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Oral medications for chronic conditions often involve a variety of instructions, including time of day/dosing, drug interactions, and food intake restrictions. However, the extent to which patients follow these instructions is unclear. We surveyed patients from the US and Europe (UK, France, Germany, Italy, Spain) who were prescribed sulfonylureas (SU: glimepiride, glipizide, or gliclazide) for diabetes or levothyroxine for hypothyroidism. Patients kept a daily diary for 3–5 days documenting their adherence to three criteria: dosing regimen including time of day, warning labels including drug interactions, and food restrictions. A total of 421 US and 493 European patients took the study medications; 546 patients took SU and 368 took levothyroxine. Overall, 48% of patients were males; 46% were age 65 years or older. Despite most patients having received instructions on medication requirements (US 71%, EU 75%), most patients reported being only somewhat knowledgeable (US 69%; EU 71%). Adherence, measured by the proportion of the days a participant was adherent to each category out of the observational period (ranging from 3–5 days), varied by type of instruction, with the poorest adherence observed for food restriction requirements (US 34% of the observation days, EU 26%) compared to warning labels (US 77%, EU 67%) and dosing regimen (US 85%, EU 87%). Patients adhered to dosing and cautionary instructions across the majority of the study period but were largely non-adherent to food intake restrictions. Improved communication and increased emphasis on food intake restrictions is needed when advising patients on their medications.

The cardiac sarcomere is a triumph of biological evolution wherein myriad contractile and regulatory proteins assemble into a quasi-crystalline lattice to serve as the central point upon which cardiac muscle contraction occurs. This review focuses on the many signaling components and mechanisms of regulation that impact cardiac sarcomere function. We highlight the roles of the thick and thin filament, both as necessary structural and regulatory building blocks of the sarcomere as well as targets of functionally impactful modifications. Currently, a new focus emerging in the field is inter-myofilament signaling, and we discuss here the important mediators of this mechanism, including myosin-binding protein C and titin. As the understanding of sarcomere signaling advances, so do the methods with which it is studied. This is reviewed here through discussion of recent live muscle systems in which the sarcomere can be studied under intact, physiologically relevant conditions.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes COVID-19 pneumonia. We hypothesize that SARS-CoV-2 causes alveolar injury and hypoxemia by damaging mitochondria in airway epithelial cells (AEC) and pulmonary artery smooth muscle cells (PASMC), triggering apoptosis and bioenergetic impairment, and impairing hypoxic pulmonary vasoconstriction (HPV), respectively.We examined the effects of: A) human betacoronaviruses, SARS-CoV-2 and HCoV-OC43, and individual SARS-CoV-2 proteins on apoptosis, mitochondrial fission, and bioenergetics in AEC; and B) SARS-CoV-2 proteins and mouse hepatitis virus (MHV-1) infection on HPV.We used transcriptomic data to identify temporal changes in mitochondrial-relevant gene ontology (GO) pathways post-SARS-CoV-2 infection. We also transduced AECs with SARS-CoV-2 proteins (M, Nsp7 or Nsp9) and determined effects on mitochondrial permeability transition pore (mPTP) activity, relative membrane potential, apoptosis, mitochondrial fission, and oxygen consumption rates (OCR). In human PASMC, we assessed the effects of SARS-CoV-2 proteins on hypoxic increases in cytosolic calcium, an HPV proxy. In MHV-1 pneumonia, we assessed HPV via cardiac catheterization and apoptosis using the TUNEL assay.SARS-CoV-2 regulated mitochondrial apoptosis, mitochondrial membrane permeabilization and electron transport chain (ETC) GO pathways within 2 hours of infection. SARS-CoV-2 downregulated ETC Complex I and ATP synthase genes, and upregulated apoptosis-inducing genes. SARS-CoV-2 and HCoV-OC43 upregulated and activated dynamin-related protein 1 (Drp1) and increased mitochondrial fission. SARS-CoV-2 and transduced SARS-CoV-2 proteins increased apoptosis inducing factor (AIF) expression and activated caspase 7, resulting in apoptosis. Coronaviruses also reduced OCR, decreased ETC Complex I activity and lowered ATP levels in AEC. M protein transduction also increased mPTP opening. In human PASMC, M and Nsp9 proteins inhibited HPV. In MHV-1 pneumonia, infected AEC displayed apoptosis and HPV was suppressed. BAY K8644, a calcium channel agonist, increased HPV and improved SpOCoronaviruses, including SARS-CoV-2, cause AEC apoptosis, mitochondrial fission, and bioenergetic impairment. SARS-CoV-2 also suppresses HPV by targeting mitochondria. This mitochondriopathy is replicated by transduction with SARS-CoV-2 proteins, indicating a mechanistic role for viral-host mitochondrial protein interactions. Mitochondriopathy is a conserved feature of coronaviral pneumonia that may exacerbate hypoxemia and constitutes a therapeutic target.

Rationale: Pulmonary arterial hypertension (PAH) often results in death from right ventricular failure (RVF). NLRP3 (nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3)-macrophage activation may promote RVF in PAH. Objectives: Evaluating the contribution of the NLRP3 inflammasome in RV macrophages to PAH RVF. Methods: Rats with decompensated RV hypertrophy (monocrotaline [MCT] and Sugen-5416 hypoxia [SuHx]) were compared with compensated RV hypertrophy rats (pulmonary artery banding). Echocardiography and right heart catheterization were performed. Macrophages, atrial natriuretic peptides, and fibrosis were evaluated by microscopy or flow cytometry. NLRP3 inflammasome activation and cardiotoxicity were confirmed by immunoblot and in vitro strategies. MCT rats were treated with SC-144 (a GP130 antagonist) or MCC950 (an NLRP3 inhibitor). Macrophage-NLRP3 activity was evaluated in patients with PAH RVF. Measurements and Main Results: Macrophages, fibrosis, and atrial natriuretic peptides were increased in MCT and SuHx RVs but not in left ventricles or pulmonary artery banding rats. Although MCT RV macrophages were inflammatory, lung macrophages were antiinflammatory. CCR2+ macrophages (monocyte-derived) were increased in MCT and SuHx RVs and highly expressed NLRP3. The macrophage-NLRP3 pathway was upregulated in patients with PAH with decompensated RVs. Cultured MCT monocytes showed NLRP3 activation, and in coculture experiments resulted in cardiomyocyte mitochondrial damage, which MCC950 prevented. In vivo, MCC950 reduced NLRP3 activation and regressed pulmonary vascular disease and RVF. SC-144 reduced RV macrophages and NLRP3 content, prevented STAT3 (signal transducer and activator of transcription 3) activation, and improved RV function without regressing pulmonary vascular disease. Conclusions: NLRP3-macrophage activation occurs in the decompensated RV in preclinical PAH models and patients with PAH. Inhibiting GP130 or NLRP3 signaling improves RV function. The concept that PAH RVF results from RV inflammation rather than solely from elevated RV afterload suggests a new therapeutic paradigm.

OBJECTIVE The aim of this study is to elucidate the unique challenges faced by pediatric emergency medicine (PEM) physicians from racial/ethnic groups underrepresented in medicine (URiM). METHODS This study is a subanalysis of data from 18 URiM faculty from a sample of 51 semistructured key informant interviews with PEM faculty in the top NIH-funded pediatric departments and highest-volume pediatric EDs in the country. Faculty are from eight hospitals representing a spectrum of geographic locations including the northeastern, midwestern, western, and southern regions of the country. RESULTS Of 18 study participants, the majority were Black (72.2%) and female (83.3%). Three main thematic categories were identified: challenges related to race, support systems, and suggested strategies to improve diversity and inclusion in PEM. A common race-related experience was microaggressions from colleagues and patients. Additionally, when attempting to lead and assert themselves, URiM women in particular were perceived as "angry" and "intimidating" in a way that non-URiM peers were not. As a result of these negative experiences, participants described the need to go above and beyond to prove themselves. Such pressure produced stress and feelings of isolation. Participants combatted these stressors through resilience strategies such as formal mentorship and peer and family support. Participants indicated the need to increase diversity and create more inclusive work environments, which would benefit both URiM physician wellness and the diverse patients they serve. CONCLUSION Those URiM in PEM face subtle racial discrimination at an institutional, peer, and patient level. The stress caused by this discrimination may further contribute to physician burnout in PEM. While URiMs adopt individual resilience strategies, their unique challenges suggest the need for departmental and institutional efforts to promote greater diversity and inclusion for physician wellness, retention, and quality patient care.

The sarcomere is the functional unit of cardiac muscle, essential for normal heart function. To date, it has not been possible to study, in real time, thin filament-based activation dynamics in live cardiac muscle. We report here results from a cardiac troponin C (TnC) FRET-based biosensor integrated into the cardiac sarcomere via stoichiometric replacement of endogenous TnC. The TnC biosensor provides, for the first time, evidence of multiple thin filament activating ligands, including troponin I interfacing with TnC and cycling myosin, during a cardiac twitch. Results show that the TnC FRET biosensor transient significantly precedes that of peak twitch force. Using small molecules and genetic modifiers known to alter sarcomere activation, independently of the intracellular Ca(2+) transient, the data show that the TnC biosensor detects significant effects of the troponin I switch domain as a sarcomere-activating ligand. Interestingly, the TnC biosensor also detected the effects of load-dependent altered myosin cycling, as shown by a significant delay in TnC biosensor transient inactivation during the isometric twitch. In addition, the TnC biosensor detected the effects of myosin as an activating ligand during the twitch by using a small molecule that directly alters cross-bridge cycling, independently of the intracellular Ca(2+) transient. Collectively, these results aid in illuminating the basis of cardiac muscle contractile activation with implications for gene, protein, and small molecule-based strategies designed to target the sarcomere in regulating beat-to-beat heart performance in health and disease.

Background Racial and ethnic disparities in outcomes for Black and Hispanic children with acute leukemia have been well documented, however little is known about the determinants of diagnostic delays in pediatric leukemia in the United States. The primary objective of this study is to identify factors contributing to delays preceding a pediatric leukemia diagnosis. Methods This qualitative study utilized in-depth semi-structured interviews. Parents and/or patients within two years of receiving a new acute leukemia diagnosis were asked to reflect upon their family’s experiences preceding the patient’s diagnosis. Subjects were purposively sampled for maximum variation in race, ethnicity, income, and language. Interviews were analyzed using inductive theory-building and the constant comparative method to understand the process of diagnosis. Chart review was conducted to complement qualitative data. Results Thirty-two interviews were conducted with a diverse population of English and Spanish speaking participants from two tertiary care pediatric cancer centers. Parents reported feeling frustrated when their intuition conflicted with providers’ management decisions. Many felt laboratory testing was not performed soon enough. Additional contributors to delays included misattribution of vague symptoms to more common diagnoses, difficulties in obtaining appointments, and financial disincentives to seek urgent or emergent care. Reports of difficulty obtaining timely appointments and financial concerns were disproportionately raised among low-income Black and Hispanic participants. Comparatively, parents with prior healthcare experiences felt better able to navigate the system and advocate for additional testing at symptom onset. Conclusions While there are disease-related factors contributing to delays in diagnosis, it is important to recognize there are multiple non-disease-related factors that also contribute to delays. Evidence-based approaches to reduce outcome disparities in pediatric cancer likely need to start in the primary care setting where timeliness of diagnosis can be addressed.

Women continue to be underrepresented in leadership positions. This underrepresentation is at least partly driven by gender stereotypes that associate men, but not women, with achievement-oriented, agentic traits (e.g., assertive and decisive). These stereotypes are expressed and perpetuated in language, with women being described in less agentic terms than men. The present research suggests that appointing women to the top tiers of management can mitigate these deep-rooted stereotypes that are expressed in language. We use natural language processing techniques to analyze over 43,000 documents containing 1.23 billion words, finding that hiring female chief executive officers and board members is associated with changes in organizations' use of language, such that the semantic meaning of being a woman becomes more similar to the semantic meaning of agency. In other words, hiring women into leadership positions helps to associate women with characteristics that are critical for leadership success. Importantly, our findings suggest that changing organizational language through increasing female representation might provide a path for women to break out of the double bind: when female leaders are appointed into positions of power, women are more strongly associated with the positive aspects of agency (e.g., independent and confident) in language but not at the cost of a reduced association with communality (e.g., kind and caring). Taken together, our findings suggest that female representation is not merely an end, but also a means to systemically change insidious gender stereotypes and overcome the trade-off between women being perceived as either competent or likeable.

Background Neutrophils play a role in innate immunity and are critical for clearance of Staphylococcus aureus. Current understanding of neutrophil bactericidal effects is that NADPH oxidase produces reactive oxygen species (ROS), mediating bacterial killing. Neutrophils also contain numerous mitochondria; since these organelles lack oxidative metabolism, their function is unclear. We hypothesize that mitochondria in human neutrophils contribute to the bactericidal capacity of S. aureus. Methods and Findings: Using human neutrophils isolated from healthy volunteers (n = 13; 7 females, 6 males), we show that mitochondria are critical in the immune response to S. aureus. Using live-cell and fixed confocal, and transmission electron microscopy, we show mitochondrial tagging of bacteria prior to ingestion and surrounding of phagocytosed bacteria immediately upon engulfment. Further, we demonstrate that mitochondria are ejected from intact neutrophils and engage bacteria during vital NETosis. Inhibition of the mitochondrial electron transport chain at Complex III, but not Complex I, attenuates S. aureus killing by 50 ± 7%, comparable to the NADPH oxidase inhibitor apocynin. Similarly, mitochondrial ROS scavenging using MitoTEMPO attenuates bacterial killing 112 ± 60% versus vehicle control. Antimycin A treatment also reduces mitochondrial ROS production by 50 ± 12% and NETosis by 53 ± 5%. Conclusions We identify a previously unrecognized role for mitochondria in human neutrophils in the killing of S. aureus. Inhibition of electron transport chain Complex III significantly impairs antimicrobial activity. This is the first demonstration that vital NETosis, an early event in the antimicrobial response, occurring within 5 min of bacterial exposure, depends on the function of mitochondrial Complex III. Mitochondria join NADPH oxidase as bactericidal ROS generators that mediate the bactericidal activities of human neutrophils., Graphical abstract Image 1, Highlights • This study evaluates the role of neutrophil mitochondria in the immune response to Staphylococcus aureus. • Mitochondrial electron transport chain inhibition at Complex III significantly attenuates neutrophil bactericidal activity.

Cardiomyopathies affect as many as 1 in 500 adults, with hypertrophic cardiomyopathy (HCM) being the most commonly inherited heart disease. Although there are various genetic mutations which cause HCM, 40-50% of mutations identified in patients with this disease are found in the cardiac myosin-binding protein C (MyBP-C) gene. Thus, understanding this protein's role in sarcomere activation is critical for the development of effective therapeutic strategies. Previous work has identified MyBP-C as a key modulator of the sarcomere through inter-myofilament signaling. Although these studies have provided valuable information on the function of MyBP-C protein, the bulk of this work has been done with either in vitro protein recombination or permeabilized muscle. Unfortunately, these systems lack significant physiological features of muscle, such as load and intact excitation-contraction coupling mechanisms. Therefore, a large gap exists in the ability to monitor muscle sarcomere activation in an intact system in real time. In order to further advance the study of sarcomere activation in HCM disease models, specifically those targeting MyBP-C, a cardiac specific myofilament-targeted FRET based biosensor has been designed and validated. This new sarcomere activation biosensor reports real-time myofilament dynamics during physiological twitch contractions in live cardiac muscle. This allows for the in vivo biophysical tracking of FRET-detected conformation changes in TnC, which reflect the ensemble of regulatory events which lead to sarcomere activation. Currently, the biosensor is being utilized to investigate changes in sarcomere activation in MyBP-C knockout mice. We find that intact cardiac muscle under load shows slowed isometric twitch relaxation kinetics in MyBP-C knockout mice versus controls. In concert with thin and thick filament modifying small molecules, this biosensor system will be used to investigate sarcomere-based mechanisms of intact cardiac muscle performance in health and disease.

OBJECTIVE To evaluate adherence to an institutional continuous infusion propofol policy for sedation in mechanically ventilated patients, investigate the rate of propofol-related infusion syndrome (PRIS), and explore areas of improvement to enhance policy compliance and safety. METHODS This was a single center, retrospective chart review of patients admitted to a pediatric or cardiac intensive care unit within a large free-standing quaternary care pediatric hospital who received continuous propofol for non-procedural continuous sedation for at least 6 hours between 2014 and 2019. Propofol exposure (dose and duration), laboratory data, and hemodynamic outcomes of patients were evaluated. RESULTS A total of 104 patients (108 admissions and 133 treatment courses) met inclusion criteria. Policy adherence to propofol dosing and duration limitations were 70% (93/133 courses) and 68% (91/133 courses), respectively. Adherence to all elements of laboratory and hemodynamic monitoring was 23%. Hypotension and bradycardia were common among patients during propofol treatment courses. Except for hypertriglyceridemia, no significant difference in specific laboratory values were detected between patients exposed to greater than 66 mcg/kg/min (4 mg/kg/hr), compared with those exposed to less than 66 mcg/kg/min of propofol. Patients receiving therapy for longer than 48 hours had the highest rates of laboratory values associated with PRIS. No patient in the study cohort met full criteria for PRIS. CONCLUSIONS Adherence to elements of an institutional propofol policy was variable. Improvements in policy adherence may be enhanced by updating policy features, leveraging the electronic medical record order-set, and gaining consensus among key stakeholders.

Dissolved silicon (DSi) is a key nutrient in the oceans, but there are few data available regarding Si isotopes in coastal aquifers. Here we investigate the Si isotopic composition of 12 fresh and 17 saline groundwater samples from Rottnest Island, Western Australia, which forms part of the world’s most extensive aeolianite deposit (the Tamala Limestone Formation). Two bedrock samples were also collected from Rottnest Island for Si isotope analysis. The δ30Si values of groundwaters ranged from −0.39 to +3.60 ‰ with an (average: +1.59 ‰) and the rock samples were −0.76 and −0.13 ‰. Due to the relatively low concentrations of DSi (64 to 196 μM) and clay-forming cations in fresh groundwaters, the correlation between δ30Si values and DSi concentrations (ρ = 0.59, p = 0.02) may be explained by Si adsorption onto Fe-Al (oxy)hydroxides present in the aquifer. An increase in groundwater δ30Si in association with the occurrence of water-rock interactions may explain the spatial pattern in δ30Si across the aquifer, and is consistent with the correlation between δ30Si and tritium activities when considering all groundwaters (ρ = −0.68, p = 0.0002). In the deeper aquifer, the inverse correlation between DSi and Cl concentrations (ρ = −0.79, p = 0.04) for the more saline groundwaters is attributed to groundwater mixing with local seawater that is depleted in DSi (

BACKGROUND: Prostate cancer is the most frequently diagnosed and treated cancer in the US Department of Veterans Affairs (VA). As the leading philanthropic source for prostate cancer research, the Prostate Cancer Foundation (PCF) entered into a unique public-private biomedical research partnership with the VA with the goal of addressing the urgent health challenges faced by veterans with prostate cancer. OBSERVATIONS: With a commitment of $50 million from PCF and the VA’s vast medical center infrastructure, the PCF-VA partnership has established 12 precision oncology Centers of Excellence to date, forming a collaborative network called the Precision Oncology Program for Cancer of the Prostate (POPCaP) Network. A 4-year review reveals the importance of executive leadership, mission-driven advocacy, setting shared ambitious goals, maximizing existing infrastructure and human capital, recruiting talent and resources, and creating space for adaptation and iteration in the context of a learning health care system. CONCLUSIONS: The PCF-VA partnership seeks to continue translating clinical research into national standards of care for veterans and serves as an innovative model of public-private collaborations for future health initiatives.

Pulmonary arterial hypertension (PAH) is a lethal vasculopathy. Hereditary cases are associated with germline mutations inTo test for a role ofWe observed an increased burden of rare, predicted deleterious germline variants inPAH is the first human disease related to potential

Effectively delegating work to others is considered critical to managerial success, as it frees up managers’ time and develops subordinates’ skills. We propose that female leaders are less likely t...

Despite a substantial amount of animal data linking deficits in memory inhibition to the development of overeating and obesity, few studies have investigated the relevance of memory inhibition to uncontrolled eating in humans. Further, although memory for recent eating has been implicated as an important contributor to satiety and energy intake, the possibility that variations in episodic memory relate to individual differences in food intake control has been largely neglected. To examine these relationships, we recruited ninety-three adult subjects to attend a single lab session where we assessed body composition, dietary intake, memory performance, and eating behaviors (Three Factor Eating Questionnaire). Episodic recall and memory inhibition were assessed using a well-established measure of memory interference (Retrieval Practice Paradigm). Hierarchical regression analyses indicated that memory inhibition was largely unrelated to participants' eating behaviors; however, episodic recall was reliably predicted by restrained vs. uncontrolled eating: recall was positively associated with strategic dieting (β = 2.45, p = 0.02), avoidance of fatty foods (β = 3.41, p = 0.004), and cognitive restraint (β = 1.55, p = 0.04). In contrast, recall was negatively associated with uncontrolled eating (β = −1.15, p = 0.03) and emotional eating (β = −2.46, p = 0.04). These findings suggest that episodic memory processing is related to uncontrolled eating in humans. The possibility that deficits in episodic memory may contribute to uncontrolled eating by disrupting memory for recent eating is discussed.

BACKGROUND Numerous studies have shown that there are links between obesity, liver fat and the gut microbiome. However, there are mixed results on whether probiotics could impact the gut microbiome and/or help to decrease liver fat and obesity outcomes. OBJECTIVE This study aimed to determine whether a probiotic supplement (VSL#3® ) intervention altered gut microbiota and/or gut hormones associated with appetite regulation. The secondary aim of this study was to determine whether VSL#3® altered body composition and liver fat and fibrosis. METHODS We conducted a double-blind, randomized placebo-controlled trial in 19 obese Latino adolescents. The intervention consisted of three packets per day of VSL#3® or a matched placebo for 16 weeks. Pre-intervention and post-intervention measures included gut microbial abundance, gut appetite regulating hormones, anthropometrics, body composition, liver fat and liver fibrosis. We conducted linear models to determine whether there were any significant differences in the changes in these outcomes following VSL#3® intervention. RESULTS Compared with placebo, adolescents that received VSL#3 had significant increases in total adiposity (%) (+1.7 ± 0.6 vs. -1.3 ± 0.5, p

Duchenne muscular dystrophy (DMD) is an X-linked recessive disease resulting in the loss of dystrophin, a key cytoskeletal protein in the dystrophin-glycoprotein complex. Dystrophin connects the extracellular matrix with the cytoskeleton and stabilizes the sarcolemma. Cardiomyopathy is prominent in adolescents and young adults with DMD, manifesting as dilated cardiomyopathy (DCM) in the later stages of disease. Sarcolemmal instability, leading to calcium mishandling and overload in the cardiac myocyte, is a key mechanistic contributor to muscle cell death, fibrosis, and diminished cardiac contractile function in DMD patients. Current therapies for DMD cardiomyopathy can slow disease progression, but they do not directly target aberrant calcium handling and calcium overload. Experimental therapeutic targets that address calcium mishandling and overload include membrane stabilization, inhibition of stretch-activated channels, ryanodine receptor stabilization, and augmentation of calcium cycling via modulation of the Serca2a/phospholamban (PLN) complex or cytosolic calcium buffering. This paper addresses what is known about the mechanistic basis of calcium mishandling in DCM, with a focus on DMD cardiomyopathy. Additionally, we discuss currently utilized therapies for DMD cardiomyopathy, and review experimental therapeutic strategies targeting the calcium handling defects in DCM and DMD cardiomyopathy.

Human and animal studies have shown that heavy cannabis (CB) use interacts with glutamatergic signaling. Additionally, recent studies have suggested that glutamate (Glu) may drive resting state functional connectivity (RSfc). The aims of the current preliminary study were to: 1) determine whether dorsal anterior cingulate cortex (dACC) Glu is related to RSfc between the dACC and two nodes of the reward network, the nucleus accumbens (NAc) and hippocampus (Hp); and 2) determine whether CB use interacts with the relationship between dACC Glu and RSfc. A group of 23 chronic CB users and 23 healthy controls participated in this multimodal MRI study. Glu levels were assessed in the dACC using magnetic resonance spectroscopy (MRS). Linear regression models were used to determine whether dACC Glu and CB use predicts RSfc between the dACC and the NAc and Hp. While the effect size is small, the results showed that the connectivity between the dACC and right NAc was predicted by the interaction between dACC Glu levels and monthly CB use. Additionally, while there is some suggestion that dACC Glu is correlated with dACC-hippocampal connectivity, unlike for dACC/NAc connectivity the relationship between them does not appear to be affected by CB use. These preliminary findings are significant in that they demonstrate the need for future studies with larger sample sizes to better characterize the relationship between resting state connectivity and neurochemistry as well as to characterize how CB use interacts with that relationship.

There is a lack of knowledge regarding in-vehicle concentrations of nitrogen dioxide (NO2) during transit through road tunnels in urban environments. Furthermore, previous studies have tended to involve a single vehicle and the range of in-vehicle NO2 concentrations that vehicle occupants may be exposed to is not well defined. This study describes simultaneous measurements of in-vehicle and outside-vehicle NO2 concentrations on a route through Sydney, Australia that included several major tunnels, minor tunnels and busy surface roads. Tests were conducted on nine passenger vehicles to assess how vehicle characteristics and ventilation settings affected in-vehicle NO2 concentrations and the in-vehicle-to-outside vehicle (I/O) concentration ratio. NO2 was measured directly using a cavity attenuated phase shift (CAPS) technique that gave a high temporal and spatial resolution. In the major tunnels, transit-average in-vehicle NO2 concentrations were lower than outside-vehicle concentrations for all vehicles with cabin air recirculation either on or off. However, markedly lower I/O ratios were obtained with recirculation on (0.08–0.36), suggesting that vehicle occupants can significantly lower their exposure to NO2 in tunnels by switching recirculation on. The highest mean I/O ratios for NO2 were measured in older vehicles (0.35–0.36), which is attributed to older vehicles having higher air exchange rates. The results from this study can be used to inform the design and operation of future road tunnels and modelling of personal exposure to NO2.

We present a review of the diversity ideologies literature from the target's perspective. In particular, we focus on how diversity ideologies—beliefs or organizational practices with regards to how to approach diversity—affect racial minorities' and women's self-perceptions and experiences at work. This review suggests that a diversity aware ideology (i.e., multiculturalism) is more beneficial than a diversity blind ideology (i.e., colorblindness) for racial-ethnic minorities (e.g., better performance outcomes; more psychological engagement, inclusion, and workplace satisfaction; more positive leadership self-perceptions; and reduced perceptions of bias and turnover intentions). In contrast, for women, gender-blindness is associated with more positive outcomes than gender awareness (e.g., enhanced self-confidence, pro-active behaviors and leadership emergence). Importantly, multiculturalism and gender-blindness can both produce negative side effects for racial minorities and women, respectively, which highlights the importance of developing approaches to address the shortcomings of these conventional ideologies. We discuss the implications and offer recommendations for future research.

BACKGROUND: Portion size is an important driver of larger meals. However, effects on food choice remain unclear.OBJECTIVE: Our aim was to identify how portion size influences the effect of palatability and expected satiety on choice.METHODS: In Study 1, adult participants (n = 24, 87.5% women) evaluated the palatability and expected satiety of 5 lunchtime meals and ranked them in order of preference. Separate ranks were elicited for equicaloric portions from 100 to 800 kcal (100-kcal steps). In Study 2, adult participants (n = 24, 75% women) evaluated 9 meals and ranked 100-600 kcal portions in 3 contexts (scenarios), believing that 1) the next meal would be at 1900, 2) they would receive only a bite of one food, and 3) a favorite dish would be offered immediately afterwards. Regression analysis was used to quantify predictors of choice.RESULTS: In Study 1, the extent to which expected satiety and palatability predicted choice was highly dependent on portion size (P < 0.001). With smaller portions, expected satiety was a positive predictor, playing a role equal to palatability (100-kcal portions: expected satiety, β: 0.42; palatability, β: 0.46). With larger portions, palatability was a strong predictor (600-kcal portions: β: 0.53), and expected satiety was a poor or negative predictor (600-kcal portions: β: -0.42). In Study 2, this pattern was moderated by context (P = 0.024). Results from scenario 1 replicated Study 1. However, expected satiety was a poor predictor in both scenario 2 (expected satiety was irrelevant) and scenario 3 (satiety was guaranteed), and palatability was the primary driver of choice across all portions.CONCLUSIONS: In adults, expected satiety influences food choice, but only when small equicaloric portions are compared. Larger portions not only promote the consumption of larger meals, but they encourage the adoption of food choice strategies motivated solely by palatability.

We recently established the feasibility of intubation and initiating ventilation prior to umbilical cord clamping (UCC) for neonates with congenital diaphragmatic hernia (CDH). The objective of the present study was to assess the maternal experience of this approach. This was a mixed-methods ancillary study of a pilot feasibility single-arm trial of intubation and ventilation prior to UCC among neonates with CDH.1 A multiple choice questionnaire was administered to mothers within 1 month after delivery. Mothers were invited to participate in an open-ended interview. Survey questions were adapted from a study of parental experiences of resuscitation before UCC in preterm neonates.2 Interview transcripts were imported into ATLAS.ti V.7 and analysed using coding and analytical memos by …

OBJECTIVES:To assess the adherence of premature infants with the American Academy of Pediatrics health supervision visit schedule, factors affecting adherence, and the association of adherence with preventive care.METHODS:Retrospective cohort of all infants ≤35 weeks’ gestation, born 2005 to 2009, receiving care at a 30-site primary care network for at least 24 months (n = 1854). Adherence was defined as having a health supervision visit within each expected time period during the first 18 months of life. Logistic regression identified sociodemographic and medical factors associated with nonadherence and risk-adjusted association between nonadherence and outcomes.RESULTS:Only 43% received all expected health supervision visits. Those with Medicaid insurance (adjusted odds ratio [AOR] 0.46, 95% confidence interval [CI] 0.35–0.60), a visit without insurance (AOR 0.46, 95% CI 0.32–0.67), chronic illness (AOR 0.7, 95% CI 0.51–0.97), and black race (AOR 0.7, 95% CI 0.50–0.98) were less adherent, whereas provider continuity of care (AOR 2.89, 95% CI 1.92–4.37) and lower birth weight (AOR 1.67, 95% CI 1.02–2.73) increased adherence. Infants CONCLUSIONS:Fewer than half of premature infants were fully adherent with the preventive health schedule with associated gaps in health monitoring and immunization delays. These data suggest the importance of health supervision visits and the need to explore scheduling facilitators for those at risk for nonadherence.

In western and westernized societies, large portions of the population live in what are considered to be “obesogenic” environments. Among other things, obesogenic environments are characterized by a high prevalence of external cues that are associated with highly palatable, energy-dense foods. One prominent hypothesis suggests that these external cues become such powerful conditioned elicitors of appetitive and eating behavior that they overwhelm the internal, physiological mechanisms that serve to maintain energy balance. The present research investigated a learning mechanism that may underlie this loss of internal relative to external control. In Experiment 1, rats were provided with both auditory cues (external stimuli) and varying levels of food deprivation (internal stimuli) that they could use to solve a simple discrimination task. Despite having access to clearly discriminable external cues, we found that the deprivation cues gained substantial discriminative control over conditioned responding. Experiment 2 found that, compared to standard chow, maintenance on a “western-style” diet high in saturated fat and sugar weakened discriminative control by food deprivation cues, but did not impair learning when external cues were also trained as relevant discriminative signals for sucrose. Thus, eating a western-style diet contributed to a loss of internal control over appetitive behavior relative to external cues. We discuss how this relative loss of control by food deprivation signals may result from interference with hippocampal-dependent learning and memory processes, forming the basis of a vicious-cycle of excessive intake, body weight gain, and progressive cognitive decline that may begin very early in life.

‘Dietary’ delay discounting is typically framed as a trade-off between immediate rewards and long-term health concerns. Our contention is that prospective thinking also occurs over shorter periods, and is engaged to select portion sizes based on the interval between meals (inter-meal interval; IMI). We sought to assess the extent to which the length of an IMI influences portion-size selection. We predicted that delay discounters would show ‘IMI insensitivity’ (relative lack of concern about hunger or fullness between meals). In particular, we were interested in participants' sensitivity to an uncertain IMI. We hypothesized that when meal times were uncertain, delay discounters would be less responsive and select smaller portion sizes. Participants (N = 90) selected portion sizes for lunch. In different trials, they were told to expect dinner at 5pm, 9pm, and either 5pm or 9pm (uncertain IMI). Individual differences in future-orientation were measured using a monetary delay-discounting task. Participants chose larger portions when the IMI was longer (p

BACKGROUND AND OBJECTIVES: Transitioning premature infants from the NICU to home is a high-risk period with potential for compromised care. Parental stress is high, and families of low socioeconomic status may face additional challenges. Home visiting programs have been used to help this transition, with mixed success. We sought to understand the experiences of at-risk families during this transition to inform interventions. METHODS: Mothers of infants born at RESULTS: Twenty-seven mothers completed interviews. Eighty-five percent were black, and 81% had Medicaid insurance. Concern about infants’ health and fragility was the primary theme identified, with mothers reporting substantial stress going from a highly monitored NICU to an unmonitored home. Issues with trust and informational consistency were mentioned frequently and could threaten mothers’ willingness to engage with providers. Strong family networks and determination compensated for limited economic resources, although many felt isolated. Mothers appreciated HVs’ ability to address infant health but preferred nurses over lay health workers. CONCLUSIONS: Low-income mothers experience significant anxiety about the transition from the NICU to home. Families value HVs who are trustworthy and have relevant medical knowledge about prematurity. Interventions to improve transition would benefit by incorporating parental input and facilitating trust and consistency in communication.

Introduction: The stark racial and ethnic disparities in outcomes for Black and Hispanic children with acute leukemia have been well documented. Socioeconomic status (SES) also has been implicated in contributing to worse outcomes. However, little is known about the role access to care plays in acute leukemia disparities. The primary objective of this study is to characterize patient and parent experiences and to identify factors contributing to delays preceding an acute leukemia diagnosis. Methods: Patients ages 0-32 years who were within 12 months of receiving a new diagnosis of acute leukemia at Children's Hospital of Philadelphia (CHOP) or University of California, San Francisco (UCSF) were purposively sampled for maximum variation. We conducted in-depth semi-structured interviews, in which caregivers (defined as a parent or guardian) and/or patients were asked to reflect upon their family's experience leading up to the patient's diagnosis of acute leukemia. Interviews were coded using AtlasTi and analyzed for emerging themes using inductive theory-building and the constant comparative method to understand the process of leukemia diagnosis. Results: A total of 23 in-depth interviews (with 20 parents and 3 patients) were conducted with a diverse population of participants; 3 self-identified as Black, 5 self-identified as Hispanic, 1 self-identified as mixed race/ethnicity, and 10 reported low income. Parents reported feeling frustrated when their intuition conflicted with the management decisions made by physicians during initial clinical visits (Table 1). Many parents felt that medical providers did not perform laboratory testing soon enough. Additional factors that contributed to delays included misattribution of vague symptoms to more common diagnoses, difficulties in obtaining an appointment with a pediatrician, and financial disincentives to seek urgent or emergent care. In contrast, parents who had experience with the healthcare system prior to the leukemia diagnosis, as either healthcare professionals or through previous medical histories, felt they were in a better position to navigate the system and advocate for blood testing at initial symptom onset. Reports of difficulty seeing a medical professional as well as financial concerns were disproportionately raised among low-income Black or Hispanic study participants. Conclusions: Interviews with patients and their parents yielded a deeper understanding of the key reasons for diagnostic challenges in pediatric acute leukemia. Implicit racial bias may affect clinical decision-making and exacerbate physician-parent tensions. Our data also suggest that socioeconomic disparities could potentially contribute to a prolonged timeline preceding an acute leukemia diagnosis. By identifying factors associated with a prolonged diagnostic interval, and their contribution to disparities in pediatric acute leukemia diagnosis, our findings highlight the need to improve leukemia diagnosis for patients who have prolonged symptoms due to barriers in accessing appropriately responsive care. Disclosures No relevant conflicts of interest to declare.

Dietary sugars have been shown to promote excess adiposity among children and adults; however, no study has examined fructose in human milk and its effects on body composition during infancy. Twenty-five mother–infant dyads attended clinical visits to the Oklahoma Health Sciences Center at 1 and 6 months of infant age. Infants were exclusively breastfed for 6 months and sugars in breast milk (i.e., fructose, glucose, lactose) were measured by Liquid chromatography-mass spectrometry (LC-MS/MS) and glucose oxidase. Infant body composition was assessed using dual-energy X-ray absorptiometry at 1 and 6 months. Multiple linear regression was used to examine associations between breast milk sugars and infant body composition at 6 months of age. Fructose, glucose, and lactose were present in breast milk and stable across visits (means = 6.7 μg/mL, 255.2 μg/mL, and 7.6 g/dL, respectively). Despite its very low concentration, fructose was the only sugar significantly associated with infant body composition. A 1-μg/mL higher breast milk fructose was associated with a 257 g higher body weight (p = 0.02), 170 g higher lean mass (p = 0.01), 131 g higher fat mass (p = 0.05), and 5 g higher bone mineral content (p = 0.03). In conclusion, fructose is detectable in human breast milk and is positively associated with all components of body composition at 6 months of age.

OBJECTIVES: To describe the epidemiology and management of gastroesophageal reflux (GER) medications started in the first year of life for premature infants. METHODS: Retrospective review of a cohort of infants ≤35 weeks’ gestation presenting for care by 168 days of age to a 30-site network between 2005 and 2009 (n = 2217) and followed to 3 years of age. Medication frequency, types, and duration of use were assessed. Logistic regression identified factors associated with treatment. RESULTS: Thirty-seven percent (812) were prescribed GER medications with 77% begun after NICU discharge. Ninety percent (727) received histamine-2 receptor antagonists, 33% (269) proton pump inhibitors, 22% (182) prokinetics; 40% (325) received >1 medication. Outpatient medication was initiated at 95 ± 69 days of life for total of 294 ± 249 days (interquartile ratio: 117–359). Feeding issues (adjusted odds ratio [aOR] 2.05, 95% confidence interval [CI]: 1.24–3.39) were associated with outpatient initiation. Forty-three percent (322) of infants started before 6 months were still on at 1 year of age associated with gestational age CONCLUSIONS: Of the 37% of the cohort on GER medications, 77% were started after NICU discharge with prolonged use of medications. Feeding difficulties were associated with starting medication and markers of chronic lung disease with continuation of treatment. With uncertain evidence of efficacy, use of these medications in a high-risk population should be carefully evaluated.

Previous research has shown that non-human animals exhibit an inverted-U pattern of sweet preference, with consumption increasing across moderate levels of sweetness and then declining for high levels of sweetness. In rodents, this pattern reflects an avoidance of the postingestive effects of consuming energy-dense sugar solutions (conditioned satiation). Here, we examined whether humans also adjust their preferences to compensate for the anticipated energy content/satiating outcomes of consuming sweetened foods. In two experiments (each N = 40), participants were asked to taste and imagine eating small (15 g) and large (250 g) portions of five novel desserts that varied in sweetness. Participants evaluated the desserts' expected satiety, expected satiation, and expected sickliness. A measure of estimated energy content was also derived using a computerized energy compensation test. This procedure was completed before and after consuming a standard lunch. Across both experiments, results confirmed that participants preferred a less sweet dessert when asked to imagine eating a large versus a small portion, and when rating the dessert in a fed versus fasted state. We also obtained evidence that participants anticipated more energy from the sweeter desserts (even in Experiment 2 when half of the participants were informed that the desserts were equated for energy content). However we found only partial evidence for anticipated satiation—expected sickliness was related systematically to increases in sweetness, but expected satiation and expected satiety were only weakly influenced. These findings raise questions about the role of sweetness in the control of food intake (in humans) and the degree to which ‘sweet-calorie learning’ occurs in complex dietary environments where sweetness may actually be a poor predictor of the energy content of foods.

Previous studies show that high-intensity sweeteners can stimulate weight gain in rats. The present studies examined whether caffeine, a stimulant commonly added to beverages consumed by humans, influences intake of saccharin- or glucose-sweetened solutions or body weight gain in rats and whether the nature of the maintenance diet influences the effects of caffeine. In two experiments, rats received glucose or saccharin solution mixed with 0.125 mg/g caffeine or no caffeine. Rats consumed significantly more caffeinated than noncaffeinated solutions when they were maintained on a low-fat chow diet (Experiment 1) and when maintained on a sweet, high-fat, high calorie chow diet (Experiment 2). Consumption of saccharin resulted in higher body weight gain in both experiments. Caffeine reversed this effect in Experiment 1 (low-fat diet) but not Experiment 2 (sweet, high-fat diet). The findings extend what is known about the conditions under which consumption of high intensity sweeteners promote energy dysregulation.

Here we report the results of a study of the formation and functioning of AM in processing tomato farm soils from across southeastern Australia. In a survey, which included the majority of processing tomato producers in the industry, mycorrhizal colonization of roots was generally low, and in many instances, completely absent. This result can be explained by the use of soil fumigants on many farms. While previous cropping history did not explain levels of AM colonization, the proportion of mycorrhizal crops in the rotation had an influence on soil C, which was generally low across most sites. In an effort to further explore the functioning of AM, a targeted glasshouse experiment was undertaken, in which a mycorrhiza defective tomato mutant and its mycorrhizal wild-type progenitor were grown under uniform conditions. While AM colonization of plants was highest when grown in soil collected from an un-farmed site in this glasshouse experiment, AM provided a greater benefit (in terms of root Zn nutrition) when grown in soil collected from more fertile farm sites. Together, these data indicate that farm management decisions (in this case soil fumigation) may have consequences for the formation of AM, which in turn, may reduce the benefits of AM in these farm soils.

Recent epidemiological evidence points to a link between a variety of negative health outcomes (e.g. metabolic syndrome, diabetes and cardiovascular disease) and the consumption of both calorically sweetened beverages and beverages sweetened with high-intensity, non-caloric sweeteners. Research on the possibility that non-nutritive sweeteners promote food intake, body weight gain, and metabolic disorders has been hindered by the lack of a physiologically-relevant model that describes the mechanistic basis for these outcomes. We have suggested that based on Pavlovian conditioning principles, consumption of non-nutritive sweeteners could result in sweet tastes no longer serving as consistent predictors of nutritive postingestive consequences. This dissociation between the sweet taste cues and the caloric consequences could lead to a decrease in the ability of sweet tastes to evoke physiological responses that serve to regulate energy balance. Using a rodent model, we have found that intake of foods or fluids containing non-nutritive sweeteners was accompanied by increased food intake, body weight gain, accumulation of body fat, and weaker caloric compensation, compared to consumption of foods and fluids containing glucose. Our research also provided evidence consistent with the hypothesis that these effects of consuming saccharin may be associated with a decrement in the ability of sweet taste to evoke thermic responses, and perhaps other physiological, cephalic phase, reflexes that are thought to help maintain energy balance.

Dendritic cells (DCs) are essential in T cell-mediated destruction of insulin-producing β cells in the islets of Langerhans in type 1 diabetes. In this study, we investigated T cell induction of intra-islet DC maturation during the progression of the disease in both autoimmune-prone NOD and resistant C57BL/6 mice. We demonstrated steady-state capture and retention of unprocessed β cell-derived proteins by semimature intra-islet DCs in both mouse strains. T cell-mediated intra-islet inflammation induced an increase in CD40 and CD80 expression and processing of captured Ag by resident DCs without inducing the expression of the p40 subunit of IL-12/23. Some of the CD40high intra-islet DCs up-regulated CCR7, and a small number of CD40high DCs bearing unprocessed islet Ags were detected in the pancreatic lymph nodes in mice with acute intra-islet inflammation, demonstrating that T cell-mediated tissue inflammation augments migration of mature resident DCs to draining lymph nodes. Our results identify an amplification loop during the progression of autoimmune diabetes, in which initial T cell infiltration leads to rapid maturation of intra-islet DCs, their migration to lymph nodes, and expanded priming of more autoreactive T cells. Therapeutic interventions that intercept this process may be effective at halting the progression of type 1 diabetes.

Sugar-sweetened beverages (SSBs) are thought to be problematic for weight management because energy delivered in liquid form may be less effective at suppressing appetite than solid foods. However, little is known about the relative ‘expected satiation’ (anticipated fullness) of SSBs and solid foods. This is relevant because expected satiation is an important determinant of portion selection and energy intake. Here, we used a method of constant stimuli to assess the expected satiation of test meals that were presented in combination with different caloric and non-caloric beverages (500 ml) (Experiment 1 and 2), as well as with high-energy solid snack foods (Experiment 2). All energy-containing beverages and snack foods were presented in 210 kcal portions. Both experiments found that expected satiation was greater for meals containing caloric versus non-caloric beverages (201.3 ± 17.3 vs. 185.4 ± 14.1 kcal in Experiment 2; p, Highlights • Sugar-sweetened beverages may promote less satiety than solid foods. • However, it is unclear whether beverages differ from all solid foods. • Here, expected satiation was similar for caloric beverages and solid snack foods. • Concerns about energy-containing beverages should be interpreted in this context.

Eating slowly is associated with a lower body mass index. However, the underlying mechanism is poorly understood. Here, our objective was to determine whether eating a meal at a slow rate improves episodic memory for the meal and promotes satiety. Participants (N = 40) consumed a 400 ml portion of tomato soup at either a fast (1.97 ml/s) or a slow (0.50 ml/s) rate. Appetite ratings were elicited at baseline and at the end of the meal (satiation). Satiety was assessed using; i) an ad libitum biscuit ‘taste test’ (3 h after the meal) and ii) appetite ratings (collected 2 h after the meal and after the ad libitum snack). Finally, to evaluate episodic memory for the meal, participants self-served the volume of soup that they believed they had consumed earlier (portion size memory) and completed a rating of memory ‘vividness’. Participants who consumed the soup slowly reported a greater increase in fullness, both at the end of the meal and during the inter-meal interval. However, we found little effect of eating rate on subsequent ad libitum snack intake. Importantly, after 3 h, participants who ate the soup slowly remembered eating a larger portion. These findings show that eating slowly promotes self-reported satiation and satiety. For the first time, they also suggest that eating rate influences portion size memory. However, eating slowly did not affect ratings of memory vividness and we found little evidence for a relationship between episodic memory and satiety. Therefore, we are unable to conclude that episodic memory mediates effects of eating rate on satiety., Highlights • Eating lunch at a slower rate promotes greater satiation and satiety. • Participants remember eating a larger meal if they eat it slowly. • Eating lunch at a slower rate does not affect subsequent snack-food intake. • Effects of eating rate on satiety might not be mediated by episodic memory.

The Affordable Care Act is triggering an increase in hospital consolidation and mergers. How other hospitals respond to these disruptions in supply could influence patient outcomes. We examined the experience of Philadelphia County, Pennsylvania (coterminous with the city of Philadelphia), where thirteen of nineteen hospital obstetric units closed between 1997 and 2012. Between October 2011 and January 2012 we interviewed twenty-three key informants from eleven hospitals (six urban and five suburban) whose obstetric units remained open, to understand how the large number of closures affected their operations. Informants reported having confronted numerous challenges as a result of the obstetric unit closures, including sharp surges in delivery volume and an increase in the proportion of patients with public insurance or no insurance. Informants reported adopting a number of strategies, such as innovative staffing models, to cope with the added demand brought about by the closure of nearby obstetric units. Informants emphasized that interhospital communication could mitigate closures' stresses on the health care system. Our study supports the need for policy makers to anticipate reductions in supply and monitor patient outcomes.

Evidence is accumulating which suggests that, in addition to leading to unprecedented rates of obesity, the current food environment is contributing to the development of cognitive impairment and dementia. Recent experimental research indicates that many of the cognitive deficits associated with obesity involve fundamental inhibitory processes that have important roles in the control of food intake, implicating these cognitive impairments as a risk factor for weight gain. Here, we review experiments that link obesity with deficits in memory, attentional, and behavioral control and contemplate how these deficits may predispose individuals to overeat. Specifically, we discuss how deficits in inhibitory control may reduce one’s ability to resist eating when confronted with the variety of foods and food cues that are ubiquitous in today’s environment. Special attention is given to the importance of memory inhibition to the control of eating and appetitive behavior, and the role of the hippocampus in this process. We also discuss the potential etiology of both obesity and obesity-related cognitive impairment, highlighting non-human animal research which links both of these effects to the consumption of the modern “Western” diet that is high in saturated fats and simple carbohydrates. We conclude that part of what makes the current food environment “obesogenic” is the increased presence of food cues and the increased consumption of a diet which compromises our ability to resist those cues. A multi-dimensional intervention which focuses on improving control over food-related cognitive processing may be useful not only for combating the obesity epidemic but also for minimizing the risk of serious cognitive disorder later in life.