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Jay Visaria,1 Neeraj N Iyer,2 Amit D Raval,3 Sheldon X Kong,2 Todd Hobbs,2 Jonathan Bouchard,2 David M Kern,4 Vincent J Willey1 1HealthCore, Inc., Wilmington, DE, USA; 2Novo Nordisk, Inc., Plainsboro Township, NJ, USA; 3Merck & Co., Inc, Kenilworth, NJ, USA; 4Janssen Research and Development, Titusville, NJ, USACorrespondence: Jay VisariaHealthCore, Inc., 123 Justison Street, Suite 200, Wilmington, DE 19801, USATel +1 302 230-2117Email jvisaria@healthcore.comObjective: The objective of this study was to estimate the incremental long-term costs associated with T2DM attributable to vascular diseases.Research Design and Methods: This retrospective cohort study identified newly diagnosed (incident) T2DM patients in 2007 (baseline to 01/01/2006) using the HealthCore Integrated Research Database, a repository of nationally representative claims data. Incident T2DM patients were 1:1 exact matched on age, gender and other factors of interest to non-DM patients, and followed until the earlier of 8 follow-up years or death. Patients with documented vascular disease diagnosis were identified during the study period. All-cause and T2DM/vascular disease-related annual healthcare costs were examined for each follow-up year.Results: The study included 13,883 individuals with T2DM and matched non-DM controls. Among individuals with T2DM, 11,792 (85%) had vascular disease versus 9251 (66.6%) non-T2DM between 01/01/2006 and 12/31/2015. Among T2DM patients, mean all-cause annual costs were greater than in non-T2DM patients ($13,806 vs $7,243, baseline, $21,745 vs $8,524, post-index year 1, $12,756-$14,793 vs $8,349-$9,940 years 2– 8, p< 0.001), respectively. A similar trend was observed for T2DM/vascular disease-related costs (p< 0. 001). T2DM/vascular disease-related costs were largest during post-index year 1, accounting for the majority of all-cause cost difference between T2DM patients and matched non-DM controls. Incident T2DM individuals without vascular disease at any time had significantly lower costs compared to non-DM controls (p< 0. 001) between years 2– 8 of follow-up.Conclusion: Vascular disease increased the cost burden for individuals with T2DM. The cost impact of diabetes and vascular disease was highest in the year after diagnosis, and persisted for at least seven additional years, while the cost of T2DM patients without vascular disease trended lower than for matched non-DM patients. These data highlight potential costs that could be offset by earlier and more effective detection and management of T2DM aimed at reducing vascular disease burden.Keywords: type 2 diabetes mellitus, microvascular complications, macrovascular complications, diabetes, healthcare costs, diabetes costs

Michael J Fisch,1 Michael Grabner,2 Daniel S Mytelka,3 Amit D Raval,2 Lee Bowman,3 David M Kern,2 Collin Churchill,3 Joseph Singer,2 Stewart Wetmore,3 John Barron,2 Michael Eleff4 1AIM Specialty Health, Chicago, IL, USA; 2HealthCore, Inc., Wilmington, DE, USA; 3Eli Lilly and Company, Indianapolis, IN, USA; 4Anthem, Inc., Indianapolis, IN, USACorrespondence: Michael GrabnerHealthCore, Inc., 123 Justison St, Suite 200, Wilmington, DE 19801, USATel +1 302-230-2000Fax +1 302-230-2020Email mgrabner@healthcore.comObjective: Choosing chemotherapy for metastatic colorectal cancer (mCRC) requires balancing clinical effectiveness and risk of complications. This study characterized real-world inpatient/emergency department (ED) hospitalizations during first-line chemotherapy among individuals with mCRC.Methods: This retrospective cohort study used data from medical and pharmacy claims. All patients had mCRC with ≥ 1 claim for ≥ 1 of the 5 most frequently utilized first-line chemotherapy agents (fluorouracil, oxaliplatin, bevacizumab, irinotecan, capecitabine). The main outcome was all-cause hospitalizations (inpatient or ED setting) identified from claims via ICD-9/10-CM coding from index date until 30 days after the end of first-line chemotherapy or last available data.Results: A total of 717 individuals (mean age 55 years; 58% male; ECOG 0/1/2+/missing in 44%/39%/6%/11%; median follow-up 116 days) met study criteria. Thirty-four distinct chemotherapy regimens were used. Overall, 40% of patients had ≥ 1 hospitalization (n=285; total 415 hospitalizations); 12% (n=85) had ≥ 2 hospitalizations. The median time to first hospitalization was 52 days; median inpatient length of stay was 4 days; infections/neutropenia (21%) and bowel-related complications (17%) were the most common issues associated with inpatient hospitalizations. In univariate analyses, insurance plan type, geographical location, ECOG, and renal disease were associated with hospitalization. In multivariable analyses, ECOG ≥ 1 was associated with a 67% increase (p< 0.01) in the odds of hospitalization vs ECOG= 0.Conclusion: Approximately 40% of patients with mCRC were hospitalized during the study period. Hospital stays were typically short. Further research is needed to determine how many of these hospitalizations may be avoidable. We also observed a large amount of variation in regimens used in the first-line setting.Keywords: colorectal cancer, chemotherapy-associated hospitalization, outcomes research, observational study, claims analysis

Long-lived PFKFB3-expressing β-cells are dysfunctional partly because of prevailing glycolysis that compromises metabolic coupling of insulin secretion. Their accumulation in type 2 diabetes (T2D) appears to be related to the loss of apoptotic competency of cell fitness competition that maintains islet function by favoring constant selection of healthy winner cells. To investigate how PFKFB3 can disguise the competitive traits of dysfunctional loser β-cells, we analyzed the overlap between human β-cells with bona fide loser signature across diabetes pathologies using the HPAP scRNA-seq and spatial transcriptomics of PFKFB3-positive β-cells from nPOD T2D pancreata. The overlapping transcriptional profile of loser β-cells was represented by down-regulated ribosomal biosynthesis and genes encoding for mitochondrial respiration. PFKFB3-positive loser β-cells had the reduced expression of HLA class I and II genes. Gene-gene interaction analysis revealed that PFKFB3 rs1983890 can interact with the anti-apoptotic gene MAIP1 implicating positive epistasis as a mechanism for prolonged survival of loser β-cells in T2D. Inhibition of PFKFB3 resulted in the clearance of dysfunctional loser β-cells leading to restored glucose tolerance in the mouse model of T2D.

In this work, continuous wave ground-penetrating radar (CW-GPR) has been used for detecting the soil water content in context to farm management. It is here speculated that CW-GPR utilized to observe variations in Soil parameters in different geographical area where traditional methods fails such as reflection-based GPR method. An experiment was performed on different farms in and around Mumbai city locality in a 20 * 14 m section of natural grassland at the SAMEER- IIT BOMBAY Research Facility in Mumbai city, INDIA. Two survey methods such as velocity analysis and GPR reflection surveys of ground wave were inefficient at the experiment site due to the signal attenuation which is related with the clay-rich soil. CW-GPR data sets were collected on regular and daily basis during a 5-d period in February 2017. The samples of soil were collected for analysis purpose from the mentioned geographical area. The clear response has been observed for early time signal amplitude to changes in soil water content using CW-GPR data. The strong correlation has been observed between the GPR data sets with Soil water content, which is uniform with the CW-GPR dependence on relative permittivity. The outcome reveals that the CW-GPR method can be utilized to acquire spatially distributed information on subsurface moisture content in clay-rich soils.

BACKGROUNDCOVID-19 convalescent plasma (CCP) virus-specific antibody levels that translate into recipient posttransfusion antibody levels sufficient to prevent disease progression are not defined.METHODSThis secondary analysis correlated donor and recipient antibody levels to hospitalization risk among unvaccinated, seronegative CCP recipients within the outpatient, double-blind, randomized clinical trial that compared CCP to control plasma. The majority of COVID-19 CCP arm hospitalizations (15/17, 88%) occurred in this unvaccinated, seronegative subgroup. A functional cutoff to delineate recipient high versus low posttransfusion antibody levels was established by 2 methods: (i) analyzing virus neutralization-equivalent anti-Spike receptor-binding domain immunoglobulin G (anti-S-RBD IgG) responses in donors or (ii) receiver operating characteristic (ROC) curve analysis.RESULTSSARS-CoV-2 anti-S-RBD IgG antibody was volume diluted 21.3-fold into posttransfusion seronegative recipients from matched donor units. Virus-specific antibody delivered was approximately 1.2 mg. The high-antibody recipients transfused early (symptom onset within 5 days) had no hospitalizations. A CCP-recipient analysis for antibody thresholds correlated to reduced hospitalizations found a statistical significant association between early transfusion and high antibodies versus all other CCP recipients (or control plasma), with antibody cutoffs established by both methods-donor-based virus neutralization cutoffs in posttransfusion recipients (0/85 [0%] versus 15/276 [5.6%]; P = 0.03) or ROC-based cutoff (0/94 [0%] versus 15/267 [5.4%]; P = 0.01).CONCLUSIONIn unvaccinated, seronegative CCP recipients, early transfusion of plasma units in the upper 30% of study donors antibody levels reduced outpatient hospitalizations. High antibody level plasma units, given early, should be reserved for therapeutic use.TRIAL REGISTRATIONClinicalTrials.gov NCT04373460.FUNDINGDepartment of Defense (W911QY2090012); Defense Health Agency; Bloomberg Philanthropies; the State of Maryland; NIH (3R01AI152078-01S1, U24TR001609-S3, 1K23HL151826NIH); the Mental Wellness Foundation; the Moriah Fund; Octapharma; the Healthnetwork Foundation; the Shear Family Foundation; the NorthShore Research Institute; and the Rice Foundation.

Abstract Anthracnose disease, caused by the Colletotrichum gloeosporioides species, affects vegetables, fruits, pulses, and cereals, leading to significant economic losses worldwide. Although many synthetic fungicides are used to control this pathogen, eco-friendly biological alternatives are gaining popularity. This study focuses on isolating and purifying chitinase ( Af Chi)from a marine bacterium and testing its antifungal efficacy against C. gloeosporioides spore germination by targeting the chitin in the fungal cell wall. The chitinase was purified from a marine bacterium A. faecalis from the Arabian Sea and had a molecular mass of 45 kDa and a specific activity of 84.6 U/mg. Af Chi worked best at 50 °C and pH 7.0 in Tris HCl buffer. Na+ ion was the highest cofactor, highlighting the halophilic nature of this chitinase. K+, Ca2+, Cu2+, Mg2+, Mn2+, and EDTA also increased activity, while Fe3+, Zn2+, Co2+, and Pb2+ decreased it. The Km and Vmax values were 1.87 µg/mL and 17.45 U/mL, respectively. Purified Af Chi at 10 mg/mL completely inhibited spore germination within 8 h and reduced the size of the spores.

This study examined the role that cytokines may have played in the beneficial outcomes found when outpatient individuals infected with SARS-CoV-2 were transfused with COVID-19 convalescent plasma (CCP) early in their infection. We found that the pro-inflammatory cytokine IL-6 decreased significantly faster in patients treated early with CCP. Participants with COVID-19 treated with CCP later in the infection did not have the same effect. This decrease in IL-6 levels after early CCP treatment suggests a possible role of inflammation in COVID-19 progression. The evidence of IL-6 involvement brings insight into the possible mechanisms involved in CCP treatment mitigating SARS-CoV-2 severity.

BACKGROUND: Breast cancer is the second most common cause of brain metastases (BM). Despite increasing incidence of BM in older women, there are limited data on the optimal management of BM in this age group. In this study, we assessed the survival outcomes and treatment patterns of older breast cancer patients ≥65 years old with BM compared to younger patients at our institution. METHODS: An IRB-approved single-institutional retrospective review of biopsy-proven breast cancer patients with BM treated with 1- to 5-fraction stereotactic radiation therapy (SRS) from 2015 to 2020 was performed. Primary endpoint was intracranial progression-free survival (PFS) defined as the time interval between the end of SRS to the date of the first CNS progression. Secondary endpoints were overall survival (OS) from the end of SRS and radiation treatment patterns. Kaplan-Meier estimates and Cox proportional hazard regression method were used for survival analyses. RESULTS: A total of 112 metastatic breast cancer patients with BMs were included of which 24 were ≥65 years old and 88 were

Abstract Miniaturization of medical tools promises to revolutionize surgery by reducing tissue trauma and accelerating recovery. Magnetic untethered devices, with their ability to access hard-to-reach areas without physical connections, emerge as potential candidates for such miniaturization. Despite the benefits, these miniature devices face challenges regarding force and torque outputs, restricting their ability to perform tasks requiring mechanical interactions such as tissue penetration and manipulation. To overcome magnetic actuation system-based force and torque limitations, this study proposes Variable Outer Radius Individually Addressable Coil Stacks (VORIACS), a novel magnetic actuation system optimized for high force output generation to magnetic devices within its workspace. The VORIACS marks significant improvements and breakthroughs in magnetic actuation within decimeter-scale workspace. The VORIACS is comprised of 12 coils that are optimized for 2D magnetic field generation under maximized power consumption of up to 12 kW. We implement six two-channel motor controllers, powered by six separate power supplies. Each of the twelve coils in the system is operated on its own motor-controller channel. This arrangement allows the system to exceed the magnetic forces and torques possible for single-coil versions of the same geometry. This study elaborates on optimizing, manufacturing, integrating, and demonstrating this system. Comparative analysis reveals that while a suboptimal, single-coil version of this system generates 0.31 N force (710 mT/m magnetic gradient magnitude), the VORIACS produces 1.673 N force (3834 mT/m magnetic gradient magnitude) on the same magnetic object placed 5 cm away from the coils. Moreover, the strong penetration force generated by VORIACS enables needle penetration to a mock gel that has the rigidity of liver tissue. In addition, we demonstrate the advantage of stacked coils with variable radii for magnetic field manipulability while maintaining the optimized force delivery property of the system, which improves control and could facilitate multi-tool manipulation. By enabling a fivefold increase in magnetic pulling force compared to its single-coil counterpart, VORICAS raises the potential penetration capabilities of untethered magnetic robotics in surgical procedures.

The present study consisted of total 45 hybrids along with 18 parents and 2 checks. These entries were evaluated in randomized block design with three replications over three locations. Observations were recorded on ten characters to study per se performance, estimates genotype × environment interaction and stability parameters. The crosses × environment interactions were significant for all the characters indicating existence of non-linear response of crosses to the changing environments. The analysis of variance for individual environment indicated significant differences among genotypes for all the traits indicating the heritable nature of inheritance of these traits. The crosses EIQ-103 × EI-2156, EIQ-180 × EI-2518-4, and EIQ-103 × EI-670-2 were found to perform well across different environmental conditions for yield and yield-contributing traits. Specifically, the crosses EIQ-103 × EI-2156 and EI-1104-1 × EI-2156 demonstrated stability across various environments, while the crosses EI-2173 × EI-2156 and EIQ-235 × EI-2518-4 were particularly suitable for unfavourable conditions.

Purpose: To develop a screening method for the induction of type-3 diabetes mellitus (T3DM) in experimental animals. MATERIALS AND METHODS: Twelve Albino Wistar rats were divided into normal control (NC) and disease control (DC) group. Animals of NC were fed with high-fat diet (HFD) for four weeks followed by intraperitoneal administration of nicotinamide (230 mg/kg) and streptozotocin (STZ) (65 mg/kg). Body weight (BW) and blood glucose levels (BGL) were measured from week 1 to 4. Glycosylated hemoglobin (HbA1C) levels were estimated on week 4. Behavioral parameters including Morris water maze test (MWMT), T-maze test, and rota-rod test were recorded. Estimation of acetylcholine (ACh) and acetylcholinesterase (AChE) was conducted on week 4. Histopathological analysis of brain hippocampus was undertaken in three animals of each group. Results: DC group showed significant elevation in levels of BW and BGL with P value < 0.05. Levels of HbA1C increased significantly in DC group with P value < 0.0001. DC group showed a significant increase (P value < 0.05 [week 1] and P value < 0.001 [weeks 2–4]) in escape latency and elapsed time in MWMT and T-maze test, respectively. In DC group, elapsed time decreased significantly (P value < 0.05 [week 1] and P value < 0.001 [weeks 2–4]) in rota-rod test. A significant deviation in the levels of ACh and AChE was recorded with P value < 0.0001. Histopathology of hippocampus part of DC group showed notable increase in the number of β-amyloid plaque. Conclusion: Animals administered with HFD, nicotinamide, and STZ showed dementia along with the diabetic condition suggesting the induction of T3DM.

Abstract Gulf War Illness (GWI) is a chronic multisymptom disorder that affects approximately 25–32% of Gulf War veterans and is characterized by a number of symptoms such as cognitive impairment, psychiatric disturbances, chronic fatigue and gastrointestinal distress, among others. While the exact etiology of GWI is unknown, it is believed to have been caused by toxic exposures encountered during deployment in combination with other factors such as stress. In the present study we sought to evaluate the hypothesis that exposure to the toxin permethrin could prime neuroinflammatory stress response and elicit psychiatric symptoms associated with GWI. Specifically, we developed a mouse model of GWI, to evaluate the effects of chronic permethrin exposure followed by unpredictable stress. We found that subjecting mice to 14 days of chronic permethrin exposure followed by 7 days of unpredictable stress resulted in the development of depression-like behavior. This behavioral change coincided with distinct alterations in the microglia phenotype, indicating microglial activation in the hippocampus. We revealed that blocking microglial activation through Gi inhibitory DREADD receptors in microglia effectively prevented the behavioral change associated with permethrin and stress exposure. To elucidate the transcriptional networks impacted within distinct microglia populations linked to depression-like behavior in mice exposed to both permethrin and stress, we conducted a single-cell RNA sequencing analysis using 21,566 single nuclei collected from the hippocampus of mice. For bioinformatics, UniCell Deconvolve was a pre-trained, interpretable, deep learning model used to deconvolve cell type fractions and predict cell identity across spatial datasets. Our bioinformatics analysis identified significant alterations in permethrin exposure followed by stress-associated microglia population, notably pathways related to neuronal development, neuronal communication, and neuronal morphogenesis, all of which are associated with neural synaptic plasticity. Additionally, we observed permethrin exposure followed by stress-mediated changes in signal transduction, including modulation of chemical synaptic transmission, regulation of neurotransmitter receptors, and regulation of postsynaptic neurotransmitter receptor activity, a known contributor to the pathophysiology of depression in a subset of the hippocampal pyramidal neurons in CA3 subregions. Our findings tentatively suggest that permethrin may prime microglia towards a state of inflammatory activation that can be triggered by psychological stressors, resulting in depression-like behavior and alterations of neural plasticity. These findings underscore the significance of synergistic interactions between multi-causal factors associated with GWI.

A commonly accepted standard protocol for noninvasive techniques for the genetic evaluation of an embryo remains elusive due to inconclusiveness regarding the volume of spent media to be acquired and the possibility of acquiring the same for subsequent analysis. Single embryo culture is imperative for standardizing noninvasive preimplantation testing using cell-free DNA (cf-DNA) released by individual developing embryos. This study aims to compare the development dynamics of single-drop embryonic culture against with group embryonic culture to establish a standardized protocol for noninvasive Preimplantation Genetic Testing (PGT) in bovine. A total of 239 cumulus–oocyte complexes were aspirated and subjected to in vitro maturation and fertilization. Among these, 120 embryos of day 3 were transferred to single-drop culture until the blastocyst stage. The single-drop culture drops were prepared using microdrops of 30 μL. At the blastocyst stage, spent media from all single-drop embryos were utilized for extracting cell-free genomic DNA to standardize the protocol. The blastocyst rate indicates no significant difference between the two culture methods, suggesting that single-drop culture is suitable for the process. Additionally, the extracted spent media yielded sufficient quantities of cf-DNA, supporting its potential use for PGT (p

This study explored the lived experiences of 21 graduate students in counselor education programs in talking about race, racism, oppression, and privilege in the classroom. We identified four themes from the data that will be shared in the study findings with implications for counselor education, counselor training, and research.

Post-COVID conditions (PCCs) are common and have significant morbidity. Risk factors for PCC include advancing age, female sex, obesity, and diabetes mellitus. Little is known about treatment, inflammation, and PCC. Among 882 individuals with confirmed SARS-CoV-2 infection participating in a randomized trial of COVID-19 convalescent plasma (CCP) vs control plasma with available biospecimens and symptom data, the association between early CCP treatment, cytokine levels, and PCC was evaluated. Cytokine and chemokine levels were assessed at baseline, day 14, and day 90 using a multiplexed sandwich immunoassay (Meso Scale Discovery). Presence of any self-reported PCC symptoms was assessed at day 90. Associations between CCP treatment, cytokine levels, and PCC were examined using multivariate logistic regression models. One third of the 882 participants had day 90 PCC symptoms, with fatigue (14.5%) and anosmia (14.5%) being most common. Cytokine levels decreased from baseline to day 90. In a multivariable analysis, female sex (adjusted odds ratio [AOR] = 2.69 [1.93-3.81]), older age (AOR = 1.32 [1.17-1.50]), and elevated baseline levels of IL-6 (AOR = 1.59 [1.02-2.47]) were independently associated with development of PCC. Those who received early CCP treatment (≤5 days after symptom onset) compared to late CCP treatment had statistically significant lower odds of PCC. IMPORTANCE Approximately 20% of individuals infected with SARS-CoV-2 experienced long-term health effects, as defined PCC. However, it is unknown if there are any early biomarkers associated with PCC or whether early intervention treatments may decrease the risk of PCC. In a secondary analysis of a randomized clinical trial, this study demonstrates that among outpatients with SARS-CoV-2, increased IL-6 at time of infection is associated with increased odds of PCC. In addition, among individuals treated early, within 5 days of symptom onset, with COVID-19 convalescent plasma, there was a trend for decreased odds of PCC after adjusting for other demographic and clinical characteristics. Future treatment studies should be considered to evaluate the effect of early treatment and anti-IL-6 therapies on PCC development.