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Abstract Background Traumatic injuries, defined as physical injuries with sudden onset, are a major cause of distress and disability, with far-reaching societal consequences. A significant proportion of trauma survivors report persistent symptoms and difficulties after the injury, and studies show unmet health care needs. Self-management programs delivered in the sub-acute phase after traumatic injuries are scarcely evaluated. The aim of the present study is to evaluate the effectiveness of a self-management program (SEMPO), delivered 3–4 months after moderate-to-severe traumatic injury. Methods This study protocol describes a pragmatic randomized controlled trial (RCT) with two classical RCT arms (intervention and control) and an explorative self-selection arm. 220 patients will be recruited from Oslo University Hospital, the largest Trauma Referral Centre in Norway. Patients aged 18–72 years residing in the south-east region of Norway, admitted to the Trauma Centre directly or within 72 h after having sustained a moderate to severe traumatic injury, defined as a New Injury Severity Score > 9, having at least 2 days hospital stay, and reporting injury-related symptoms and impairment at discharge from the acute hospital will be included. Patients will be randomly assigned to either a classical RCT randomization arm (intervention or control arm) or to a self-selection arm. In the randomization arm, participants are further randomized into intervention or control group. Participants allocated to the self-selection arm will choose to partake either in the intervention or control arm. The primary outcome is the level of self-efficacy in trauma coping assessed 6 months after completion of the intervention, with a similar time point for the control group. Secondary outcomes include symptom burden, physical functioning and disability, return to work and health care utilization, health-related quality of life, and communication competency. In addition, patients will be asked to nominate one domain-related measurement as their preferred outcome measure. Discussion This RCT will determine the effect of a self-management program tailored to patients with moderate to severe physical trauma, and the self-selection arm incorporates the potential influence of patient treatment preferences on intervention results. If the intervention proves effective, cost-effectiveness and cost-utility analyses will be performed and thereby provide important information for clinicians and policy makers. Trial registration The study is registered in Clinical Trials with the identifier: NCT06305819. Registered on March 05, 2004.

Abstract Background Northern ecosystems are strongly influenced by herbivores that differ in their impacts on the ecosystem. Yet the role of herbivore diversity in shaping the structure and functioning of tundra ecosystems has been overlooked. With climate and land-use changes causing rapid shifts in Arctic species assemblages, a better understanding of the consequences of herbivore diversity changes for tundra ecosystem functioning is urgently needed. This systematic review synthesizes available evidence on the effects of herbivore diversity on different processes, functions, and properties of tundra ecosystems. Methods Following a published protocol, our systematic review combined primary field studies retrieved from bibliographic databases, search engines and specialist websites that compared tundra ecosystem responses to different levels of vertebrate and invertebrate herbivore diversity. We used the number of functional groups of herbivores (i.e., functional group richness) as a measure of the diversity of the herbivore assemblage. We screened titles, abstracts, and full texts of studies using pre-defined eligibility criteria. We critically appraised the validity of the studies, tested the influence of different moderators, and conducted sensitivity analyses. Quantitative synthesis (i.e., calculation of effect sizes) was performed for ecosystem responses reported by at least five articles and meta-regressions including the effects of potential modifiers for those reported by at least 10 articles. Review findings The literature searches retrieved 5944 articles. After screening titles, abstracts, and full texts, 201 articles including 3713 studies (i.e., individual comparisons) were deemed relevant for the systematic review, with 2844 of these studies included in quantitative syntheses. The available evidence base on the effects of herbivore diversity on tundra ecosystems is concentrated around well-established research locations and focuses mainly on the impacts of vertebrate herbivores on vegetation. Overall, greater herbivore diversity led to increased abundance of feeding marks by herbivores and soil temperature, and to reduced total abundance of plants, graminoids, forbs, and litter, plant leaf size, plant height, and moss depth, but the effects of herbivore diversity were difficult to tease apart from those of excluding vertebrate herbivores. The effects of different functional groups of herbivores on graminoid and lichen abundance compensated each other, leading to no net effects when herbivore effects were combined. In turn, smaller herbivores and large-bodied herbivores only reduced plant height when occurring together but not when occurring separately. Greater herbivore diversity increased plant diversity in graminoid tundra but not in other habitat types. Conclusions This systematic review underscores the importance of herbivore diversity in shaping the structure and function of Arctic ecosystems, with different functional groups of herbivores exerting additive or compensatory effects that can be modulated by environmental conditions. Still, many challenges remain to fully understand the complex impacts of herbivore diversity on tundra ecosystems. Future studies should explicitly address the role of herbivore diversity beyond presence-absence, targeting a broader range of ecosystem responses and explicitly including invertebrate herbivores. A better understanding of the role of herbivore diversity will enhance our ability to predict whether and where shifts in herbivore assemblages might mitigate or further amplify the impacts of environmental change on Arctic ecosystems.

Abstract Miscanthus is a perennial grass that can yield substantial amounts of biomass in land areas considered marginal. In the Coastal Plain region of North Carolina, marginal lands are typically located in coarse‐textured soils with low nutrient retention and water‐holding capacity, and high erosivity potential. Little is known about miscanthus water use under these conditions. We conducted a study to better understand the efficiency with which miscanthus uses natural resources such as water and radiant energy to produce harvestable dry biomass in comparison to corn, a typical commodity crop grown in the region. We hypothesized that under non‐limiting soil water conditions, miscanthus would have greater available energy and water use rates owing to its greater leaf area, thus leading to greater agronomic yields. Conversely, these effects would be negated under drought conditions. Our measurements showed that miscanthus intercepted more radiant energy than corn, which led to greater albedo (by 0.05), lower net radiation (by 4% or 0.4 MJ m−2 day−1), and lower soil heat flux (by 69% or 1.0 MJ m−2 day−1) than corn on average. Consequently, miscanthus had greater available energy (by 7% or 0.6 MJ m−2 day−1) and water use rates (by 14% or 0.5 mm day−1) than corn throughout the growing season on average, which partially confirmed our hypothesis. Greater water use rates and radiation interception by miscanthus did not translate to greater water‐use (1.5 g kg−1 vs. 1.6 g kg−1) and radiation‐use (0.9 g MJ−1 vs. 1.1 g MJ−1) efficiencies than corn. Compared to literature values, our data indicated that water and radiation availability were not limiting at our study site. Thus, it is likely that marginal land features present at the Coastal Plain region such as low soil fertility and high air temperatures throughout the growing season may constrain agronomic yields even if soil water and radiant energy are non‐limiting.

Abstract Background Endoscopic resection is widely accepted as a local treatment for rectal neuroendocrine tumors sized ≤ 10 mm. However, there is no consensus on the best method for the endoscopic resection of rectal neuroendocrine tumors. As a simplified endoscopic procedure, endoscopic submucosal resection with a ligation device (ESMR-L) indicates a histologically complete resection rate comparable to that of endoscopic submucosal dissection (ESD). We hypothesized that ESMR-L than ESD would be preferred for rectal neuroendocrine tumors. Hence, this trial aimed to verify whether ESMR-L is non-inferior to ESD in terms of histologically complete resection rate. Methods This is a prospective, open-label, multicenter, non-inferiority, randomized controlled trial of two parallel groups, conducted at the Shizuoka Cancer Center and 31 other institutions in Japan. Patients with a lesion endoscopically diagnosed as a rectal neuroendocrine tumor ≤ 10 mm are eligible for inclusion. A total of 266 patients will be recruited and randomized to undergo either ESD or ESMR-L. The primary endpoint is the rate of en bloc resection with histologically tumor-free margins (R0 resection). Secondary endpoints include en bloc resection rate, procedure time, adverse events, hospitalization days, total devices and agents cost, adverse event rate between groups with and without resection site closure, outcomes between expert and non-expert endoscopists, and factors associated with R0 resection failure. The sample size is determined based on the assumption that the R0 resection rate will be 95.2% in the ESD group and 95.3% in the ESMR-L group, with a non-inferiority margin of 8%. With a one-sided significance level of 0.05 and a power of 80%, 226 participants are required. Assuming a dropout rate of 15%, 266 patients will be included in this study. Discussion This is the first multicenter randomized controlled trial comparing ESD and ESMR-L for the R0 resection of rectal neuroendocrine tumors ≤ 10 mm. This will provide valuable information for standardizing endoscopic resection methods for rectal neuroendocrine tumors. Trial registration Japan Registry of Clinical Trials, jRCTs042210124. Registered on Jan 6, 2022.

Objective: To describe the needs for subacute inpatient rehabilitation and community-based healthcare services, rehabilitation, and social support in patients with moderate-to-severe traumatic injury in the first 6 months post-injury. Further, to explore associations between sociodemographic and clinical characteristics and unmet needs. Design: Multicentre prospective cohort study. Subjects: Of 601 persons (75% males), mean (standard deviation) age 47 (21) years, admitted to trauma centres in 2020 with moderate-to-severe injury, 501 patients responded at the 6-month follow-up and thus were included in the analyses. Methods: Sociodemographic and injury-related characteristics were recorded at inclusion. Estimation of needs was assessed with the Rehabilitation Complexity Scale Extended–Trauma and the Needs and Provision Complexity Scale on hospital discharge. Provision of services was recorded 6 months post-injury. Multivariable logistic regressions explored associations between baseline variables and unmet inpatient rehabilitation and community-based service needs. Results: In total, 20% exhibited unmet needs for subacute inpatient rehabilitation, compared with 60% for community-based services. Predictors for unmet community-based service needs included residing in less central areas, profound injury severity, severe head injury, and rehabilitation referral before returning home. Conclusion: Inadequate provision of healthcare and rehabilitation services, particularly in the municipalities, resulted in substantial unmet needs in the first 6 months following injury.

The world is currently in the midst of a global food crisis brought about and exacerbated by a series of mutually reinforcing shocks to food systems This study investigated the resilience of food systems in six Asian countries (Bangladesh, Kyrgyz Republic, Lao PDR, Pakistan, Philippines, and Sri Lanka) amidst the global ‘polycrisis’ caused by COVID-19, geopolitical conflicts, and climate change. Trend analyses were performed for 19 indicators sourced from global databases and World Food Programme national data, representing the four domains of food system resilience: exposure to shocks; resilience capacities and agro- and food diversity, resilience responses and strategies; and long-term resilience outcomes. The analysis revealed that all six countries experienced the effects of the ‘polycrisis’, leading to diverse impacts on exchange rates, with Sri Lanka, Pakistan, and Lao PDR facing significant currency depreciation. While most countries increased crop production and decreased food imports during the crisis, government economic support during the pandemic varied widely. Resilience outcomes, including national food price inflation and the proportion of populations facing food insecurity, witnessed upward variations. Overall, countries with higher resilience capacities at the start of the ‘polycrisis’ showed less severe long-term resilience outcomes. Our findings highlight the varied challenges and resilience capacities across each country, influenced by a complex interplay of economic, political, agricultural, and food affordability factors crucial for determining long-term resilience in their food systems. Recommendations for future research include focusing on resilience assessment in food systems, integrating climate change adaptation measures, and developing early intervention strategies.

BackgroundCognitive impairment, a core feature of schizophrenia, is associated with poor outcomes. Pharmacotherapy and psychosocial treatment, when used alone, have inadequate effect sizes for cognitive impairment, leading to recent interest in combination interventions. A previous study examined the additive effect of cognitive remediation on lurasidone in patients with schizophrenia, which was negative. Although improvement in cognitive function was suggested for lurasidone, it was inconclusive because there was no antipsychotic control in the study. To clarify whether lurasidone has a meaningful impact on cognitive function in combination with cognitive remediation, we use paliperidone as a control antipsychotic in this study. We hypothesize that combination with lurasidone will improve cognitive and social function to a greater extent than paliperidone.MethodsThe valuable interaction with cognitive remediation and optimal antipsychotics for recovery in schizophrenia study is a multicenter, interventional, open-label, rater-blind, randomized comparison study, comparing the effect of lurasidone plus cognitive remediation with that of paliperidone plus cognitive remediation in patients with schizophrenia. The Neuropsychological Educational Approach to Remediation (NEAR) is used for cognitive remediation. Eligible patients will be randomized 1:1 to receive lurasidone or paliperidone combined with NEAR (6 weeks antipsychotic alone followed by 24 weeks combination antipsychotic plus NEAR). The primary endpoint is the change from baseline in the tablet-based Brief Assessment of Cognition in Schizophrenia composite T-score at the end of the NEAR combination treatment period. Secondary endpoints will include change from baseline in social function, schizophrenia symptoms, and quality of life at the end of the NEAR combination treatment period. Furthermore, change from baseline to the end of the pharmacotherapy period and change from the end of the pharmacotherapy period to the end of the NEAR combination treatment period will be assessed for all endpoints. Safety will also be evaluated.DiscussionAchievement of adequate cognitive function is central to supporting social function, which is a key treatment goal for patients with schizophrenia. We think this study will fill in the gaps of the previous study and provide useful information regarding treatment decisions for patients with schizophrenia.Clinical trial registrationJapan Registry of Clinical Trials ID, jRCTs031200338.

Abstract Background Persistent post-concussion symptoms (PPCS) affect between 34 and 46% after a mild traumatic brain injury (mTBI). Many also experience exercise intolerance. Sub-symptom threshold aerobic exercise, SSTAE (exercise at an intensity level that does not increase symptoms) is proposed as a treatment to both reduce the symptom burden and increase the exercise tolerance after the injury. It is unclear if this also applies in a more chronic phase after mTBI. Main purpose The main purpose of this study is to evaluate whether SSTAE in addition to ordinary rehabilitation will lead to clinically meaningful improvement of symptom burden, normalize exercise tolerance, increase physical activity, improve health-related quality of life, and reduce patient-specific activity limitations compared to a control group that only receives ordinary rehabilitation. Design Randomized, controlled, single-blind parallel-group study with three measurement times; T0 at baseline, T1 after the intervention and T2 six months after T1. Methods Patients between the ages of 18 and 60 with exercise intolerance and persistent PPCS (> 3 months) will be recruited to the study and randomized to two groups. All patients will receive follow-up at the outpatient TBI clinic. The intervention group will in addition receive SSTAE for 12 weeks with exercise diaries and a retest every 3 weeks for optimal dosage and progression. The Rivermead post-concussion symptoms questionnaire will be the main outcome measure. The secondary outcome measure will be a test of exercise tolerance—the Buffalo Concussion Treadmill Test. Other outcome measures include the patient-specific functional scale that measures patient-specific activity limitations, as well as outcome measures for diagnosis-specific health-related quality of life, anxiety and depression, specific symptoms such as dizziness, headache and fatigue, and physical activity. Discussion This study will add knowledge about the effect of SSTAE and whether it should be implemented in rehabilitation for the adult population with persistent PPCS after mTBI. The nested feasibility trial showed that the SSTAE intervention was safe and that the study procedures and delivery of the intervention overall were feasible. However, minor amendments to the study protocol were made prior to the commencement of the RCT. Trial registration Clinical Trials.gov, NCT05086419. Registered on September 5th, 2021.

BackgroundThe clinical usefulness of cognitive behavioral therapy (CBT) for patients with depression who do not remit with pharmacotherapy has been recognized. However, the longer time burden on health care providers associated with conducting CBT and the lack of a system for providing CBT lead to inadequate CBT provision to patients who wish to receive it. ObjectiveWe aim to evaluate the feasibility of introducing virtual reality (VR) into CBT for patients with depression. MethodsThis is a single-center, interventional, exploratory, single-arm, nonrandomized, open, pre-post–comparative feasibility study of an unapproved medical device program to evaluate the acceptability, preliminary efficacy, and safety of the study device. Eligible patients meet the diagnostic criteria of the DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, 5th Edition) for major depressive disorder, have a 17-item Hamilton Depression Rating Scale (HAMD-17) score of ≥12, and are aged 18-65 years. The sample will comprise 12 patients. VR-based CBT (CBT-VR) sessions will be conducted once a week in an outpatient setting. CBT-VR has been developed in accordance with 6 stages and 16 sessions in the current CBT therapist manual. VR contents and other components correspond to the themes of these 16 sessions. The flow of CBT-VR treatment is similar to that of normal CBT; however, this product replaces the in-person portion of CBT. The primary end point will be the change in the HAMD-17 score from baseline up to 16 sessions. Secondary end points will be treatment retention; psychiatrist consultation time; satisfaction with the equipment or program; ease of use; homework compliance; change in the HAMD-17 score from baseline up to 8 sessions; change in Montgomery-Åsberg Depression Rating Scale (MADRS), Quick Inventory of Depressive Symptomatology Self-Report (QIDS-SR), EQ-5D-5L, and Clinical Global Impressions (CGI) scores from baseline up to 8 and 16 sessions; and change in remission and response rates and HAMD-17, MADRS, QIDS-SR, and EQ-5D-5L scores from baseline to 3 and 6 months post intervention (or discontinuation). CBT-VR’s feasibility will be assessed at baseline, after 8 sessions, after 16 sessions, or treatment discontinuation, by measuring the time required for testing and medical care during each session and with a patient questionnaire. After intervention discontinuation, a follow-up evaluation will be conducted unless the patient withdraws consent or otherwise discontinues participation in the study after 3 and 6 months. ResultsParticipant recruitment started on November 30, 2022, and data collection is ongoing as of September 2023. ConclusionsThis study is the first step in testing the acceptability, feasibility, and preliminary efficacy and safety of CBT-VR for patients with depression without controls in an open-label trial. If its feasibility for depression treatment is confirmed, we intend to proceed to a large-scale validation study. Trial RegistrationJapan Registry of Clinical Trials jRCTs032220481; https://jrct.niph.go.jp/en-latest-detail/jRCTs032220481 International Registered Report Identifier (IRRID)DERR1-10.2196/49698

In animal models, maternal obesity is associated with development of neurodevelopmental disorder like phenotypes. Here the authors show in a macaque model that in obese dams, cell-free fetal DNA methylation, inflammatory cytokines, and metabolites correlated with infant brain DNA methylation, lipids, and metabolites.

Abstract Background Multiple micronutrient (MN) deficiencies remain highly prevalent among women of reproductive age (WRA) and preschool-aged children (PSC) in many areas within India. Salt is an attractive vehicle for MN fortification in this context, as it is universally consumed in fairly consistent amounts and coverage of iodized salt (IS) is 94%. The overall objective of this trial is to evaluate the nutritional impact of quintuply-fortified salt with iron in the form of encapsulated ferrous fumarate, zinc, vitamin B12, folic acid, and iodine (eFF-Q5S) vs. quintuply-fortified salt with iron in the form of ferric pyrophosphate plus EDTA, zinc, vitamin B12, folic acid, and iodine (FePP-Q5S) vs. IS for the improvement of MN status among non-pregnant WRA and PSC. Methods The study is a community-based, randomized, controlled trial that will be conducted in Punjab, India. 780 non-pregnant WRA 18–49 years old and 468 PSC 12–59 months old will be enrolled and assigned to one of three intervention groups. Salt will be provided to participants monthly for 12 months. Primary outcomes include changes in mean concentration of biomarkers of iron, zinc, vitamin B12, folate and iodine. Secondary outcomes include changes in the composition of the gut microbiome, and discretionary salt intake of PSC. Discussion If proven efficacious, multiply-fortified salt (MFS) has the potential to drastically reduce the burden of MN deficiencies in India, and around the world. Although effectiveness research will be needed to examine the impact of MFS under programmatic conditions, salt fortification will piggy-back on existing platforms to produce IS and doubly-fortified salt (DFS), making it possible to scale-up the intervention quickly. Trial registration Clinicaltrials.gov: NCT05166980; date of registration: December 22, 2021. Clinical Trials Registry-India: CTRI/2022/040332 and CTRI/2022/02/040333; date of registration: February 15, 2022.

Abstract Zinc is an essential micronutrient that promotes normal growth, development and immune function. In the context of persistent dietary zinc inadequacies, large‐scale food fortification can help fill the gap between intake and requirements. Burkina Faso mandates wheat flour fortification with iron and folic acid. We used activity‐based cost modelling to estimate the cost of adding zinc to the country's wheat flour fortification standard assuming (1) no change in compliance with the national standard, and (2) a substantial improvement in compliance. We used household food consumption data to model effective coverage, that is, the number of women of reproductive age (WRA) predicted to achieve adequate zinc density (zinc intake/1000 kcal) with the addition of fortification to diets. Without interventions, the prevalence of inadequate dietary zinc density was ~35.5%. With no change in compliance, the annual average incremental cost of adding zinc to fortified wheat flour was $10,347, which would effectively cover

Objective: To evaluate adherence to 3 central operational recommendations for acute rehabilitation in the Norwegian trauma plan. Methods: A prospective multi-centre study of 538 adults with moderate and severe trauma with New Injury Severity Score > 9. Results: Adherence to the first recommendation, assessment by a physical medicine and rehabilitation physician within 72 h following admission to the intensive care unit (ICU) at the trauma centre, was documented for 18% of patients. Adherence to the second recommendation, early rehabilitation in the intensive care unit, was documented for 72% of those with severe trauma and ≥ 2 days ICU stay. Predictors for early rehabilitation were ICU length of stay and spinal cord injury. Adherence to the third recommendation, direct transfer of patients from acute ward to a specialized rehabilitation unit, was documented in 22% of patients, and occurred more often in those with severe trauma (26%), spinal cord injury (54%) and traumatic brain injury (39%). Being employed, having head or spinal chord injury and longer ICU stay were predictors for direct transfer to a specialized rehabilitation unit. Conclusion: Adherence to acute rehabilitation guidelines after trauma is poor. This applies to documented early assessment by a physical medicine and rehabilitation physician, and direct transfer from acute care to rehabilitation after head and extremity injuries. These findings indicate a need for more systematic integration of rehabilitation in the acute treatment phase after trauma. LAY ABSTRACT Three recommendations for acute rehabilitation in the Norwegian trauma plan were evaluated in 538 adults with moderate to severe injuries. Recommendation one: Examination by a rehabilitation physician within 72 h after hospital admission. This was documented in 18% of the patients. Recommendation two: Start of early rehabilitation in the intensive care unit. This was given to 72% of those with severe trauma. Early rehabilitation was more frequent in patients with spinal cord injury, and with long intensive care stays. Recommendation three: Patients are directly transferred from acute care in the trauma centre to specialized rehabilitation. This was followed for 22% of the patients. This happened more often in patients with severe injuries, spinal cord injury and brain injury. Being in work and longer intensive care stays increased the probability for direct transfer. Conclusion: Overall compliance with the guidelines is poor, except for early therapist rehabilitation in the intensive care unit.

BackgroundMaternal obesity has been associated with a higher risk of pregnancy-related complications in mothers and offspring; however, effective interventions have not yet been developed. We tested two interventions, calorie restriction and pravastatin administration, during pregnancy in a rhesus macaque model with the hypothesis that these interventions would normalize metabolic dysregulation in pregnant mothers leading to an improvement in infant metabolic and cognitive/social development.MethodsA total of 19 obese mothers were assigned to either one of the two intervention groups (n = 5 for calorie restriction; n = 7 for pravastatin) or an obese control group (n = 7) with no intervention, and maternal gestational samples and postnatal infant samples were compared with lean control mothers (n = 6) using metabolomics methods.ResultsGestational calorie restriction normalized one-carbon metabolism dysregulation in obese mothers, but altered energy metabolism in her offspring. Although administration of pravastatin during pregnancy tended to normalize blood cholesterol in the mothers, it potentially impacted the gut microbiome and kidney function of their offspring. In the offspring, both calorie restriction and pravastatin administration during pregnancy tended to normalize the activity of AMPK in the brain at 6 months, and while results of the Visual Paired-Comparison test, which measures infant recognition memory, was not significantly impacted by either of the interventions, gestational pravastatin administration, but not calorie restriction, tended to normalize anxiety assessed by the Human Intruder test.ConclusionsAlthough the two interventions tested in a non-human primate model led to some improvements in metabolism and/or infant brain development, negative impacts were also found in both mothers and infants. Our study emphasizes the importance of assessing gestational interventions for maternal obesity on both maternal and offspring long-term outcomes.

Abstract Concern that synthetic food dyes may impact behavior in children prompted a review by the California Office of Environmental Health Hazard Assessment (OEHHA). OEHHA conducted a systematic review of the epidemiologic research on synthetic food dyes and neurobehavioral outcomes in children with or without identified behavioral disorders (particularly attention and activity). We also conducted a search of the animal toxicology literature to identify studies of neurobehavioral effects in laboratory animals exposed to synthetic food dyes. Finally, we conducted a hazard characterization of the potential neurobehavioral impacts of food dye consumption. We identified 27 clinical trials of children exposed to synthetic food dyes in this review, of which 25 were challenge studies. All studies used a cross-over design and most were double blinded and the cross-over design was randomized. Sixteen (64%) out of 25 challenge studies identified some evidence of a positive association, and in 13 (52%) the association was statistically significant. These studies support a relationship between food dye exposure and adverse behavioral outcomes in children. Animal toxicology literature provides additional support for effects on behavior. Together, the human clinical trials and animal toxicology literature support an association between synthetic food dyes and behavioral impacts in children. The current Food and Drug Administration (FDA) acceptable daily intakes are based on older studies that were not designed to assess the types of behavioral effects observed in children. For four dyes where adequate dose-response data from animal and human studies were available, comparisons of the effective doses in studies that measured behavioral or brain effects following exposure to synthetic food dyes indicate that the basis of the ADIs may not be adequate to protect neurobehavior in susceptible children. There is a need to re-evaluate exposure in children and for additional research to provide a more complete database for establishing ADIs protective of neurobehavioral effects.

Introduction: This subanalysis aimed to provide real-world data on venous thromboembolism (VTE) from patients with lung cancer in the Cancer-VTE Registry. Methods: The primary outcome was the number of baseline VTE events in patients with lung cancer. The 1-year cumulative incidences of symptomatic VTE; composite VTE (symptomatic and incidental VTE requiring treatment); bleeding; cerebral infarction, transient ischemic attack, and systemic embolic events; and all-cause death were calculated. Clinical trial registration: UMIN000024942. Results: The study enrolled a total of 2377 patients with lung cancer; of these, 119 (5.0%) had VTE (six [0.3%], symptomatic, and 113 [4.8%], asymptomatic) and 14 (0.6%) had pulmonary embolism at baseline. During the follow-up period (mean, 337.7 d), the incidence was 0.6% for symptomatic VTE, 1.8% for composite VTE, 1.5% for bleeding events, 1.3% for cerebral infarction, transient ischemic attack, and systemic embolism, and 19.1% for all-cause death. Composite VTE frequency did not vary by anticancer drug type. Patients with (versus without) VTE at baseline had higher hazard ratios (HRs) for composite VTE (unadjusted HR: 5.29; Gray test p < 0.001) and symptomatic VTE (unadjusted HR: 4.89; Gray test p = 0.007). Patients with VTE at baseline had higher HRs for bleeding events (unadjusted HR: 3.27; Gray test p = 0.010) and all-cause death (unadjusted HR: 2.73; log-rank test p < 0.001) than patients without. In multivariable analysis, patients with baseline VTE prevalence and Eastern Cooperative Oncology Group Performance Status of 2 had increased composite VTE risk during cancer therapy. There were no other risk factors for composite VTE. Conclusions: Our findings emphasize the importance of VTE screening at cancer diagnosis.

Dietary intake and biomarkers of micronutrient status of 100 non-pregnant women of reproductive age (NPWRA) were assessed to determine optimal levels of iron, zinc, vitamin B12, and folic acid to include in multiply-fortified salt (MFS) that will be evaluated in an upcoming trial. Weighed food records were obtained from participants to measure intake of micronutrients and discretionary salt, and to assess adequacy using Indian Nutrient Reference Values (NRVs). Statistical modeling was used to determine optimal fortification levels to reduce inadequate micronutrient intake while limiting intake above the upper limit. Fasting blood samples were obtained to assess iron, zinc, vitamin B12, and folate status. In usual diets, inadequate intake of iron (46%), zinc (95%), vitamin B12 (83%), and folate (36%) was high. Mean intake of discretionary salt was 4.7 g/day. Prevalence estimates of anemia (37%), iron deficiency (67%), zinc deficiency (34%), vitamin B12 insufficiency (37%), and folate insufficiency (70%) were also high. Simulating the addition of optimized MFS to usual diets resulted in percentage point (pp) reductions in inadequate intake by 29 pp for iron, 76 pp for zinc, 81 pp for vitamin B12, and 36 pp for folate. MFS holds potential to reduce the burden of micronutrient deficiencies in this setting.

Objective To clarify the impact of Japan’s Clinical Trials Act (CTA), which was enacted in April 2018, on subsequent clinical trial activity through an analysis of Japanese registry data.Design Retrospective database study.Setting We extracted information on clinical intervention studies registered between 1 April 2018 and 30 September 2020 in the conventional University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR) and the new Japan Registry of Clinical Trials (jRCT). We collected and analysed information on registration dates, intervention types, funding, secondary sponsors and use of designated staff in multidisciplinary roles (research planning support, research administration, data management, statistical analysis, monitoring and auditing). The temporal trends in clinical trial activity after CTA enactment were examined.Results A total of 577 CTA-compliant specified clinical trials (ie, studies funded by pharmaceutical companies or studies evaluating the efficacy and safety of off-label drugs or devices in humans) were registered in the jRCT. During the same period, 5068 clinical trials were registered in the UMIN-CTR. The number of specific clinical trials increased immediately after the implementation of the CTA and stabilised in late 2019, whereas the number of clinical trials registered in the UMIN-CTR generally declined over time. Specified clinical trials that received industry funding and public grants were more likely to use designated staff in multidisciplinary roles.Conclusions The implementation of the CTA has not reduced the number of specified clinical trials, but has reduced the total number of intervention trials. The use of designated staff in multidisciplinary roles is associated with funding, secondary sponsors and multicentre studies. It was inferred that funding was needed to establish research infrastructure systems that support high-quality research.

Background: Cronkhite-Canada syndrome (CCS), chronic enteropathy associated with SLCO2A1 gene (CEAS), and intestinal Behçet’s disease (BD) are classified as intractable intestinal disorders in Japan. However, the national prevalence of these diseases remains unknown. We performed a nationwide survey to estimate the patient numbers and prevalence rates of these diseases throughout Japan in 2017. Methods: We conducted a mail-based survey targeting hospitals across Japan to estimate the annual numbers of patients with CCS, CEAS, and intestinal BD in 2017. Using a stratified random sampling method, we selected 2,979 hospital departments and asked them to report the number of patients who met specific diagnostic criteria. The total number of patients for each disease was estimated by multiplying the reported numbers by the reciprocal of the sampling rate and response rate. The corresponding prevalence rates per 1,000,000 population were calculated based on the mid-year population of Japan in 2017. Results: The overall survey response rate was 68.1% (2,029 departments). The estimated numbers of patients with CCS, CEAS, and intestinal BD were 473 (95% confidence interval [CI], 357–589), 388 (95% CI, 289–486), and 3,139 (95% CI, 2,749–3,529), respectively; the prevalence rates per 1,000,000 population were 3.7 (male: 4.0; female: 3.5), 3.1 (male: 3.0; female: 3.1), and 24.8 (male: 24.5; female: 25.0), respectively. The male-to-female ratios were 1.10, 0.94, and 0.93 for patients with CCS, CEAS, and intestinal BD, respectively. Conclusions: Estimates of the national prevalence of CCS, CEAS, and intestinal BD in Japan were generated and found to be higher than those previously reported.

Objectives Lupron 11.25 mg has both a narrow indication and a high cost compared to other Lupron presentations. Prior to our study initiation there was no clear distinction between presentations when ordering within the health-system’s Electronic Health Record (EHR). This resulted in inappropriate product selection, payment and billing errors that negatively impact our healthcare system. To reinforce prior education efforts, a new approach was considered leveraging the EHR with information to steer prescribers to the proper Lupron presentation based on indication. This study aimed to reduce off-label prescribing for Lupron 11.25 mg (NDC 00074-3663-03) by 25% by 02/28/2022 without negatively impacting the insurance collection rate.Methods Baseline Lupron 11.25 mg adult kit administrations one year prior to intervention and off-label prescribing was found to account for 22.7% of administrations. In December 2021 intervention order questions were added to Lupron 11.25 mg in the EHR. One and two-month data was obtained after implementing order questions within the EHR. Lupron 11.25 mg administrations were classified into one of four categories to determine impact on off-label prescribing.Results In the one- and two-month post-implementation periods off-label prescribing was 0% and 15.3% respectively, a reduction of 22.7% to and 7.4% respectively from the baseline assessment. There were no clinical denials found in either post-implementation reporting period.Conclusion This report adds to the body of evidence that leveraging the EHR can lead to healthcare savings and illustrates how patient and healthcare system burden can be reduced by prompting thought and direction when a medication has indication specific dose requirements.

Abstract Background The rates of newly diagnosed cases of sexually transmitted diseases, including genital chlamydial infection and gonorrhea, are important for prevention and control of these diseases. However, nationwide rates are not reported in Japan. Methods We used the number of cases of sexually transmitted diseases reported by nationwide sentinel surveillance in 2015, together with the number of all disease outpatients in September 2014 at all medical institutions, drawn from the Survey of Medical Institutions of Japan. The number of cases of sexually transmitted diseases in the total population was estimated using the ratio estimation method with the number of all disease outpatients as auxiliary information. This method is currently used for estimating influenza cases from sentinel surveillance data in Japan. Results The estimated number of newly diagnosed cases per 100,000 population in 2015 in Japan was 244 (95% confidence interval 211–277) for genital chlamydial infection, 87 (95% confidence interval 74–100) for genital herpes, 61 (95% confidence interval 29–93) for condyloma acuminatum, and 89 (95% confidence interval 64–113) for gonorrhea. Conclusion We estimated the nationwide number of newly diagnosed cases of sexually transmitted diseases in Japan from sentinel surveillance data. This provides useful information for public health policy-making.

In the direct searches for Weakly Interacting Massive Particles (WIMPs) as Dark Matter candidates, the sensitivity of the detector to the incom- ing particle direction could provide a smoking gun signature for an interesting event. The SCENE collaboration firstly suggested the possible directional de- pendence of a dual-phase argon Time Projection Chamber through the columnar recombination effect. The Recoil Directionality project (ReD) within the Global Argon Dark Matter Collaboration aims to characterize the light and charge re- sponse of a liquid Argon dual-phase TPC to neutron-induced nuclear recoils to probe for the hint by SCENE. In this work, the directional sensitivity of the de- tector in the energy range of interest for WIMPs (20-100 keV) is investigated with a data-driven analysis involving a Machine Learning algorithm.

Reactive control of response inhibition is associated with a right-lateralised cortical network, as well as frontal-midline theta (FM-theta) activity measured at the scalp. However, response inhibition is also governed by proactive control processes, and how such proactive control is reflected in FM-theta activity and associated neural source activity remains unclear. To investigate this, simultaneous recordings of electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) data was performed while participants performed a cued stop-signal task. The cues (0%, 25% or 66%) indicated the likelihood of an upcoming stop-signal in the following trial. Results indicated that participants adjusted their behaviour proactively, with increasing go-trial reaction times following increasing stop-signal probability, as well as modulations of both go-trial and stop-trial accuracies. Target-locked theta activity was higher in stop-trials than go-trials and modulated by probability. At the single-trial level, cue-locked theta was associated with shorter reaction-times, while target-locked theta was associated with both faster reaction times and higher probability of an unsuccessful stop-trial. This dissociation was also evident at the neural source level, where a joint ICA revealed independent components related to going, stopping and proactive preparation. Overall, the results indicate that FM-theta activity can be dissociated into several mechanisms associated with proactive control, response initiation and response inhibition processes. We propose that FM-theta activity reflects both heightened preparation of the motor control network, as well as stopping-related processes associated with a right lateralized cortical network.

There is a significant interest in novel waste management solutions to treat wastewater from swine operations. Anaerobic digestion is a rising and prominent solution, but this technology still generates highly concentrated effluent that requires further remediation. Therefore, the aim of this study was to explore the feasibility of cultivating the cyanobacterium Spirulina platensis in swine effluent for future applications in biological waste treatment and value-added fermentation. To accomplish this goal, growth of S. platensis was characterized in varying proportions of ideal, synthetic Zarrouk medium and anaerobically digested pig effluent (ADPE) to obtain growth rate models. Results yielded a positive correlation between S. platensis growth rate and Zarrouk medium proportion, with the highest growth rate in 100% Zarrouk media but comparable growth in the 50/50% Zarrouk/ADPE mixture. This study demonstrates the potential for S. platensis to further improve the treatment efficacy of anaerobic digestion systems, and the exploratory analysis also highlights that further testing is required to investigate possible carbon availability, chemical inhibition, and overall nutrient reduction in ADPE. This research contributes important data toward the feasibility of producing value-added cyanobacterial biomass while simultaneously consuming excess nutrients to aid in agricultural wastewater management efforts and generate cost-effective products in a more sustainable manner.

In recent years the discourse regarding the effective use of dwindling agricultural spaces for food, fiber, or fuel production has grown and it is becoming increasingly important to manage non-agricultural or marginal spaces that make them suitable for crop production. Highly eroded, highly compacted, low nutrient soils, similar to those found along highway rights-of-way (ROWs) offer unique field characteristics that can be used to study crop production potentials and land use decisions. This work evaluated the feasibility of maintaining a canola crop production system on the non-agricultural soils of highway ROWs across the humid subtropical climate within North Carolina, USA as a bioenergy feedstock for renewable fuels. Specific objectives included examination of (1) three different North Carolina geoclimatic conditions and (2) three levels of tillage (conventional (CT), minimum (MT), and no-till (NT)) on canola (Brassica napus L.) grain yields cultivated on ROW soils. Field experiments were conducted for two growing seasons in the Inner Coastal Plain, Piedmont, and Mountains regions and assessed main and interaction effects among tillage, site, and year of cultivation on crop productivity. After season 1, CT produced the highest average yield (1.24 Mg ha−1) followed by MT (0.93 Mg ha−1) and NT (0.86 Mg ha−1), respectively. In the second year, the comparative intensity of productive effects from CT was lower, and plots cultivated under MT resulted in the highest average yields (2.70 Mg ha−1), followed by CT (2.69 Mg ha−1) and NT (1.96 Mg ha−1), respectively. Yields observed were comparable to regional canola grain yields, and no significant difference was observed between yields under CT versus MT. These findings suggest that reduced levels of tillage on ROW soils in North Carolina hold the potential to produce yields comparable to those realized in traditional agricultural soils, and targeted tillage practices can support improved suitability of marginal crop production spaces.

Background: Although the guidelines in most countries do not recommend continuous inhalation of l-isoproterenol to treat pediatric patients with acute severe exacerbation of asthma, lower dose of l-isoproterenol has been widely used in Japan. To determine whether the efficacy of low-dose l-isoproterenol was superior to that of salbutamol, we conducted a double-blind, randomized controlled trial. Methods: Hospitalized patients aged 1–17 years were eligible if they had severe asthma exacerbation defined by the modified pulmonary index score (MPIS). Patients were randomly assigned (1:1) to receive inhalation of l-isoproterenol (10 μg/kg/h) or salbutamol (500 μg/kg/h) for 12 hours via a large-volume nebulizer with oxygen. The primary outcome was the change in MPIS from baseline to 3 hours after starting inhalation. Trial registration number UMIN000001991. Results: From December 2009 to October 2013, 83 patients (42 in the l-isoproterenol group and 41 in the salbutamol group) were enrolled into the study. Of these, one patient in the l-isoproterenol group did not receive the study drug and was excluded from the analysis. Compared with salbutamol, l-isoproterenol reduced MPIS more rapidly. Mean (SD) changes in MPIS at 3 hours were −2.9 (2.5) in the l-isoproterenol group and −0.9 (2.3) in the salbutamol group (difference −2.0, 95% confidence interval −3.1 to −0.9; P

Maternal gestational obesity is associated with elevated risks for neurodevelopmental disorder, including autism spectrum disorder. However, the mechanisms by which maternal adiposity influences fetal developmental programming remain to be elucidated. We aimed to understand the impact of maternal obesity on the metabolism of both pregnant mothers and their offspring, as well as on metabolic, brain, and behavioral development of offspring by utilizing metabolomics, protein, and behavioral assays in a non-human primate model. We found that maternal obesity was associated with elevated inflammation and significant alterations in metabolites of energy metabolism and one-carbon metabolism in maternal plasma and urine, as well as in the placenta. Infants that were born to obese mothers were significantly larger at birth compared to those that were born to lean mothers. Additionally, they exhibited significantly reduced novelty preference and significant alterations in their emotional response to stress situations. These changes coincided with differences in the phosphorylation of enzymes in the brain mTOR signaling pathway between infants that were born to obese and lean mothers and correlated with the concentration of maternal plasma betaine during pregnancy. In summary, gestational obesity significantly impacted the infant systemic and brain metabolome and adaptive behaviors.

Including biomarkers of micronutrient status in existing or planned national surveys or surveillance systems is a critical step in improving capacity to promote, design, monitor, and evaluate micronutrient policies and programs. We aimed to identify the barriers to and enablers of the inclusion of micronutrient biomarker assessment in national surveys and surveillance systems, to identify the main challenges faced during the survey process, and to review experiences using existing platforms for micronutrient surveys. We conducted a series of key informant interviews with in-country and external representatives from six countries where national-level data on micronutrient status were collected in the past 5 years: Cambodia, Pakistan, Malawi, Uganda, Ghana, and Uzbekistan. Micronutrients associated with specific public health programs were always prioritized for inclusion in the survey. If funding, time, and/or logistics allowed, other considered micronutrients were also included. The most important and frequently reported barrier to inclusion of a more comprehensive panel of micronutrient biomarkers was inadequate funding to cover the laboratory analysis cost for all micronutrients considered at the planning stage. Government support and commitment was stressed as the most important enabling factor by all key informants. Advocacy for funding for micronutrient status assessment is needed.

Fluoxetine is an antidepressant commonly prescribed not only to adults but also to children for the treatment of depression, obsessive-compulsive disorder, and neurodevelopmental disorders. The adverse effects of the long-term treatment reported in some patients, especially in younger individuals, call for a detailed investigation of molecular alterations induced by fluoxetine treatment. Two-year fluoxetine administration to juvenile macaques revealed effects on impulsivity, sleep, social interaction, and peripheral metabolites. Here, we built upon this work by assessing residual effects of fluoxetine administration on the expression of genes and abundance of lipids and polar metabolites in the prelimbic cortex of 10 treated and 11 control macaques representing two monoamine oxidase A (MAOA) genotypes. Analysis of 8871 mRNA transcripts, 3608 lipids, and 1829 polar metabolites revealed substantial alterations of the brain lipid content, including significant abundance changes of 106 lipid features, accompanied by subtle changes in gene expression. Lipid alterations in the drug-treated animals were most evident for polyunsaturated fatty acids (PUFAs). A decrease in PUFAs levels was observed in all quantified lipid classes excluding sphingolipids, which do not usually contain PUFAs, suggesting systemic changes in fatty acid metabolism. Furthermore, the residual effect of the drug on lipid abundances was more pronounced in macaques carrying the MAOA-L genotype, mirroring reported behavioral effects of the treatment. We speculate that a decrease in PUFAs may be associated with adverse effects in depressive patients and could potentially account for the variation in individual response to fluoxetine in young people.

Adequate zinc nutrition is important for child growth, neurodevelopment, immune function, and normal pregnancy outcomes. Seventeen percent of the global population is estimated to be at risk for inadequate zinc intake. However, zinc is not included in the fortification standards of several low- and middle-income countries with mandatory fortification programs, despite data suggesting a zinc deficiency public health problem. To guide policy decisions, we investigated the factors enabling and impeding the inclusion of zinc as a fortificant by conducting in-depth interviews with 17 key informants from 10 countries. Findings revealed the decision to include zinc was influenced by guidance from international development partners and enabled by the assessment of zinc deficiency, mandatory regional food fortification standards which included zinc, the World Health Organization (WHO) guidelines for zinc fortification, and the low cost of zinc compound commonly used. Barriers included the absence of zinc from regional fortification standards, limited available data on the efficacy and effectiveness of zinc fortification, and the absence of national objectives related to the prevention of zinc deficiency. To promote zinc fortification there is a need to put the prevention of zinc deficiency higher on the international nutrition agenda and to promote large-scale food fortification as a key deficiency mitigation strategy.

Potential long term effects on brain development are a concern when drugs are used to treat depression and anxiety in childhood. In this study, male juvenile rhesus monkeys (three-four years of age) were dosed with fluoxetine or vehicle (N = 16/group) for two years. Histomorphometric examination of cortical dendritic spines conducted after euthanasia at one year postdosing (N = 8/group) suggested a trend toward greater dendritic spine synapse density in prefrontal cortex of the fluoxetine-treated monkeys. During dosing, subjects were trained for automated cognitive testing, and evaluated with a test of sustained attention. After dosing was discontinued, sustained attention, recognition memory and cognitive flexibility were evaluated. Sustained attention was affected by fluoxetine, both during and after dosing, as indexed by omission errors. Response accuracy was not affected by fluoxetine in post-dosing recognition memory and cognitive flexibility tests, but formerly fluoxetine-treated monkeys compared to vehicle controls had more missed trial initiations and choices during testing. Drug treatment also interacted with genetic and environmental variables: MAOA genotype (high- and low transcription rate polymorphisms) and testing location (upper or lower tier of cages). Altered development of top-down cortical regulation of effortful attention may be relevant to this pattern of cognitive test performance after juvenile fluoxetine treatment. Keywords: Fluoxetine, Juvenile, Cognitive, Nonhuman primate, Serotonin, Dendritic spine synapses

Welfare states increasingly rely on aging in place policies and have cut back on institutional long-term care (LTC) provision. Simultaneously, the major determinants of LTC use, that is, dementia and living to very old age, are increasing. We investigated how increasing longevity and concomitant dementia were associated with changes in round-the-clock LTC use in the last 5 years of life between 1996 and 2013. Retrospective data drawn from national registers included all those who died aged 70+ in 2007 and 2013, plus a 40% random sample from 2001 ( N = 86,554). A generalized estimating equations (GEE) were used to estimate the association of dementia and age with LTC use during three study periods 1996-2001, 2002-2007, and 2008-2013. Between the study periods, the total number of days spent in LTC increased by around 2 months. Higher ages at death and the increased number of persons with dementia contributed to this increase. The group of the most frequent LTC users, that is, people aged 90+ with or without dementia, grew the most in size, yet their LTC use decreased. The implications of very old age and concomitant dementia for care needs must be acknowledged to guarantee an adequate quantity and quality of care.

The aim of this study was to address feasibility aspects of a multidisciplinary, family-centered rehabilitation intervention for persons with traumatic brain injury and their family. The study was done in preparation of a full-scale RCT and conducted as a collaboration between specialist and municipal health-care service, with two municipal health professionals included as collaborating partners. By applying the intervention on six persons, two families, we evaluated the attendance rate, the appropriateness of the intervention’s topics, the collaboration with the municipal health professionals, and the data collection method. Predefined success-criteria were used to evaluate feasibility. The family intervention and study procedures were evaluated as feasible. Some challenges arose and were discussed prior to commencing the full-scale trial. They concerned the logistics regarding the delivery of the intervention and making appropriate adjustments to meet the families’ unique needs and facilitate participation. A pragmatic approach was considered necessary in the full-scale RCT.

Seabirds breed in high density colonies, but the factors determining colony position aren't clear. Here, Sandvik et al. show that small-scale coastal topography is related to likely variation in fish larval abundance, which predicts the distribution of seabird colonies along the Norwegian coast.

Increased interest in biomass cultivation requires detailed analysis of spatial production potential of possible biorefinery locations, with emphasis on feedstock production cost minimization. Integrated assessment of publicly available spatial data on current crop production, soil type, and yield potential, coupled with techno-economic production cost estimates, can support a functional method for rapid analysis of potential biorefinery sites. A novel predictive model was developed to determine cropland conversion using a probabilistic profit based equation for multiple biomass crops: giant reed, miscanthus, switchgrass, and sorghum (with either canola or barley as a winter crop). The three primary regions of North Carolina (Mountains, Piedmont, and Coastal Plain) were used as a case study and with a single parameter uncertainty analysis was completed. According to the model, the county chosen to represent the Coastal Plain (Duplin County) had the largest potential acreage that would be converted (15,071 ha, 7.1% total land, 9.3% of cropland) primarily to sorghum with canola as a winter crop. Large portions were also predicted to convert to giant reed and switchgrass, depending on the price and yield parameters used. The Piedmont (Granville County, 7697 ha, 5.5% total land, 6.9% cropland) and Mountain (Henderson County, 2117 ha, 2.2% total land, 2.3% cropland) regions were predicted to convert primarily to switchgrass acreage for biomass production, with much less available biomass overall compared to the Coastal Plain. This model provided meaningful insight into regional cropping systems and feedstock availability, allowing for improved business planning in designated regions. Determination of cropland conversion is imperative to develop realistic biomass logistical operations, which in conjunction can assist with rapid determination of profitable biomass availability. After this rapid analysis method is conducted in-depth on-ground biorefinery feasibility analysis can occur, ensuring resource are used only in locations with a high potential for available low cost biomass feedstocks.

Traumatic brain injury (TBI) affects the family as a whole. This study aimed to describe and compare mental health and family functioning in TBI patients and their family members, and to identify individual and family-related factors that were associated with mental health. It was conducted at an urban, specialized, TBI outpatient clinic and included 61 patients with mild to severe TBI and 63 family members. Baseline demographics and injury-related data were collected, and the participants answered standardized, self-reported questionnaires 6–18 months post-injury that assessed mental health; general health; family functioning, communication, and satisfaction; depression and anxiety; self-efficacy; resilience; and condition-specific quality of life. The patients reported significantly worse mental health, depression, resilience, self-efficacy, and general health compared with the family members. Patients and family members had similar perceptions, showing balanced family functioning, high family communication levels, and moderate family satisfaction. Factors significantly associated with mental health in patients and family members were depression, anxiety, and resilience, explaining 56% of the variance (p < 0.001). Family-related factors were not associated with mental health. The disease burden was mainly on the patients; however, the family members also reported emotional distress. Family-targeted interventions across the TBI continuum should be considered.

Fluoxetine therapy has been approved for children with major depressive disorder and obsessive compulsive disorder for over 14 years and has expanded to other childhood behavior disorders. As use increases, more detail on fluoxetine effects during juvenile brain development can help maintain safe and effective use of this therapy. Here, a narrative review is provided of previously published findings from a large nonhuman primate project. Fluoxetine was administered to juvenile male rhesus monkeys for an extended period (2 years) prior to puberty. Compared to controls, treated monkeys showed sleep disruption, facilitated social interaction, greater impulsivity, and impaired sustained attention during treatment. No effects on growth were seen. Metabolomics assays characterized a distinctive response to fluoxetine and demonstrated individual differences that were related to the impulsivity measure. Fluoxetine interactions with monoamine oxidase A polymorphisms that influenced behavior and metabolomics markers were an important, previously unrecognized finding of our studies. After treatment was discontinued, some behavioral effects persisted, but short-term memory and cognitive flexibility testing did not show drug effects. This detailed experimental work can contribute to clinical research and continued safe and effective fluoxetine pharmacotherapy in children.

Ciliopathies presenting as inherited hepatorenal fibrocystic disorders are rare in humans and in dogs. We describe here a novel lethal ciliopathy in Norwich Terrier puppies that was diagnosed at necropsy and characterized as diffuse cystic renal disease and hepatic fibrosis. The histopathological findings were typical for cystic renal dysplasia in which the cysts were located in the straight portion of the proximal tubule, and thin descending and ascending limbs of Henle's loop. The pedigree of the affected puppies was suggestive of an autosomal recessive inheritance and therefore, whole exome sequencing and homozygosity mapping were used for identification of the causative variant. The analyses revealed a case-specific homozygous splice donor site variant in a cilia related gene, INPP5E: c.1572+5G>A. Association of the variant with the defect was validated in a large cohort of Norwich Terriers with 3 cases and 480 controls, the carrier frequency being 6%. We observed that the identified variant introduces a novel splice site in INPP5E causing a frameshift and formation of a premature stop codon. In conclusion, our results suggest that the INPP5E: c.1572+5G>A variant is causal for the ciliopathy in Norwich Terriers. Therefore, genetic testing can be carried out in the future for the eradication of the disease from the breed.

Recent work suggests that diet affects brain metabolism thereby impacting cognitive function. Our objective was to determine if a western diet altered brain metabolism, increased blood-brain barrier (BBB) transport and inflammation, and induced cognitive impairment in C57BL/6 (WT) mice and low-density lipoprotein receptor null (LDLr -/-) mice, a model of hyperlipidemia and cognitive decline. We show that a western diet and LDLr -/- moderately influence cognitive processes as assessed by Y-maze and radial arm water maze. Also, western diet significantly increased BBB transport, as well as microvessel factor VIII in LDLr -/- and microglia IBA1 staining in WT, both indicators of activation and neuroinflammation. Interestingly, LDLr -/- mice had a significant increase in 18F- fluorodeoxyglucose uptake irrespective of diet and brain 1H-magnetic resonance spectroscopy showed increased lactate and lipid moieties. Metabolic assessments of whole mouse brain by GC/MS and LC/MS/MS showed that a western diet altered brain TCA cycle and β-oxidation intermediates, levels of amino acids, and complex lipid levels and elevated proinflammatory lipid mediators. Our study reveals that the western diet has multiple impacts on brain metabolism, physiology, and altered cognitive function that likely manifest via multiple cellular pathways.