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Mild traumatic brain injury (mTBI), often referred to as concussion, is a major cause of morbidity and mortality worldwide. Sleep disturbances are common after mTBI. Moreover, subjects who develop subjective sleep complaints after mTBI also report more severe somatic, mental health, and cognitive impairment and take longer to recover from mTBI sequelae. Despite many previous studies addressing the role of sleep in post-mTBI morbidity, the mechanisms linking sleep to recovery after mTBI remain poorly understood. The glymphatic system is a brain-wide network that supports fluid movement through the cerebral parenchyma and the clearance of interstitial solutes and wastes from the brain. Notably, the glymphatic system is active primarily during sleep. Clearance of cellular byproducts related to somatic, mental health, and neurodegenerative processes (e.g., amyloid-β and tau, among others) depends in part on intact glymphatic function, which becomes impaired after mTBI. In this viewpoint, we review the current knowledge regarding the association between sleep disturbances and post-mTBI symptoms. We also discuss the role of glymphatic dysfunction as a potential link between mTBI, sleep disruption, and post-traumatic morbidity. We outline a model where glymphatic dysfunction and sleep disruption caused by mTBI may have an additive effect on waste clearance, leading to cerebral dysfunction and impaired recovery. Finally, we review the novel techniques being developed to examine glymphatic function in humans and explore potential interventions to alter glymphatic exchange that may offer a novel therapeutic approach to those suffering from poor sleep and prolonged symptoms after mTBI.

Common methods for evaluating history of traumatic brain injury (TBI) include self-report, electronic medical record review (EMR), and structured interviews such as the Head Trauma Events Characteristics (HTEC). Each has strengths and weaknesses, but little is known regarding how TBI diagnostic rates or the associated symptom profile differ among them. This study examined 200 Veterans recruited within the VA Portland Health Care System, each evaluated for TBI using self-report, EMR, and HTEC. Participants also completed validated questionnaires assessing chronic symptom severity in broad health-related domains (pain, sleep, quality of life, post-concussive symptoms). The HTEC was more sensitive (80% of participants in our cohort) than either self-report or EMR alone (40%). As expected from the high sensitivity, participants screening positive for TBI through the HTEC included many people with mild or no post-concussive symptoms. Participants were grouped according to degree of concordance across these diagnostic methods: no TBI, n = 43; or TBI-positive in any one method (TBI-1dx, n = 53), positive in any two (TBI-2dx, n = 45), or positive in all three (TBI-3dx, n = 59). The symptom profile of the TBI-1dx group was indistinguishable from the no TBI group. The TBI-3dx group had the most severe symptom profile. Our results show that understanding the exact methods used to ascertain TBI is essential when interpreting results from other studies, given that results and conclusions may differ dramatically depending on the method. This issue will become even more critical when interpreting data merged from multiple sources within newer, centralized repositories (e.g., Federal Interagency Traumatic Brain Injury Research [FITBIR]).

Purpose The objective of this study was determine the prevalence of low health literacy (HL) and low reading ability among patients with chronic lung disease referred for pulmonary rehabilitation (PR) in the Netherlands and their loved ones; and to understand whether low HL or low reading ability influence PR outcomes. Methods Health literacy was measured using the Health Literacy Survey-Europe Q16 (HLS-EU-Q16). Reading ability and cognitive functioning were measured using the Rapid Estimate of Adult Literacy in Medicine-Dutch (REALM-D) and the Montreal Cognitive Assessment. Exercise capacity, health status, and symptoms of anxiety and depression were assessed. Results Patients (n = 120) entering PR and loved ones (n = 41) participated. Of all patients, 51% had low HL and 29% had low reading ability. Also, 39% of all loved ones had low HL. PR outcomes were comparable between patients with low or adequate HL. Patients with adequate reading ability showed greater improvement in symptoms of depression than patients with low reading ability (P = .047). Conclusion Low HL and low reading ability are common among patients entering PR and their loved ones. For patients with low or adequate HL, PR is an effective treatment. Whether considering low HL and low reading ability by offering tailored education during treatment could augment the benefits of PR warrants further study.

Juan Piantino,1 Madison Luther,1 Christina Reynolds,2 Miranda M Lim2– 4 1Department of Pediatrics, Division of Child Neurology, Doernbecher Children’s Hospital, Oregon Health and Science University, Portland, OR, USA; 2Department of Neurology, Department of Medicine, Division of Pulmonary and Critical Care Medicine, Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR, USA; 3Oregon Institute of Occupational Health Sciences, Oregon Health & Science University, Portland, OR, USA; 4Neurology Research Service and National Center for Rehabilitative Auditory Research, VA Portland Health Care System, Portland, OR, USACorrespondence: Juan Piantino Email piantino@ohsu.eduPurpose: Wrist-worn actigraphy via research-grade devices, a well-established approach to the assessment of rest-activity, is limited by poor compliance, battery life, and lack of direct evidence for time spent physically in the bed. A non-invasive bed sensor (Emfit) may provide advantages over actigraphy for long-term sleep assessment in the home. This study compared sleep-wake measurements between this sensor and a validated actigraph.Patients and Methods: Thirty healthy subjects (6 to 54 years) underwent simultaneous monitoring with both devices for 14 days and filled out a daily sleep diary. Parameters included bed entry time, sleep start, sleep end, bed exit time, rest interval duration, and wake after sleep onset (WASO). The agreement between the two devices was measured using Bland–Altman plots and inter-class correlation coefficients (ICC). In addition, sensitivity, specificity, and accuracy were obtained from epoch-by-epoch comparisons of Emfit and actigraphy.Results: Fifteen percent of the subjects reported that wearing the actigraph was a burden. None reported that using the bed sensor was a burden. The minimal detectable change between Emfit and actigraphy was 11 minutes for bed entry time, 14 minutes for sleep start, 14 minutes for sleep end, 10 minutes for bed exit time, 20 minutes for rest interval duration, and 110 minutes for WASO. Inter-class correlation coefficients revealed an excellent agreement for all sleep parameters (ICC=0.99, 95% CI 98– 99) except for WASO (ICC=0.46, 95% CI 0.33– 0.56). Sensitivity, specificity, and accuracy were 0.62, 0.93, and 0.88, respectively. Kappa correlation analysis revealed a moderate correlation between the two devices (κ=0.55, p< 0.0001).Conclusion: Emfit is an acceptable alternative to actigraphy for the estimation of bed entry time, sleep start, sleep end, bed exit time, and rest interval duration. However, WASO estimates are poorly correlated between the two devices. Emfit may offer methodological advantages in situations where actigraphy is challenging to implement.Keywords: Actiwatch 2, Emfit, ambulatory, sleep-wake monitoring

Arbuscular mycorrhizal fungi (AMF) community assembly has been investigated at regional and local scales, but was largely unknown at micro-scale. The AMF community at soil aggregate level was studied to promote the understanding of their distribution at micro-scale. Surface soil associated with Eremochloa ophiuroides, Imperata cylindrica and Paspalum notatum were sieved into three fractions: large macroaggregates (LMA, >2mm), small macroaggregates (SMA, 0.25–2mm) and microaggregates (MA, Glomus (>90%) and Paraglomus (>6%), across plants. Higher AMF diversity was found in SMA or MA than LMA, which was positively related to soil nutrient levels. The soil pH and available phosphorus were related to the AMF diversity in SMA, while available potassium (AK) was related to the AMF diversity in MA. The correlation between Glomus, Claroideoglomus, or Paraglomus and soil pH or available phosphorus in SMA, and between Glomus and AK in MA could explain AMF diversity changes. The AMF community composition was consistent in three soil aggregate fractions. Our results demonstrate that AMF diversity, but not community composition, differ across soil aggregate sizes. The AMF diversity changes are related to edaphic factors, following a microscale-dependent pattern.

Dentoalveolar surgery is probably the major risk factor for MRONJ and for other complications following a tooth extraction, especially in patients affected by systemic diseases. The aim of this retrospective study is to evaluate whether a PRF plug inserted in the post extraction socket can prevent the onset of MRONJ. The patients were divided into two groups according to the surgical protocol that included the insertion or not of the PRF following the extraction and all the anamnestic, and clinical data were analyzed. In the control group, 5 patients developed MRONJ (19.23%) while in the study group, any case of MRONJ was reported. In the control group, patients who developed MRONJ had a CTX with less than 100 pg/mL (5 high-risk patients, Spearman’s rank r = .547 , p < .001 ). The use of platelet concentrates in patients with high risk of MRONJ is a user-friendly technique with an excellent cost-benefit ratio in oral surgery.

Background Prodromal Parkinson's disease of skin, genitourinary, and gastrointestinal systems offers a unique window for understanding early disease pathogenesis and developing disease modifying treatments. However, prior studies are limited by incomplete timing information, small sample size, and lack of adjustment for known confounders. Verifying prodromal timing and identifying new disorders in these accessible organs is critically important given their broad use. Objective We aimed to measure onset timing for gastrointestinal, genitourinary, and skin disorders in a large, nationwide clinically characterized cohort of 1.5 million participants. Methods Patients with Parkinson's disease (n = 303,693) were identified using diagnostic codes in the medical records database of the United States Veterans Affairs healthcare system and were compared 4:1 with matched controls. Disorder prevalence and estimated onset times were assessed for 20 years preceding diagnosis. Results The earliest significantly increased prodromal disorders were gastroesophageal reflux, sexual dysfunction, and esophageal dyskinesia at 17, 16, and 15 years before diagnosis. Estimated onset times for each disorder occurred 5.5 ± 3.4 years before the first measured increase. The earliest estimated onset times were smell/taste, upper gastrointestinal tract, and sexual dysfunction at 20.9, 20.6, and 20.1 years before diagnosis. Onset times for constipation and urinary dysfunction were notably longer by 7 and 9 years compared to prior studies in sleep disorder patients. Dermatophytosis and prostatic hypertrophy were identified as new high prevalence prodromal disorders. Conclusions Gastrointestinal, genitourinary, and skin disorders manifest decades before diagnosis of Parkinson's disease, reiterating their potential as sites for developing early diagnostic testing and understanding pathogenesis.

Cerebrospinal fluid (CSF), a clear fluid bathing the central nervous system (CNS), undergoes pulsatile movements, and plays a critical role for the removal of waste products from the brain including amyloid beta, a protein associated with Alzheimer’s disease. Regulation of CSF dynamics is critical for maintaining CNS health, and increased pulsatile CSF dynamics may alter brain’s waste clearance due to increased mixing and diffusion. As such, understanding the mechanisms driving CSF movement, and interventions that influence its resultant removal of wastes from the brain is of high scientific and clinical impact. Since pulsatile CSF dynamics is sensitive and synchronous to respiratory movements, we are interested in identifying potential integrative therapies such as yogic breathing to regulate and enhance CSF dynamics, which has not been reported before. Here, we investigated the pre-intervention baseline data from our ongoing randomized controlled trial, and examined whether yogic breathing immediately impacts pulsatile CSF dynamics compared to spontaneous breathing. We utilized our previously established non-invasive real-time phase contrast magnetic resonance imaging (RT-PCMRI) approach using a 3T MRI instrument, and computed and rigorously tested differences in CSF velocities (instantaneous, respiratory, cardiac 1st and 2nd harmonics) at the level of foramen magnum during spontaneous versus four yogic breathing patterns. In examinations of 18 healthy participants (eight females, ten males; mean age 34.9 ± 14 (SD) years; age range: 18-61 years), we discovered immediate increase in cranially-directed velocities of instantaneous-CSF 16% - 28% and respiratory-CSF 60% - 118% during yogic versus spontaneous breathing, with most statistically significant changes during deep abdominal breathing (28%, p=0.0008, and 118%, p=0.0001, respectively). Further, cardiac pulsation was the primary source of pulsatile CSF during all breathing conditions except during deep abdominal breathing, when there was a comparable contribution of respiratory and cardiac 1st harmonic power [0.59 ± 0.78], demonstrating respiration can be the primary regulator of CSF depending on individual differences in breath depth and location. Further work is needed to investigate the impact of sustained training yogic breathing on increased pulsatile CSF dynamics and brain waste clearance for CNS health.

Periodontal disease is a chronic disease, affects the supporting tissues of the tooth. The clinical manifestation varies from gingivitis to periodontitis. Periodontal disease is caused by bacterial infection that release toxins. The imbalance between oxidants and antioxidants determines the progression of periodontal disease. Melatonin (MEL), (N-acetyl-5-methoxytrittamine) is a hormone in the human body. Its production takes place in various organs including the retina, gastrointestinal tract, bone marrow, leukocytes, lymphocytes, skin, and principally pineal gland. Its main function is the regulation of the circadian and seasonal rhythm, body weight, reproduction, bone metabolism, and tumor growth. An important function of melatonin is the ability to reduce oxidative stress. The aim of this review is to evaluate the necessary effects on melatonin on the progression of periodontal disease and diabetes. The purpose of this review is to answer to the following questions using a PICO method (P: patient problem/population; I: intervention; C: comparison; O: outcome): (1) Can adding melatonin in diabetic and periodontal patients lead to improved periodontal health? (2) Does melatonin also affect the control of blood sugar levels in the diabetic patient? The study was conducted utilizing the main scientific databases (PubMed, MEDLINE, and WEB of SCIENCE). The time window considered for the electronic search was from March 1, 2007, to March 1, 2020. The following inclusion criterion was used: articles in English, human studies and clinical trials. Two independent people search with the same keywords all article and select the article founding. The risk of bias in this phase is solved by an independent author that conduct the same search. We can hypothesize that melatonin may indirectly help control blood sugar levels. Further studies will be needed to evaluate a direct healing effect of melatonin on diabetes.

Background: Few studies using criterion measures of insulin sensitivity (SI) and insulin secretory capacity (ISC) have been conducted across puberty to adulthood. We examined how SI and ISC change from pre-puberty through adulthood.Methods: Hyperglycemic clamp studies were performed in a convenience sample of non-Hispanic Black (NHB) and White children evaluated at age 6 to 12 years and at approximately 5-year intervals into adulthood (maximum age 27 years). SI and ISC (first-phase and steady-state insulin secretion) were determined cross-sectionally in 133 unique participants across puberty and in adulthood. Additionally, longitudinal changes in SI and ISC were compared at two timepoints among three groups defined by changes in pubertal development: pre-pubertal at baseline and late-pubertal at follow-up (n=27), early-pubertal at baseline and late-pubertal at follow-up (n=27), and late-pubertal at baseline and adult at follow-up (n=24).Results: Cross-sectionally, SI was highest in pre-puberty and early puberty and lowest in mid-puberty (analysis of covariance [ANCOVA] P=0.001). Longitudinally, SI decreased from pre-puberty to late puberty (PPPP=0.003) and greater first-phase and steady-state ISC (P≤0.001), independent of pubertal development.Conclusion: This study confirms that SI decreases and ISC increases transiently during puberty and shows that these changes largely resolve in adulthood.

Early postnatal experiences are important for shaping the development of the stress response and may contribute to the later emergence of alcohol use disorders. We have previously found that early life sleep disruption impairs social development and alters GABA neurons in the brain of adult prairie voles, a socially monogamous rodent that displays natural ethanol preference in the laboratory. However, it is unclear whether these effects on social behavior are due, in part, to overall anhedonia and/or altered behavioral response to stress. To address this question, litters containing prairie vole pups were sleep disrupted by gentle cage agitation for 7 consecutive days from postnatal days (P) 14 to 21 (early life sleep disruption, or ELSD group) or allowed to sleep undisturbed (Control). Adult voles underwent a 2-bottle choice ethanol drinking procedure integrated with a single session of footshocks. Ethanol intake after footshock was measured as well as c-Fos immunoreactivity in the lateral and central amygdala. ELSD animals showed increased ethanol consumption and increased neural activity in these amygdala regions after footshock compared to control animals. There were no differences in baseline ethanol drinking prior to exposure to a stressor. These results suggest that early life sleep disruption in prairie voles does not produce anhedonia but can have long-lasting effects on stress reactivity. In addition to shaping species-typical social behavior, early life sleep may be important in the development of stress induced ethanol consumption and the activation of limbic pathways associated with stress. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Summary Background Breast cancer has distinct causes, prognoses, and outcomes and effects in patients at premenopausal and postmenopausal ages. We sought to assess the global burden and trends in breast cancer by menopausal status. Methods We did a population-based analysis of global breast cancer incidence and mortality among premenopausal and postmenopausal women. Menopausal status was defined using age as a proxy, whereby breast cancer cases or deaths at age 50 years or older were regarded as postmenopausal. Age-standardised breast cancer incidence and mortality in 2018 were calculated using GLOBOCAN data. Incidence trends for 1998–2012 were assessed in 44 populations from 41 countries using the Cancer in Five Continents plus database, by calculating the annual average percent change. Findings Approximately 645 000 premenopausal and 1·4 million postmenopausal breast cancer cases were diagnosed worldwide in 2018, with more than 130 000 and 490 000 deaths occurring in each menopausal group, respectively. Proportionally, countries with a low UNDP human development index (HDI) faced a greater burden of premenopausal breast cancer for both new cases and deaths compared with higher income countries. Countries with a very high HDI had the highest premenopausal and postmenopausal breast cancer incidence (30·6 and 253·6 cases per 100 000, respectively), whereas countries with low and medium HDI had the highest premenopausal and postmenopausal mortality, respectively (8·5 and 53·3 deaths per 100 000, respectively). When examining breast cancer trends, we noted significantly increasing age-standardised incidence rates (ASIRs) for premenopausal breast cancer in 20 of 44 populations and significantly increasing ASIRs for postmenopausal breast cancer in 24 of 44 populations. The growth exclusively at premenopausal ages largely occurred in high-income countries, whereas the increasing postmenopausal breast cancer burden was most notable in countries under transition. Interpretation We provide evidence of a rising burden of both premenopausal and postmenopausal breast cancer worldwide. Although early diagnosis and access to treatment remain crucial in low-income and middle-income countries, primary prevention efforts seeking to decrease exposure to known breast cancer risk factors are warranted in all world regions to curb the future breast cancer burden. Funding None.

Purpose: Sedentary time relates to higher anxiety and more negative affect in children. This study assessed whether interrupting sitting over 3 hours is sufficient to influence state anxiety, positive affect, or negative affect, and tested weight status as a moderator. Methods: Analyses were the second (preplanned) purpose of a larger study. Children (N = 61; age: mean [SD] = 9.5 [1.3]; 43% healthy weight) completed 2 experimental conditions: continuous sitting for 3 hours and sitting for 3 hours interrupted with walking for 3 minutes in every 30 minutes. State anxiety, positive affect, and negative affect were reported at pretest and posttest. Multilevel models for repeated measures assessed whether experimental condition predicted posttest scores. Results: Experimental condition was unrelated to posttest state anxiety or positive affect. Weight status moderated how experimental condition influenced posttest negative affect (P = .003). Negative affect was lower in the children of healthy weight after interrupted sitting (vs continuous sitting; β = −0.8; 95% confidence interval, −1.5 to 0.0, P = .05), but it was higher in the children with overweight/obesity after interrupted sitting (vs continuous sitting; β = 0.6; 95% confidence interval, 0.0 to 1.2, P = .06). Conclusions: Interrupting sitting acutely reduced negative affect in children of healthy weight, but not in children with overweight. Further research is needed to better understand the potential emotional benefits of sitting interruptions in youth.

Background Although adolescent and young adult (AYA) cancers represent a unique spectrum of malignancies, epidemiological studies of cancer incidence often group AYAs together with younger or older populations, obscuring patterns specific to this population. Methods We examined AYA cancer incidence trends in 41 countries over a 15-year period using the CI5plus database. Truncated age-standardized incidence rates were calculated and the annual percentage change was assessed, with statistical significance corresponding to a 95% confidence interval that does not include zero. Results From 1998 to 2012, the 41 included countries contributed a total of 1 846 588 cancer cases and 3.1 billion person-years among AYAs. Although statistically significant increases in the overall cancer burden were observed in 23 countries, the magnitude varied considerably, with the greatest increase in incidence observed in South Korea (annual percentage change2002–2012 = 8.5%, 95% confidence interval = 7.6% to 9.4%) due to thyroid cancer. Notable trends included sharp increases in the incidence of obesity-related malignancies among AYAs; indeed, statistically significant increases were observed among AYAs for 10 of 11 and 9 of 11 obesity-related cancer sites in the US and UK, respectively, with at least five obesity-related cancers statistically significantly increasing in Canada, Japan, South Korea, Australia, and the Netherlands. Other striking trends were noted for thyroid and testicular cancer, with statistically significantly increasing rates observed in 33 and 22 countries, respectively, whereas statistically significant declines in incidence were observed for smoking-related cancers, cervical cancer, and Kaposi sarcoma in many countries. Conclusions Our results highlight the future health-care needs related to treatment as well as the urgency for public health initiatives that can mitigate the increasing burden of cancer in AYAs.

Previous studies have reported converging lung cancer rates between sexes. We examine lung cancer incidence rates in young women vs. young men in 40 countries across five continents. Lung and bronchial cancer cases by 5-year age group (ages 30-64) and 5-year calendar period (1993-2012) were extracted from Cancer Incidence in Five Continents. Female-to-male incidence rate ratios (IRRs) and 95% confidence intervals (95%CIs) were calculated by age group and birth cohort. Among men, age-specific lung cancer incidence rates generally decreased in all countries, while in women the rates varied across countries with the trends in most countries stable or declining, albeit at a slower pace compared to those in men. As a result, the female-to-male IRRs increased among recent birth cohorts, with IRRs significantly greater than unity in Canada, Denmark, Germany, New Zealand, the Netherlands and the United States. For example, the IRRs in ages 45-49 year in the Netherlands increased from 0.7 (95% CI: 0.6-0.8) to 1.5 (95% CI: 1.4-1.7) in those born circa 1948 and 1963, respectively. Similar patterns, though nonsignificant, were found in 23 additional countries. These crossovers were largely driven by increasing adenocarcinoma incidence rates in women. For those countries with historical smoking data, smoking prevalence in women approached, but rarely exceeded, those of men. In conclusion, the emerging higher lung cancer incidence rates in young women compared to young men is widespread and not fully explained by sex differences in smoking patterns. Future studies are needed to identify reasons for the elevated incidence of lung cancer among young women.

Background Sleep-wake disturbances are underevaluated among children with acquired brain injury surviving critical care. We aimed to quantify severity, phenotypes, and risk factors for sleep-wake disturbances. Methods We performed a prospective cohort study of 78 children aged ≥3 years with acquired brain injury within three months of critical care hospitalization. Diagnoses included traumatic brain injury (n = 40), stroke (n = 11), infectious or inflammatory disease (n = 10), hypoxic-ischemic injury (n = 9), and other (n = 8). Sleep Disturbances Scale for Children standardized T scores measured sleep-wake disturbances. Overall sleep-wake disturbances were dichotomized as any total or subscale T score ≥60. Any T score ≥70 defined severe sleep-wake disturbances. Subscale T scores ≥60 identified sleep-wake disturbance phenotypes. Results Sleep-wake disturbances were identified in 44 (56%) children and were classified as severe in 36 (46%). Sleep-wake disturbances affected ≥33% of patients within each diagnosis and were not associated with severity of illness measures. The most common phenotype was disturbance in initiation and maintenance of sleep (47%), although 68% had multiple concurrent sleep-wake disturbance phenotypes. One third of all patients had preadmission chronic conditions, and this increased risk for sleep-wake disturbances overall (43% vs 21%, P = 0.04) and in the traumatic brain injury subgroup (52% vs 5%, P = 0.001). Conclusions Over half of children surviving critical care with acquired brain injury have sleep-wake disturbances. Most of these children have severe sleep-wake disturbances independent of severity of illness measures. Many sleep-wake disturbances phenotypes were identified, but most children had disturbance in initiation and maintenance of sleep. Our study underscores the importance of evaluating sleep-wake disturbances after acquired brain injury.

Aims The aim of this study was to evaluate the possible value of dobutamine stress cardiac magnetic resonance imaging (CMR) to predict adverse outcome in Tetralogy of Fallot (TOF) patients. Methods and results In previous prospective multicentre studies, TOF patients underwent low-dose dobutamine stress CMR (7.5 µg/kg/min). Subsequently, during regular-care patient follow-up, patients were assessed for reaching the composite endpoint (cardiac death, arrhythmia-related hospitalization, or cardioversion/ablation, VO2 max ≤65% of predicted). A normal stress response was defined as a decrease in end-systolic volume (ESV) and increase in ejection fraction. The relative parameter change during stress was calculated as relative parameter change = [(parameterstress − parameterrest)/parameterrest] * 100. The predictive value of dobutamine stress CMR for the composite endpoint was determined using time-to-event analyses (Kaplan–Meier) and Cox proportional hazard analysis. We studied 100 patients [67 (67%) male, median age at baseline CMR 17.8 years (interquartile range 13.5–34.0), age at TOF repair 0.9 years (0.6–2.1)]. After a median follow-up of 8.6 years (6.7–14.1), 10 patients reached the composite endpoint. An abnormal stress response (30% vs. 4.4%, P = 0.021) was more frequently observed in composite endpoint patients. Also in endpoint patients, the relative decrease in right ventricular ESV decreased less during stress compared with the patients without an endpoint (−17 ± 15 vs. −26 ± 13 %, P = 0.045). Multivariable analyses identified an abnormal stress response (hazard ratio 10.4; 95% confidence interval 2.5–43.7; P = 0.001) as predictor for the composite endpoint. Conclusion An abnormal ventricular response to dobutamine stress is associated with adverse outcome in patients with repaired TOF.

Allogeneic blood or marrow transplantation (BMT) is a potentially curative therapy for patients with primary immunodeficiency (PID). Safe and effective reduced-intensity conditioning (RIC) approaches that are associated with low toxicity, use alternative donors, and afford good immune reconstitution are needed to advance the field. Twenty PID patients, ranging in age from 4 to 58 years, were treated on a prospective clinical trial of a novel, radiation-free and serotherapy-free RIC, T-cell-replete BMT approach using pentostatin, low-dose cyclophosphamide, and busulfan for conditioning with post-transplantation cyclophosphamide-based graft-versus-host-disease (GVHD) prophylaxis. This was a high-risk cohort with a median hematopoietic cell transplantation comorbidity index of 3. With median follow-up of survivors of 1.9 years, 1-year overall survival was 90% and grade III to IV acute GVHD-free, graft-failure-free survival was 80% at day +180. Graft failure incidence was 10%. Split chimerism was frequently observed at early post-BMT timepoints, with a lower percentage of donor T cells, which gradually increased by day +60. The cumulative incidences of grade II to IV and grade III to IV acute GVHD (aGVHD) were 15% and 5%, respectively. All aGVHD was steroid responsive. No patients developed chronic GVHD. Few significant organ toxicities were observed. Evidence of phenotype reversal was observed for all engrafted patients, even those with significantly mixed chimerism (n = 2) or with unknown underlying genetic defect (n = 3). All 6 patients with pre-BMT malignancies or lymphoproliferative disorders remain in remission. Most patients have discontinued immunoglobulin replacement. All survivors are off immunosuppression for GVHD prophylaxis or treatment. This novel RIC BMT approach for patients with PID has yielded promising results, even for high-risk patients.

Diabetes is a growing public health epidemic in the U.S. African Americans are particularly at-risk for diabetes with rates twice as high as whites. Health professionals are recommended to encourage their at-risk patients to participate in evidence-based lifestyle change programs, such as CDC's National Diabetes Prevention Program (DPP) and support their weight loss efforts. This chapter describes feasibility/outcomes of a community-based collaborative care model used to implement a weekly-group DPP facilitated by interprofessional teams of medical school students with three African American churches (N=72 participants; 93% overweight/obese). At 12-weeks, 30% of participants had lost at least 5 lbs.; among those attending at least nine sessions, 55% achieved at least 3% weight loss. Findings suggest interprofessional student teams can feasibly partner with churches to deliver the DPP and achieve weight-loss outcomes associated with reducing diabetes risk. Future research is needed to determine scalability/costs of using community-based collaborative care student models to address diabetes.

Background New treatments are currently offering new opportunities and challenges in clinical management and research in the migraine field. There is the need of homogenous criteria to identify candidates for treatment escalation as well as of reliable criteria to identify refractoriness to treatment. To overcome those issues, the European Headache Federation (EHF) issued a Consensus document to propose criteria to approach difficult-to-treat migraine patients in a standardized way. The Consensus proposed well-defined criteria for resistant migraine (i.e., patients who do not respond to some treatment but who have residual therapeutic opportunities) and refractory migraine (i.e., patients who still have debilitating migraine despite maximal treatment efforts). The aim of this study was to better understand the perceived impact of resistant and refractory migraine and the attitude of physicians involved in migraine care toward those conditions. Methods We conducted a web-questionnaire-based cross-sectional international study involving physicians with interest in headache care. Results There were 277 questionnaires available for analysis. A relevant proportion of participants reported that patients with resistant and refractory migraine were frequently seen in their clinical practice (49.5% for resistant and 28.9% for refractory migraine); percentages were higher when considering only those working in specialized headache centers (75% and 46% respectively). However, many physicians reported low or moderate confidence in managing resistant (8.1% and 43.3%, respectively) and refractory (20.7% and 48.4%, respectively) migraine patients; confidence in treating resistant and refractory migraine patients was different according to the level of care and to the number of patients visited per week. Patients with resistant and refractory migraine were infrequently referred to more specialized centers (12% and 19%, respectively); also in this case, figures were different according to the level of care. Conclusions This report highlights the clinical relevance of difficult-to-treat migraine and the presence of unmet needs in this field. There is the need of more evidence regarding the management of those patients and clear guidance referring to the organization of care and available opportunities.

There is a global industry built upon the production of ‘bioinoculants’, which include both bacteria and fungi. The recent increase in bioinoculant uptake by land users coincides with a drive for more sustainable land use practises. But are bioinoculants sustainable? These microbes are believed to improve plant performance, but knowledge of their effect on resident microbial communities is scant. Without a clear understanding of how they affect soil microbial communities, their utility is unclear. To assess how different inoculation practises may affect bioinoculant effects on soil microbial communities, we surveyed the existing literature. Our results show that bioinoculants significantly affect soil microbial diversity and that these effects are mediated by inoculant type, diversity, and disturbance regime. Further, these changes to soil microbes affect plant outcomes. Knowledge that these products may influence crop performance indirectly through changes to soil microbial diversity attests to the importance of considering the soil microbiome when assessing both bioinoculant efficacy and threats to soil ecosystems.

Background: Remdesivir (RDV) was approved for treatment of coronavirus disease 2019 (COVID-19), in May 2020 under US Food and Drug Administration emergency use authorization (EUA). Clinical outcomes related to RDV use in hospitalized patients during the EUA period are not well described. Methods: We conducted a retrospective study of patients who received RDV under EUA. The primary outcome was clinical recovery by day 14 as determined by an eight-category ordinal scale. Secondary outcomes included recovery and survival to day 28, and adverse events. Recovery and survival were calculated using a stratified log-rank Kaplan–Meier estimator and a Cox proportional hazards model. Results: Overall, 164 patients received RDV between May and October 2020, and 153 (93.3%) had evaluable data. Most (77.1%) were hospitalized within 10 days of symptom onset, and 79.7% started RDV within 48 hours. By days 14 and 28, 96 (62.7%) and 117 patients (76.5%) met the definition of clinical recovery, respectively. Median time to recovery was 6 days [interquartile range (IQR) 4–12]. Mortality rates were 6.5% and 11.8% by days 14 and 28, respectively. Age and time to start of RDV after hospital admission were predictive of recovery and 28-day mortality. Conclusions: In this real-world experience, outcomes after 5 days of RDV therapy were comparable to those of clinical trials. Disease severity, age, and dexamethasone use influenced clinical outcomes. Time to RDV initiation appeared to affect recovery and 28-day mortality, a finding that should be explored further. Mortality rate decreased over the analysis period, which could be related to dexamethasone use and improved management of COVID-19.

BackgroundTrauma-related disorders such as traumatic brain injury (TBI) and posttraumatic stress disorder (PTSD) are emerging as risk factors for Parkinson’s Disease (PD), but their association with development of PD and independence from comorbid disorders remains unknown. This case-control study examines TBI and PTSD related to early trauma in military veterans.MethodsPD was identified by ICD code, recurrent PD-specific prescriptions, and availability of 5+ years of earlier records. Validation was performed by chart review by a movement disorder-trained neurologist. Controls were matched 4:1 by age, duration of preceding health care, race, ethnicity, birth year, and sex. TBI and PTSD were identified by ICD code and onset based on active duty. Association and interaction were measured for TBI and PTSD with PD going back sixty years. Interaction was measured for comorbid disorders.Results71,933 cases and 287,732 controls were identified. TBI and PTSD increased odds of subsequent PD at all preceding five-year intervals back to year -60 (OR range: 1.5 [1.4,1.7] to 2.1 [2.0,2.1]). TBI and PTSD showed synergism (synergy index range: 1.14 [1.09,1.29] to 1.28 [1.09,1.51]) and additive association (OR range: 2.2 [1.6,2.8] to 2.7 [2.5,2.8]). Chronic pain and migraine showed greatest synergy with PTSD and TBI. Effect sizes for trauma-related disorders were comparable to established prodromal disorders.DiscussionTBI and PTSD are associated with later PD and are synergistic with chronic pain and migraine. These findings provide evidence for TBI and PTSD as risk factors preceding PD by decades and could aid in prognostic calculation and earlier intervention.

Cancer stem cells are a subpopulation of tumor cells that have the ability to self-renew, initiate tumors in model systems, and differentiate into non-cancer stem cells. They are also resistant to current standard of care treatments, such as radiotherapy and chemotherapy. Due to these properties, cancer stem cells contribute to tumor progression and recurrence and need to be inclusively targeted with therapeutic paradigms used in the clinical setting. This chapter covers the most up-to-date published information on cancer stem cells in the context of pediatric brain tumors. The characteristics of pediatric brain tumor cancer stem cells, including resistance mechanisms and differential genetic regulation that allow for the stem like phenotype, are presented. The current research on cancer stem cells in medulloblastoma, ependymoma, diffuse intrinsic pontine glioma, and pediatric gliomas as well as potential approaches that are being developed to target cancer stem cells are highlighted. Challenges in targeting cancer stem cells in the pediatric patient population are also discussed.

Few studies have assessed the accuracy of the FreeStyle Libre Pro (FLP) continuous glucose monitor for estimating plasma glucose (PG) in non-diabetic children. OBJECTIVE Determine the accuracy of FLP compared to PG during OGTT in healthy children. SUBJECTS Children (7-11.99 years) with healthy weight and overweight/obesity (n = 33; 52% male). METHODS Participants wore the FLP before and during a 2-hour OGTT; PG was measured at 30 minutes intervals. Potential systematic- and magnitude-related biases for FLP vs PG were examined. RESULTS FLP 15-minute averages and PG were correlated at most timepoints during OGTT (r2 = 0.35-0.69, P's

Bladder pain syndrome (BPS) is a common cause of chronic pelvic pain with associated lower urinary symptoms. BPS is incurable; management requires an interdisciplinary team (nutritionist, physical therapist, behavioral health specialist) focusing on maximizing patient function. For patients, dietary changes (avoiding acidic, spicy, and caffeinated foods) are effective at relieving symptoms. Medications may be considered in patients who do not respond to these treatments. Referral to urology or urogynecology should be considered if bladder cancer is suspected (especially in patients who smoke or have environmental exposures) and in patients with refractive symptoms for consideration of intravesicular therapy.

Purpose: To investigate the intervention effects of using traditional Chinese Guqin music and Chinese Calligraphy handwriting (CCH) for patients with Primary Insomnia. Methods: A total of ninety patients were assigned to control group, Guqin group, and calligraphy group for 8 weeks. For 5 days a week, patients' heart rate variability (HRV) and frontal midline (FZ) electroencephalographic signals were recorded in a clinic during interventional period while either listening to Guqin music or writing calligraphy. Patients in the control group remained in rest condition. Results: For the Guqin group, the higher low-frequency-range HRV of coherence was found with marginal significance (P = 0.055), and heart rate was significantly reduced (P < 0.05) during the 4th week in listening to Guqin music compared to the prerest period. For listening to Guqin music or calligraphy intervention, FZ δ, FZ θ, and FZ α waves in the 8th week compared to the 0th week (Pre Intervention) showed a significantly enhanced effect (P < 0.05). Between the three groups, for heart rate and FZ δ and FZ θ waves, calligraphy group showed significantly increased heart rate than the Guqin group (P < 0.001)and the control group (P = 0.004); increased FZ δ wave than the Guqin group (P < 0.001) and the control group (P < 0.001); and increased FZ θ wave than the Guqin group (P = 0.024) and the control group (P = 0.008) respectively. Conclusion: Positive intervention effects on HRV coherence of Guqin music; FZ δ, FZ θ, and FZ α waves of Guqin music and calligraphy proved that Guqin music together with calligraphy training helping to promote physical and mental health, thereby it contributes to the clinical application of TCM Psychology for patients with insomnia syndrome.

Objective biomarkers of the presence and severity of posttraumatic stress disorder (PTSD) are elusive, yet badly needed. Electroencephalographic (EEG) coherence represents a promising approach to identifying and understanding brain biomarker activity in PTSD. Overnight polysomnography data containing EEG across sleep and wake states was collected in n = 76 Veterans with and without PTSD from a single site under IRB approval. Brain coherence markers (BCM) were calculated from EEG signals using a novel approach to produce one index for PTSD diagnosis (PTSDdx), and another index for PTSD severity (PTSDsev). PTSDdx showed strong sensitivity to the presence of PTSD in the awake state, during non-rapid eye movement (NREM) stage N2 sleep, and in a hybrid BCM incorporating both awake and NREM sleep states. PTSDsev showed a strong correlation with PTSD symptom severity (using the PTSD Checklist 5, or PCL5 survey) in the awake state, during N2 sleep, and in a hybrid BCM incorporating both awake and NREM sleep states. Thus, sleep EEG-based brain coherence markers can be utilized as an objective means for determining the presence and severity of PTSD. This portable, inexpensive, and non-invasive tool holds promise for better understanding the physiological mechanisms underlying PTSD and for tracking objective responses to treatment.

Purpose: This study compared the relative effectiveness of Chinese calligraphy handwriting (CCH) and acupuncture in the treatment of patients with senile dementia. Materials and Methods: A randomized controlled trial (RCT) with 17 mild-to-moderate dementia patients with an average age of 77.29 years were randomly assigned with 9 to the calligraphy handwriting group and 8 to the acupuncture treatment group for a month of consecutive treatment. The participants' cognitive abilities, as well as symptoms of senile dementia, were measured by the Chinese version of the Mini-mental State Examination (CMMSE) and the Chinese Medicine Quantitative Diagnostic Survey for Senile Dementia Symptoms, respectively, before and after the treatment. Results: The calligraphy group showed a significant increase in calculation and memory as well as a decline in the symptoms of senile dementia. Patients in the acupuncture group experienced a significant growth in total CMMSE scores and the subscales in orientation to time and place, behavioral operations, as well as reduced clinical symptoms. However, no significant changes were found in their memory and calculation abilities. Conclusion: Both CCH and acupuncture treatments were found significantly effective for, respectively, enhancing the patients' cognitive abilities and reducing their clinical symptoms. Further, calligraphy handwriting also improved the level of their attention and concentration, physical relaxation, and emotional stability.

The objective of this study was to compare the image quality of iodine maps derived from subtraction CT and from dual-energy CT (DECT) in patients with suspected pulmonary embolism (PE).In this prospective study conducted between July 2016 and April 2017, consecutive patients with suspected PE underwent unenhanced CT at 100 kV and dual-energy pulmonary CT angiography at 100 and 140 kV on a dual-source scanner. The scanner was set to generate subtraction and DECT iodine maps at similar radiation doses. In 55 patients (30 women, 25 men; mean age ± SD, 63.4 ± 11.9 years old), various subjective image quality criteria including diagnostic acceptability were rated on a 5-point scale by four radiologists and a radiology resident. In 29 patients (17 women, 12 men; mean age, 62.4 ± 11.7 years old) with confirmed perfusion defects, the signal-difference-to-noise ratio (SDNR) between perfusion defects and adjacent normally perfused parenchyma was measured in corresponding ROIs on subtraction and DECT iodine maps. McNemar and Wilcoxon signed-rank tests were used for statistical comparisons.Diagnostic acceptability was rated excellent or good in a mean of 67% (range, 31-80%) of subtraction CT studies and 36% (5-69%) of DECT studies (p0.05 for four of the five radiologists), mainly because of fewer artifacts on subtraction CT. Mean SDNR was marginally higher for subtraction CT than for DECT (18.6 vs 17.1, p = 0.06) and was significantly higher in the upper lobes (21.8 vs 17.9, p0.05).Radiologist-judged image quality of pulmonary iodine maps was higher for subtraction CT than for DECT with similar to higher SDNR. Subtraction CT is a software-only solution, so it may be an attractive alternative to DECT for depicting perfusion defects.

Background and objective Low fat‐free mass (FFM) is common in patients with chronic obstructive pulmonary disease (COPD) and contributes to morbidity and mortality. Few studies have evaluated longitudinal changes in body composition in patients with COPD compared with non‐COPD controls. This study aimed to compare longitudinal changes in total and regional body composition between patients with COPD and non‐COPD controls and investigate predictors of changes in body composition in COPD. Methods Patients with COPD and non‐COPD controls participating in the Individualized COPD Evaluation in relation to Ageing (ICE‐Age) study, a single‐centre, longitudinal, observational study, were included. Subjects were assessed at baseline and after 2 years of follow‐up. Among other procedures, body composition was measured by dual‐energy X‐ray absorptiometry scan. The number of exacerbations/hospitalizations 1 year before inclusion and during follow‐up were assessed in patients with COPD. Results A total of 405 subjects were included (205 COPD, 87 smoking and 113 non‐smoking controls). Patients with COPD and smoking controls presented a significant decline in total FFM (mean [95% CI]: −1173 [−1527/−820] g and −486 [−816/−156] g, respectively) while body composition remained stable in non‐smoking controls. In patients with COPD, the decline in FFM was more pronounced in legs (−174 [−361/14] g) and trunk (−675 [−944/406] g) rather than in arms (54 [−19/126] g). The predictors of changes in total and regional FFM in patients with COPD were gender, number of previous hospitalizations, baseline values of FFM and BMI. Conclusion Patients with COPD present a significant decline in FFM after 2 years of follow‐up, this decline is more pronounced in their legs and trunk., Patients with chronic obstructive pulmonary disease (COPD) present a significant decline in total, leg and trunk low fat‐free mass (FFM), while arms FFM remains stable after 2 years of follow‐up. We identified a subgroup of patients with preserved FFM at baseline and history of previous hospitalizations that present greater decline in total and leg FFM compared to other patients with COPD. See related Editorial

Clinical reports indicate a bidirectional relationship between mental illness and chronic systemic diseases. However, brain mechanisms linking chronic stress and development of mood disorders to accompanying peripheral organ dysfunction are still not well characterized in animal models. In the current study, we investigated whether activation of hippocampal mitogen-activated protein kinase phosphatase-1 (MKP-1), a key factor in depression pathophysiology, also acts as a mediator of systemic effects of stress. First, we demonstrated that treatment with the glucocorticoid receptor (GR) agonist dexamethasone or acute restraint stress (ARS) significantly increased Mkp-1 mRNA levels within the rat hippocampus. Conversely, administration of the GR antagonist mifepristone 30 min before ARS produced a partial blockade of Mkp-1 upregulation, suggesting that stress activates MKP-1, at least in part, through upstream GR signaling. Chronic corticosterone (CORT) administration evoked comparable increases in hippocampal MKP-1 protein levels and produced a robust increase in behavioral emotionality. In addition to behavioral deficits, chronic CORT treatment also produced systemic pathophysiological effects. Elevated levels of renal inflammation protein markers (NGAL and IL18) were observed suggesting tissue damage and early kidney impairment. In a rescue experiment, the effects of CORT on development of depressive-like behaviors and increased NGAL and IL18 protein levels in the kidney were blocked by CRISPR-mediated knockdown of hippocampal Mkp-1 prior to CORT exposure. In sum, these findings further demonstrate that MKP-1 is necessary for development of enhanced behavioral emotionality, while also suggesting a role in stress mechanisms linking brain dysfunction and systemic illness such as kidney disease.

We sought to understand the role of stage at diagnosis in observed age disparities in colon cancer survival among people aged 50 to 99 years using population-based cancer registry data from seven high-income countries: Australia, Canada, Denmark, Ireland, New Zealand, Norway and the United Kingdom. We used colon cancer incidence data for the period 2010 to 2014. We estimated the 3-year net survival, as well as the 3-year net survival conditional on surviving at least 6 months and 1 year after diagnosis, by country and stage at diagnosis (categorised as localised, regional or distant) using flexible parametric excess hazard regression models. In all countries, increasing age was associated with lower net survival. For example, 3-year net survival (95% confidence interval) was 81% (80-82) for 50 to 64 year olds and 58% (56-60) for 85 to 99 year olds in Australia, and 74% (73-74) and 39% (39-40) in the United Kingdom, respectively. Those with distant stage colon cancer had the largest difference in colon cancer survival between the youngest and the oldest patients. Excess mortality for the oldest patients with localised or regional cancers was observed during the first 6 months after diagnosis. Older patients diagnosed with localised (and in some countries regional) stage colon cancer who survived 6 months after diagnosis experienced the same survival as their younger counterparts. Further studies examining other prognostic clinical factors such as comorbidities and treatment, and socioeconomic factors are warranted to gain further understanding of the age disparities in colon cancer survival.

Glioblastomas (GBMs) are aggressive and devastating tumors, and are exceedingly difficult to clinically manage. There are many reasons that these tumors are difficult to treat, one of which is the presence of a cancer stem cell (CSC), or alternatively called glioblastoma cancer stem cell (GSC), subpopulation within these tumors. GSCs are resistant to both chemotherapy and radiotherapy, which are the standard of care for GBM patients. Not only do these cells evade current treatments, they also have the ability to self-renew and lead to recurrence in almost all GBM patients. Clearly, any curative treatment will need to inclusively target GSCs, so it is vital that this subpopulation can be isolated and studied. This chapter will cover how GSCs are identified, expanded, and ultimately how they are used to determine if a new treatment is able to target this highly malignant cell subpopulation.

Preclinical studies of traumatic brain injury (TBI) are often performed using a murine model of mild traumatic brain injury (mTBI) due to highly controlled settings and high reproducibility in this experimental model, compared to studies of human TBI. We have previously demonstrated persistent changes in the sleep wake cycle using a widely accepted mouse model of mTBI. The gold standard of sleep wake assessment is achieved by recording brain electroencephalogram (EEG), which not only allows for standard sleep staging but also allows further signal processing through quantitative EEG methods. Conventional methods of sleep staging require manual scoring by a trained expert. Here, a 1-D deep convolutional neural network (Deep CNN) is proposed to automatically score sleep stages and identify mTBI from a single-channel EEG signal with duration of 64 seconds by classifying the EEG signal into one of four classes: sham (control) wake, sham (control) sleep, mTBI wake, and mTBI sleep. We demonstrated that the proposed Deep CNN has the ability to learn features to classify the target classes. Deployment of the trained model on Raspberry Pi further indicates the capacity to perform classification in real time and mobile applications. Thus, the proposed system has the potential to provide a low-cost and fast method for detection of TBI in individuals.

BackgroundArbuscular mycorrhizal (AM) fungi associate with most plants and can increase nutrient uptake. As a result, commercial inoculants called “biofertilizers” containing AM fungi have been developed and marketed to increase plant performance. However, successful establishment of these inoculants remains a challenge, and may be negatively impacted by competition with fungi already present (priority effects). Perennial agriculture may be more amenable if inoculants can be successfully established on crops prior to field planting.MethodsHere, we inoculate grapevine (Vitis vinifera) with a commercial inoculant in three treatments designed to manipulate the strength and direction of priority effects and quantified the abundance of the fungal strain before and after introduction using droplet digital PCR (ddPCR).ResultsWe found that the introduced strain did not establish in any treatment, even with priority advantage, and inoculated vines did not differ in performance from non-inoculated vines. Fungal abundance was not greater than in pre-inoculation soil samples during any of the five years sampled and may have been impaired by high available phosphorus levels in the soil. This study highlights the need to understand and evaluate how the management of the agricultural system will affect establishment before introduction of “biofertilizers”, which is often unpredictable.

International audience; In the last few decades, microbial inoculants have been used as organic fertilizers worldwide. Among the most widely used commercial products are arbuscular mycorrhizal (AM) fungi, as these fungi can associate with a variety of crops. Despite the potential benefits for soil quality and crop yield associated with AM fungal colonization, experiments assessing the persistence of the fungi in the field have yielded inconsistent results. Additionally, it is not yet clear whether or not the introduction of commercial inoculants could lead to changes to the resident fungal community, and eventually to invasion of the commercial products with a possible displacement of resident species. Here we use a partial differential equation model to assess the potential biodiversity risks and productivity benefits deriving from inoculation. We study the impact of AM fungal inoculation on the resident fungal community and on plant growth at a landscape scale. We determine how inoculant persistence and spread is affected by its competition with resident fungal species, by its mutualist quality, and by fungal dispersal. Our findings suggest that the increase in fungal abundance due to inoculation always leads to a short-term increase in host productivity, regardless of inoculant identity. However, the use of strongly competing inoculants constitutes a biodiversity risk, and may result in the invasion of low quality mutualists.

Introduction Chronic pain and sleep disturbances are intricately linked to one another, especially in individuals with a history of traumatic brain injury (TBI) who are at greater risk for both symptoms. Although prior studies have analyzed differences in sleep electroencephalogram (EEG) in these clinical populations, the association between sleep EEG slow wave coherence and pain complaints is not fully examined or known. Our novel slow wave coherence approach may provide new insights into the relationship between TBI, chronic pain, and sleep Methods Ninety-six veterans were recruited and enrolled under a VA IRB-approved protocol. Participants completed a semi-structured clinical interview to determine their history of TBI, Symptom Impact Questionnaire Revised (SIQR), a measure of chronic pain complaints, and underwent an attended overnight in-lab polysomnogram (PSG). We developed a novel computational signal processing algorithm to identify and quantify EEG slow waves within 100 ms bins across the 6 standard PSG EEG channels. When a slow wave was simultaneously observed in 4 or more of the 6 leads, slow wave coherence was inferred, and a percentage of slow wave coherence across each of the sleep stages was then calculated for each subject. Results In our sample, 65 participants (67.7%) endorsed experiencing chronic pain lasting 3 months or longer, and 54 had a history of TBI (56.3%). Participants endorsing chronic pain had a significantly lowered percent of EEG slow wave coherence during NREM sleep than subjects without chronic pain (p = 0.01). NREM EEG slow wave coherence did not correlate with SIQR scores in subjects without TBI (r = -0.03, p = 0.90), but was significantly negatively correlated in subjects with TBI (r = -0.32, p = 0.02). Conclusion EEG slow wave coherence during NREM sleep is correlated with chronic pain complaints in Veterans with a history of TBI, and could be indicative of neuronal dysfunction during sleep. Further research on slow wave coherence is warranted to understand the underlying mechanisms for the association between chronic pain and poor sleep following TBI. Support (if any) D01 W81XWH-17-1-0423

Introduction Cellular mechanisms underlying changes in small animal brain lactate concentrations have been investigated for more than 70 years and report sharp reductions in lactate (12-35%) during sleep or anesthesia relative to wakefulness. The goal of this study was to investigate alterations in human cerebral lactate concentrations across sleep-wake cycles. Toward this goal, we developed a novel non-invasive methodology, quantified changes in human cerebral lactate during sleep stages, and investigated potential mechanisms associated with changes in lactate. Methods Nine subjects (four females, five males; 21-27 y-o, mean age 24.2 ±2) were sleep deprived overnight, and underwent (5:45~11:00 am) experiments combining simultaneous MR-spectroscopy (MRS) and polysomnography (PSG) in a 3 T MR instrument using a 64-channel head/neck coil. A single voxel MRS (1H-MRS) acquired signals from a volume of interest (12~24 cm3) for every 7.5-s for 88~180-min. Lactate signal intensity was determined from each 7.5-s spectrum, normalized to corresponding water signal, and averaged over 30-s for each PSG epochs. Artifact corrected PSG data were scored for each 30-s epoch using the standard criteria and classified into one of four stages: W, N1, N2 and N3. Group mean lactate levels were quantified using LCModel. Three subjects returned for lactate diffusivity measurements using diffusion-sensitized PRESS MRS sequence. Results Compared to W, group mean lactate levels within each sleep stage showed a reduction of [4.9 ± 4.9] % in N1, [10.4 ± 5.2] % in N2, and [24.0 ± 5.8] % in N3. We observed a significant decrease in lactate apparent diffusion coefficient (ADC) accompanied by reduced brain lactate in sleep compared to wake (P Conclusion This is the first in-vivo report of alterations in human brain lactate concentrations across sleep-wake cycles. Observed decline in lactate levels during sleep compared to wakefulness is consistent with, and extends results from invasive small animal brain studies first reported more than 70 years ago, and support the notion of altered lactate metabolism and/or increased glymphatic activity in sleeping human brain. Support (if any) The Paul. G. Allen Family Foundation funded the study.

Background Research among adults suggests that weight stigma is associated with worsened cardiometabolic health. However, these relationships have not been examined among youth. Objective Assess associations between weight-based teasing (WBT) and metabolic and inflammatory markers among two samples of youth: (1) a non-treatment-seeking sample and (2) a weight loss treatment-seeking sample with obesity. Method Weight, height, adiposity, waist circumference and blood pressure were measured. Fasting blood samples were collected for metabolic (triglycerides, glucose, high-density lipoprotein cholesterol) and inflammatory analytes (high-sensitivity C-reactive protein in Study 1 and erythrocyte sedimentation rate in both studies). Youths completed the Perception of Teasing Scale, a measure of WBT. Metabolic and inflammatory indices were compared between those with and without teasing, adjusting for demographics and body composition. Results Study 1 enrolled 201 non-treatment-seeking youth (Mage = 13.1y; 54.2% female; 44.8% non-Hispanic White; 32.8% with overweight/obesity); 15.4% reported WBT. Study 2 enrolled 111 treatment-seeking adolescents with obesity (Mage = 14.0y; 66.7% female; 37.8% non-Hispanic White); 73.0% reported WBT. Adjusting for covariates, WBT was not associated with cardiometabolic risk factors in either study. Conclusions WBT was not associated with worsened cardiometabolic health. Longitudinal research is needed to elucidate associations between WBT and health in youth.

Health care workers engaged in work that they find personally meaningful are less likely to experience professional burnout. However, health care often involves tedious and burdensome tasks. While physicians are often asked to complete tasks that are less satisfying, creating space to focus on the meaningful parts of patient care is helpful to changing the focus of the mind. We report on the integration of Meaning in Medicine groups in a faculty development program at family medicine residency programs. These groups were created to increase faculty satisfaction, team cohesion, and engagement. Each session starts with an item for reflection – a video, article, or story – and is designed to provide a safe space for discussion of the joys in medicine. Group sizes of 8 to 15, dedicated time, and establishment of ground rules have been essential for success of these meetings.

OBJECTIVE: Ongoing exploration of factors related to poor sleep in collegiate athletes is important as understanding of the risks and consequences of poor sleep in this specific population increases. DESIGN: Retrospective cohort study. SETTING: University in the Pacific Northwest. PARTICIPANTS: One-hundred thirty-seven male and female collegiate athletes across 5 collision, contact, and limited contact team sports. MEASUREMENTS: Depressive symptoms (Patient Health Questionnaire 9; PHQ-9), anxiety symptoms (General Anxiety Disorder 7; GAD-7), and somatic complaints (Patient Health Questionnaire 15; PHQ-15). Sleep quality (Pittsburgh Sleep Quality Index; PSQI) used both a cutoff score ≥6 and a cutoff score of ≥8, indicating “poor sleep quality” to reduce threats to divergent validity. RESULTS: Poor sleep quality as defined by PSQI ≥6 was present in 53% of athletes, and as defined by PSQI ≥8 was identified in 33.5% of the cohort. There were no differences in the incidence of poor sleepers between sport, race/ethnicity, or sex. Multiple regression analysis revealed that depressive symptoms, somatic complaints, Caucasian race, male sex, and number of concussions were significant predictors of poor sleep (P < .05). The model accounted for 43% of the variance in PSQI and primarily by depressive symptoms explaining 9% of reported sleep quality variability. Anxiety symptoms, sport category, and history of migraines were not significant predictors of poor sleep quality. CONCLUSIONS: A high incidence of poor sleep among collegiate athletes was observed regardless of sport, and may be related to depressive symptoms, somatic complaints, Caucasian race, male sex, and historical number of concussions.

Background We previously reported that lung cancer incidence between Blacks and Whites younger than 40 years of age converged in women and approached convergence in men. Whether this pattern has continued in contemporary young birth cohorts is unclear. Methods We examined 5-year age-specific lung cancer incidence in Blacks and Whites younger than 55 years of age by sex and calculated the Black-to-White incidence rate ratios (IRRs) and smoking prevalence ratios by birth cohort using nationwide incidence data from 1997 to 2016 and smoking data from 1970 to 2016 from the National Health Interview Survey. Results Five-year age-specific incidence decreased in successive Black and White men born since circa 1947 and women born since circa 1957, with the declines steeper in Blacks than Whites. Consequently, the Black-to-White IRRs became unity in men born 1967-1972 and reversed in women born since circa 1967. For example, the Black-to-White IRRs in ages 40-44 years born between 1957 and 1972 declined from 1.92 (95% confidence interval [CI] = 1.82 to 2.03) to 1.03 (95% CI = 0.93 to 1.13) in men and from 1.32 (95% CI = 1.24 to 1.40) to 0.71 (95% CI = 0.64 to 0.78) in women. Similarly, the historically higher sex-specific smoking prevalence in Blacks than Whites disappeared in men and reversed in women born since circa 1965. The exception to these patterns is that the incidence became higher in Black men than White men born circa 1977-1982. Conclusions The historically higher lung cancer incidence in young Blacks than young Whites in the United States has disappeared in men and reversed in women, coinciding with smoking patterns, though incidence again became higher in Black men than White men born circa 1977-1982.

Glioblastoma (GBM) is an incurable brain tumor with inevitable recurrence. This is in part due to a highly malignant cancer stem cell (CSC) subpopulation of tumor cells that is particularly resistant to conventional treatments, including radiotherapy. Here we show that CBL0137, a small molecule anti-cancer agent, sensitizes GBM CSCs to radiotherapy. CBL0137 sequesters the FACT (facilitates chromatin transcription) complex to chromatin, resulting in cytotoxicity preferentially within tumor cells. We show that when combined with radiotherapy, CBL0137 inhibited GBM CSC growth and resulted in more DNA damage in the CSCs compared to irradiation or drug alone. Using an in vivo subcutaneous model, we showed that the frequency of GBM CSCs was reduced when tumors were pretreated with CBL0137 and then exposed to irradiation. Survival studies with orthotopic GBM models resulted in significantly extended survival for mice treated with combinatorial therapy. As GBM CSCs contribute to the inevitable recurrence in patients, targeting them is imperative. This work establishes a new treatment paradigm for GBM that sensitizes CSCs to irradiation and may ultimately reduce tumor recurrence.

Traditional tensegrity mechanisms comprise compressive (rigid rods) and tensile members (cables). Compliant tensegrity mechanisms (CoTM) include springs alongside cables. Introduction of spring elements allows these structures to be more adaptable and robust. The kinematic and stability analyses of such mechanisms will facilitate better understanding of their behaviors for developing control and design methodologies. The analysis of CoTM often involves making the zero free-length (ZFL) assumption, i.e., the free-length of the spring is zero, which disqualifies the analysis for most real-word applications. The paper illustrates the drastic increase in computational complexity for finding static solutions as the assumption of ZFL for spring elements are relaxed for a simple planar compliant tensegrity mechanism comprising two rigid triangular platforms connected by a compressive member and two spring elements. The resulting nonlinear behavior of obtained static solutions shows intersecting manifolds of equilibrium orientation angles where the number of solutions vary from minimum of 4 to beyond 10 as the spring free-lengths are varied.