Science of the Van Allen Probes Science Operations Centers.

The Van Allen Probes mission operations materialized through a distributed model in which operational responsibility was divided between the Mission Operations Center (MOC) and separate instrument specific SOCs. The sole MOC handled all aspects of telemetering and receiving tasks as well as certain scientifically relevant ancillary tasks. Each instrument science team developed individual instrument specific SOCs proficient in unique capabilities in support of science data acquisition, data processing, instrument performance, and tools for the instrument team scientists. In parallel activities, project scientists took on the task of providing a significant modeling tool base usable by the instrument science teams and the larger scientific community. With a mission as complex as Van Allen Probes, scientific inquiry occurred due to constant and significant collaboration between the SOCs and in concert with the project science team. Planned cross-instrument coordinated observations resulted in critical discoveries during the seven-year mission. Instrument cross-calibration activities elucidated a more seamless set of data products. Specific topics include post-launch changes and enhancements to the SOCs, discussion of coordination activities between the SOCs, SOC specific analysis software, modeling software provided by the Van Allen Probes project, and a section on lessons learned. One of the most significant lessons learned was the importance of the original decision to implement individual team SOCs providing timely and well-documented instrument data for the NASA Van Allen Probes Mission scientists and the larger magnetospheric and radiation belt scientific community.

Non-binary and binary transgender youth: Comparison of mental health, self-harm, suicidality, substance use and victimization experiences.

Background : Little research has compared the mental health and victimization experiences of non-binary youth depending on their sex assigned at birth (SAAB), or compared these two groups with binary transgender youth. Aims : To compare mental health, self-harm and suicidality, substance use and victimization experiences between non-binary and binary transgender young adults, both male assigned at birth (MAAB) and female assigned at birth (FAAB). Methods : Online survey data from 677 participants from the "Youth Chances" community study of 16 to 25 year olds in the United Kingdom was analyzed, comparing across binary participants (transgender females (n = 105) and transgender males (n = 210)) and non-binary participants (MAAB (n = 93) and FAAB (n = 269)). Results : Female SAAB participants (binary and non-binary) were more likely to report a current mental health condition and history of self-harm than male SAAB participants (binary and non-binary). Similarly, female SAAB participants (binary and non-binary) were more likely to report childhood sexual abuse than male SAAB participants (binary and non-binary); the reverse pattern was found for lifetime physical assault relating to being LGBTQ. Non-binary MAAB participants were less likely than the other groups to report past suicide attempts and previous help-seeking for depression/anxiety. Binary participants reported lower life satisfaction than non-binary participants. For all four groups, mental health problems, self-harm, suicidality, alcohol use and victimization experiences were generally higher than that of youth in general population studies. Conclusions : These findings highlight the importance of considering both non-binary versus binary gender identity and SAAB in relation to mental health problems, self-harm, suicidality and substance use in transgender youth. The roles of sexual abuse, other abuse and discrimination in contributing to increased rates of mental illness and self-harm in non-binary and binary transgender individuals, particularly those who were assigned female at birth, relative to those assigned male, require investigation.

Psychosocial Factors Associated With Suicide Attempts, Ideation, and Future Risk in Lesbian, Gay, and Bisexual Youth.

BACKGROUND: Lesbian, gay, and bisexual (LGB) youth have elevated suicidality rates. AIMS: To investigate LGB-related and other factors associated with suicide attempts, suicidal ideation, and future suicide risk in a large UK sample. METHOD: Logistic regression was used to investigate factors associated with suicidality in 3,275 LGB young adults from the Youth Chances project. RESULTS: Suicide attempts (lifetime) were reported by 13.6% of participants; 45.2 % had suicidal ideation in the past year and 9.5% said future suicide attempts were likely. LGB stigma and discrimination experiences were significantly associated with all three aspects of suicidality. These included school stigma factors (e.g., teachers not speaking out against prejudice, lessons being negative about sexual minorities), negative reactions to coming out from family and friends, and LGB-related harassment or crime experiences. Bisexuality, not feeling accepted where one lives, younger sexual minority identification, and younger coming out were also associated with suicidality. Significant non-LGB factors included female gender, lower social support, anxiety/depression help-seeking, experiences of abuse/violence, and sexual abuse. LIMITATIONS: This study is cross-sectional and further research is needed to test out whether any of these factors have a causal relationship with suicidality. CONCLUSION: A wide range of LGB stigma and discrimination experiences are associated with increased suicidality in LGB youth. Health, social care, and education professionals supporting young people should address LGB-specific risk factors.

Reimmunization increases contraceptive effectiveness of gonadotropin-releasing hormone vaccine (GonaCon-Equine) in free-ranging horses (Equus caballus): Limitations and side effects.

Wildlife and humans are increasingly competing for resources worldwide, and a diverse, innovative, and effective set of management tools is needed. Controlling abundance of wildlife species that are simultaneously protected, abundant, competitive for resources, and in conflict with some stakeholders but beloved by others, is a daunting challenge. Free-ranging horses (Equus caballus) present such a conundrum and managers struggle for effective tools for regulating their abundance. Controlling reproduction of female horses presents a potential alternative. During 2009-2017, we determined the long-term effectiveness of GnRH vaccine (GonaCon-Equine) both as a single immunization and subsequent reimmunization on reproduction and side effects in free-ranging horses. At a scheduled management roundup in 2009, we randomly assigned 57 adult mares to either a GonaCon-Equine treatment group (n = 29) or a saline control group (n = 28). In a second roundup in 2013, we administered a booster vaccination to these same mares. We used annual ground observations to estimate foaling proportions, social behaviors, body condition, and injection site reactions. We found this vaccine to be safe for pregnant females and neonates, with no overt deleterious behavioral side effects during the breeding season. The proportion of treated mares that foaled following a single vaccination was lower than that for control mares for the second (P = 0.03) and third (P = 0.08) post-treatment foaling seasons but was similar (P = 0.67) to untreated mares for the fourth season, demonstrating reversibility of the primary vaccine treatment. After two vaccinations, however, the proportion of females giving birth was lower (P <0.001) than that for control mares for three consecutive years and ranged from 0.0-0.16. The only detectable adverse side effect of vaccination was intramuscular swelling at the vaccination site. Regardless of vaccine treatment (primary/secondary), approximately 62% (34/55) of immunized mares revealed a visible reaction at the vaccine injection site. However, none of these mares displayed any evidence of lameness, altered gait or abnormal range of movement throughout the 8 years they were observed in this study. Our research suggests that practical application of this vaccine in feral horses will require an initial inoculation that may provide only modest suppression of fertility followed by reimmunization that together could result in greater reduction in population growth rates over time.

White sturgeon (Acipenser transmontanus) acid-base regulation differs in response to different types of acidoses.

White sturgeon (Acipenser transmontanus) completely protect intracellular tissue pH (pHi) despite large reductions in extracellular (blood) pH (pHe), termed preferential pHi regulation, in response to elevated environmental PCO2 (hypercarbia) and in general appear to be relatively resilient to stressors. Preferential pHi regulation is thought to be associated with hypercarbia tolerance in general, but has also recently been observed to protect pHi against metabolic acidoses induced by exhaustive exercise and anoxia in a tropical air breathing catfish. We hypothesized that preferential pHi regulation may also be a general strategy of acid-base regulation in sturgeon. To address this hypothesis, severe acidoses were imposed to reduce pHe, and the presence or absence of preferential pHi regulation was assessed in red blood cells (RBC), heart, brain, liver and white muscle. A respiratory acidosis was imposed using hyperoxia, while metabolic acidoses were induced by exhaustive exercise, anoxia or air exposure. Reductions in pHe occurred following hyperoxia (0.15 units), exhaustive exercise (0.30 units), anoxia (0.10 units) and air exposure (0.35 units); all acidoses reduced RBC pHi. Following hyperoxia, heart, brain and liver pHi were preferentially regulated against the reduction in pHe, similar to hypercarbia exposure. Following all metabolic acidoses heart pHi was protected and brain pHi remained unchanged following exhaustive exercise and air exposure, however, brain pHi was reduced following anoxia. Liver and white muscle pHi were reduced following all metabolic acidoses. These results suggest preferential pHi regulation may be a general strategy during respiratory acidoses but during metabolic acidoses, the response differs between source of acidoses and tissues.

Haploinsufficiency of the Insulin Receptor in the Presence of a Splice-Site Mutation in Ppp2r2a Results in a Novel Digenic Mouse Model of Type 2 Diabetes.

Insulin resistance in mice typically does not manifest as diabetes due to multiple compensatory mechanisms. Here, we present a novel digenic model of type 2 diabetes in mice heterozygous for a null allele of the insulin receptor and an N-ethyl-N-nitrosourea-induced alternative splice mutation in the regulatory protein phosphatase 2A (PP2A) subunit PPP2R2A. Inheritance of either allele independently results in insulin resistance but not overt diabetes. Doubly heterozygous mice exhibit progressive hyperglycemia, hyperinsulinemia, and impaired glucose tolerance from 12 weeks of age without significant increase in body weight. Alternative splicing of Ppp2r2a decreased PPP2R2A protein levels. This reduction in PPP2R2A containing PP2A phosphatase holoenzyme was associated with decreased serine/threonine protein kinase AKT protein levels. Ultimately, reduced insulin-stimulated phosphorylated AKT levels were observed, a result that was confirmed in Hepa1-6, C2C12, and differentiated 3T3-L1 cells knocked down using Ppp2r2a small interfering RNAs. Altered AKT signaling and expression of gluconeogenic genes in the fed state contributed to an insulin resistance and hyperglycemia phenotype. This model demonstrates how genetic changes with individually small phenotypic effects interact to cause diabetes and how differences in expression of hypomorphic alleles of PPP2R2A and potentially other regulatory proteins have deleterious effects and may therefore be relevant in determining diabetes risk.

Interaction of osmoregulatory and acid-base compensation in white sturgeon (Acipenser transmontanus) during exposure to aquatic hypercarbia and elevated salinity.

Migratory fishes encounter a variety of environmental conditions, including changes in salinity, temperature and dissolved gases, and it is important to understand how these fishes are able to acclimate to multiple environmental stressors. The gill is the primary site of both acid-base balance and ion regulation in fishes. Many ion transport mechanisms involved with acid-base compensation are also required for the regulation of plasma Na(+) and Cl(+), the predominant extracellular ions, potentially resulting in a strong interaction between ionoregulation and acid-base regulation. The present study examined the physiological interaction of elevated dissolved CO2 (an acid-base disturbance) on osmoregulation during seawater acclimation (an ionoregulatory disturbance) in juvenile white sturgeon (Acipenser transmontanus). Blood pH (pHe), plasma [HCO3 (-)], [Na(+)], [Cl(-)] and osmolality, white muscle water content, and gill Na(+)/K(+)-ATPase (NKA) and Na(+)/K(+)/2Cl(-) co-transporter (NKCC) abundance were examined over a 10 day seawater (SW) acclimation period under normocarbia (NCSW) or during prior and continued exposure to hypercarbia (HCSW), and compared with a normocarbic freshwater (NCFW) control. Hypercarbia induced a severe extracellular acidosis (from pH 7.65 to pH 7.2) in HCSW sturgeon, and these fish had a 2-fold greater rise in plasma osmolarity over NCSW by day 2 of SW exposure. Interestingly, pHe recovery in HCSW was associated more prominently with an elevation in plasma Na(+) prior to osmotic recovery and more prominently with a reduction in plasma Cl(-) following osmotic recovery, indicating a biphasic response as the requirements of osmoregulation transitioned from ion-uptake to ion-excretion throughout SW acclimation. These results imply a prioritization of osmoregulatory recovery over acid-base recovery in this period of combined exposure to acid-base and ionoregulatory disturbances.

Interaction of osmoregulatory and acid-base compensation in white sturgeon (Acipenser transmontanus) during exposure to aquatic hypercarbia and elevated salinity.

Migratory fishes encounter a variety of environmental conditions, including changes in salinity, temperature, and dissolved gases, and it is important to understand how these fishes are able to acclimate to multiple environmental stressors. The gill is the primary site of both acid-base balance and ion regulation in fishes. Many ion transport mechanisms involved with acid-base compensation are also required for the regulation of plasma Na+ and Cl+, the predominant extracellular ions, potentially resulting in a strong interaction between iono- and acid-base regulation. The present study examined the physiological interaction of elevated dissolved CO2 (an acid-base disturbance) on osmoregulation during seawater acclimation (an ionoregulatory disturbance) in juvenile white sturgeon (Acipenser transmontanus). Blood pH (pHe), plasma [HCO3-], [Na+], [Cl-], and osmolality, white muscle water content, and gill Na+/K+-ATPase (NKA) and Na+/K+/2Cl- cotransporter (NKCC) abundance were examined over a 10-day seawater (SW) acclimation period under normocarbia (NCSW) or during prior and continued exposure to hypercarbia (HCSW), and compared to a normocarbic freshwater (NCFW) control. Hypercarbia induced a severe extracellular acidosis (from pH 7.65 to pH 7.2) in HCSW sturgeon, and these fish had a 2-fold greater rise in plasma osmolarity over NCSW by day 2 of SW exposure. Interestingly, pHe recovery in HCSW was associated more prominently with an elevation in plasma Na+ prior to osmotic recovery and more prominently with a reduction in plasma Cl- following osmotic recovery, indicating a biphasic response as the requirements of osmoregulation transitioned from ion-uptake to ion-excretion throughout SW acclimation. These results imply a prioritization of osmoregulatory recovery over acid-base recovery in this period of combined exposure to acid-base and ionoregulatory disturbances.

The effect of intravenous golimumab on health-related quality of life in rheumatoid arthritis: 24-week results of the phase III GO-FURTHER trial.

OBJECTIVE: To evaluate the effects of intravenous (IV) golimumab 2 mg/kg + methotrexate (MTX) on patient-reported measures of health-related quality of life (HRQOL) in patients with active rheumatoid arthritis (RA) despite prior MTX therapy. METHODS: In this randomized, multicenter, double-blind, placebo-controlled, phase III trial, adults with RA were randomly assigned to receive IV placebo (n = 197) or golimumab 2 mg/kg (n = 395) infusions at Week 0, Week 4, and every 8 weeks thereafter. All patients continued stable oral MTX (15-25 mg/wk). HRQOL assessments included Health Assessment Questionnaire-Disability Index (HAQ-DI; physical function), Medical Outcomes Study Short Form-36 questionnaire physical/mental component summary (SF-36 PCS/MCS) scores, EQ-5D assessment of current health state, Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) questionnaire, and disease effect on productivity [10-cm visual analog scale (VAS)]. RESULTS: Mean HAQ-DI improvements from baseline were significantly greater with golimumab + MTX than placebo + MTX at Week 14 and Week 24 (p < 0.001). Significantly greater improvements in all 8 individual SF-36 subscores and both the SF-36 PCS and MCS scores (p < 0.001) also accompanied golimumab + MTX therapy. Improved EQ-5D and EQ-5D VAS (p < 0.001) and FACIT-Fatigue (p < 0.001) scores were also observed for golimumab + MTX-treated patients at Week 12, Week 16, and Week 24, and greater proportions of golimumab + MTX-treated patients had clinically meaningful improvements in these measures. Greater reductions in disease effect on productivity were observed with golimumab + MTX versus placebo + MTX at Week 24 (p < 0.001). Improvements in physical function, HRQOL, fatigue, and productivity significantly correlated with disease activity improvement. CONCLUSION: In active RA, IV golimumab + MTX significantly improved physical function, HRQOL, fatigue, and productivity using multiple measurement tools; all correlated with improvements in disease activity (NCT00973479, EudraCT 2008-006064-11).

Ecological feedbacks can reduce population-level efficacy of wildlife fertility control.

Anthropogenic stress on natural systems, particularly the fragmentation of landscapes and the extirpation of predators from food webs, has intensified the need to regulate abundance of wildlife populations with management. Controlling population growth using fertility control has been considered for almost four decades, but nearly all research has focused on understanding effects of fertility control agents on individual animals. Questions about the efficacy of fertility control as a way to control populations remain largely unanswered.Collateral consequences of contraception can produce unexpected changes in birth rates, survival, immigration and emigration that may reduce the effectiveness of regulating animal abundance. The magnitude and frequency of such effects vary with species-specific social and reproductive systems, as well as connectivity of populations. Developing models that incorporate static demographic parameters from populations not controlled by contraception may bias predictions of fertility control efficacy.Many population-level studies demonstrate that changes in survival and immigration induced by fertility control can compensate for the reduction in births caused by contraception. The most successful cases of regulating populations using fertility control come from applications of contraceptives to small, closed populations of gregarious and easily accessed species.Fertility control can result in artificial selection pressures on the population and may lead to long-term unintentional genetic consequences. The magnitude of such selection is dependent on individual heritability and behavioural traits, as well as environmental variation.Synthesis and applications. Understanding species' life-history strategies, biology, behavioural ecology and ecological context is critical to developing realistic expectations of regulating populations using fertility control. Before time, effort and funding are invested in wildlife contraception, managers may need to consider the possibility that many species and populations can compensate for reduction in fecundity, and this could minimize any reduction in population growth rate.

Effects of gonadotropin-releasing hormone immunization on reproductive function and behavior in captive female Rocky Mountain elk (Cervus elaphus nelsoni).

Fertility control is a potential method for managing overabundant wildlife populations; however, current technology is limited by duration of treatment efficacy and unacceptable side effects. The objective of this study was to determine the efficacy of a single immunization with gonadotropin-releasing hormone (GnRH) vaccine to suppress reproductive function in pregnant female elk and to evaluate potential behavioral and pathological side effects of treatment. Eighteen captive adult female elk were randomly allocated to one of two experimental groups. Ten females were administered a conjugated and adjuvanted GnRH vaccine intramuscularly, and eight elk received an adjuvant sham vaccine without conjugated GnRH. We compared success of existing pregnancy, neonatal survival, subsequent fertility, reproductive behavior rates, and side effects of treatment between January 2006 and January 2010. The GnRH vaccination did not affect existing pregnancy or calf survival during the year that it was applied; however, it reduced the proportion of pregnant females for 3 yr. Male precopulatory behavior rates exhibited toward GnRH-vaccinated females tended to be greater than those directed at sham-vaccinated females during the second half of the breeding season, when GnRH vaccinates continued to be proceptive. Strong immune and inflammatory responses, including robust GnRH antibody concentrations in GnRH vaccinates, and sterile pyogranulomatous injection site abscesses in both groups, were consistent with vaccination. In conclusion, this GnRH vaccine resulted in prolonged, albeit reversible, impairment of fertility, and is associated with extended reproductive behaviors and partial suppression of hypothalamic-pituitary-gonadal axis function in captive female elk.

Evaluation of remotely delivered leuprolide acetate as a contraceptive agent in female elk (Cervus elaphus nelsoni).

Practical application of fertility control technology in free-ranging wild ungulates often requires remote delivery of the contraceptive agent. The objective of this investigation was to evaluate the potential of remote delivery of leuprolide acetate for suppressing fertility in female elk (Cervus elaphus nelsoni). Fifteen captive adult female elk were randomly allocated to one of three experimental groups. Six elk were injected intramuscularly with a dart containing leuprolide, and the remaining nine elk received the same formulation without leuprolide. We determined pregnancy rates, suppression of luteinizing hormone (LH) and progesterone concentrations, and reversibility of treatments during 1 August 2002 to 3 September 2003. Leuprolide formulation caused a decrease in concentrations of LH and progesterone, temporary suppression of ovulation and steroidogenesis, and effective contraception (100%) for one breeding season. These results extend the practical application of this contraceptive agent to include dart delivery, where in the absence of such technology, wild elk must first be captured and restrained before treatment.

Gonadotropin-releasing hormone agonist: a new approach to reversible contraception in female deer.

Fertility control offers a potential alternative for controlling an abundance of wild ungulate populations where lethal methods are infeasible or unacceptable. A promising nonsteroidal, nonimmunologic approach to reversible contraception consists of agonist of gonadotropin-releasing hormone (GnRH). We evaluated the effects of the GnRH agonist, leuprolide, on reproduction, the suppression of luteinizing hormone (LH) and progesterone, blood parameters, and reproductive behavior in captive female mule deer (Odocoileus hemionus) during December 1999 through June 2001. Leuprolide, administered as a controlled release formulation (ATRIGEL), was 100% effective in preventing pregnancy for one breeding season. Infertility was achieved by suppressing LH levels, which prevented ovulation and the formation of corpus luteum. Treated females regained normal ovarian function and conceived the following breeding season. Leuprolide had no adverse effects on blood chemistry and hematology, body weight dynamics, or the general health of treated females. In contrast to our predictions, leuprolide did not suppress estrous behavior in female deer during the "normal" breeding period, nor did treated females return to normal ovarian function and exhibit reproductive behaviors during the post-breeding period. This prolonged-release leuprolide formulation offers an alternative approach to reversible contraception in female deer that overcomes some of the problems associated with existing technology.

Milwaukee shoulder: correlating possible etiologic variables.

The current study evaluated the relative correlation of apatite crystal-induced inflammation and rotator cuff deficiency in the development of cuff tear arthropathy. Thirty-seven patients with full thickness rotator cuff tears were evaluated by history, physical examination, and plain radiographs. Thirty patients had surgical intervention for their rotator cuff defects, and calipers were used intraoperatively to quantify the size of the tear in its largest diameter. The remaining seven patients were treated nonoperatively and the size of the tear was quantified using magnetic resonance imaging. Synovial fluid was obtained from all patients and analyzed for crystal content using an alizarin red stain. Synovial fluid also was analyzed for leukocyte count and differential, prostaglandin E, and matrix metalloproteinase. An unpaired Student's t test revealed that significantly higher levels of prostaglandin E were found in the synovial fluid of patients with apatite crystals, shown by alizarin red stain. Chi squared analysis showed that patients with elevated crystal levels were significantly more likely to have large rotator cuff tears or glenohumeral arthritis. Establishing such relations potentially can elucidate the etiology and treatment of this complex disorder.(2) (2)