metastatic melanoma (MM), but treatment may cause serious immune-related adverse events (irAEs) that require the use of immunosuppressive steroids. Skin toxicity (ST), the most common side effect, has been reported to be associated with better response to ICI in some studies but not others. Herein, we tested the hypothesis that the portended survival benefit associated with ICI-related ST reaches a threshold in MM patients, dependent on the severity of the ST. Methods: We analyzed MM patients enrolled prospectively in a clinicopathological database with protocol-driven follow up and treated with ICI at NYULH. The patient and/or physician reported the ST, and an immunologist-dermatologist independently confirmed the event was ICI-related. Severe ST was defined as a skin event that required treatment with systemic steroids. Other site-specific toxicities were recorded using the CTCAE v5.0. We tested the associations between ST and PFS and OS, stratified by no, mild, and severe ST, adjusting for age, gender, number of metastatic sites, LDH, and ECOG score at treatment initiation. Results: The cohort included 256 MM patients (387 lines of ICI treatments). ST was the most common irAE (34%), and was significantly associated with development of endocrine toxicity (P = 0.007). Of the ST events (n = 130), 66% were mild and 34% were severe. Compared to none, mild ST was significantly associated with improved PFS (adjusted hazard ratio [aHR] = 0.58 [0.38, 0.89], P = 0.01), and a similar trend was observed with OS (aHR = 0.68 [0.45, 1.03], P = 0.06). However, the positive effect was reduced to insignificant (PFS P = 0.53; OS P = 0.25) in patients who developed severe ST irAEs that required systemic steroids. Conclusions: Our data demonstrate that ICI-induced ST is a complex phenomenon and might explain the discordance of reported data. While the worse outcome in patients with severe ST compared to mild may stem from steroidal immunosuppression, a threshold may also exist wherein severe ST itself might contribute to a relative reduction in ICI efficacy. More research is needed to elucidate the mechanisms that link ST and response to ICI in order to better characterize and treat skin irAEs without systemically suppressing anti-tumor immunity.

Proprioceptive feedback from Group Ia/II muscle spindle afferents and Group Ib Golgi tendon afferents is critical for the normal execution of most motor tasks, yet how these distinct proprioceptor subtypes emerge during development remains poorly understood. Using molecular genetic approaches in mice of either sex, we identified 24 transcripts that have not previously been associated with a proprioceptor identity. Combinatorial expression analyses of these markers reveal at least three molecularly distinct proprioceptor subtypes. In addition, we find that 12 of these transcripts are expressed well after proprioceptors innervate their respective sensory receptors, and expression of three of these markers, including the heart development moleculeHeg1, is significantly reduced in mice that lack muscle spindles. These data revealHeg1as a putative marker for proprioceptive muscle spindle afferents. Moreover, they suggest that the phenotypic specialization of functionally distinct proprioceptor subtypes depends, in part, on extrinsic sensory receptor organ-derived signals.SIGNIFICANCE STATEMENTSensory feedback from muscle spindle (MS) and Golgi tendon organ (GTO) sensory end organs is critical for normal motor control, but how distinct MS and GTO afferent sensory neurons emerge during development remains poorly understood. Using (bulk) transcriptome analysis of genetically identified proprioceptors, this work reveals molecular markers for distinct proprioceptor subsets, including some that appear selectively expressed in MS afferents. Detailed analysis of the expression of these transcripts provides evidence that MS/GTO afferent subtype phenotypes may, at least in part, emerge through extrinsic, sensory end organ-derived signals.

Ulcerated melanomas may have a unique biology and microenvironment. We test whether markers of immune infiltration correlate with clinical outcome in ulcerated compared to non-ulcerated primary melanoma tumors.Sixty-two stage II-III cutaneous melanomas, 32 ulcerated and 30 non-ulcerated, were analyzed for tumor-infiltrating lymphocytes (TILs). Immunohistochemistry (IHC) was performed for CD2, a marker previously shown to correlate with overall survival (OS) and recurrence-free survival (RFS) in this patient population. IHC using antibody, VE1, to BRAF V600E was also performed on a subset of 41 tumors to assess the relationship of BRAF mutation to immune markers.We found, using Cox regression models, that the presence of TILs was associated with improved OS (p = 0.034) and RFS (p = 0.002) in ulcerated melanoma tumors, but not in non-ulcerated melanoma (p = 0.632, 0.416). CD2 expression also was correlated with improved OS (p = 0.021) and RFS (p = 0.001) in ulcerated melanoma, but no relationship was seen in non-ulcerated melanoma (p = 0.427, 0.682). In this small population, BRAF status did not correlate with TILs or CD2+ count.Our data show that immune markers including TILs and CD2 count correlate more closely with survival in ulcerated melanomas than that in non-ulcerated melanomas. We propose that immune biomarkers may be particularly relevant to ulcerated, as compared to non-ulcerated, melanomas and that this merits study in larger populations.

O1 IL-15 primes an mTOR-regulated gene-expression program to prolong anti-tumor capacity of human natural killer cells #### Andreas Lundqvist1, Vincent van Hoef1, Xiaonan Zhang1, Erik Wennerberg2, Julie Lorent1, Kristina Witt1, Laia Masvidal Sanz1, Shuo Liang1, Shannon Murray3, Ola Larsson1