Search

Congenitally corrected transposition of the great arteries (ccTGA) is a rare malformation with diverse morphology. We assessed features of fetuses with ccTGA and evaluated neonatal and pediatric outcomes. This was a retrospective review of fetuses with ccTGA at Birmingham Women's and Children's Hospital born from 2005 to 2019. Of thirty-six fetuses identified, six had unavailable prenatal data, one was postnatally diagnosed with isomerism and 29 fetuses were evaluated. ccTGA without associated cardiac lesions was found in 28% (8/29), ccTGA with significant VSD in 31% (9/29), ccTGA with pulmonary obstruction in 24% (7/29) and ccTGA with complex anomalies in 17% (5/29). Tricuspid regurgitation (TR) was observed in 17% (5/29) and heart block (HB) in 10% (3/29) prenatally. Six, that is 21% underwent genetic testing of which one was abnormal. Five extra-cardiac anomalies were reported prenatally and postnatally. Pregnancy was discontinued in five, of which two had moderate TR. There were thirty-one liveborn. Coarctation of the aorta was found in five postnatally but not suspected prenatally. In one, pulmonary stenosis was underestimated; otherwise, prenatal morphology was confirmed. Cardiac interventions were performed in 77% (24/31) liveborn with 39% (12/31) undergoing neonatal intervention. Overall, 6/31 liveborn died including all three with prenatal heart block and one with TR. Estimated survival for all liveborn at 1, 5 and 10 years was 87% (95% CI 76–100%), 83% (95% CI 72–98%) and 80% (95% CI 66–96%) respectively. Accurate prenatal diagnosis of ccTGA is critical for counseling. Early outcomes are favorable with 77% of liveborn undergoing surgery. Fetuses with prenatal diagnosis of complex associated abnormalities, HB and TR appear to do less well. [ABSTRACT FROM AUTHOR]

Neural circuits with multiple discrete attractor states could support a variety of cognitive tasks according to both empirical data and model simulations. We assess the conditions for such multistability in neural systems using a firing rate model framework, in which clusters of similarly responsive neurons are represented as single units, which interact with each other through independent random connections. We explore the range of conditions in which multistability arises via recurrent input from other units while individual units, typically with some degree of self-excitation, lack sufficient self-excitation to become bistable on their own. We find many cases of multistability—defined as the system possessing more than one stable fixed point—in which stable states arise via a network effect, allowing subsets of units to maintain each others' activity because their net input to each other when active is sufficiently positive. In terms of the strength of within-unit self-excitation and standard deviation of random cross-connections, the region of multistability depends on the response function of units. Indeed, multistability can arise with zero self-excitation, purely through zero-mean random cross-connections, if the response function rises supralinearly at low inputs from a value near zero at zero input. We simulate and analyze finite systems, showing that the probability of multistability can peak at intermediate system size, and connect with other literature analyzing similar systems in the infinite-size limit. We find regions of multistability with a bimodal distribution for the number of active units in a stable state. Finally, we find evidence for a log-normal distribution of sizes of attractor basins, which produces Zipf's Law when enumerating the proportion of trials within which random initial conditions lead to a particular stable state of the system. [ABSTRACT FROM AUTHOR]

Strong, ongoing high-latitude warming is causing changes to vegetation composition and plant productivity, modifying plant emissions of biogenic volatile organic compounds (BVOCs). In the sparsely populated high latitudes with clean background air, climate feedback resulting from BVOCs as precursors of atmospheric aerosols could be more important than elsewhere on the globe. Here, we quantitatively assess changes in vegetation composition, BVOC emissions, and secondary organic aerosol (SOA) formation under different climate scenarios. We show that warming-induced vegetation changes largely determine the spatial patterns of future BVOC impacts on SOA. The northward advances of boreal needle-leaved woody species result in increased SOA optical depth by up to 41%, causing cooling feedback. However, areas with temperate broad-leaved trees replacing boreal needle-leaved trees likely experience a large decline in monoterpene emissions and SOA formation, causing warming feedback. We highlight the necessity of considering warming-induced vegetation shifts when assessing land radiative feedback on climate following the BVOC-SOA pathway. [ABSTRACT FROM AUTHOR]

Defoliation caused by strong tropical cyclones can modify the partitioning of incident solar radiation between the sensible, latent, and substrate heat fluxes. While previous work has shown hurricane defoliation to warm near-surface air temperature along its track, this study more directly contextualizes the warming to human heat stress and exposure via the heat index (HI). For this case study, the spatial extent and temporal persistence of defoliation produced by Hurricane Laura (2020) in southwestern Louisiana was characterized using the normalized difference vegetation index (NDVI). The defoliated land surface was then assimilated into the Weather Research and Forecasting (WRF) model version 4.2 and compared to a control, normal-foliage simulation for the 30 days following landfall. Over southwest Louisiana, the largest HI increase occurred at 0600 UTC (1:00 AM LT) with an average increase of + 0.25 °C, and the exposure time to HI ≥ 30 °C increased by 8.1% after accounting for the defoliated landscape. Meanwhile, Cameron, Louisiana, the site of Laura's landfall where defoliation was most severe, cumulatively experienced an extra 33 h of HI values exceeding 26 °C, while mean HI increased by 1.2 °C at 0300 UTC. Additional WRF experiments were performed with altered "landfall" years of 2017 and 2018 to determine the sensitivity of defoliation-driven HI changes to the ambient synoptic conditions. While synoptic conditions modulated the magnitude of increase, HIs nonetheless experienced statistically significant increases in both hypothetical "landfall" years. Such findings are valuable for emergency managers and community health officials because overnight minimum temperatures are a strong indicator of heat mortality. [ABSTRACT FROM AUTHOR]

Objective: Surgical outcome data differs from overall outcomes of prenatally diagnosed fetuses with hypoplastic left heart syndrome (HLHS). Our aim was to describe outcome of prenatally diagnosed fetuses with this anomaly. Methods: Retrospective review of prenatally diagnosed classical HLHS at a tertiary hospital over a 13-year period, estimated due dates 01/08/2006 to 31/12/2019. HLHS-variants and ventricular disproportion were excluded. Results: 203 fetuses were identified with outcome information available for 201. There were extra-cardiac abnormalities in 8% (16/203), with genetic variants in 14% of those tested (17/122). There were 55 (27%) terminations of pregnancy, 5 (2%) intrauterine deaths and 10 (5%) babies had prenatally planned compassionate care. There was intention to treat (ITT) in the remaining 131/201(65%). Of these, there were 8 neonatal deaths before intervention, two patients had surgery in other centers. Of the other 121 patients, Norwood procedure performed in 113 (93%), initial hybrid in 7 (6%), and 1 had palliative coarctation stenting. Survival for the ITT group from birth at 6-months, 1-year and 5-years was 70%, 65%, 62% respectively. Altogether of the initial 201 prenatally diagnosed fetuses, 80 patients (40%) are currently alive. A restrictive atrial septum (RAS) is an important sub-category associated with death, HR 2.61, 95%CI 1.34–5.05, p = 0.005, with only 5/29 patients still alive. Conclusion: Medium-term outcomes of prenatally diagnosed HLHS have improved however it should be noted that almost 40% do not get to surgical palliation, which is vital to those doing fetal counselling. There remains significant mortality particularly in fetuses with in-utero diagnosed RAS. What is already known on this topic: Most patients with hypoplastic left heart syndrome are diagnosed prenatally in the UK. Survival for staged univentricular palliation including for HLHS is reported annually by the National Institute for Cardiovascular Outcomes Research. What this study adds: This study describes mortality between fetal diagnosis and surgical intervention. How this study might affect practice: This data helps with counselling a pregnant woman expecting a fetus with hypoplastic left heart syndrome, giving clearer outcome data than using surgical survival alone. [ABSTRACT FROM AUTHOR]

Antenatal depression (AND) affects 1 in 10 fathers, potentially negatively impacting maternal mental health and well-being during and after the transition to parenthood. However, few studies have assessed the social predictors of paternal AND or their possible associations with maternal mental health. We analysed data from 180 couples participating in the Queensland Family Cohort longitudinal study. Both parents completed surveys measuring mental health, relationship quality, social support, and sleep quality at 24 weeks of pregnancy. Mothers also completed the same surveys 6 weeks' postpartum. Antenatal depression, stress, and anxiety were highest among fathers reporting lower social support and higher sleep impairment. Maternal AND, stress, and anxiety were higher among mothers reporting higher physical pain and poor sleep quality. Postnatally, mothers reporting lower social support also reported higher depression, anxiety, stress, and psycho-social well-being. While there were no significant associations between AND among fathers and maternal antenatal or postnatal depression, an exploratory analysis revealed that mothers whose partners reported lower antenatal social support also reported lower postnatal social support and higher postnatal depression. Our findings highlight the importance of including data among fathers to achieve a whole family approach to well-being during the transition to parenthood. [ABSTRACT FROM AUTHOR]

Background: Membranous nephropathy is an uncommon cause of nephrotic syndrome in pediatrics. Methods: We reviewed our kidney biopsy records for patients ≤ 20 years of age with membranous nephropathy without evidence of systemic lupus erythematosus within 6 months of biopsy (January 1995–September 2020). Staining for PLA2R, NELL1, THSD7A, SEMA3B, EXT2 (3 biopsies), and IgG-subclass were performed. Results: Sixteen children (≤ 12 years) and 25 adolescents (13–20 years) were identified. Four children and 15 adolescents showed autoantigen positivity: PLA2R+/SEMA3B- (13), SEMA3B+/PLA2R+ (2), SEMA3B+/PLA2R− (1), NELL1 (1), EXT2+ (2), and THSD7A (0). Co-morbidities associated with PLA2R positivity included IPEX syndrome, active hepatitis B, Von Hippel Lindau syndrome, solitary kidney, type 1 diabetes, hyperuricemia, pregnancy (1), obesity (3), type II diabetes, H. pylori, viral prodrome, and nephrolithiasis. The SEMA3B+/PLA2R− adolescent was pregnant, the NELL1+ adolescent was obese, and the two EXT2+ adolescents eventually met the clinical criteria for lupus (4, 9 years post-biopsy). Co-morbidities among the remaining 24 patients included remote hepatitis B (2), Down's syndrome, lysinuric protein intolerance, recurrent UTIs, hypothyroidism, pregnancy (3), and obesity (2). Follow-up data was available for 12 children and 16 adolescents. Of the 12 children, 6 achieved complete remission, 4 achieved partial remission, and 2 had no response to treatment (1 transplant). Of the 16 adolescents, 4 achieved complete remission, 4 achieved partial remission, and 8 had no response to treatment (3 transplants). A child with "full-house" immunofluorescence staining achieved spontaneous disease remission. Conclusion: Our non-lupus membranous nephropathy cohort represents one of the largest pediatric studies to date. A higher resolution version of the Graphical abstract is available as Supplementary information. [ABSTRACT FROM AUTHOR]

This study assessed the attitudes and needs of physicians and health professional staff at a tertiary care hospital in Canada regarding the introduction of physician assisted dying (PAD) during 2015–16. This research aimed to develop an understanding of the wishes, concerns and hopes of stakeholders related to handling requests for PAD; to determine what supports/structures/resources health care professionals (HCP) require in order to ensure high quality and compassionate care for patients requesting PAD, and a supportive environment for all healthcare providers across the moral spectrum. This study constituted a mixed methods design with a qualitative descriptive approach for the study's qualitative component. A total of 303 HCPs working in a tertiary care hospital completed an online survey and 64 HCPs working in hospital units with high mortality rates participated in 8 focus group discussions. Both focus group and survey data coalesced around several themes to support the implementation of PAD following the decriminalization of this practice: the importance of high quality care; honoring moral diversity; supporting values (such as autonomy, privacy, beneficence); and developing resources, including collaboration with palliative care, education, policies and a specialized team. This study provided the foundational evidence to support the development of the PAD program described in other papers in this collection, and can be a model for gathering evidence from stakeholders to inform the implementation of PAD in any healthcare organization. [ABSTRACT FROM AUTHOR]

This paper focuses on the ethics of how to approach the introduction of MAiD as an organizational ethics challenge, a focus that diverges from the traditional focus in healthcare ethics on the ethics of why MAiD is right or wrong. It describes a method co-designed and implemented by ethics and medical leadership at a tertiary hospital to develop a values-based, grassroots response to the decriminalization of assisted dying in Canada. This organizational ethics engagement method embodied core tenants that drew inspiration from a variety of sources, including poetic ones. These tenants are: make the problem bigger; focus on values; cultivate open moral spaces; and trust emergence. The paper describes how these tenants were put into practice in order to create a rigorous and sustainable MAiD program that delivers high-quality care to patients and families while honoring the moral diversity of the hospital workforce. One of the goals in sharing this method is to provide a roadmap for healthcare organizations in Canada and other jurisdictions around the world that are facing the challenge of responding to patient requests for MAiD following the decriminalization of this care option. [ABSTRACT FROM AUTHOR]

This paper depicts a case study of an organizational strategy for the promotion of ethical practice when introducing a new, high-risk, ethically-charged medical practice like Medical Assistance in Dying (MAiD). We describe the development of an interprofessional program that enables the delivery of high-quality, whole-person MAiD care that is values-based and sustainable. A "care ecology" strategy recognizes the interconnected web of relationships and structures necessary to support a quality experience of MAiD for patients, families, and clinicians. This program exemplifies a care ecology approach that addresses common barriers to entry to MAiD practice, and also meets the needs of a variety of stakeholders through the creation of patient and family resources, team supports, standards of practice, professional development opportunities, organizational infrastructure, and community partnerships. We also describe how a thriving care ecology evolves to remain resilient, and to enable integration as the needs of the organization, team and program change over time. The design and development of this program may be adapted to other jurisdictions and organizations where MAiD is introduced, or where new patient populations become eligible for MAiD. This care ecology model may also be applicable to the creation of sustainable programs that provide other morally controversial or novel clinical services. [ABSTRACT FROM AUTHOR]

Following an initial study of the needs of healthcare providers (HCP) regarding the introduction of Medical Assistance in Dying (MAiD), and the subsequent development of an assisted dying program, this study sought to determine the efficacy and impact of MAiD services following the first two years of implementation. The first of three aims of this research was to understand if the needs, concerns and hopes of stakeholders related to patient requests for MAiD were addressed appropriately. Assessing how HCPs and families perceived the quality of MAiD services, and determining if the program successfully accommodated the diverse needs and perspectives of HCPs, rounded out this quality evaluation. This research implemented a mixed-methods design incorporative of an online survey with Likert scale and open-ended questions, as well as focus groups and interviews with staff and physicians, and interviews with MAiD-involved family members. There were 356 online surveys, as well as 39 participants in six focus groups with HCP, as well as fourteen interviews with MAiD-involved family members. Participants indicated that high-quality MAiD care could only be provided with enabling resources such as policies and guidelines to ensure safe, evidence-based, standardized care, as well as a specialized, trained MAiD team. Both focus group and survey data from HCPs suggest the infrastructure developed by the hospital was effective in delivering high-quality MAiD care that supports the diverse needs of various stakeholders. This study may serve as a model for evaluating the impact and quality of services when novel and ethically-contentious clinical practices are introduced to healthcare organizations. [ABSTRACT FROM AUTHOR]

Optical phase shifters constitute the fundamental building blocks that enable programmable photonic integrated circuits (PICs)—the cornerstone of on-chip classical and quantum optical technologies [1-2]. Thus far, carrier modulation and thermo-optical effect are the chosen phenomena for ultrafast and low-loss phase shifters, respectively; however, the state and information they carry are lost once the power is turned off—they are volatile. The volatility not only compromises energy efficiency due to their demand for constant power supply, but also precludes them from emerging applications such as in-memory computing. To circumvent this limitation, we introduce a phase shifting mechanism that exploits the nonvolatile refractive index modulation upon structural phase transition of Sb2Se3, a bi-state transparent phase change material (PCM). A zero-static power and electrically-driven phase shifter is realized on a CMOS-backend silicon-on-insulator platform, featuring record phase modulation up to 0.09 π/µm and a low insertion loss of 0.3 dB/π, which can be further improved upon streamlined design. Furthermore, we demonstrate phase and extinction ratio trimming of ring resonators and pioneer a one-step partial amorphization scheme to enhance speed and energy efficiency of PCM devices. A diverse cohort of programmable photonic devices is demonstrated based on the ultra-compact PCM phase shifter. [ABSTRACT FROM AUTHOR]

Human visual systems have evolved to extract ecologically relevant information from complex scenery. In some cases, the face in the crowd visual search task demonstrates an anger superiority effect, where anger is allocated preferential attention. Across three studies (N = 419), we tested whether facial hair guides attention in visual search and influences the speed of detecting angry and happy facial expressions in large arrays of faces. In Study 1, participants were faster to search through clean-shaven crowds and detect bearded targets than to search through bearded crowds and detect clean-shaven targets. In Study 2, targets were angry and happy faces presented in neutral backgrounds. Facial hair of the target faces was also manipulated. An anger superiority effect emerged that was augmented by the presence of facial hair, which was due to the slower detection of happiness on bearded faces. In Study 3, targets were happy and angry faces presented in either bearded or clean-shaven backgrounds. Facial hair of the background faces was also systematically manipulated. A significant anger superiority effect was revealed, although this was not moderated by the target's facial hair. Rather, the anger superiority effect was larger in clean-shaven than bearded face backgrounds. Together, results suggest that facial hair does influence detection of emotional expressions in visual search, however, rather than facilitating an anger superiority effect as a potential threat detection system, facial hair may reduce detection of happy faces within the face in the crowd paradigm. [ABSTRACT FROM AUTHOR]

Type A GABA (γ-aminobutyric acid) receptors represent a diverse population in the mammalian brain, forming pentamers from combinations of α-, β-, γ-, δ-, ε-, ρ-, θ- and π-subunits1. αβ, α4βδ, α6βδ and α5βγ receptors favour extrasynaptic localization, and mediate an essential persistent (tonic) inhibitory conductance in many regions of the mammalian brain1,2. Mutations of these receptors in humans are linked to epilepsy and insomnia3,4. Altered extrasynaptic receptor function is implicated in insomnia, stroke and Angelman and Fragile X syndromes1,5, and drugs targeting these receptors are used to treat postpartum depression6. Tonic GABAergic responses are moderated to avoid excessive suppression of neuronal communication, and can exhibit high sensitivity to Zn2+ blockade, in contrast to synapse-preferring α1βγ, α2βγ and α3βγ receptor responses5,7–12. Here, to resolve these distinctive features, we determined structures of the predominantly extrasynaptic αβ GABAA receptor class. An inhibited state bound by both the lethal paralysing agent α-cobratoxin13 and Zn2+ was used in comparisons with GABA–Zn2+ and GABA-bound structures. Zn2+ nullifies the GABA response by non-competitively plugging the extracellular end of the pore to block chloride conductance. In the absence of Zn2+, the GABA signalling response initially follows the canonical route until it reaches the pore. In contrast to synaptic GABAA receptors, expansion of the midway pore activation gate is limited and it remains closed, reflecting the intrinsic low efficacy that characterizes the extrasynaptic receptor. Overall, this study explains distinct traits adopted by αβ receptors that adapt them to a role in tonic signalling.Cryo-electron microscopy structures are used to identify mechanisms underlying distinct features of extrasynaptic type A γ-aminobutyric acid receptors. [ABSTRACT FROM AUTHOR]

Background: Pancreatic neuroendocrine tumors (PanNETs) are increasingly common. Experts debate whether small tumors should be resected. Tumor destruction via injection of cytotoxic agents could offer a minimal invasive approach to this controversy. We hypothesize that a new drug delivery system comprising chondroitin sulfate (CS) hydrogels loaded with sunitinib (SUN) suppresses tumor growth in PanNET cells. Methods: Injectable hydrogels composed of CS modified with methacrylate groups (MA) were fabricated and loaded with SUN. Loading target was either 200 µg (SUN200-G) or 500 µg (SUN500-G) as well as sham hydrogel with no drug loading (SUN0-G). SUN release from hydrogels was monitored in vitro over time and cytotoxicity induced by the released SUN was evaluated using QGP-1 and BON1 PanNET cell lines. QGP-1 xenografts were developed in 35 mice and directly injected with 25 µL of either SUN200-G, SUN500-G, SUN0-G, 100 µL of Sunitinib Malate (SUN-inj), or given 40 mg/kg/day oral sunitinib (SUN-oral). Results: SUN-loaded CSMA hydrogel retained complete in vitro cytotoxicity toward the QGP-1 PanNET and BON-1 PanNET cell lines for 21 days. Mouse xenograft models with QGP-1 PanNETs showed a significant delay in tumor growth in the SUN200/500-G, SUN-inj and SUN-oral groups compared with SUN0-G (p = 0.0014). SUN500-G hydrogels induced significantly more tumor necrosis than SUN0-G (p = 0.04). There was no difference in tumor growth delay between SUN200/500G, SUN-inj, and SUN-oral. Conclusions: This study demonstrates that CSMA hydrogels loaded with SUN suppress PanNETs growth. This drug delivery could approach represents a novel way to treat PanNETs and other neoplasms via intratumoral injection. [ABSTRACT FROM AUTHOR]

Late sodium current (late INa) inhibition has been proposed to suppress the incidence of arrhythmias generated by pathological states or induced by drugs. However, the role of late INa in the human heart is still poorly understood. We therefore investigated the role of this conductance in arrhythmias using adult primary cardiomyocytes and tissues from donor hearts. Potentiation of late INa with ATX-II (anemonia sulcata toxin II) and E-4031 (selective blocker of the hERG channel) slowed the kinetics of action potential repolarization, impaired Ca2+ homeostasis, increased contractility, and increased the manifestation of arrhythmia markers. These effects could be reversed by late INa inhibitors, ranolazine and GS-967. We also report that atrial tissues from donor hearts affected by atrial fibrillation exhibit arrhythmia markers in the absence of drug treatment and inhibition of late INa with GS-967 leads to a significant reduction in arrhythmic behaviour. These findings reveal a critical role for the late INa in cardiac arrhythmias and suggest that inhibition of this conductance could provide an effective therapeutic strategy. Finally, this study highlights the utility of human ex-vivo heart models for advancing cardiac translational sciences. [ABSTRACT FROM AUTHOR]

Background: Proliferative glomerulonephritis with monoclonal IgG deposits (PGNMID) is a glomerular disease defined by non-organized glomerular deposits of heavy and light chain–restricted immunoglobulin and is rarely reported in children. Methods: We characterized a series of nine pediatric patients from two academic centers with biopsy-proven PGNMID and additionally describe two patients with monotypic IgG in the setting of IgM deposition. Results: Each patient presented with hematuria and/or proteinuria; however, only five had elevated serum creatinine. Prodromal or concurrent infection was identified in six patients, low C3 in five, and alternate complement pathway gene variants in two. No monoclonal serum proteins were identified in five tested patients. Seven patients had monotypic deposits composed of IgG3-λ, two showed IgG3-κ, and one each IgG1 and IgG3 with lambda dominance in the setting of IgM deposition. The glomerular pattern was predominantly mesangial proliferative or membranoproliferative glomerulonephritis (MPGN). Treatment and outcomes were variable; four patients have recent PGNMID diagnoses and therefore minimal follow up, one had relatively stable kidney function for over a decade, and six experienced kidney failure, with four receiving transplants. Recurrent deposits of the same isotype were identified in five of six transplanted kidneys, corresponding to three of four transplanted patients. One of these patients developed PGNMID recurrences in three separate kidney allografts over a 20-year disease course. Conclusions: Our study emphasizes the need for upfront IgG subclass investigation in pediatric mesangial or MPGN with IgG deposition and monotypic or biased light-chain staining. Furthermore, this pediatric experience suggests expanded pathogenic considerations in PGNMID. [ABSTRACT FROM AUTHOR]

Background and Objective: Abaloparatide, an anabolic osteoporosis treatment administered by subcutaneous (SC) injection, increases bone mineral density (BMD) and reduces fracture risk in postmenopausal women with osteoporosis. The abaloparatide-solid Microstructured Transdermal System [abaloparatide-sMTS (Kindeva, St Paul, MN, USA)], which delivers abaloparatide intradermally, is in development to provide an alternative method for abaloparatide delivery. The objective of this study was to evaluate the ability of subjects to self-administer abaloparatide-sMTS, based on pharmacokinetic and pharmacodynamic markers. Methods: In this single-arm, open-label, Phase 1b study, 22 healthy postmenopausal women aged 50–85 years with low BMD were trained to self-administer abaloparatide-sMTS 300 μg once daily to the thigh for 5 min for 29 days. The primary endpoint was systemic exposure to abaloparatide. Secondary endpoints included percent change from baseline in serum procollagen type I N-terminal propeptide (s-PINP), patient experience, and safety. Results: All 22 subjects completed the study. At baseline, mean age was 65.2 years, mean total hip T-score was − 1.32, and mean lumbar spine T-score was − 1.98. On Day 1, the median time to reach maximum concentration (Tmax) for abaloparatide-sMTS was 0.33 h and geometric mean (CV %) maximum concentration (Cmax) and area under the concentration-time curve from time 0 to the time of the last quantifiable concentration (AUC0–t) were 447 (38.0) pg/mL and 678 (45.3) pg·h/mL, respectively; the pharmacokinetic profile was similar on Days 15 and 29. Median percentage change in s-PINP was 45.4% and 64.4% at Days 15 and 29, respectively. The most common adverse events (AEs) were application site erythema, pain, and swelling, which were mostly of mild or moderate severity. No AEs led to study drug withdrawal and no serious AEs were reported. The success rate for self-administration at first application was 99.7%, and subject acceptability was high (~ 4.5 on a 5-point Likert Scale). Conclusions: Subjects successfully self-administered abaloparatide-sMTS, which provided a consistent pharmacokinetic profile over 29 days and produced s-PINP increases from baseline similar to that observed in the pivotal trial with abaloparatide-SC. Observed patient experience along with the clinical data support continued clinical development of abaloparatide-sMTS. Trial Registration Number: NCT04366726, Date of registration 04/29/2020, retrospectively registered Plain Language Summary: Osteoporosis is a serious health condition that causes more than 2 million fractures in the USA annually. Treatment options for osteoporosis include drugs that prevent bone resorption and anabolic agents that build new bone. Bone anabolic agents, such as abaloparatide, have been shown to increase bone mineral density and reduce the risk of fracture in postmenopausal women with osteoporosis. Currently, all bone anabolic agents are delivered by subcutaneous injection. However, some patients do not like injectable treatments, which can negatively impact patients' adherence to prescribed medication. In this study, we describe a novel mode of administration, the abaloparatide-solid Microstructured Transdermal System (abaloparatide-sMTS), which is applied to the thigh for 5 min and delivers abaloparatide intradermally. The study showed that this new method delivered abaloparatide into the blood as effectively as subcutaneous injections and demonstrated signs of activity in the body. Study participants were satisfied with abaloparatide-sMTS and found it easy to use. The most common side effects were skin related, including redness, pain, and swelling, which resolved shortly after dosing. [ABSTRACT FROM AUTHOR]

Nuisance flooding (NF; also known as high-tide, or "sunny day" flooding) is an increasingly prevalent phenomenon afflicting coastal developments worldwide. NF often results when high tides, exacerbated by global sea level rise, coincide with onshore-directed surface winds. The elevated tidal condition, compounded by frictionally forced ocean currents, then inundates coastal infrastructure, posing a non-life-threatening inconvenience for local residents. Even though NF events are formed by a coupling of atmospheric and oceanic conditions, the large-scale atmospheric circulations favorable for NF have received little attention. Using a 40 year NF database derived from coastal gauge data, this study identifies the mid-tropospheric synoptic atmospheric patterns within days of NF events along the Atlantic and Gulf of Mexico coasts of the USA. ERA-Interim reanalysis supplies 500 hPa geopotential height patterns over North America that coincide with NF events. Subsequently, a principal components analysis is performed upon all NF-associated 500 hPa patterns, disaggregated by region (New England, Mid-Atlantic, and Gulf Coast), to identify dominant intra-variability NF-related circulations. Consistent with prior work, results show that NF frequency is increasing with time. Further, each region is characterized by a unique set of dominant NF synoptic patterns. Most patterns have clear physical associations to NF mechanisms, such as a nearby 500 hPa trough that would support a surface cyclone and strong onshore surface winds, or a mid-level high-pressure cell that would direct onshore-oriented return flow along its western periphery. However, some patterns correspond less obviously to oft-referenced NF mechanisms and may instead reflect low-frequency modes of variability and/or localized influences. [ABSTRACT FROM AUTHOR]

Synthetic biology is a powerful tool to create therapeutics which can be rationally designed to enable unique and combinatorial functionalities. Here we utilize non-pathogenic E coli Nissle as a versatile platform for the development of a living biotherapeutic for the treatment of cancer. The engineered bacterial strain, referred to as SYNB1891, targets STING-activation to phagocytic antigen-presenting cells (APCs) in the tumor and activates complementary innate immune pathways. SYNB1891 treatment results in efficacious antitumor immunity with the formation of immunological memory in murine tumor models and robust activation of human APCs. SYNB1891 is designed to meet manufacturability and regulatory requirements with built in biocontainment features which do not compromise its efficacy. This work provides a roadmap for the development of future therapeutics and demonstrates the transformative potential of synthetic biology for the treatment of human disease when drug development criteria are incorporated into the design process for a living medicine. Synthetic biology can be used to create rationally designed living therapeutics. Here the authors engineer E. coli Nissle to target STING activation in antigen presenting cells for the treatment of solid tumors and demonstrate preclinical activity in murine models. [ABSTRACT FROM AUTHOR]

Effects of non-cardiac drugs on cardiac contractility can lead to serious adverse events. Furthermore, programs aimed at treating heart failure have had limited success and this therapeutic area remains a major unmet medical need. The challenges in assessing drug effect on cardiac contractility point to the fundamental translational value of the current preclinical models. Therefore, we sought to develop an adult human primary cardiomyocyte contractility model that has the potential to provide a predictive preclinical approach for simultaneously predicting drug-induced inotropic effect (sarcomere shortening) and generating multi-parameter data to profile different mechanisms of action based on cluster analysis of a set of 12 contractility parameters. We report that 17 positive and 9 negative inotropes covering diverse mechanisms of action exerted concentration-dependent increases and decreases in sarcomere shortening, respectively. Interestingly, the multiparametric readout allowed for the differentiation of inotropes operating via distinct mechanisms. Hierarchical clustering of contractility transient parameters, coupled with principal component analysis, enabled the classification of subsets of both positive as well as negative inotropes, in a mechanism-related mode. Thus, human cardiomyocyte contractility model could accurately facilitate informed mechanistic-based decision making, risk management and discovery of molecules with the most desirable pharmacological profile for the correction of heart failure. [ABSTRACT FROM AUTHOR]

Psychological trauma is a silent epidemic which presents as a global public health issue, often in the form of post-traumatic stress disorder (PTSD). Eye Movement Desensitisation and Reprocessing (EMDR) Therapy is an empirically supported treatment intervention for PTSD and has been used as part of trauma-capacity building, particularly in low- and middle-income countries (LMIC). For some survivor's, their trauma experiences cannot be spoken of: they may be alluded to, suggested and though not directly expressed. There are several factors as to why these implicit trauma experiences are 'unspoken', for example, when the trauma involves a deep-rooted sense of shame or guilt, a distorted sense of over-responsibility or when to speak of the trauma engenders fear of retribution, reprisal and consequence. This paper will explore the effectiveness of using two protocol variations of EMDR Therapy—standard versus a 'Blind 2 Therapist' protocol version as part of a quasi-experimental study which took place in Northern Iraq. The study contains two projects and subsequently tested several hypotheses regarding safety, effectiveness, efficiency and relevance of the 'Blind 2 Therapist' protocol within EMDR Therapy. Results indicated support for the B2T protocol intervention with various trauma populations including Yezidi survivors of Islamic State of Iraq and the Levant (ISIL)—also known as Daesh. [ABSTRACT FROM AUTHOR]

The 2017 and 2018 Atlantic hurricane seasons poignantly illustrated the dangers tropical cyclones pose to US, Central American, and Caribbean coastlines. In particular, Hurricane Maria inflicted widespread damage, including catastrophic defoliation, to Puerto Rico, altering surface heat fluxes and possibly modifying precipitation patterns. This study assesses whether defoliation-driven changes to surface energy fluxes redistribute precipitation in the months following a powerful hurricane landfall. Remote sensing analyses of Maria-related vegetation reduction and recovery from Puerto Rico were adapted to the Georgia coastline. In this novel methodology, the resulting landscape evolution, characterized by an instantaneous vegetation reduction with a gradual recovery, was assimilated into the Weather Research and Forecasting model at a convection-allowing a 3-km grid spacing for the 1 June–1 August 2017 period. The experiment revealed that Maria-scale defoliation reduced precipitation by 14% during the month following landfall within a 50 × 50 km zone containing the hypothetical landfall location. A maximum deficit of 20.0% was reached 4 weeks after landfall. For June 2017, the modeled 14% deficit would have shifted the precipitation total from the 61st to the 47th percentile for years 1981–2016. Meanwhile, precipitation totals were unchanged on the domain scale. The near-landfall drying was also evident in three less-severe defoliation simulations, suggesting that systematic precipitation redistribution near the landfall location is possible following storms considerably weaker than Hurricane Maria. Analyses of the temperature and wind fields suggest that coastal kinematic flow is altered by the introduction of a thermally driven pressure gradient in the defoliated zone. [ABSTRACT FROM AUTHOR]

Purpose: Metastatic neuroendocrine tumors (mNETs) are rare, heterogeneous tumors that present diagnostic and treatment challenges, with limited data on the management of mNETs in clinical practice. The present study was designed to identify current diagnostic and treatment patterns in mNET patients treated in the US community oncology setting. Methods: Patient-level data was collected from medical records of adults with mNETs from the Vector Oncology Data Warehouse, a comprehensive US community oncology network database. Results: Of the 263 patients included (median follow-up, 22 months; range, 0.1–193.9), 30.4% (80/263) had intestinal tumors, 11.0% (29/263) had pancreatic, and 58.6% (154/263) had tumors of other or unknown location. Progression-free survival (PFS) from the start of first-line therapy differed significantly by tumor grade (log rank P = 0.0016) and location (P = 0.0044), as did overall survival (OS) (grade, P < 0.0001; location, P = 0.0068). Median PFS and OS for patients with undocumented tumor grade were shorter than for patients with G1/G2 tumors and longer than patients with G3 tumors. Median PFS and OS for patients with other or unknown tumors were shorter than for patients with intestinal tumors. Conclusions: While potentially confounded by the high number of patients with other or unknown tumor locations, this retrospective study of patients in a US community oncology setting identified the importance of awareness of tumor grade and tumor location at diagnosis, as these were direct correlates of PFS and OS. [ABSTRACT FROM AUTHOR]

This study investigates differences in the word processing skills of students with and without reading difficulties who read Turkish, an entirely transparent orthography. Thirty-five students diagnosed as poor readers and 51 typically developing controls were tested across two experiments, one that assessed their ability to process identicalness of isolated real words as opposed to pseudowords and another that assessed their ability to judge semantic relatedness of two real words. Participants were from two education levels; half of them were 3rd-4th graders and half were 6th–7th graders. An integrative view of the findings points to an apparent failure of Turkish poor readers to develop a lexicalized reading route that mediates word recognition by means of permanent orthographic knowledge. Moreover, their ability to effectively process word letter sequences along a non-lexical grapheme-to-phoneme conversion-based reading route was found to be seriously restricted. Findings are discussed with direct reference to orthographic transparency, dual-route reading theory and the orthographic self-teaching concept. [ABSTRACT FROM AUTHOR]

Objectives: The International Continence Society defines nocturia as the need to void one or more times during the night, with each of the voids preceded and followed by sleep. The chronic sleep disturbance and sleep deprivation experienced by patients with nocturia affects quality of life, compromising both mental and physical well-being. This paper aims to characterise the burden of nocturia by comparing published data from patients with nocturia with data from patients with any of 12 other common chronic conditions, specifically focusing on its impact on work productivity and activity impairment, as measured by the instrument of the same name (WPAI).Methods: A systematic literature review of multiple data sources identified evaluable studies for inclusion in the analysis. Study eligibility criteria included use of the WPAI instrument in patients with one of a predefined list of chronic conditions. We assessed the quality of each included study using the Newcastle-Ottawa scale and extracted basic study information, work and activity impairment data. To assess how work and activity impairment from nocturia compares with impairment from other common chronic diseases, we conducted two data syntheses (pooled and unpooled).Results: The number of evaluable studies and the range of overall work productivity impairment reported, respectively, were as follows: nocturia (3; 14-39 %), overactive bladder (5; 11-41 %), irritable bowel syndrome/constipation (14; 21-51 %), gastroesophageal reflux disease (GERD) (13; 6-42 %), asthma/allergies (11; 6-40 %), chronic obstructive pulmonary disease (COPD) (7; 19-42 %), sleep problems (3; 12-37 %), arthritis (13; 21-69 %), pain (9; 29-64 %), depression (4; 15-43 %) and gout (2; 20-37 %).Conclusions: The overall work productivity impairment as a result of nocturia is substantial and was found to be similar to impairment observed as a result of several other more frequently researched common chronic diseases. Greater awareness of the burden of nocturia, a highly bothersome and prevalent condition, will help policy makers and healthcare decision makers provide appropriate management of nocturia. [ABSTRACT FROM AUTHOR]

We demonstrate that a randomly connected attractor network with dynamic synapses can discriminate between similar sequences containing multiple stimuli suggesting such networks provide a general basis for neural computations in the brain. The network contains units representing assemblies of pools of neurons, with preferentially strong recurrent excitatory connections rendering each unit bi-stable. Weak interactions between units leads to a multiplicity of attractor states, within which information can persist beyond stimulus offset. When a new stimulus arrives, the prior state of the network impacts the encoding of the incoming information, with short-term synaptic depression ensuring an itinerancy between sets of active units. We assess the ability of such a network to encode the identity of sequences of stimuli, so as to provide a template for sequence recall, or decisions based on accumulation of evidence. Across a range of parameters, such networks produce the primacy (better final encoding of the earliest stimuli) and recency (better final encoding of the latest stimuli) observed in human recall data and can retain the information needed to make a binary choice based on total number of presentations of a specific stimulus. Similarities and differences in the final states of the network produced by different sequences lead to predictions of specific errors that could arise when an animal or human subject generalizes from training data, when the training data comprises a subset of the entire stimulus repertoire. We suggest that such networks can provide the general purpose computational engines needed for us to solve many cognitive tasks. [ABSTRACT FROM AUTHOR]

Spikes in the membrane potential of neurons comprise the currency of information processing in the brain. The ability of neurons to convert any information present across their multiple inputs into a significant modification to the pattern of their emitted spikes depends on the rate at which they emit spikes. If the mean rate is near the neuron's maximum, or if the rate is near zero, then changes in the inputs have minimal impact on the neuron's firing rate. Therefore, a neuron needs to control its mean rate. Protocols that either dramatically increase or decrease a neuron's firing rate lead to multiple compensatory changes that return the neuron's mean rate toward its prior value. In this primer, first as a summary of our previous work (Cannon and Miller in J Neurophysiol 116(5):2004-2022, 2016; Cannon and Miller in J Math Neurosci 7(1):1, 2017), we describe the advantages and disadvantages of having more than one such control mechanism responding to the neuron's firing rate. We suggest how problems of two, coexisting, potentially competing mechanisms can be overcome. Key requirements are: (1) the control be of a distribution of values, which the controlled variable achieves over a fast timescale compared to the timescale of the control system; (2) at least one of the control mechanisms be nonlinear; and (3) the two control systems are satisfied by a stable distribution or range of values that can be achieved by the variable. We show examples of functional control systems, including the previously studied integral feedback controller and new simulations of a "bang-bang" controller, that allow for compensation when inputs to the system change. Finally, we present new results describing how the underlying signal processing pathways would produce mechanisms of dual control, as opposed to a single mechanism with two outputs, and compare the responses of these systems to changes of input statistics. [ABSTRACT FROM AUTHOR]

Background: Heart failure (HF) is a well-recognized public health concern and imposes high economic and societal costs. Decision analytic models exist for evaluating the economic ramifications associated with HF. Despite this, studies that appraise these modelling approaches for augmenting best-practice decisions remain scarce.Objective: Our objective was to conduct a systematic literature review (SLR) of published economic models for the management of HF and describe their general and methodological features.Methods: This SLR employed a combination of relevant search terms associated with HF, which were used in a number of databases, including MEDLINE, Embase, the National Health Service Economic Evaluation Database, Cost-Effectiveness Analysis Registry, ScHARR Health Utilities Database and Cochrane Library Database. A number of model features (i.e. model structure, specification, outcomes assessed, scenario and sensitivity analysis, key model drivers) were extracted and subsequently summarized.Results: Of 64 publications retained, a selection of modelling approaches were identified, including Markov (n = 28), trial-based analytic (n = 22), discrete-event simulation (n = 6), survival analytic (n = 7) and decision-tree modelling (n = 1) approaches. The bulk of publications employed either a cost-utility (n = 27) or cost-effectiveness (n = 36) analysis and evaluated more than one study outcome, which typically included overall costs (n = 59), incremental cost-effectiveness ratios (n = 55), life-years gained (n = 48) and willingness-to-pay thresholds (n = 37). Most publications focused on patients with chronic HF (n = 40) and used New York Heart Association (NYHA) disease classifications to categorize patients and determine disease severity. Few (n = 19) publications documented the use of hospitalization states for modelling patient outcomes and associated costs. A quality assessment of the included publications revealed most articles demonstrated reasonable methodological value.Conclusions: We identified numerous decision analytic modelling approaches for evaluating the cost effectiveness of pharmacologic treatments in HF. A Markov cohort model approach was most commonly used, and most models relied on NYHA classes as a proxy of HF severity, disease progression and prognosis. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the effect of medical or surgical treatment prior to embryo transfer in women with elevated endometrial BCL6 expression and suspected endometriosis in a prospective, cohort study design at a university-associated infertility clinic. Methods: All subjects had at least 1 year of unexplained infertility (UI) and each prospectively underwent endometrial biopsy and immunostaining for the oncogene BCL6, prior to embryo transfer during an assisted reproductive technology (ART) cycle. To be included, subjects had to have an abnormal BCL6 result, defined by elevated HSCORE ≥ 1.4. Women that were pre-treated with laparoscopy or medical suppression with GnRH agonist (depot leuprolide acetate; Lupron®, Abbvie, Inc., Chicago, IL) for 2 months were compared to a group that went untreated (controls). Endpoints included implantation rate (IR), clinical pregnancy rate (CPR), and live birth rate (LBR), and as well as cycle characteristics. Miscarriage rate were also compared between treatment and control group. Results: Women in each group had similar characteristics. Those treated by medical suppression and those undergoing laparoscopy for endometriosis had a significantly higher LBR, (5/10; 50%; 95%CI 23.7 to 76.3%) and (11/21; 52.4%; 95%CI 32.4 to 71.7), respectively, compared to controls (4/54; 7.4%; 95%CI 2.9 to 17.6). An absolute benefit of 44.2% (16/31; 95%CI 24.6 to 61.2) and a number need to treat of 3 for those that received treatment (medical suppression and laparoscopy), compared to no treatment. Miscarriages were significantly more common in the control group. Conclusions: Women with suspected endometriosis and aberrant endometrial BCL6 expression have worse reproductive outcomes following embryo transfer, including a high miscarriage rate, poor IR, and low LBR and CPR compared to cycles pre-treated with medical and surgical management. [ABSTRACT FROM AUTHOR]

To investigate the potential of psychological capital as a resource for academic adjustment, 250 BA students were asked to complete two questionnaires, one assessing participants' psychological capacity, the other academic adjustment. Average grade-point scores were collected at two points in time as an additional measure of academic adjustment. Correlational as well as SEM analyses suggest that psychological capital is a positive resource with a central role in students' academic adjustment. The study extends knowledge on the impact of psychological capital on positive organizational behavior by generalizing it to higher education. [ABSTRACT FROM AUTHOR]

Synthetic probiotic for a human metabolic disease is taken through a drug development pathway to enable translation into clinic trials.Phenylketonuria (PKU) is a genetic disease that is characterized by an inability to metabolize phenylalanine (Phe), which can result in neurotoxicity. To provide a potential alternative to a protein-restricted diet, we engineered Escherichia coli Nissle to express genes encoding Phe-metabolizing enzymes in response to anoxic conditions in the mammalian gut. Administration of our synthetic strain, SYNB1618, to the Pahenu2/enu2 PKU mouse model reduced blood Phe concentration by 38% compared with the control, independent of dietary protein intake. In healthy Cynomolgus monkeys, we found that SYNB1618 inhibited increases in serum Phe after an oral Phe dietary challenge. In mice and primates, Phe was converted to trans-cinnamate by SYNB1618, quantitatively metabolized by the host to hippurate and excreted in the urine, acting as a predictive biomarker for strain activity. SYNB1618 was detectable in murine or primate feces after a single oral dose, permitting the evaluation of pharmacodynamic properties. Our results define a strategy for translation of live bacterial therapeutics to treat metabolic disorders. [ABSTRACT FROM AUTHOR]

Peatlands are important carbon reserves in terrestrial ecosystems. The microtopography of a peatland area has a strong influence on its carbon balance, determining carbon fluxes at a range of spatial scales. These patterned surfaces are very sensitive to changing climatic conditions. There are open research questions concerning the stability, behaviour and transformation of these microstructures, and the implications of these changes for the long-term accumulation of organic matter in peatlands. A simple two-dimensional peat microtopographical model was developed, which accounts for the effects of microtopographical variations and a dynamic water table on competitive interactions between peat-forming plants. In a case study of a subarctic mire in northern Sweden, we examined the consequences of such interactions on peat accumulation patterns and the transformation of microtopographical structure. The simulations demonstrate plausible interactions between peatland growth, water table position and microtopography, consistent with many observational studies, including an observed peat age profile from the study area. Our model also suggests that peatlands could exhibit alternative compositional and structural dynamics depending on the initial topographical and climatic conditions, and plant characteristics. Our model approach represents a step towards improved representation of peatland vegetation dynamics and net carbon balance in Earth system models, allowing their potentially important implications for regional and global carbon balances and biogeochemical and biophysical feedbacks to the atmosphere to be explored and quantified. [ABSTRACT FROM AUTHOR]

This paper uses the pooled data from 2005 to 2009 American Community Survey to analyze the economic benefits associated with bilingualism for adult men born in the United States. Bilingualism among the native born is defined as speaking a language at home other than or in addition to English. Native born bilingualism is rare; only 6.5% report a non-English language, and of those 71% report Spanish. Most of the native-born bilinguals report speaking English “very well” (85%), with most of the others speaking it “well” (10%). Other variables the same, overall bilinguals earn 4.7% less than monolingual English speakers, but the earnings differential varies sharply by the language spoken. Those who speak Native American languages, Pennsylvania Dutch and Yiddish have very low earnings due to a tendency to live in geographic or cultural enclaves. Spanish speakers earn 20% less than the monolingual English speakers overall, and other variables the same, have statistically significant 7% lower earnings. On the other hand, those who speak certain Western European and East Asian languages and Hebrew earn significantly more than monolingual English speakers. [ABSTRACT FROM AUTHOR]

Geographic heterogeneity has been observed in fracture risk and efficacy of therapeutic intervention in postmenopausal osteoporosis. The objectives of these analyses were to assess across geographic and ethnic subgroups the heterogeneity of fracture incidence and baseline risk, and consistency of effect of abaloparatide-SC vs placebo on fracture risk reduction in the 18-month, phase 3, multinational, ACTIVE randomized controlled trial. Prespecified exploratory analyses of geographic subgroups (North America, South America, Europe, Asia) and post hoc analyses of ethnic subgroups (Hispanic or Latino, other) of postmenopausal women with osteoporosis enrolled in the abaloparatide-SC and placebo cohorts (n = 1645) were performed. Country-specific FRAX models were used to calculate 10-year absolute fracture risks. Relative risk reductions for vertebral fractures and hazard ratios for non-vertebral, clinical, and major osteoporotic fractures were calculated. Forest plots were constructed to assess treatment-by-subgroup interactions for each geographic region and ethnicity. Baseline prevalence of vertebral fractures was similar across geographies; baseline prevalence of non-vertebral fractures was more variable. Ten-year major osteoporosis fracture and hip fracture risks were variable across and within regions. The effects of abaloparatide-SC on reducing the risk of vertebral, non-vertebral, clinical, and major osteoporotic fractures were similar across regions, and for Hispanic or Latino vs other ethnicities. A limitation was the limited power to detect interactions with few events. In conclusion, despite geographic variability in fracture incidence and risk at baseline, no differences were detected in the effects of abaloparatide-SC in reducing vertebral, non-vertebral, clinical, and major osteoporotic fracture risk across assessed geographic regions and ethnicities. [ABSTRACT FROM AUTHOR]

Introduction: Despite the availability of multiple effective therapies, discontinuation/switching of treatment is common for many patients with rheumatoid arthritis (RA). This study was designed to examine initiation of biologic disease-modifying anti-rheumatic drugs (bDMARDs) within the Consortium of Rheumatology Researchers of North America (Corrona) RA Registry, and characterize reasons for discontinuation. Methods: Inclusion criteria were: Corrona-registered adults (≥18 years) with RA (2002-2011); age of RA onset: ≥16 years; ≥6 months' follow-up after initiation of first/subsequent bDMARD. Patients receiving both tumor necrosis factor antagonists and non-TNF antagonists were included. Treatment discontinuation was defined as first report of stopping initial therapy or initiation of new bDMARD at/between visits, using a follow-up physician questionnaire. Results: Overall, 6209 patients met inclusion criteria and 80.7% received TNF antagonists. Median time to discontinuation/change of therapy was 25.1 months (26.5 months with TNF antagonists vs. 20.5 months with non-TNF antagonists; log-rank p < 0.0001); 82.2, 67.3, and 51.1% of patients remained on therapy at 6, 12, and 24 months, respectively. Reasons for discontinuation were captured for 49.2% of patients, including: loss of efficacy (35.8%); physician preference (27.8%); safety (20.1%); patient preference (17.9%); and no access to treatment (9.0%). Baseline factors with greatest correlation to discontinuation were modified Health Assessment Questionnaire scores, patient-reported anxiety/depression, initiation of bDMARD treatment in 2007-2010 versus 2002-2003, and Clinical Disease Activity Index scores. Conclusions: Almost one-third of patients in the US discontinue currently available bDMARD therapies for RA by 12 months and almost half by 24 months, most commonly due to loss of efficacy. Funding: Corrona LLC and MedImmune. [ABSTRACT FROM AUTHOR]

The EC-Earth earth system model has been recently developed to include the dynamics of vegetation. In its original formulation, vegetation variability is simply operated by the Leaf Area Index (LAI), which affects climate basically by changing the vegetation physiological resistance to evapotranspiration. This coupling has been found to have only a weak effect on the surface climate modeled by EC-Earth. In reality, the effective sub-grid vegetation fractional coverage will vary seasonally and at interannual time-scales in response to leaf-canopy growth, phenology and senescence. Therefore it affects biophysical parameters such as the albedo, surface roughness and soil field capacity. To adequately represent this effect in EC-Earth, we included an exponential dependence of the vegetation cover on the LAI. By comparing two sets of simulations performed with and without the new variable fractional-coverage parameterization, spanning from centennial (twentieth century) simulations and retrospective predictions to the decadal (5-years), seasonal and weather time-scales, we show for the first time a significant multi-scale enhancement of vegetation impacts in climate simulation and prediction over land. Particularly large effects at multiple time scales are shown over boreal winter middle-to-high latitudes over Canada, West US, Eastern Europe, Russia and eastern Siberia due to the implemented time-varying shadowing effect by tree-vegetation on snow surfaces. Over Northern Hemisphere boreal forest regions the improved representation of vegetation cover tends to correct the winter warm biases, improves the climate change sensitivity, the decadal potential predictability as well as the skill of forecasts at seasonal and weather time-scales. Significant improvements of the prediction of 2 m temperature and rainfall are also shown over transitional land surface hot spots. Both the potential predictability at decadal time-scale and seasonal-forecasts skill are enhanced over Sahel, North American Great Plains, Nordeste Brazil and South East Asia, mainly related to improved performance in the surface evapotranspiration. [ABSTRACT FROM AUTHOR]

Homeostatic processes that provide negative feedback to regulate neuronal firing rates are essential for normal brain function. Indeed, multiple parameters of individual neurons, including the scale of afferent synapse strengths and the densities of specific ion channels, have been observed to change on homeostatic time scales to oppose the effects of chronic changes in synaptic input. This raises the question of whether these processes are controlled by a single slow feedback variable or multiple slow variables. A single homeostatic process providing negative feedback to a neuron's firing rate naturally maintains a stable homeostatic equilibrium with a characteristic mean firing rate; but the conditions under which multiple slow feedbacks produce a stable homeostatic equilibrium have not yet been explored. Here we study a highly general model of homeostatic firing rate control in which two slow variables provide negative feedback to drive a firing rate toward two different target rates. Using dynamical systems techniques, we show that such a control system can be used to stably maintain a neuron's characteristic firing rate mean and variance in the face of perturbations, and we derive conditions under which this happens. We also derive expressions that clarify the relationship between the homeostatic firing rate targets and the resulting stable firing rate mean and variance. We provide specific examples of neuronal systems that can be effectively regulated by dual homeostasis. One of these examples is a recurrent excitatory network, which a dual feedback system can robustly tune to serve as an integrator. [ABSTRACT FROM AUTHOR]