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Cynthia L Grant,1,2 Jaimie L Lusk3 1Arapahoe/Douglas Mental Health Network, Englewood, CO, 2School of Education and Human Development, University of Colorado Denver, Denver, CO, 3Mental Health Service, VA Portland Health Care System, Portland, OR, USA Abstract: As health care trends toward a system of care approach, providers from various disciplines strive to collaborate to provide optimal care for their patients. While a multidisciplinary approach to suicide risk assessment and management has been identified as important for reducing suicidality, standardized clinical guidelines for such an approach do not yet exist. In this article, the authors propose the adoption of the therapeutic risk management of the suicidal patient (TRMSP) to improve suicide risk assessment and management within multidisciplinary systems of care. The TRMSP, which has been fully articulated in previous articles, involves augmenting clinical risk assessment with structured instruments, stratifying risk in terms of both severity and temporality, and developing and documenting a safety plan. Augmenting clinical risk assessments with reliable and valid structured instruments serves several functions, including ensuring important aspects of suicide are addressed, establishing a baseline for suicidal thoughts and behaviors, facilitating interprofessional communication, and mitigating risk. Similarly, a two-dimensional risk stratification qualifying suicide risk in terms of both severity and temporality can enhance communication across providers and settings and improve understanding of acute crises in the context of chronic risk. Finally, safety planning interventions allow providers and patients to collaboratively create a personally meaningful plan for managing a suicidal crisis that can be continually modified across time with multiple providers in different care settings. In a busy care environment, the TRMSP can provide concrete guidance on conducting clinically and medicolegally sound suicide risk assessment and management. This collaborative and comprehensive process would potentially improve care of patients with suicidality, optimize clinical resources, decrease unnecessary and costly admissions, and mitigate medicolegal risk. The TRMSP may serve as a foundation for building a standardized, collaborative, stepped-care approach that patients, individual providers, and the health care system can all benefit from. Keywords: suicide risk assessment, multidisciplinary, systems of care

Academic advisors in higher education are often incoming students’ first exposure to college curriculum and academic expectations. Additionally, academic advisors serve as an on-going support to students throughout their college careers. As the number of students beginning college full-time with a significant amount of dual enrollment (DE) credits increases, academic advisors must develop approaches to advising this population of students based on academic and developmental needs. This study explored the approaches college academic advisors take when advising high DE credit-bearing incoming college students.

Testing and accountability measures have continued to expand since the passage of the No Child Left Behind Act in 2001. In addition to school and district accountability, student test scores increasingly formed the foundation of teacher performance metrics. State participation rates exceeded the 95% minimum prescribed by law despite increasing opposition to many testing requirements. However, the rollout of the Common Core aligned PARCC tests in 2015 marked the start of a backlash against state mandated testing. The movement, commonly called opt-out, encouraged families not to participate in required tests. We use pooled OLS regression on statewide panel data from Colorado schools to examine school-level characteristics in one of the states with the largest declines in test participation. We find the prevalence of opt-out is largest in charter schools, suburban and rural areas, higher performing schools, and schools with a higher proportion of White students.

In this written commentary for the special issue of Education Policy Analysis Archives focused on “Redesigning Assessment and Accountability,” we call for teacher preparation to embrace a multiple measures philosophy by providing teacher candidates with rich opportunities to engage with data from a variety of sources, beyond teacher test scores and principal evaluations. We apply and extend Bae’s (2018) argument to teacher preparation policies, urging teacher educators to develop programs that promote continuous improvement. We argue that teacher education can and should prepare candidates to engage in multiple measure systems, critically evaluate data and sense make to construct meaning, reflect on and improve their practice to meet the needs of all students, and ultimately advocate for next-generation accountability systems that authentically foreground and prioritize continuous improvement.

The concept of sustainability is becoming more and more important in the face of dwindling resources and increasing demand. Despite this, there are still many industries and disciplines in which sustainability is not actively addressed. The requirement of meeting current and future needs is not an issue from which IT projects are exempt. Ensuring sustainability requires managing sustainability in all activities. The field of IT and sustainability is one in which literature is appearing, but at a slow pace and this leaves many unanswered questions regarding the state of sustainability in IT projects and the commitment of IT project managers to sustainability. In not knowing what the state of sustainability is, potential shortcomings remain unknown and corrective action cannot be taken. Quantitative research was conducted through the use of a survey in the form of a structured questionnaire. This research was cross-sectional as the focus was to assess the state of sustainability at a single point in time. IT project managers were randomly sampled to get an objective view of how committed they were to sustainability. This research made use of a project management sustainability maturity model to measure the extent to which sustainability is incorporated into IT projects. The findings are that IT project managers are not committed to sustainability. While the economic dimension yielded the best results, they were not ideal, and it is in fact the social and environmental dimensions that require the most attention. This lacking commitment to the social and environmental dimensions is not limited to select aspects within each dimension, as each dimension’s aspects are addressed to a similarly poor extent. This research suggests that sustainability needs to become a focus for IT project managers, but for this to happen, they require the relevant project management sustainability knowledge.

Abstract Understanding the mechanisms that maintain protective antibody levels after immunisation is important for vaccine design. In this study, we have determined the kinetics of plasma and memory B cells detectable in the blood of cattle immunised with model T-dependent or T-independent antigens. Immunisation with the T-D antigen resulted in an expansion of TNP-specific plasma cells post-TNP primary and booster immunisations, which was associated with increased titres of TNP-specific IgG antibodies. Although no TNP-specific memory B cells were detected in the T-D group following the primary immunisation, we detected an increase in the number of TNP-specific memory B cells post-TNP boost. In contrast, no TNP-specific plasma or memory B cells were detected after primary or secondary immunisation with the T-I antigen. We then investigated if immunisation with a third party antigen (tetanus toxin fragment C, TTC) would result in a bystander stimulation and increase the number of TNP-specific plasma and memory B cells in the T-D and/or T-I group. TTC immunisation in the T-D group resulted in a small increase in the number of TNP-specific plasma cells post-TTC primary immunisation and boost, and in an increase in the number of TNP-specific memory B cells post-TTC boost. This bystander effect was not observed in the animals previously immunised with the T-I antigen. In conclusion, the present study characterised for the first time the B cell response in cattle to immunisation with T-D and T-I antigens and showed that bystander stimulation of an established T-D B cell memory response may occur in cattle.

Around 60% of individuals with neurodevelopmental disorders (NDD) remain undiagnosed after comprehensive genetic testing, primarily of protein-coding genes 1 . Large genome-sequenced cohorts are improving our ability to discover new diagnoses in the non-coding genome. Here we identify the non-coding RNA RNU4-2 as a syndromic NDD gene. RNU4-2 encodes the U4 small nuclear RNA (snRNA), which is a critical component of the U4/U6.U5 tri-snRNP complex of the major spliceosome 2 . We identify an 18 base pair region of RNU4-2 mapping to two structural elements in the U4/U6 snRNA duplex (the T-loop and stem III) that is severely depleted of variation in the general population, but in which we identify heterozygous variants in 115 individuals with NDD. Most individuals (77.4%) have the same highly recurrent single base insertion (n.64_65insT). In 54 individuals in whom it could be determined, the de novo variants were all on the maternal allele. We demonstrate that RNU4-2 is highly expressed in the developing human brain, in contrast to RNU4-1 and other U4 homologues. Using RNA sequencing, we show how 5' splice-site use is systematically disrupted in individuals with RNU4-2 variants, consistent with the known role of this region during spliceosome activation. Finally, we estimate that variants in this 18 base pair region explain 0.4% of individuals with NDD. This work underscores the importance of non-coding genes in rare disorders and will provide a diagnosis to thousands of individuals with NDD worldwide., (© 2024. The Author(s).)

Background: Mucopolysaccharidosis VII (MPS VII) is an ultra-rare, autosomal recessive, debilitating, progressive lysosomal storage disease caused by reduced activity of β-glucuronidase (GUS) enzyme. Vestronidase alfa (recombinant human GUS) intravenous enzyme replacement therapy is an approved treatment for patients with MPS VII., Methods: This disease monitoring program (DMP) is an ongoing, multicenter observational study collecting standardized real-world data from patients with MPS VII (N ≈ 50 planned) treated with vestronidase alfa or any other management approach. Data are monitored and recorded in compliance with Good Clinical Practice guidelines and planned interim analyses of captured data are performed annually. Here we summarize the safety and efficacy outcomes as of 17 November 2022., Results: As of the data cutoff date, 35 patients were enrolled: 28 in the Treated Group and seven in the Untreated Group. Mean (SD) age at MPS VII diagnosis was 4.5 (4.0) years (range, 0.0 to 12.4 years), and mean (SD) age at DMP enrollment was 13.9 (11.1) years (range, 1.5 to 50.2 years). Ten patients (29%) had a history of nonimmune hydrops fetalis. In the 23 patients who initiated treatment prior to DMP enrollment, substantial changes in mean excretion from initial baseline to DMP enrollment were observed for the three urinary glycosaminoglycans (uGAGs): dermatan sulfate (DS), -84%; chondroitin sulfate (CS), -55%; heparan sulfate (HS), -42%. Also in this group, mean reduction from initial baseline to months 6, 12, and 24 were maintained for uGAG DS (-84%, -87%, -89%, respectively), CS (-70%, -71%, -76%, respectively), and HS (+ 3%, -32%, and - 41%, respectively). All adverse events (AEs) were consistent with the known vestronidase alfa safety profile. No patients discontinued vestronidase alfa. One patient died., Conclusions: To date, the DMP has collected invaluable MPS VII disease characteristic data. The benefit-risk profile of vestronidase alfa remains unchanged and favorable for its use in the treatment of pediatric and adult patients with MPS VII. Reductions in DS and CS uGAG demonstrate effectiveness of vestronidase alfa to Month 24. Enrollment is ongoing., (© 2024. The Author(s).)

Introduction: High sustained anti-rhGAA antibody titers (HSAT; ≥12,800) are directly linked to reduced efficacy of enzyme replacement therapy (ERT) and subsequent clinical deterioration in infantile-onset Pompe disease (IOPD). We have previously demonstrated the safety and effectiveness of a bortezomib-based immune-tolerance induction (ITI) regimen (bortezomib, rituximab, methotrexate, and IVIG) in eliminating HSAT., Methods: Here, we describe two IOPD cases (patients 6 and 8) who developed HSAT at 8 and 10 weeks on ERT despite transient low-dose methotrexate ITI administration in the ERT-naïve setting and were treated with a bortezomib-based ITI regimen, and we compare their courses to a series of six historical patients (patients 1-5, and 7) with a similar presentation who exemplify our evolving approach to treatment., Results: In total, patients 6 and 8 received 16 and 8 doses of bortezomib (4 doses=1 cycle) respectively reducing titers from 25,600 to seronegative, but differences in the course of their therapy were instructive regarding the optimal approach to initial treatment of HSAT; specifically, patient 6 was treated initially with only a single course of bortezomib rescue therapy, while patient 8 received two back-to-back courses. Patient 8 received IVIG therapy throughout the immunosuppression whereas patient 6 received IVIG therapy and was switched to subcutaneous IgG replacement. Patient 6 had a transient reduction in anti-rhGAA antibodies, after receiving a single initial cycle of bortezomib, but had a recurrence of high anti-rhGAA antibody titer after 160 weeks that required 3 additional cycles of bortezomib to ultimately achieve tolerance. In contrast, patient 8 achieved tolerance after being given two consecutive cycles of bortezomib during their initial treatment and had B cell recovery by week 54. Since the reduction in anti-rhGAA antibodies, both patients are doing well clinically, and have decreasing ALT, AST, and CK. No major infections leading to interruption of treatment were observed in either patient. The bortezomib-based ITI was safe and well-tolerated, and patients continue to receive ERT at 40 mg/kg/week., Discussion: These case studies and our previous experience suggest that to achieve an effective reduction of anti-rhGAA antibodies in the setting of HSAT, bortezomib should be initiated at the earliest sign of high anti-rhGAA antibodies with a minimum of two consecutive cycles as shown in the case of patient 8. It is important to note that, despite initiation of ERT at age 2.3 weeks, patient 8 quickly developed HSAT. We recommend close monitoring of anti-rhGAA antibodies and early intervention with ITI as soon as significantly elevated anti-rhGAA antibody titers are noted., Competing Interests: AD has received grant support from Sanofi Genzyme and the Lysosomal Disease Network. AD has received honoraria from Sanofi Genzyme. CG has received Honoraria from Sanofi, Amicus Therapeutics, and RegenX Bio. RW serves on the Scientific Advisory Board for and owns equity in M6P Therapeutics. PK has received research/grant support from Sanofi Genzyme and Amicus Therapeutics. PK has received consulting fees and honoraria from Sanofi Genzyme, Amicus Therapeutics, Maze Therapeutics, Bayer, and Asklepios Biopharmaceutical, Inc. (AskBio). PK is a member of the Pompe and Gaucher Disease Registry Advisory Board for Sanofi Genzyme, Pompe Disease Advisory Board for Amicus Therapeutics, and Advisory Board for Babies. PK has equity with Maze Therapeutics and has held equity in Asklepios Biopharmaceuticals and may receive milestone payments related to that equity in the future. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be constructed as a potential conflict of interest., (Copyright © 2024 Desai, Shrivastava, Grant, Wang, Burt and Kishnani.)

Mucopolysaccharidosis type VII (MPS VII) is an ultra-rare, life-threatening, progressive disease caused by genetic mutations that affect lysosomal storage/function. MPS VII has an estimated prevalence of <1:1,000,000 and accounts for <3% of all MPS diagnoses. Given the rarity of MPS VII, comprehensive information on the disease is limited and we present a review of the current understanding. In MPS VII, intracellular glycosaminoglycans accumulate due to a deficiency in the lysosomal enzyme that is responsible for their degradation, β-glucuronidase, which is encoded by the GUSB gene. MPS VII has a heterogeneous presentation. Features can manifest across multiple systems and can vary in severity, age of onset and progression. The single most distinguishing clinical feature of MPS VII is non-immune hydrops fetalis (NIHF), which presents during pregnancy. MPS VII usually presents within one month of life and become more prominent at 3 to 4 years of age; key features are skeletal deformities, hepatosplenomegaly, coarse facies, and cognitive impairment, although phenotypic variation is a hallmark. Current treatments include hematopoietic stem cell transplantation and enzyme replacement therapy with vestronidase alfa. Care should be individualized for each patient. Development of consensus guidelines for MPS VII management and treatment is needed, as consolidation of expert knowledge and experience (for example, through the MPS VII Disease Monitoring Program) may provide a significant positive impact to patients., Competing Interests: Declaration of competing interest Deborah Marsden is an employee and shareholder of Ultragenyx Pharmaceutical Inc. Fatih Ezgü has been an investigator for Ultragenyx clinical trials. Christina Grant has received honoraria from Sanofi and Amicus Therapeutics, and her place of employment received research support from Ultragenyx. Jaime López-Valdez has received research funding and grants from Ultragenyx., (Copyright © 2023. Published by Elsevier Inc.)

The histone H3 variant H3.3, encoded by two genes H3-3A and H3-3B, can replace canonical isoforms H3.1 and H3.2. H3.3 is important in chromatin compaction, early embryonic development, and lineage commitment. The role of H3.3 in somatic cancers has been studied extensively, but its association with a congenital disorder has emerged just recently. Here we report eleven de novo missense variants and one de novo stop-loss variant in H3-3A (n = 6) and H3-3B (n = 6) from Baylor Genetics exome cohort (n = 11) and Matchmaker Exchange (n = 1), of which detailed phenotyping was conducted for 10 individuals (H3-3A = 4 and H3-3B = 6) that showed major phenotypes including global developmental delay, short stature, failure to thrive, dysmorphic facial features, structural brain abnormalities, hypotonia, and visual impairment. Three variant constructs (p.R129H, p.M121I, and p.I52N) showed significant decrease in protein expression, while one variant (p.R41C) accumulated at greater levels than wild-type control. One H3.3 variant construct (p.R129H) was found to have stronger interaction with the chaperone death domain-associated protein 6., (© 2021. The Author(s).)

The consumption of caffeine has been linked to osteoporosis, believed to be due to enhanced bone resorption as a result of increased calcium excretion in the urine. However, the amount of calcium in the urine may not necessarily reflect the true effect of caffeine on calcium clearance. This study therefore examined the impact of high-dose, short-term caffeine intake on renal clearance of calcium, sodium and creatinine in healthy adults. In a double-blind clinical study, participants chewed caffeine (n = 12) or placebo (n = 12) gum for 5 minutes at 2-hour intervals over a 6-hour treatment period (800 mg total caffeine). Caffeine increased renal calcium clearance by 77%. Furthermore, the effect was positively correlated with sodium clearance and urine volume, suggesting that caffeine may act through inhibition of sodium reabsorption in the proximal convoluted tubule. This study confirmed that caffeine does increase renal calcium clearance and fosters further investigation into safe consumption of caffeine., (© 2021 British Pharmacological Society.)

Introduction: Trauma registries in low- and middle-income countries (LMICs) are critical for improving trauma care; however, while some registries have been established in low-income settings, few are sustained due to a lack of sustainable funding. In many LMIC institutions, funding is dependent on documentation of trauma patients, but patient records may be of poor quality, missing, or incomplete. The development of a trauma registry and electronic patient registration system could be used to improve documentation of trauma patients in a low-income setting and lead to increased funding for trauma care., Methods: A retrospective chart review of trauma patients at Mbarara Regional Referral Hospital in Uganda was performed, documenting the monthly admissions from January 2015-July 2016 prior to the establishment of a trauma registry. A trauma registry and electronic patient registration system were established in 2017, and monthly admissions from February 2017-December 2019 were documented. A negative binomial regression analysis was performed comparing the incident rate of admission pre-implementation of the registry compared to post-implementation, adjusting for month and year. Completeness of trauma patient records was also assessed., Results: Prior to the implementation of the trauma registry and patient registration system (2015-2016), there was a mean of 5.2 (SD 4.4) trauma records per month identified. Following the implementation of the trauma registry, a mean of 103.4 trauma records per month were documented (SD 32.0) for an increased incident rate ratio of 20.9 (95% CI 15.7-27.6, p<0.001). There was also a significant increase in percentage of documents completed (OR 49.1, CI 12.4-193.7, p<0.001)., Discussion: Following the implementation of a trauma registry and electronic patient registration system at this low-income country hospital, an increase of 20.9 times completed trauma patient documentation was identified, and completion of the records improved. This more accurate documentation could be used to apply for increased government funding for trauma patients and sustain the trauma registry in the long term and could represent a means of long-term sustainability for other trauma registries in LMICs., Competing Interests: Declaration of Competing Interest CG, CT, CS, TR, DE, DB, and MS have no affiliations or involvement in any organization or entity with any financial interest in the subject matter or materials discussed in this manuscript. AS is Chief Executive Director and Co-Founder of a not-for-profit organization Innovative Canadians for Change (ICChange) which contributed funding for the establishment of the Mbarara Regional Referral Hospital trauma registry., (Copyright © 2021. Published by Elsevier Ltd.)

Mucopolysaccharidosis type I (MPS I)/Hurler syndrome newborn screening was added to the recommended uniform screening panel (RUSP) in 2016. As states have added screening for MPS I, programs have reported increased rates of false positives. Reasons for false positive screens include carrier status, true false positive, late-onset/attenuated forms, and in about half of cases, pseudodeficiency alleles. These alleles have DNA variants that can cause falsely decreased enzyme activity on biochemical enzyme studies and have increased frequency in individuals of African American and African descent. We describe the District of Columbia (DC) experience with MPS I screening from December 2017 to February 2019. In the context of a review of the literature on newborn screening and family experiences and this DC-based experience, we offer potential solutions to address preliminary concerns regarding this screening. The impact of overrepresentation of screen positives in a minority group and unintentional creation of health disparities and community wariness regarding medical genetics evaluations must be considered to improve the newborn screen programs nationally and internationally., (© 2020 Wiley Periodicals LLC.)

Introduction: An unmet burden of surgical disease exists worldwide and is disproportionately shouldered by low-income and middle-income countries (LMICs). As the field of global surgery grows to meet this need, ethical considerations need to be addressed. Currently, there are no formal guidelines to help inform relevant stakeholders of the ethical challenges and considerations facing global surgical collaborations. The aim of this scoping review is to synthesise the existing literature on ethics in global surgery and identify gaps in the current knowledge., Methods: A scoping review of relevant databases to identify the literature pertaining to ethics in global surgery was performed. Eligible articles addressed at least one ethical consideration in global surgery. A grounded theory approach to content analysis was used to identify themes in the included literature and guide the identification of gaps in existing literature., Results: Four major ethical domains were identified in the literature: clinical care and delivery; education and exchange of trainees; research, monitoring and evaluation; and engagement in collaborations and partnerships. The majority of published literature related to issues of clinical care and delivery of the individual patient. Most of the published literature was published exclusively by authors in high-income countries (HICs) (80%), and the majority of articles were in the form of editorials or commentaries (69.1%). Only 12.7% of articles published were original research studies., Conclusion: The literature on ethics in global surgery remains sparse, with most publications coming from HICs, and focusing on clinical care and short-term surgical missions. Given that LMICs are frequently the recipients of global surgical initiatives, the relative absence of literature from their perspective needs to be addressed. Furthermore, there is a need for more literature focusing on the ethics surrounding sustainable collaborations and partnerships., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose of Review: This paper provides a concise update on the management of peripheral artery disease (PAD)., Recent Findings: PAD continues to denote a population at high risk for mortality but represents a threat for limb loss only when associated with foot ulcers, gangrene, or infections. Performing either angiogram or non-invasive testing for all patients with foot ulcers, gangrene, or foot infections will help increase the detection of PAD, and refined revascularization strategies may help optimize wound healing in this patient group. Structured exercise programs are becoming available to more patients with claudication as methods to improve adherence to community-based exercise programs will improve. Finally, ensuring more patients with PAD receive aspirin therapy and statins may improve long-term survival, while further research will help determine if adding newer antiplatelet or anticoagulant medications may reduce leg amputations in selected patients. Clinicians should have a low threshold to obtain an angiogram and to pursue revascularization in patients with foot ulcers, gangrene, or foot infections. In patients with claudication, clinicians should maximize the benefits derived from exercise therapy and medical management before offering percutaneous or surgical revascularization.

Sleep loss is one of the most common causes of accidents and errors in operational environments. Currently, no single method satisfies all of the requisite criteria of an effective system for assessing the risk of injury prior to safety being compromised. Research has concentrated towards the development of a biomarker for individualized assessment of sleepiness-related deficits in neurobehavioral alertness, with salivary alpha-amylase (sAA) recently reported as a potential biomarker during acute total sleep deprivation. The present study extends on previous research by investigating the association between sAA and neurobehavioral alertness during simulated night-shift work, during individuals are required to work at night when biological processes are strongly promoting sleep and sleep during the day when endogenous processes are promoting wakefulness. In a laboratory-controlled environment, 10 healthy non-shift working males aged 24.7 ± 5.3 years (mean ± SD) underwent four consecutive nights of simulated night-shift work. Between 17:30-04:30 h participants provided saliva samples and completed a 3 min psychomotor vigilance test (PVT-B), 40 min simulated driving task, and 3 min digit symbol substitution test (DSST). Higher sAA levels were associated with faster response speed on the PVT-B, reduced lane variability on the simulated driving task, and improved information processing speed on the DSST during the first night-shift. There were no associations between sAA levels and performance outcomes during subsequent night-shifts. Findings indicate that the usability of sAA to assess the risk of neurobehavioral deficits during shift-work operations is limited. However, the robust circadian rhythm exhibited by sAA during the protocol of circadian misalignment suggests that sAA could serve as a potential circadian marker., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Self-assessment is the most common method for monitoring performance and safety in the workplace. However, discrepancies between subjective and objective measures have increased interest in physiological assessment of performance. In a double-blind placebo-controlled study, 23 healthy adults were randomly assigned to either a placebo (n = 11; 5 F, 6 M) or caffeine condition (n = 12; 4 F, 8 M) while undergoing 50 h (i.e. two days) of total sleep deprivation. In previous work, higher salivary alpha-amylase (sAA) levels were associated with improved psychomotor vigilance and simulated driving performance in the placebo condition. In this follow-up article, the effects of strategic caffeine administration on the previously reported diurnal profiles of sAA and performance, and the association between sAA and neurobehavioural performance were investigated. Participants were given a 10 h baseline sleep opportunity (monitored via standard polysomnography techniques) prior to undergoing sleep deprivation (total sleep time: placebo = 8.83 ± 0.48 h; caffeine = 9.01 ± 0.48 h). During sleep deprivation, caffeine gum (200 mg) was administered at 01:00 h, 03:00 h, 05:00 h, and 07:00 h to participants in the caffeine condition (n = 12). This strategic administration of caffeine gum (200 mg) has been shown to be effective at maintaining cognitive performance during extended wakefulness. Saliva samples were collected, and psychomotor vigilance and simulated driving performance assessed at three-hour intervals throughout wakefulness. Caffeine effects on diurnal variability were compared with previously reported findings in the placebo condition (n = 11). The impact of caffeine on the circadian profile of sAA coincided with changes in neurobehavioural performance. Higher sAA levels were associated with improved performance on the psychomotor vigilance test during the first 24 h of wakefulness in the caffeine condition. However, only the association between sAA and response speed (i.e. reciprocal-transform of mean reaction time) was consistent across both days of sleep deprivation. The association between sAA and driving performance was not consistent across both days of sleep deprivation. Results show that the relationship between sAA and reciprocal-transform of mean reaction time on the psychomotor vigilance test persisted in the presence of caffeine, however the association was relatively weaker as compared with the placebo condition., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Caffeine is known for its capacity to mitigate performance decrements. The metabolic side-effects are less well understood. This study examined the impact of cumulative caffeine doses on glucose metabolism, self-reported hunger and mood state during 50 hr of wakefulness. In a double-blind laboratory study, participants were assigned to caffeine (n = 9, 6M, age 21.3 ± 2.1 years; body mass index 21.9 ± 1.6 kg/m 2 ) or placebo conditions (n = 8, 4M, age 23.0 ± 2.8 years; body mass index 21.8 ± 1.6 kg/m 2 ). Following a baseline sleep (22:00 hours-08:00 hours), participants commenced 50 hr of sleep deprivation. Meal timing and composition were controlled throughout the study. Caffeine (200 mg) or placebo gum was chewed for 5 min at 01:00 hours, 03:00 hours, 05:00 hours and 07:00 hours during each night of sleep deprivation. Continual glucose monitors captured interstitial glucose 2 hr post-breakfast, at 5-min intervals. Hunger and mood state were assessed at 10:00 hours, 16:30 hours, 22:30 hours and 04:30 hours. Caffeine did not affect glucose area under the curve (p = 0.680); however, glucose response to breakfast significantly increased after 2 nights of extended wakefulness compared with baseline (p = 0.001). There was a significant main effect of day, with increased tiredness (p < 0.001), mental exhaustion (p < 0.001), irritability (p = 0.002) and stress (p < 0.001) on the second day of extended wake compared with day 1. Caffeine attenuated the rise in tiredness (p < 0.001), mental exhaustion (p = 0.044) and irritability (p = 0.018) on day 1 but not day 2. Self-reported hunger was not affected by sleep deprivation or caffeine. These data confirm the effectiveness of caffeine in improving performance under conditions of sleep deprivation by reducing feelings of tiredness, mental exhaustion and irritability without exacerbating glucose metabolism and feelings of hunger., (© 2018 European Sleep Research Society.)

This study examined the impact of eating during simulated night shift on performance and subjective complaints. Subjects were randomized to eating at night (n=5; 23.2 ± 5.5 y) or not eating at night (n=5; 26.2 ± 6.4 y). All participants were given one sleep opportunity of 8 h (22:00 h-06:00 h) before transitioning to the night shift protocol. During the four days of simulated night shift participants were awake from 16:00 h-10:00 h with a daytime sleep of 6 h (10:00 h-16:00 h). In the simulated night shift protocol, meals were provided at ≈0700 h, 1900 h and 0130 h (eating at night); or ≈0700 h, 0930 h, 1410 h and 1900 h (not eating at night). Subjects completed sleepiness, hunger and gastric complaint scales, a Digit Symbol Substitution Task and a 10-min Psychomotor Vigilance Task. Increased sleepiness and performance impairment was evident in both conditions at 0400 h (p<0.05). Performance impairment at 0400 h was exacerbated when eating at night. Not eating at night was associated with elevated hunger and a small but significant elevation in stomach upset across the night (p<0.026). Eating at night was associated with elevated bloating on night one, which decreased across the protocol. Restricting food intake may limit performance impairments at night. Dietary recommendations to improve night-shift performance must also consider worker comfort.

Increased abundance of the prostate-specific membrane antigen (PSMA) on prostate epithelium is a hallmark of advanced metastatic prostate cancer (PCa) and correlates negatively with prognosis. However, direct evidence that PSMA functionally contributes to PCa progression remains elusive. We generated mice bearing PSMA-positive or PSMA-negative PCa by crossing PSMA-deficient mice with transgenic PCa (TRAMP) models, enabling direct assessment of PCa incidence and progression in the presence or absence of PSMA. Compared with PSMA-positive tumors, PSMA-negative tumors were smaller, lower-grade, and more apoptotic with fewer blood vessels, consistent with the recognized proangiogenic function of PSMA. Relative to PSMA-positive tumors, tumors lacking PSMA had less than half the abundance of type 1 insulin-like growth factor receptor (IGF-1R), less activity in the survival pathway mediated by PI3K-AKT signaling, and more activity in the proliferative pathway mediated by MAPK-ERK1/2 signaling. Biochemically, PSMA interacted with the scaffolding protein RACK1, disrupting signaling between the β 1 integrin and IGF-1R complex to the MAPK pathway, enabling activation of the AKT pathway instead. Manipulation of PSMA abundance in PCa cell lines recapitulated this signaling pathway switch. Analysis of published databases indicated that IGF-1R abundance, cell proliferation, and expression of transcripts for antiapoptotic markers positively correlated with PSMA abundance in patients, suggesting that this switch may be relevant to human PCa. Our findings suggest that increase in PSMA in prostate tumors contributes to progression by altering normal signal transduction pathways to drive PCa progression and that enhanced signaling through the IGF-1R/β 1 integrin axis may occur in other tumors., (Copyright © 2017, American Association for the Advancement of Science.)

Shiftworkers have impaired performance when driving at night and they also alter their eating patterns during nightshifts. However, it is unknown whether driving at night is influenced by the timing of eating. This study aims to explore the effects of timing of eating on simulated driving performance across four simulated nightshifts. Healthy, non-shiftworking males aged 18-35 years (n = 10) were allocated to either an eating at night (n = 5) or no eating at night (n = 5) condition. During the simulated nightshifts at 1730, 2030 and 0300 h, participants performed a 40-min driving simulation, 3-min Psychomotor Vigilance Task (PVT-B), and recorded their ratings of sleepiness on a subjective scale. Participants had a 6-h sleep opportunity during the day (1000-1600 h). Total 24-h food intake was consistent across groups; however, those in the eating at night condition ate a large meal (30% of 24-h intake) during the nightshift at 0130 h. It was found that participants in both conditions experienced increased sleepiness and PVT-B impairments at 0300 h compared to 1730 and 2030 h (p < 0.001). Further, at 0300 h, those in the eating condition displayed a significant decrease in time spent in the safe zone (p < 0.05; percentage of time within 10 km/h of the speed limit and 0.8 m of the centre of the lane) and significant increases in speed variability (p < 0.001), subjective sleepiness (p < 0.01) and number of crashes (p < 0.01) compared to those in the no eating condition. Results suggest that, for optimal performance, shiftworkers should consider restricting food intake during the night.

Eating during the night may increase the risk for obesity and type 2 diabetes in shift workers. This study examined the impact of either eating or not eating a meal at night on glucose metabolism. Participants underwent four nights of simulated night work (SW1-4, 16:00-10:00 h, <50 lux) with a daytime sleep opportunity each day (10:00-16:00 h, <3 lux). Healthy males were assigned to an eating at night (NE; n = 4, meals; 07:00, 19:00 and 01:30 h) or not eating at night (NEN; n = 7, meals; 07:00 h, 09:30, 16:10 and 19:00 h) condition. Meal tolerance tests were conducted post breakfast on pre-night shift (PRE), SW4 and following return to day shift (RTDS), and glucose and insulin area under the curve (AUC) were calculated. Mixed-effects ANOVAs were used with fixed effects of condition and day, and their interactions, and a random effect of subject identifier on the intercept. Fasting glucose and insulin were not altered by day or condition. There were significant effects of day and condition × day (both p < 0.001) for glucose AUC, with increased glucose AUC observed solely in the NE condition from PRE to SW4 (p = 0.05) and PRE to RTDS (p < 0.001). There was also a significant effect of day (p = 0.007) but not condition × day (p = 0.825) for insulin AUC, with increased insulin from PRE to RTDS in both eating at night (p = 0.040) and not eating at night (p = 0.006) conditions. Results in this small, healthy sample suggest that not eating at night may limit the metabolic consequences of simulated night work. Further study is needed to explore whether matching food intake to the biological clock could reduce the burden of type 2 diabetes in shift workers.

Background: Aberrant growth of blood vessels in the eye forms the basis of many incapacitating diseases and currently the majority of patients respond to anti-angiogenic therapies based on blocking the principal angiogenic growth factor, vascular endothelial growth factor (VEGF). While highly successful, new therapeutic targets are critical for the increasing number of individuals susceptible to retina-related pathologies in our increasingly aging population. Prostate specific membrane antigen (PSMA) is a cell surface peptidase that is absent on normal tissue vasculature but is highly expressed on the neovasculature of most solid tumors, where we have previously shown to regulate angiogenic endothelial cell invasion. Because pathologic angiogenic responses are often triggered by distinct signals, we sought to determine if PSMA also contributes to the pathologic angiogenesis provoked by hypoxia of the retina, which underlies many debilitating retinopathies., Methodology/principal Findings: Using a mouse model of oxygen-induced retinopathy, we found that while developmental angiogenesis is normal in PSMA null mice, hypoxic challenge resulted in decreased retinal vascular pathology when compared to wild type mice as assessed by avascular area and numbers of vascular tufts/glomeruli. The vessels formed in the PSMA null mice were more organized and highly perfused, suggesting a more 'normal' phenotype. Importantly, the decrease in angiogenesis was not due to an impaired hypoxic response as levels of pro-angiogenic factors are comparable; indicating that PSMA regulation of angiogenesis is independent of VEGF. Furthermore, both systemic and intravitreal administration of a PSMA inhibitor in wild type mice undergoing OIR mimicked the PSMA null phenotype resulting in improved retinal vasculature., Conclusions/significance: Our data indicate that PSMA plays a VEGF-independent role in retinal angiogenesis and that the lack of or inhibition of PSMA may represent a novel therapeutic strategy for treatment of angiogenesis-based ocular diseases.

Background: The alphaproteobacterium Wolbachia pipientis, the most common endosymbiont in eukaryotes, is found predominantly in insects including many Drosophila species. Although Wolbachia is primarily vertically transmitted, analysis of its genome provides evidence for frequent horizontal transfer, extensive recombination and numerous mobile genetic elements. The genome sequence of Wolbachia in Drosophila simulans Riverside (wRi) is available along with the integrated bacteriophages, enabling a detailed examination of phage genes and the role of these genes in the biology of Wolbachia and its host organisms. Wolbachia is widely known for its ability to modify the reproductive patterns of insects. One particular modification, cytoplasmic incompatibility, has previously been shown to be dependent on Wolbachia density and inversely related to the titer of lytic phage. The wRi genome has four phage regions, two WORiBs, one WORiA and one WORiC., Results: In this study specific primers were designed to distinguish between these four prophage types in wRi, and quantitative PCR was used to measure the titer of bacteriophages in testes, ovaries, embryos and adult flies. In all tissues tested, WORiA and WORiB were not found to be present in excess of their integrated prophages; WORiC, however, was found to be present extrachromosomally. WORiC is undergoing extrachromosomal replication in wRi. The density of phage particles was found to be consistent in individual larvae in a laboratory population. The WORiC genome is organized in conserved blocks of genes and aligns most closely with other known lytic WO phages, WOVitA and WOCauB., Conclusions: The results presented here suggest that WORiC is the lytic form of WO in D. simulans, is undergoing extrachromosomal replication in wRi, and belongs to a conserved family of phages in Wolbachia.

The robust and consistent expression of the CD13 cell surface marker on very early as well as differentiated myeloid hematopoietic cells has prompted numerous investigations seeking to define roles for CD13 in myeloid cells. To address the function of myeloid CD13 directly, we created a CD13 null mouse and assessed the responses of purified primary macrophages or DCs from WT and CD13 null animals in cell assays and inflammatory disease models, where CD13 has been implicated previously. We find that mice lacking CD13 develop normally with normal hematopoietic profiles except for an increase in thymic but not peripheral T cell numbers. Moreover, in in vitro assays, CD13 appears to be largely dispensable for the aspects of phagocytosis, proliferation, and antigen presentation that we tested, although we observed a slight decrease in actin-independent erythrocyte uptake. However, in agreement with our published studies, we show that lack of monocytic CD13 completely ablates anti-CD13-dependent monocyte adhesion to WT endothelial cells. In vivo assessment of four inflammatory disease models showed that lack of CD13 has little effect on disease onset or progression. Nominal alterations in gene expression levels between CD13 WT and null macrophages argue against compensatory mechanisms. Therefore, although CD13 is highly expressed on myeloid cells and is a reliable marker of the myeloid lineage of normal and leukemic cells, it is not a critical regulator of hematopoietic development, hemostasis, or myeloid cell function.

In Western countries the increasing prevalence of obesity in young people is a major public health concern. While the focus has been on reducing obesity, paradoxically the success of these campaigns may result in unhealthy nutritional practices. The aim of this study was to investigate the use and impact of weight control techniques on the health of adolescent females. Using Analysis of Variance we compared physiological and biochemical markers of health against responses to a modified, Schools Physical Activity and Nutrition Survey (SPANS) in 482 adolescent females (14-17 yrs) from secondary schools in the northern Sydney and Central Coast regions of New South Wales, Australia. Participants who 'often' used weight control methods had, on average, a healthy BMI of 22.5 (SD=3.7). However, comparison of blood derived markers between participants who 'never', 'occasionally' or 'often' used weight reduction techniques showed that, those who 'often' used weight control methods had significantly lower haemoglobin (p<0.05), alkaline phosphatase (p<0.001), bilirubin (p<0.05), albumin (p<0.05), total protein (p<0.05), and calcium (p<0.05), but higher blood levels of creatinine (p<0.05) and potassium (p<0.05). These data suggest that the use of common weight control techniques by healthy weight adolescent females can produce a metabolically divergent group whose biochemical markers are consistent with subtle levels of chronic under-nutrition.

During inflammation, cell surface adhesion molecules guide the adhesion and migration of circulating leukocytes across the endothelial cells lining the blood vessels to access the site of injury. The transmembrane molecule CD13 is expressed on monocytes and endothelial cells and has been shown to mediate homotypic cell adhesion, which may imply a role for CD13 in inflammatory monocyte trafficking. Here, we show that ligation and clustering of CD13 by mAb or viral ligands potently induce myeloid cell/endothelial adhesion in a signal transduction-dependent manner involving monocytic cytoskeletal rearrangement and filopodia formation. Treatment with soluble recombinant (r)CD13 blocks this CD13-dependent adhesion, and CD13 molecules from monocytic and endothelial cells are present in the same immunocomplex, suggesting a direct participation of CD13 in the adhesive interaction. This concept is strengthened by the fact that activated monocytic cells adhere to immobilized recombinant CD13. Furthermore, treatment with anti-CD13 antibodies in a murine model of peritonitis results in a decrease in leukocyte infiltration into the peritoneum, suggesting a potential role for CD13 in leukocyte trafficking in vivo. Therefore, this work supports a new direction for CD13 biology, where these cell surface molecules act as true molecular interfaces that induce and participate in critical inflammatory cell interactions.

Environmental investigations have been conducted at 23 military firing ranges in the United States and Canada. The specific training facilities most frequently evaluated were hand grenade, antitank rocket, and artillery ranges. Energetic compounds (explosives and propellants) were determined and linked to the type of munition used and the major mechanisms of deposition.

Data comparisons were made for split or co-located samples analyzed in contract laboratories and quality assurance (QA) laboratories during environmental studies directed by the U.S. Army Corps of Engineers. Archived results were analyzed statistically as concentration ratios (contract laboratory/QA laboratory). Concentration ratios were found to be lognormally distributed, and this was the model used for comparisons. For metals in soils and volatile organic compounds (VOCs) in groundwater, 10.2% of metal ratios in soils and 5.6% of VOC ratios in groundwater exceeded limits of 0.40-2.50. Considering that both methods are multianalyte, we find that only 4.0% of the metal samples and 2.0% of the VOC samples had more than one outlier ratio per sample. More recent data produced very similar results. For VOCs, total petroleum hydrocarbons (TPHs), and explosives in soils, limits of 0.25-4.00 are suggested with the understanding that large improvements are badly needed. Even with these wide limits, approximately 42% of VOCs, 14% of TPHs, and 11% of explosives contract laboratory/QA laboratory ratios were outside these limits. Here, too, the most recent data yielded very comparable results. Sampling and preparation procedures for VOCs in soils requires immediate attention, but all methods can and should be capable of producing improved agreement between laboratories.

Four hundred and eleven workers from 4 different companies participated in a worksite screening program designed, in part, to estimate the prevalence of carpal tunnel syndrome (CTS). Each worker completed a discomfort survey and underwent limited nerve conduction testing of the median and ulnar sensory nerves in both wrists. The discomfort survey included a hand diagram which allowed subjects to shade in area(s) affected by numbness, burning, tingling, or pain. The discomfort survey also asked each worker to indicate whether she or he had experienced neuropathic symptoms (i.e., numbness, burning, tingling, or pain) in the wrist, hand or fingers of each hand, without regard to localization (i.e., median versus ulnar versus radial distribution), and also nocturnal occurrence of symptoms. Analyses involved comparing hand diagram scores and non localized wrist/hand/finger symptoms with electrodiagnostic test results. All configurations of hand diagram scores of the dominant hands had a statistically significant association with electrophysiologically determined median nerve dysfunction, but so did non localized symptom reports. The sensitivity, specificity, and positive predicted values of hand diagrams were poorer than those reported previously. While some test performance characteristics of hand diagrams were better than those for non localized distal extremity symptoms consistent with CTS, some were worse. Overall, our data suggest that hand diagrams are no better than using a questionnaire to determine if workers have experienced symptoms consistent with CTS in their wrists, hands or fingers without regard to localization. The choice of screening tool would depend on the goal of screening, in particular, whether it is more desirable to have slightly higher sensitivity or positive predictive value.

Five experiments reexamined color aftereffects contingent on the semantic properties of text (Allan, Siegel, Collins, & MacQueen, 1989). The influence of different assessment techniques and the effect of eye movements and overlapping contour information on the induction of color aftereffects by word and nonword letter strings were determined. Experiment 1 showed that no aftereffect was found when a traditional method of assessing color aftereffects was used. Experiments 2 and 4 demonstrated color aftereffects for both words and nonwords, but only when subjects fixated the same locus during induction and testing and only when assessed with the technique described by Allan et al. (1989). If, however, eye movements were made during induction, no color aftereffect was obtained (Experiment 3). Induction to nontext patterns with properties similar to those of text but with fewer overlapping contours resulted in a strong color aftereffect (Experiment 5). These results suggest that the color aftereffect contingent on text is very weak and is not dependent on semantic factors, but that it is a product of induction to local color and orientation information.

This study explored the relationship between anorexic behavior and selected dimensions of body image. Anorexic behavior was assessed by two scales, the Eating Attitudes Test (EAT 26) (Garner, Olmstead, Bohr, & Garfinkel, 1982) and the Eating Disorders Inventory (EDI) (Garner, Olmstead, & Polivy, 1983). Predictor variables, selected dimensions of body image, physical attractiveness, self-esteem, and physical effectiveness, were measured by scales adapted by Lerner and Karabenick (1974) and Lerner, Orlos, and Knapp (1976). Multiple regression techniques were used to determine how much of the tendency toward anorexic behavior can be predicted by selected dimensions of body image. The major focus of the analysis was to explore the contributions of each of the dimensions of body image to predicting tendencies toward anorexic behavior in adolescents. The research sample consisted of 169 high school students, aged 15 to 18, who were enrolled in health, physical education, or psychology classes in the spring of 1983. Results indicated that the dimension of self-esteem was the major factor in the prediction of anorexic behaviors as measured by the Eating Disorders Inventory.