Interplay of management and environmental drivers shifts size structure of reef fish communities.

Countries are expanding marine protected area (MPA) networks to mitigate fisheries declines and support marine biodiversity. However, MPA impact evaluations typically assess total fish biomass. Here, we examine how fish biomass disaggregated by adult and juvenile life stages responds to environmental drivers, including sea surface temperature (SST) anomalies and human footprint, and multiple management types at 139 reef sites in the Mesoamerican Reef (MAR) region. We found that total fish biomass generally appears stable across the region from 2006 to 2018, with limited rebuilding of fish stocks in MPAs. However, the metric of total fish biomass masked changes in fish community structure, with lower adult than juvenile fish biomass at northern sites, and adult:juvenile ratios closer to 1:1 at southern sites. These shifts were associated with different responses of juvenile and adult fish to environmental drivers and management. Juvenile fish biomass increased at sites with high larval connectivity and coral cover, whereas adult fish biomass decreased at sites with greater human footprint and SST anomalies. Adult fish biomass decreased primarily in Honduran general use zones, which suggests insufficient protection for adult fish in the southern MAR. There was a north-south gradient in management and environmental drivers, with lower coverage of fully protected areas and higher SST anomalies and coastal development in the south that together may undermine the maintenance of adult fish biomass in the southern MAR. Accounting for the interplay between environmental drivers and management in the design of MPAs is critical for increasing fish biomass across life history stages.

Los países están ampliando las redes de áreas marinas protegidas (AMP) para mitigar la disminución de las pesquerías y apoyar la biodiversidad marina. Sin embargo, las evaluaciones de impacto de las AMP típicamente estudian la biomasa total de peces. Aquí, examinamos cómo la biomasa de peces desagregada por etapas de vida adultas y juveniles responde a factores ambientales como anomalías de la temperatura superficial del mar (SST) e impacto humano, y múltiples tipos de manejo en 139 sitios de arrecifes en el sistema arrecifal mesoamericano (SAM). Encontramos que la biomasa total de peces en general parece estable en toda la región entre 2006 y 2018, con una recuperación limitada de las poblaciones de peces en las AMP. Sin embargo, la métrica de biomasa total de peces enmascaró los cambios en la estructura de la comunidad de peces, con una biomasa de peces adultos más baja que juveniles en los sitios del norte, y proporciones adulto:juvenil más cercana a 1:1 en los sitios del sur. Estos cambios fueron asociados con diferentes respuestas de peces juveniles y adultos a variables ambientales y de manejo. La biomasa de peces juveniles aumentó en sitios con alta conectividad larvaria y cobertura coralina, mientras que la biomasa de peces adultos disminuyó en sitios con mayor impacto humano y anomalías en la SST. La biomasa de peces adultos disminuyó principalmente en las zonas de uso general (GUZ) hondureñas, lo cual sugiere una protección insuficiente para peces adultos en el sur del SAM. Hubo un gradiente norte­sur en el manejo y los factores ambientales, con menor cobertura de áreas totalmente protegidas y mayores anomalías de SST y desarrollo costero en el sur. En conjunto esto puede degradar el mantenimiento de la biomasa de peces adultos en el sur del SAM. La interacción entre factores ambientales y el manejo en el diseño de las AMP es fundamental para aumentar la biomasa de peces en todas las etapas del ciclo de vida.

Integrating larval connectivity into the marine conservation decision-making process across spatial scales.

Larval dispersal connectivity is typically integrated into spatial conservation decisions at regional or national scales, but implementing agencies struggle with translating these methods to local scales. We used larval dispersal connectivity at regional (hundreds of kilometers) and local (tens of kilometers) scales to aid in design of networks of no-take reserves in Southeast Sulawesi, Indonesia. We used Marxan with Connectivity informed by biophysical larval dispersal models and remotely sensed coral reef habitat data to design marine reserve networks for 4 commercially important reef species across the region. We complemented regional spatial prioritization with decision trees that combined network-based connectivity metrics and habitat quality to design reserve boundaries locally. Decision trees were used in consensus-based workshops with stakeholders to qualitatively assess site desirability, and Marxan was used to identify areas for subsequent network expansion. Priority areas for protection and expected benefits differed among species, with little overlap in reserve network solutions. Because reef quality varied considerably across reefs, we suggest reef degradation must inform the interpretation of larval dispersal patterns and the conservation benefits achievable from protecting reefs. Our methods can be readily applied by conservation practitioners, in this region and elsewhere, to integrate connectivity data across multiple spatial scales.

Integración de la conectividad larval al proceso de toma de decisiones en la conservación marina en escalas espaciales Resumen Comúnmente se integra la conectividad de la dispersión larval a las decisiones de conservación espacial a escalas regionales o nacionales, pero las agencias de implementación luchan con la transferencia de estos métodos a las escalas locales. Usamos la conectividad de la dispersión larval a escalas regionales (cientos de kilómetros) y locales (decenas de kilómetros) para ayudar en el diseño de redes de reservas con protección total en Sulawesi Sudoriental, Indonesia. Usamos Marxan con la conectividad guiada por los modelos biofísicos de dispersión larval y detectamos a distancia los datos de hábitat de los arrecifes de coral para diseñar redes de reservas marinas para cuatro especies de importancia comercial en la región. Complementamos la priorización espacial regional con árboles de decisión que combinaron medidas de conectividad basadas en las redes y la calidad del hábitat para diseñar localmente los límites de la reserva. Usamos los árboles de decisión con los actores en talleres basados en el consenso para evaluar cualitativamente la conveniencia del sitio. También usamos Marxan para identificar áreas para la expansión subsecuente de la red. Las áreas prioritarias para la protección y los beneficios esperados difirieron entre especies, con un traslape reducido en las soluciones de la red de reservas. Ya que la calidad del arrecife varió considerablemente entre los arrecifes, sugerimos que la degradación de estos debe orientar la interpretación de los patrones de dispersión larval y los beneficios de conservación alcanzables con la protección de los arrecifes. Los practicantes de la conservación pueden aplicar nuestros métodos inmediatamente, en esta región o en cualquier otra, para integrar los datos de conectividad en varias escalas espaciales.

Comparing spatial conservation prioritization methods with site- versus spatial dependency-based connectivity.

Larval dispersal is an important component of marine reserve networks. Two conceptually different approaches to incorporate dispersal connectivity into spatial planning of these networks exist, and it is an open question as to when either is most appropriate. Candidate reserve sites can be selected individually based on local properties of connectivity or on a spatial dependency-based approach of selecting clusters of strongly connected habitat patches. The first acts on individual sites, whereas the second acts on linked pairs of sites. We used a combination of larval dispersal simulations representing different seascapes and case studies of biophysical larval dispersal models in the Coral Triangle region and the province of Southeast Sulawesi, Indonesia, to compare the performance of these 2 methods in the spatial planning software Marxan. We explored the reserve design performance implications of different dispersal distances and patterns based on the equilibrium settlement of larvae in protected and unprotected areas. We further assessed different assumptions about metapopulation contributions from unprotected areas, including the case of 100% depletion and more moderate scenarios. The spatial dependency method was suitable when dispersal was limited, a high proportion of the area of interest was substantially degraded, or the target amount of habitat protected was low. Conversely, when subpopulations were well connected, the 100% depletion was relaxed, or more habitat was protected, protecting individual sites with high scores in metrics of connectivity was a better strategy. Spatial dependency methods generally produced more spatially clustered solutions with more benefits inside than outside reserves compared with site-based methods. Therefore, spatial dependency methods potentially provide better results for ecological persistence objectives over enhancing fisheries objectives, and vice versa. Different spatial prioritization methods of using connectivity are appropriate for different contexts, depending on dispersal characteristics, unprotected area contributions, habitat protection targets, and specific management objectives. Comparación entre los métodos de priorización de la conservación espacial con sitio y la conectividad espacial basada en la dependencia.

La dispersión larval es un componente importante de las redes de reservas marinas. Existen dos estrategias conceptualmente distintas para incorporar la conectividad de la dispersión en la planeación espacial de estas redes y es una pregunta abierta cuándo alguna de las dos es la más apropiada. Los sitios candidatos a reserva pueden ser seleccionados individualmente con base en las propiedades locales de la conectividad o en la estrategia espacial basada en la dependencia que consiste en seleccionar grupos de fragmentos de hábitat con un vínculo fuerte. La primera estrategia actúa sobre sitios individuales, mientras que la segunda actúa sobre pares de sitios vinculados. Usamos una combinación de simulaciones de dispersión larval que representaban a diferentes paisajes marinos y estudios de caso de modelos biofísicos de dispersión larval en la región del Triángulo de Coral y en la provincia de Sulawesi Sudoriental, Indonesia, para comparar el desempeño de estos dos métodos en el software de planeación espacial Marxan. Exploramos las implicaciones del desempeño del diseño de la reserva de diferentes distancias y patrones de dispersión basados en el establecimiento del equilibrio de larvas en las áreas protegidas y sin protección. Además, analizamos las suposiciones sobre las contribuciones metapoblacionales de las áreas sin protección, incluyendo el caso de la reducción al 100% y escenarios más moderados. El método de la dependencia espacial fue adecuado cuando la dispersión estuvo limitada, una proporción elevada del área de interés estaba sustancialmente degradada o era baja la cantidad meta de hábitat protegido. Al contrario, cuando las subpoblaciones estaban bien conectadas, la reducción al 100% estuvo relajada, o si una mayor parte del hábitat estaba protegido, la protección de los sitios individuales con altos puntajes en las medidas de conectividad fue una mejor estrategia. Los métodos de dependencia espacial generalmente produjeron soluciones con una agrupación más espacial y con más beneficios dentro que fuera de las reservas en comparación con los métodos basados sitios. Por lo tanto, los métodos de dependencia espacial tienen el potencial de proporcionar mejores resultados para los objetivos de persistencia ecológica por encima de los objetivos de mejora de las pesquerías, y viceversa. Los diferentes métodos de priorización espacial que usan la conectividad son apropiados para contextos diferentes, dependiendo de las características de dispersión, las contribuciones del área sin protección, las metas de protección del hábitat y los objetivos específicos del manejo.

Effects of management objectives and rules on marine conservation outcomes.

Understanding the relative effectiveness and enabling conditions of different area-based management tools is essential for supporting efforts that achieve positive biodiversity outcomes as area-based conservation coverage increases to meet newly set international targets. We used data from a coastal social-ecological monitoring program in 6 Indo-Pacific countries to analyze whether social, ecological, and economic objectives and specific management rules (temporal closures, fishing gear-specific, species-specific restrictions) were associated with coral reef fish biomass above sustainable yield levels across different types of area-based management tools (i.e., comparing those designated as marine protected areas [MPAs] with other types of area-based management). All categories of objectives, multiple combinations of rules, and all types of area-based management had some sites that were able to sustain high levels of reef fish biomass-a key measure for coral reef functioning-compared with reference sites with no area-based management. Yet, the same management types also had sites with low biomass. As governments advance their commitments to the Kunming-Montreal Global Biodiversity Framework and the target to conserve 30% of the planet's land and oceans by 2030, we found that although different types of management can be effective, most of the managed areas in our study regions did not meet criteria for effectiveness. These findings underscore the importance of strong management and governance of managed areas and the need to measure the ecological impact of area-based management rather than counting areas because of their designation.

Efectos de las reglas y objetivos de manejo sobre los resultados de conservación marina Resumen Es esencial entender la efectividad relativa y las condiciones habilitantes de las diferentes herramientas de manejo basadas en el área para respaldar los esfuerzos que brindan resultados positivos para la biodiversidad conforme aumenta la cobertura de la conservación basada en el área para alcanzar los objetivos internacionales recién establecidos. Usamos los datos de un programa de monitoreo socioeconómico costero en seis países del Indo-Pacífico para analizar si los objetivos sociales, ecológicos y económicos y las reglas específicas de manejo (cierres temporales, restricciones de equipo de pesca, vedas de especies) se asociaban con la biomasa de los peces de arrecife de coral por encima de los niveles de producción sustentable en diferentes tipos de herramientas de manejo basadas en el área (es decir, comparar aquellas designadas como áreas marinas protegidas[AMP] con otros tipos de manejo basado en el área). Todas las categorías de objetivos, las múltiples combinaciones de reglas y todos los tipos de manejo basado en el área tuvieron algunos sitios capaces de mantener los niveles altos de biomasa de peces de arrecife-una medida importante para el funcionamiento de los arrecifes-en comparación con los sitios de referencia sin manejo basado en el área. Sin embargo, los mismos tipos de manejo también tuvieron sitios con baja biomasa. Conforme los gobiernos avanzan en sus compromisos con el Marco Global de Biodiversidad de Kunming-Montreal y hacia el objetivo de conservar el 30% del suelo y los océanos del planeta para el 2030, descubrimos que, aunque diferentes tipos de manejo pueden ser efectivos, la mayoría de las áreas manejadas en nuestras regiones de estudio no cumplieron con los criterios de efectividad. Este descubrimiento enfatiza la importancia de una gestión y un gobierno sólidos de las áreas manejadas y la necesidad de medir el impacto ecológico del manejo basado en el área en lugar de contar las áreas por su designación.

Tranexamic acid use in the setting of ACE inhibitor induced angioedema.

Tranexamic acid (TXA) is an antifibrinolytic agent which reduces bradykinin production through its blockade of the conversion of plasminogen to plasmin and subsequently pre-kallikrein to kallikrein. It has been utilized in angiotensin converting enzyme (ACE) inhibitor-induced angioedema (ACEi-AE) in small case reports and series however overall data is limited. This report describes a patient who historically received TXA for ACEi-AE and represented with ACEi-AE after an accidental exposure and was successfully treated with TXA again. This case suggests TXA may be a safe and effective treatment option for ACEi-AE.

Factors Associated with Information Breach in Healthcare Facilities: A Systematic Literature Review.

This systematic review aimed to identify the factors associated with information breaches in healthcare settings. We searched electronic databases, including PubMed, Embase, Scopus, and Wiley, for all publications until March 6, 2022 (no start date restriction) and outlined the eligibility criteria framework using Population, Concept, and Context (PCC). Our search strategies yielded 2,156 results, with nine studies included in the final review. We grouped the factors attributed to data breaches into four categories: organizational, information technology (IT), professionals/employees, and clients/patients. Hospital type, hospital size (more beds), higher operationalexpenses and revenue, higher admissions and discharges, and higher Electronic Medical Record (EMR) use, being at earlier phases of EMR adoption, were associated with higher information breaches. Professional factors such as the type of personnel involved and the hospital area can potentially impact the breaches' frequency and magnitude. Patients' sociodemographic, clinical, and behavioral characteristics, such as gender and educational attainment, appear to influence the perceived breach of confidentiality in healthcare settings. Identifying different factors contributing to health information breaches is crucial to protecting healthcare organizations and patients from the devastating consequences of data breaches.

Suicidal Ideation in a Veterans Affairs Residential Posttraumatic Stress Disorder Treatment Setting: The Roles of Thwarted Belongingness and Perceived Burdensomeness.

Suicide is a significant public health concern, and, specifically, the veteran population has exhibited a 22% higher risk of death by suicide than the general population (Department of Veterans Affairs, 2017). The interpersonal psychological theory of suicide (IPTS; Joiner, 2005) appears to be the most widely researched theory to examine factors associated with suicidal ideation. The IPTS applies to veteran suicidal ideation in that veterans may feel they are burdensome to others or that they do not belong following their transition from active duty. The current study sought to (a) identify the prevalence and correlates of the IPTS constructs perceived burdensomeness and thwarted belongingness; (b) examine the main and interactive effects of these constructs on suicidal ideation; and (c) examine their indirect effects in the associations between posttraumatic stress disorder (PTSD) symptomatology, depressive symptomatology, and substance use with suicidal ideation in a sample of veterans in PTSD residential treatment (N = 125). Regression results demonstrated that perceived burdensomeness was significantly associated with suicidal ideation, ß = .50, p < .001; however, thwarted belongingness and the interaction of the two were not. In the models of indirect effects, perceived burdensomeness emerged as the only significant indirect effect in the association between PTSD symptomatology and suicidal ideation, ß = .01 (SE = .00), 95% CI [.0050, .0149], as well as between depressive symptomatology and suicidal ideation, ß = .02 (SE = .01), 95% CI [.0109, .0311]. Study limitations and future directions are also discussed.

Residential Cognitive Processing Therapy Decreases Suicidality by Reducing Perceived Burdensomeness in Veterans with Posttraumatic Stress Disorder.

The interpersonal theory of suicide (Joiner, 2005) may help explain high suicide rates among veterans with posttraumatic stress disorder (PTSD). It suggests that suicidal ideation results from believing that one is a burden on others (i.e., perceived burdensomeness) and does not belong among family, friends, or other social groups (i.e., thwarted belongingness). Evidence-based PTSD treatments, including cognitive processing therapy (CPT), decrease suicidal ideation, potentially through changes in these two theory constructs. The current study examined whether (a) changes in PTSD severity and suicidal ideation and (b) changes in negative cognitions about self and suicidal ideation were indirectly associated through changes in perceived burdensomeness and thwarted belongingness across PTSD treatment. Participants (N = 107) were veterans in a residential treatment program who were diagnosed with full or subthreshold PTSD and received CPT. Changes in PTSD symptom severity and negative cognitions about self predicted changes in suicidal ideation, B = 0.18, p < .001 and B = 0.50, p < .001, respectively. Changes in PTSD symptom severity and negative cognitions about self were indirectly associated with suicidal ideation through changes in perceived burdensomeness, B = 0.16, 95% CI [0.07, 0.25]; B = 0.27, 95% CI [0.05, 0.50], but not thwarted belongingness, B = -0.002; 95% CI [-0.06, 0.06]; B = 0.06, 95% CI [-0.12, 0.21] in separate models. These findings suggest that residential CPT may be uniquely equipped to decrease suicidality by restructuring negative beliefs, including perceptions of being a burden on others, and/or by alleviating the objective burden of PTSD.

Immediate impact of COVID-19 across tropical small-scale fishing communities.

The volume and value of fish catches by Indonesia's small-scale fisheries have declined significantly since national government restrictions on travel and social distancing were imposed in response to the COVID-19 pandemic. Using a digital data collection system (OurFish), that records purchases by fish traders from small-scale fishers, data was collected across 82 coastal communities in Southeast Sulawesi. We found that the number of active fishers and traders declined by more than 90% after the onset of the pandemic and the average weight of catch per fishing trip increased across fishers. Although the average price per kilogram of fish declined after the pandemic began, fishers that were able to maintain fishing had on average higher catches and therefore daily catch value was maintained. High value fisheries that usually enter export supply chains were more negatively impacted compared with lower value species that are commonly sold to local markets. We interviewed 185 small scale fishers and fish traders across 20 of the 82 communities in Southeast Sulawesi province, recording the perceived level of impact on local fisheries and the fish trade, causes of this impact and proposed coping strategies. Over 50% of both fishers and fish traders believed low demand for fish from traders and a decline in the price received for fish were disrupting their lives. Approximately 75% of both male and female fishers are coping by continuing to fish, highlighting that there were few alternative livelihoods available at the time of the interviews. Our results provide key insights into the vulnerability of small-scale fishing communities to impacts of the COVID-19 pandemic.

Catalyzing sustainable fisheries management through behavior change interventions.

Small-scale fisheries are an important livelihood and primary protein source for coastal communities in many of the poorest regions in the world, yet many are overfished and thus require effective and scalable management solutions. Positive ecological and socioeconomic responses to management typically lag behind immediate costs borne by fishers from fishing pressure reductions necessary for fisheries recovery. These short-term costs challenge the long-term success of these interventions. However, social marketing may increase perceptions of management benefits before ecological and socioeconomic benefits are fully realized, driving new social norms and ultimately long-term sustainable behavior change. By conducting underwater visual surveys to quantify ecological conditions and by conducting household surveys with community members to quantify their perceptions of management support and socioeconomic conditions, we assessed the impact of a standardized small-scale fisheries management intervention that was implemented across 41 sites in Brazil, Indonesia, and the Philippines. The intervention combines TURF reserves (community-based territorial use rights for fishing coupled with no-take marine reserves) with locally tailored social-marketing behavior change campaigns. Leveraging data across 22 indicators and 4 survey types, along with data from 3 control sites, we found that ecological and socioeconomic impacts varied and that communities supported the intervention and were already changing their fishing practices. These results suggest that communities were developing new social norms and fishing more sustainably before long-term ecological and socioeconomic benefits of fisheries management materialized.

Catalización del Manejo de Pesquerías Sustentables por medio de Intervenciones de Cambio de Comportamiento Resumen Las pesquerías a pequeña escala son un sustento importante y la principal fuente de proteína para las comunidades costeras en muchas de las regiones más pobres del mundo, sin embargo, muchas sufren de sobrepesca y por lo tanto requieren soluciones de manejo efectivas y escalables. Las respuestas ecológicas y socioeconómicas positivas al manejo generalmente se retrasan con respecto a los costos inmediatos asumidos por los pescadores a partir de las reducciones de la presión ocasionada por la pesca necesarias para la recuperación de la pesquería. Estos costos a corto plazo son un reto para el éxito a largo plazo de las intervenciones. Sin embargo, la mercadotecnia social puede incrementar las percepciones de los beneficios del manejo antes de que se conozcan por completo los beneficios ecológicos y socioeconómicos, lo que genera nuevas normas sociales y finalmente un cambio en el comportamiento a largo plazo. Realizamos censos submarinos visuales para cuantificar las condiciones ecológicas y censos domésticos a los miembros de la comunidad para cuantificar sus percepciones del apoyo al manejo y de las condiciones socioeconómicas. Con esto, evaluamos el impacto de la intervención de manejo para pesquerías estandarizadas a pequeña escala que fue implementada en 41 sitios de Brasil, Indonesia y las Filipinas. La intervención combina las reservas TURF (derechos de uso de pesca territorial basados en la comunidad acoplados con reservas marinas con restricción de pesca) con campañas de mercadotecnia social para el cambio de comportamiento ajustadas al contexto local. Con la movilización de datos a lo largo de 22 indicadores y cuatro tipos de censos, junto con los datos de tres sitios de control, encontramos que los impactos ecológicos y socioeconómicos variaron y que las comunidades apoyaban la intervención y ya se encontraban cambiando sus prácticas de pesca. Estos resultados sugieren que las comunidades ya estaban desarrollando nuevas normas sociales y pescando de manera más sustentable antes de que los beneficios ecológicos y socioeconómicos a largo plazo del manejo de las pesquerías se materializaran.

Marginal zone B cells are critical to factor VIII inhibitor formation in mice with hemophilia A.

Although factor VIII (FVIII) replacement therapy can be lifesaving for patients with hemophilia A, neutralizing alloantibodies to FVIII, known as inhibitors, develop in a significant number of patients and actively block FVIII activity, making bleeding difficult to control and prevent. Although a variety of downstream immune factors likely regulate inhibitor formation, the identification and subsequent targeting of key initiators in inhibitor development may provide an attractive approach to prevent inhibitor formation before amplification of the FVIII immune response occurs. As the initial steps in FVIII inhibitor development remain incompletely understood, we sought to define early regulators of FVIII inhibitor formation. Our results demonstrate that FVIII localizes in the marginal sinus of the spleen of FVIII-deficient mice shortly after injection, with significant colocalization with marginal zone (MZ) B cells. FVIII not only colocalizes with MZ B cells, but specific removal of MZ B cells also completely prevented inhibitor development following FVIII infusion. Subsequent rechallenge with FVIII following MZ B-cell reconstitution resulted in a primary antibody response, demonstrating that MZ B-cell depletion did not result in FVIII tolerance. Although recipient exposure to the viral-like adjuvant polyinosinic:polycytidylic acid enhanced anti-FVIII antibody formation, MZ B-cell depletion continued to display similar effectiveness in preventing inhibitor formation following FVIII infusion in this inflammatory setting. These data strongly suggest that MZ B cells play a critical role in initiating FVIII inhibitor formation and suggest a potential strategy to prevent anti-FVIII alloantibody formation in patients with hemophilia A.

Impact of Psychosocial Risk on Outcomes among Families Seeking Treatment for Obesity.

OBJECTIVES: To test the hypothesis that children with elevated psychosocial risk would have increased attrition and worse weight outcomes in weight management treatment. STUDY DESIGN: This was a prospective cohort study of 100 new patients, aged 4-12 years, in a weight management clinic. Parents completed the Psychosocial Assessment Tool. Logistic regression analyses were conducted to calculate the odds of attrition from the clinic and a nonmeaningful change in body mass index (BMI) z-score (ie, <0.1 unit decrease in BMI z-score) over a 6-month period based on psychosocial risk category, adjusting for child demographics and baseline weight category. RESULTS: The majority of patients were male (59%), black (36%) or white (43%), and had severe obesity (55%), and 59% of families were categorized as having moderate or high psychosocial risk. Over the 6-month period, 53% of families were lost to follow-up, and 67% did not have a clinically meaningful decrease in BMI z-score. Compared with children of families with low psychosocial risk, children of families with moderate or high psychosocial risk were 3.1 times (95% CI, 1.3-7.2 times) more likely to be lost to follow-up and 2.9 times (95% CI, 1.1-7.9 times) more likely to have a non-clinically meaningful change in BMI z-score. CONCLUSIONS: Children presenting with increased psychosocial risk have higher attrition and poorer weight outcomes, supporting the need for psychosocial screening as a standard component of pediatric weight management treatment.

A subset of high-titer anti-factor VIII A2 domain antibodies is responsive to treatment with factor VIII.

The primary B-cell epitopes of factor VIII (fVIII) are in the A2 and C2 domains. Within the C2 domain, antibody epitope and kinetics are more important than inhibitor titer in predicting pathogenicity in a murine bleeding model. To investigate this within the A2 domain, the pathogenicity of a diverse panel of antihuman fVIII A2 domain monoclonal antibodies (MAbs) was tested in the murine model. MAbs were injected into hemophilia A mice, followed by injection of human B domain-deleted fVIII. Blood loss after a 4-mm tail snip was measured. The following anti-A2 MAbs were tested: high-titer type 1 inhibitors 4A4, 2-76, and 1D4; 2-54, a high-titer type 2 inhibitor; B94, a type 2 inhibitor; and noninhibitory MAbs GMA-012, 4C7, and B25. All high-titer type 1 MAbs produced blood loss that was significantly greater than control mice, whereas all non-inhibitory MAbs produced blood loss that was similar to control. The type 2 MAbs were not pathogenic despite 2-54 having an inhibitor titer of 34 000 BU/mg immunoglobulin G. In addition, a patient with a high-titer type 2 anti-A2 inhibitor who is responsive to fVIII is reported. The discrepancy between inhibitor titer and bleeding phenotype combined with similar findings in the C2 domain stress the importance of inhibitor properties not detected in the standard Bethesda assay in predicting response to fVIII therapy.

High-affinity, noninhibitory pathogenic C1 domain antibodies are present in patients with hemophilia A and inhibitors.

Inhibitor formation in hemophilia A is the most feared treatment-related complication of factor VIII (fVIII) therapy. Most inhibitor patients with hemophilia A develop antibodies against the fVIII A2 and C2 domains. Recent evidence demonstrates that the C1 domain contributes to the inhibitor response. Inhibitory anti-C1 monoclonal antibodies (mAbs) have been identified that bind to putative phospholipid and von Willebrand factor (VWF) binding epitopes and block endocytosis of fVIII by antigen presenting cells. We now demonstrate by competitive enzyme-linked immunosorbent assay and hydrogen-deuterium exchange mass spectrometry that 7 of 9 anti-human C1 mAbs tested recognize an epitope distinct from the C1 phospholipid binding site. These mAbs, designated group A, display high binding affinities for fVIII, weakly inhibit fVIII procoagulant activity, poorly inhibit fVIII binding to phospholipid, and exhibit heterogeneity with respect to blocking fVIII binding to VWF. Another mAb, designated group B, inhibits fVIII procoagulant activity, fVIII binding to VWF and phospholipid, fVIIIa incorporation into the intrinsic Xase complex, thrombin generation in plasma, and fVIII uptake by dendritic cells. Group A and B epitopes are distinct from the epitope recognized by the canonical, human-derived inhibitory anti-C1 mAb, KM33, whose epitope overlaps both groups A and B. Antibodies recognizing group A and B epitopes are present in inhibitor plasmas from patients with hemophilia A. Additionally, group A and B mAbs increase fVIII clearance and are pathogenic in a hemophilia A mouse tail snip bleeding model. Group A anti-C1 mAbs represent the first identification of pathogenic, weakly inhibitory antibodies that increase fVIII clearance.

Rux largely restores lungs in Iraq PM-exposed mice, Up-regulating regulatory T-cells (Tregs).

Background Military personnel post-deployment to Iraq and Afghanistan have noted new-onset respiratory illness. This study's primary objective was to further develop an animal model of Iraq Afghanistan War Lung Injury (IAW-LI) and to test a novel class of anti-injury drug called RuX. Methods Particulate Matter (PM) samples were obtained in Iraq then characterized by spectromicroscopy. C57BL/6 mice underwent orotracheal instillation with PM, followed by drinkable treatment with RuX. Lung histology, inspiratory capacity (FlexiVent), thymic/splenic regulatory T cell (Treg) number, and whole-lung genomics were analyzed. Results Tracheal instillation of Iraq PM led to lung septate thickening and lymphocytic inflammation. PM-exposed mice had suppression of thymic/splenic regulatory T-cells (Tregs). Drinking RuX after PM exposure attenuated the histologic lung injury response, improved lung inspiratory capacity, and increased Tregs. Pooled whole lung genomics suggest differences among gene expression of IL-15 among control, PM, and PM + RuX groups. Conclusions RuX, a ruthenium and alpha-lipoic acid complex, attenuates lung injury by improving histology and inspiratory capacity via upregulation of Tregs in Iraq PM-exposed C57BL/6. Plausible genomic effects may involve IL-15 whole lung gene expression.

Combining MOSCED with molecular simulation free energy calculations or electronic structure calculations to develop an efficient tool for solvent formulation and selection.

Solubility parameter based methods have long been a valuable tool for solvent formulation and selection. Of these methods, the MOdified Separation of Cohesive Energy Density (MOSCED) has recently been shown to correlate well the equilibrium solubility of multifunctional non-electrolyte solids. However, before it can be applied to a novel solute, a limited amount of reference solubility data is required to regress the necessary MOSCED parameters. Here we demonstrate for the solutes methylparaben, ethylparaben, propylparaben, butylparaben, lidocaine and ephedrine how conventional molecular simulation free energy calculations or electronic structure calculations in a continuum solvent, here the SMD or SM8 solvation model, can instead be used to generate the necessary reference data, resulting in a predictive flavor of MOSCED. Adopting the melting point temperature and enthalpy of fusion of these compounds from experiment, we are able to predict equilibrium solubilities. We find the method is able to well correlate the (mole fraction) equilibrium solubility in non-aqueous solvents over four orders of magnitude with good quantitative agreement.

Discovery of a new ATP-binding motif involved in peptidic azoline biosynthesis.

Despite intensive research, the cyclodehydratase responsible for azoline biogenesis in thiazole/oxazole-modified microcin (TOMM) natural products remains enigmatic. The collaboration of two proteins, C and D, is required for cyclodehydration. The C protein is homologous to E1 ubiquitin-activating enzymes, whereas the D protein is within the YcaO superfamily. Recent studies have demonstrated that TOMM YcaOs phosphorylate amide carbonyl oxygens to facilitate azoline formation. Here we report the X-ray crystal structure of an uncharacterized YcaO from Escherichia coli (Ec-YcaO). Ec-YcaO harbors an unprecedented fold and ATP-binding motif. This motif is conserved among TOMM YcaOs and is required for cyclodehydration. Furthermore, we demonstrate that the C protein regulates substrate binding and catalysis and that the proline-rich C terminus of the D protein is involved in C protein recognition and catalysis. This study identifies the YcaO active site and paves the way for the characterization of the numerous YcaO domains not associated with TOMM biosynthesis.

The genomic landscape of ribosomal peptides containing thiazole and oxazole heterocycles.

BACKGROUND: Ribosomally synthesized and post-translationally modified peptides (RiPPs) are a burgeoning class of natural products with diverse activity that share a similar origin and common features in their biosynthetic pathways. The precursor peptides of these natural products are ribosomally produced, upon which a combination of modification enzymes installs diverse functional groups. This genetically encoded peptide-based strategy allows for rapid diversification of these natural products by mutation in the precursor genes merged with unique combinations of modification enzymes. Thiazole/oxazole-modified microcins (TOMMs) are a class of RiPPs defined by the presence of heterocycles derived from cysteine, serine, and threonine residues in the precursor peptide. TOMMs encompass a number of different families, including but not limited to the linear azol(in)e-containing peptides (streptolysin S, microcin B17, and plantazolicin), cyanobactins, thiopeptides, and bottromycins. Although many TOMMs have been explored, the increased availability of genome sequences has illuminated several unexplored TOMM producers. METHODS: All YcaO domain-containing proteins (D protein) and the surrounding genomic regions were were obtained from the European Molecular Biology Laboratory (EMBL) and the European Bioinformatics Institute (EBI). MultiGeneBlast was used to group gene clusters contain a D protein. A number of techniques were used to identify TOMM biosynthetic gene clusters from the D protein containing gene clusters. Precursor peptides from these gene clusters were also identified. Both sequence similarity and phylogenetic analysis were used to classify the 20 diverse TOMM clusters identified. RESULTS: Given the remarkable structural and functional diversity displayed by known TOMMs, a comprehensive bioinformatic study to catalog and classify the entire RiPP class was undertaken. Here we report the bioinformatic characterization of nearly 1,500 TOMM gene clusters from genomes in the European Molecular Biology Laboratory (EMBL) and the European Bioinformatics Institute (EBI) sequence repository. Genome mining suggests a complex diversification of modification enzymes and precursor peptides to create more than 20 distinct families of TOMMs, nine of which have not heretofore been described. Many of the identified TOMM families have an abundance of diverse precursor peptide sequences as well as unfamiliar combinations of modification enzymes, signifying a potential wealth of novel natural products on known and unknown biosynthetic scaffolds. Phylogenetic analysis suggests a widespread distribution of TOMMs across multiple phyla; however, producers of similar TOMMs are generally found in the same phylum with few exceptions. CONCLUSIONS: The comprehensive genome mining study described herein has uncovered a myriad of unique TOMM biosynthetic clusters and provides an atlas to guide future discovery efforts. These biosynthetic gene clusters are predicted to produce diverse final products, and the identification of additional combinations of modification enzymes could expand the potential of combinatorial natural product biosynthesis.

Identification of an Auxiliary Leader Peptide-Binding Protein Required for Azoline Formation in Ribosomal Natural Products.

Thiazole/oxazole-modified microcins (TOMMs) are a class of post-translationally modified peptide natural products bearing azole and azoline heterocycles. The first step in heterocycle formation is carried out by a two component cyclodehydratase comprised of an E1 ubiquitin-activating and a YcaO superfamily member. Recent studies have demonstrated that the YcaO domain is responsible for cyclodehydration, while the TOMM E1 homologue is responsible for peptide recognition during azoline formation. Although all characterized TOMM biosynthetic clusters contain this canonical TOMM E1 homologue (C domain), we also identified a second, highly divergent E1 superfamily member, annotated as an Ocin-ThiF-like protein (F protein), associated with more than 300 TOMM biosynthetic clusters. Here we describe the in vitro reconstitution of a novel TOMM cyclodehydratase from such a cluster and demonstrate that this auxiliary protein is required for cyclodehydration. Using a combination of biophysical techniques, we demonstrate that the F protein, rather than the C domain, is responsible for engaging the peptide substrate. The C domain instead appears to serve as a scaffolding protein, bringing the catalytic YcaO domain and the peptide binding Ocin-ThiF-like protein into proximity. Our findings provide an updated biosynthetic framework that provides a foundation for the characterization and reconstitution of approximately 25% of bioinformatically identifiable TOMM synthetases.