Contiguous Days Research Articles

Assessing for race, ethnicity, and socioeconomic disparities in central line-associated bloodstream infection risk in a large academic health system.

To examine the relationship between race and ethnicity and central line-associated bloodstream infections (CLABSI) while accounting for inherent differences in CLABSI risk related to central venous catheter (CVC) type. Retrospective cohort analysis. Acute care facilities within an academic healthcare system. Adult inpatients from January 2012 through December 2017 with CVC present for ≥2 contiguous days. We describe variability in demographics, comorbidities, CVC type/configuration, and CLABSI rate by patient's race and ethnicity. We estimated the unadjusted risk of CLABSI for each demographic and clinical characteristic and then modelled the effect of race on time to CLABSI, adjusting for total parenteral nutrition use and CVC type. We also performed exploratory analysis replacing race and ethnicity with social vulnerability index (SVI) metrics. 32,925 patients with 57,642 CVC episodes met inclusion criteria, most of which (51,348, 89%) were among non-Hispanic White or non-Hispanic Black patients. CVC types differed between race/ethnicity groups. However, after adjusting for CVC type, configuration, and indication in an adjusted cox regression, the risk of CLABSI among non-Hispanic Black patients did not significantly differ from non-Hispanic White patients (adjusted hazard ratio [aHR] 1.19; 95% confidence interval [CI]: 0.94, 1.51). The odds of having a CLABSI among the most vulnerable SVI subset compared to the less vulnerable was no different (odds ratio [OR] 0.95; 95% CI: 0.75-1.2). We did not find a difference in CLABSI risk between non-Hispanic White and non-Hispanic Black patients when adjusting for CLABSI risk inherent in type and configuration of CVC.

Dysregulation of PRMT5 in Chronic Lymphocytic Leukemia Supports Transformation to Diffuse Large B-Cell Lymphoma

Background: Richter's transformation (RT) is the progression of chronic lymphocytic leukemia (CLL) to a high-grade lymphoma, most commonly resembling a diffuse large B-cell-like lymphoma, that has a bleak prognosis of 6-12 months. Many of the recurrent somatic alterations identified in RT are also associated with the CLL-phase of disease, suggesting additional unidentified genetic, epigenetic, or molecular events underlie transformation. Aberrant PRMT5 expression is known to promote and maintain oncogenic signaling in non-Hodgkin's lymphomas but its role in CLL and RT remains unclear. Methods: Tissue microarrays and western blots were used to evaluate PRMT5 expression in CLL/SLL and RT lymph nodes (LN). Differentially expressed genes between patient-matched RT LNs and CLL PBMCs were identified with scRNA-seq & scV(D)J-seq. ScRNA-seq was utilized to identify transcriptional changes between Eμ-PRMT5/TCL1 & Eμ-TCL1 mice. Tumor allografts were generated by administering 5 x 10^6 CD19+CD5+ spleen cells from Eμ-PRMT5/TCL1 mice intravenously to C57/BL6J mice. One week post-engraftment mice were enrolled in treatment groups (PRT382 10mg/kg, n=10; vehicle, n=7) with all treatments administered for 4 contiguous days per week by oral gavage. Results: Tissue microarray analysis on 70 CLL and 15 RT LN cases showed robust PRMT5 staining in RT LNs and minimal staining in CLL tissues. Immunoblot analysis revealed that CLL cells from patients that eventually undergo transformation displayed significant increase in PRMT5 expression months prior to transformation, whereas CLL patients maintained variable to minimal PRMT5 expression. ScRNA-seq & scV(D)J-seq on RT LN biopsies and CLL PBMCs from two patients revealed that PRMT5 expression was restricted to distinct nodal B cell subpopulations co-expressing MYC, BIRC5, CD83, and CD69. One PRMT5+ cluster displayed overlapping expression of proliferative markers (Mki67, TOP2A, PCNA, CALM2/3, and HMGB1/2) with enriched EIF4 signaling. Anti-apoptotic and immune modulating genes (BCL21A, IL4I1, TCL1A, and CCL3/4) were enriched in the second PRMT5+ nodal cluster. Interestingly, transcriptional diversity was enhanced in clonally related RT B cell populations with an increased proportion of cells expressing PRMT5 when compared to the CLL-phase of disease. To further evaluate the role of PRMT5 in CLL disease progression, we conducted histopathologic analysis on the spleen and lymph nodes of 6 month old animals from Eµ-PRMT5/TCL1 & Eµ-TCL1 mouse models, revealing a RT-like histology with loss of germinal centers and effacement of normal architecture exclusively in Eµ-PRMT5/TCL1 animals. Transcriptional changes underlying phenotypic differences between Eµ-PRMT5/TCL1 & Eµ-TCL1 mice were also assessed by scRNA-seq, where splenic B cells of the Eµ-PRMT5/TCL1 exhibited increased expression of oncogenic and immune regulating genes (Myc, Mki67, Egr1, Cxcr5, Ccr7, Il-10, Ctla4, and Pd-L1). Interestingly, the dominant B-cell clusters enriched in Eµ-PRMT5/TCL1 spleen and LNs showed significant transcriptional overlap with human RT PRMT5 expressing LN clusters (e.g., Myc, Cd83, and Cd69). With the observation that PRMT5 may play a significant role in CLL-to-RT evolution, we then aimed to evaluate the use of targeted PRMT5 inhibition against murine RT-like tumors in vivo. Using the selective SAM-competitive PRMT5 inhibitor, PRT382, in Eµ-PRMT5/TCL1 allografts, we observed PRT382 treatment delayed leukemic expansion, increased median survival (p<0.0001), and reduced spleen mass compared to vehicle treated mice. Conclusion: We show that PRMT5 is upregulated in the lymph nodes of CLL patients prior to and after transformation, suggesting a role for PRMT5 in CLL transformation to RT. Likewise, the Eμ-PRMT5/TCL1 mouse model develops a RT-like histology and shows significant overlap in the transcriptional profile to human RT tumors. And further, inhibition of PRMT5 with PRT382 provides significant improvement in median overall survival and slows disease progression in Eμ-PRMT5/TCL1 adoptive transfer models. Our preclinical data identifies PRMT5 as a high-risk marker in CLL and provides rationale for the clinical evaluation of PRMT5 inhibition in the treatment of high-risk CLL/RT.

Perioperative glycemic status is linked to postoperative complications in non-intensive care unit patients with type-2 diabetes: a retrospective study.

Background:Perioperative hyperglycemia is a risk factor for postoperative complications in the general population. However, it has not been clarified whether perioperative hyperglycemia increases postoperative complications in patients with type-2 diabetes mellitus (T2D). Therefore, we aimed to analyze the relationship between perioperative glycemic status and postoperative complications in non-intensive care unit (non-ICU) hospitalized patients with T2D.Materials and Methods:Medical records of 1217 patients with T2D who were admitted to the non-ICU in our hospital were analyzed retrospectively. Relationships between clinical characteristics including perioperative glycemic status and postoperative complications were assessed using univariate and multivariate analyses. Perioperative glycemic status was evaluated by calculating the mean, standard deviation (SD), and coefficient of variation (CV) of blood glucose (BG) measurements in preoperative and postoperative periods for three contiguous days before and after surgery, respectively. Postoperative complications were defined as infections, delayed wound healing, postoperative bleeding, and/or thrombosis.Results:Postoperative complications occurred in 139 patients (11.4%). These patients showed a lower BG immediately before surgery (P = 0.04) and a higher mean postoperative BG (P = 0.009) than those without postoperative complications. There were no differences in the other perioperative BG parameters including BG variability and the frequency of hypoglycemia. The multivariate analysis showed that BG immediately before surgery (adjusted odds ratio (95% confidence interval [CI]), 0.91 (0.85–0.98), P = 0.01) and mean postoperative BG (1.11 (1.05–1.18), P < 0.001) were independently associated with postoperative complications.Conclusion:Perioperative glycemic status, that is, a low BG immediately before surgery and a high mean postoperative BG, are associated with the increased incidence of postoperative complications in non-ICU patients with T2D.

Rehabilitation of Persistent Symptoms and Neurocognitive Deficits Following Sports-Related Concussion in a Professional Hockey Player: Case Study

To demonstrate decreased post-concussive symptomatology and neurocognitive improvements in a professional hockey player following a multimodal, functional neurology approach to neurorehabilitation. Hockey is one of the top 3 sports in which concussions occur and has one of the top 10 highest participation numbers of sports in the northern hemisphere. The investigation of treatment modalities is warranted given the prevalence of hockey throughout society. This case study presents a 31-year-old male professional hockey athlete who had sustained 5 diagnosed concussions with additional suspected concussions throughout his career. His symptoms remained after independently receiving physical therapy and vestibular rehabilitation, causing an inability to continue playing hockey at a professional level. The patient was prescribed 10 treatment sessions over 5 contiguous days at an outpatient neurorehabilitation center specializing in functional neurology. The C3Logix neurocognitive assessment and graded symptom checklist were utilized at intake and discharge. Multimodal treatment interventions included transcranial photobiomodulation, non-invasive neuromodulation of the lingual branch of the trigeminal nerve, hand-eye coordination training, vestibular rehabilitation utilizing a three-axis whole-body off-axis rotational device, and cognitive training. On intake, their composite symptom score was reported as 16/162, Trail Making Test Part B was 24.1 seconds, Simple Reaction Time was 274 milliseconds, and Choice Reaction Time was 496 milliseconds. On discharge, the patient experienced an 81% in self-reported symptoms, Trail Making Test Part B improved to 17 seconds (+29.46%), Simple Reaction Time was 252 milliseconds (8% faster), and Choice Reaction Time was 465 milliseconds (24% faster). The present case study results demonstrated meaningful improvements in both self-rated concussion symptoms and neurocognitive performance for this patient. The Press suggest further investigation into functional neurology-based, multimodal, intensive approaches to decrease chronic post-concussion symptoms and improve neurocognitive performance in athletes that engage in hockey.

Apocynum Leaf Extract Suppresses the Progress of Atherosclerosis in Rats via the FKN/SYK/p38 Signal Pathway.

To investigate the antiatherosclerotic effects of flavonoids extracted from Apocynum venetum (AVF) leaves in atherosclerotic rats and the underlying mechanisms, a total of 72 male Wistar rats were randomly divided into six groups: control group, model group, simvastatin group, low-dose AVF group, medium-dose AVF group, and high-dose AVF group. Atherosclerosis in rats was induced with a high-fat diet and an intraperitoneal injection of VD3 once daily for three contiguous days at a total injection dose of 70 U/kg. At the end of the 13th week, total serum cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) contents were measured. The hematoxylin-eosin (HE) staining was applied to evaluate the morphological changes. The ELISA method was used to detect related inflammatory factors and oxidative stress indicators. The corresponding protein expression and the mRNA level were detected by western blot analysis and reverse transcriptase PCR. HE staining showed that the thoracic aorta wall was thickened, and the aortic subendothelial foam cells and lipid vacuoles were reduced in the medium/high-AVF groups. Similarly, the TC, TG, LDL-C, and malondialdehyde (MDA) levels in the model group were significantly higher, but the HDL-C level and superoxide dismutase (SOD) activity were lower than those of the control group, and these effects were ameliorated by treatment with simvastatin or AVF. ELISA results showed that compared with the control group, the model group C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) results were significantly increased, and the medium AVF and high AVF could significantly reduce the expression of related inflammatory factors. The AVF inhibited intercellular cell adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin mRNA and related protein expression in the aorta in atherosclerotic rats. Western blot analysis also showed that AVF can significantly reduce the protein expression of fractalkine (FKN), spleen tyrosine kinase (SYK), and p38 mitogen-activated protein kinase (p38) in the rat aorta. We believe that the AVF can effectively reduce blood lipid levels in rats with atherosclerosis and delay atherosclerotic progression by inhibiting excessive inflammatory factors and inhibiting related adhesion factors. The underlying mechanism may be related to the FKN/SYK/p38 signaling pathway activity. Our results contribute to validating the traditional use of the Apocynum leaf extract in the treatment of atherosclerosis.

Response of the invasive Alliaria petiolata to extreme temperatures and drought

AbstractAlliaria petiolata, a strict biennial in North America, can have an annual alternating high abundance of rosettes and flowering plants. We monitored changes in abundance of rosettes and flowering plants in permanent plots (2004–2014). Three times during our study, the alternating yearly cycle was not observed (2007–2008, 2008–2009, and 2013–2014). We concluded stochastic extreme climate events (ECEs), deviating from long‐term climatic data norms (10th or 90th percentile), likely caused negative organism responses. Long‐term data from a local NOAA station located 25 km from our study site included monthly data (1) total precipitation, (2) number of days with &gt;0.13 cm precipitation, and (3) mean and minimum temperatures. September 2007 met the criteria for ECEs for all monthly variables. We first observed A. petiolata on our study site in 1988, and by the early 1990s, it was abundant. To determine whether September 2007 significantly differed from other September (1984–2014), we used six variables related to drought: (1) total precipitation, (2) number of days with precipitation, (3) number of contiguous days without precipitation, (4) mean monthly temperature, (5) mean maximum daily temperature, and (6) the number of days with temperatures &gt;30°C. The first two variables likely increase plant stress as they decrease, whereas stress declines as the remaining variables decrease. We used the six variables to generate a principal component analysis (PCA) biplot. Axes 1 and 2 accounted for 74.3% of the variance. Record‐breaking minimum temperatures (ECEs) for January (2009) and February–March (2014) likely reduced rosette abundance and disrupted reestablishment of alternating high abundance of rosettes and flowering plants. Our data suggest that a single ECE variable, minimum temperature, and multiple ECE variables related to drought likely had negative effects on A. petiolata.

Assessment of Care Handoffs Among Hospitalist Physicians and 30-Day Mortality in Hospitalized Medicare Beneficiaries

Inpatients treated by hospitalist physicians, who often work contiguous days, experience handoffs at the end of a scheduled shift block. Evidence suggests that transitions of patient care, or handoffs, among physician trainees are associated with adverse patient outcomes. However, little is known about the association between handoffs and patient outcomes among attending physicians, even though similar concerns apply. To examine the association between inpatient handoffs of hospitalist physicians and patient mortality among hospitalized Medicare beneficiaries. This cross-sectional study analyzed a random sample of Medicare beneficiaries who were hospitalized with a general medical condition between January 1, 2011, and December 31, 2016, and treated by a hospitalist. The study compared outcomes of patients with low vs high probability of physician handoff based on date of patient admission relative to the admitting hospitalist's last working day in a scheduled block, hypothesizing that otherwise similar patients admitted toward the end of a physician's shift block would be more likely to be handed off to another physician compared with patients admitted earlier in the shift block. Data analysis was performed from July 1, 2018, to January 12, 2021. High vs low probability of physician handoff. The main outcome was patient 30-day mortality rate. A total of 1 074 000 patients (mean [SD] age, 75.9 [13.7] years; 57.4% female; 82.1% White) were studied. Multivariable regression models adjusted for beneficiary clinical and demographic characteristics and hospital fixed effects (a within-hospital analysis, effectively comparing patients treated at the same hospital). Among 597 288 hospitalizations, no overall difference in 30-day mortality was observed between patients admitted in the 2 days prior (days -1 and -2) to the treating hospitalist's last working day (a high handoff probability) compared with days -6 and -7 (a low handoff probability) (adjusted rate, 10.6%; 95% CI, 10.5%-10.7% vs 10.6%; 95% CI, 10.5%-10.7%; adjusted difference, 0.0%; 95% CI, -0.2% to 0.1%). However, in an exploratory analysis, among patients with high illness severity, defined as those in the top quartile of estimated mortality, 30-day mortality was higher for those with high vs low likelihood of physician handoff (adjusted mortality, 27.8%; 95% CI, 27.6%-27.9% vs 26.8%; 95% CI, 26.6%-27.1%; absolute adjusted difference, 1.0%; 95% CI, 0.5%-1.4%). In this national analysis of Medicare beneficiaries hospitalized with a general medical condition and treated by a hospitalist physician, physician handoff was not associated with increased mortality overall.

Astraea: Predicting Long Rotation Periods with 27 Day Light Curves

Abstract The rotation periods of planet-hosting stars can be used for modeling and mitigating the impact of magnetic activity in radial velocity measurements and can help constrain the high-energy flux environment and space weather of planetary systems. Millions of stars and thousands of planet hosts are observed with the Transiting Exoplanet Survey Satellite (TESS). However, most will only be observed for 27 contiguous days in a year, making it difficult to measure rotation periods with traditional methods. This is especially problematic for field M dwarfs, which are ideal candidates for exoplanet searches, but which tend to have periods in excess of the 27 day observing baseline. We present a new tool, Astraea, for predicting long rotation periods from short-duration light curves combined with stellar parameters from Gaia DR2. Using Astraea, we can predict the rotation periods from Kepler 4 yr light curves with 13% uncertainty overall (and a 9% uncertainty for periods &gt;30 days). By training on 27 day Kepler light-curve segments, Astraea can predict rotation periods up to 150 days with 9% uncertainty (5% for periods &gt;30 days). After training this tool on these 27 day Kepler light-curve segments, we applied Astraea to real TESS data. For the 195 stars that were observed by both Kepler and TESS, we were able to predict the rotation periods with 55% uncertainty despite the wild differences in systematics.

Results from a commercial-scale experimental validation of a quantitative strategy to minimize energy used in conditioning of dry air in buildings in summer with fluctuating ambient and room occupancy rate

Conditioning of room air in summer is important globally. Many building however do not have an energy strategy predicated on quantitative unit-operations principles. To address this, a new probabilistic model was synthesised (Chem. Eng. Sci. XXX (2017) xxx-xxx) and a quantitative on-only strategy proposed to minimize electrical energy used. Here for the first time we report an extensive commercial-scale test of this strategy over 77 contiguous days of summer (Jan. to Mar.) in a large hotel (169 rooms) in S-E Australia (latitude −37.819708, longitude 144.959936) – a hot and dry clime. Two, dimensionally-identical suites (each of two rooms), with the same fit-out and (S-E) aspect, together with identical air conditioner (8.1 kW) and ‘smart’ (National Meter Identification) meters to automatically transmit contiguous (24–7) electrical use (at 30 min intervals) (n = 3696). Each suite (10.164 × 9.675 m floor plan) was auto-set to a bulk interior air temperature of 22 °C. In one (treated) the air conditioner was operated continuously (on-only), whilst in the other (control) it was left to wide-spread industry practice of switching on whilst the room is occupied, and off, when un-occupied (on-off). The suites had standard, single-glazed pane windows or curtain wall with heat-attenuating (fabric) internal curtains. Ambient peak temperature ranged from 17.8 to 39.1 °C. There were 32 days with recorded rainfall. Overall occupancy rate of both suites was almost identical at 69.6 and 71.2% respectively for the treated and control suite. This coincided with a typical business period for the hotel. Based on independent electrical energy invoices, results showed the treated suite used less energy on 47 days (61%) of the experimental period. Greenhouse gases were reduced by 12%. Savings in electrical energy cost of AUD $0.75 per day (9%), averaged over the period, were found for the treated suite adopting the alternative on-only strategy. Experimental findings overall therefore support the energy strategy hypothesis that continuous on-only air conditioning will use less energy in summer. The hypothesis appears generalizable and could be adapted to a range of room geometries and seasons. Results will be of immediate interest to operators and managers of large public and commercial buildings that rely on conditioning of bulk dry air in summer.

Preventable perinatal deaths in indigenous Wix\xe1rika communities: an ethnographic study of pregnancy, childbirth and structural violence

BackgroundPreventable maternal and infant mortality continues to be significantly higher in Latin American indigenous regions compared to non-indigenous, with inequalities of race, gender and poverty exacerbated by deficiencies in service provision. Standard programmes aimed at improving perinatal health have had a limited impact on mortality rates in these populations, and state and national statistical data and evaluations of services are of little relevance to the environments that most indigenous ethnicities inhabit. This study sought a novel perspective on causes and solutions by considering how structural, cultural and relational factors intersect to make indigenous women and babies more vulnerable to morbidity and mortality.MethodsWe explored how structural inequalities and interpersonal relationships impact decision-making about care seeking during pregnancy and childbirth in Wixarika communities in Northwestern Mexico. Sixty-two women were interviewed while pregnant and followed-up after the birth of their child. Observational data was collected over 18 months, producing more than five hundred pages of field notes.ResultsOf the 62 women interviewed, 33 gave birth at home without skilled attendance, including 5 who delivered completely alone. Five babies died during labour or shortly thereafter, we present here 3 of these events as case studies. We identified that the structure of service provision, in which providers have several contiguous days off, combined with a poor patient-provider dynamic and the sometimes non-consensual imposition of biomedical practices acted as deterrents to institutional delivery. Data also suggested that men have important roles to play supporting their partners during labour and birth.ConclusionsStillbirths and neonatal deaths occurring in a context of unnecessary lone and unassisted deliveries are structurally generated forms of violence: preventable morbidities or mortalities that are the result of systematic inequalities and health system weaknesses. These results counter the common assumption that the choices of indigenous women to avoid institutional delivery are irrational, cultural or due to a lack of education. Rather, our data indicate that institutional arrangements and interpersonal interactions in the health system contribute to preventable deaths. Addressing these issues requires important, but achievable, changes in service provision and resource allocation in addition to long term, culturally-appropriate strategies.

Green or blue spaces? Assessment of the effectiveness and costs to mitigate the urban heat island in a Latin American city

We measured air temperature at 14 sites with different land cover composition within the urban canopy layer of a mid-sized Brazilian city. The intensity (ΔT) of the urban heat island (UHI) was calculated using data collected above a lake and at an urban park as references. We investigated the spatio-temporal variability of ΔT during four contiguous days with varying weather. The first day was overcast and rainy, giving rise to a moderate UHI. The second day was sunny, which caused the diurnal ΔT fields to become heterogeneous, due to larger heating rates at sites with more man-made surfaces compared to natural surfaces. A high-pressure system observed on the last days brought cloudless skies, causing smaller ΔT during the day and greater at night. We hypothesise that the effect was due to the reduction of cooling via evapotranspiration caused by closing of the stomata as the soil dried out, which reduced the daytime temperature differences among the sites. The night-time effect was caused by stronger radiative cooling due to clear skies. The temperature within the park was always lower than over the lake, confirming that urban forestry is a more effective mechanism to combat the UHI. Introducing a park would be about sevenfold cheaper than building a city pond. Hence, green spaces are not only more efficient to combat the UHI but it is also a cheaper strategy compared to blue spaces. Moreover, vegetation delivers other benefits, such as removal of air pollutants, attenuation of urban noise, improvement of city aesthetic and their use as recreational spaces.

Imaging Melphalan Therapy Response in Preclinical Extramedullary Multiple Myeloma with 18F-FDOPA and 18F-FDG PET.

Multiple myeloma (MM) is a debilitating neoplasm of terminally differentiated plasma B cells that resulted in over 13,000 deaths in 2017 alone. Combination therapies involving melphalan, a small-molecule DNA alkylating agent, are commonly prescribed to patients with relapsed or refractory MM, necessitating the stratification of responding patients to minimize toxicities and improve quality of life. Here, we evaluated the use of 3,4-dihydroxy-6-18F-fluoro-l-phenylalanine (18F-FDOPA), a clinically available PET radiotracer with specificity to the L-type amino acid transporter 1 (LAT1), which also mediates melphalan uptake, for imaging melphalan therapy response in a preclinical immunocompetent model of MM. Methods: C57BL/KaLwRij mice were implanted subcutaneously with unilateral murine green fluorescent protein-expressing 5TGM1 tumors and divided into 3 independent groups: untreated, treated beginning week 2 after tumor implantation, and treated beginning week 3 after tumor implantation. The untreated and week 2 treated groups were imaged with preclinical MRI and dynamic 18F-FDG and 18F-FDOPA PET/CT at week 4 on separate, contiguous days, whereas the week 3 treated group was longitudinally imaged weekly for 3 wk. Metabolic tumor volume, total lesion avidity, SUVmax, and total uptake were calculated for both tracers. Immunohistochemistry was performed on representative tissue from all groups for LAT1 and glucose transporter 1 (GLUT1) expression. Results: Melphalan therapy induced a statistically significant reduction in lesion avidity and uptake for both 18F-FDG and 18F-FDOPA. There was no visible effect on GLUT1 expression, but LAT1 density increased in the week 2 treated group. Longitudinal imaging of the week 3 treated group showed variable changes in 18F-FDG and 18F-FDOPA uptake, with an increase in 18F-FDOPA lesion avidity in the second week relative to baseline. LAT1 and GLUT1 surface density in the untreated and week 3 treated groups were qualitatively similar. Conclusion:18F-FDOPA PET/CT complemented 18F-FDG PET/CT in imaging melphalan therapy response in preclinical extramedullary MM. 18F-FDOPA uptake was linked to LAT1 expression and melphalan response, with longitudinal imaging suggesting stabilization of LAT1 levels and melphalan tumor cytotoxicity. Future work will explore additional MM cell lines with heterogeneous LAT1 expression and response to melphalan therapy.

Continuous assessment of schizophrenia using heart rate and accelerometer data

Objective: Schizophrenia has been associated with changes in heart rate (HR) and physical activity measures. However, the relationship between analysis window length and classifier accuracy using these features has yet to be quantified. Approach: Here we used objective HR and activity data to classify contiguous days of data as belonging to a schizophrenia patient or a healthy control. HR and physical activity recordings were made on 12 medicated subjects with schizophrenia and 12 healthy controls. Features derived from these data included classical statistical characteristics, rest-activity metrics, transfer entropy, and multiscale fuzzy entropy. We varied the analysis window length from two to eight days, and selected features via minimal-redundancy-maximal-relevance. A support vector machine was trained to classify schizophrenia from control windows on a daily basis. Model performance was assessed via subject-wise leave-one-out-crossfold-validation. Main results: An analysis window length of eight days resulted in an area under a receiver operating characteristic curve (AUC) of 0.96. Reducing the analysis window length to two days only lowered the AUC to 0.91. The type of most predictive features varied with analysis window length. Significance: Our results suggest continuous tracking of subjects with schizophrenia over short time scales may be sufficient to estimate illness severity on a daily basis.

Apocynum leaf extract inhibits the progress of atherosclerosis in rats via the AMPK/mTOR pathway.

Apocynum leaf extract is an extract of the dried leaves of Apocynum venetum (a member of the Apocynaceae family) that has many effects on the cardiovascular system. The aim of the present study was to evaluate the protective effects of apocynum leaf extract on the atherosclerosis in rats induced by high-fat diet combined with vitamin D3 intraperitoneal injection. The atherosclerosis in rats were induced with a high-fat diet and an intraperitoneal injection of VD3 once daily for three contiguous days at a total injection dose of 70 U/kg. At the end of the 18th week, serum total cholesterol (TC) and triglyceride (TG) contents were measured. Hydroxyproline content in the aorta were measured by the alkali hydrolysis method. The hematoxylin-eosin (HE) and immunohistochemical staining were applied to evaluate the morphological changes and the collagen I and α-smooth muscle actin expression. The protein expression and the mRNA level of AMPK and mTOR were detected by western blot analysis and reverse transcript PCR. After treatment with apocynum leaf extract, the serum total cholesterol and triglyceride concentration of the atherosclerotic rats were significantly decreased, both the Collagen I expression and the hydroxyproline content in the aorta were significantly reduced, and the α-SMA, a smooth muscle-specific marker, expression were also lower than the untreated atherosclerotic rats. Western blot analyses showed that the apocynum can marked increase the p-AMPK but decrease the mTOR protein expression. The apocynum leaf extract also exhibited higher AMPK and lower mTOR mRNA expression of the aorta in the atherosclerotic rats. We believe that the apocynum leaf extract can effectively reduce blood lipid levels in rats with atherosclerosis, delay atherosclerotic progression by inhibiting excessive collagen synthesis and inhibiting smooth muscle cell over-proliferation. The underlying mechanism may be related to the AMPK/mTOR signaling pathway activity. Our results contribute towards validation of the traditional use of apocynum leaf extract in the treatment of atherosclerosis.

Regulation of the NR2B-CREB-CRTC1 Signaling Pathway Contributes to Circadian Pain in Murine Model of Chronic Constriction Injury.

Numerous clinical investigations have revealed the circadian rhythm changes in the perception of chronic pain, and most clinical chronic pain types peak in the night. However, it is still undiscovered whether circadian rhythm of pain exists in rodents and the specific mechanism that may underlie it. Our study was conducted to investigate the rhythmic changes of hyperalgesia behavior in a chronic constrictive injury (CCI) model of rodents and to explore the role of the N-methyl-d-aspartate receptor 2B (NR2B)-cAMP response element binding protein (CREB)-CREB-regulated transcription coactivator 1 (CRTC1) signaling pathway in this pain rhythm. A CCI operation was performed to mimic clinical chronic pain. Paw mechanical withdrawal threshold and paw withdrawal thermal latency were used to test pain behavior in rats; a von Frey cilia test was used to test mechanical hyperalgesia in mice at Zeitgeber time (ZT) 4, ZT10, ZT16, and ZT22 for 14 contiguous days. The relative mRNA and protein expression of NR2B, CREB and CRTC1 in the suprachiasmatic nuclei and the dorsal horn were measured by real-time polymerase chain reaction and Western blot. CRTC1 and CREB interference adenovirus vectors were injected intrathecally at 2 time points, respectively (ZT12 and ZT0), to further explore the proper time point for pain treatment. During the period of chronic pain state, the pain behavior of CCI rodents showed a circadian rhythm with the peak at ZT4 or ZT10 daily. The pain thresholds were significantly different between the activity period and the rest period. The expressions of NR2B, CRTC1, and CREB at the spinal level were consistent with the pain rhythm. The intrathecal treatment with CRTC1 or CREB interference adenovirus from day 7 to day 9 after CCI surgery markedly improved pain behaviors. Nevertheless, when given at ZT0, they were both more effective at relieving peak pain than drugs given at ZT12. Pain behavior in the chronic pain of CCI displayed circadian rhythm and was associated with circadian secretion of pain-related receptors. The NR2B-CREB-CRTC1 signaling pathway may play a crucial role in this rhythm. Moreover, our results suggest that measures to relieve pain should be taken before pain reaches its peak.

Statistical modeling of the spatial variability of environmental noise levels in Montreal, Canada, using noise measurements and land use characteristics.

The availability of noise maps to assess exposure to noise is often limited, especially in North American cities. We developed land use regression (LUR) models for LAeq24h, Lnight, and Lden to assess the long-term spatial variability of environmental noise levels in Montreal, Canada, considering various transportation noise sources (road, rail, and air). To explore the effects of sampling duration, we compared our LAeq24h levels that were computed over at least five complete contiguous days of measurements to shorter sampling periods (20 min and 24 h). LUR models were built with General Additive Models using continuous 2-min noise measurements from 204 sites. Model performance (adjusted R2) was 0.68, 0.59, and 0.69 for LAeq24h, Lnight, and Lden, respectively. Main predictors of measured noise levels were road-traffic and vegetation variables. Twenty-minute non-rush hour measurements corresponded well with LAeq24h levels computed over 5 days at road-traffic sites (bias: -0.7 dB(A)), but not at rail (-2.1 dB(A)) nor at air (-2.2 dB(A)) sites. Our study provides important insights into the spatial variation of environmental noise levels in a Canadian city. To assess long-term noise levels, sampling strategies should be stratified by noise sources and preferably should include 1 week of measurements at locations exposed to rail and aircraft noise.

Abstract 10979: ACE-inhibitor or ARB Therapy Reduces the Risk for GI Bleeding in LVAD Patients

Introduction: Gastrointestinal bleeding (GIB) due to arteriovenous malformations (AVMs) is a major source of morbidity for patients supported with left ventricular assist devices (LVADs). Recent studies implicate angiogenesis mediated by vascular endothelial growth factor (VEGF) in AVM formation. Transforming growth factor-β is biochemically upstream of VEGF and is up-regulated after LVAD implantation. Angiotensin converting enzyme inhibitors (ACE-inhibitors) and angiotensin receptor blockers (ARBs) inhibit TGF-β. Hypothesis: ACE-inhibitor/ARB therapy will be independently associated with a reduced risk of GIB overall and GIB due to AVMs in LVAD patients. Methods: We reviewed the records of all patients aged 18 years or older receiving a continuous flow LVAD (HeartMate II or Heartware) at Johns Hopkins Hospital from 1/2004 to 9/2013 (n=186). We excluded patients for whom follow-up records were not available (n=3), those supported with a LVAD for less than 100 contiguous days (n=51), and those missing covariates included in statistical models (n=8), leaving 124 patients included for analyses. Cox proportional hazards models adjusted for demographic, cardiovascular, and laboratory variables were used to assess the association of ACE-inhibitor/ARB therapy with GIB. Results: Mean age of patients was 52 years and 75% were male. Ninety-seven patients received ACE-inhibitor and/or ARB therapy during LVAD support. Thirty-six patients (29%) had at least one GIB after discharge from their LVAD implantation; 15 of these 36 episodes (42%) were due to confirmed AVMs. Among ACE/ARB patients, 24% had a post-discharge GIB (23/97) versus 48% (13/27) of non-ACE/ARB patients. Fully adjusted Cox proportional hazards model demonstrated that ACE-inhibitor/ARB therapy was independently associated with a reduced risk of GIB after hospital discharge (HR 0.37, 95% CI 0.17-0.81, p=0.012) with suggestion of reduced risk of GIB due to AVMs (HR 0.32, 95% CI 0.10-1.06, p=0.06). Conclusions: ACE-inhibitor and ARBs are independently associated with a reduced risk of GIB in LVAD patients and should be considered for all LVAD patients without contraindications. Possible biologic mechanisms of this observation remain unexplored and warrant further investigation.

An Internet-based Controlled Trial Aimed to Improve Osteoporosis Prevention among Chronic Glucocorticoid Users

To address the low prevention and treatment rates for those at risk of glucocorticoid-induced osteoporosis (GIOP), we evaluated the influence of a direct-to-patient, Internet-based educational video intervention using "storytelling" on rates of antiosteoporosis medication use among chronic glucocorticoid users who were members of an online pharmacy refill service. We identified members who refilled ≥ 5 mg/day of prednisone (or equivalent) for 90 contiguous days and had no GIOP therapy for ≥ 12 months. Using patient stories, we developed an online video addressing risk factors and treatment options, and delivered it to members refilling a glucocorticoid prescription. The intervention consisted of two 45-day "Video ON" periods, during which the video automatically appeared at the time of refill, and two 45-day "Video OFF" periods, during which there was no video. Members could also "self-initiate" watching the video by going to the video link. We used an interrupted time series design to evaluate the effectiveness of this intervention on GIOP prescription therapies over 6 months. Among 3017 members (64.8%) exposed to the intervention, 59% had measurable video viewing time, of which 3% "self-initiated" the video. The GIOP prescription rate in the "Video ON" group was 2.9% versus 2.7% for the "Video OFF" group. There was a nonsignificant trend toward greater GIOP prescription in members who self-initiated the video versus automated viewing (5.7% vs 2.9%, p = 0.1). Among adults at high risk of GIOP, prescription rates were not significantly affected by an online educational video presented at the time of glucocorticoid refill. ClinicalTrials.gov Identifier: NCT01378689.

Rumination as a Mediator and Moderator of the Relationship between Unpleasant Events and Unhappy Mood: A Daily Diary Study

Research is lacking on whether and how stressful events trigger ruminative episodes and whether and how rumination, in turn, exerts a perpetuating influence on negative mood on a daily basis. To answer these questions, an experience sampling study was conducted with 101 undergraduate students who reported momentary unpleasant events, rumination, and unhappy mood once a day for 30 days. Our findings showed, as expected, that daily rumination mediated the relationship between daily unpleasant events and daily unhappy mood. A significant daily moderation finding was also obtained: rumination exacerbated reports of unhappy mood under low levels of unpleasant events. Day to day stability was noted for momentary rumination and unhappy mood, and these two variables also exhibited a weak bidirectional relationship over contiguous days. And finally, a moderated mediation analysis showed that individuals who reported high trait rumination evidenced a stronger indirect effect in the daily mediation pattern. The new findings suggest that: 1) rumination functions as a daily mediator and moderator of the basic stress to depression relationship; 2) rumination perpetuates negative mood over time; and 3) rumination is a stronger predictor of negative mood from day to day than stressful events. These findings illuminate how psychopathological interpretations of day to day life experiences can lead to negative mood states in a community sample.

Performance sustaining intracortical neural prostheses

Objective. Neural prostheses, or brain–machine interfaces, aim to restore efficient communication and movement ability to those suffering from paralysis. A major challenge these systems face is robust performance, particularly with aging signal sources. The aim in this study was to develop a neural prosthesis that could sustain high performance in spite of signal instability while still minimizing retraining time. Approach. We trained two rhesus macaques implanted with intracortical microelectrode arrays 1–4 years prior to this study to acquire targets with a neurally-controlled cursor. We measured their performance via achieved bitrate (bits per second, bps). This task was repeated over contiguous days to evaluate the sustained performance across time. Main results. We found that in the monkey with a younger (i.e., two year old) implant and better signal quality, a fixed decoder could sustain performance for a month at a rate of 4 bps, the highest achieved communication rate reported to date. This fixed decoder was evaluated across 22 months and experienced a performance decline at a rate of 0.24 bps yr-1. In the monkey with the older (i.e., 3.5 year old) implant and poorer signal quality, a fixed decoder could not sustain performance for more than a few days. Nevertheless, performance in this monkey was maintained for two weeks without requiring additional online retraining time by utilizing prior days’ experimental data. Upon analysis of the changes in channel tuning, we found that this stability appeared partially attributable to the cancelling-out of neural tuning fluctuations when projected to two-dimensional cursor movements. Significance. The findings in this study (1) document the highest-performing communication neural prosthesis in monkeys, (2) confirm and extend prior reports of the stability of fixed decoders, and (3) demonstrate a protocol for system stability under conditions where fixed decoders would otherwise fail. These improvements to decoder stability are important for minimizing training time and should make neural prostheses more practical to use.