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Multimodal single-cell assays profile multiple sets of features in the same cells and are widely used for identifying and mapping cell states between chromatin and mRNA and linking regulatory elements to target genes. However, the high dimensionality of input features and shallow sequencing depth compared to unimodal assays pose challenges in data analysis. Here we present scPair, a multimodal single-cell data framework that overcomes these challenges by employing an implicit feature selection approach. scPair uses dual encoder-decoder structures trained on paired data to align cell states across modalities and predict features from one modality to another. We demonstrate that scPair outperforms existing methods in accuracy and execution time, and facilitates downstream tasks such as trajectory inference. We further show scPair can augment smaller multimodal datasets with larger unimodal atlases to increase statistical power to identify groups of transcription factors active during different stages of neural differentiation. Multimodal single-cell analysis faces challenges due to high feature dimensionality and shallow sequencing depth. Here, authors present scPair for aligning cell states across modalities with implicit feature selection and enhancing data analysis tasks such as identifying key transcription factors in neural differentiation. [ABSTRACT FROM AUTHOR]

Dominant X-linked diseases are uncommon due to female X chromosome inactivation (XCI). While random XCI usually protects females against X-linked mutations, Rett syndrome (RTT) is a female neurodevelopmental disorder caused by heterozygous MECP2 mutation. After 6-18 months of typical neurodevelopment, RTT girls undergo a poorly understood regression. We performed longitudinal snRNA-seq on cerebral cortex in a construct-relevant Mecp2e1 mutant mouse model of RTT, revealing transcriptional effects of cell type, mosaicism, and sex on progressive disease phenotypes. Across cell types, we observed sex differences in the number of differentially expressed genes (DEGs) with 6x more DEGs in mutant females than males. Unlike males, female DEGs emerged prior to symptoms, were enriched for homeostatic gene pathways in distinct cell types over time and correlated with disease phenotypes and human RTT cortical cell transcriptomes. Non-cell-autonomous effects were prominent and dynamic across disease progression of Mecp2e1 mutant females, indicating that wild-type-expressing cells normalize transcriptional homeostasis. These results advance our understanding of RTT progression and treatment. Longitudinal snRNA-seq 5' in a Mecp2e1 mutant mouse model reveals sex-specific gene expression differences in specific cell types, with mutant females showing early and dynamic transcriptional changes linked to disease progression, enhancing our understanding of RTT. [ABSTRACT FROM AUTHOR]

Objective: Early in the COVID-19 pandemic, many children with appendicitis and COVID-19 were initially treated non-operatively and later underwent interval appendectomy. Currently, children with both appendicitis and COVID-19 frequently undergo upfront appendectomy. The impact of this return to upfront surgical management on patient outcomes is unknown. This study compared outcomes of pediatric patients with and without COVID-19 infection undergoing appendectomy. Study design: A retrospective cohort study of children < 21y who underwent appendectomy from 3/19/2020 to 7/31/2022 at 50 Pediatric Health Information System children's hospitals was conducted. Children with documented COVID-19 were identified. Exclusions included preoperative ventilator or supplemental oxygen dependence, and missing data. To evaluate COVID-19 positive versus COVID-19 negative patients, we used a propensity score matched on sociodemographics, comorbidities, laparoscopy, perforation, and hospital. Chi-square and Mann–Whitney U tests identified differences between groups in length of stay, postoperative drain placement, 30-day re-admission, and mechanical ventilation requirements. Results: Overall, 51,861 children of median age 11y (IQR: 8–14) underwent appendectomy, of whom 1,440 (2.3%) had COVID-19. Most were male (60.3%), White (72.1%) and non-Hispanic (61.4%). Public insurance was the most common (47.5%). We created a matched cohort of 1,360 COVID-19 positive and 1,360 COVID-19 negative children. Children with COVID-19 had shorter hospitalizations (1d, IQR: 1–4 vs. 2d, IQR: 1–5, p = 0.03), less postoperative peritoneal drain placement (2.4% vs. 4.1%, p = 0.01), and fewer 30-day readmissions (9.0% vs. 11.4%, p = 0.04). However, no difference in incidence or duration of mechanical ventilation (p > 0.05) was detected. Conclusions: Our findings suggest that upfront appendectomy for children with appendicitis and COVID-19 has similar outcomes compared to children without COVID-19. Level of evidence: Level III. [ABSTRACT FROM AUTHOR]

Purpose: Fibroblast activation protein (FAP)-inhibitor (FAPI)-PET tracers allow imaging of the FAP-expressing cancer associated fibroblasts (CAF) and also the normal activated fibroblasts (NAF) involved in inflammation/fibrosis that may be present after invasive medical interventions. We evaluated [68Ga]Ga-FAPI-46 uptake patterns post-medical/invasive non-systemic interventions. Methods: This single-center retrospective analysis was conducted in 79 consecutive patients who underwent [68Ga]Ga-FAPI-46 PET/CT. Investigators reviewed prior patient medical/invasive interventions (surgery, endoscopy, biopsy, radiotherapy, foreign body placement (FBP) defined as implanted medical/surgical material present at time of scan) and characterized the anatomically corresponding FAPI uptake intensity both visually (positive if above surrounding background) and quantitatively (SUVmax). Interventions with missing data/images or confounders of [68Ga]Ga-FAPI-46 uptake (partial volume effect, other cause of increased uptake) were excluded. Available correlative FDG, DOTATATE and PSMA PET/CTs were analyzed when available. Results: 163 medical/invasive interventions (mostly surgeries (49%), endoscopies (18%) and non-surgical biopsies (10%)) in 60 subjects were included for analysis. 43/163 (26%) involved FBP. FAPI uptake occurred in 24/163 (15%) of interventions (average SUVmax 3.2 (mild), range 1.5–5.1). The median time-interval post-intervention to FAPI-PET was 47.5 months and was shorter when FAPI uptake was present (median 9.5 months) than when absent (median 60.1 months; p = 0.001). Cut-off time beyond which no FAPI uptake would be present post-intervention without FBP was 8.2 months, with a sensitivity, specificity, positive predictive value and negative predictive value of 82, 90, 99 and 31% respectively. No optimal cutoff point could be determined when considering interventions with FBP. No significant difference was detected between frequency of [68Ga]Ga-FAPI-46 and [18F]FDG uptake in intervention sites. Compared to [68Ga]Ga-PSMA-11, [68Ga]Ga-FAPI-46 revealed more frequent and intense post-interventional tracer uptake. Conclusion: [68Ga]Ga-FAPI-46 uptake from medical/invasive interventions without FBP appears to be time dependent, nearly always absent beyond 8 months post-intervention, but frequently present for years with FBP. [ABSTRACT FROM AUTHOR]

Multi-modal single cell RNA assays capture RNA content as well as other data modalities, such as spatial cell position or the electrophysiological properties of cells. Compared to dedicated scRNA-seq assays however, they may unintentionally capture RNA from multiple adjacent cells, exhibit lower RNA sequencing depth compared to scRNA-seq, or lack genome-wide RNA measurements. We present scProjection, a method for mapping individual multi-modal RNA measurements to deeply sequenced scRNA-seq atlases to extract cell type-specific, single cell gene expression profiles. We demonstrate several use cases of scProjection, including identifying spatial motifs from spatial transcriptome assays, distinguishing RNA contributions from neighboring cells in both spatial and multi-modal single cell assays, and imputing expression measurements of un-measured genes from gene markers. scProjection therefore combines the advantages of both multi-modal and scRNA-seq assays to yield precise multi-modal measurements of single cells. Many expression deconvolution approaches have been developed to estimate % RNA contributions of diverse cell types to mixed RNA measurements. Here, the authors have developed a complementary approach called scProjection to recover cell type-specific expression profiles from mixed RNA measurements. [ABSTRACT FROM AUTHOR]

The effects of climate change, population growth, and future hydrologic uncertainties necessitate increased water conservation, new water resources, and a shift towards sustainable urban water supply portfolios. Diversifying water portfolios with non-traditional water sources can play a key role. Rooftop harvested rainwater (RHRW), atmospheric and condensate harvesting, stormwater, recycled wastewater and greywater, and desalinated seawater and brackish water are all currently utilized and rapidly emerging non-traditional water sources. This review explores the status and trends around these non-traditional water sources, and reviews approaches and models for prioritizing, predicting, and quantifying metrics of concern. The analysis presented here suggests that understanding the challenges of location specific scenarios, socioeconomic knowledge gaps, water supply technologies, and/or water management structure is the crucial first step in establishing a model or framework approach to provide a strategy for improvement going forward. The findings of this study also suggest that clear policy guidance and onsite maintenance is necessary for variable water quality concerns of non-traditional sources like harvested rainwater and greywater. In addition, use of stormwater or reuse of wastewater raises public health concerns due to unknown risks and pathogen levels, thus rapid monitoring technologies and transparent reporting systems can facilitate their adoption. Finally, cost structure of desalination varies significantly around the world, largely due to regulatory requirements and local policies. Further reduction of its capital cost and energy consumption is identified as a hurdle for implementation. Overall, models and process analyses highlight the strength of comparative assessments across scenarios and water supply options. [ABSTRACT FROM AUTHOR]

Cystic fibrosis (CF) is a progressive multi-organ disease with significant morbidity placing extensive demands on the healthcare system. Little is known about those individuals with CF who continually incur high costs over multiple years. Understanding their characteristics may help inform opportunities to improve management and care, and potentially reduce costs. The purpose of this study was to identify and understand the clinical and demographic attributes of frequent high-costing CF individuals and characterize their healthcare utilization and costs over time. A longitudinal study of retrospective data was completed in British Columbia, Canada by linking the Canadian CF Registry with provincial healthcare administrative databases for the period between 2009 and 2017. Multivariable Cox regression models were employed to identify baseline factors associated with becoming a frequent high-cost CF user (vs. not a frequent high-cost CF user) in the follow-up period. We found that severe lung impairment (Hazard Ratio [HR]: 3.71, 95% confidence interval [CI], 1.49–9.21), lung transplantation (HR: 4.23, 95% CI, 1.68–10.69), liver cirrhosis with portal hypertension (HR: 10.96, 95% CI: 3.85–31.20) and female sex (HR: 1.97, 95% CI: 1.13–3.44) were associated with becoming a frequent high-cost CF user. Fifty-nine (17% of cohort) frequent high-cost CF users accounted for more than one-third of the overall total healthcare costs, largely due to inpatient hospitalization and outpatient medication costs. [ABSTRACT FROM AUTHOR]

Gestational hypoxia is a major contributor to fetal growth restriction (FGR) and perinatal morbidity and mortality and has been closely linked to the activation of the unfolded protein response (UPR) in the placenta. Recent studies on adverse pregnancy conditions show differential adaptive responses in pregnancies carrying male or female fetuses. Here, we use an established rat model of hypoxic pregnancy and FGR to test the hypothesis that chronic hypoxia promotes sexually dimorphic activation of the placental UPR. Our data showed that gestational hypoxia increased glucose regulatory protein 78 (GRP78) expression in male placentae, increased activating transcription factor 6 activation (ATF6) in female placentae, and did not induce changes in other UPR markers. In addition, gestational hypoxia reduced fetal weight only in males and ATF6 activation correlated with an increase in the fetal crown-rump-length/body weight ratio only in females. These results suggest sex-specific divergence in the placental adaptive response to gestational hypoxia, which may account for the sexual dimorphism observed in placental function and pregnancy outcomes in complicated pregnancies. [ABSTRACT FROM AUTHOR]

We examine how governments use accounting information, specifically administrative ratios, in their decisions regarding the funding of nonprofit organizations (NPOs). Using data in the setting of Canada, we find that when funding NPOs for the first time, governments consider NPOs' sustainability and are more likely to award funds to NPOs with reasonably high administrative ratios, as long as these ratios are below the government-suggested threshold. In subsequent funding decisions, governments tend to ignore administrative ratios and stick with previously funded NPOs to extend subsequent funding(s). We further find that governments react to low-quality accounting ratios by reducing the likelihood and the value of funds awarded, and this reaction is more pronounced at initial funding than at subsequent funding(s). The practical and policy implications of these findings are discussed. [ABSTRACT FROM AUTHOR]

Understanding the neural correlates of perception of hierarchical structure in music presents a direct window into auditory organization. To examine the hypothesis that high-level and low-level structures—i.e. phrases and notes—elicit different neural responses, we collected intracranial electroencephalography (iEEG) data from eight subjects during exposure to Mozart's K448 and directly compared Event-related potentials (ERPs) due to note onsets and those elicited by phrase boundaries. Cluster-level permutation tests revealed that note-onset-related ERPs and phrase-boundary-related ERPs were significantly different at - 150 , 200, and 450 ms relative to note onset and phrase markers. We also observed increased activity in frontal brain regions when processing phrase boundaries. We relate these observations to (1) a process which syntactically binds notes together hierarchically to form larger phrases; (2) positive emotions induced by successful prediction of forthcoming phrase boundaries and violations of melodic expectations at phrase boundaries. [ABSTRACT FROM AUTHOR]

This study aimed to investigate the relationship between intensity-modulated radiation therapy (IMRT) dosimetry and swallowing kinematic and timing measures. Thirteen kinematic and timing measures of swallowing from videofluoroscopic analysis were used as outcome measures to reflect swallowing function. IMRT dosimetry was accessed for thirteen swallowing-related structures. A cohort of 44 nasopharyngeal carcinoma (NPC) survivors at least 3 years post-IMRT were recruited. The cohort had a mean age of 53.2 ± 11.9 years, 77.3% of whom were male. There was an average of 68.24 ± 14.15 months since end of IMRT; 41 (93.2%) had undergone concurrent chemotherapy. For displacement measures, female sex and higher doses to the cricopharyngeus, glottic larynx, and base of tongue were associated with reduced hyolaryngeal excursion and pharyngeal constriction, and more residue. For timing measures, higher dose to the genioglossus was associated with reduced processing time at all stages of the swallow. The inferior pharyngeal constrictor emerged with a distinctly different pattern of association with mean radiation dosage compared to other structures. Greater changes to swallowing kinematics and timing were observed for pudding thick consistency than thin liquid. Increasing radiation dosage to swallowing-related structures is associated with reduced swallowing kinematics. However, not all structures are affected the same way, therefore organ sparing during treatment planning for IMRT needs to consider function rather than focusing on select muscles. Dose-response relationships should be investigated with a comprehensive set of swallowing structures to capture the holistic process of swallowing. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this study was to investigate factors impacting transplant-free survival among infants with biliary atresia. Methods: A multi-institutional, retrospective cohort study was performed at nine tertiary-level children's hospitals in the United States. Infants who underwent Kasai portoenterostomy (KP) from January 2009 to May 2017 were identified. Clinical characteristics included age at time of KP, steroid use, surgical approach, liver pathology, and surgeon experience. Likelihood of transplant-free survival (TFS) was evaluated using logistic regression, adjusting for patient and surgeon-level factors. Secondary outcomes at 1 year included readmission, cholangitis, reoperation, mortality, and biliary clearance. Results: Overall, 223 infants underwent KP, and 91 (40.8%) survived with their native liver. Mean age at surgery was 63.9 days (± 24.7 days). At 1 year, 78.5% experienced readmission, 56.9% developed cholangitis, 3.8% had a surgical revision, and 5 died. Biliary clearance at 3 months was achieved in 76.6%. Controlling for patient and surgeon-level factors, each additional day of age toward operation was associated with a 2% decrease in likelihood of TFS (OR 0.98, 95% CI 0.97–0.99). Conclusion: Earlier surgical intervention by Kasai portoenterostomy at tertiary-level centers significantly increases likelihood for TFS. Policy-level interventions to facilitate early screening and surgical referral for infants with biliary atresia are warranted to improve outcomes. [ABSTRACT FROM AUTHOR]

Purpose: Intravenous (IV) sodium bicarbonate is considered standard therapy for high-dose methotrexate (HDMTX) urine alkalinization. Due to a national IV sodium bicarbonate shortage, an oral (PO) sodium bicarbonate protocol was implemented by Alberta Health Services (AHS) for HDMTX urine alkalinization. This study aims to evaluate the efficacy and safety of the PO sodium bicarbonate protocol compared to IV sodium bicarbonate for HDMTX urine alkalinization. Methods: A retrospective chart review of adult patients who received HDMTX (> 500 mg/m2) with sodium bicarbonate for urine alkalinization at 4 hospitals in Alberta was conducted. Patients who received IV sodium bicarbonate between January and June 2017 and PO sodium bicarbonate between July and December 2017 were compared for the primary outcome of time to methotrexate clearance. Results: A total of 84 and 78 HDMTX cycles were included in the IV and PO cohorts, respectively. No difference in time to methotrexate clearance was seen between the IV and PO cohorts, 91.6 (± 35.4) hours and 95.2 (± 44) hours respectively; p = 0.5. The proportion of HDMTX cycles that experienced a > 25% increase in serum creatinine was not statistically significant, IV protocol 12% and PO protocol 5%; p = 0.13. Nausea and emesis occurred more frequently in the PO cohort than the IV cohort, though rarely resulted in refused doses or change to alternate sodium bicarbonate formulations. Conclusions: The results of this study indicate that the AHS PO sodium bicarbonate protocol was no different in time to methotrexate clearance or rates of increased serum creatinine when compared to IV sodium bicarbonate. [ABSTRACT FROM AUTHOR]

Summary: Background: For people with chronic pain, cigarette smoking is associated with greater pain intensity and impairment. Researchers have hypothesized a reciprocal relationship in which pain and smoking exacerbate each other, resulting in greater pain and increased smoking. This study aimed to qualitatively examine patient perspectives on this association. Methods: A retrospective thematic analysis of smoking cessation counseling notes for 136 veterans in the Pain and Smoking Study, a tailored smoking cessation trial, was conducted. A validated codebook was applied to each counseling note by four independent coders using Atlas.ti (Atlas.ti, Berlin, Germany). Coders participated in a consensus-forming exercise with salient themes validated among the wider research team. Key results: Participants averaged 60 years of age (range 28–77 years) and were 9% female. The median number of cigarettes smoked per day was 15, with a mean pain intensity score in the last week (from 0–10) of 5.1. While not all patients acknowledged a connection between pain and smoking, we found that (1) pain motivates smoking and helps manage pain-related distress, as a coping strategy and through cognitive distraction, and (2) pain motivates smoking but smoking does not offer pain relief. Concerns about managing pain without smoking was identified as a notable barrier to cessation. Conclusion: Many patients with chronic pain who smoke readily identified pain as a motivator of their smoking behavior and are reluctant to quit for this reason. Integrated interventions for smokers with pain should address these perceptions and expectancies and promote uptake of more adaptive self-management strategies for pain. [ABSTRACT FROM AUTHOR]

There is growing evidence for the efficacy of music, specifically Mozart's Sonata for Two Pianos in D Major (K448), at reducing ictal and interictal epileptiform activity. Nonetheless, little is known about the mechanism underlying this beneficial "Mozart K448 effect" for persons with epilepsy. Here, we measured the influence that K448 had on intracranial interictal epileptiform discharges (IEDs) in sixteen subjects undergoing intracranial monitoring for refractory focal epilepsy. We found reduced IEDs during the original version of K448 after at least 30-s of exposure. Nonsignificant IED rate reductions were witnessed in all brain regions apart from the bilateral frontal cortices, where we observed increased frontal theta power during transitions from prolonged musical segments. All other presented musical stimuli were associated with nonsignificant IED alterations. These results suggest that the "Mozart K448 effect" is dependent on the duration of exposure and may preferentially modulate activity in frontal emotional networks, providing insight into the mechanism underlying this response. Our findings encourage the continued evaluation of Mozart's K448 as a noninvasive, non-pharmacological intervention for refractory epilepsy. [ABSTRACT FROM AUTHOR]

Prior to its successful flights on Mars, the Ingenuity Mars Helicopter system underwent extensive flight dynamics testing in the 25-ft Space Simulator facility, a low pressure environmental chamber at NASA's Jet Propulsion Laboratory (JPL), which can re-create relevant Martian conditions on Earth. This facility, while large, is not large enough for free or tethered forward flight tests. In this work, an open-jet, multi-fan wind tunnel concept is presented, which was integrated into the JPL facility to simulate the external freestream flow of forward flight scenarios in a low-density environment. A theoretical and experimental analysis was performed to evaluate the possibility of utilizing commercially available 80 x 80 mm axial flow cooling fan units for this type of wind tunnel. Sub-scale tests found that under Martian conditions, fans deliver approximately 30% reduced flow rates for the same RPM compared to Earth conditions due to decreased efficiencies at low Reynolds numbers. However, fans can run at higher RPM in low-density fluids, with the RPM increase being specific to the fan motor. While power consumption dropped by more than 90%, fans experienced higher thermal loads due to reduced heat convection. The study concludes that the investigated type of cooling fan can operate without modification in a low-density environment, offering a low-cost and easily adaptable wind tunnel solution. Informed by ambient flow field measurements on a comparable multi-fan wind tunnel, a low-density full-scale facility with 441 individually controlled fan units was constructed and used for aerodynamic testing of an engineering model of Ingenuity. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study is to determine whether patient age and procedure type are associated with duration of opioid use in pediatric patients undergoing ambulatory urologic procedures. Methods: We retrospectively reviewed pediatric patients who underwent outpatient urologic procedures from 2013 to 2017. At postoperative visits, parents reported the number of days their child took opioid pain medication. Factors associated with duration of opioid use were evaluated using negative binomial regression models. Results: 805 patients were included: 320 infants (39.8%), 430 children (53.4%), and 55 adolescents (6.8%). Overall mean length of opioid use was 1.7 (± 2.6) days. On average, infants used opioids for the shortest duration: 1.5 (± 2.3) days, followed by children: 1.7 (± 2.5) days, and adolescents: 3.1 (± 4.6) days. In adjusted models, adolescents used opioids for 85.2% longer (95% CI 13.1–161.8%; p < 0.001) than children and infants used opioids for 19.4% shorter duration (95% CI 0.4–34.7%; p = 0.05) than children. Each 1-year increase in age was associated with 6.1% increased duration of opioid use (95% CI 3.9–8.5%; p < 0.0001). Patients who underwent circumcision, hypospadias repair, and penile reconstruction took opioids for 75.9% (95% CI 42.6–117.1%; p < 0.001), 144.2% (95% CI 76.4–238.0%; p < 0.001), and 126.7% (95% CI 48.8–245.3%; p < 0.001) longer respectively than patients who underwent inguinal procedures. Conclusions: Increasing age, circumcision, hypospadias repair, and penile reconstruction are associated with increased duration of opioid use. [ABSTRACT FROM AUTHOR]

Purpose: To determine whether interim 3′-deoxy-3′-[18F]fluorothymidine (iFLT) PET/CT is a superior predictor of progression-free survival (PFS) compared with interim 18F-fluorodeoxyglucose (iFDG) PET/CT in patients with diffuse large B cell lymphoma (DLBCL) treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) or rituximab, etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (R-EPOCH). Methods: Ninety-two prospectively enrolled patients with DLBCL underwent both FLT-PET/CT and FDG-PET/CT 18–24 days after two cycles of R-CHOP/R-EPOCH. Deauville-criteria, PERCIST1.0, standardized uptake value (SUV), total lesion glycolysis (TLG), and metabolic tumor volume were used to interpret iFDG-PET/CT while dichotomous visual interpretation was used to interpret iFLT-PET/CT and the results were compared with the 3- and 5-year PFS. Results: iFLT-PET/CT was negative in 67 (73%) and positive in 25 (27%) patients. iFDG-PET/CT by Deauville criteria was negative (Deauville scores [DS] of 1–3) in 53 (58%) and positive (DS = 4–5) in 39 (42%) patients. Of the 67 iFLT-PET/CT-negative patients, 7 (10.4%) progressed at a median of 14.1 months whereas 14/25 (56.0%) iFLT-PET/CT-positive patients progressed at a median of 7.8 months (P <.0001). Of the 53 Deauville-negative patients, 9 (17.0%) progressed at a median of 14.1 months whereas 12/39 (30.8%) Deauville-positive patients progressed at a median of 5.6 months (P =.11). In multivariate analysis, including iFLT-PET/CT, PERCIST, interim TLG, and interim SUVmax, only iFLT-PET/CT was an independent predictor for 3- and 5-year PFS (P <.0001 and P =.001, respectively). Conclusions: In patients with DLBCL given R-CHOP/R-EPOCH, iFLT-PET/CT is a superior independent predictor of outcome compared with iFDG-PET/CT. [ABSTRACT FROM AUTHOR]

Cystic fibrosis (CF) is a multi-system disease that is characterized by lung disease due to recurrent airway infection and inflammation. Endocrine complications, such as CF bone disease (CFBD), are increasingly identified as patients are living longer. The cause of CFBD is multifactorial with chronic systemic inflammation theorized to be a contributing factor. Thus, we attempted to identify inflammatory biomarkers that are associated with CFBD. We conducted a retrospective observational study of 56 adult patients with CF with an average percentage predictive forced expiratory volume in one second (ppFEV1) of 73.7% (standard deviation: 30.0) who underwent baseline serum analysis for osteoprotegerin (OPG) and pro-inflammatory biomarkers (IL-1β, IL-6, IL-8 and TNF-α), and had repeated dual-energy x-ray absorptiometry (DXA) scans separated by at least 2 years to examine correlations between serum biomarkers and bone mineral density (BMD) measurements. Univariate linear regression model analysis demonstrated that serum IL-1β and IL-8, but not other pro-inflammatory markers, were negatively correlated with baseline BMD results. However, after accounting for confounding variables, only the relationship between IL-8 and left femoral neck BMD remained statistically significant. Additionally, IL-8 level was associated with BMD decline over time. These results suggest that IL-8 might play a unique role in the pathophysiology of CFBD relative to other pro-inflammatory cytokines but further study is warranted before firm conclusions can be made. [ABSTRACT FROM AUTHOR]

Cell therapy limits ischemic injury following myocardial infarction (MI) by preventing cell death, modulating the immune response, and promoting tissue regeneration. The therapeutic efficacy of cardiosphere-derived cells (CDCs) and mesenchymal stem cells (MSCs) is associated with extracellular vesicle (EV) release. Prior head-to-head comparisons have shown CDCs to be more effective than MSCs in MI models. Despite differences in cell origin, it is unclear why EVs from different adult stem cell populations elicit differences in therapeutic efficacy. Here, we compare EVs derived from multiple human MSC and CDC donors using diverse in vitro and in vivo assays. EV membrane protein and non-coding RNA composition are highly specific to the parent cell type; for example, miR-10b is enriched in MSC-EVs relative to CDC-EVs, while Y RNA fragments follow the opposite pattern. CDC-EVs enhance the Arg1/Nos2 ratio in macrophages in vitro and reduce MI size more than MSC-EVs and suppress inflammation during acute peritonitis in vivo. Thus, CDC-EVs are distinct from MSC-EVs, confer immunomodulation, and protect the host against ischemic myocardial injury and acute inflammation. [ABSTRACT FROM AUTHOR]

To simulate the airflow through a wind farm across a wide range of atmospheric conditions, microscale models (e.g., large-eddy simulation, LES, models) have to be coupled with mesoscale models, because microscale models lack the atmospheric physical processes to represent time-varying local forcing. Here we couple mesoscale model outputs to a LES solver by applying mesoscale momentum- and temperature-budget components from the Weather Research and Forecasting model to the governing equations of the Simulator fOr Wind Farm Applications model. We test whether averaging the budget components affects the LES results with regard to quantities of interest to wind energy. Our study focuses on flat terrain during a quiescent diurnal cycle. The simulation results are compared with observations from a 200-m tall meteorological tower and a wind-profiling radar, by analyzing time series, profiles, rotor-averaged quantities, and spectra. While results show that averaging reduces the spatio-temporal variability of the mesoscale momentum-budget components, when coupled with the LES model, the mesoscale bias (in comparison with observations of wind speed and direction, and potential temperature) is not reduced. In contrast, the LES technique can correct for shear and veer. In both cases, however, averaging the budget components shows no significant impact on the mean flow quantities in the microscale and is not necessary when coupling mesocale budget components to the LES model. [ABSTRACT FROM AUTHOR]

Gene regulatory elements are central drivers of phenotypic variation and thus of critical importance towards understanding the genetics of complex traits. The Functional Annotation of Animal Genomes consortium was formed to collaboratively annotate the functional elements in animal genomes, starting with domesticated animals. Here we present an expansive collection of datasets from eight diverse tissues in three important agricultural species: chicken (Gallus gallus), pig (Sus scrofa), and cattle (Bos taurus). Comparative analysis of these datasets and those from the human and mouse Encyclopedia of DNA Elements projects reveal that a core set of regulatory elements are functionally conserved independent of divergence between species, and that tissue-specific transcription factor occupancy at regulatory elements and their predicted target genes are also conserved. These datasets represent a unique opportunity for the emerging field of comparative epigenomics, as well as the agricultural research community, including species that are globally important food resources. In order to interpret non-coding variants, information about regulatory elements in the genome is essential. Here, the authors annotate regulatory elements in chicken, pig and cattle, and characterize conservation of these elements between species. [ABSTRACT FROM AUTHOR]

Through the efforts of many groups, a wide range of fluorescent protein reporters and sensors based on green fluorescent protein and its relatives have been engineered in recent years. Here we explore the incorporation of sensing modalities into de novo designed fluorescence-activating proteins, called mini-fluorescence-activating proteins (mFAPs), that bind and stabilize the fluorescent cis-planar state of the fluorogenic compound DFHBI. We show through further design that the fluorescence intensity and specificity of mFAPs for different chromophores can be tuned, and the fluorescence made sensitive to pH and Ca2+ for real-time fluorescence reporting. Bipartite split mFAPs enable real-time monitoring of protein–protein association and (unlike widely used split GFP reporter systems) are fully reversible, allowing direct readout of association and dissociation events. The relative ease with which sensing modalities can be incorporated and advantages in smaller size and photostability make de novo designed fluorescence-activating proteins attractive candidates for optical sensor engineering. Fluorescent protein reporters based on GFP exist, but have intrinsic disadvantages. Here the authors incorporate pH, Ca2+ and protein–protein interaction sensing modalities into de novo designed mini-fluorescence-activating proteins (mFAPs), with increased photostability and smaller size, which bind a range of DFHBI chromophore variants. [ABSTRACT FROM AUTHOR]

Mesoscale-to-microscale coupling (MMC) aims to address the limited scope of traditional large-eddy simulations by driving the microscale flow with information concerning large-scale weather patterns provided by mesoscale models. We present a new offline MMC technique for horizontally homogeneous microscale flow conditions, in which internal forcing terms are computed based on mesoscale time–height profiles of mean-flow quantities. The advantage of such an approach is that it can be used to drive a microscale simulation with either mesoscale or observational data, and that it does not rely on specific terms in the mesoscale budget equations, which are typically not part of the default output of a mesoscale solver. The performance of the proposed profile assimilation technique is assessed based on the simulation of a typical diurnal cycle over the Scaled Wind Farm Technology site in west Texas. Results indicate that simple data assimilation techniques lead to unphysically high levels of shear and turbulence caused by the algorithm's inability to cope with inaccuracies in the mesoscale time–height profiles. Modifying the algorithm to account for vertical coherence in the mesoscale source terms gives the microscale solver a greater ability to correct the provided mesoscale time–height profiles, leading to improved predictions of shear and turbulence statistics. The resulting turbulence statistics are in good agreement with meteorological tower observations and simulation results obtained with state-of-the-art coupling techniques using mesoscale budget components. [ABSTRACT FROM AUTHOR]

Vascular complications in pregnancy (e.g. preeclampsia) are a major source of maternal and foetal morbidity and mortality, and may be due to excessive release of placental syncytiotrophoblast-derived extracellular vesicles (STBEVs) into the maternal circulation. Increased activity of the multi-ligand scavenger receptor Lectin-like Oxidized LDL Receptor-1 (LOX-1) is associated with vascular dysfunction, and LOX-1 has been shown to interact with angiotensin II receptor type 1 (AT1). We hypothesized that STBEVs contribute to vascular dysfunction via LOX-1 and AT1 receptors during pregnancy. Uterine arteries from late pregnant wildtype and LOX-1 overexpressing mice were incubated overnight with or without STBEVs and vascular function was assessed using wire myography. STBEV-incubation decreased angiotensin II responsiveness only in wildtype mice, which coincided with decreased AT1 contribution and expression. Thus, STBEVs reduced angiotensin II responsiveness in normal pregnancy, but not in conditions of increased LOX-1 expression, suggesting that STBEVs (via LOX-1) play a role in normal adaptations to pregnancy. Oxidized LDL (a LOX-1 ligand) increased angiotensin II-induced vasoconstriction in STBEV-incubated arteries from both mouse strains, suggesting that the LOX-1 pathway may be involved in complicated pregnancies with elevated STBEVs and oxidized LDL levels (such as preeclampsia). These data increase our understanding of vascular complications during pregnancy. [ABSTRACT FROM AUTHOR]

Epilepsy self-management practices enhance a patient's competence and confidence in managing their chronic condition, which is assumed to lead to an improved quality of life (QoL). We analyzed the relationship between the Epilepsy Self-Management Scale (ESMS) responses and the Quality of Life in Epilepsy (QOLIE-31) scores. Baseline questionnaires from HOBSCOTCH, a self-management program for cognitive problems, were administered in four New England epilepsy centers on adults (n = 100) with epilepsy and subjective memory complaints. There was no correlation between overall self-management scores and overall quality-of-life scores; however, subscale analyses indicated that certain self-management practices were strongly correlated with the overall QOLIE-31 score. Specifically, improved ESMS lifestyle management was associated with an increased quality-of-life score (adjusted p < 0.01), while enhanced ESMS safety management practices were associated with a decreased overall quality-of-life score (adjusted p < 0.01). Our item-level analysis highlighted specific items within the ESMS safety management, ESMS lifestyle management, and ESMS information management subdomains that were significant predictors for QoL. Depression was also shown to be significantly correlated with the QOLIE-31 (p < 0.01). Our study suggests that an overemphasis on safety practices may negatively affect quality of life, while enhanced lifestyle management has positive effects. Furthermore, our finding that quality of life is greatly dependent on depressive symptoms underscores the importance of treating depression in epilepsy. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate whether the extent of restricted diffusion and 2-deoxy-2-[18F] fluoro-D-glucose ([18F]FDG) uptake of pediatric rhabdomyosarcomas (RMS) on positron emission tomography (PET)/magnetic resonance (MR) images provides prognostic information.Procedure: In a retrospective, IRB-approved study, we evaluated [18F]FDG PET/CT and diffusion-weighted (DW) MR imaging studies of 21 children and adolescents (age 1-20 years) with RMS of the head and neck. [18F]FDG PET and DW MR scans at the time of the initial tumor diagnosis were fused using MIM software. Quantitative measures of the tumor mass with restricted diffusion, [18F]FDG hypermetabolism, or both were dichotomized at the median and tested for significance using Gray's test. Data were analyzed using a survival analysis and competing risk model with death as the competing risk.Results: [18F]FDG PET/MR images demonstrated a mismatch between tumor areas with increased [18F]FDG uptake and restricted diffusion. The DWI, PET, and DWI + PET tumor volumes were dichotomized at their median values, 23.7, 16.4, and 9.5 cm3, respectively, and were used to estimate survival. DWI, PET, and DWI + PET overlap tumor volumes above the cutoff values were associated with tumor recurrence, regardless of post therapy COG stage (p = 0.007, p = 0.04, and p = 0.07, respectively).Conclusion: The extent of restricted diffusion within RMS and overlap of hypermetabolism plus restricted diffusion predict unfavorable clinical outcomes. [ABSTRACT FROM AUTHOR]

Herbivory is poorly characterized in the endangered California sage scrub ecosystem, because previous studies were conducted only in winter and spring. To better understand vertebrate herbivore impacts, we first examined if and when vertebrate herbivores influence Artemisia californica seedling survivorship by examining differences in mortality between caged and uncaged seedlings. Then, we examined: (1) vertebrate herbivore preference of common sage scrub shrub species, and (2) which vertebrate species constitute important herbivores in the ecosystem. We found that mortality for uncaged A. californica seedlings was twice that of caged seedlings, and occurred in the summer and early fall, when previous studies in the system were not conducted. Short leaved shrubs, Artemisia californica and Eriogonum fasciculatum, were more susceptible to herbivory than broader leaved Salvia apiana and Eriodictyon trichocalyx. However, susceptibility likely depends on the herbivore assemblage, as the three main herbivore species [Sylvilagus audubonii (desert cottontail), Zonotrichia leucophrys (white-crowned sparrow; a bird, not a mammal), and Otospermophilus beecheyi (California gray squirrel)] all had different shrub preferences. Our results contrast with previous studies that suggests that native vertebrate herbivores facilitate shrub seedling survivorship by highlighting that late-season vertebrate herbivory may negatively affect shrub seedling survivorship. We demonstrate the complex but understudied role herbivores play in the sage scrub ecosystem, and highlight that further study of these key ecological interactions is warranted. [ABSTRACT FROM AUTHOR]

The site-directed spin labeling (SDSL) technique was used to examine the antifreeze mechanisms of type-I antifreeze proteins (AFPs). The effects on the growth of seed ice crystals by the spin-label groups attached to different side chains of the AFPs were observed, and the states of water molecules surrounding the spin-label groups were probed via analyses of variable-temperature (VT) dependent electron paramagnetic resonance (EPR) spectra. The first set of experiments revealed the antifreeze activities of the spin-labeled AFPs at the microscopic level, while the second set of experiments displayed those at the molecular level. The experimental results confirmed the putative ice-binding surface (IBS) of type-I AFPs. The VT EPR spectra indicate that type-I AFPs can inhibit the nucleation of seed ice crystals down to ~ − 20 °C in their aqueous solutions. Thus, the present authors believe that AFPs protect organisms from freezing damage in two ways: (1) inhibiting the nucleation of seed ice crystals, and (2) hindering the growth of seed ice crystals once they have formed. The first mechanism should play a more significant role in protecting against freezing damage among organisms living in cold environments. The VT EPR spectra also revealed that liquid-like water molecules existed around the spin-labeled non-ice-binding side chains of the AFPs frozen within the ice matrices, and ice surrounding the spin-label groups melted at subzero temperatures during the heating process. This manuscript concludes with the proposed model of antifreeze mechanisms of AFPs based on the experimental results. [ABSTRACT FROM AUTHOR]

Purpose: To provide clinically useful gadolinium-free whole-body cancer staging of children and young adults with integrated positron emission tomography/magnetic resonance (PET/MR) imaging in less than 1 h.Procedures: In this prospective clinical trial, 20 children and young adults (11-30 years old, 6 male, 14 female) with solid tumors underwent 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) PET/MR on a 3T PET/MR scanner after intravenous injection of ferumoxytol (5 mg Fe/kg) and [18F]FDG (2-3 MBq/kg). Time needed for patient preparation, PET/MR image acquisition, and data processing was compared before (n = 5) and after (n = 15) time-saving interventions, using a Wilcoxon test. The ferumoxytol-enhanced PET/MR images were compared with clinical standard staging tests regarding radiation exposure and tumor staging results, using Fisher's exact tests.Results: Tailored workflows significantly reduced scan times from 36 to 24 min for head to mid thigh scans (p < 0.001). These streamlined PET/MR scans were obtained with significantly reduced radiation exposure (mean 3.4 mSv) compared to PET/CT with diagnostic CT (mean 13.1 mSv; p = 0.003). Using the iron supplement ferumoxytol "off label" as an MR contrast agent avoided gadolinium chelate administration. The ferumoxytol-enhanced PET/MR scans provided equal or superior tumor staging results compared to clinical standard tests in 17 out of 20 patients. Compared to PET/CT, PET/MR had comparable detection rates for pulmonary nodules with diameters of equal or greater than 5 mm (94 vs. 100 %), yet detected significantly fewer nodules with diameters of less than 5 mm (20 vs 100 %) (p = 0.03). [18F]FDG-avid nodules were detected with slightly higher sensitivity on the PET of the PET/MR compared to the PET of the PET/CT (59 vs 49 %).Conclusion: Our streamlined ferumoxytol-enhanced PET/MR protocol provided cancer staging of children and young adults in less than 1 h with equivalent or superior clinical information compared to clinical standard staging tests. The detection of small pulmonary nodules with PET/MR needs to be improved. [ABSTRACT FROM AUTHOR]

Dysphagia following treatment for head and neck cancer is one of the most significant morbidities impacting quality of life. Despite the value of prophylactic exercises to mitigate the impact of radiation on long-term swallowing function, adherence to treatment is limited. The purpose of this investigation was to explore the feasibility of a mobile health application to support patient adherence to swallowing therapy during radiation-based treatment. 36 patients undergoing radiation therapy were provided with the Vibrent™ mobile application as an adjunct to standard swallowing therapy. The application included exercise videos, written instructions, reminders, exercise logging, and educational content. 80% of participants used the app during treatment and logged an average of 102 exercise sessions over the course of treatment. 25% of participants logged at least two exercise sessions per day over the 7-week treatment period, and 53% recorded at least one session per day. Exit interviews regarding the patient experience with the Vibrent™ mobile application were largely positive, but also provided actionable strategies to improve future versions of the application. The Vibrent™ mobile application appears to be a tool that can be feasibly integrated into existing patient care practices and may assist patients in adhering to treatment recommendations and facilitate communication between patients and providers between encounters. [ABSTRACT FROM AUTHOR]

The purpose of this study was twofold: (1) to determine the incidence of positive computed tomography (CT) findings in patients presenting to the emergency department (ED) with non-traumatic headache at our institution and (2) to examine follow-up exams, including lumbar puncture, non-enhanced CT, CT angiogram, CT venogram, and magnetic resonance imaging (MRI), to see how often the use of further testing changes the diagnosis. With IRB approval, 865 patients were identified through ED requisitions for CT head with the indication of headache during the calendar year 2011. Exclusion criteria included head trauma, prior intracranial surgery, focal neurologic symptoms, and known intracranial mass. CT results were divided into three categories: P0, P1, and P2. Negative studies were graded as P0. Positive studies were subdivided into clinically insignificant or P1 and clinically significant or P2. Clinically significant was defined as requiring medical treatment. Subsequently, the electronic medical records and picture archiving and communication system (PACS) were reviewed to determine the incidence of follow-up exams, including lumbar puncture or imaging. The secondary tests were divided into the same P0, P1, and P2 categories. There were 254 positive studies: P1 clinically insignificant (27.1 %, 235/865) and P2 clinically significant (2.2 %, 19/865). Of 257 follow-up exams performed, the majority were lumbar punctures (36.0 %) or CT angiograms (29.5 %). In 19/257 exams or 7.4 %, the additional testing changed the clinically insignificant (P0/P1) diagnosis to a significant (P2) result. At our institution, there was a 2.2 % incidence of significant positive CT findings in patients presenting to the ED with non-traumatic headache. Follow-up testing was variable and resulted in a 7.4 % increase in the severity of diagnosis compared to the initial negative CT scan. [ABSTRACT FROM AUTHOR]

Objective: To describe the role of magnetic resonance enterography (MRE) in patients with inflammatory bowel disease (IBD), and to review the expected post-operative appearance, as well as, potential surgical complications in this unique patient population. Conclusion: MRE compares favorably to CT Enterography (CTE) in terms of overall diagnostic accuracy and may provide better functional assessment of the small bowel through cine-MRI, diffusion-weighted imaging and dynamic contrast-enhancement. In the post-operative population, MRE provides critical information including: normal post-surgical anatomy, chronic strictures vs. active inflammation and disease/treatment-related complications. The post-operative IBD patient undergoes frequent repeated imaging and MRE may significantly reduce cumulative radiation dose while providing similar or improved diagnostic accuracy compared to CTE. MRE should be considered as an alternative imaging modality in this population. [ABSTRACT FROM AUTHOR]

Recent investigations by our study team have demonstrated patients using gabapentin for pain management during chemoradiotherapy (CRT) do well maintaining swallowing during treatment with less need for narcotic pain medication, PEG dependence, weight loss, and short-term swallowing morbidity. The purpose of this investigation was to characterize the long-term swallowing function of these patients 1-year following treatment. Sequential patients receiving CRT for oropharyngeal cancer and concurrent gabapentin were evaluated 1-year following treatment for swallowing outcomes. Functional Oral Intake Scores (FOIS) were utilized to assess diet level. The MD Anderson Dysphagia Inventory (MDADI) was chosen to evaluate patient perception of swallowing function. Videofluoroscopic swallowing studies were completed approximately 1 year after treatment to assess physiologic outcomes as well as Penetration Aspiration Scores (PAS). Data from 26 consecutive participants were available for analysis. The majority of patients had advanced stage disease (Stage 3-4). No patients had a PEG tube 1-year following treatment, and the mean FOIS score was 6.83. Pharyngeal deficits were infrequent with reduced pharyngeal constriction and prominence/early closure of cricopharyngeus predominating. Mean PAS score was 1.5, indicating that the majority of patients had either no laryngeal penetration/aspiration, or transient penetration that was fully cleared. Mean MDADI score was 85.52, indicating that, in general, patients perceived their swallowing to be minimally impaired. Patients receiving gabapentin pain management as part of a comprehensive dysphagia prevention protocol during CRT have excellent long-term swallowing outcomes as reflected in diet levels, physiologic functioning, and patient-perceived quality of life. [ABSTRACT FROM AUTHOR]

Objective: Combining 18F-FDG PET with whole-body MR for paediatric cancer staging is practically feasible if imaging protocols can be streamlined. We compared 18F-FDG PET/STIR with accelerated 18F-FDG PET/FSPGR for whole-body tumour imaging in children and young adults.Methods: Thirty-three children and young adults (17.5 ± 5.5 years, range 10-30) with malignant lymphoma or sarcoma underwent a 18F-FDG PET staging examination, followed by ferumoxytol-enhanced STIR and FSPGR whole-body MR. 18F-FDG PET scans were fused with MR data and the number and location of tumours on each integrated examination were determined. Histopathology and follow-up imaging served as standard of reference. The agreement of each MR sequence with the reference and whole-body imaging times were compared using Cohen's kappa coefficient and Student's t-test, respectively.Results: Comparing 18F-FDG PET/FSPGR to 18F-FDG PET/STIR, sensitivities were 99.3 % for both, specificities were statistically equivalent, 99.8 versus 99.9 %, and the agreement with the reference based on Cohen's kappa coefficient was also statistically equivalent, 0.989 versus 0.992. However, the total scan-time for accelerated FSPGR of 19.8 ± 5.3 minutes was significantly shorter compared to 29.0 ± 7.6 minutes for STIR (p = 0.001).Conclusion: F-FDG PET/FSPGR demonstrated equivalent sensitivities and specificities for cancer staging compared to 18F-FDG PET/STIR, but could be acquired with shorter acquisition time.Key Points: • Breath-hold FSPGR sequences shorten the data acquisition time for whole-body MR and PET/MR. • Ferumoxytol provides long-lasting vascular contrast for whole-body MR and PET/MR. • 18 F-FDG PET/FSPGR data provided equal sensitivity and specificity for cancer staging compared to 18 F-FDG PET/STIR. [ABSTRACT FROM AUTHOR]

The prophylactic placement of a percutaneous endoscopic gastrostomy (PEG) tube in the head and neck cancer (HNC) patient is controversial. We sought to identify factors associated with prophylactic PEG placement and actual PEG use. Since 2010, data regarding PEG placement and use were prospectively recorded in a departmental database from January 2010 to December 2012. HNC patients treated with intensity-modulated radiation therapy (IMRT) were retrospectively evaluated from 2010 to 2012. Variables potentially associated with patient post-radiation dysphagia from previous literature, and our experience was evaluated. We performed multivariate logistic regression on these variables with PEG placement and PEG use, respectively, to compare the difference of association between the two arms. We identified 192 HNC patients treated with IMRT. Prophylactic PEG placement occurred in 121 (63.0 %) patients, with PEG use in 97 (80.2 %) patients. PEG placement was associated with male gender (p < .01), N stage ≥ N2 (p < .05), pretreatment swallowing difficulties (p < .01), concurrent chemotherapy (p < .01), pretreatment KPS ≥80 (p = .01), and previous surgery (p = .02). Concurrent chemotherapy (p = .03) was positively associated with the use of PEG feeding by the patient, whereas pretreatment KPS ≥80 (p = .03) and prophylactic gabapentin use (p < .01) were negatively associated with PEG use. The analysis suggests there were discrepancies between prophylactic PEG tube placement and actual use. Favorable pretreatment KPS, no pretreatment dysphagia, no concurrent chemotherapy, and the use of gabapentin were significantly associated with reduced PEG use. This analysis may help refine the indications for prophylactic PEG placement. [ABSTRACT FROM AUTHOR]

Radiation oncologists have focused on the pharyngeal constrictors as the primary muscles of concern for dysphagia. However, our prior investigations have demonstrated that radiation dose to the geniohyoid rather than the constrictor muscles was more closely related to penetration aspiration scores (PAS). We examined the relationship between (1) radiation dose and swallowing temporal kinematics, and (2) between PAS and swallowing kinematics in these patients. Videofluoroscopic swallowing studies of 41 patients following radiation therapy for oropharyngeal cancer were analyzed for thin liquid boluses. Timing measures included duration of laryngeal vestibule closure (DLVC), duration to maximum hyoid elevation (DTMHE), duration to cricopharyngeal opening (DTCPO), and pharyngeal transit time (PTT). PAS was extracted for each swallow and considered normal if ≤ 2. As minimum and mean dose to the geniohyoid increased, DTMHE, DTCPO, and PTT increased. Worse PA scores were most strongly correlated with radiation dose received by geniohyoid (r = 0.445, p < 0.0001). Mean DLVC varied according to PAS group (normal PAS mean = 0.67 s, abnormal PAS mean = 0.13 s; p < 0.001). Similarly, DTCPO was significantly different based upon PAS (normal PAS mean = 0.22 s, abnormal PAS mean = 0.37 s, p = 0.016). As PAS increased, DTPCO and PTT increased (r = 0.208, p = 0.04; r = 0.204, p = 0.043). A negative correlation was noted between PAS and DLVC (r = -0.375, p = 0.001). Higher doses of radiation to the geniohyoid muscles are associated with increased severity of dysphagia as measured through both kinematics and PAS. Consideration of dose to the geniohyoid should be considered when planning radiation. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a severe age-related neurodegenerative disorder characterized by accumulation of amyloid-β plaques and neurofibrillary tangles, synaptic and neuronal loss, and cognitive decline. Several genes have been implicated in AD, but chromatin state alterations during neurodegeneration remain uncharacterized. Here we profile transcriptional and chromatin state dynamics across early and late pathology in the hippocampus of an inducible mouse model of AD-like neurodegeneration. We find a coordinated downregulation of synaptic plasticity genes and regulatory regions, and upregulation of immune response genes and regulatory regions, which are targeted by factors that belong to the ETS family of transcriptional regulators, including PU.1. Human regions orthologous to increasing-level enhancers show immune-cell-specific enhancer signatures as well as immune cell expression quantitative trait loci, while decreasing-level enhancer orthologues show fetal-brain-specific enhancer activity. Notably, AD-associated genetic variants are specifically enriched in increasing-level enhancer orthologues, implicating immune processes in AD predisposition. Indeed, increasing enhancers overlap known AD loci lacking protein-altering variants, and implicate additional loci that do not reach genome-wide significance. Our results reveal new insights into the mechanisms of neurodegeneration and establish the mouse as a useful model for functional studies of AD regulatory regions. [ABSTRACT FROM AUTHOR]

The reference human genome sequence set the stage for studies of genetic variation and its association with human disease, but epigenomic studies lack a similar reference. To address this need, the NIH Roadmap Epigenomics Consortium generated the largest collection so far of human epigenomes for primary cells and tissues. Here we describe the integrative analysis of 111 reference human epigenomes generated as part of the programme, profiled for histone modification patterns, DNA accessibility, DNA methylation and RNA expression. We establish global maps of regulatory elements, define regulatory modules of coordinated activity, and their likely activators and repressors. We show that disease- and trait-associated genetic variants are enriched in tissue-specific epigenomic marks, revealing biologically relevant cell types for diverse human traits, and providing a resource for interpreting the molecular basis of human disease. Our results demonstrate the central role of epigenomic information for understanding gene regulation, cellular differentiation and human disease. [ABSTRACT FROM AUTHOR]

The protein binding of weakly acidic and basic drugs has been shown to be altered in cancer patients. Brequinar is a weakly acidic, low-clearance, and highly protein-bound (> 98% bound) antitumor agent. The pharmacokinetic parameters of brequinar are subject to large interpatient variability. This large interpatient variability may be related to brequinar's plasma protein-binding capacity (assuming no change in the intrinsic clearance of the unbound drug). The objectives of this study, therefore, were (a) to characterize brequinar's protein binding in the plasma of healthy donors and cancer patients and (b) to examine the relationships between brequinar's plasma protein binding and its pharmacokinetics in patients. Brequinar protein binding was determined in human serum albumin (HSA) solution, drug-free donor plasma, and brequinar-free, predose plasma samples obtained from a phase I cancer trial. Pharmacokinetic results from this study were used to examine relationships between plasma protein binding and drug disposition. In HSA solution and healthy donor plasma, brequinar's protein binding as determined using spiked samples was concentration-dependent. The unbound brequinar fraction increased by a factor of 3 (from 0.3% to 0.9% free) in 4% HSA solution and by a factor of 4 (from 0.4% to 1.6% free) in donor plasma as the brequinar concentrations increased from 0.1 to 2.3 mM in the HSA solution and from 0.076 to 1.5 mM in the donor plasma. Analysis of brequinar binding characteristics using the binding ratio and Rosenthal binding plots showed that albumin was the primary protein for brequinar binding in human plasma. The addition of various concentrations of alpha 1-acid glycoprotein to 4% HSA solution did not affect the protein binding of brequinar to HSA. The protein binding determined in the plasma of cancer patients was not quantitatively different, except for variability, from that observed in the plasma of healthy donors. Examination of relationships between the unbound brequinar fraction and pharmacokinetics suggested that plasma protein binding was not a major determinant of brequinar disposition in cancer patients. [ABSTRACT FROM AUTHOR]

The aim of this study was to examine the impact of gabapentin (neurontin) on swallowing and feeding tube use during chemoradiation (CRT) for oropharyngeal squamous cell carcinoma (OPSCC), and physiologic swallowing outcomes following completion of treatment. A total of 23 patients treated for OPSCC with concurrent CRT and prophylactically treated for pain using gabapentin were assessed. Historical controls were matched for T stage and primary site of disease. Timing of PEG use and removal were recorded. Video fluoroscopic swallowing studies were completed post-treatment to assess physiologic outcomes as well as penetration-aspiration scores (PAS). Functional oral intake scale (FOIS) scores were determined at the time of swallowing evaluation to assess diet level. Patients treated with gabapentin began using their PEG tubes later (3.7 vs. 2.29 weeks; P = 0.013) and had their PEG tubes removed earlier (7.29 vs. 32.56 weeks; P = 0.039) than the historical controls. A number of physiologic parameters were found to be less impacted in the gabapentin group, including oral bolus control ( P = 0.01), epiglottic tilt ( P = 0.0007), laryngeal elevation ( P = 0.0017), and pharyngeal constriction ( P = 0.002). PAS scores were significantly lower in the group treated with gabapentin (1.89 vs. 4; P = 0.0052). Patients receiving gabapentin had more advanced diet levels at the time of the initial swallowing study as evidenced by their FOIS scores (5.4 vs. 3.21; P = 0.0003). We conclude that patients using gabapentin for pain management during CRT appears to do well maintaining swallow function during treatment and have favorable post-treatment physiologic swallowing outcomes. Prospective evaluation is warranted. [ABSTRACT FROM AUTHOR]