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With the increasing availability of large-scale multimodal neuroimaging datasets, it is necessary to develop data fusion methods which can extract cross-modal features. A general framework, multidataset independent subspace analysis (MISA), has been developed to encompass multiple blind source separation approaches and identify linked cross-modal sources in multiple datasets. In this work we utilized the multimodal independent vector analysis model in MISA to directly identify meaningful linked features across three neuroimaging modalities — structural magnetic resonance imaging (MRI), resting state functional MRI and diffusion MRI — in two large independent datasets, one comprising of control subjects and the other including patients with schizophrenia. Results show several linked subject profiles (the sources/components) that capture age-associated decline, schizophrenia-related biomarkers, sex effects, and cognitive performance. For sources associated with age, both shared and modality-specific brain-age deltas were evaluated for association with non-imaging variables. In addition, each set of linked sources reveals a corresponding set of multi-tissue spatial patterns that can be studied jointly.

In order to determine, document, and communicate the value of respiratory therapists performing respiratory care procedures, the respiratory care profession needs to position itself to capture and report both time and value standards that can be applied in allocating respiratory care resources. To do this, we propose a new metric called value-efficiency. If we wish to use value-efficiency as a metric to justify respiratory care activities and support labor budgets, there are three key considerations: (1) What value does respiratory care add to the health care organization? (2) Are the interventions provided necessary and of clinical value? (3) What is the value of the respiratory therapist in the delivery of these services? Significant challenges are facing the respiratory care profession and a focus on value-efficiency is a direction the profession must pursue. This approach is a practical response to the increasing demands of payers, administrators, consultants, and patients.

The gut bacterial community is involved in the metabolism of bile acids and short-chain fatty acids (SCFAs). Bile acids are involved in the absorption of fat and the regulation of lipid homeostasis through emulsification and are transformed into unconjugated bile acids by the gut microbiota. The gut microbiota is actively involved in the production of bile acid metabolites, such as deoxycholic acid, lithocholic acid, choline, and SCFAs such as acetate, butyrate, and propionate. Metabolites derived from the gut microbiota or modified gut microbiota metabolites contribute significantly to host pathophysiology. Gut bacterial metabolites, such as deoxycholic acid, contribute to the development of hepatocellular carcinoma and colon cancer by factors such as inflammation and oxidative DNA damage. Butyrate, which is derived from gut bacteria such as Megasphaera, Roseburia, Faecalibacterium, and Clostridium, is associated with the activation of Treg cell differentiation in the intestine through histone acetylation. Butyrate averts the action of class I histone deacetylases (HDAC), such as HDAC1 and HDAC3, which are responsible for the transcription of genes such as p21/Cip1, and cyclin D3 through hyperacetylation of histones, which orchestrates G1 cell cycle arrest. It is essential to identify the interaction between the gut microbiota and bile acid and SCFA metabolism to understand their role in gastrointestinal carcinogenesis including colon, gastric, and liver cancer. Metagenomic approaches with bioinformatic analyses are used to identify the bacterial species in the metabolism of bile acids and SCFAs. This review provides an overview of the current knowledge of gut microbiota-derived bile acid metabolism in tumor development and whether it can stand as a marker for carcinogenesis. Additionally, this review assesses the evidence of gut microbiota-derived short-chain fatty acids including butyric acid in antitumor activity. Future research is required to identify the beneficial commensal gut bacteria and their metabolites which will be considered to be therapeutic targets in inflammation-mediated gastrointestinal cancers.

Background In search of innovative approaches to the challenge of uncontrolled hypertension, we assessed the association between preference for immediate gratification (i.e., high discounting rate), low medication adherence, and uncontrolled blood pressure (BP) in adults with hypertension. Methods Using a probability discounting model and the Collier–Williams hypothetical discount rate framework, participants in this cross-sectional study reported their preference for a smaller amount of money available immediately (high discount rate; immediate gratification preference) vs. a larger amount available 1 year later (low discount rate; delayed gratification preference). Multivariable Poisson regression was used to test the association of high discounting rates with low antihypertensive medication adherence using the validated 4-item Krousel-Wood Medication Adherence Scale (K-Wood-MAS-4 score ≥1). Mediation of the association between high discounting rate and uncontrolled BP (systolic/diastolic BP ≥ 130/80 mm Hg) by low adherence was tested using the counterfactual approach. Results Among 235 participants (mean age 63.7 ± 6.7 years; 51.1% women; 41.9% Black), 50.6% had a high 1-year discount rate, 51.9% had low K-Wood-MAS-4 adherence, and 59.6% had uncontrolled BP. High discounting rates were associated with low adherence (adjusted prevalence ratio 1.58, 95% confidence interval (CI) 1.18, 2.12). Forty-three percent (95% CI 40.9%, 45.8%) of the total effect of high discount rate on uncontrolled BP was mediated by low adherence. Conclusions Adults with preference for immediate gratification had worse adherence; low adherence partially mediated the association of high discount rate with uncontrolled BP. These results support preference for immediate gratification as an innovative factor underlying low medication adherence and uncontrolled BP.

Deep learning techniques have been applied to electroencephalogram (EEG) signals, with promising applications in the field of psychiatry. Schizophrenia is one of the most disabling neuropsychiatric disorders, often characterized by the presence of auditory hallucinations. Auditory processing impairments have been studied using EEG-derived event-related potentials and have been associated with clinical symptoms and cognitive dysfunction in schizophrenia. Due to consistent changes in the amplitude of ERP components, such as the auditory N100, some have been proposed as biomarkers of schizophrenia. In this paper, we examine altered patterns in electrical brain activity during auditory processing and their potential to discriminate schizophrenia and healthy subjects. Using deep convolutional neural networks, we propose an architecture to perform the classification based on multi-channels auditory-related EEG single-trials, recorded during a passive listening task. We analyzed the effect of the number of electrodes used, as well as the laterality and distribution of the electrical activity over the scalp. Results show that the proposed model is able to classify schizophrenia and healthy subjects with an average accuracy of 78% using only 5 midline channels (Fz, FCz, Cz, CPz, and Pz). The present study shows the potential of deep learning methods in the study of impaired auditory processing in schizophrenia with implications for diagnosis. The proposed design can provide a base model for future developments in schizophrenia research.

BackgroundWhile functional connectivity is widely studied, there has been little work studying functional connectivity at different spatial scales. Likewise, the relationship of functional connectivity between spatial scales is unknown.MethodsWe proposed an independent component analysis (ICA) - based approach to capture information at multiple model orders (component numbers) and to evaluate functional network connectivity (FNC) both within and between model orders. We evaluated the approach by studying group differences in the context of a study of resting fMRI (rsfMRI) data collected from schizophrenia (SZ) individuals and healthy controls (HC). The predictive ability of FNC at multiple spatial scales was assessed using support vector machine (SVM)-based classification.ResultsIn addition to consistent predictive patterns at both multiple-model orders and single model orders, unique predictive information was seen at multiple-model orders and in the interaction between model orders. We observed that the FNC between model order 25 and 50 maintained the highest predictive information between HC and SZ. Results highlighted the predictive ability of the somatomotor and visual domains both within and between model orders compared to other functional domains. Also, subcortical-somatomotor, temporal-somatomotor, and temporal-subcortical FNCs had relatively high weights in predicting SZ.ConclusionsIn sum, multi-model order ICA provides a more comprehensive way to study FNC, produces meaningful and interesting results which are applicable to future studies. We shared the spatial templates from this work at different model orders to provide a reference for the community, which can be leveraged in regression-based or fully automated (spatially constrained) ICA approaches.Impact StatementMulti-model order ICA provides a comprehensive way to study brain functional network connectivity within and between multiple spatial scales, highlighting findings that would have been ignored in single model order analysis. This work expands upon and adds to the relatively new literature on resting fMRI-based classification and prediction. Results highlighted the differentiating power of specific intrinsic connectivity networks on classifying brain disorders of schizophrenia patients and healthy participants, at different spatial scales. The spatial templates from this work provide a reference for the community, which can be leveraged in regression-based or fully automated ICA approaches.

Plastic pollution is a global environmental and human health issue, with plastics now ubiquitous in the environment and biota. Despite extensive international research, key knowledge gaps ("known unknowns") remain around ecosystem-scale and human health impacts of plastics in the environment, particularly in limnetic, coastal and marine systems. Here we review aquatic plastics research in three contrasting geographic and cultural settings, selected to present a gradient of heavily urbanised (and high population density) to less urbanised (and low population density) areas: China, the United Kingdom (UK), and Australia. Research from each country has varying environmental focus (for example, biota-focussed studies in Australia target various bird, fish, turtle and seal species, while UK and China-based studies focus on commercially important organisms such as bivalves, fish and decapods), and uses varying methods and reporting units (e.g. mean, median or range). This has resulted in aquatic plastics datasets that are hard to compare directly, supporting the need to converge on standardised sampling methods, and bioindicator species. While all the study nations show plastics contamination, often at high levels, datasets are variable and do not clearly demonstrate pollution gradients.

Hazardous, heavy drinking increases risk for developing alcohol use disorder (AUD), which affects ~ 7% of adult Americans. Thus understanding the molecular mechanisms promoting risk for heavy drinking is essential to developing more effective AUD pharmacotherapies than those currently approved by the FDA. Using genome-wide bisulfate sequencing, we identified DNA methylation (DNAm) signals within the nucleus accumbens core (NAcC) that differentiate non-heavy and heavy ethanol drinking rhesus macaques. One differentially DNAm region (D-DMR) located within the gene neurobeachin (NBEA), which promotes synaptic membrane protein trafficking, was hypermethylated in heavy drinking macaques. A parallel study identified a similar NBEA D-DMR in human NAcC that distinguished alcoholic and non-alcoholic individuals. To investigate the role of NBEA in heavy ethanol drinking, we engineered a viral vector carrying a short hairpin RNA (shRNA) to reduce the expression of NBEA. Using two murine models of ethanol consumption: four-days of drinking-in-the-dark and four-weeks of chronic intermittent access, the knockdown of NBEA expression did not alter average ethanol consumption in either model. However it did lead to a significant increase in the ethanol preference ratio. Following withdrawal, whole-cell patch clamp electrophysiological experiments revealed that Nbea knockdown led to an increase in spontaneous excitatory postsynaptic current amplitude with no alteration in spontaneous inhibitory postsynaptic currents, suggesting a specific role of NBEA in trafficking of glutamatergic receptors. Together, our findings suggest that NBEA could be targeted to modulate the preference for alcohol use.

Background: Talazoparib, a PARP1 inhibitor, is active in germline BRCA1/2 mutant advanced HER2-negative breast cancer, but its activity beyond BRCA1/2 less well understood. The Talazoparib Beyond BRCA clinical trial treated 20 patients with germline (g) or somatic (s) mutations in HR pathways genes other than BRCA1/2, which included PALB2, CHEK2, ATM, BRIP1, RAD50, ATR, PTEN, and FANCA. Talazoparib treatment was associated with a 31% overall response rate in patients with breast cancer, including tumor regression from baseline as best response in 6 out of 6 patients treated gPALB2 mutations. We now present the results of additional genomic studies to further characterize treatment responses and resistance mechanisms. Methods: Primary and metastatic tumor biopsies were assessed using the commercially-available next-generation sequencing HRD assay (Myriad). Panel gene sequencing of tumors was performed for 108 genes associated with genomic instability. Loss-of-heterozygosity (LOH) was assessed in tumors. Tumor/normal exome sequencing identified pre-treatment somatic variants. Circulating-tumor DNA at baseline and disease progression was assessed by targeted panel sequencing and plasma whole exome sequencing. Results: Of the 18 HRD assays performed, 3 failed and were thus excluded. Seven patients had HRD analysis performed on both primary and metastatic tumors. For these patients the HRD score was significantly higher in the metastasis versus the primary (means 46.2 versus 36.5, p = 0.018 by paired t-test). By panel sequencing of tumors (n=18) the most common alterations detected included mutations in PIK3CA (n=8), PALB2 (n=6), ATM (n=5), KRAS (n=4), PTEN (n=5) and TP53 (n=4). In all cases except one, the HR-associated mutation used as entry criteria were detected. LOH analysis showed that of tumors with gPALB2 mutations, 3 of the 6 had LOH for PALB2, and an additional two tumors had 2 independent PALB2 mutations suggesting bi-allelic inactivation. The one remaining tumor had an uncertain LOH result due to test failure. Thus, it is likely that most, if not all, of the tumors in our cohort with gPALB2 mutations had complete inactivation of PALB2 gene function. Other detected mutations that were associated with LOH included all sTP53 mutations (n=4), all gCHEK2 mutations (n=3), gFANCA (n=1), all sRB1 mutations (n=3) and NF1 (n=1). Of the three gATM mutations one had LOH, while the others had two independent mutations, suggestive of bi-allelic inactivation. sATM mutations were associated with LOH in a breast cancer and with 2 independent (possibly bi-allelic) mutations in a non-breast cancer. Additional results from ctDNA targeted sequencing and plasma whole exome sequencing of baseline and progression samples will be presented. Conclusions: In this proof-of-concept phase II study, talazoparib demonstrated activity in HER2-negative advanced breast cancer patients with a HR pathway mutation beyond BRCA1/2, especially in patients with gPALB2 mutations and high HRD scores. These additional genomic analyses provide evidence that HRD scores may be significantly higher in metastatic samples compared to primary tumors. Also, we detected either LOH or bi-allelic inactivation for most HR-associated mutations used to determine eligibility. These findings may inform selection of patients for PARP inhibitor monotherapy beyond BRCA1/2. Citation Format: Joshua J Gruber, Anosheh Afghahi, Alyssa Hatton, Wyatt Gross, Jessica Foran, Alex McMillan, James M Ford, Melinda L Telli. Genomic analysis from the talazoparib beyond BRCA clinical trial: Homologous recombination (HR) deficiency scores, loss-of-heterozygosity and mutations in non-BRCA1/2 mutant tumors with other HR mutations [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD10-12.

BRCA1 mutation carriers are predisposed to developing aggressive breast, ovarian, and other cancers at a relatively early age. Unfortunately, these cancers lack an effective chemoprevention option. We have found that cells containing mutant BRCA1 harbor defective repair of oxidative DNA damage, an early trigger to tumorigenesis. Therefore, we sought to target this defect and discover a novel chemoprevention agent for these cancers. High-throughput screening of a chemical library identified a novel class of small-molecules that enhance repair of oxidative DNA damage, which we termed DNA repair-activating agents. One of these agents, benserazide, increased base-excision repair of oxidative DNA damage utilizing a cell-based DNA repair assay, decreased levels of 8-oxo-g (i.e. most common oxidized lesion in human genome) using flow cytometric analysis, and decreased levels of oxidative DNA damage as determined by alkaline comet assay modified for detection of oxidized DNA lesions. These results were observed in mutant but not wild-type BRCA1 breast cancer cells. Benserazide, but not tamoxifen (current FDA-approved breast cancer chemoprevention agent), also decreased in vitro tumorigenesis of mutant BRCA1 or BRCA1-depleted breast cancer cells according to the soft-agar colony formation assay, and delayed tumor formation in vivo using a xenograft mouse model. Lastly, benserazide led to elevated levels of 8-oxo-dG (a by-product of base-excision repair) in conditioned media of mutant BRCA1 breast cancer cells, and concurrently increased serum levels of 8oxodG and decreased tumor burden in mice. Taken together, benserazide is a DNA-repair activating agent that enhances repair of oxidative DNA damage and decreases tumorigenesis in vitro and in vivo, and thus may serve as a potential chemoprevention agent for BRCA1-mutated cancers. Further, circulating levels of 8oxoG/8oxodG may function as a predictive biomarker for the efficacy of benserazide, which would prove useful in the clinical evaluation of benserazide for cancer chemoprevention. Citation Format: Sujeeth Shanmugam, Eboni Hosch, Dipasri Konar, James M. Ford, Elizabeth Alli. Identification of a potential chemoprevention agent for BRCA1- mutated cancers [abstract]. In: Proceedings of the Second Biennial NCI Meeting: Translational Advances in Cancer Prevention Agent Development (TACPAD); 2022 Sep 7-9. Philadelphia (PA): AACR; Can Prev Res 2022;15(12 Suppl_2): Abstract nr A003.

Background. The auditory steady state response (ASSR) is generated in bilateral auditory cortex and is the most used electroencephalographic (EEG) or magnetoencephalographic measure of gamma band abnormalities in schizophrenia. While the finding of reduced 40-Hz ASSR power and phase consistency in schizophrenia have been replicated many times, the 40-Hz ASSR phase locking angle (PLA), which assesses oscillation latency or phase delay, has rarely been examined. Furthermore, whether 40-Hz ASSR phase delay in schizophrenia is lateralized or common to left and right auditory cortical generators is unknown. Methods. Previously analyzed EEG data recorded from 24 schizophrenia patients and 24 healthy controls presented with 20-, 30-, and 40-Hz click trains to elicit ASSRs were re-analyzed to assess PLA in source space. Dipole moments in the right and left hemisphere were used to assess both frequency and hemisphere specificity of ASSR phase delay in schizophrenia. Results. Schizophrenia patients exhibited significantly reduced (ie, phase delayed) 40-Hz PLA in the left, but not the right, hemisphere, but their 20- and 30-Hz PLA values were normal. This left-lateralized 40-Hz phase delay was unrelated to symptoms or to previously reported left-lateralized PLF reductions in the schizophrenia patients. Conclusions. Consistent with sensor-based studies, the 40-Hz ASSR source-localized to left, but not right, auditory cortex was phase delayed in schizophrenia. Consistent with prior studies showing left temporal lobe volume deficits in schizophrenia, our findings suggest sluggish entrainment to 40-Hz auditory stimulation specific to left auditory cortex that are distinct from well-established deficits in gamma ASSR power and phase synchrony.

Of all congenital heart defects (CHDs), anomalies in heart valves and septa are among the most common and contribute about fifty percent to the total burden of CHDs. Progenitors to heart valves and septa are endocardial cushions formed in looping hearts through a multi-step process that includes localized expansion of cardiac jelly, endothelial-to-mesenchymal transition, cell migration and proliferation. To characterize the development of endocardial cushions, previous studies manually measured cushion size or cushion cell density from images obtained using histology, immunohistochemistry, or optical coherence tomography (OCT). Manual methods are time-consuming and labor-intensive, impeding their applications in cohort studies that require large sample sizes. This study presents an automated strategy to rapidly characterize the anatomy of endocardial cushions from OCT images. A two-step deep learning technique was used to detect the location of the heart and segment endocardial cushions. The acellular and cellular cushion regions were then segregated by K-means clustering. The proposed method can quantify cushion development by measuring the cushion volume and cellularized fraction, and also map 3D spatial organization of the acellular and cellular cushion regions. The application of this method to study the developing looping hearts allowed us to discover a spatial asymmetry of the acellular cardiac jelly in endocardial cushions during these critical stages, which has not been reported before.

Post-fundoplication dyspepsia is a common complication of gastric fundoplication surgeries. This can be attributable to the loss of fundal relaxation, decreased gastric accommodation, and/or alterations in gastric motility and sensitivity following fundoplication. The role of neuromodulators in the management of such symptoms is unknown. We retrospectively assessed the efficacy of neuromodulators such as tricyclic antidepressants, buspirone, and mirtazapine for the management of post-fundoplication dyspepsia.

BackgroundSchizophrenia is associated with aberrant gamma band power, hypothesized to reflect imbalance in the excitation-inhibition (E/I) ratio and undermine neural signal efficiency. Relationships between resting-state gamma, E/I balance, and regional hemodynamics from the fMRI BOLD signal are unknown.MethodsWe recorded simultaneous EEG-fMRI at rest, with eyes open, in people with schizophrenia (n= 57) and people without a psychiatric diagnosis (n= 46) and identified gamma and aperiodic EEG parameters associated with E/I balance. Measures from all EEG channels were entered into a whole-brain, parametric modulation analysis followed by statistical correction for multiple comparisons. Sensory gating was assessed using the Sensory Gating Inventory, and psychotic symptoms were assessed using the Positive and Negative Syndrome Scale.ResultsAcross groups, gamma power modestly predicts a steeper aperiodic slope (greater inhibition), without group differences in either gamma power or aperiodic slope. In schizophrenia, gamma-BOLD coupling was reduced in bilateral auditory regions of the superior temporal gyri and inversely correlated with sensory gating deficits and symptom severity. Analysis of the spectral features of scanner sounds revealed distinct peaks in the gamma range, reflecting a rapidly repeating scanner pulse sound present throughout the resting state recording.ConclusionRegional hemodynamic support for putative inhibitory and excitatory contributions to resting EEG are aberrant in SZ. Deficient gamma coupling to auditory BOLD may reflect impaired gating of fMRI-scanner sound.

Cyclosporine A (CsA) is a nephrotoxicant that causes fibrosis via induction of epithelial–mesenchymal transition (EMT). The flavonoid chrysin has been reported to have anti-fibrotic activity and inhibit signaling pathways that are activated during EMT. This study investigated the nephroprotective role of chrysin in the prevention of CsA-induced renal fibrosis and elucidated a mechanism of inhibition against CsA-induced EMT in proximal tubule cells. Treatment with chrysin prevented CsA-induced renal dysfunction in Sprague Dawley rats measured by blood urea nitrogen (BUN), serum creatinine and creatinine clearance. Chrysin inhibited CsA-induced tubulointerstitial fibrosis, characterized by reduced tubular damage and collagen deposition. In vitro, chrysin significantly inhibited EMT in LLC-PK1 cells, evidenced by inhibition of cell migration, decreased collagen expression, reduced presence of mesenchymal markers and elevated epithelial junction proteins. Furthermore, chrysin co-treatment diminished CsA-induced TGF-β1 signaling pathways, decreasing Smad 3 phosphorylation which lead to a subsequent reduction in Snail expression. Chrysin also inhibited activation of the Akt/ GSK-3β pathway. Inhibition of both pathways diminished the cytosolic accumulation of β-catenin, a known trigger for EMT. In conclusion, flavonoids such as chrysin offer protection against CsA-induced renal dysfunction and interstitial fibrosis. Chrysin was shown to inhibit CsA-induced TGF-β1-dependent EMT in proximal tubule cells by modulation of Smad-dependent and independent signaling pathways.

Cyclosporine A (CsA) is a nephrotoxicant that causes fibrosis via induction of epithelial–mesenchymal transition (EMT). The flavonoid chrysin has been reported to have anti-fibrotic activity and inhibit signaling pathways that are activated during EMT. This study investigated the nephroprotective role of chrysin in the prevention of CsA-induced renal fibrosis and elucidated a mechanism of inhibition against CsA-induced EMT in proximal tubule cells. Treatment with chrysin prevented CsA-induced renal dysfunction in Sprague Dawley rats measured by blood urea nitrogen (BUN), serum creatinine and creatinine clearance. Chrysin inhibited CsA-induced tubulointerstitial fibrosis, characterized by reduced tubular damage and collagen deposition. In vitro, chrysin significantly inhibited EMT in LLC-PK1 cells, evidenced by inhibition of cell migration, decreased collagen expression, reduced presence of mesenchymal markers and elevated epithelial junction proteins. Furthermore, chrysin co-treatment diminished CsA-induced TGF-β1 signaling pathways, decreasing Smad 3 phosphorylation which lead to a subsequent reduction in Snail expression. Chrysin also inhibited activation of the Akt/ GSK-3β pathway. Inhibition of both pathways diminished the cytosolic accumulation of β-catenin, a known trigger for EMT. In conclusion, flavonoids such as chrysin offer protection against CsA-induced renal dysfunction and interstitial fibrosis. Chrysin was shown to inhibit CsA-induced TGF-β1-dependent EMT in proximal tubule cells by modulation of Smad-dependent and independent signaling pathways.

OBJECTIVES Although pharmacy benefit carve-outs are promoted as a cost-containment tool, their impact on medical spending is not well understood. We compare the health care spending of Blue Cross and Blue Shield of Louisiana (BCBSLA) members covered by an integrated ("carved-in") pharmacy benefit with that of members covered under a pharmacy benefit carve-out. STUDY DESIGN Matched, longitudinal cohort study. METHODS We identified members with coverage through an employer contracting for administrative services only (ie, self-insured) and determined whether they received a pharmacy benefit through BCBSLA. We matched members with and without integrated benefits using a baseline year and compared their medical spending trajectories in 3 subsequent years. These comparisons were repeated in the subset of patients with chronic comorbidities. RESULTS Among patients with chronic illnesses, relative growth in per-member per-month (PMPM) medical spending was significantly lower in the integrated benefit group by the second and third follow-up years. Neither the level nor the growth of PMPM medical spending significantly differed in the full population sample, although point estimates suggest that the integrated benefit members may be on a lower cost growth trajectory over time. CONCLUSIONS Members with chronic illnesses receiving an integrated pharmacy benefit experienced slower medical cost growth compared with members covered by a pharmacy carve-out. Group leaders and brokers should consider the additional cost savings achieved by integrated pharmacy benefits when comparing the total costs of carve-in vs carve-out prescription drug programs.

Type VI Secretion Systems (T6SSs) are widespread in bacteria and can dictate the development and organisation of polymicrobial ecosystems by mediating contact dependent killing. In Neisseria species, including Neisseria cinerea a commensal of the human respiratory tract, interbacterial contacts are mediated by Type four pili (Tfp) which promote formation of aggregates and govern the spatial dynamics of growing Neisseria microcolonies. Here, we show that N. cinerea expresses a plasmid-encoded T6SS that is active and can limit growth of related pathogens. We explored the impact of Tfp on N. cinerea T6SS-dependent killing within a colony and show that pilus expression by a prey strain enhances susceptibility to T6SS compared to a non-piliated prey, by preventing segregation from a T6SS-wielding attacker. Our findings have important implications for understanding how spatial constraints during contact-dependent antagonism can shape the evolution of microbial communities.

In this work, we focus on explicitly nonlinear relationships in functional networks. We introduce a technique using normalized mutual information (MI), that calculates the nonlinear correlation between different brain regions. We demonstrate our proposed approach using simulated data, then apply it to a dataset previously studied in (Damaraju et al., 2014). This resting-state fMRI data included 151 schizophrenia patients and 163 age- and gender-matched healthy controls. We first decomposed these data using group independent component analysis (ICA) and yielded 47 functionally relevant intrinsic connectivity networks. Our analysis showed a modularized nonlinear relationship among brain functional networks that was particularly noticeable in the sensory and visual cortex. Interestingly, the modularity appears both meaningful and distinct from that revealed by the linear approach. Group analysis identified significant differences in nonlinear dependencies between schizophrenia patients and healthy controls particularly in visual cortex, with controls showing more nonlinearity in most cases. Certain domains, including cognitive control, and default mode, appeared much less nonlinear, whereas links between the visual and other domains showed evidence of substantial nonlinear and modular properties. Overall, these results suggest that quantifying nonlinear dependencies of functional connectivity may provide a complementary and potentially important tool for studying brain function by exposing relevant variation that is typically ignored.Further, we propose a method that captures both linear and nonlinear effects in a ‘boosted’ approach. This method increases the sensitivity to group differences in comparison to the standard linear approach, at the cost of being unable to separate linear and nonlinear effects.

Many terrestrial vertebrate species are exhibiting geographic distribution changes including poleward range limit shifts in response to increases in regional temperature. Bats are a highly mobile taxa capable of rapid responses to changes in abiotic or biotic conditions. In North America, recent extralimital records of the non-hibernating Lasiurus seminolus (Seminole bat) have been attributed to climate change, however such attributions remain speculative and potentially subject to sampling bias in the form of increased recent sampling efforts at latitudes north of the historical range. We used historical occurrence records and simple environmental variables within a Maxent modeling framework to model the historical distribution of suitable areas for this species. We transferred the model using near current environmental conditions and measured the ability of the model to capture the apparent expansion in distribution using recent extralimital occurrence records. Our model transferred well over time concluding that the distribution expansion may be largely attributed to increasing minimum temperatures. We used the model to forecast the expansion in distribution of suitable areas at three 20-year intervals and various climate change scenarios and provide extrapolation risk maps for each scenario. Although increasing temperatures may increase potentially occupiable areas, the species is associated with forests and often roosts in pines (Pinus spp.). This suitable habitat is more limited to the northwest of the species' range, which may constrain the future species expansion despite favorable temperatures. We demonstrated this effect by mapping limiting factors through future climate change scenarios. We discovered a broad shift of effects that constrained the distribution from minimum temperature to an abundance metric of evergreen cover type as time and climate change intensity increased. Although uncertainties exist, we predict further expansion of the Seminole bat widely over the next 60 years across the eastern United States where suitable habitat and climate conditions converge. Our results appear consistent with other bat species showing similar range extensions and in turn provide further evidence that bats may serve as bioindicators of global change. Virginia Department of Wildlife Resources [AT-63514, EP2489066] Published version We thank S. Loeb and M. B. Adams for earlier reviews of this manuscript. Additionally, we thank R. Odom for miscellaneous collaborative efforts and E. A. Frimpong and S. N. Winter for statistical modeling advice. This work was supported by the Virginia Department of Wildlife Resources contracts AT-63514 and EP2489066 to Virginia Polytechnic Institute and State University Department of Fish and Wildlife Conservation Manipulation and filtering of occurrence data, manipulating and calculating environmental raster datasets, and all Maxent modeling were performed in R (R Core Team, 2019) and associated codes are available on a GitHub repository (github.com/mtrue2/seminolebats) for reproducibility purposes. Questions about codes should be directed to the corresponding author (mtrue@vt.edu). Public domain – authored by a U.S. government employee

Obstruction from stricturing Crohn's disease remains one of the most common reasons for intervention. Acute inflammation is often responsive to medications, but chronic fibrosis is unlikely to respond and will generally go on to require additional treatment. Newer methods, such as endoscopic balloon dilation, are gaining grounds in strictures that are amenable, but with high recurrence and strictures that may not be endoscopically accessible, surgery still plays a key role in the treatment of obstructing Crohn's disease.

Wine made from grapes subjected to accelerated ripening, an increasingly frequent phenomenon occurring in many wine regions due to peaks of heat and water stress, displays higher alcohol levels and lacks balance with color and flavor compounds. Herein, the rate of sugar accumulation of grapes was manipulated by varying the crop load and irrigation regime and the development of secondary metabolites was monitored by gas chromatography-mass spectrometry (GC-MS) and high-performance liquid chromatography (HPLC). A 3-week delay in ripening correlated to an increase in the concentration of some monoterpenes and norisoprenoids and a greater decrease of green aroma compounds. Delayed ripening had a positive impact on the phenolic composition of grapes, displaying higher contents of total anthocyanins, total phenolics, quercetin glycosides, and polymeric pigments. A map of the chemical composition of grapes close to harvest allowed discrimination of compounds mainly responsive to delayed ripening from those driven by crop load or irrigation.

Clostridium (or Clostridioides) difficile infection (CDI) is a common side effect of antimicrobial therapy and is increasingly linked with health care-associated transmissions. Antimicrobial stewardship programs (ASP) have demonstrated success in decreasing in-hospital CDI cases. We implemented an ASP targeting inappropriate or unnecessary use of all antibiotics especially empiric piperacillin-tazobactam and fluoroquinolone use. Concurrently, we monitored all health-care associated CDI. Our CDI cases were markedly decreased after initiation of our ASP.

Functional traits can be used to identify the importance of various community assembly mechanisms such as ecological drift, environmental filtering, and limiting similarity. These processes act in concert, not isolation, and different processes may act upon separate traits, potentially concealing the ecological signal of one or more of the mechanisms. Nine functional attributes of marine fish were used to identify changes in the importance of various mechanisms in the assembly of marine fish communities over a latitudinal gradient along the Western Australian coast. Complementary null modelling approaches were used to test the relative importance of assembly processes (ecological drift, environmental filtering, and limiting similarity) in structuring fish communities. Ecological drift was found to be a major driver of the structure of fish communities, and dispersal limitation was strongest in the tropical region, with homogenising dispersal strongest in the temperate region. Dispersion of functional traits identified environmental filtering acting on most traits incorporated in this study, in addition to limiting similarity acting on traits associated with acquisition of trophic resources. The coexistence of Western Australian marine fishes thus results from concurrent ecological drift, environmental filtering, and limiting similarity structuring the communities. The observed ecological drift may be the result of priority effects and/or context-dependent biotic interactions. Both niche complementarity and predator avoidance may be the drivers of the observed limiting similarity in the communities.