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.

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.

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.

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.

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.

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.

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.

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.

Ex vivo and in vivo evaluation of a modified interrupted Lembert pattern for small intestinal anastomoses in horses.

OBJECTIVE: To compare single-layer anastomoses (modified continuous Lembert [mod-CL] and modified-interrupted Lembert [mod-IL]) and a 2-layer simple continuous anastomosis (2 L; seromuscular and mucosal) for jejunojejunal anastomoses in equine cadavers and to compare ex vivo to in vivo time to complete the anastomosis and stoma size with a mod-IL pattern. STUDY DESIGN: Measurements in jejunum from cadaver and anesthetized horses. ANIMALS: Ten live horses and 18 equine cadavers. METHODS: Time to complete anastomosis, bursting pressures (BP), leakage sites, and anastomotic index (size ratio of anastomotic lumen to control lumen) were recorded. Time to completion and lumen size were compared between in vivo and ex vivo mod-IL patterns. RESULTS: The mod-CL pattern was fastest (8.44 ± 1.30 min, p < .05), and the 2 L pattern was slower (17.07 ± 2.0 min) than the mod-CL and mod-IL (p < .05). The anastomotic index exceeded 100 and did not differ between patterns. Segments reached higher bursting pressures when anastomosed with mod-IL (145.94 ± 24.18 mm Hg) than mod-CL (p < .05). In vivo closure was approximately 8 minutes slower than ex vivo, and with a smaller anastomotic index. CONCLUSIONS: All anastomoses increased lumen size over control segments ex vivo. Lumen size after placement of a mod-IL was greater ex vivo than in vivo, and completion was slower in vivo than ex vivo. [Corrections added on 26 Dec 2022, after online publication: added "ex vivo" to the first line of Conclusions in the Abstract.] CLINICAL SIGNIFICANCE: Slower and smaller anastomoses should be anticipated in vivo compared to ex vivo results. Anastomoses with a mod-IL pattern appear clinically advantageous, producing a comparable lumen size in less time than 2 L.

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.

Temperature Dynamics in Rat Brains Exposed to Near-Field Waveguide Outputs at 2.8 GHz.

Biological effects in the microwave band of the radiofrequency (RF) spectrum are thermally mediated. For acute high-power microwave exposures, these effects will depend on transient time-temperature histories within the tissue. In this article, we summarize the transient temperature response of rats exposed to RF energy emanating from an open-ended rectangular waveguide. These exposures produced specific absorption rates of approximately 36 and 203 W/kg in the whole body and brain, respectively. We then use the experimentally measured thermal data to infer the baseline perfusion rate in the brain and modify a custom thermal modeling tool based upon these findings. Finally, we compare multi-physics simulations of rat brain temperature against empirical measurements in both live and euthanized subjects and find close agreement between model and experimentation. This research revealed that baseline brain perfusion rates in rat subjects could be larger than previously assumed in the RF thermal modeling literature, and plays a significant role in the transient thermal response to high-power microwave exposures. © 2021 Bioelectromagnetics Society.

The paraventricular thalamus serves as a nexus in the regulation of stress and immunity.

Many temperate zone animals exhibit seasonal rhythms in physiology and behavior, including seasonal cycles of reproduction, energetics, stress responsiveness, and immune function, among many others. These rhythms are driven by seasonal changes in the duration of pineal melatonin secretion. The neural melatonin target tissues that mediate several of these rhythms have been identified, though the target(s) mediating melatonin's regulation of glucocorticoid secretion, immune cell numbers, and bacterial killing capacity remain unspecified. The present results indicate that one melatonin target tissue, the paraventricular nucleus of the thalamus (PVT), is necessary for the expression of these seasonal rhythms. Thus, while radiofrequency ablations of the PVT failed to alter testicular and body mass response to short photoperiod exposure, they did block the effect of short day lengths on cortisol secretion and bacterial killing efficacy. These results are consistent with the independent regulation by separate neural circuits of several physiological traits that vary seasonally in mammals.

mTOR signaling regulates central and peripheral circadian clock function.

The circadian clock coordinates physiology and metabolism. mTOR (mammalian/mechanistic target of rapamycin) is a major intracellular sensor that integrates nutrient and energy status to regulate protein synthesis, metabolism, and cell growth. Previous studies have identified a key role for mTOR in regulating photic entrainment and synchrony of the central circadian clock in the suprachiasmatic nucleus (SCN). Given that mTOR activities exhibit robust circadian oscillations in a variety of tissues and cells including the SCN, here we continued to investigate the role of mTOR in orchestrating autonomous clock functions in central and peripheral circadian oscillators. Using a combination of genetic and pharmacological approaches we show that mTOR regulates intrinsic clock properties including period and amplitude. In peripheral clock models of hepatocytes and adipocytes, mTOR inhibition lengthens period and dampens amplitude, whereas mTOR activation shortens period and augments amplitude. Constitutive activation of mTOR in Tsc2-/-fibroblasts elevates levels of core clock proteins, including CRY1, BMAL1 and CLOCK. Serum stimulation induces CRY1 upregulation in fibroblasts in an mTOR-dependent but Bmal1- and Period-independent manner. Consistent with results from cellular clock models, mTOR perturbation also regulates period and amplitude in the ex vivo SCN and liver clocks. Further, mTOR heterozygous mice show lengthened circadian period of locomotor activity in both constant darkness and constant light. Together, these results support a significant role for mTOR in circadian timekeeping and in linking metabolic states to circadian clock functions.

Whence CRIPTO: The Reemergence of an Oncofetal Factor in 'Wounds' That Fail to Heal.

There exists a set of factors termed oncofetal proteins that play key roles in ontogeny before they decline or disappear as the organism's tissues achieve homeostasis, only to then re-emerge in cancer. Although the unique therapeutic potential presented by such factors has been recognized for more than a century, their clinical utility has yet to be fully realized1. This review highlights the small signaling protein CRIPTO encoded by the tumor derived growth factor 1 (TDGF1/Tdgf1) gene, an oft cited oncofetal protein whose presence in the cancer literature as a tumor promoter, diagnostic marker and viable therapeutic target continues to grow. We touch lightly on features well established and well-reviewed since its discovery more than 30 years ago, including CRIPTO's early developmental roles and modulation of SMAD2/3 activation by a selected set of transforming growth factor ß (TGF-ß) family ligands. We predominantly focus instead on more recent and less well understood additions to the CRIPTO signaling repertoire, on its potential upstream regulators and on new conceptual ground for understanding its mode of action in the multicellular and often stressful contexts of neoplastic transformation and progression. We ask whence it re-emerges in cancer and where it 'hides' between the time of its fetal activity and its oncogenic reemergence. In this regard, we examine CRIPTO's restriction to rare cells in the adult, its potential for paracrine crosstalk, and its emerging role in inflammation and tissue regeneration-roles it may reprise in tumorigenesis, acting on subsets of tumor cells to foster cancer initiation and progression. We also consider critical gaps in knowledge and resources that stand between the recent, exciting momentum in the CRIPTO field and highly actionable CRIPTO manipulation for cancer therapy and beyond.

J-incision to approach the cranial abdomen in the adult horse.

OBJECTIVE: To describe a modified celiotomy to improve access to cranial abdominal structures in horses. ANIMALS: Four horses. STUDY DESIGN: Short case series. METHODS: Three horses with gastric impactions were treated with gastrotomies. One horse was treated for a diaphragmatic hernia with herniorrhaphy and mesh augmentation. In all horses, the ventral midline celiotomy was modified cranially with a J-incision through the body wall, along the paracostal arch. RESULTS: The only surgical complications were midline incisional infections in all horses. Three of the four horses had good long-term outcomes; the remaining horse underwent euthanasia for reasons likely unrelated to incisional complications. CONCLUSION: The J-incision improved access to the stomach and diaphragm in these horses. The paracostal component healed in all cases without evidence of infection or dehiscence. CLINICAL SIGNIFICANCE: This modified celiotomy may be considered to improve access during gastrotomy and repair of dorsally located diaphragmatic hernias.

CRIPTO antagonist ALK4L75A-Fc inhibits breast cancer cell plasticity and adaptation to stress.

BACKGROUND: CRIPTO is a multi-functional signaling protein that promotes stemness and oncogenesis. We previously developed a CRIPTO antagonist, ALK4L75A-Fc, and showed that it causes loss of the stem cell phenotype in normal mammary epithelia suggesting it may similarly inhibit CRIPTO-dependent plasticity in breast cancer cells. METHODS: We focused on two triple negative breast cancer cell lines (MDA-MB-231 and MDA-MB-468) to measure the effects of ALK4L75A-Fc on cancer cell behavior under nutrient deprivation and endoplasmic reticulum stress. We characterized the proliferation and migration of these cells in vitro using time-lapse microscopy and characterized stress-dependent changes in the levels and distribution of CRIPTO signaling mediators and cancer stem cell markers. We also assessed the effects of ALK4L75A-Fc on proliferation, EMT, and stem cell markers in vivo as well as on tumor growth and metastasis using inducible lentiviral delivery or systemic administration of purified ALK4L75A-Fc, which represents a candidate therapeutic approach. RESULTS: ALK4L75A-Fc inhibited adaptive responses of breast cancer cells under conditions of nutrient and ER stress and reduced their proliferation, migration, clonogenicity, and expression of EMT and cancer stem cell markers. ALK4L75A-Fc also inhibited proliferation of human breast cancer cells in stressed tumor microenvironments in xenografts and reduced both primary tumor size and metastatic burden. CONCLUSIONS: Cancer cell adaptation to stresses such as nutrient deprivation, hypoxia, and chemotherapy can critically contribute to dormancy, metastasis, therapy resistance, and recurrence. Identifying mechanisms that govern cellular adaptation, plasticity, and the emergence of stem-like cancer cells may be key to effective anticancer therapies. Results presented here indicate that targeting CRIPTO with ALK4L75A-Fc may have potential as such a therapy since it inhibits breast cancer cell adaptation to microenvironmental challenges and associated stem-like and EMT phenotypes.

Extracellular vesicles in diabetes mellitus induce alterations in endothelial cell morphology and migration.

BACKGROUND: Inflammation-related atherosclerotic peripheral vascular disease is a major end organ complication of diabetes mellitus that results in devastating morbidity and mortality. Extracellular vesicles (EVs) are nano-sized particles that contain molecular cargo and circulate in the blood. Here, we examined EV protein cargo from diabetic individuals and whether these EVs cause functional changes in endothelial cells. METHODS: We quantified inflammatory protein levels in plasma-derived EVs from a longitudinal cohort of euglycemic and diabetic individuals and used in vitro endothelial cell biological assays to assess the functional effects of these EVs with samples from a cross-sectional cohort. RESULTS: We found several significant associations between EV inflammatory protein levels and diabetes status. The angiogenic factor, vascular endothelial growth factor A (VEGF-A), was associated with diabetes status in our longitudinal cohort. Those with diabetes mellitus had higher EV VEGF-A levels compared to euglycemic individuals. Additionally, EV levels of VEGF-A were significantly associated with homeostatic model assessment of insulin resistance (HOMA-IR) and ß-cell function (HOMA-B). To test whether EVs with different inflammatory cargo can demonstrate different effects on endothelial cells, we performed cell migration and immunofluorescence assays. We observed that EVs from diabetic individuals increased cell lamellipodia formation and migration when compared to EVs from euglycemic individuals. CONCLUSIONS: Higher levels of inflammatory proteins were found in EVs from diabetic individuals. Our data implicate EVs as playing important roles in peripheral vascular disease that occur in individuals with diabetes mellitus and suggest that EVs may serve as an informative diagnostic tool for the disease.

A novel role for the pineal gland: Regulating seasonal shifts in the gut microbiota of Siberian hamsters.

The gut microbiota plays a significant role in a variety of host behavioral and physiological processes. The mechanisms by which the gut microbiota and the host communicate are not fully resolved but include both humoral and direct neural signals. The composition of the microbiota is affected by internal (host) factors and external (environmental) factors. One such signal is photoperiod, which is represented endogenously by nocturnal pineal melatonin (MEL) secretion. Removal of the MEL signal via pinealectomy abolishes many seasonal responses to photoperiod. In Siberian hamsters (Phodopus sungorus), MEL drives robust seasonal shifts in physiology and behavior, such as immunity, stress, body mass, and aggression. While the profile of the gut microbiota also changes by season, it is unclear whether these changes are driven by pineal signals. We hypothesized that the pineal gland mediates seasonal alterations in the composition of the gut microbiota. To test this, we placed pinealectomized and intact hamsters into long or short photoperiods for 8 weeks, collected weekly fecal samples, and measured weekly food intake, testis volume, and body mass. We determined microbiota composition using 16S rRNA sequencing (Illumina MiSeq). We found significant effects of treatment and time on the abundances of numerous bacterial genera. We also found significant associations between individual OTU abundances and body mass, testis mass, and food intake, respectively. Finally, results indicate a relationship between overall community structure, and body and testis masses. These results firmly establish a role for the pineal gland in mediating seasonal alterations in the gut microbiota. Further, these results identify a novel neuroendocrine pathway by which a host regulates seasonal shifts in gut community composition, and indicates a relationship between seasonal changes in the gut microbiota and seasonal physiological adjustments.

Prediction of discharge destination after traumatic brain injury in children using the head abbreviated injury scale.

INTRODUCTION: Traumatic brain injury (TBI) is a major public health problem, particularly in children. Prognostication of injury severity at the time of presentation is difficult. The Abbreviated Injury Scale (AIS) is a commonly used anatomical-based coding system created to classify and describe injury severity after initial presentation, once test results are able to better define the anatomical characteristics of the injury. We hypothesize that the Head AIS can predict discharge destination in children after TBI. METHODS: The trauma registry database for a Pediatric Level 1 Trauma center was queried for patients age ≤14 years from 2006 to 2015 with a Head AIS>2. All diagnoses with head AIS>2 were retrieved. Since one patient can have multiple diagnoses with an AIS>2, we selected the diagnosis with highest Head AIS associated with each patient. The demographics, length of stay, and the discharge disposition of patients were retrieved. Descriptive statistics were performed and association of Head AIS with the length of stay and discharge disposition was determined using logistic regression. RESULTS: 393 pediatric patients (age≤14 years) with an Head AIS ≥3, (64.0% males, mean age = 6.2 S.D. 4.58) presented over 10 years. Head AIS was strongly associated with mortality; with 0.8%, 1.1% and 42.0% of patients with Head AIS of 3, 4 and 5, respectively, dying - odds ratio for Head AIS 5 over Head AIS 3 = 89 (logistic regression, p-value<0.001). 80.0% of deaths (23 patients) in this cohort occurred within 24-h of presentation. Head AIS was associated with an increase likelihood of discharge to rehabilitation with 1.2%, 7.7% and 47.0% of survivors discharging to rehabilitation for Head AIS of 3, 4 and 5. CONCLUSION: Head AIS can reliably predict discharge disposition to home, rehab or death. Calculation of Head AIS prior to discharge could lead to accurate prediction of discharge destination.