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Warehouse layout optimization is critical to inventory and logistics management in organizations. In many instances, limited warehouse space is a constraint and a barrier to expanding operations and increasing demand. We present a multi-step solution using mixed integer programming to improve space utilization and increase order retrieval and fulfillment efficiency. We present a real-world case study to demonstrate the applicability and efficiency of the proposed mixed integer programming heuristics at a large distribution center.

Abstract Background Renal cell carcinoma (RCC) was historically considered to be less responsive to radiation therapy (RT) compared to other cancer indications. However, advancements in precision high-dose radiation delivery through single-fraction and multi-fraction stereotactic ablative radiotherapy (SABR) have led to better outcomes and reduced treatment-related toxicities, sparking renewed interest in using RT to treat RCC. Moreover, numerous studies have revealed that certain therapeutic agents including chemotherapies can increase the sensitivity of tumors to RT, leading to a growing interest in combining these treatments. Here, we developed a rational combination of two radiosensitizers in a tumor-targeted liposomal formulation for augmenting RT in RCC. The objective of this study is to assess the efficacy of a tumor-targeted liposomal formulation combining the mTOR inhibitor everolimus (E) with the survivin inhibitor YM155 (Y) in enhancing the sensitivity of RCC tumors to radiation. Experimental design We slightly modified our previously published tumor-targeted liposomal formulation to develop a rational combination of E and Y in a single liposomal formulation (EY-L) and assessed its efficacy in RCC cell lines in vitro and in RCC tumors in vivo. We further investigated how well EY-L sensitizes RCC cell lines and tumors toward radiation and explored the underlying mechanism of radiosensitization. Results EY-L outperformed the corresponding single drug-loaded formulations E-L and Y-L in terms of containing primary tumor growth and improving survival in an immunocompetent syngeneic mouse model of RCC. EY-L also exhibited significantly higher sensitization of RCC cells towards radiation in vitro than E-L and Y-L. Additionally, EY-L sensitized RCC tumors towards radiation therapy in xenograft and murine RCC models. EY-L mediated induction of mitotic catastrophe via downregulation of multiple cell cycle checkpoints and DNA damage repair pathways could be responsible for the augmentation of radiation therapy. Conclusion Taken together, our study demonstrated the efficacy of a strategic combination therapy in sensitizing RCC to radiation therapy via inhibition of DNA damage repair and a substantial increase in mitotic catastrophe. This combination therapy may find its use in the augmentation of radiation therapy during the treatment of RCC patients.

Background: The downstream regional effect of the Comprehensive Care for Joint Replacement (CJR) program on care pathway-adjacent patients, including revision arthroplasty patients, is poorly understood. Prior studies have demonstrated that care pathways targeting primary total joint arthroplasty may produce a halo effect, impacting more complex patients with parallel care pathways. However, neither the effect of regional referral changes from CJR nor the durability of these positive changes with prolonged bundle participation has been assessed. Methods: Blinded data were pulled from electronic medical records. Primary analyses focused on the effect of CJR participation from 2015 (baseline) to 2020 (final participation year) at a tertiary care safety-net hospital. Patient demographics were evaluated using multivariate analysis of variance and chi-square calculations between procedure types over time. Results: Patients who underwent revision total knee arthroplasty (N = 376) and revision total hip arthroplasty (N = 482) were included. More patients moved through the revision-care pathway over the participation period, with volume increasing by 42% over time. Patients became more medically complex: the Charlson comorbidity index increased from 3.91 to 4.65 (P = .01). The mean length of stay decreased from 5.14 days to 4.50 days (P = .03), but the all-cause complication (8.3%-15.2%; P = .02) and readmission rates (13.6%-16.6%; P = .19) increased over time. Conclusions: Despite care pathway improvements over 5 years of CJR participation, revision patients did not display clear benefits in quality metrics but demonstrated a considerable increase in volume and medical complexity over time. The care of these patients may supersede even thoughtfully implemented care pathways, especially when referral burden increases, as may be prone to happen in regional, financial risk-conferring value-based programs. Understanding the impact of mandatory bundled payment programs like CJR on the care of arthroplasty patients regionally will be essential as value-based programs evolve.

IntroductionAnthracyclines are effective in treating acute myeloid leukemia (AML) but limited by cardiotoxicity. CPX-351, a liposomal daunorubicin and cytarabine, may provide therapeutic benefit with less cardiotoxicity. Acute changes in left ventricular systolic function and cardiac biomarkers were evaluated after a cycle of CPX-351 in children with relapsed AML treated on the phase 1/2 Children's Oncology Group study, AAML1421.MethodsSubjects received 135 units/m2/dose of CPX-351 on days 1, 3, and 5 as cycle 1. Echocardiograms were performed and centrally quantitated at baseline and at the end of cycle 1 (day 29 +/− 1 week). High sensitivity troponin (hs-cTnT) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) were measured at baseline and serially through the end of cycle 1 (days 5, 8, 15, 22 and 29). Differences between baseline and post-CPX-351 echo/biomarker measures were analyzed using Wilcoxon signed rank tests. Linear regression was used to model post-CPX-351 left ventricular ejection fraction (LVEF) with cTnT/NT-proBNP at each time point, controlling for baseline LVEF. Cancer therapy related cardiac dysfunction (CTRCD) was defined as a decline in LVEF of ≥10%–

Digital PCR (dPCR) is emerging as an ideal platform for the detection and tracking of genomic variants in cancer due to its high sensitivity and simple workflow. The growing number of clinically actionable cancer biomarkers creates a need for fast, accessible methods that allow for dense information content and high accuracy. Here, we describe a proof‐of‐concept amplitude modulation‐based multiplex dPCR assay capable of detecting 12 single‐nucleotide and insertion/deletion (indel) variants in EGFR, KRAS, BRAF, and ERBB2, 14 gene fusions in ALK, RET, ROS1, and NTRK1, and MET exon 14 skipping present in non‐small cell lung cancer (NSCLC). We also demonstrate the use of multi‐spectral target‐signal encoding to improve the specificity of variant detection by reducing background noise by up to an order of magnitude. The assay reported an overall 100% positive percent agreement (PPA) and 98.5% negative percent agreement (NPA) compared with a sequencing‐based assay in a cohort of 62 human formalin‐fixed paraffin‐embedded (FFPE) samples. In addition, the dPCR assay rescued actionable information in 10 samples that failed to sequence, highlighting the utility of a multiplexed dPCR assay as a potential reflex solution for challenging NSCLC samples.

Background: Following total hip arthroplasty (THA) and total knee arthroplasty (TKA), increased opioid use is associated with poor clinical outcomes. This study investigates implications of Florida legislative mandates on prescribing practices and opioid utilization following primary THA and TKA. Methods: We retrospectively reviewed patients undergoing primary TKA or THA between January 1, 2018, to December 31, 2020 at our academic medical center. Three groups were identified: procedures performed prior to mandates, after seven-day prescription limit, and after mandated electronic prescribing. A multivariate analyses of variance evaluated length of stay, morphine milligram equivalents (MMEs), age, body mass index and number of prescription refills. Chi-square tests compared preoperative opioid use, readmissions, and discharge disposition. Results: There were 198 patients in group one, 238 patients in group two, and 215 patients in group three (N = 651). Prior to any mandates, patients were prescribed 822.3 + 626.7 MMEs. Following a seven-day prescription limit this decreased to 465.0 + 296.0 MMEs (P < .001), which further decreased after mandated electronic prescribing (228.0 + 284.4 MMEs [P < 0.001]). Patients undergoing THA were prescribed less MME than those undergoing TKA. There was a 2.6% 90-day readmission rate, with no pain-related readmissions. Conclusions: Florida legislative mandates for opioid prescription quantities and electronic prescribing have effectively reduced average MMEs prescribed following primary arthroplasty. Despite a shift towards ambulatory surgery, opioid utilization decreased without compromising patient outcomes. These findings underscore the significance of both legislative and surgical practices influencing opioid prescribing habits among orthopaedic surgeons.

BackgroundSedentary behavior among breast cancer survivors is associated with increased risk of poor physical function and worse quality of life. While moderate to vigorous physical activity can improve outcomes for cancer survivors, many are unable to engage in that intensity of physical activity. Decreasing sitting time may be a more feasible behavioral target to potentially mitigate the impact of cancer and its treatments. ObjectiveThe purpose of this study was to investigate the feasibility and preliminary impact of an intervention to reduce sitting time on changes to physical function and quality of life in breast cancer survivors, from baseline to a 3-month follow-up. MethodsFemale breast cancer survivors with self-reported difficulties with physical function received one-on-one, in-person personalized health coaching sessions aimed at reducing sitting time. At baseline and follow-up, participants wore the activPAL (thigh-worn accelerometer; PAL Technologies) for 3 months and completed physical function tests (4-Meter Walk Test, Timed Up and Go, and 30-Second Chair Stand) and Patient-Reported Outcomes Measurement Information System (PROMIS) self-reported outcomes. Changes in physical function and sedentary behavior outcomes were assessed by linear mixed models. ResultsOn average, participants (n=20) were aged 64.5 (SD 9.4) years; had a BMI of 30.4 (SD 4.5) kg/m2; and identified as Black or African American (n=3, 15%), Hispanic or Latina (n=4, 20%), and non-Hispanic White (n=14, 55%). Average time since diagnosis was 5.8 (SD 2.2) years with participants receiving chemotherapy (n=8, 40%), radiotherapy (n=18, 90%), or endocrine therapy (n=17, 85%). The intervention led to significant reductions in sitting time: activPAL average daily sitting time decreased from 645.7 (SD 72.4) to 532.7 (SD 142.1; β=–112.9; P=.001) minutes and average daily long sitting bouts (bout length ≥20 min) decreased from 468.3 (SD 94.9) to 366.9 (SD 150.4; β=–101.4; P=.002) minutes. All physical function tests had significant improvements: on average, 4-Meter Walk Test performance decreased from 4.23 (SD 0.95) to 3.61 (SD 2.53; β=–.63; P=.002) seconds, Timed Up and Go performance decreased from 10.30 (SD 3.32) to 8.84 (SD 1.58; β=–1.46; P=.003) seconds, and 30-Second Chair Stand performance increased from 9.75 (SD 2.81) to 13.20 completions (SD 2.53; β=3.45; P

Abstract In addition to the challenge of meeting global demand for food production, there are increasing concerns about food safety and the need to protect consumer health from the negative effects of foodborne allergies. Certain bio‐molecules (usually proteins) present in food can act as allergens that trigger unusual immunological reactions, with potentially life‐threatening consequences. The relentless working lifestyles of the modern era often incorporate poor eating habits that include readymade prepackaged and processed foods, which contain additives such as peanuts, tree nuts, wheat, and soy‐based products, rather than traditional home cooking. Of the predominant allergenic foods (soybean, wheat, fish, peanut, shellfish, tree nuts, eggs, and milk), peanuts (Arachis hypogaea) are the best characterized source of allergens, followed by tree nuts (Juglans regia, Prunus amygdalus, Corylus avellana, Carya illinoinensis, Anacardium occidentale, Pistacia vera, Bertholletia excels), wheat (Triticum aestivum), soybeans (Glycine max), and kidney beans (Phaseolus vulgaris). The prevalence of food allergies has risen significantly in recent years including chance of accidental exposure to such foods. In contrast, the standards of detection, diagnosis, and cure have not kept pace and unfortunately are often suboptimal. In this review, we mainly focus on the prevalence of allergies associated with peanut, tree nuts, wheat, soybean, and kidney bean, highlighting their physiological properties and functions as well as considering research directions for tailoring allergen gene expression. In particular, we discuss how recent advances in molecular breeding, genetic engineering, and genome editing can be used to develop potential low allergen food crops that protect consumer health.

BackgroundPediatric acute myeloid leukemia (AML) therapy is associated with substantial short- and long-term treatment-related cardiotoxicity mainly due to high-dose anthracycline exposure. Early left ventricular systolic dysfunction (LVSD) compromises anthracycline delivery and is associated with inferior event-free and overall survival in de novo pediatric AML. Thus, effective cardioprotective strategies and cardiotoxicity risk predictors are critical to optimize cancer therapy delivery and enable early interventions to prevent progressive LVSD. While dexrazoxane-based cardioprotection reduces short-term cardiotoxicity without compromising cancer survival, liposomal anthracycline formulations have the potential to mitigate cardiotoxicity while improving antitumor efficacy. This overview summarizes the rationale and methodology of cardiac substudies within AAML1831, a randomized Children's Oncology Group Phase 3 study of CPX-351, a liposomal formulation of daunorubicin and cytarabine, in comparison with standard daunorubicin/cytarabine with dexrazoxane in the treatment of de novo pediatric AML.Methods/designChildren (age

Abstract Background In peripheral blood, DNA methylation (DNAm) patterns in inflammatory bowel disease patients reflect inflammatory status rather than disease status. Here, we examined DNAm in diseased rectal mucosa from ulcerative colitis (UC) patients, focusing on constituent cell types with the goal of identifying therapeutic targets for UC other than the immune system. We profiled DNAm of rectal mucosal biopsies of pediatric UC at diagnosis (n = 211) and non-IBD control (n = 85) patients and performed epigenome-wide association studies (EWAS) of specific cell types to understand DNAm changes in epithelial, immune and fibroblast cells across disease states, course, and clinical outcomes. We also examined longitudinal analysis on follow-up samples (n = 73), and comparisons were made among patients with clinical outcomes including those undergoing colectomy versus those who did not. Additionally, we included RNA-seq from the same subjects to assess the impact of CpG sites on the transcription of nearby genes during the disease course. Results At diagnosis, UC rectal mucosa exhibited a lower proportion of epithelial cells and fibroblasts, and higher proportion of immune cells, in conjunction with variation in the DNAm pattern. While treatment had significant effects on the methylation signature of immune cells, its effects on fibroblasts and epithelial cells were attenuated. Individuals who required colectomy exhibited cell composition and DNAm patterns at follow-up more similar to disease onset than patients who did not require colectomy. Combining these results with gene expression profiles, we identify CpG sites whose methylation patterns are most consistent with a contribution to poor disease outcomes and could thus be potential therapeutic targets. Conclusions Cell-specific epigenetic changes in the rectal mucosa in UC are associated with disease severity and outcome. Current therapeutics may more effectively target the immune than the epithelial and fibroblast compartments. Graphical abstract

Abstract The Eguchi-Hanson-AdS5 family of spacetimes are a class of static, geodesically complete asymptotically locally AdS5 soliton solutions of the vacuum Einstein equations with negative cosmological constant. They have negative mass and are parameterized by an integer p ≥ 3 with a conformal boundary with spatial topology L(p, 1). We investigate mode solutions of the scalar wave equation on this background and show that, similar to AdS5, the geometry admits a normal mode spectrum (i.e. solutions that neither grow or decay in time). In addition, we also discuss other geometric properties of these soliton spacetimes, including the behaviour of causal geodesics and their thermodynamic properties. We also point out a surprising connection with the AdS soliton.

IntroductionProstate cancer (PCa) presents a significant health challenge in men, with a substantial number of deaths attributed to metastatic castration resistant PCa (mCRPC). Moreover, African American men experience disproportionately high mortality rates due to PCa. This study delves into the pivotal role of SPDEF, a prostate specific Ets transcription factor, and its regulation by DNA methylation in the context of PCa progression.MethodsWe performed Epigenetic reprogramming using daily treatment with non-toxic dose of 5Aza-2-deoxycytidine (5Aza-dC) for two weeks to assess its impact on PDEF expression in prostate cancer cells. Next, we conducted functional studies on reprogrammed cells, including cell migration (wound-healing assay), invasion (Boyden-Chamber test), and proliferation (MTT assay) to comprehensively evaluate the consequences of altered PDEF expression. We used bisulfite sequencing (BSP) to examine DNA methylation at SPDEF promoter. Simultaneously, we utilized siRNA-mediated targeting of key DNMTs (DNMT1, DNMT3A, and DNMT3B) to elucidate their specific role in regulating PDEF. We measured mRNA and protein expressions using qRT-PCR and immune-blotting techniques, respectively.ResultsIn this report, we observed that: a) there is a gradual decrease in SPDEF expression with a concomitant increase in methylated CpG sites within the SPDEF gene during prostate cancer progression from lower to higher Gleason grade; b) Expression of DNMT’s (DNMT1, 3a and 3b) is increased during prostate cancer progression, and there is an inverse correlation between SPDEF and DNMT expression; c) SPDEF levels are decreased in RC77/T, a line of PCa cells from African American origin similar to PC3 and DU145 cells (CRPC cells), as compared to LNCaP cells , a line of androgen dependent cells,; d) the 5′ CpG island of SPDEF gene are hypermethylated in SPDEF-negative CRPC ( PC3, DU145 and RC77/T) cell lines but the same regions are hypomethylated in SPDEF-positive castrate sensitive (LNCaP) cell line ; (e) expression of SPDEF in PCa cells lacking SPDEF decreases cell migration and invasion, but has no significant effect on cell proliferation, and; (f) treatment with the demethylating agent, 5-aza-2′-deoxycytidine, or silencing of the DNMT’s by siRNA, partially restores SPDEF expression in SPDEF-negative PCa cell lines, and decreases cell migration and invasion.DiscussionThese results indicate hypermethylation is a prevalent mechanism for decreasing SPDEF expression during prostate cancer progression. The data demonstrate that loss of SPDEF expression in prostate cancer cells, a critical step in cellular plasticity, results from a potentially reversible process of aberrant DNA methylation. These studies suggest DMNT activity as a potential therapeutic vulnerability that can be exploited for limiting cellular plasticity, tumor progression, and therapy resistance in prostate cancer.

Abstract Opioid prescribing for postoperative pain management is challenging because of inter‐patient variability in opioid response and concern about opioid addiction. Tramadol, hydrocodone, and codeine depend on the cytochrome P450 2D6 (CYP2D6) enzyme for formation of highly potent metabolites. Individuals with reduced or absent CYP2D6 activity (i.e., intermediate metabolizers [IMs] or poor metabolizers [PMs], respectively) have lower concentrations of potent opioid metabolites and potentially inadequate pain control. The primary objective of this prospective, multicenter, randomized pragmatic trial is to determine the effect of postoperative CYP2D6‐guided opioid prescribing on pain control and opioid usage. Up to 2020 participants, age ≥8 years, scheduled to undergo a surgical procedure will be enrolled and randomized to immediate pharmacogenetic testing with clinical decision support (CDS) for CYP2D6 phenotype‐guided postoperative pain management (intervention arm) or delayed testing without CDS (control arm). CDS is provided through medical record alerts and/or a pharmacist consult note. For IMs and PM in the intervention arm, CDS includes recommendations to avoid hydrocodone, tramadol, and codeine. Patient‐reported pain‐related outcomes are collected 10 days and 1, 3, and 6 months after surgery. The primary outcome, a composite of pain intensity and opioid usage at 10 days postsurgery, will be compared in the subgroup of IMs and PMs in the intervention (n = 152) versus the control (n = 152) arm. Secondary end points include prescription pain medication misuse scores and opioid persistence at 6 months. This trial will provide data on the clinical utility of CYP2D6 phenotype‐guided opioid selection for improving postoperative pain control and reducing opioid‐related risks.

Introduction: Pain is a complex subjective sensation that is difficult to quantify in a repeatable manner. Surgical pain is observed to be more intense post-surgery and then fades in the next 24 h. Epidural anesthesia/analgesia is the most widely used technique for lower limb surgeries because of its good sensory and motor block property, reduces stress response, and maintains sufficient spontaneous respiration and hemodynamic stability. Materials and Methods: The study looked at 100 individuals between the ages of 20 and 60 who underwent elective lower limb surgery and were classified as ASA I and II. The patients were split into two 50-person groups. The adverse effects of nausea, vomiting, respiratory depression, urine retention, and pruritus, as well as the quality and duration of postoperative analgesia, were investigated. The patient was monitored for 48 h after surgery. Results: A total of 100 patients were included in the study, where the least age of the patient was 19 years and the greatest age was 75 years. In group T, maximum patients belong to the age group of 26–35 years, whereas in group F maximum patients belong to the age group of 36–45years. In group T, 41 (82%) were males and 9 (18%) were females. In group F, 37 (74%) were males and 13 (26%) were females. Conclusion: Our findings show that epidural tramadol and epidural fentanyl are equally effective, except for fentanyl’s shorter duration of action. Fentanyl also has a moderate sedative effect, which is beneficial in the postoperative period.

Introduction4D cardiac CT (cineCT) is increasingly used to evaluate cardiac dynamics. While echocardiography and CMR have demonstrated the utility of longitudinal strain (LS) measures, measuring LS from cineCT currently requires reformatting the 4D dataset into long-axis imaging planes and delineating the endocardial boundary across time. In this work, we demonstrate the ability of a recently published deep learning framework to automatically and accurately measure LS for detection of wall motion abnormalities (WMA).MethodsOne hundred clinical cineCT studies were evaluated by three experienced cardiac CT readers to identify whether each AHA segment had a WMA. Fifty cases were used for method development and an independent group of 50 were used for testing. A previously developed convolutional neural network was used to automatically segment the LV bloodpool and to define the 2, 3, and 4 CH long-axis imaging planes. LS was measured as the perimeter of the bloodpool for each long-axis plane. Two smoothing approaches were developed to avoid artifacts due to papillary muscle insertion and texture of the endocardial surface. The impact of the smoothing was evaluated by comparison of LS estimates to LV ejection fraction and the fractional area change of the corresponding view.ResultsThe automated, DL approach successfully analyzed 48/50 patients in the training cohort and 47/50 in the testing cohort. The optimal LS cutoff for identification of WMA was −21.8, −15.4, and −16.6% for the 2-, 3-, and 4-CH views in the training cohort. This led to correct labeling of 85, 85, and 83% of 2-, 3-, and 4-CH views, respectively, in the testing cohort. Per-study accuracy was 83% (84% sensitivity and 82% specificity). Smoothing significantly improved agreement between LS and fractional area change (R2: 2 CH = 0.38 vs. 0.89 vs. 0.92).ConclusionAutomated LV blood pool segmentation and long-axis plane delineation via deep learning enables automatic LS assessment. LS values accurately identify regional wall motion abnormalities and may be used to complement standard visual assessments.

A simple and efficient protocol for the construction of 1-aminoisoquinolines was achieved by treating 2-(2-oxo-2-phenylethyl)benzonitriles with amines in the presence of Me3Al. The reaction proceeds via a domino nucleophilic addition with subsequent intramolecular cyclisation. This method provides a wide variety of substituted 1-aminoisoquinolines with good functional group tolerance. Furthermore, the synthetic utility of this protocol was demonstrated in the successful synthesis of the antitumor agent CWJ-a-5 in gram scale.

The 1-phenylbenzazepine template has yielded a number of D1R-like ligands, which, though useful as pharmacological tools, have significant drawbacks in terms of selectivity versus D5R as well as pharmacokinetic behavior. A number of 1-phenylbenzazepines contain a 6-chloro functional group, but extensive SAR studies around the 6-chloro-1-phenylbenzazepine framework have not been reported in the literature. To further understand the tolerance of the 6-chloro-1-phenylbenzazepine template for various substituent groups towards affinity and selectivity at D1R, we synthesized two series of analogs with structural variations at the C-7, C-8, N-3, C-3′ and C-4′ positions. The series 2 analogs differed from series 1 analogs in possessing a nitrogenated functionality at C-8 and lacked a C-4′ substituent, but were otherwise similar. Analogs were assessed for affinity at D1R, D2R and D5R. For both series, we found that the analogs lacked affinity for D2R and showed modest D1R versus D5R selectivity. For series 1 analogs, an N-3 methyl substituent group was better tolerated than N-H or an N-3 allyl substituent. The C-8 position appears to be tolerant of amino and methanesulfonamide substituents for high D1R affinity, but C-8 amides displayed low to moderate D1R affinities. A C-3′ methyl substituent appeared to be critical for the D1R affinity of some analogs, but the C-4′ substituents tried (hydroxy and methoxy; series 1) did not result in any significant boost in D1R affinity. Compound 15a was the most potent and selective D1R ligand identified from these studies (Ki at D1R = 30 nM; 6-fold selectivity versus D5R). Further functional activity assessments indicate that 15a functions as a D1R antagonist towards cAMP-mediated signaling. The predicted drug-like properties of 15a are encouraging for further pharmacological assessments on the compound.

Abstract Within the framework of the “complexity equals action” and “complexity equals volume” conjectures, we study the properties of holographic complexity for rotating black holes. We focus on a class of odd-dimensional equal-spinning black holes for which considerable simplification occurs. We study the complexity of formation, uncovering a direct connection between complexity of formation and thermodynamic volume for large black holes. We consider also the growth-rate of complexity, finding that at late-times the rate of growth approaches a constant, but that Lloyd’s bound is generically violated.

Background: Ultrasound biomicroscopy (UBM) is a noninvasive imaging modality that enables in-vivo visualization of the structures of the anterior segment of the eye. Unlike routine ophthalmic diagnostic ultrasound which uses frequencies of 5–10 MHz, UBM utilizes ultrasound frequencies in the range of 50–100 MHz. The high-frequency probes in UBM allows for higher resolution and better visualization of subsurface ocular structures, even in the presence of anatomic or pathological obscuration. UBM has qualitative as well as quantitative applications in various disorders affecting the anterior segment of the eye. Despite its huge importance, many clinicians lack in knowledge about the technique and its clinical usefulness. The current educational video aims to address this gap in knowledge by highlighting the technique and various clinical indications of UBM. Purpose: The purpose of this video is to demonstrate the technique of UBM and showcase its quantitative and qualitative implications and importance through various clinical cases. Synopsis: UBM is an imaging technique that assesses the depth of tissue structures by measuring the time delay of the returning ultrasound signal. This modality is capable of measuring the size of various structures within the eye, such as the cornea, iris, ciliary body, sclera, and the depth of the anterior and posterior chamber. To perform a UBM, a transducer is inserted into a specially designed eye cup filled with distilled water, creating a water bath environment. Axial and longitudinal scans can be performed in a similar fashion as in routine diagnostic B-scan ultrasound. Quantitative indications for UBM depicted in this video include measurements of corneal thickness, depth of the anterior chamber, and the width of the angle. The video also showcases how UBM can aid in the diagnosis and management of various anterior segment disorders like angle-closure glaucoma, plateau iris configuration, secondary glaucoma, and anterior uveitis with complicated cataract. Qualitative indications for UBM highlighted in this video include its role in intermediate uveitis, ocular hypotony, ocular surface tumors, cystic lesions of iris, and identifying the location and type of intraocular foreign bodies in the anterior segment based on the type of artifact seen. Additionally, the video shows the applications of UBM in scleral and episcleral pathologies. Highlights: This video will educate clinicians about the technique of UBM and showcase a bouquet of UBM findings in various case scenarios, helping one to better understand the potential of this modality in clinical practice. Video link: https://youtu.be/F626TMbJXoU

BackgroundThe presence of left ventricular (LV) wall motion abnormalities (WMA) is an independent indicator of adverse cardiovascular events in patients with cardiovascular diseases. We develop and evaluate the ability to detect cardiac wall motion abnormalities (WMA) from dynamic volume renderings (VR) of clinical 4D computed tomography (CT) angiograms using a deep learning (DL) framework.MethodsThree hundred forty-three ECG-gated cardiac 4DCT studies (age: 61 ± 15, 60.1% male) were retrospectively evaluated. Volume-rendering videos of the LV blood pool were generated from 6 different perspectives (i.e., six views corresponding to every 60-degree rotation around the LV long axis); resulting in 2058 unique videos. Ground-truth WMA classification for each video was performed by evaluating the extent of impaired regional shortening visible (measured in the original 4DCT data). DL classification of each video for the presence of WMA was performed by first extracting image features frame-by-frame using a pre-trained Inception network and then evaluating the set of features using a long short-term memory network. Data were split into 60% for 5-fold cross-validation and 40% for testing.ResultsVolume rendering videos represent ~800-fold data compression of the 4DCT volumes. Per-video DL classification performance was high for both cross-validation (accuracy = 93.1%, sensitivity = 90.0% and specificity = 95.1%, κ: 0.86) and testing (90.9, 90.2, and 91.4% respectively, κ: 0.81). Per-study performance was also high (cross-validation: 93.7, 93.5, 93.8%, κ: 0.87; testing: 93.5, 91.9, 94.7%, κ: 0.87). By re-binning per-video results into the 6 regional views of the LV we showed DL was accurate (mean accuracy = 93.1 and 90.9% for cross-validation and testing cohort, respectively) for every region. DL classification strongly agreed (accuracy = 91.0%, κ: 0.81) with expert visual assessment.ConclusionsDynamic volume rendering of the LV blood pool combined with DL classification can accurately detect regional WMA from cardiac CT.

BackgroundThere has been a rapid increase in the use of commercially available activity trackers, such as Fitbit, in physical activity intervention research. However, little is known about the long-term sustained use of trackers and behavior change after short-term interventions. ObjectiveThis study aims to use minute-level data collected from a Fitbit tracker for up to 2 years after the end of a randomized controlled trial to examine patterns of Fitbit use and activity over time. MethodsParticipants in this secondary data analysis were 75 female breast cancer survivors who had been enrolled in a 12-week physical activity randomized controlled trial. Participants randomized to the exercise intervention (full intervention arm) received a Fitbit One, which was worn daily throughout the 12-week intervention, and then were followed for 2 years after the intervention. Participants randomized to the waitlist arm, after completing the randomized controlled trial, received a Fitbit One and a minimal version of the exercise intervention (light intervention arm), and then were followed for 2 years after the intervention. Average and daily adherence and MVPA were compared between the 2 groups in the interventional and postinterventional periods using both linear and generalized additive mixed effects models. ResultsAdherence to wearing the Fitbit during the 12-week intervention period was significantly higher in the full intervention arm than in the light intervention arm (85% vs 60%; P

Orthopaedic surgeons account for the largest proportion of opioid prescriptions in the United States among surgical specialties. In total joint arthroplasty, increased opioid use has been associated with poorer clinical and functional outcomes. Despite an abundance of literature on opioid mitigation strategies, most fail to provide personalized prescriptions. Typically, most protocols prescribe the same opioid regimen regardless of patient factors or the extent of the planned procedure. We present a simple opioid stratification pathway that can be used by physicians and office staff as they prepare patients for arthroplasty. We have found this to be easy to implement, effective, and sustainable at a tertiary academic institution and allows for iterative improvements over time.

Abstract Background Tau neurofibrillary tangle pathology characterizes Alzheimer’s disease and other neurodegenerative tauopathies. Brain gene expression profiles can reveal mechanisms; however, few studies have systematically examined both the transcriptome and proteome or differentiated Tau- versus age-dependent changes. Methods Paired, longitudinal RNA-sequencing and mass-spectrometry were performed in a Drosophila model of tauopathy, based on pan-neuronal expression of human wildtype Tau (TauWT) or a mutant form causing frontotemporal dementia (TauR406W). Tau-induced, differentially expressed transcripts and proteins were examined cross-sectionally or using linear regression and adjusting for age. Hierarchical clustering was performed to highlight network perturbations, and we examined overlaps with human brain gene expression profiles in tauopathy. Results TauWT induced 1514 and 213 differentially expressed transcripts and proteins, respectively. TauR406W had a substantially greater impact, causing changes in 5494 transcripts and 697 proteins. There was a ~ 70% overlap between age- and Tau-induced changes and our analyses reveal pervasive bi-directional interactions. Strikingly, 42% of Tau-induced transcripts were discordant in the proteome, showing opposite direction of change. Tau-responsive gene expression networks strongly implicate innate immune activation. Cross-species analyses pinpoint human brain gene perturbations specifically triggered by Tau pathology and/or aging, and further differentiate between disease amplifying and protective changes. Conclusions Our results comprise a powerful, cross-species functional genomics resource for tauopathy, revealing Tau-mediated disruption of gene expression, including dynamic, age-dependent interactions between the brain transcriptome and proteome.

Abstract Background Adverse cardiac remodeling is an important precursor to anthracycline-related cardiac dysfunction, however conventional remodeling indices are limited. We sought to examine the utility of statistical atlas-derived measures of ventricular shape to improve the identification of adverse anthracycline-related remodeling in childhood cancer survivors. Methods We analyzed cardiac magnetic resonance imaging from a cross-sectional cohort of 20 childhood cancer survivors who were treated with low (

Background: With the removal of total knee arthroplasty (TKA) from the Medicare inpatient-only list, outpatient TKA can now be offered, irrespective of payer, in multiple sites. We compared time- and cost-effectiveness of outpatient TKA performed in a hospital outpatient department (HOPD) to that at an inpatient academic medical center (AMC). Methods: We reviewed all outpatient TKAs performed at our AMC and our HOPD from August 2018 to July 2019. Time efficiency by phase of care was determined, and cost data were obtained from the hospital financial department. Patient selection for outpatient surgery was identical for each site of care. Results: We identified 21 knees that had surgery at the HOPD and 65 knees that had surgery at the AMC. Demographics were similar in both groups. The AMC group had significantly longer in-facility to operating room (Δ (difference) = 33.5 minute, P = .0003), postanesthesia care unit to discharge (Δ = 158.8 minute, P < .0001) and in-facility to discharge (Δ = 199.3 minute, P < .0001) time periods compared to the HOPD group. The HOPD was significantly more cost-effective for the preoperative period (Δ = $75.7, P < .0001), postoperative period (Δ = $315.1, P < .0001), and total cost (Δ = $241, P < .0001). Conclusions: Outpatient TKAs performed in an HOPD spend significantly less time within the facility than the ones performed in an AMC and cost significantly less. It is expected that approval of Medicare TKAs at ambulatory surgery centers will further improve cost and efficiency.

AbstractRecently, we identified 1,189 CpG sites whose DNA methylation level in blood associated with Crohn’s disease. Here, we examined associations between DNA methylation and genetic variants to identify methylation quantitative trait loci across disease states in (1) 402 blood samples from 164 newly diagnosed pediatric Crohn’s disease patients taken at 2 time points (diagnosis and follow-up), and 74 non-inflammatory bowel disease controls, (2) 780 blood samples from a non-Crohn’s disease adult population, and (3) 40 ileal biopsies (17 Crohn’s disease cases and 23 non-inflammatory bowel disease controls) from group (1). Genome-wide DNAm profiling and genotyping were performed using the Illumina MethylationEPIC and Illumina Multi-Ethnic arrays. SNP-CpG associations were identified via linear models adjusted for age, sex, disease status, disease subtype, estimated cell proportions, and genotype-based principal components. In total, we observed 535,448 SNP-CpG associations between 287,881 SNPs and 12,843 CpG sites (P −14

Purpose: To report on clinical presentations and outcomes in patients who underwent an isolated endoscopic gluteus medius (GM) repair. Methods: We retrospectively reviewed and prospectively collected data on patients who underwent a primary isolated endoscopic GM repair. Patients were included if the following patient-reported outcome scores were obtained preoperatively and at minimum 2-year follow-up: modified Harris Hip Score (mHHS), Non-arthritic Hip Score (NAHS), and visual analog scale (VAS) score. The minimal clinically important difference (MCID) for the mHHS, NAHS, and Hip Outcome Score–Sports Specific Scale was uniquely calculated for this study. Patients who underwent concomitant procedures including hip arthroplasty and hip arthroscopy were excluded. Results: A total of 26 hips met all inclusion and exclusion criteria, of which 23 hips (88.5%) (22 patients) had a minimum 2-year follow-up. Nineteen hips had a partial-thickness GM tear; 17 (89.5%) were high-grade partial-thickness tears treated with a side-to-side repair through a transtendinous window. Four full-thickness tears with no retraction or fatty infiltration were able to be repaired endoscopically. The mHHS, NAHS, and VAS score all significantly improved (P < .05) from baseline: The mHHS improved from 55.9 to 75.4 (P = .005); the NAHS, from 58.8 to 79.2 (P = .003); and the VAS score, from 5.9 to 3.6 (P = .009). The MCID was calculated for the mHHS, NAHS, and Hip Outcome Score–Sports Specific Scale as 5.8, 7.1, and 11.0, respectively. Most patients achieved the MCID for all 3 patient-reported outcome scores. Conclusions: Appropriately selected patients without concomitant intra-articular hip pathology may achieve successful outcomes at a minimum 2-year follow-up after an isolated endoscopic GM repair. Most isolated endoscopic GM repairs were performed for partial-thickness GM tears. Level of Evidence: Level IV, case-series study.

Bronchial thermoplasty (BT) is an interventional bronchoscopic treatment for severe asthma. There is a need to define patient selection criteria to guide clinicians in offering the appropriate treatment options to patients with severe asthma. Methodology: An expert group formed this statement under the aegis of the Indian Chest Society. We performed a systematic search of the MEDLINE and EMBASE databases to extract evidence on patient selection and the technical performance of BT. Results: The experts agreed that the appropriate selection of patients is crucial and proposed identification of the asthma phenotype, a screening algorithm, and inclusion/exclusion criteria for BT. In the presence of atypical clinical or chest radiograph features, there should be a low threshold for obtaining a thoracic computed tomography scan before BT. The patient should not have had an asthma exacerbation in the preceding two weeks from the day of the procedure. A 5-day course of glucocorticoid should be administered, beginning three days before the procedure day, and continued until the day following the procedure. General Anesthesia (total intravenous anesthesia with a neuromuscular blocker) provides ideal conditions for performing BT. A thin bronchoscope with a 2.0 mm working channel is preferable. An attempt should be made to deliver the maximum radiofrequency activations. Middle lobe treatment is not recommended. Following the procedure, overnight observation in the hospital, and a follow-up visit, a week following each treatment session, is desirable. Conclusion: This position statement provides practical guidance regarding patient selection and the technical performance of BT for severe asthma.

Abstract Background Cap-dependent mRNA translation is essential for the translation of key oncogenic proteins at optimal levels and is highly regulated by the rate limiting, initiation step in protein synthesis. Eukaryotic Translation Initiation Factor 4 Gamma 1 (EIF4G1) serves as a scaffold for assembly of cap-dependent translation components in EIF4F complex formation. In the current study, we analyzed the role and expression of EIF4G1 in Pan human cancer panels through various approaches. Methods Immunohistochemistry analysis of EIF4G1 protein was done on high-density multi-organ Human Cancer tissue microarray (TMA) derived from the patient samples from different cancers. We used multiple clinical cohorts to analyze the EIF4G1 mRNA expression across human cancers. TCGA data analysis of EIF4G1 was done through Ualcan and c-bioportal web servers. Western blots for EIF4G1 protein was done for different cell lines in representing the multiple cancer types. Dependency score was calculated through Cancer Dependency Map. Clonogenic, tumorosphere assay and cell invasion assay were done with EIF4G complex inhibitor. Association of EIF4G1 mRNA and Kaplan–Meier survival analysis was done on available TCGA datasets. Results We observed an increase in EIF4G1 protein levels in tissue sections from different cancers as compared to their respective normal tissue. Our analysis of the TCGA data revealed that EIF4G1 mRNA expression is significantly increased in tumor tissues compared to respective control tissues across human cancers and variable expression was observed among different datasets. We discovered that alteration frequency in EIF4G1 is prevalent in human cancers e.g. prostate cancer (~ 25%), ovarian cancer (~ 15%), Head and Neck cancer (~ 13%) and cervical cancer (~ 12.5%). EIF4G1 mRNA and protein levels were high across cancer cell lines from multiple organs. Our analysis of DepMap datasets utilizing depletion assays revealed that EIF4G1 is critical for cancer cell survival. Treatment with EIF4G complex inhibitor impaired clonogenic, tumorosphere formation potential and inhibited cell invasion. Moreover, higher EIF4G1 mRNA level was associated with a lower median survival of patients in multiple tumor types. Conclusions These studies show that EIF4G1 is amplified/over-expressed in multiple cancers and plays an essential role in cancer cell survival, as such EIF4G1 could serve as a novel potential target for therapeutic intervention across many cancers.

Background: Interest in outpatient total hip arthroplasty (THA) and total knee arthroplasty (TKA) has increased recently as part of value-based care and early recovery protocols. Outpatient pathways require significant paradigm shifts, are not used widely, and are mostly implemented at outpatient surgery centers or orthopedic specialty hospitals. In this article, we report on the outcomes of implementation of an outpatient arthroplasty protocol at a tertiary care academic medical center. Methods: We performed a retrospective review on a series of 105 consecutive patients who underwent THA or TKA following our newly implemented outpatient arthroplasty protocol. We compared these patients to a group of inpatient arthroplasty patients from the same time period. Results: Eighty-three of 105 (79%) patients were successfully discharged home on the day of surgery. Successful same-day discharge was predicted by early ambulation (P = .01), TKA over THA (P = .04), and shorter duration of surgery (P = .01). General anesthesia correlated with better early ambulation distances (P = .03) and a lower incidence of urinary retention (P = .049). The outpatient readmission and complication rates were 0.95% and 1.9%, respectively, whereas the matched inpatient rates were 3.7% and 2.9%, respectively. Conclusions: Outpatient THA and TKA in a well-selected patient is feasible in an academic multidisciplinary tertiary care hospital, with complication rates approximating inpatient surgery. The findings reported here can be used to further optimize outpatient arthroplasty protocols. Keywords: Outpatient arthroplasty, Anesthesia, Ambulation, Urinary retention, Rapid recovery

Aging well is directly associated with a healthy lifestyle. The focus of this paper is to relate that attenuation of postoperative loss of muscle function after a total knee arthroplasty (TKA) is an important consideration. Because patients usually do not tolerate standard high-resistance exercise in the preoperative or postoperative period, they often experience a decline in strength and function. Therefore, we tested the feasibility and acceptability of an alternative low-resistance exercise protocol with blood flow restriction (BFR) using a tourniquet in the preoperative period for patients awaiting TKA. We recruited patients undergoing a TKA and randomized six to the BFR exercise for 4 weeks prior to surgery and four to standard of care (no exercise). We measured physical function using the Short Physical Performance Battery (SPPB), the 6-Minute Walk Test (6MWT), leg strength (peak torque), and pain (numerical pain score) 4 to 5 weeks preoperatively and 2 weeks postoperatively. The clinical management, e.g., anesthetic management, did not differ between groups. No complications were observed. Our findings demonstrate the feasibility and acceptability of the BFR intervention. Although preliminary and not powered for comparison, the BFR group demonstrated less decline in SPPB following surgery (−2.2, 95%CI:−4.4,0.1) compared to the no exercise group (−4.8, 95%CI:−7.8,−1.7). No differences were noted for the 6MWT, leg strength, and pain measurements. We conclude that preoperative low-resistance exercise using the BFR is feasible and acceptable, and this test warrants investigation as an intervention to potentially attenuate the postoperative loss of physical function after TKA.

COVID-19 ranges from asymptomatic in 35% of cases to severe in 20% of patients. Differences in the type and degree of inflammation appear to determine the severity of the disease. Recent reports show an increase in circulating monocytic-myeloid-derived suppressor cells (M-MDSC) in severe COVID 19 that deplete arginine but are not associated with respiratory complications. Our data shows that differences in the type, function and transcriptome of granulocytic-MDSC (G-MDSC) may in part explain the severity COVID-19, in particular the association with pulmonary complications. Large infiltrates by Arginase 1+ G-MDSC (Arg+G-MDSC), expressing NOX-1 and NOX-2 (important for production of reactive oxygen species) were found in the lungs of patients who died from COVID-19 complications. Increased circulating Arg+G-MDSC depleted arginine, which impaired T cell receptor and endothelial cell function. Transcriptomic signatures of G-MDSC from patients with different stages of COVID-19, revealed that asymptomatic patients had increased expression of pathways and genes associated with type I interferon (IFN), while patients with severe COVID-19 had increased expression of genes associated with arginase production, and granulocyte degranulation and function. These results suggest that asymptomatic patients develop a protective type I IFN response, while patients with severe COVID-19 have an increased inflammatory response that depletes arginine, impairs T cell and endothelial cell function, and causes extensive pulmonary damage. Therefore, inhibition of arginase-1 and/or replenishment of arginine may be important in preventing/treating severe COVID-19.

Gross hip instability in an active adult with previous normal hip anatomy is usually due to disruption of the static stabilizers of the hip joint. Although such a disruption can result from a high-grade injury, it can be iatrogenic after previous hip arthroscopy. The patient may present with a painful limp and recurrent subluxation sensation in the affected hip joint. Revision hip arthroscopy in this scenario is generally complicated, and it is not uncommon for all the soft-tissue stabilizers to be compromised. The labrum, ligamentum teres (LT), and capsule of the hip joint are often so damaged that reparation is not an option. Reconstruction of the torn LT is an established method to add secondary stability while addressing the labral pathology in the hip joint with microinstability. Concomitant reconstruction of all the static restraints has yet to be described addressing triple instability. This Technical Note presents a stepwise approach, including tips and pearls, for arthroscopic triple reconstruction of the labrum, LT, and capsule. We believe this method is a safe and reproducible way to effectively treat gross hip instability in young patients.

Measurements of physical function after total knee arthroplasty (TKA) are uncertain and require investments for special equipment, space, and staff. Therefore, we evaluated the Short Physical Performance Battery (SPPB) 4 to 6 weeks preoperatively and 2 weeks following TKA as this test battery addresses lower extremity strength, coordination, and balance, without additional special investments. For context, we also employed the Six-Minute Walk test (6MWT) and peak torque knee extension. Our analysis consisted of three women and one man, with average ages of 68.3±3.9 years. Patients showed a decrease in all functional measurements: SPPB (mean change: −4.8±1.9, 44% decrease), 6MWT (−0.37±.21 m/s, 34% decrease), and peak torque (−11.8±8.8°/s, 68% decrease). Our findings suggest the SPPB is feasible and can be integrated easily in daily clinical practice.

Treatment of hip joint chondral damage is a well-recognized aspect of the arthroscopic management of femoroacetabular impingement syndrome. Hip chondral resurfacing has evolved from microfracture to different forms of cartilage grafting, all with variable long-term outcomes. Recent literature has focused on techniques using different cartilage sources (native and synthetic products) that are available for clinicians to choose from during hip arthroscopy. None of the published reports on cartilage grafts have commented on hip joint capsular management as part of the procedure. This is likely because of the increased difficulty of capsular closure in the dry arthroscopic environment required for graft stabilization. However, potential iatrogenic hip instability induced by an unrepaired interportal capsulotomy can be detrimental to the existing joint architecture and possibly to the cartilage graft. This article presents a step-by-step approach, including tips and pearls, for capsular closure during arthroscopic acetabular chondral resurfacing with BioCartilage (Arthrex, Naples, FL). This method is a safe and reproducible way to close the joint capsule during chondral resurfacing in patients undergoing hip preservation that can potentially enhance the chances of a successful outcome.

Gluteus medius (GM) tears are a well-established source of pain and disability. Considering previous studies, which have reported rates of incidental GM tears in 20% of patients undergoing primary total hip arthroplasty (THA) and a 3-fold greater rate in elderly female patients, additional focus should be placed on identifying treatment options. The direct anterior approach (DAA) for primary THA has gained popularity within the past few years. However, there has been a paucity in the literature on how to address symptomatic and partial GM tears through this approach. The purpose of this Technical Note is to describe a method to repair partial GM tears during primary THA using the DAA.

Case. An 82-year-old woman underwent right total knee replacement with a sequentially irradiated and annealed highly cross-linked polyethylene insert. At 9 years, she was found to have a massive femoral osteolysis with an impending fracture. Conclusion. This case demonstrates a rare occurrence of massive femoral osteolysis, requiring revision surgery, with a sequentially irradiated and annealed highly cross-linked polyethylene.

Intraosseous bioplasty (IOBP), has been previously described for arthroscopic-assisted treatment of subchondral bone cysts in the proximal tibia associated with early stages of knee osteoarthritis (OA). This technique entails combining bone marrow aspirate concentrate or concentrated platelet-rich plasma with demineralized bone matrix as a bone substitute before injecting into a subchondral bone defect under fluoroscopic guidance. The principles of IOBP as a procedure that combines core decompression with biologic bone substitute augmentation can be extended to treat subchondral bone marrow lesions such as acetabular and femoral cysts in degenerative hip OA. Intraosseous bioplasty of the hip, in particular the acetabulum, when done using this technique, is a useful alternative that can be beneficial in treating young patients with early hip arthritis to achieve successful outcomes while delaying more invasive procedures. The Technical Note described here presents a step-by-step approach, including tips and pearls for arthroscopic-assisted IOBP with decompression of the subchondral cyst in the acetabulum followed by bone substitute injection under fluoroscopic guidance. We believe this method is a safe and reproducible way to treat subchondral defects in young patients with signs of early osteoarthritis of the hip joint.

Older adults have significantly worse morbidity and mortality after severe trauma than younger cohorts. The competency of the innate immune response decreases with advancing age, especially after an inflammatory insult. Subsequent poor outcomes after trauma are caused in part by dysfunctional leukocytes derived from the host's hematopoietic stem and progenitor cells (HSPCs). Our objective was to analyze the bone marrow (BM) HSPC transcriptomic [mRNA and microRNA (miR)] responses to trauma in older and younger adults. BM was collected intraoperatively

Aflatoxins are secondary metabolites produced by soilborne saprophytic fungus Aspergillus flavus and closely related species that infect several agricultural commodities including groundnut and maize. The consumption of contaminated commodities adversely affects the health of humans and livestock. Aflatoxin contamination also causes significant economic and financial losses to producers. Research efforts and significant progress have been made in the past three decades to understand the genetic behavior, molecular mechanisms, as well as the detailed biology of host-pathogen interactions. A range of omics approaches have facilitated better understanding of the resistance mechanisms and identified pathways involved during host-pathogen interactions. Most of such studies were however undertaken in groundnut and maize. Current efforts are geared toward harnessing knowledge on host-pathogen interactions and crop resistant factors that control aflatoxin contamination. This study provides a summary of the recent progress made in enhancing the understanding of the functional biology and molecular mechanisms associated with host-pathogen interactions during aflatoxin contamination in groundnut and maize.

Background: In an effort to minimize backside polyethylene wear and osteolysis associated with titanium tibial baseplates, many manufacturers have transitioned to cobalt chromium alloys. Recent literature has implicated thicker cobalt chromium designs as a potential source of increased stress shielding and resorption. We report the incidence of proximal tibial bone resorption in a large consecutive series of patients undergoing total knee arthroplasty, with a modern total knee design. Methods: Four hundred thirty-two consecutive primary total knee arthroplasties, performed by 2 fellowship-trained arthroplasty surgeons were identified over a 24-month period. In addition to review of the medical records, analysis of preoperative and postoperative radiographs was performed. Utilizing a novel classification system, the severity of resorption was quantified and correlated with patient and implant characteristics. Results: After exclusions, 339 knees were evaluated in 292 patients. Mean follow-up was 13.2 months (range 6-41). Resorption was present in 119 knees (35.1%). Average time to diagnosis of bone loss was 6.9 months (range 2-32) postoperatively. There was a statistically significant difference between resorption and nonresorption groups with regards to gender and preoperative alignment. Most cases were classified as Grade 1. During the study period, 2 patients required revision for aseptic tibial loosening. Conclusions: Our findings suggest that proximal tibial resorption is common with this particular implant, particularly in men and patients with preoperative varus deformity. Although this typically occurs relatively early in postoperative period and in most cases appears to remodel and stabilize, its ultimate clinical significance and effect on implant survivorship remains unclear.

Background: Total joint arthroplasty (TJA) remains the highest expenditure in the Centers for Medicare and Medicaid Services (CMS) budget. One model to control cost is the Comprehensive Care for Joint Replacement (CJR) model. There has been no published literature to date examining the efficacy of CJR on value-based outcomes. The purpose of this study was to determine the efficacy and sustainability of a multidisciplinary care redesign for total joint arthroplasty under the CJR paradigm at an academic tertiary care center. Methods: We implemented a system-wide care redesign, affecting all patients who underwent a total hip or total knee arthroplasty at our academic medical center. The main study outcomes were cost (to CMS), discharge destination, complications and readmissions, and length of stay (LOS); these were measured using the 2017 initial CJR reconciliation report, as well as our institutional database. Results: The study included 1536 patients (41% Medicare). Per-episode cost to CMS declined by 19.5% to 11% below the CMS-designated national target. Home discharge increased from 62% to 87%. CMS readmissions declined from 15% to 6%; major complications decreased from 2.3% to 1.9%; and LOS declined from 3.6 to 2.1 days. Conclusions: A mandatory episode-based bundled-payment program can induce favorable changes to value-based metrics, improving quality and outcomes for health-care consumers. Quality and value were improved in this study, evidenced by lower 90-day episode cost, more home discharges, lower readmissions and complications, and shorter LOS. This approach has implications not just for CMS, but for private payers, corporate health programs, and fixed-budget health-care models.

Abstract eIF4G1, a critical component of the eIF4F complex, is required for cap-dependent mRNA translation, a process necessary for tumor growth and survival. However, the role of eIF4G1 has not been evaluated in Prostate Cancer (PCa). We observed an increased eIF4G1 protein levels in PCa tissues as compared to normal tissues. Analysis of the TCGA data revealed that eIF4G1 gene expression positively correlated with higher tumor grade and stage. Furthermore, eIF4G1 was over-expressed and or amplified, in 16% patients with metastatic PCa (SU2C/PCF Dream Team dataset) and in 59% of castration-resistant prostate cancer (CRPC) patients (Trento/Cornell/Broad dataset). We showed for the first time that eIF4G1 expression was increased in PCa and that increased eIF4G1 expression associated with tumor progression and metastasis. We also observed high protein levels of eIF4G1 in PCa cell lines and prostate tissues from the TRAMP model of PCa as compared to normal prostate cell line and prostate tissues from the wild type mice. Knockdown of eIF4G1 in PCa cells resulted in decreased Cyclin D1 and p-Rb protein level, cell cycle delay, reduced cell viability and proliferation, impaired clonogenic activity, reduced cell migration and decreased mRNA loading to polysomes. Treatment with eIF4G complex inhibitor also impaired prostasphere formation. eIF4G1 knockdown or treatment with eIF4G complex inhibitor sensitized CRPC cells to Enzalutamide and Bicalutamide. Our results showed that eIF4G1 plays an important role in PCa growth and therapeutic resistance. These data suggested that eIF4G1 functions as an oncoprotein and may serve as a novel target for intervention in PCa and CRPC.

Background: Hip osteoarthritis typically manifests with groin or thigh pain. Other atypical pain patterns, including knee pain, have been described. Except for 2 case reports, there is no literature on this subject. Methods: From our institutional database, between 2011 and 2016, we identified 21 patients who were referred for treatment of knee pain but ultimately diagnosed with hip pathology as the cause of their pain. This group was evaluated for duration of symptoms prior to diagnosis, previous interventions, presence of walking aids, and symptom resolution after treatment of the hip pathology. Results: Fifteen of the 21 patients were referred from musculoskeletal providers (12 from orthopaedic surgeons). Prior to diagnosis of the hip etiology, 16 patients were reduced to major assistive devices including wheelchairs. Twelve of 21 patients had undergone surgical knee interventions, including total knee arthroplasty, with minimal to no relief of their pain. Seventeen of 21 referred patients underwent total hip arthroplasty at our institution. Fourteen patients had complete resolution of knee pain after total hip arthroplasty. Conclusions: Although knee pain referred from hip disease may be considered a basic and common knowledge, it continues to be an overlooked phenomenon. Most of the cases were misdiagnosed by musculoskeletal providers including orthopaedic surgeons and this highlights the need for continued education and awareness of this clinical scenario. Keywords: Hip pain, Knee pain, Referred pain, Delay in diagnosis, Unnecessary surgery

People living with HIV/AIDS (PLWHA) are at an increased risk of severe and critical COVID-19 infection. There is a steady increase in neurological complications associated with COVID-19 infection, exacerbating HIV-associated neurocognitive disorders (HAND) in PLWHA. Nutraceuticals, such as phytochemicals from medicinal plants and dietary supplements, have been used as adjunct therapies for many disease conditions, including viral infections. Appropriate use of these adjunct therapies with antiviral proprieties may be beneficial in treating and/or prophylaxis of neurological complications associated with these co-infections. However, most of these nutraceuticals have poor bioavailability and cannot cross the blood–brain barrier (BBB). To overcome this challenge, extracellular vesicles (EVs), biological nanovesicles, can be used. Due to their intrinsic features of biocompatibility, stability, and their ability to cross BBB, as well as inherent homing capabilities, EVs hold immense promise for therapeutic drug delivery to the brain. Therefore, in this review, we summarize the potential role of different nutraceuticals in reducing HIV- and COVID-19-associated neurological complications and the use of EVs as nutraceutical/drug delivery vehicles to treat HIV, COVID-19, and other brain disorders.

For decades, sulfonylureas (SUs) have been important drugs in the antidiabetic therapeutic armamentarium. They have been used as monotherapy as well as combination therapy. Focus on newer drugs and concerns about the risk of severe hypoglycemia and weight gain with some SUs have led to discussion on their safety and utility. It has to be borne in mind that the adverse events associated with SUs should not be ascribed to the whole class, as many modern SUs, such as glimepiride and gliclazide modified release, are associated with better safety profiles. Furthermore, individualization of treatment, using SUs in combination with other drugs, backed with careful monitoring and patient education, ensures maximum benefits with minimal side effects. The current guidelines, developed by experts from Africa, Asia, and the Middle East, promote the safe and smart use of SUs in combination with other glucose-lowering drugs.

Abstract Human immunodeficiency virus (HIV) has been associated with inflammatory effects that may potentially result in neurodegenerative changes and a number of newer chemotherapeutic agents are being tested to ameliorate these effects. In this study, we investigated the anti-neuroinflammatory activity of a novel resveratrol analog 4-(E)-{(p-tolylimino)-methylbenzene-1,2-diol} (TIMBD) against HIV1-gp120 induced neuroinflammation in SVG astrocytes. SVG astrocytic cells were pretreated with TIMBD or resveratrol (RES) and then transfected with a plasmid encoding HIV1-gp120. The mRNA and protein expression levels of proinflammatory cytokines IL6, IL8 and CCL5 were determined. Protein expression levels of NF-κB, AP1, p-STAT3, p-AKT, p-IKKs and p-p38 MAPK were also determined. TIMBD inhibited gp120-induced RNA and protein expression levels of IL6 and IL8, but not that of CCL5 in SVG astrocytes. Moreover, TIMBD attenuated gp120-induced phosphorylation of cJUN, cFOS, STAT3, p38-MAPK, AKT and IKKs, and the nuclear translocation of NF-κB p-65 subunit whereas RES mostly affected NF-κB protein expression levels. Our results suggest that TIMBD exerts anti-inflammatory effects better than that of RES in SVG astrocytes in vitro. These effects seem to be regulated by AP1, STAT-3 and NF-κB signaling pathways. TIMBD may thus have a potential of being a novel agent for treating HIV1-gp120-mediated neuroinflammatory diseases.

Abstract In five-dimensional minimal supergravity, there are spherical black holes with nontrivial topology outside the horizon which have the same conserved charges at infinity as the BMPV solution. We show that some of these black holes have greater entropy than the BMPV solution. These spacetimes are all asymptotically flat, stationary, and supersymmetric. We also show that there is a limit in which the black hole shrinks to zero size and the solution becomes a nonsingular “bubbling” geometry. Thus, these solutions provide explicit analytic examples of placing black holes inside solitons.

Abstract Background Prenatal urinary concentrations of phthalates in women participants in an urban birth cohort were associated with outcomes in their children related to neurodevelopment, autoimmune disease risk, and fat mass at 3,5,7, and 8 years of life. Placental biomarkers and outcomes at birth may offer biologic insight into these associations. This is the first study to address these associations with candidate genes from the phthalate and placenta literature, accounting for sex differences, and using absolute quantitation methods for mRNA levels. Methods We measured candidate mRNAs in 180 placentas sampled at birth (HSD17B1, AHR, CGA, CYP19A1, SLC27A4, PTGS2, PPARG, CYP11A1) by quantitative PCR and an absolute standard curve. We estimated associations of loge mRNA with quartiles of urinary phthalate monoesters using linear mixed models. Phthalate metabolites (N = 358) and mRNAs (N = 180) were transformed to a z-score and modeled as independent, correlated vectors in relation to large for gestational age (LGA) and gestational diabetes mellitus (GDM). Results CGA was associated with 4 out of 6 urinary phthalates. CGA was 2.0 loge units lower at the 3rd vs. 1st quartile of mono-n-butyl phthalate (MnBP) (95% confidence interval (CI): −3.5, −0.5) in male placentas, but 0.6 loge units higher (95% CI: −0.8, 1.9) in female placentas (sex interaction p = 0.01). There was an inverse association of MnBP with PPARG in male placentas (−1.1 loge units at highest vs. lowest quartile, 95% CI: −2.0, −0.1). CY19A1, CYP11A1, CGA were associated with one or more of the following in a sex-specific manner: monobenzyl phthalate (MBzP), MnBP, mono-iso-butyl phthalate (MiBP). These 3 mRNAs were lower by 1.4-fold (95% CI: −2.4, -1.0) in male GDM placentas vs. female and non-GDM placentas (p-value for interaction = 0.04). The metabolites MnBP/MiBP were 16% higher (95% CI: 0, 22) in GDM pregnancies. Conclusions Prenatal concentrations of certain phthalates and outcomes at birth were modestly associated with molecular changes in fetal placental tissue during pregnancy. Associations were stronger in male vs. female placentas, and associations with MnBP and MiBP were stronger than other metabolites. Placental mRNAs are being pursued further as potential mediators of exposure-induced risks to the health of the child.