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Artificial intelligence (AI) focuses on processing and interpreting complex information as well as identifying relationships and patterns among complex data. Artificial intelligence- and machine learning (ML)-driven predictions have shown promising potential in influencing real-time decisions and improving surgical outcomes by facilitating screening, diagnosis, risk assessment, preoperative planning, and shared decision-making. Fundamental understanding of the algorithms, as well as their development and interpretation, is essential for the evolution of AI in surgery. In this article, we provide surgeons with a fundamental understanding of AI-driven predictive models through an overview of common ML and deep learning algorithms, model development, performance metrics and interpretation. This would serve as a basis for understanding ML-based research, while fostering new ideas and innovations for furthering the reach of this emerging discipline.

Background: There is a potential for longitudinal and horizontal transfer of the cytotoxic effects of cypermethrin, and evidence suggests that date fruit extracts can ameliorate these cytotoxic effects. Thus, the current study evaluated female Wister rats’ fertility and pup parameters after mating males treated with cypermethrin and date fruit (Phoenix dactylifera) extract. Methods: Adult Wistar rats (n = 74; 140 – 207 g) were used to conduct this experiment in two phases: The first phase was a single dose toxicity study (n = 18), while the second phase (n = 56) evaluated female Wister rats’ reproductive and pup development parameters after mating with male Wistar rats exposed to date fruit extract and cypermethrin. Male rats were distributed randomly into four groups (n = 7 per group) and administered distilled water (Group I); 60 mg/kg cypermethrin (Group II) to simulate infertility; 250 mg/kg date fruit extract alone (Group III); and date fruit extracts plus 60 mg/kg cypermethrin (Group IV). Treated males were then mated with healthy female rats at a ratio of 1:1. Successfully mated females were appraised for conception and pregnancy rates, gestation length, litter size, and weights at birth, and on days 5, 10, 15, and 21 post-partum, an anogenital distance at day-20, sex ratio, and age of pup when hair growth was evident. Results: Significant differences (p < 0.05) were observed in litter size and male anogenital distance but not in reproductive performance. Also, the study demonstrated that date fruit extract skewed the sex ratio of offspring to more female than male pups when female Wister rats were mated with males that received date fruit extracts alone or cypermethrin and date fruit extracts. The body weight gain did not differ significantly between the control and cypermethrin-treated groups Conclusion: This evidence suggested a longitudinal transfer of the protective effects of date fruit extracts following a weekly exposure of male rats to cypermethrin at 60 mg/kg.

Lesser (or central) metatarsalgia is defined as pain in the forefoot under or around the lesser metatarsals and their respective metatarsophalangeal joints. Two common causes of central metatarsalgia are Morton's neuroma (MN) and plantar plate (PP) injury. Because both clinical and imaging features overlap, establishing the correct differential diagnosis may be challenging. Imaging has a pivotal role in the detection and characterization of metatarsalgia. Different radiologic modalities are available to assess the common causes of forefoot pain, so the strengths and weakness of these imaging tools should be kept in mind. It is crucial to be aware of the pitfalls that can be encountered in daily clinical practice when dealing with these disorders. This review describes two main causes of lesser metatarsalgia, MN and PP injury, and their differential diagnoses.

The Swan Point site in interior Alaska contains a significant multi-component archaeological record dating back to 14,200 cal BP. The site’s radiocarbon (14C) chronology has been presented in scattered publications that mostly focus on specific archaeological periods in Alaska, in particular its terminal Pleistocene components associated with the East Beringian tradition. This paper synthesizes the site’s 14C data and provides sequential Bayesian models for its cultural zones and subzones. The 14C and archaeological record at Swan Point attests that the location was persistently used over the last 14,000 years, even though major changes are evident within regional vegetation and local faunal communities, reflecting long-term trends culminating in Dene-Athabascan history.

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Desiccation cracking in clay soils is a combined mechanical and hydraulic problem and such soils can be improved by various methods including reinforcement with fibres. The relationships between tensile strength, cracking resistance and water-retention properties of fibre-reinforced fine-grained soils lack coverage in the literature to date. In this study, these three properties are evaluated and connected by way of a series of tensile strength and desiccation cracking tests on fibre-reinforced London clay. The results confirm that increased fibre addition delays the occurrence of peak stress and changes failure behaviour from brittle to ductile. The tensile strength increment gets higher as water content decreases, and reaches a maximum value of 460 kPa when the water content is 12%. The crack intensity factor reduces from 7.20% to 0.89% when 12 mm long fibre is used at a ratio of 0.9%. Fibre reinforcement also changes the crack development pattern by reducing the size of large cracks and increasing the proportion of small individual cracks. However, the presence of fibres was not observed to change the water-retention properties of the soil, indicating that the tensile improvement comes from the pull-out resistance of the fibres rather than suction changes.

Laparoscopic resection of the pancreas (LRP) has been implemented to a varying degree because it is technically demanding and requires a long learning curve. In the present study we analyze the risk factors for complications and hospital readmissions in a single center study of 105 consecutive LRPs.We conducted a retrospective study using a prospective database. Data were collected on age, gender, BMI, ASA score, type of surgery, histologic type, operative time, hospital stay, postoperative complications, degree of severity and hospital readmission.The cohort included 105 patients, 63 females and 42 males with a median age and BMI of 58 (53-70) and 25.5 (22,2-27.9) respectively. Eighteen (17%) central pancreatectomies, 5 (4.8%) enucleations, 81 (77.6%) distal pancreatectomies and one total pancreatectomy were performed. Fifty-six patients (53.3%) experienced some type of complication, of which 13 (12.3%) were severe (Clavien-DindoIIIb) and 11 (10.5%) patients were readmitted in the first 30 days after surgery. In the univariate analysis, age, male gender, ASA score, central pancreatectomy and operative time were significantly associated with the development of complications (P0.05). In the multivariate analysis, male gender (OR 7.97; 95% CI 1.08-58.88)), severe complications (OR 59.40; 95% CI, 7.69-458.99), and the development of intrabdominal collections (OR 8.97; 95% CI, 1.28-63.02)) were associated with hospital readmission.Age, male gender, ASA score, operative time and central pancreatectomy are associated with a higher incidence of complications. Male gender, severe complications and intraabdominal collections are associated with more hospital readmissions.

There is limited evidence about when, why, and which individuals incur costs to acquire nonpublic information about a firm, largely due to the difficulty of observing private information acquisition. To overcome this difficulty, we obtain data on Freedom of Information Act (FOIA) requests submitted to the Securities and Exchange Commission (SEC). We predict and find that perceived information asymmetry between managers and outsiders resulting from both proprietary and agency costs triggers FOIA search. We categorize organizations making FOIA requests using their business descriptions and find that many, including law and intellectual property firms, are not expressly interested in obtaining information for near-term equity trading. Instead, their search activity relates to determinants beyond financial characteristics, including patent litigation and executive turnover. Taken together, we provide evidence on private information search by a relatively unexamined set of organizations and shed new light on the function of the SEC’s Office of FOIA Services. JEL Classifications: D82; D83; M41.

Prior measurements of the sound field produced by a laboratory-scale, Mach 3 jet flow (Baars and Tinney, Journal of Sound and Vibration, Vol. 333, No. 12, 2014, pp. 2539–2553; Fiévet et al., AIAA Journal, Vol. 54, No. 1, 2016, pp. 254–265) suggest that acoustic waveforms steepen early on in their development. This explained the discrepancy between theoretical predictions, based on effective Gol’dberg numbers, that shocks should not form, and observations of steepened Mach waves close to laboratory-scale jets. The present work continues studying this phenomenon by exploring coalescence processes that occur when neighboring waveforms intersect, forming larger-amplitude waveforms with increased cumulative nonlinear distortion. A numerical model based on the Khokhlov–Zabolotskaya–Kuznetsov (KZK) equation is developed to show that coalescence-induced steepening is sensitive to the intersection angle between adjacent waveforms, waveform duration, and cylindrical spreading effects. High frame-rate schlieren images of sound waves propagating from the post-potential core region of a laboratory-scale Mach 3 jet are then captured along an angle following the ridge of most intense noise to study the development and evolution of coalescence. A shock detection algorithm isolates shock-like events, which are tracked using a translating coordinate system and decomposed using proper orthogonal decomposition. Reduced-order reconstructions of both schlieren images and the KZK model identify common patterns that characterize the shock coalescence process.

The generalized risk-adjusted cost-effectiveness (GRACE) analysis method modifies standard cost-effectiveness analysis (CEA), the primary method currently used worldwide to value health improvements arising from healthcare interventions. Generalizing standard CEA, GRACE allows for decreasing or even increasing returns to health. Previous presentations of GRACE have relied extensively on Taylor Series expansion methods to specify key model parameters, including those that properly adjust for illness severity and preexisting disability, consequences of uncertain treatment outcomes, and the marginal rate of substitution between life expectancy and health-related quality of life. Standard CEA cannot account for these sources of value or cost in its valuation of medical treatments. However, calculations of GRACE measures based on Taylor Series are approximations, which may be poorly behaved in some contexts. This paper provides a new approach for implementing GRACE, using exact utility functions instead of Taylor Series approximations. While any proper utility function will suffice, we illustrate with three well-known functions: constant relative risk aversion (CRRA) utility; hyperbolic absolute risk aversion (HARA) utility, of which CRRA is a special case; and expo-power (EP) utility, of which constant absolute risk aversion (CARA) is a special case. The analysis then extends from two-period to multiperiod models. We discuss methods to estimate parameters of HARA and EP functions using two different types of data, one from discrete choice experiments and the other from “happiness economics” methods. We conclude with some reflections on how this analysis might affect benefit-cost analysis studies of healthcare interventions.

Hyper- and hypotensive emergencies represent some of the most severe clinical issues that can occur during or around an interventional radiology procedure. While some patients are known to be more predisposed to cardiovascular collapse, nearly all patients are at risk for such an outcome. This is particularly true of patients undergoing moderate sedation, with the possibility of cardiovascular compromise occurring not just due to the underlying pathology for which the patient is being treated, but as a complication of sedation itself. Understanding the underlying cause of hyper- or hypotension is paramount to performing an appropriate and timely intervention. While the underlying cause is being corrected—if possible—the changes in blood pressure themselves may need to be intervened upon to maintain cardiovascular stability in these patients. Interventional radiologists must be familiar with measures taken to correct hyper- or hypotensive emergencies, including the most commonly used medications to treat these disorders. This article discusses the most common etiologies of such clinical scenarios, and the most common interventions performed for these settings.

Objective: Essential tremor (ET) is a common neurological disorder that has been associated with 60% increased risk of developing dementia. The goals of the present study were to: (a) learn whether individuals with advanced ET symptoms seeking deep brain stimulation (DBS) surgery would fall into distinct cognitive subgroups, and (b) learn how empirically derived subgroups map onto criteria for mild cognitive impairment (MCI). Method: Patients with ET (N = 201; mean age = 68.9 ± 8.9 years) undergoing pre-surgical evaluation for DBS completed a multi-domain neurocognitive assessment consisting of memory, executive function, visuospatial skill, language, and processing speed. Two cluster analytic approaches (K-means, hierarchical) were independently conducted to classify cognitive patterns using domain composites. Demographics, clinical characteristics, and proportion of cases meeting neuropsychologically defined criteria for MCI were examined among clusters. Results: A three-cluster solution reflected a Low Executive group (N = 64), Low Memory Multi-Domain group (N = 41), and Cognitively Normal group (N = 96). The Cognitively Normal group was older and more educated, with a higher Dementia Rating Scale-2 score. In total, 27.4% of participants met criteria for MCI. Of the MCI cases, most were in the Low Executive (41.8%) or Low Memory Multi-Domain groups (49.1%). In the latter, 65.9% of its members were classified as MCI versus 35.9% in the Low Executive group. Conclusions: Our study identified three cognitive subtypes of ET patients presenting for DBS. Future work should examine the subgroups for progression to dementia, particularly the Low Memory Multi-Domain subgroup which may be at highest risk.

Many Neotropical tree species are widespread at continental and even inter-continental scales, but phenotypic variation across their respective ranges has rarely been quantified. We measured traits in the widespread, unisexual Neotropical tree Virola sebifera (Myristicaceae) across its continental-scale range, and predicted that, given its hyperdominant status, generalist-pollinated flower type, high dispersal capacity and wide ecological amplitude there would be: (1) a weak relationship among and within reproductive and vegetative characters with environmental, spatial and biome correlates; (2) undetectable canalization of reproductive traits; and (3) high phenotypic variation of vegetative characters. We measured five foliar and seven floral traits from 187 male-expressing individuals of V. sebifera in specimens collected from Central to South America. Spatial regression models were employed to test for the importance of distance, elevation, mean annual rainfall and temperature on phenotypic variation. Pairwise correlations of vegetative and reproductive characters were calculated to examine intraspecific trait variation among and within these two classes. We found that most phenotypic variation was weakly explained by spatial predictors such as certain major South American domains like the Andes Cordillera and the Amazon Basin. Within-class comparisons of floral characters were no different than among-class (floral-foliar) correlates, suggesting the absence of canalization of reproductive structures. Greater phenotypic variation in flowers relative to leaves may be due to the generalist pollinator regime and high dispersal capacity thus relaxing divergences in the evolutionary process of its floral morphology. The results of these morphometric analyses (e.g. weak signals of isolation by distance) in combination with the biology of this Neotropical tree suggest that V. sebifera operates as a well-dispersed metapopulation across most of its range.

During the COVID-19 pandemic, public health workers were at an increased risk for violence and harassment due to their public health work and experienced adverse mental health conditions. This article quantifies the prevalence of job-related threats, harassment, and discrimination against public health workers and measures the association of these incidents with mental health symptoms during the COVID-19 pandemic.A nonprobability convenience sample of state, local, and tribal public health workers completed a self-administered, online survey in April 2021. The survey link was emailed to members of national public health associations and included questions on workplace violence, demographics, workplace factors, and mental health symptoms. Mental health symptoms were measured using standardized, validated tools to assess depression, anxiety, post-traumatic stress disorder, and suicidal ideation. Multivariable Poisson models calculated adjusted prevalence ratios of mental health symptoms, with workplace violence as the primary risk factor. Analyses were conducted in 2021-2022.Experiencing any type or combination of workplace violence was significantly associated with an increased likelihood of reporting depression symptoms (prevalence ratio=1.21, 95% CI=1.15, 1.27), anxiety (prevalence ratio=1.21, 95% CI=1.15, 1.27), post-traumatic stress disorder (prevalence ratio=1.31, 95% CI=1.25, 1.37), and suicidal ideation (prevalence ratio=1.26, 95% CI=1.14, 1.38), after adjusting for confounders. A dose‒response relationship was found between the number of workplace violence events experienced by a public health worker and the likelihood of reporting mental health symptoms.Violence targeted at the public health workforce is detrimental to workers and their communities. Ongoing training, workplace support, and increased communication after a workplace violence incident may be helpful. Efforts to strengthen public health capacities and support the public health workforce are also needed.

Background: The primary aim of the NRG Oncology/NSABP B-52 clinical trial was to test if estrogen deprivation (ED) administered concomitantly with neoadjuvant docetaxel, carboplatin, trastuzumab, and pertuzumab (TCHP), would improve the pCR rate in patients with HER2+/ER+ early breast cancer. A numerical increase in the pCR rate was observed with ED (46.1% v 40.9%), but the difference was not statistically significant. The purposes of this study were to assess the association of sTILs in pretreatment biopsies with pCR in the total population and within the molecular subtypes of breast cancer and to assess changes in sTILs between pre- and on-treatment biopsies. The secondary endpoints of recurrence-free interval (RFI) and overall survival (OS) are currently being analyzed and will be presented along with association of these endpoints with sTILs in pretreatment biopsies in the total cohort and within molecular subtypes. Methods: Scoring of sTILs on routine H&E slides from pre-treatment biopsies with sufficient tumor from 249 of the 315 patients (79%) entered in B-52 were performed by one of two pathologists (SKM, RSM). Both pathologists scored sTILs on a subset of 64 patients to document concordance. Wilcoxon two-sided test, box and whisker plots, and forest plots were used to assess associations with pCR. Molecular subtypes were determined utilizing RNA-seq data and AIMS subtyping method. On-treatment biopsies were available in 46 patients and were scored and compared to paired baseline samples. Results: Good concordance between pathologists was established with an inter-pathologist difference of ˂20% difference between scores in 92% of cases. sTILs in pre-treatment samples were associated with pCR across both arms of the trial (p=0.0074) and in the TCHP+ED arm (p=0.033), but not in the TCHP arm (p=0.093). The distribution of intrinsic subtypes was 34% luminal B, 29% luminal A, 28% HER2E, 5.8% normal, and 2.7% basal, with no significant differences between the arms. Presence of sTILs showed a trend for association with pCR in HER2E pre-treatment samples (p=0.054) but not in non-HER2E (p=0.75). Similarly, sTILs were associated with pCR in non-luminal tumors (p=0.055) but not in luminal tumors (p=0.44). Stratification by treatment arm and menopausal status suggested sTILs are associated with pCR in premenopausal women treated with TCHP (OR: 1.04, 95% CI=1.00-1.09). Interestingly, decreases in the sTIL scores with treatment were associated with pCR in the TCHP+ED arm (p=0.01) but not in the TCHP arm. Analysis of RFI and OS on B-52 is ongoing and will be presented along with associations of sTILs with intrinsic subtypes for RFI and OS. Conclusions: Although a positive correlation between sTILs and pCR was observed, the clinical utility appears limited because of the extensive overlap in the TIL scores between pCR and non-pCR tumors. Significance for a positive association of sTILs with pCR was detected in HER2E but not in luminal tumors. This may be due to the molecular differences of the subtypes, or the make-up of the TILs, or both. The association of a decrease in sTILs with TCHP+ED treatment needs further investigation. The small number of samples is a limitation of the study; however, the B-52 protocol specified that the collection of the B-52 samples was for the purpose of exploratory analysis. Our results highlight the molecular heterogeneity of the HER+/ER+ patient population and suggests that different treatment strategies may be required in future treatment regimens for this patient population. Support: NSABP Foundation; BCRF; 3U10CA180868-03S2, -180822; UG1CA189867; Genentech. Citation Format: Katherine L. Pogue-Geile, Sai K. Maley, Rim S. Kim, Ying Wang, Roberto Salgado, Corey Lipchik, Huichen Feng, Reena S. Cecchini, Samuel A. Jacobs, Ashok Srinivasan, Eleftherios (Terry) Mamounas, Charles E. Geyer Jr, Priya Rastogi, C. Kent Osborne, Soonmyung Paik, Norman Wolmark, Peter C. Lucas, Mothaffar Rimawi. Association of stromal tumor infiltrating lymphocytes (sTILs) in pretreatment biopsies in different molecular subtypes of HER2+/ER+ breast cancer: Assessment of NRG Oncology/NSABP B-52 [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-04-10.

Background: The CLEOPATRA trial established trastuzumab, pertuzumab and a taxane (THP) as a standard of care for first line metastatic, HER2-positve breast cancer with median progression-free survival (PFS) of 18.7 months and median OS of 57 months. NRG BR004 was a phase III, placebo-controlled trial designed to determine whether the addition of the PD-L1 inhibitor, atezolizumab, to THP would improve progression-free survival (PFS), relative to THP/placebo in patients with newly documented HER2-positive measurable metastatic breast cancer. Methods: BR004 was designed to detect an improvement in the primary endpoint of PFS in patients with measurable disease from 16.5 to 22.5 months with addition of atezolizumab (HR 0.733). A sample size of 600 would provide 80% power with a type I error rate of 0.05 to detect such an improvement when 326 PFS events had been reported. Monthly accrual was projected at 30 patients per month with completion of accrual in 24 months. In addition to routine monitoring of safety data by the IDMC every 6 months, a formal analysis of the toxicity data was to be performed 16 weeks after the 100th patient had been randomized with review by the IDMC. Results: First patient was randomized on May 1, 2019, and after 37 months 190 patients had been randomized. Several amendments were not successful in addressing the low accrual rate. The IDMC began regular monitoring of safety and accrual data in July 2020 and reviewed the formal safety analysis in February 2022. As of the February 2022 IDMC meeting, four Grade 5 adverse events (AEs) had been reported (2 occurring in 2020 and 2 in 2021), one of which occurred in a patient with evolving liver failure due to rapid disease progression at the start of therapy. The recommendation was to continue without modification, but notice was given the Grade 5 AEs had occurred on the same treatment arm without unblinding. When additional Grade 5 AEs occurred on 3/4/2022 and 4/27/2022 both on the same study arm with none reported on the other arm, accrual was held until the IDMC could review updated safety data, narratives of the Grade 5 AEs and the overall context of the trial. There was no evidence of clinically important imbalances between Grade 3 and Grade 4 AEs between the arms., Based on an uncertain but material safety signal, the ongoing accrual challenges, and determination that the clinical question being addressed was no longer sufficiently compelling, the IDMC recommended that the trial should be permanently closed to further enrollment. Summary safety data from 187 treated patients are provided in the Table. A decision was made to discontinue atezolizumab/placebo in patients receiving the investigational component of the trial therapy and unblind investigators and patients. The study will continue to collect information on PFS events, deaths and late immune AEs through April of 2024 when PFS and OS will be analyzed. Conclusions: The imbalance in Grade 5 AEs which occurred on BR004 coupled with continued poor accrual and the changing landscape in HER2+ MBC resulted in early closure of enrollment and unblinding of patients. Follow-up continues to assess PFS, OS and monitor for delayed immune AEs. Support: U10CA180868, -189867, -180822; U24CA196067; and Genentech. Citation Format: Charles E. Geyer, Jr, Gong Tang, Priya Rastogi, Vicente Valero, Stephen K. Chia, Erin F. Cobain, Elias Obeid, David B. Page, Andrew S. Poklepovic, William J. Irvin, Jr., Adam M. Brufsky, Irene L. Wapnir, Jennifer M. Suga, Eleftherios (Terry) Mamounas, Norman Wolmark. Safety Analyses of NRG BR004: A Randomized, Double-blind, Phase III Trial of Taxane/Trastuzumab/Pertuzumab with Atezolizumab or Placebo in First-line HER2-Positive Metastatic Breast Cancer (MBC) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT2-16-05.

The diffusion of molecules (penetrants) of variable size, shape, and chemistry through dense crosslinked polymer networks is a fundamental scientific problem that is broadly relevant in materials, polymer, physical and biological chemistry. Relevant applications include molecular separations in membranes, barrier materials for coatings, drug delivery, and nanofiltration. A major open question is the relationship between molecular transport, thermodynamic state, and chemical structure of the penetrant and polymeric media. Here we address this question by combining experiment, simulation, and theory to unravel the competing effects of penetrant chemistry on its transport in rubbery and supercooled polymer permanent networks over a wide range of crosslink densities, size ratios, and temperatures. The crucial importance of the coupling of local penetrant hopping to the polymer structural relaxation process, and the secondary importance of geometric mesh confinement effects, are established. Network crosslinks induce a large slowing down of nm-scale polymer relaxation which greatly retards the rate of penetrant activated relaxation. The demonstrated good agreement between experiment, simulation, and theory provides strong support for the size ratio variable (effective penetrant diameter to the polymer Kuhn length) as a key variable, and the usefulness of coarse-grained simulation and theoretical models that average over Angstrom scale chemical details. The developed microscopic theory provides a fundamental understanding of the physical processes underlying the behaviors observed in experiment and simulation. Penetrant transport is theoretically predicted to become even more size sensitive in a more deeply supercooled regime not probed in our present experiments or simulations, which suggests new strategies for enhancing selective polymer membrane design., Comment: including a main text and a supporting information. For the main text, 28 pages and 5 figures; For the supporting information, 23 pages and 14 figures. Totally, 51 pages and 19 figures

Since anthropo-zoonotic outbreaks of SARS-CoV-2 have been reported in mink farms, it is important to monitor the seroprevalence within this population. To investigate the accuracy of nucleo (N) or spike (S) protein-based assays to detect anti-SARS-CoV-2 antibodies in animal serum, we compared four assays, two commercial N-based enzyme-linked immunosorbent assays (ELISA) validated for animal sera and two luciferase immunoprecipitation systems (LIPS-N and LIPS-S), to the reference standard plaque reduction neutralisation test (PRNT). Samples included in this study were derived from a naturally infected mink population. For the first time in this study, serum samples of mink were collected over a 307-day period, at different time points, thus providing an overview of performances of four different rapid serological tests over time. The assays were compared by performing a correlation analysis using R2, Spearman’s rank-order correlation coefficient, and Fleiss’ and Cohen’s kappa for analysis of agreement to PRNT, and an UpSet chart was created to visualize the number of shared positive samples between assays. Cohen’s kappa test on categorical data showed an excellent agreement between PRNT and LIPS-S, while agreements between PRNT and N-based methods decreased from fair for LIPS-N to poor agreements for the ELISA kits. In addition, LIPS-S revealed the highest number of true-positive SARS-CoV-2 samples compared to N-based methods. Despite an excellent agreement between LIPS-S and PRNT, a weak correlation was detectable between PRNT titres and relative light units. This study shows that the LIPS-S assay can be used for serological surveillance within a naturally exposed mink population, while N-based serological assays are less accurate providing a higher number of false-negative results, especially at a later stage of infection, thus indicating that N antibodies are less persistent in naturally exposed mink. Our findings provide crucial information for veterinarians and competent authorities involved in surveillance and outbreak investigation in wild and farmed minks.

Purpose Meningioma is the most common primary central nervous system tumor often causing serious complications, and presently no medical treatment is available. The goal of this study was to discover miRNAs dysregulated in meningioma, and explore miRNA-associated pathways amenable for therapeutic interventions. Methods Small RNA sequencing was performed on meningioma tumor samples to study grade-dependent changes in microRNA expression. Gene expression was analyzed by chromatin marks, qRT-PCR and western blot. miRNA modulation, anti-IGF-2 neutralizing antibodies, and inhibitors against IGF1R were evaluated in a tumor-derived primary cultures of meningioma cells. Results Meningioma tumor samples showed high, grade-dependent expression of miR-483-5p, associated with high mRNA and protein expression of its host gene IGF-2. Inhibition of miR-483-5p reduced the growth of cultured meningioma cells, whereas a miR-483 mimic increased cell proliferation. Similarly, inhibition of this pathway with anti-IGF-2 neutralizing antibodies reduced meningioma cell proliferation. Small molecule tyrosine kinase inhibitor blockade of the IGF-2 receptor (IGF1R) resulted in rapid loss of viability of cultured meningioma tumor-derived cells, suggesting that autocrine IGF-2 feedback is obligatory for meningioma tumor cell survival and growth. The observed IGF1R-inhibitory IC50 for GSK1838705A and ceritinib in cell-based assays along with the available pharmacokinetics data predicted that effective drug concentration could be achieved in vivo as a new medical treatment of meningioma. Conclusion Meningioma cell growth is critically dependent on autocrine miR-483/IGF-2 stimulation and the IGF-2 pathway provides a feasible meningioma treatment target.

Purpose: In KATHERINE, adjuvant T-DM1 reduced risk of disease recurrence or death by 50% compared with trastuzumab in patients with residual invasive breast cancer after neoadjuvant therapy (NAT) comprised of HER2-targeted therapy and chemotherapy. This analysis aimed to identify biomarkers of response and differences in biomarker expression before and after NAT. Experimental Design: Exploratory analyses investigated the relationship between invasive disease-free survival (IDFS) and HER2 protein expression/gene amplification, PIK3CA hotspot mutations, and gene expression of HER2, PD-L1, CD8, predefined immune signatures, and Prediction Analysis of Microarray 50 intrinsic molecular subtypes, classified by Absolute Intrinsic Molecular Subtyping. HER2 expression on paired pre- and post-NAT samples was examined. Results: T-DM1 appeared to improve IDFS versus trastuzumab across most biomarker subgroups, except the HER2 focal expression subgroup. High versus low HER2 gene expression in residual disease was associated with worse outcomes with trastuzumab [HR, 2.02; 95% confidence interval (CI), 1.32–3.11], but IDFS with T-DM1 was independent of HER2 expression level (HR, 1.01; 95% CI, 0.56–1.83). Low PD-L1 gene expression in residual disease was associated with worse outcomes with trastuzumab (HR, 0.66; 95% CI, 0.44–1.00), but not T-DM1 (HR, 1.05; 95% CI, 0.59–1.87). PIK3CA mutations were not prognostic. Increased variability in HER2 expression was observed in post-NAT versus paired pre-NAT samples. Conclusions: T-DM1 appears to overcome HER2 resistance. T-DM1 benefit does not appear dependent on immune activation, but these results do not rule out an influence of the tumor immune microenvironment on the degree of response.

Objective: We evaluated longitudinal rates, risk factors, and costs of superficial and deep incisional surgical-site infection (SSI) 6 months after primary total knee arthroplasty (pTKA) and revision total knee arthroplasty (rTKA). Methods: Patients were identified from January 1, 2016 through March 31, 2018, in the IBM MarketScan administrative claims databases. Kaplan-Meier survival curves evaluated time to SSI over 6 months. Cox proportional hazard models evaluated SSI risk factors. Generalized linear models estimated SSI costs up to 12 months. Results: Of the 26,097 pTKA patients analyzed (mean age, 61.6 years; SD, 9.2; 61.4% female; 60.4% commercial insurance), 0.65% (95% CI, 0.56%–0.75%) presented with a deep incisional SSI and 0.82% (95% CI, 0.71%–0.93%) with a superficial incisional SSI. Also, 3,663 patients who had rTKA (mean age, 60.9 years; SD, 10.1; 60.6% female; 53.0% commercial insurance), 10.44% (95% CI, 9.36%–11.51%) presented with a deep incisional SSI and 2.60% (95% CI, 2.07%–3.13%) presented with a superficial incisional SSI. Infections were associated with male sex and multiple patient comorbidities including chronic pulmonary disease, pulmonary circulatory disorders, fluid and electrolyte disorders, malnutrition, drug abuse, and depression. Adjusted average all-cause incremental commercial cost ranged from $14,298 to $29,176 and from $41,381 to 59,491 for superficial and deep incisional SSI, respectively. Conclusions: SSI occurred most frequently following rTKA and among patients with pulmonary comorbidities and depression. The incremental costs associated with SSI following TKA were substantial.

Hallmark features of systolic heart failure are reduced contractility and impaired metabolic flexibility of the myocardium. Cardiomyocytes (CMs) with elevated deoxy ATP (dATP) via overexpression of ribonucleotide reductase (RNR) enzyme robustly improve contractility. However, the effect of dATP elevation on cardiac metabolism is unknown. Here, we developed proteolysis-resistant versions of RNR and demonstrate that elevation of dATP/ATP to ~1% in CMs in a transgenic mouse (TgRRB) resulted in robust improvement of cardiac function. Pharmacological approaches showed that CMs with elevated dATP have greater basal respiratory rates by shifting myosin states to more active forms, independent of its isoform, in relaxed CMs. Targeted metabolomic profiling revealed a significant reprogramming towards oxidative phosphorylation in TgRRB-CMs. Higher cristae density and activity in the mitochondria of TgRRB-CMs improved respiratory capacity. Our results revealed a critical property of dATP to modulate myosin states to enhance contractility and induce metabolic flexibility to support improved function in CMs.HighlightsUbiquitylation-resistant variant RRB in a transgenic mice model (TgRRB) elevates dATP level up to 1% (of the total ATP pool) in the heart and improves function.TgRRB-CMs show greater basal oxygen consumption due to changes in myosin state by dATP.TgRRB-CMs respond to elevated function with a metabolic shift, such that there are higher pools of oxidative metabolites, with elevated OXPHOS, FAO, and energy reserve.Long-term mitochondrial remodeling may occur to accommodate for the higher energy demands of the high functioning TgRRB-CMs.Graphical abstract