Modelled impact of virtual fractional flow reserve in patients undergoing coronary angiography (VIRTU-4).

BACKGROUND: The practical application of 'virtual' (computed) fractional flow reserve (vFFR) based on invasive coronary angiogram (ICA) images is unknown. The objective of this cohort study was to investigate the potential of vFFR to guide the management of unselected patients undergoing ICA. The hypothesis was that it changes management in >10% of cases. METHODS: vFFR was computed using the Sheffield VIRTUheart system, at five hospitals in the North of England, on 'all-comers' undergoing ICA for non-ST-elevation myocardial infarction acute coronary syndrome (ACS) and chronic coronary syndrome (CCS). The cardiologists' management plan (optimal medical therapy, percutaneous coronary intervention (PCI), coronary artery bypass surgery or 'more information required') and confidence level were recorded after ICA, and again after vFFR disclosure. RESULTS: 517 patients were screened; 320 were recruited: 208 with ACS and 112 with CCS. The median vFFR was 0.82 (0.70-0.91). vFFR disclosure did not change the mean number of significantly stenosed vessels per patient (1.16 (±0.96) visually and 1.18 (±0.92) with vFFR (p=0.79)). A change in intended management following vFFR disclosure occurred in 22% of all patients; in the ACS cohort, there was a 62% increase in the number planned for medical management, and in the CCS cohort, there was a 31% increase in the number planned for PCI. In all patients, vFFR disclosure increased physician confidence from 8 of 10 (7.33-9) to 9 of 10 (8-10) (p<0.001). CONCLUSION: The addition of vFFR to ICA changed intended management strategy in 22% of patients, provided a detailed and specific 'all-in-one' anatomical and physiological assessment of coronary artery disease, and was accompanied by augmentation of the operator's confidence in the treatment strategy.

Radiation Reveal: Moving from research engagement to involvement.

Here, we report on the process of a highly impactful and successful creative, collaborative, and multi-partner public engagement project, Radiation Reveal. It brought together ten young adults aged 17-25-year-olds with experience of radiotherapy with researchers at Cancer Research UK RadNet City of London across three 2-hour online workshops. Our aims were to 1) initiate discussions between young adults and radiation researchers, and 2) identify what people wish they had known about radiotherapy before or during treatment. These aims were surpassed; other benefits included peer support, participants' continued involvement in subsequent engagement projects, lasting friendships, creation of support groups for others, and creation and national dissemination of top ten tips for medical professionals and social media resources. A key learning was that this project required a dedicated and (com)passionate person with connections to national cancer charities. When designing the project, constant feedback is also needed from charities and young adults with and without radiotherapy experience. Finally, visually capturing discussions and keeping the door open beyond workshops further enhanced impact. Here, we hope to inform and inspire people to help project the patient voice in all we do.

A non-pharmacological multi-modal therapy to improve sleep and cognition and reduce mild cognitive impairment risk: Design and methodology of a randomized clinical trial.

Aging populations are at increased risk of sleep deficiencies (e.g., insomnia) that are associated with a variety of chronic health risks, including Alzheimer's disease and related dementias (ADRD). Insomnia medications carry additional risk, including increased drowsiness and falls, as well as polypharmacy risks. The recommended first-line treatment for insomnia is cognitive behavioral therapy for insomnia (CBTi), but access is limited. Telehealth is one way to increase access, particularly for older adults, but to date telehealth has been typically limited to simple videoconferencing portals. While these portals have been shown to be non-inferior to in-person treatment, it is plausible that telehealth could be significantly improved. This work describes a protocol designed to evaluate whether a clinician-patient dashboard inclusive of several user-friendly features (e.g., patterns of sleep data from ambulatory devices, guided relaxation resources, and reminders to complete in-home CBTi practice) could improve CBTi outcomes for middle- to older-aged adults (N = 100). Participants were randomly assigned to one of three telehealth interventions delivered through 6-weekly sessions: (1) CBTi augmented with a clinician-patient dashboard, smartphone application, and integrated smart devices; (2) standard CBTi (i.e., active comparator); or (3) sleep hygiene education (i.e., active control). All participants were assessed at screening, pre-study evaluation, baseline, throughout treatment, and at 1-week post-treatment. The primary outcome is the Insomnia Severity Index. Secondary and exploratory outcomes span sleep diary, actiwatch and Apple watch assessed sleep parameters (e.g., efficiency, duration, timing, variability), psychosocial correlates (e.g., fatigue, depression, stress), cognitive performance, treatment adherence, and neurodegenerative and systemic inflammatory biomarkers.

Mean affect and affect variability may interact to predict inflammation.

INTRODUCTION: Individuals with greater affect variability (i.e., moment-to-moment fluctuations possibly reflecting emotional dysregulation) are at risk for greater systemic inflammation, which is associated with cardiovascular disease. Some evidence suggests that affect variability is linked with poorer health indicators only among those with higher average levels of affect, particularly for positive affect (PA), and that associations may be non-linear. The present study sought to examine whether links between both PA and negative affect (NA) variability and inflammation are moderated by average level of affect. METHODS: Participants (N = 300, 50 % female, ages 21-70, 60 % non-Hispanic White, 19 % Hispanic, 15 % non-Hispanic Black) completed a lab assessment and provided a blood sample to measure systemic inflammation (i.e., TNF-α, IL-6, CRP). Affect was collected via a two-day ecological momentary assessment protocol where reports were collected about every 45-min during waking hours. Momentary affect ratings were averaged across both days (i.e., iM), separately for PA and NA, for each participant. Affect variability was calculated as the person-specific SD (i.e., iSD) of affect reports, separately for PA and NA. Linear and quadratic interactions were tested. Models included covariates for sex, race, and body mass index. RESULTS: There were significant interactions between NA iM and NA iSD predicting TNF-α (b = 6.54; p < 0.05) and between PA iM and PA iSD predicting IL-6 (b = 0.45; p < 0.05). Specifically, the association between these affect variability indicators and inflammatory markers were suggestive of a positive association among those with higher average affect but a negative association among those with lower average affect. There was no evidence of non-linear associations between affect and inflammation. DISCUSSION: Incorporating interactive effects between affect variability and average affect may be an important consideration in understanding affective-inflammatory associations.

Indolent multicentric chordoma - A previously undescribed entity: A Case report and literature review.

Background: Chordomas are rare neuraxial tumors arising from remnants of primitive notochord. They are generally slow-growing malignant neoplasms. Only four adult cases of multicentric chordomas have been reported, all with aggressive and rapid growth. Here, we present an unusual case of indolent multicentric chordomas involving cervical and thoracic spine, sacrum, and calvarium. Case Description: A 60-year-old male was found to have multiple lesions throughout his neuroaxis incidentally on workup for colitis. A needle biopsy documented the diagnosis of chordoma. This has been followed for more than 4 years with no progression. Conclusion: We present the first reported case of indolent multicentric chordomas. Due to the extreme rarity of indolent multicentric chordomas, close follow-up is needed and recommended.

Structural mechanism of tapasin-mediated MHC-I peptide loading in antigen presentation.

Loading of MHC-I molecules with peptide by the catalytic chaperone tapasin in the peptide loading complex plays a critical role in antigen presentation and immune recognition. Mechanistic insight has been hampered by the lack of detailed structural information concerning tapasin-MHC-I. We present here crystal structures of human tapasin complexed with the MHC-I molecule HLA-B*44:05, and with each of two anti-tapasin antibodies. The tapasin-stabilized peptide-receptive state of HLA-B*44:05 is characterized by distortion of the peptide binding groove and destabilization of the ß2-microglobulin interaction, leading to release of peptide. Movements of the membrane proximal Ig-like domains of tapasin, HLA-B*44:05, and ß2-microglobulin accompany the transition to a peptide-receptive state. Together this ensemble of crystal structures provides insights into a distinct mechanism of tapasin-mediated peptide exchange.

Racial/ethnic variations in inflammatory markers: exploring the role of sleep duration and sleep efficiency.

Individuals from minoritized racial/ethnic groups have higher levels of circulating inflammatory markers. However, the mechanisms underlying these differences remain understudied. The objective of this study was to examine racial/ethnic variations in multiple markers of inflammation and whether impaired sleep contributes to these racial/ethnic differences. Nurses from two regional hospitals in Texas (n = 377; 71.62% White; 6.90% Black; 11.14% Hispanic, 10.34% Asian; mean age = 39.46; 91.78% female) completed seven days of sleep diaries and actigraphy to assess mean and variability in total sleep time (TST) and sleep efficiency (SE). On day 7, blood was drawn to assess 4 inflammatory markers: C-reactive protein (CRP), Interleukin-6 (IL-6), Interleukin-1 beta (IL-1ß), and tumor necrosis factor-alpha (TNF-α). Results from regression models showed differences in inflammatory markers by race/ethnicity, adjusting for age and gender. The associations between sleep parameters and inflammatory markers also varied by race/ethnicity. Among White nurses, lower mean and greater variability in actigraphy-determined TST and greater variability in diary-determined TST were associated with higher levels of IL-6. Among Black nurses, lower mean diary-determined SE was associated with higher levels of IL-6 and IL-1ß. Among Hispanic nurses, greater diary-determined mean TST was associated with higher CRP. Among Asian nurses, greater intraindividual variability in actigraphy-determined SE was associated with lower CRP. Among nurses, we did not find racial/ethnic disparities in levels of inflammation. However, analyses revealed differential relationships between sleep and inflammatory markers by race/ethnicity. Results highlight the importance of using a within-group approach to understand predictors of inflammatory markers.

Chaperones and Catalysts: How Antigen Presentation Pathways Cope With Biological Necessity.

Immune recognition by T lymphocytes and natural killer (NK) cells is in large part dependent on the identification of cell surface MHC molecules bearing peptides generated from either endogenous (MHC I) or exogenous (MHC II) dependent pathways. This review focuses on MHC I molecules that coordinately fold to bind self or foreign peptides for such surface display. Peptide loading occurs in an antigen presentation pathway that includes either the multimolecular peptide loading complex (PLC) or a single chain chaperone/catalyst, TAP binding protein, related, TAPBPR, that mimics a key component of the PLC, tapasin. Recent structural and dynamic studies of TAPBPR reveal details of its function and reflect on mechanisms common to tapasin. Regions of structural conservation among species suggest that TAPBPR and tapasin have evolved to satisfy functional complexities demanded by the enormous polymorphism of MHC I molecules. Recent studies suggest that these two chaperone/catalysts exploit structural flexibility and dynamics to stabilize MHC molecules and facilitate peptide loading.

Characterizing Patterns of Nurses' Daily Sleep Health: a Latent Profile Analysis.

BACKGROUND: Nursing is a demanding occupation characterized by dramatic sleep disruptions. Yet most studies on nurses' sleep treat sleep disturbances as a homogenous construct and do not use daily measures to address recall biases. Using person-centered analyses, we examined heterogeneity in nurses' daily sleep patterns in relation to psychological and physical health. METHODS: Nurses (N = 392; 92% female, mean age = 39.54 years) completed 14 daily sleep diaries to assess sleep duration, efficiency, quality, and nightmare severity, as well as measures of psychological functioning and a blood draw to assess inflammatory markers interleukin-6 (IL-6) and C-reactive protein (CRP). Using recommended fit indices and a 3-step approach, latent profile analysis was used to identify the best-fitting class solution. RESULTS: The best-fitting solution suggested three classes: (1) "Poor Overall Sleep" (11.2%), (2) "Nightmares Only" (8.4%), (3) "Good Overall Sleep" (80.4%). Compared to nurses in the Good Overall Sleep class, nurses in the Poor Overall Sleep or Nightmares Only classes were more likely to be shift workers and had greater stress, PTSD symptoms, depression, anxiety, and insomnia severity. In multivariate models, every one-unit increase in insomnia severity and IL-6 was associated with a 33% and a 21% increase in the odds of being in the Poor Overall Sleep compared to the Good Overall Sleep class, respectively. CONCLUSION: Nurses with more severe and diverse sleep disturbances experience worse health and may be in greatest need of sleep-related and other clinical interventions.

Organic Anion Transporting Polypeptide 2B1 (OATP2B1) Genetic Variants: In Vitro Functional Characterization and Association With Circulating Concentrations of Endogenous Substrates.

Organic anion transporting polypeptide 2B1 (OATP2B1, gene SLCO2B1) is an uptake transporter that is thought to determine drug disposition and in particular, the oral absorption of medications. At present, the clinical relevance of SLCO2B1 genetic variation on pharmacokinetics is poorly understood. We sought to determine the functional activity of 5 of the most common missense OATP2B1 variants (c.76_84del, c.601G>A, c.917G>A, c.935G>A, and c.1457C>T) and a predicted dysfunctional variant (c.332G>A) in vitro. Furthermore, we measured the basal plasma concentrations of endogenous OATP2B1 substrates, namely estrone sulfate, dehydroepiandrosterone sulfate (DHEAS), pregnenolone sulfate, coproporphyrin I (CPI), and CPIII, and assessed their relationships with SLCO2B1 genotypes in 93 healthy participants. Compared to reference OATP2B1, the transport activities of the c.332G>A, c.601G>A and c.1457C>T variants were reduced among the substrates examined (estrone sulfate, DHEAS, CPI, CPIII and rosuvastatin), although there were substrate-dependent effects. Lower transport function of OATP2B1 variants could be explained by diminished cell surface expression. Other OATP2B1 variants (c.76-84del, c.917G>A and c.935G>A) had similar activity to the reference transporter. In the clinical cohort, the SLCO2B1 c.935G>A allele was associated with both higher plasma CPI (42%) and CPIII (31%) concentrations, while SLCO2B1 c.917G>A was linked to lower plasma CPIII by 28% after accounting for the effects of age, sex, and SLCO1B1 genotypes. No association was observed between SLCO2B1 variant alleles and estrone sulfate or DHEAS plasma concentrations, however 45% higher plasma pregnenolone sulfate level was associated with SLCO2B1 c.1457C>T. Taken together, we found that the impacts of OATP2B1 variants on transport activities in vitro were not fully aligned with their associations to plasma concentrations of endogenous substrates in vivo. Additional studies are required to determine whether circulating endogenous substrates reflect OATP2B1 activity.

Cigarette use, anxiety, and insomnia from adolescence to early adulthood: A longitudinal indirect effects test.

BACKGROUND: Cigarette use during adolescence has been linked to increased risk for insomnia symptoms, but limited work has examined factors that may account for this association. Adolescent cigarette use and anxiety symptoms characterized by physiological hyperarousal evidence bidirectional associations, as do anxiety symptoms and insomnia symptoms. This suggests that adolescent cigarette use, anxiety symptoms characterized by physiological hyperarousal, and insomnia symptoms may increase and maintain one another. The current study tests physiological hyperarousal anxiety symptoms as a potential indirect effect in the cigarette-insomnia symptoms link across adolescence and young adulthood. METHODS: We examined data from adolescents and young adults from Waves 1, 2, 3 and 4 of the National Longitudinal Study of Adolescent to Adult Health (N = 2,432 with full data). Insomnia symptoms were assessed at baseline (ages 12-16 years), 1 year later (13-17 years), and 14 years after baseline (26 - 30 years) among a nationally representative sample of adolescents. Cigarette use was assessed at baseline, 1 year later, 6 years after baseline, and 14 years after baseline. Anxiety symptoms were assessed at baseline and 1 year later. RESULTS: Structural equation models indicated that anxiety symptoms exerted an indirect effect on the longitudinal associations between adolescent cigarette use and adult insomnia symptoms. Anxiety symptoms and cigarette use evidenced bidirectional associations during adolescence. CONCLUSIONS: These results suggest that increases in anxiety symptoms characterized by physiological hyperarousal may be one mechanism whereby cigarette use during adolescence is associated with increased insomnia symptoms during early adulthood. Prevention efforts aimed at reducing cigarette use during adolescence may have long term additional benefits for anxiety symptoms and insomnia symptoms.

Efficacy of unsupervised exercise in adults with obstructive lung disease: a systematic review and meta-analysis.

INTRODUCTION: The benefits of unsupervised exercise programmes in obstructive lung disease are unclear. The aim of this systematic review was to synthesise evidence regarding the efficacy of unsupervised exercise versus non-exercise-based usual care in patients with obstructive lung disease. METHODS: Electronic databases (MEDLINE, CINAHL, Embase, Allied and Complementary Medicine Database, Web of Science, Cochrane Central Register of Controlled Trials and Physiotherapy Evidence Database) and trial registers (ClinicalTrials.gov, Current Controlled Trials, UK Clinical Trials Gateway and WHO International Clinical Trials Registry Platform) were searched from inception to April 2020 for randomised trials comparing unsupervised exercise programmes with non-exercise-based usual care in adults with chronic obstructive pulmonary disease (COPD), non-cystic fibrosis bronchiectasis or asthma. Primary outcomes were exercise capacity, quality of life, mortality, exacerbations and respiratory cause hospitalisations. RESULTS: Sixteen trials (13 COPD, 2 asthma, 1 chronic bronchitis: 1184 patients) met the inclusion criteria. Only data on COPD populations were available for meta-analysis. Unsupervised exercise resulted in a statistically but not clinically significant improvement in the 6-Minute Walk Test (n=5, MD=22.0 m, 95% CI 4.4 to 39.6 m, p=0.01). However, unsupervised exercise did lead to statistically significant and clinically meaningful improvements in St. George's Respiratory Questionnaire (n=4, MD=-11.8 points, 95% CI -21.2 to -2.3 points, p=0.01) and Chronic Respiratory Disease Questionnaire domains (dyspnoea: n=4, MD=0.5 points, 95% CI 0.1 to 0.8 points, p<0.01; fatigue: n=4, MD=0.7 points, 95% CI 0.4 to 1.0 points, p<0.01; emotion: n=4, MD=0.5 points, 95% CI 0.2 to 0.7 points, p<0.01; mastery: unable to perform meta-analysis) compared with non-exercise-based usual care. DISCUSSION: This review demonstrates clinical benefits of unsupervised exercise interventions on health-related quality of life in patients with COPD. High-quality randomised trials are needed to examine the effectiveness of prescription methods.

A case of broncho-cutaneous fistula secondary to tuberculosis successfully managed with awake veno-venous extracorporeal membrane oxygenation.

A broncho-cutaneous fistula (BCF) is a communicating tract between the bronchus and the cutaneous surface of the thoracic wall and can be the primary presenting sign of several disease processes. It has been associated with positive pressure ventilation (PPV), post pneumonectomy, thoracostomy tubes, perforating chest trauma, neoplasia and chronic empyema. We report a case of a 45-year-old immunocompetent man presenting with severe hypercapnic respiratory failure secondary to a BCF as a result of tuberculosis (TB)-related empyema necessitans. Veno-venous extracorporeal membrane oxygenation (VV ECMO) was employed during spontaneous breathing to mitigate the risks of PPV, to facilitate diagnostics and enable targeted treatment. Awake VV ECMO is an effective supportive therapy for complex, destructive lung pathologies with a known reversible aetiology in which PPV would be potentially detrimental.

Age-dependent associations among insomnia, depression, and inflammation in nurses.

OBJECTIVE: Insomnia and depression have been inconsistently associated with inflammation. Age may be one important moderator of these associations. This study examined associations between insomnia and depression with inflammatory biomarkers in nurses and how these associations varied by age. Design: Participants were 392 nurses ages 18-65 (Mage = 39.54 years ± 11.15, 92% female) recruited from two hospitals. Main outcome measures: Participants completed surveys to assess insomnia and depression symptoms. Serum samples were obtained and analysed for inflammatory biomarkers interleukin-6 (IL-6), C-reactive protein (CRP), interleukin-1 beta (IL-1ß), and tumour necrosis factor alpha (TNF-α). Results: Neither insomnia nor depression symptoms were associated with inflammatory biomarkers. Older age was associated with higher IL-1ß, and age moderated the effects of depression symptoms on CRP and TNF-α: Greater depression symptoms were associated with higher CRP (b = .14, p = .017) and TNF-α (b = .008, p = .165) among older nurses only. Conclusion: Results suggest older nurses with higher depression symptoms may be at increased risk for elevated inflammation. Interventions should consider the role of age-related processes in modifying health and well-being. Given relatively low levels of depression in the current sample, future studies should replicate results in clinical and non-nurse samples.

Intraindividual Variability in Sleep and Levels of Systemic Inflammation in Nurses.

OBJECTIVE: Disturbed sleep is common among nurses and is associated with morbidity and mortality. Inflammation may be one mechanism linking sleep and disease. However, most studies rely on retrospective questionnaires to assess sleep, which fail to account for night-to-night fluctuations in sleep across time (i.e., intraindividual variability [IIV]). We examined prospective associations between mean and IIV in sleep with inflammation markers in nurses. METHODS: Participants were 392 nurses (mean age = 39.54 years, 92% female, 23% night-shift working) who completed 7 days of sleep diaries and actigraphy to assess mean and IIV in total sleep time and sleep efficiency. Blood was drawn on day 7 to assess inflammation markers C-reactive protein, interleukin (IL)-6, tumor necrosis factor α, and IL-1ß. RESULTS: Greater IIV in total sleep time-measured via both actigraphy and sleep diary-was associated with higher IL-6 (actigraphy: b = 0.05, p = .046, sr = 0.01; diary: b = 0.04, p = .030, sr = 0.01) and IL-1ß (actigraphy: b = 0.12, p = .008, sr = 0.02; diary: b = 0.09, p = .025, sr = 0.01), but not C-reactive protein or tumor necrosis factor α. IIV in actigraphy- and sleep diary-determined sleep efficiency was not associated with inflammation biomarkers, nor were any mean sleep variables. Shift work did not moderate any associations. CONCLUSIONS: Nurses with more variable sleep durations had elevated levels of inflammation, which may increase risk for development of inflammatory-related diseases. Research should investigate how sleep regularization may change levels of inflammation and improve health.

Attitudes of Patients and Their Relatives Toward Artificial Intelligence in Neurosurgery.

BACKGROUND: Artificial intelligence (AI) may favorably support surgeons but can result in concern among patients and their relatives. The aim of this study was to evaluate attitudes of patients and their relatives regarding use of AI in neurosurgery. METHODS: In a 2-stage cross-sectional survey, a qualitative survey was administered to a focus group of former patients to investigate their perception of AI and its role in neurosurgery. Five themes were identified and used to generate a case-based quantitative survey administered to inpatients and their relatives over a 2-week period. Presented AI platforms were rated appropriate and acceptable using 5-point Likert scales. Demographic data were collected. χ2 test was used to determine whether demographics influenced participants' attitudes. RESULTS: In the first stage, 20 participants responded. Five themes were identified: interpretation of imaging (4/20; 20%), operative planning (5/20; 25%), real-time alert of potential complications (10/20; 50%), partially autonomous surgery (6/20; 30%), and fully autonomous surgery (3/20; 15%). In the second stage, 107 participants responded. Most thought it appropriate and acceptable to use AI for imaging interpretation (76.7%; 66.3%), operative planning (76.7%; 75.8%), real-time alert of potential complications (82.2%; 72.9%), and partially autonomous surgery (58%; 47.7%). Conversely, most did not think that fully autonomous surgery was appropriate (27.1%) or acceptable (17.7%). Demographics did not have a significant influence on perception. CONCLUSIONS: Most patients and their relatives believed that AI has a role in neurosurgery and found it acceptable. Notable exceptions were fully autonomous systems, with most wanting the neurosurgeon ultimately to remain in control.

Cannabis Use Is Associated With Increased Risk for Diabetic Ketoacidosis in Adults With Type 1 Diabetes: Findings From the T1D Exchange Clinic Registry.

OBJECTIVE: We examined the frequency of diabetic ketoacidosis (DKA) in cannabis users compared with nonusers in the T1D Exchange clinic registry (T1DX). RESEARCH DESIGN AND METHODS: The association between cannabis use by total substance score for cannabis (TSC) and DKA in the past 12 months was examined using a logistic regression model adjusted for potential confounders among adults in the T1DX. RESULTS: Of 932 adults with type 1 diabetes, 61 had a TSC >4, which classified them as moderate cannabis users. Adjusting for sex, age at study visit, and HbA1c, cannabis use was associated with a twofold increase in risk for DKA among adults with type 1 diabetes (odds ratio 2.5 [95% CI 1.0-5.9]). CONCLUSIONS: Cannabis use was associated with an increased risk for DKA among adults in the T1DX. Providers should inform their patients of the potential risk of DKA with cannabis use.

Targeting cellular heterogeneity with CXCR2 blockade for the treatment of therapy-resistant prostate cancer.

Hormonal therapy targeting androgen receptor (AR) is initially effective to treat prostate cancer (PCa), but it eventually fails. It has been hypothesized that cellular heterogeneity of PCa, consisting of AR+ luminal tumor cells and AR- neuroendocrine (NE) tumor cells, may contribute to therapy failure. Here, we describe the successful purification of NE cells from primary fresh human prostate adenocarcinoma based on the cell surface receptor C-X-C motif chemokine receptor 2 (CXCR2). Functional studies revealed CXCR2 to be a driver of the NE phenotype, including loss of AR expression, lineage plasticity, and resistance to hormonal therapy. CXCR2-driven NE cells were critical for the tumor microenvironment by providing a survival niche for the AR+ luminal cells. We demonstrate that the combination of CXCR2 inhibition and AR targeting is an effective treatment strategy in mouse xenograft models. Such a strategy has the potential to overcome therapy resistance caused by tumor cell heterogeneity.

A novel host-adapted strain of Salmonella Typhimurium causes renal disease in olive ridley turtles (Lepidochelys olivacea) in the Pacific.

Salmonella spp. are frequently shed by wildlife including turtles, but S. enterica subsp. enterica serovar Typhimurium or lesions associated with Salmonella are rare in turtles. Between 1996 and 2016, we necropsied 127 apparently healthy pelagic olive ridley turtles (Lepidochelys olivacea) that died from drowning bycatch in fisheries and 44 live or freshly dead stranded turtles from the west coast of North and Central America and Hawaii. Seven percent (9/127) of pelagic and 47% (21/44) of stranded turtles had renal granulomas associated with S. Typhimurium. Stranded animals were 12 times more likely than pelagic animals to have Salmonella-induced nephritis suggesting that Salmonella may have been a contributing cause of stranding. S. Typhimurium was the only Salmonella serovar detected in L. olivacea, and phylogenetic analysis from whole genome sequencing showed that the isolates from L. olivacea formed a single clade distinct from other S. Typhimurium. Molecular clock analysis revealed that this novel clade may have originated as recently as a few decades ago. The phylogenetic lineage leading to this group is enriched for non-synonymous changes within the genomic area of Salmonella pathogenicity island 1 suggesting that these genes are important for host adaptation.

Insomnia symptoms are associated with elevated C-reactive protein in young adults.

OBJECTIVE: Insomnia is associated with elevated inflammation; however, studies have not investigated if this relationship is confounded with depression and neuroticism, which are associated with insomnia and inflammation. The current study examined the association of insomnia symptoms with C-reactive protein (CRP) and with interleukin-6 (IL-6), independently and after controlling for depressive symptoms and neuroticism. DESIGN: Fifty-two young adults (mean age = 25.2 ± 3.9 years, 52% female) completed a baseline survey to assess psychological characteristics, followed by a plasma blood draw. MAIN OUTCOME MEASURES: Plasma CRP and IL-6. RESULTS: When examined alone, insomnia symptoms were significantly associated with elevated CRP (ß = 0.52; R2 = 0.27), as was neuroticism (ß = 0.41, R2 = 0.17), but not depressive symptoms (ß = 0.21, R2 = 0.05). The association between insomnia symptoms and CRP remained significant when depressive symptoms and neuroticism were entered into the model simultaneously; this model did not explain more variance than the model with insomnia symptoms alone. No variables were associated with IL-6. CONCLUSIONS: Results suggest that insomnia symptoms are independently associated with elevated CRP in young adults, even after controlling for presumed overlapping psychological constructs. Findings highlight the potential importance of treating insomnia to reduce systemic inflammation.