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Abstract In May and June of 2021, marine microbial samples were collected for DNA sequencing in East Sound, WA, USA every 4 hours for 22 days. This high temporal resolution sampling effort captured the last 3 days of a Rhizosolenia sp. bloom, the initiation and complete bloom cycle of Chaetoceros socialis (8 days), and the following bacterial bloom (2 days). Metagenomes were completed on the time series, and the dataset includes 128 size-fractionated microbial samples (0.22–1.2 µm), providing gene abundances for the dominant members of bacteria, archaea, and viruses. This dataset also has time-matched nutrient analyses, flow cytometry data, and physical parameters of the environment at a single point of sampling within a coastal ecosystem that experiences regular bloom events, facilitating a range of modeling efforts that can be leveraged to understand microbial community structure and their influences on the growth, maintenance, and senescence of phytoplankton blooms.

Abstract Genome-wide association studies implicate multiple loci in risk for systemic lupus erythematosus (SLE), but few contain exonic variants, rendering systematic identification of non-coding variants essential to decoding SLE genetics. We utilized SNP-seq and bioinformatic enrichment to interrogate 2180 single-nucleotide polymorphisms (SNPs) from 87 SLE risk loci for potential binding of transcription factors and related proteins from B cells. 52 SNPs that passed initial screening were tested by electrophoretic mobility shift and luciferase reporter assays. To validate the approach, we studied rs2297550 in detail, finding that the risk allele enhanced binding to the transcription factor Ikaros (encoded by IKZF1), thereby modulating expression of IKBKE. Correspondingly, primary cells from genotyped healthy donors bearing the risk allele expressed higher levels of the interferon / NF-κB regulator IKKε. Together, these findings define a set of likely functional non-coding lupus risk variants and identify a regulatory pathway involving rs2297550, Ikaros, and IKKε implicated by human genetics in risk for SLE.

Coastal observations along the Texas coast are valuable for many stakeholders in diverse domains. However, the management of the collected data has been limited, creating gaps in hydrological and atmospheric datasets. Among these, water and air temperature measurements are particularly crucial for water temperature predictions, especially during freeze events. These events can pose a serious threat to endangered sea turtles and economically valuable fish, which can succumb to hypothermic stunning, making them vulnerable to cold-related illness or death. Reliable and complete water and air temperature measurements are needed to provide accurate predictions of when cold-stunning events occur. To address these concerns, the focus of this paper is to describe the method used to create a complete 10-year dataset that is representative of the upper Laguna Madre, TX using multiple stations and various gap-filling methods. The raw datasets consist of a decade's worth of air and water temperature measurements within the Upper Laguna Madre from 2012 to 2022 extracted from the archives of the Texas Coastal Ocean Observation Network and the National Park Service. Large portions of data from the multiple stations were missing from the raw datasets, therefore a systematic gap-filling approach was designed and applied to create a near-continuous dataset. The proposed imputation method consists of three steps, starting with a short gap interpolation method, followed by a long gap-filling process using nearby stations, and finalized by a second short gap interpolation method. This systematic data imputation approach was evaluated by creating random artificial gaps within the original datasets, filling them using the proposed data imputation method, and assessing the viability of the proposed methods using various performance metrics. The evaluation results help to ensure the reliability of the newly imputed dataset and the effectiveness of the data imputation method. The newly created dataset is a valuable resource that transcends the local cold-stunning issue, offering viable utility for analyzing temporal variability of air and water temperatures, exploring temperature interdependencies, reducing forecasting uncertainties, and refining natural resource and weather advisory decision-making processes. The cleaned dataset with minimal gaps (

Abstract Background Adolescents and young adults (AYAs) with cancer are at high risk of poor psychosocial outcomes, and evidence-based interventions designed to meet their psychosocial and communication needs are lacking. The main objective of this project is to test the efficacy of a new adaptation of the Promoting Resilience in Stress Management intervention for AYAs with Advanced Cancer (PRISM-AC). Methods/design The PRISM-AC trial is a 2-arm, parallel, non-blinded, multisite, randomized controlled trial. 144 participants with advanced cancer will be enrolled and randomized to either usual, non-directive, supportive care without PRISM-AC (“control” arm) or with PRISM-AC (“experimental” arm). PRISM is a manualized, skills-based training program comprised of four 30–60 min, one-on-one sessions targeting AYA-endorsed resilience resources (stress-management, goal-setting, cognitive-reframing, and meaning-making). It also includes a facilitated family meeting and a fully equipped smartphone app. The current adaptation includes an embedded advance care planning module. English- or Spanish-speaking individuals 12–24 years old with advanced cancer (defined as progressive, recurrent, or refractory disease, or any diagnosis associated with

Abstract Systemic lupus erythematosus (SLE) is a multi-organ autoimmune disorder with a prominent genetic component. Individuals of Asian-Ancestry (AsA) disproportionately experience more severe SLE compared to individuals of European-Ancestry (EA), including increased renal involvement and tissue damage. However, the mechanisms underlying elevated severity in the AsA population remain unclear. Here, we utilized available gene expression data and genotype data based on all non-HLA SNP associations in EA and AsA SLE patients detected using the Immunochip genotyping array. We identified 2778 ancestry-specific and 327 trans-ancestry SLE-risk polymorphisms. Genetic associations were examined using connectivity mapping and gene signatures based on predicted biological pathways and were used to interrogate gene expression datasets. SLE-associated pathways in AsA patients included elevated oxidative stress, altered metabolism and mitochondrial dysfunction, whereas SLE-associated pathways in EA patients included a robust interferon response (type I and II) related to enhanced cytosolic nucleic acid sensing and signaling. An independent dataset derived from summary genome-wide association data in an AsA cohort was interrogated and identified similar molecular pathways. Finally, gene expression data from AsA SLE patients corroborated the molecular pathways predicted by SNP associations. Identifying ancestry-related molecular pathways predicted by genetic SLE risk may help to disentangle the population differences in clinical severity that impact AsA and EA individuals with SLE.

Zika virus (ZIKV) remains a public health concern, with epidemics in endemic regions and sporadic outbreaks in new areas posing significant threats. Several mosquito-borne flaviviruses that can cause human illness, including West Nile, Usutu, and St. Louis encephalitis, have associations with birds. However, the susceptibility of chickens to ZIKV and their role in viral epidemiology is not currently known. We investigated the susceptibility of chickens to experimental ZIKV infection using chickens ranging from 1-day-old chicks to 6-week-old birds. ZIKV caused no clinical signs in chickens of all age groups tested. Viral RNA was detected in the blood and tissues during the first 5 days post-inoculation in 1-day and 4-day-old chicks inoculated with a high viral dose, but ZIKV was undetectable in 6-week-old birds at all timepoints. Minimal antibody responses were observed in 6-week-old birds, and while present in younger chicks, they waned by 28 days post-infection. Innate immune responses varied significantly between age groups. Robust type I interferon and inflammasome responses were measured in older chickens, while limited innate immune activation was observed in younger chicks. Signal transducer and activator of transcription 2 (STAT2) is a major driver of host restriction to ZIKV, and chicken STAT2 is distinct from human STAT2, potentially contributing to the observed resistance to ZIKV infection. The rapid clearance of the virus in older chickens coincided with an effective innate immune response, highlighting age-dependent susceptibility. Our study indicates that chickens are not susceptible to productive ZIKV infection and are unlikely to play a role in the ZIKV epidemiology.

Tau-mediated neurodegeneration is driven by disease-activated microglia and suppressed by their pharmacological blockade. The authors identified drug dose- and sex-dependent residual microglial phenotypes, neuronal excitotoxicity, and animal survival.

Abstract Background Effective systemic treatments have revolutionized the management of patients with metastatic melanoma, including those with brain metastases. The extent to which these treatments influence disease trajectories close to death is unknown. Therefore, this study aimed to gain insight into provided treatments and healthcare consumption during the last 3 months of life in patients with melanoma brain metastases. Methods Retrospective, single-center study, including consecutive patients with melanoma brain metastases diagnosed between June-2015 and June-2018, referred to the medical oncologist, and died before November-2019. Patient and tumor characteristics, anti-tumor treatments, healthcare consumption, presence of neurological symptoms, and do-not-resuscitate status were extracted from medical charts. Results 100 patients were included. A BRAF-mutation was present in 66 patients. Systemic anti-tumor therapy was given to 72% of patients during the last 3 months of life, 34% in the last month, and 6% in the last week. Patients with a BRAF-mutation more frequently received systemic treatment during the last 3 (85% vs. 47%) and last month (42% vs. 18%) of life than patients without a BRAF-mutation. Furthermore, patients receiving systemic treatment were more likely to visit the emergency room (ER, 75% vs. 36%) and be hospitalized (75% vs. 36%) than those who did not. Conclusion The majority of patients with melanoma brain metastases received anti-tumor treatment during the last 3 months of life. ER visits and hospitalizations occurred more often in patients on anti-tumor treatment. Further research is warranted to examine the impact of anti-tumor treatments close to death on symptom burden and care satisfaction.

Objective To investigate how GPs manage women with urinary incontinence (UI) in the Netherlands and to assess whether this is in line with the relevant Dutch GP guideline. Because UI has been an underreported and undertreated problem for decades despite appropriate guidelines being created for general practitioners (GPs). Design Retrospective cohort study. Setting Routine primary care data for 2017 in the Netherlands. Subjects We included the primary care records of women aged 18–75 years with at least one contact registered for UI, and then extracted information about baseline characteristics, diagnosis, treatment, and referral to pelvic physiotherapy or secondary care. Results In total, 374 records were included for women aged 50.3 ± 15.1 years. GPs diagnosed 31.0%, 15.2%, and 15.0% women with stress, urgency, or mixed UI, respectively; no diagnosis of type was recorded in 40.4% of women. Urinalysis was the most frequently used diagnostic test (42.5%). Education was the most common treatment, offered by 17.9% of GPs; however, no treatment or referral was reported in 15.8% of cases. As many as 28.7% and 21.7% of women were referred to pelvic physiotherapy and secondary care, respectively. Conclusion Female UI is most probably not managed in line with the relevant Dutch GP guideline. It is also notable that Dutch GPs often fail to report the type of UI, to use available diagnostic approaches, and to provide appropriate education. Moreover, GPs referred to specialists too often, especially for the management of urgency UI.Key points Urinary incontinence (UI) has been an underreported and undertreated problem for decades. Despite various guidelines, UI often lies outside the GPs comfort zone. •According to this study: general practitioners do not treat urinary incontinence according to guidelines. •The type of incontinence is frequently not reported and diagnostic approaches are not fully used. •We believe that increased awareness will help improve treatment and avoidable suffering.

Background and aimThe identification of, and timely intervention for, patients with impaired nutritional status may reduce inflammatory bowel disease (IBD) complications. This study aimed to develop and validate an IBD-specific nutrition self-screening tool (IBD-NST) that identifies patients at nutrition risk.MethodsAn expert IBD panel was consulted to support development of an IBD-NST. The tool was assessed in different cohorts of patients attending IBD outpatient clinics for face, content and convergent validity and repeat reliability. The tool was compared with (i) the malnutrition universal screening tool to assess face validity and (ii) subjective global assessment (SGA), hand-grip strength (HGS) and mid-arm muscle circumference to assess convergent validity. Tool content was informed by agreement between assessment tools, sensitivity analysis and chi-squared tests. The IBD-NST was completed electronically twice, 1 week apart to assess repeat reliability using observed agreement and kappa statistic. Statistical significance assumed at p < 0.05.ResultsIn total, 282 IBD patients (175 with Crohn’s disease) were recruited to validate the IBD-NST. The final validated IBD-NST includes body mass index (BMI), weight loss and IBD-specific nutrition-focussed questions which were acceptable to patients. It identified patients at risk of malnutrition, moderately or severely malnourished patients and patients at nutritional risk. The IBD-NST identified 54/179 (30%) patients at moderate or high nutrition risk and had excellent repeat reliability in 85 patients [r = 0.77 (95% CI 0.669 to 0.746)].ConclusionThe IBD-NST is a self-screening tool, validated for use as either a paper or e-health version, that identifies patients at nutrition risk who are likely to benefit from dietetic assessment and intervention. Furthermore, patients with IBD symptoms who are concerned about their dietary intake can potentially access dietetic care more easily therefore encouraging greater self-management of IBD-related symptoms. The routine use of the IBD-NST as a self-screening tool would enable patient-led care in the outpatient setting and may facilitate timely access to dietetic care.

Abstract Background Novel treatments make long‐term survival possible for subsets of patients with melanoma brain metastases. Brain magnetic resonance imaging (MRI) may aid in early detection of brain metastases and inform treatment decisions. This study aimed to determine the impact of screening MRI scans in patients with metastatic melanoma and follow‐up MRI scans in patients with melanoma brain metastases. Methods This retrospective cohort study included patients diagnosed with metastatic melanoma or melanoma brain metastases between June 2015 and January 2018. The impact of screening MRI scans was evaluated in the first 2 years after metastatic melanoma diagnosis. The impact of follow‐up MRI scans was examined in the first year after brain metastases diagnosis. The number of MRI scans, scan indications, scan outcomes, and changes in treatment strategy were analyzed. Results In total, 116 patients had no brain metastases at the time of the metastatic melanoma diagnosis. Twenty‐eight of these patients (24%) were subsequently diagnosed with brain metastases. Screening MRI scans detected the brain metastases in 11/28 patients (39%), of which 8 were asymptomatic at diagnosis. In the 96 patients with melanoma brain metastases, treatment strategy changed after 75/168 follow‐up MRI scans (45%). In patients treated with immune checkpoint inhibitors, the number of treatment changes after follow‐up MRI scans was lower when patients had been treated longer. Conclusion(s) Screening MRI scans aid in early detection of melanoma brain metastases, and follow‐up MRI scans inform treatment strategy. In patients with brain metastases responding to immune checkpoint inhibitors, treatment changes were less frequently observed after follow‐up MRI scans. These results can inform the development of brain imaging protocols for patients with immune checkpoint inhibitor sensitive tumors.

Anti-SSA/Ro antibodies, while strongly linked to fetal cardiac injury and neonatal rash, can associate with a spectrum of disease in the mother, ranging from completely asymptomatic to overt Systemic Lupus Erythematosus (SLE) or Sjögren’s Syndrome (SS). This study was initiated to test the hypothesis that the microbiome, influenced in part by genetics, contributes to disease state. The stool microbiome of healthy controls (HC) was compared to that of anti-SSA/Ro positive women whose children had neonatal lupus. At the time of sampling, these women were either asymptomatic (Asym), had minor rheumatic symptoms or signs considered as an undifferentiated autoimmune syndrome (UAS), or were diagnosed with SLE or SS. Differences in microbial relative abundances among these three groups were tested assuming an ordering in clinical severity (HC

Objectives To improve continence care in the Netherlands, a new framework has been developed in which a shift has been made from incontinence severity as the sole criterion for selecting incontinence products to a focus on patient need for daily life activities. The impact of the framework on daily care has not been assessed. We aimed to compare treatment effectiveness and costs between participants who did and did not undergo re-evaluation according to the new framework.Design Cohort studySetting Twelve pharmacies in the NetherlandsParticipants Existing users of absorbent incontinence materials for urinary incontinence.Interventions Participants were offered the option to have their incontinence products re-evaluated within the new framework at their pharmacy.Primary and secondary outcome measures Effectiveness and cost outcomes were assessed at 3 and 6 months through questionnaires. These questionnaires included the International Consultation on Incontinence Questionnaire (ICIQ) Lower Urinary Tract Symptoms Quality of Life Module, ICIQ Urinary Incontinence Short Form, ICIQ Absorbent Pads, questions about satisfaction and the iPCQ and iMCQ.Results 303 users consented and 279 completed the baseline questionnaire. Of these participants, 72 agreed to a re-evaluation of their incontinence materials. There was a small improvement at 3 months in the re-evaluation group compared with the other group on most outcomes. However, these improvements were not clinically relevant. Moreover, these differences did not change much from 3 to 6 months. Small differences were also observed in the changes in costs, but with very wide CIs on both sides of zero (€99.38; 95% CI −633.48 to 832.23).Conclusions The current study showed no clinically relevant effect of a newly implemented framework for selecting incontinence materials in pharmacies when compared with an existing method. Given that the study also showed no differences in effectiveness and costs, introducing the new framework in pharmacies may not lead to better incontinence care.

There is a paucity of data relating to the vitamin D status of racehorses. We hypothesised that the management of racehorses in Hong Kong (HK) predisposes to low vitamin D status unless they receive dietary supplementation. Serum concentrations of 25-hydroxyvitamin D2 (25OHD2), 25-hydroxyvitamin D3 (25OHD3) and total 25-hydroxyvitamin D (total 25OHD) for 79 non-grazing HK racehorses were compared with those for 22 racehorses training in the United Kingdom (UK) that grazed for ≥1 h/d, and for which published data exists. A nested group of 41 HK horses was sampled twice to determine the effect of the duration in HK on vitamin D status. The HK horses had significantly lower serum concentrations of total 25OHD and 25OHD2 than the UK horses; 25OHD2 was undetectable in 15/79 HK sera and serum concentrations of 25OHD2 declined with the duration in HK. The main determinants of vitamin D status were assessed using linear regression; the retained variables were the 25OHD3 concentration and the duration in HK. The inverse relationship between the serum concentrations of 25OHD2 and 25OHD3, previously identified in humans, was observed for the first time in horses. In conclusion, HK racehorses have low serum 25OHD2 and total 25OHD concentrations and rely on D3 supplementation to maintain adequate vitamin D status. Further study is required to determine the optimal form of dietary vitamin D supplementation for Thoroughbred racehorses.

In May and June of 2021, marine microbial samples were collected for DNA sequencing in East Sound, WA, USA every 4 hours for 22 days. This high temporal resolution sampling effort captured the last 3 days of a Rhizosolenia sp. bloom, the initiation and complete bloom cycle of Chaetoceros socialis (8 days), and the following bacterial bloom (2 days). Metagenomes were completed on the time series, and the dataset includes 128 size-fractionated microbial samples (0.22-1.2 μm), providing gene abundances for the dominant members of bacteria, archaea, and viruses. This dataset also has time-matched nutrient analyses, flow cytometry data, and physical parameters of the environment at a single point of sampling within a coastal ecosystem that experiences regular bloom events, facilitating a range of modeling efforts that can be leveraged to understand microbial community structure and their influences on the growth, maintenance, and senescence of phytoplankton blooms.

PurposeThe COVID-19 pandemic has been a major stressor for adolescents. Given the unique implications of the pandemic for youth with type 1 diabetes (T1D), who already navigate multiple stressors as a function of their chronic condition, we aimed to describe the impact of the pandemic on adolescents with T1D and describe their coping strategies and resilience resources.Research MethodIn a 2-site (Seattle WA, Houston TX) clinical trial of a psychosocial intervention targeting stress/resilience, adolescents 13-18 years old with T1D ≥ 1 year and elevated diabetes distress were enrolled August 2020 – June 2021. Participants completed a baseline survey about the pandemic, including open-ended questions about the effects of the pandemic, what was helping them navigate, and how it impacted T1D management. Hemoglobin A1c (A1c) was extracted from clinical records. Free text responses were analyzed using an inductive content approach. Survey responses and A1c were summarized using descriptive statistics and associations were assessed by Chi-squared tests.ResultsAdolescents (n=122) were 56% female. 11% of adolescents reported diagnosis of COVID-19 and 12% had a family member/other important person die from COVID-19 complications. Adolescents described Social Relationships, Personal Health/Safety Practices, Mental Health, Family Relationships, and School to be primary areas affected by COVID-19. Helpful resources included: Learned Skills/Behaviors, Social Support/Community, and Meaning-Making/Faith. Among participants indicating that the pandemic had an impact on their T1D management (n=35), the most commonly described areas were: Food, Self-Care, Health/Safety, Diabetes Appointments, and Exercise. Compared to adolescents who reported minimal difficulty managing T1D during the pandemic (71%), those reporting moderate to extreme difficulty (29%) were more likely to have A1C ≥ 8% (80% vs. 43%, p

Purpose. Quantitative in vivo [18F]-(2S,4R)4-fluoroglutamine ([18F]4-FGln or more simply [18F]FGln) metabolic kinetic parameters are compared with activity levels of glutamine metabolism in different types of hepatocellular carcinoma (HCC). Methods. For this study, we used two transgenic mouse models of HCC induced by protooncogenes, MYC, and MET. Biochemical data have shown that tumors induced by MYC have increased levels of glutamine metabolism compared to those induced by MET. One-hour dynamic [18F]FGln PET data were acquired and reconstructed for fasted MYC mice (n=11 tumors from 7 animals), fasted MET mice (n=8 tumors from 6 animals), fasted FVBN controls (n=8 normal liver regions from 6 animals), nonfasted MYC mice (n=16 tumors from 6 animals), and nonfasted FVBN controls (n=8 normal liver regions from 3 animals). The influx rate constants (K1) using the one-tissue compartment model were derived for each tumor with the left ventricular blood pool input function. Results. Influx rate constants were significantly higher for MYC tumors (K1=0.374±0.133) than for MET tumors (K1=0.141±0.058) under fasting conditions (P=0.0002). Rate constants were also significantly lower for MET tumors (K1=0.141±0.135) than normal livers (K1=0.332±0.179) under fasting conditions (P=0.0123). Fasting conditions tested for MYC tumors and normal livers did not result in any significant difference with P values > 0.005. Conclusion. Higher influx rate constants corresponded to elevated levels of glutamine metabolism as determined by biochemical assays. The data showed that there is a distinctive difference in glutamine metabolism between MYC and MET tumors. Our study has demonstrated the potential of [18F]FGln PET imaging as a tool to assess glutamine metabolism in HCC tumors in vivo with a caution that it may not be able to clearly distinguish HCC tumors from normal liver tissue.

We aim to develop and transfer to the wine sector a decision support system (DSS) in the frame of WANEGRAPE4.0 project that, integrated into a geographic information system, helps wine growers in i) selecting the most suitable rootstock given some agroecological conditions and oenological objectives; and ii) managing irrigation and nitrogen fertilization in the most suitable way for the selected rootstock and agroecological conditions. The following goals have been achieved. First, the modular structure and information flow of the DSS has been defined. Second, the main algorithms of the water balance module (DSS core part) have been formulated and the module coded in a spreadsheet. Third, this water balance module has been tested with data from field experiments in several regions of Spain. Fourth, the relationships between grapevine water status and production and harvest quality variables have been established, revealing an always-significant effects of the decrease in water stress on vegetative development, yield, and grape composition. Fifth, the nitrogen fertilizer effects on vine performance has been assessed. Sixth, the effects rootstocks have on 5 parameters of vine production and grape quality for winemaking have been established too by doing another meta-analysis of rootstock trials. Seventh, a rootstock selection module has been defined. The WANUGRAPE4.0 project goes on with the integration of all its modules, their coding in a World Wide Web language and their publication on an Internet portal.

Based on complaints that patients with urinary incontinence were not receiving the correct medical aids, the Dutch Ministry of Health, Wellbeing, and Sports requested further exploration. This resulted in a new framework based on considering individual activities of daily living when providing continence products. We aimed to explore the expectations of pharmacy staff regarding this new framework for continence care in the Netherlands and to establish the facilitators and barriers associated with that care. In total, 15 participants from 7 different pharmacies participated in 2 focus groups. Data analysis was by thematic content analysis. Pharmacy employees were positive about the idea of considering individual daily activities when providing continence products in the new framework, but they did have some reservations about the feasibility of implementation in daily practice. Barriers to optimal continence care included low reimbursement for patients with incontinence, especially with non-standard needs, and poor communication between the various stakeholders in continence care. Efforts must be extended to review the current reimbursement system and to change the policies and information provided by stakeholders in continence care, before the new framework will make a real impact in clinical practice.

Bacteria and phytoplankton form close associations in the ocean that are driven by the exchange of chemical compounds. The bacterial signal 2-heptyl-4-quinolone (HHQ) slows phytoplankton growth; however, the mechanism responsible remains unknown.

For most graduate writers, acclimating to doctoral-level inquiry is fraught with numerous tensions, whether regarding the development of scholarly identity (Gardner et al., 2014), navigating graduate school's newly decentralized sources for support (Simpson, 2012), or mastering the writing and research conventions that govern disciplinary practice. Using a Cultural Historical Activity Theory (CHAT) framework, this case study analyzes the first-term experiences of Miranda, a first-year PhD student from the field of gerontology (who is also a co-author), and the tensions she feels around the drafting and revision of a single paper. Drawing from Engeström (1987), we theorize Miranda's challenges around motive, authority, and expert feedback as comprising three "contradictions" engendered by the contemporary activity system of doctoral-level learning-to-write, contradictions that at once challenge the writer's going presumptions about writing even while they enable new concepts and solutions to emerge. This analysis finally encourages researchers to take a wide, cultural-historical view of the many contexts in which doctoral students write during their first terms, including the instructor-led classroom, the larger culture of the program and institution, and the current high-pressure realities of doctoral-level academic study in the United States.

Abstract We show that certain BPS counting functions for both fundamental strings and strings arising from fivebranes wrapping divisors in Calabi-Yau threefolds naturally give rise to skew-holomorphic Jacobi forms at rational and attractor points in the moduli space of string compactifications. For M5-branes wrapping divisors these are forms of weight negative one, and in the case of multiple M5-branes skew-holomorphic mock Jacobi forms arise. We further find that in simple examples these forms are related to skew-holomorphic (mock) Jacobi forms of weight two that play starring roles in moonshine. We discuss examples involving M5-branes on the complex projective plane, del Pezzo surfaces of degree one, and half-K3 surfaces. For del Pezzo surfaces of degree one and certain half-K3 surfaces we find a corresponding graded (virtual) module for the degree twelve Mathieu group. This suggests a more extensive relationship between Mathieu groups and complex surfaces, and a broader role for M5-branes in the theory of Jacobi forms and moonshine.

Fractionation of alfalfa (Medicago sativa L.) into leaves and stems can reduce cutting frequency while producing a high-value feedstuff. A difficulty with fractionation is the higher moisture content at ensiling due to the inability to wilt leaves without substantial dry matter loss or financial cost. To evaluate whether the silage quality of fractionated alfalfa is competitive with conventional methods under long-term storage conditions, high-moisture leaves (250–280 g·kg−1 dry matter, DM) and stems (190–240 g·kg−1 DM) were ensiled for 21 and 350 days and compared to wilted whole-plant silage for two alfalfa developmental stages. At 21 days, leaf and whole-plant silage fermentation characteristics indicated suitable lactic acid bacterial fermentation through decreased pH, high lactic acid–to-acetic acid ratio, and a lack of clostridial fermentation. At 350 days, leaf silage fermentation and nutritional quality decreased due to sustained proteolysis, but true protein still exceeded that of whole-plant silage. High-moisture stem fractions fermented poorly; at 21 days, stage 3 stems had significant amounts of butyric acid, while stage 5 stems became clostridial at 350 days. Long-term storage of high-moisture leaf silages can produce good-quality silage despite exceeding moisture contents typically recommended for alfalfa, while wilting is required for stem silages.

Introducción: Valorar niveles séricos de 25-hidroxivitamina D -25(OH)D-, hormonas con influencia sobre el metabolismo óseo (parathormona -PTH- y factor de crecimiento insulínico -IGF-I-), marcadores de remodelado óseo (MRO) (telopéptido carboxilo-terminal del colágeno tipo I -?-CTX- y propéptido aminoterminal del procolágeno tipo I -PINP-), densidad mineral ósea (DMO), microestructura y biomecánica de cuello de fémur, en pacientes con fractura de cadera osteoporótica (OP) vs. pacientes artrósicos (OA). Material y métodos: Estudio observacional transversal de 29 pacientes OP y 14 OA, edad ?50 años. Cuantificamos niveles séricos hormonales y MRO (inmunoensayo), DMO de cadera (DXA), microestructura (micro-CT) y biomecánica (ensayos de compresión uniaxial, sistema IGFA). Análisis estadístico (SPSS 20.0.) Resultados: Los pacientes OP presentaron niveles inferiores de 25(OH)D (p=0,02) y DMO de cadera (p

Reduced activity of nutrient-sensing signaling networks can extend organismal lifespan, yet the underlying biology remains unclear. We show that the anti-aging effects of rapamycin and reduced intestinal insulin/insulin growth factor (IGF) signaling (IIS) require the Drosophila FoxA transcription factor homolog Fork Head (FKH). Intestinal FKH induction extends lifespan, highlighting a role for the gut. FKH binds to and is phosphorylated by AKT and Target of Rapamycin. Gut-specific FKH upregulation improves gut barrier function in aged flies. Additionally, it increases the expression of nutrient transporters, as does lowered IIS. Evolutionary conservation of this effect of lowered IIS is suggested by the upregulation of related nutrient transporters in insulin receptor substrate 1 knockout mouse intestine. Our study highlights a critical role played by FKH in the gut in mediating anti-aging effects of reduced IIS. Malnutrition caused by poor intestinal absorption is a major problem in the elderly, and a better understanding of the mechanisms involved will have important therapeutic implications for human aging.

Systemic lupus erythematosus (SLE) is an autoimmune disease with a strong ethnic and gender bias. In a transancestral genetic association study, Langefeldet al. identify 24 novel regions associated with risk to lupus and propose a cumulative hits hypothesis for loci conferring risk to SLE.

Michael Goyfman,1 Paul Zamudio,2 Kristine Jang,3 Jennifer Chee,3 Catherine Miranda,2 Javed Butler,1 Nand K Wadhwa2 1Division of Cardiology, 2Division of Nephrology, 3Department of Medicine, Stony Brook School of Medicine, Stony Brook, NY, USA Introduction: Acute heart failure (AHF) is a leading cause of hospitalization and readmission in the US. The present study evaluated maximum diuresis while minimizing electrolyte imbalances, hemodynamic instability, and kidney dysfunction, to achieve a euvolemic state safely in a shorter period of time.Methods and results: A protocol of combined therapy with furosemide, metolazone, and spironolactone, with or without tolvaptan and acetazolamide, was used in 17 hospitalized patients with AHF. The mean number of days on combination diuretic protocol was 3.8 days. The mean daily fluid balance was 3.0±2.1 L negative. The mean daily urine output (UOP) was 4.1±2.0 L (range 1.8–10.5 L). There were minimal fluctuations in serum electrolyte levels and serum creatinine over the duration of diuretic therapy. There was no statistically significant change in patients’ creatinine from immediately prior to therapy to the last day of therapy, with a mean increase in creatinine of 0.14 mg/dL (95% CI −0.03, +0.30, p=0.10).Conclusion: Our strategy of treating AHF by achieving high UOP, while maintaining stable electrolytes and creatinine in a short period to euvolemic state, is safe. Keywords: diuretics, aquaretic, acute heart failure, volume overload

Introducción: La obesidad y la osteoporosis (OP) son dos patologías muy prevalentes en nuestra sociedad actual. El efecto de la obesidad sobre la calidad ósea se encuentra en debate en la actualidad. Objetivo: Valorar el efecto del peso corporal sobre la microestructura y las propiedades biomecánicas de hueso trabecular procedente de biopsias de extremidad proximal de fémur de pacientes con fractura de cadera por fragilidad. Material y método: Estudio transversal de 16 pacientes con fractura de cadera. 2 grupos según su IMC: (A) sujetos normopeso y (B) con obesidad. Recogimos biopsias de hueso trabecular de cabeza femoral. Valoramos determinaciones bioquímicas (PTH, 25(OH) vitamina D e IGF-1), marcadores de remodelado óseo (PINP,CTX), masa ósea (DMO cuello y cadera total), microestructura ósea y estudio biomecánico (µCt). El análisis estadístico: t-Student (SPSS 22.0) significación p

Los micro-ARN (miRs) son pequeñas moléculas de ARN no codificantes que regulan la expresión génica a nivel post-transcripcional. Generalmente actúan sobre la expresión genética mediante el silenciamiento o degradación de los ARNm, y están implicados en la regulación de varios procesos biológicos, como la diferenciación celular, la proliferación, la apoptosis y en el desarrollo embrionario y tisular. Actualmente son un importante foco de interés para el estudio de diversas enfermedades como el cáncer o la diabetes mellitus tipo 2. A nivel del metabolismo óseo, están surgiendo diversos miRs implicados en su regulación, abriendo un campo de investigación importante para identificar nuevos biomarcadores para el diagnóstico de la enfermedad osteoporótica, de su evolución, así como para diseñar nuevas terapias farmacológicas.

IKr is the rapidly activating component of the delayed rectifier potassium current, the ion current largely responsible for the repolarization of the cardiac action potential. Inherited forms of long QT syndrome (LQTS) (Lees-Miller et al., 1997) in humans are linked to functional modifications in the Kv11.1 (hERG) ion channel and potentially life threatening arrhythmias. There is little doubt now that hERG-related component of IKr in the heart depends on the tetrameric (homo- or hetero-) channels formed by two alternatively processed isoforms of hERG, termed hERG1a and hERG1b. Isoform composition (hERG1a- vs. the b-isoform) has recently been reported to alter pharmacologic responses to some hERG blockers and was proposed to be an essential factor pre-disposing patients for drug-induced QT prolongation. Very little is known about the gating and pharmacological properties of two isoforms in heart membranes. For example, how gating mechanisms of the hERG1a channels differ from that of hERG1b is still unknown. The mechanisms by which hERG 1a/1b hetero-tetramers contribute to function in the heart, or what role hERG1b might play in disease are all questions to be answered. Structurally, the two isoforms differ only in the N-terminal region located in the cytoplasm: hERG1b is 340 residues shorter than hERG1a and the initial 36 residues of hERG1b are unique to this isoform. In this study, we combined electrophysiological measurements for HEK cells, kinetics and structural modeling to tease out the individual contributions of each isoform to Action Potential formation and then make predictions about the effects of having various mixture ratios of the two isoforms. By coupling electrophysiological data with computational kinetic modeling, two proposed mechanisms of hERG gating in two homo-tetramers were examined. Sets of data from various experimental stimulation protocols (HEK cells) were analyzed simultaneously and fitted to Markov-chain models (M-models). The minimization procedure presented here, allowed assessment of suitability of different Markov model topologies and the corresponding parameters that describe the channel kinetics. The kinetics modeling pointed to key differences in the gating kinetics that were linked to the full channel structure. Interactions between soluble domains and the transmembrane part of the channel appeared to be critical determinants of the gating kinetics. The structures of the full channel in the open and closed states were compared for the first time using the recent Cryo-EM resolved structure for full open hERG channel and an homology model for the closed state, based on the highly homolog EAG1 channel. Key potential interactions which emphasize the importance of electrostatic interactions between N-PAS cap, S4-S5, and C-linker are suggested based on the structural analysis. The derived kinetic parameters were later used in higher order models of cells and tissue to track down the effect of varying the ratios of hERG1a and hERG1b on cardiac action potentials and computed electrocardiograms. Simulations suggest that the recovery from inactivation of hERG1b may contribute to its physiologic role of this isoform in the action potential. Finally, the results presented here contribute to the growing body of evidence that hERG1b significantly affects the generation of the cardiac Ikr and plays an important role in cardiac electrophysiology. We highlight the importance of carefully revisiting the Markov models previously proposed in order to properly account for the relative abundance of the hERG1 a- and b- isoforms.

BACKGROUND & AIMS:Ingestion of poorly digested, fermentable carbohydrates (fermentable oligo-, di-, mono-saccharides and polyols; FODMAPs) have been implicated in exacerbating intestinal symptoms and the reduction of intake with symptom alleviation. Restricting FODMAP intake is believed to relieve colonic distension by reducing colonic fermentation but this has not been previously directly assessed. We performed a randomised controlled trial comparing the effect of a low FODMAP diet combined with either maltodextrin or oligofructose on colonic contents, metabolites and microbiota. METHODS:A parallel randomised controlled trial in healthy adults (n = 37). All subjects followed a low FODMAP diet for a week and supplemented their diet with either maltodextrin (MD) or oligofructose (OF) 7g twice daily. Fasted assessments performed pre- and post-diet included MRI to assess colonic volume, breath testing for hydrogen and methane, and stool collection for microbiota analysis. RESULTS:The low FODMAP diet was associated with a reduction in Bifidobacterium and breath hydrogen, which was reversed by oligofructose supplementation. The difference in breath hydrogen between groups post-intervention was 27ppm (95% CI 7 to 50, P

Background/Purpose. Understanding the practices of pediatric rheumatologists in diagnosing and treating chronic nonbacterial osteomyelitis (CNO) can provide important information to guide the development of consensus treatment plans. The objectives of this study were to determine physicians’ approaches to (1) diagnosing and monitoring CNO, (2) ordering a bone biopsy, and (3) making treatment decisions. Methods. A survey was distributed among members of the Childhood Arthritis and Rheumatology Research Alliance using a web-based questionnaire. Results. 121 of 277 (41%) attending physician members completed the survey. Plain radiographs (89%) were most commonly used followed by regional MRI (78%), bone scintigraphy (43%), and whole-body MRI (36%). The top three reasons for performing a biopsy were constitutional findings (66%), unifocal bone lesions (64%), and nocturnal bone pain (45%). Nearly all responders (95%) prescribed nonsteroidal anti-inflammatory drugs (NSAIDs) as initial therapy. For patients who failed NSAID treatment, methotrexate (67%), tumor necrosis factor inhibitors (65%), and bisphosphonates (46%) were the next most commonly used treatments. The presence of a spinal lesion increased the use of bisphosphonate treatment. Conclusion. The diagnostic approach and disease activity monitoring for CNO varied among surveyed physicians. Our survey findings provided important background for the development of consensus treatment plans for CNO.

Promoting Resilience in Stress Management (PRISM), a psychosocial intervention for adolescents and young adults (AYAs) with serious illness, enhances resilience resources via four skills-based training sessions. A recent randomized controlled trial showed PRISM improved health-related quality of life (HRQOL) compared to usual care (UC). This post hoc exploratory analysis aimed to better understand the effect of PRISM on HRQOL by describing changes in HRQOL subdomain scores. English-speaking AYAs (12−25 years) with cancer were randomized to PRISM or UC. At enrollment and six months later, HRQOL was assessed using the Pediatric Quality of Life Inventory (PedsQL) Generic Short Form (SF-15) and Cancer Module. Scores at each time point were summarized descriptively and individual HRQOL trajectories were categorized (

The discovery of a class of galaxies called Green Peas provides an example of scientific work done by volunteers. This unique situation arose out of a science crowdsourcing website called Galaxy Zoo. It gave the ability to investigate the research process used by the volunteers. The volunteers’ process was analyzed in terms of three models of scientific research and an iterative work model to show the path to this discovery. As has been illustrated in these models of science, the path was iterative, not predetermined, and driven by empirical data. This paper gives a narrative of the 11-month, volunteer-led discovery process of the Green Pea galaxies and the transition to the Galaxy Zoo science team’s involvement to analyze and report on a new class of galaxy. This study identified the cycles of the volunteers’ work and situated them in the proposed integrated model of the scientific research process to show that the volunteers engaged in meaningful scientific research.

Studies have demonstrated ways in which climate-related shifts in the distributions and relative abundances of marine species are expected to alter the dynamics and catch potential of global fisheries. While these studies assess impacts on large-scale commercial fisheries, few efforts have been made to quantitatively project impacts on small-scale subsistence and commercial fisheries that are economically, socially and culturally important to many coastal communities. This study uses a dynamic bioclimate envelope model to project scenarios of climate-related changes in the relative abundance, distribution and richness of 98 exploited marine fishes and invertebrates of commercial and cultural importance to First Nations in coastal British Columbia, Canada. Declines in abundance are projected for most of the sampled species under both the lower (Representative Concentration Pathway [RCP] 2.6) and higher (RCP 8.5) emission scenarios (-15.0% to -20.8%, respectively), with poleward range shifts occurring at a median rate of 10.3 to 18.0 km decade(-1) by 2050 relative to 2000. While a cumulative decline in catch potential is projected coastwide (-4.5 to -10.7%), estimates suggest a strong positive correlation between the change in relative catch potential and latitude, with First Nations' territories along the northern and central coasts of British Columbia likely to experience less severe declines than those to the south. Furthermore, a strong negative correlation is projected between latitude and the number of species exhibiting declining abundance. These trends are shown to be robust to alternative species distribution models. This study concludes by discussing corresponding management challenges that are likely to be encountered under climate change, and by highlighting the value of joint-management frameworks and traditional fisheries management approaches that could aid in offsetting impacts and developing site-specific mitigation and adaptation strategies derived from local fishers' knowledge.