Inhibition of Mast Cell Degranulation by Novel Small Molecule MRGPRX2 Antagonists.

BACKGROUND: Mas-related G-protein coupled receptor X2 (MRGPRX2) is a promiscuous receptor on mast cells that mediates IgE-independent degranulation and has been implicated in multiple mast cell-mediated disorders, including chronic urticaria, atopic dermatitis, and pain disorders. Although it is a promising therapeutic target, few potent, selective, small molecule antagonists have been identified, and functional effects of human MRGPRX2 inhibition have not been evaluated in vivo. OBJECTIVE: We identified and characterized novel, potent, and selective orally active small molecule MRGPRX2 antagonists for potential treatment of mast cell-mediated disease. METHODS: Antagonists were identified using multiple functional assays in cell lines overexpressing human MRGPRX2, LAD2 mast cells, human peripheral stem cell-derived mast cells, and isolated skin mast cells. Skin mast cell degranulation was evaluated in Mrgprb2em(-/-) knockout (KO) and Mrgprb2em(MRGPRX2) transgenic human MRGPRX2 knock-in (KI) mice by assessment of agonist-induced skin vascular permeability. Ex vivo skin mast cell degranulation and associated histamine release was evaluated by microdialysis of human skin tissue samples. RESULTS: MRGPRX2 antagonists potently inhibited agonist-induced MRGPRX2 activation and mast cell degranulation in all mast cell types tested, in an IgE-independent manner. Orally administered MRGPRX2 antagonists also inhibited agonist-induced degranulation and resulting vascular permeability in MRGPRX2 KI mice. In addition, antagonist treatment dose dependently inhibited agonist-induced degranulation in ex vivo human skin. CONCLUSION: MRGPRX2 small molecule antagonists potently inhibited agonist-induced mast cell degranulation in vitro and in vivo as well as ex vivo in human skin, supporting potential therapeutic utility as a novel treatment for multiple human diseases involving clinically relevant mast cell activation.

Mcam stabilizes luminal progenitor breast cancer phenotypes via Ck2 control and Src/Akt/Stat3 attenuation.

Breast cancers are categorized into subtypes with distinctive therapeutic vulnerabilities and prognoses based on their expression of clinically targetable receptors and gene expression patterns mimicking different cell types of the normal gland. Here, we tested the role of Mcam in breast cancer cell state control and tumorigenicity in a luminal progenitor-like murine tumor cell line (Py230) that exhibits lineage and tumor subtype plasticity. Mcam knockdown Py230 cells show augmented Stat3 and Pi3K/Akt activation associated with a lineage state switch away from a hormone-sensing/luminal progenitor state toward alveolar and basal cell related phenotypes that were refractory to growth inhibition by the anti-estrogen therapeutic, tamoxifen. Inhibition of Stat3, or the upstream activator Ck2, reversed these cell state changes. Mcam binds Ck2 and acts as a regulator of Ck2 substrate utilization across multiple mammary tumor cell lines. In Py230 cells this activity manifests as increased mesenchymal morphology, migration, and Src/Fak/Mapk/Paxillin adhesion complex signaling in vitro, in contrast to Mcam's reported roles in promoting mesenchymal phenotypes. In vivo, Mcam knockdown reduced tumor growth and take rate and inhibited cell state transition to Sox10+/neural crest like cells previously been associated with tumor aggressiveness. This contrasts with human luminal breast cancers where MCAM copy number loss is highly coupled to Cyclin D amplification, increased proliferation, and the more aggressive Luminal B subtype. Together these data indicate a critical role for Mcam and its regulation of Ck2 in control of breast cancer cell state plasticity with implications for progression, evasion of targeted therapies and combination therapy design.

Comparison of Pain Scores and Functional Outcomes of Patients Undergoing Arthroscopic Hip Labral Repair and Concomitant Capsular Repair or Plication Versus No Closure.

Background: The need for capsular closure during arthroscopic hip labral repair is debated. Purpose: To compare pain and functional outcomes in patients undergoing arthroscopic hip labral repair with concomitant repair or plication of the capsule versus no closure. Study Design: Cohort study. Methods: Outcomes were compared between patients undergoing arthroscopic hip labral repair with concomitant repair or plication of the capsule versus no closure at up to 2 years postoperatively and with stratification by age and sex. Patients with lateral center-edge angle <20°, a history of instability, a history of prior arthroscopic surgery in the ipsilateral hip, or a history of labral debridement only were excluded. Subanalysis was performed between patients undergoing no capsular closure who were propensity score matched 1:1 with patients undergoing repair or plication based on age, sex, and preoperative Modified Harris Hip Score (MHHS). We compared patients who underwent T-capsulotomy with concomitant capsular closure matched 1:5 with patients who underwent an interportal capsulotomy with concomitant capsular repair based on age, sex, and preoperative MHHS. Results: Patients undergoing capsular closure (n = 1069), compared with the no-closure group (n = 230), were more often female (68.6% vs 53.0%, respectively; P < .001), were younger (36.4 ± 13.3 vs 47.9 ± 14.7 years; P < .001), and had superior MHHS scores at 2 years postoperatively (85.8 ± 14.5 vs 81.8 ± 18.4, respectively; P = .020). In the matched analysis, no difference was found in outcome measures between patients in the capsular closure group (n = 215) and the no-closure group (n = 215) at any follow-up timepoint. No significant difference was seen between the 2 closure techniques at any follow-up timepoint. Patients with closure of the capsule achieved the minimal clinically important difference (MCID) and the patient acceptable symptom state (PASS) for the 1-year MHHS at a similar rate as those without closure (MCID, 50.3% vs 44.9%, P = .288; PASS, 56.8% vs 51.1%, P = .287, respectively). Patients with T-capsulotomy achieved the MCID and the PASS for the 1-year MHHS at a similar rate compared with those with interportal capsulotomy (MCID, 50.1% vs 44.9%, P = .531; PASS, 65.7% vs 61.2%, P = .518, respectively). Conclusion: When sex, age, and preoperative MHHS were controlled, capsular closure and no capsular closure after arthroscopic hip labral repair were associated with similar pain and functional outcomes for patients up to 2 years postoperatively.

Growth Differentiation Factor 15 and Diet Quality Trajectory Interact to Determine Frailty Incidence among Middle-Aged Urban Adults.

BACKGROUND: Elevated plasma growth differentiation factor 15 (GDF15) and poor diet quality may be associated with increased frailty incidence, although their interactive associations have not been assessed in urban middle-aged adults. OBJECTIVES: We aimed to examine GDF15 and its interactive association with diet quality in relation to frailty incidence among a sample of middle-aged urban adults. METHODS: The relationship between GDF15 and diet quality trajectories in relation to incident frailty was examined in a longitudinal study of participants in the Healthy Aging in Neighborhoods of Diversity across the Life Span (2004-2017). Serum GDF15 concentration and frailty incidence were primary exposure and outcome, respectively. Group-based trajectory models were used to assess diet quality trajectories (≤3 visits/participant, N = 945, N' = 2247 observations) using the Healthy Eating Index 2010 version (HEI-2010), Dietary Inflammatory Index, and mean adequacy ratio (MAR). Cox proportional hazards models were used, testing interactive associations of GDF15 and diet quality trajectories with frail/prefrail incidence (N = 400 frailty-free at first visit, N' = 604 observations, n = 168 incident frail/prefrail). RESULTS: Both elevated GDF15 and lower diet quality trajectories were associated with a lower probability of remaining nonfrail (≤13 y follow-up). Among females, the "high diet quality" HEI-2010 trajectory had a hazard ratio (HR) of 0.15 [95% confidence interval (CI): 0.04, 0.54; P = 0.004; fully adjusted model] when compared with the "low diet quality" trajectory group. Among males only, there was an antagonistic interaction between lower HEI-2010 trajectory and elevated GDF15. Specifically, the HR for GDF15-frailty in the higher diet quality trajectory group (high/medium combined), and among males, was 2.69 (95% CI: 1.06, 6.62; P = 0.032), whereas among the lower diet quality trajectory group, the HR was 0.94 (95% CI: 0.49, 1.80; P = 0.86). Elevated GDF15 was independently associated with frailty among African American adults. CONCLUSIONS: Pending replication, we found an antagonistic interaction between GDF15 and HEI-2010 trajectory in relation to frailty incidence among males.

CRIPTO promotes extracellular vesicle uptake and activation of cancer associated fibroblasts.

Expression of CRIPTO, a factor involved in embryonic stem cells, fetal development, and wound healing, is tied to poor prognosis in multiple cancers. Prior studies in triple negative breast cancer (TNBC) models showed CRIPTO blockade inhibits tumor growth and dissemination. Here, we uncover a previously unidentified role for CRIPTO in orchestrating tumor-derived extracellular vesicle (TEV) uptake and fibroblast activation through discrete mechanisms. We found a novel mechanism by which CRIPTO drives aggressive TNBC phenotypes, involving CRIPTO-laden TEVs that program stromal fibroblasts, toward cancer associated fibroblast cell states, which in turn prompt tumor cell invasion. CRIPTO-bearing TEVs exhibited markedly elevated uptake in target fibroblasts and activated SMAD2/3 through NODAL-independent and - dependent mechanisms, respectively. Engineered expression of CRIPTO on EVs enhanced the delivery of bioactive molecules. In vivo , CRIPTO levels dictated TEV uptake in mouse lungs, a site of EV-regulated premetastatic niches important for breast cancer dissemination. These discoveries reveal a novel role for CRIPTO in coordinating heterotypic cellular crosstalk which offers novel insights into breast cancer progression, delivery of therapeutic molecules, and new, potentially targetable mechanisms of heterotypic cellular communication between tumor cells and the TME.

Safety, feasibility, and impact on the gut microbiome of kefir administration in critically ill adults.

BACKGROUND: Dysbiosis of the gut microbiome is frequent in the intensive care unit (ICU), potentially leading to a heightened risk of nosocomial infections. Enhancing the gut microbiome has been proposed as a strategic approach to mitigate potential adverse outcomes. While prior research on select probiotic supplements has not successfully shown to improve gut microbial diversity, fermented foods offer a promising alternative. In this open-label phase I safety and feasibility study, we examined the safety and feasibility of kefir as an initial step towards utilizing fermented foods to mitigate gut dysbiosis in critically ill patients. METHODS: We administered kefir in escalating doses (60 mL, followed by 120 mL after 12 h, then 240 mL daily) to 54 critically ill patients with an intact gastrointestinal tract. To evaluate kefir's safety, we monitored for gastrointestinal symptoms. Feasibility was determined by whether patients received a minimum of 75% of their assigned kefir doses. To assess changes in the gut microbiome composition following kefir administration, we collected two stool samples from 13 patients: one within 72 h of admission to the ICU and another at least 72 h after the first stool sample. RESULTS: After administering kefir, none of the 54 critically ill patients exhibited signs of kefir-related bacteremia. No side effects like bloating, vomiting, or aspiration were noted, except for diarrhea in two patients concurrently on laxatives. Out of the 393 kefir doses prescribed for all participants, 359 (91%) were successfully administered. We were able to collect an initial stool sample from 29 (54%) patients and a follow-up sample from 13 (24%) patients. Analysis of the 26 paired samples revealed no increase in gut microbial α-diversity between the two timepoints. However, there was a significant improvement in the Gut Microbiome Wellness Index (GMWI) by the second timepoint (P = 0.034, one-sided Wilcoxon signed-rank test); this finding supports our hypothesis that kefir administration can improve gut health in critically ill patients. Additionally, the known microbial species in kefir were found to exhibit varying levels of engraftment in patients' guts. CONCLUSIONS: Providing kefir to critically ill individuals is safe and feasible. Our findings warrant a larger evaluation of kefir's safety, tolerability, and impact on gut microbiome dysbiosis in patients admitted to the ICU. TRIAL REGISTRATION: NCT05416814; trial registered on June 13, 2022.

Pain scores and functional outcomes of patients with shoulder labral repair using all-suture anchors versus conventional anchors.

HYPOTHESIS/PURPOSE: The purpose of this study was to compare PROMs in patients undergoing anterior glenoid labral repair using all-suture versus conventional anchors. We hypothesized PROMs would be similar between groups. METHODS: We performed a retrospective review of the Arthrex Global Surgical Outcomes System (SOS) database, querying patients who underwent arthroscopic glenoid labral repair between 01/01/2015 and 12/31/2020. Patients aged 18-100, who had isolated glenoid labrum repair with at least 12-month follow-up were included. The visual analog pain scale (VAS), Western Ontario Shoulder Instability Index, Veteran's RAND 12-items health survey, single assessment numeric evaluation and the American Shoulder and Elbow Surgeons score (ASES) were compared preoperatively, 3 months, 6 months, 1 year and 2 years postoperatively in patients who received all-suture anchors versus conventional anchors in the setting of anterior glenoid labrum repair. Our primary aim was comparison of PROMs between patients receiving all-suture versus conventional suture anchors. Secondarily, a sub-analysis was performed comparing outcomes based on anchor utilization for patients with noted anterior instability. RESULTS: We evaluated 566 patients, 54 patients receiving all-suture anchors and 512 patients receiving conventional anchors. At two-year follow-up there was no significant difference between the two groups in PROMs. In a sub-analysis of isolated anterior labrum repair, there was an improvement in ASES (P = 0.034) and VAS (P = 0.039) with the all-suture anchor at two-year follow-up. CONCLUSIONS: All-suture anchors provide similar or superior pain and functional outcome scores up to 2 years postoperatively compared to conventional anchors. CLINICAL RELEVANCE: As all-suture anchors gain popularity among surgeons, this is the largest scale study to date validating their use in the setting of glenoid labrum repair. Institutional Review Board (IRB): IRB202102550.

Influence of lateralized versus medialized reverse shoulder arthroplasty design on external and internal rotation: a systematic review and meta-analysis.

BACKGROUND: Restoration of external (ER) and internal rotation (IR) after Grammont-style reverse shoulder arthroplasty (RSA) is often unreliable. The purpose of this systematic review was to evaluate the influence of RSA medio-lateral offset and subscapularis repair on axial rotation after RSA. METHODS: We conducted a systematic review of studies evaluating axial rotation (ER, IR, or both) after RSA with a defined implant design. Medio-lateral implant classification was adopted from Werthel et al. Meta-analysis was conducted using a random-effects model. RESULTS: Thirty-two studies reporting 2,233 RSAs were included (mean patient age, 72.5 years; follow-up, 43 months; 64% female). The subscapularis was repaired in 91% (n=2,032) of shoulders and did not differ based on global implant lateralization (91% for both, P=0.602). On meta-analysis, globally lateralized implants achieved greater postoperative ER (40° [36°-44°] vs. 27° [22°-32°], P<0.001) and postoperative improvement in ER (20° [15°-26°] vs. 10° [5°-15°], P<0.001). Lateralized implants with subscapularis repair or medialized implants without subscapularis repair had significantly greater postoperative ER and postoperative improvement in ER compared to globally medialized implants with subscapularis repair (P<0.001 for both). Mean postoperative IR was reported in 56% (n=18) of studies and achieved the minimum necessary IR in 51% of lateralized (n=325, 5 cohorts) versus 36% (n=177, 5 cohorts) of medialized implants. CONCLUSIONS: Lateralized RSA produces superior axial rotation compared to medialized RSA. Lateralized RSA with subscapularis repair and medialized RSA without subscapularis repair provide greater axial rotation compared to medialized RSA with subscapularis repair. Level of evidence: 2A.

Endoscope-assisted three-wire technique for extensive nasal septum resection in horses.

OBJECTIVE: To describe a 3-wire method with endoscopic guidance for extensive nasal septum resection. STUDY DESIGN: Retrospective study. SAMPLE POPULATION: Thirteen horses with nasal septum diseases. METHODS: In anesthetized horses in left lateral recumbency, endoscopic guidance was used to place obstetrical wires for the ventral and caudal incisions in the nasal septum and a trephine opening was used to place the dorsal wire. The rostral aspect of the septum was incised with a scalpel, followed by incisions with the preplaced wires, and the nasal passages were packed with gauze. Horses were recovered with a temporary tracheotomy. RESULTS: Conversion to intraoral placement of wires was required in two horses, one to correct entangled wires and the other because hemorrhage obscured the endoscopic view. Exercise tolerance was improved postoperatively, abnormal respiratory noise was decreased or eliminated by surgery in all horses, and all owners were satisfied. One Thoroughbred racehorse performed with modest success. CONCLUSIONS: Modification of the 3-wire method was effective and safe for extensive nasal septum removal. Technical complications of the procedure include entangling of wires and intraoperative hemorrhage. CLINICAL SIGNIFICANCE: Endoscopic guidance can be used to place obstetrical wires for nasal septum resection in small horses and precludes use of a large tracheotomy for anesthetic delivery. Reasons for athletic failures were difficult to establish retrospectively, although assessment of postoperative noise at speed might be more relevant to recovery of athletic potential than assessment at slower gaits.

Nonsteroidal antiinflammatory drugs reduce anion secretion and increase apoptosis in equine colonic mucosa ex vivo.

OBJECTIVE: Right dorsal colitis causes chronic colic associated with long-term treatment with nonsteroidal antiinflammatory drugs (NSAIDs). This study was designed to determine if NSAIDs could inhibit anion transporters that protect against intestinal mucosal injury in other species. ANIMALS: 20 healthy horses. METHODS: The effects of indomethacin (INDO) and firocoxib (FIR), on short-circuit current (Isc) in mucosa from the right dorsal colon (RDC) and right ventral colon (RVC) were measured in Ussing chambers by standard electrophysiological techniques. Immunohistochemical methods were used to detect apoptosis (caspase-3) with these NSAIDs and phenylbutazone (PBZ) and to locate the NKCC1 transporter. RESULTS: The Isc in RDC and RVC incubated with INDO or FIR was increased almost 3-fold (P < .0001) by prostaglandin E2 (PGE2) through a system inhibited by loop diuretics (P < .0001). Although these findings and anion replacement studies were consistent with anion secretion, the RDC also displayed an Isc response suggestive of a unique transporter apparently absent in RVC or NSAID-free solutions. In RDC, FIR, INDO, and PBZ induced apoptosis in the lower half of crypts. However, significant differences in apoptotic index were recorded in the RDC between NSAID-treated and control tissues (no NSAID). CLINICAL RELEVANCE: The effects of NSAIDs on Isc were consistent with reduced anion secretion, which could represent the pharmacological equivalent of the transport failure responsible for Cystic Fibrosis (CF) in other species. Failure of anion secretion could interfere with buffering acid from intraluminal fermentation, which could suggest a treatment target for right dorsal colitis.

Discovery of KB-0742, a Potent, Selective, Orally Bioavailable Small Molecule Inhibitor of CDK9 for MYC-Dependent Cancers.

Transcriptional deregulation is a hallmark of many cancers and is exemplified by genomic amplifications of the MYC family of oncogenes, which occur in at least 20% of all solid tumors in adults. Targeting of transcriptional cofactors and the transcriptional cyclin-dependent kinase (CDK9) has emerged as a therapeutic strategy to interdict deregulated transcriptional activity including oncogenic MYC. Here, we report the structural optimization of a small molecule microarray hit, prioritizing maintenance of CDK9 selectivity while improving on-target potency and overall physicochemical and pharmacokinetic (PK) properties. This led to the discovery of the potent, selective, orally bioavailable CDK9 inhibitor 28 (KB-0742). Compound 28 exhibits in vivo antitumor activity in mouse xenograft models and a projected human PK profile anticipated to enable efficacious oral dosing. Notably, 28 is currently being investigated in a phase 1/2 dose escalation and expansion clinical trial in patients with relapsed or refractory solid tumors.

Three-dimensional models of the equine larynx can be used to perform traditional measures of arytenoid abduction and permit the positioning of modeled implants to demonstrate the anatomic feasibility of placing a rigid implant across the cricoarytenoid joint.

OBJECTIVE: To develop 3D models of larynges to compare arytenoid abduction measurements between specimens and models, and to investigate the anatomic feasibility of placing an implant across the cricoarytenoid joint (CAJ) with or without arthrotomy. SAMPLES: Cadaveric equine larynges (n = 9). PROCEDURES: Equine larynges underwent sequential CT scans in a neutral position and with 2 arytenoid treatments: bilateral arytenoid abduction (ABD) and bilateral arytenoid abduction after left cricoarytenoid joint arthrotomy (ARTH). Soft tissue, cartilage, and luminal volume 3-dimensional models were generated. Rima glottidis cross-sectional area (CSA) and left-to-right quotient (LRQ) angles were measured on laryngeal specimens and models. Arytenoid translation, articular contact area, and length of modeled implants placed across the CAJ were measured on models. Data were analyzed using paired t test or ANOVA and Tukey's post hoc test or non-parametric equivalents (P < .05). RESULTS: ARTH CSA was larger for laryngeal specimens than models (P = .0096). There was no difference in all other measures of CSA and LRQ angle between treatment groups or between specimens and models. There was no difference between ABD and ARTH groups for arytenoid cartilage translation, contact area, and implant length. The articular contact area was sufficient for modeled implant placement across the CAJ with a narrow range of implant lengths (17.59 mm to 23.87 mm) across larynges with or without arthrotomy. CLINICAL RELEVANCE: These results support further investigation of a CT-guided, minimally invasive surgical procedure. Future studies will evaluate the outcomes of the new procedure for technical precision, biomechanical stability, and post-operative success rates for horses with recurrent laryngeal neuropathy (RLN).

Repeat Celiotomy-Current Status.

Repeat celiotomy can be lifesaving in horses with a surgically treatable postoperative obstruction, although guidelines for its use are lacking, except for uncontrollable postoperative pain. Overdiagnosis of ileus as the cause of postoperative obstruction could delay a second surgery so the disease progresses beyond a manageable level of severity. Although many horses respond favorably to repeat celiotomy, complications can be severe and life threatening, such as incisional infection and adhesions. Repeat celiotomy does not seem to exacerbate postoperative ileus, despite additional surgical manipulation. An important benefit of repeat celiotomy is termination of hopeless cases, thereby reducing cost and suffering.

Continuous Measurement of Lactate Concentration in Human Subjects through Direct Electron Transfer from Enzymes to Microneedle Electrodes.

Microneedle lactate sensors may be used to continuously measure lactate concentration in the interstitial fluid in a minimally invasive and pain-free manner. First- and second-generation enzymatic sensors produce a redox-active product that is electrochemically sensed at the electrode surface. Direct electron transfer enzymes produce electrons directly as the product of enzymatic action; in this study, a direct electron transfer enzyme specific to lactate has been immobilized onto a microneedle surface to create lactate-sensing devices that function at low applied voltages (0.2 V). These devices have been validated in a small study of human volunteers; lactate concentrations were raised and lowered through physical exercise and subsequent rest. Lactazyme microneedle devices show good agreement with concurrently obtained and analyzed serum lactate levels.

Evaluation of Viral Inactivation on Dry Surface by High Peak Power Microwave (HPPM) Exposure.

Previous research has shown that virus infectivity can be dramatically reduced by radio frequency exposure in the gigahertz (GHz) frequency range. Given the worldwide SARS-CoV-2 pandemic, which has caused over 1 million deaths and has had a profound global economic impact, there is a need for a noninvasive technology that can reduce the transmission of virus among humans. RF is a potential wide area-of-effect viral decontamination technology that could be used in hospital rooms where patients are expelling virus, in grocery and convenience stores where local populations mix, and in first responder settings where rapid medical response spans many potentially infected locations within hours. In this study, we used bovine coronavirus (BCoV) as a surrogate of SARS-CoV-2 and exposed it to high peak power microwave (HPPM) pulses at four narrowband frequencies: 2.8, 5.6, 8.5, and 9.3 GHz. Exposures consisted of 2 µs pulses delivered at 500 Hz, with pulse counts varied by decades between 1 and 10,000. The peak field intensities (i.e. the instantaneous power density of each pulse) ranged between 0.6 and 6.5 MW/m2 , depending on the microwave frequency. The HPPM exposures were delivered to plastic coverslips containing BCoV dried on the surface. Hemagglutination (HA) and cytopathic effect analyses were performed 6 days after inoculation of host cells to assess viral infectivity. No change in viral infectivity was seen with increasing dose (pulse number) across the tested frequencies. Under all conditions tested, exposure did not reduce infectivity more than 1.0 log10. For the conditions studied, high peak power pulsed RF exposures in the 2-10 GHz range appear ineffective as a virucidal approach for hard surface decontamination. © 2023 Bioelectromagnetics Society.

Data assimilation in operator algebras.

We develop an algebraic framework for sequential data assimilation of partially observed dynamical systems. In this framework, Bayesian data assimilation is embedded in a nonabelian operator algebra, which provides a representation of observables by multiplication operators and probability densities by density operators (quantum states). In the algebraic approach, the forecast step of data assimilation is represented by a quantum operation induced by the Koopman operator of the dynamical system. Moreover, the analysis step is described by a quantum effect, which generalizes the Bayesian observational update rule. Projecting this formulation to finite-dimensional matrix algebras leads to computational schemes that are i) automatically positivity-preserving and ii) amenable to consistent data-driven approximation using kernel methods for machine learning. Moreover, these methods are natural candidates for implementation on quantum computers. Applications to the Lorenz 96 multiscale system and the El Niño Southern Oscillation in a climate model show promising results in terms of forecast skill and uncertainty quantification.

Surgical enlargement of the epiploic foramen in horses.

OBJECTIVE: To assess the safety and efficacy of a method for digitally enlarging the caudal aspect of the epiploic foramen (EF). STUDY DESIGN: Healthy horses and clinical cases of EF entrapment (EFE). ANIMALS: Fourteen healthy horses and three clinical cases. METHODS: Through a ventral midline celiotomy under general anesthesia, the EF was enlarged by digital separation of the caudal attachments of the caudate lobe of the liver from right dorsal colon, right kidney, gastropancreatic fold, and pancreas. Healthy horses were euthanized under anesthesia, and the enlarged EF was measured at necropsy. RESULTS: The method used for enlarging the EF did not cause clinically relevant hemorrhage, as determined by visual inspection of the EF in 14 horses at necropsy and by vital parameters under anesthesia in all horses. In clinical cases, EFE was reduced following enlargement of the EF, and no intraoperative complications were encountered. In one clinical case, necropsy at 30 days confirmed partial closure of the enlarged EF. CONCLUSION: The method proposed enlarged the EF safely and effectively. Limitations of the study include the small number of clinical cases and the lack of postoperative follow-up on the healthy horses. CLINICAL SIGNIFICANCE: Enlargement of the EF at its caudal extent should be considered in selected cases of EFE in which manual reduction is difficult or protracted. Although the procedure was safe in this study, knowledge of the anatomy, practice on cadavers, and careful selection of cases with greatest need are recommended before clinical use.

GDF15 and its association with cognitive performance over time in a longitudinal study of middle-aged urban adults.

Serum GDF15 levels are correlated with multiple neurodegenerative diseases. Few studies have tested this marker's association with middle-aged cognitive performance over time, and whether race affects this association is unknown. We examined associations of initial serum GDF15 concentrations with longitudinal cognitive performance, spanning domains of global mental status, visual and verbal memory, attention, fluency, and executive function in a sub-sample of adults participating in the Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS) study (n = 776, Agev1:30-66y, 45.6 % male, 57.0 % African American, 43.0 % below poverty). This analysis consisted of mixed-effects regression models applied to the total selected sample, while also stratifying the analyses by race in the main analyses and further stratifying by sex, age group and poverty status in an exploratory analysis. Our main findings, which passed multiple testing and covariate-adjustment, indicated that GDF15 was associated with poorer baseline performance on several cognitive tests, including animal fluency [overall sample: (Model 1: γ0 ± SE: -0.664 ± 0.208, P < 0.001; Model 2, γ0 ± SE: -0.498 ± 0.217, P < 0.05)]. Among White adults, GDF15 was linked to poorer performance on a brief test of attention (Model 1: γ0 ± SE: -0.426 ± 0.126, P < 0.001; Model 2, γ0 ± SE: -0.281 ± 0.139, P < 0.05); and Trailmaking test, part B (Model 1: γ0 ± SE: +0.129 ± 0.040, P < 0.001; Model 2, γ0 ± SE: +0.089 ± 0.041, P < 0.05), the latter being also linked to higher GDF15 among individuals living below poverty. Among women, GDF15 was associated with poor global mental status (Normalized MMSE: Model 1: γ0 ± SE: -2.617 ± 0.746, P < 0.001; Model 2: γ0 ± SE: -1.729 ± 0.709, P < 0.05). GDF15 was not associated with decline on any of the 11 cognitive test scores considered in âˆ¼ 4 years of follow-up. In sum, we detected cross-sectional associations between GDF15 and cognition, although GDF15 did not predict rate of change in cognitive performance over time among a sample of middle-aged adults. More longitudinal studies are needed to address the clinical utility of this biomarker for early cognitive defects.