The effect of light on circadian entrainment: Risk mitigation techniques for shifting from day to night flight operations

Prepared for: Assistant Commandant of the Marine CorpsA midair collision in the early morning hours of December 6, 2018 resulted in the tragic deaths of six US Marine Corps aircrew members and the loss of two aircraft, a KC-130 tanker and an F/A-18. The mishap occurred around 2 AM during a routine nighttime air refueling training mission off the coast of Japan. In the investigation that followed, fatigue was identified as a major contributor; the transition from day to night flights was called out as a problem area that continues to plague aviation commands. Subsequent investigations confirmed findings and requested help from the Naval Postgraduate School (NPS) Crew Endurance Team to study the problem and make recommendations for safer transition from day to night flight operations. The study goal was to provide recommendations to the fleet regarding the limitations and best practices for shifting aviators from day to night operations. After reviewing the scientific literature, NPS designed a study to determine the efficacy of high energy visible (HEV) light exposure in shifting the circadian rhythms of study participants. The project was a hybrid study of military aviators who, as graduate students at NPS, continued normal daily schedules but came into the laboratory for 6 to 8 hours on three consecutive evenings. The study attempted to replicate the patterns of aviators who could potentially be required to abruptly shift to night flight operations. Results showed that a single 4-hour exposure of blue-enriched white light (~1000 lux) successfully delayed the circadian phase of all participants an average of 1 hour 19 minutes (range 53 minutes to 1 hour 56 minutes). Melatonin onset was delayed in all participants. This circadian shift is estimated to be a 10-fold increase over what would be achieved without the HEV light. Light was shown to have an alerting effect with participants reporting less sleepiness and reduced subjective workload with improved flight performance. Conclusions from the literature review and our study indicate that circadian entrainment in military operational settings should use light management as the dominant method for shifting the circadian clock. In general, it is expected that higher rates of adaptation (i.e., more rapid entrainment) will occur by aligning and applying multiple synchronization methods simultaneously, i.e., light management combined with strategically timed exercise, meals, melatonin, and caffeine. Based on these conclusions, we developed general recommendations and two circadian synchronization plans for crewmembers switching from day to night operations. One plan shows a schedule that prepares for night operations shifting over multiple days. The other shows a schedule for crewmembers required to shift from abruptly without notice. These plans warrant further development in an operational environment to ensure they can be implemented safely and effectively.Assistant Commandant of the Marine CorpsAssistant Commandant of the Marine CorpsApproved for public release; distribution is unlimite

Non-contrast renal magnetic resonance imaging to assess perfusion and corticomedullary differentiation in health and chronic kidney disease

AIMS Arterial spin labelling (ASL) MRI measures perfusion without administration of contrast agent. While ASL has been validated in animals and healthy volunteers (HVs), application to chronic kidney disease (CKD) has been limited. We investigated the utility of ASL MRI in patients with CKD. METHODS We studied renal perfusion in 24 HVs and 17 patients with CKD (age 22-77 years, 40% male) using ASL MRI at 3.0T. Kidney function was determined using estimated glomerular filtration rate (eGFR). T1 relaxation time was measured using modified look-locker inversion and xFB02;ow-sensitive alternating inversion recovery true-fast imaging and steady precession was performed to measure cortical and whole kidney perfusion. RESULTS T1 was higher in CKD within cortex and whole kidney, and there was association between T1 time and eGFR. No association was seen between kidney size and volume and either T1, or ASL perfusion. Perfusion was lower in CKD in cortex (136 ± 37 vs. 279 ± 69 ml/min/100 g; p < 0.001) and whole kidney (146 ± 24 vs. 221 ± 38 ml/min/100 g; p < 0.001). There was significant, negative, association between T1 longitudinal relaxation time and ASL perfusion in both the cortex (r = -0.75, p < 0.001) and whole kidney (r = -0.50, p < 0.001). There was correlation between eGFR and both cortical (r = 0.73, p < 0.01) and whole kidney (r = 0.69, p < 0.01) perfusion. CONCLUSIONS Significant differences in renal structure and function were demonstrated using ASL MRI. T1 may be representative of structural changes associated with CKD; however, further investigation is required into the pathological correlates of reduced ASL perfusion and increased T1 time in CKD

Demonstration of differences in colonic volumes, transit, chyme consistency and response to psyllium between healthy and constipated subjects using magnetic resonance imaging

Background: In functional gastrointestinal disorders a lack of objective biomarkers limits evaluation of underlying mechanisms. We aimed to demonstrate the utility of Magnetic Resonance Imaging (MRI) for this task using psyllium, an effective constipation treatment, in patients and controls. Methods: Two crossover studies: 1) adults without constipation (controls, n=9) took three treatments in randomised order for 6 days - maltodextrin (placebo), psyllium 3.5g t.d.s and 7g t.d.s.; 2) adults with chronic constipation (patients, n=20) took placebo and psyllium 7g t.d.s. for 6 days. MRI was performed fasting and postprandially on day 6. Measurements included small bowel and ascending colon water content, colonic volume, transit time and MR relaxometry (T1, T2) to assess colonic chyme. Stool water percentage was measured. Results: 7g psyllium t.d.s. increased fasting colonic volumes in controls from median 372mL (IQR 284-601) to 578 mL (IQR 510-882), and in patients from median 831mL (IQR 745–934) to 1104mL (847–1316),

Demonstration of differences in colonic volumes, transit, chyme consistency and response to psyllium between healthy and constipated subjects using magnetic resonance imaging

Background: In functional gastrointestinal disorders a lack of objective biomarkers limits evaluation of underlying mechanisms. We aimed to demonstrate the utility of Magnetic Resonance Imaging (MRI) for this task using psyllium, an effective constipation treatment, in patients and controls. Methods: Two crossover studies: 1) adults without constipation (controls, n=9) took three treatments in randomised order for 6 days - maltodextrin (placebo), psyllium 3.5g t.d.s and 7g t.d.s.; 2) adults with chronic constipation (patients, n=20) took placebo and psyllium 7g t.d.s. for 6 days. MRI was performed fasting and postprandially on day 6. Measurements included small bowel and ascending colon water content, colonic volume, transit time and MR relaxometry (T1, T2) to assess colonic chyme. Stool water percentage was measured. Results: 7g psyllium t.d.s. increased fasting colonic volumes in controls from median 372mL (IQR 284-601) to 578 mL (IQR 510-882), and in patients from median 831mL (IQR 745–934) to 1104mL (847–1316), P<0.05). Mean postprandial small bowel water was higher in controls and patients after 7g psyllium t.d.s. vs. placebo. Whole gut transit was slower in patients than controls (P <0.05). T1 of the descending colon chyme (fasting) was lower in patients [213ms, 176–420] than controls [440ms, 352–884, P <0.05] on placebo, but increased by 7 g psyllium t.d.s. [590ms, 446–1338), P<0.001]. Descending colon T1 correlated with baseline stool water content and stool frequency on treatment. Conclusions and Inferences: MRI measurements can objectively demonstrate the mode of action of therapy targeting intestinal fluid content in constipation

BRCA2 polymorphic stop codon K3326X and the risk of breast, prostate, and ovarian cancers

Background: The K3326X variant in BRCA2 (BRCA2*c.9976A&gt;T; p.Lys3326*; rs11571833) has been found to be associated with small increased risks of breast cancer. However, it is not clear to what extent linkage disequilibrium with fully pathogenic mutations might account for this association. There is scant information about the effect of K3326X in other hormone-related cancers. Methods: Using weighted logistic regression, we analyzed data from the large iCOGS study including 76 637 cancer case patients and 83 796 control patients to estimate odds ratios (ORw) and 95% confidence intervals (CIs) for K3326X variant carriers in relation to breast, ovarian, and prostate cancer risks, with weights defined as probability of not having a pathogenic BRCA2 variant. Using Cox proportional hazards modeling, we also examined the associations of K3326X with breast and ovarian cancer risks among 7183 BRCA1 variant carriers. All statistical tests were two-sided. Results: The K3326X variant was associated with breast (ORw = 1.28, 95% CI = 1.17 to 1.40, P = 5.9x10- 6) and invasive ovarian cancer (ORw = 1.26, 95% CI = 1.10 to 1.43, P = 3.8x10-3). These associations were stronger for serous ovarian cancer and for estrogen receptor–negative breast cancer (ORw = 1.46, 95% CI = 1.2 to 1.70, P = 3.4x10-5 and ORw = 1.50, 95% CI = 1.28 to 1.76, P = 4.1x10-5, respectively). For BRCA1 mutation carriers, there was a statistically significant inverse association of the K3326X variant with risk of ovarian cancer (HR = 0.43, 95% CI = 0.22 to 0.84, P = .013) but no association with breast cancer. No association with prostate cancer was observed. Conclusions: Our study provides evidence that the K3326X variant is associated with risk of developing breast and ovarian cancers independent of other pathogenic variants in BRCA2. Further studies are needed to determine the biological mechanism of action responsible for these associations

Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche.

Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P < 5 × 10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and γ-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition

Global Perspectives on Immunization During Pregnancy and Priorities for Future Research and Development: An International Consensus Statement.

Immunization during pregnancy has been recommended in an increasing number of countries. The aim of this strategy is to protect pregnant women and infants from severe infectious disease, morbidity and mortality and is currently limited to tetanus, inactivated influenza, and pertussis-containing vaccines. There have been recent advancements in the development of vaccines designed primarily for use in pregnant women (respiratory syncytial virus and group B Streptococcus vaccines). Although there is increasing evidence to support vaccination in pregnancy, important gaps in knowledge still exist and need to be addressed by future studies. This collaborative consensus paper provides a review of the current literature on immunization during pregnancy and highlights the gaps in knowledge and a consensus of priorities for future research initiatives, in order to optimize protection for both the mother and the infant

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London

The InterLACE study: design, data harmonization and characteristics across 20 studies on women's health

The International Collaboration for a Life Course Approach to Reproductive Health and Chronic Disease Events (InterLACE) project is a global research collaboration that aims to advance understanding of women's reproductive health in relation to chronic disease risk by pooling individual participant data from several cohort and cross-sectional studies. The aim of this paper is to describe the characteristics of contributing studies and to present the distribution of demographic and reproductive factors and chronic disease outcomes in InterLACE

Transdisciplinary Research Priorities for Human and Planetary Health in the Context of the 2030 Agenda for Sustainable Development

Ebi KL, Harris F, Sioen GB, et al. Transdisciplinary Research Priorities for Human and Planetary Health in the Context of the 2030 Agenda for Sustainable Development. International journal of environmental research and public health. 2020;17(23): 8890.Human health and wellbeing and the health of the biosphere are inextricably linked. The state of Earth's life-support systems, including freshwater, oceans, land, biodiversity, atmosphere, and climate, affect human health. At the same time, human activities are adversely affecting natural systems. This review paper is the outcome of an interdisciplinary workshop under the auspices of the Future Earth Health Knowledge Action Network (Health KAN). It outlines a research agenda to address cross-cutting knowledge gaps to further understanding and management of the health risks of these global environmental changes through an expert consultation and review process. The research agenda has four main themes: (1) risk identification and management (including related to water, hygiene, sanitation, and waste management); food production and consumption; oceans; and extreme weather events and climate change. (2) Strengthening climate-resilient health systems; (3) Monitoring, surveillance, and evaluation; and (4) risk communication. Research approaches need to be transdisciplinary, multi-scalar, inclusive, equitable, and broadly communicated. Promoting resilient and sustainable development are critical for achieving human and planetary health