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The glycosylated form of bovine pancreatic ribonuclease, RNase B, was crystallized from polyethylene glycol 4000 at low ionic strength in space group C2 with unit cell dimensions of a = 101.81 A, b = 33.36 A, c = 73.60 A, and beta = 90.4 degrees. The crystals, which contained two independent molecules of RNase B as the asymmetric unit, were solved by a combination of multiple isomorphous replacement and molecular replacement approaches. The structures of the two molecules were refined to 2.5-A resolution and a conventional R factor of 0.22 using a constrained-restrained least squares procedure (CORELS). Complexes were also investigated of RNase B plus ruthenium pentaamine and between RNase B and a substrate analogue iodouridine. The polypeptide backbones of the two molecules of RNase B in the asymmetric unit were found to be statistically identical and their differences from RNase A to be statistically insignificant. The carbohydrate chains of both molecules extended into solvent cavities in the crystal lattice and appear to be disordered for the most part. The oligosaccharides appear to exert no influence on the structure of the protein. Iodouridine was observed to bind identically in the pyrimidine site of both RNase B molecules and in a way apparently the same as that previously observed for RNase A. Ruthenium pentaamine bound at histidine 105 of both RNase B molecules in the asymmetric unit, but at a number of secondary sites as well. An array of bound ions was observed by Fo-Fc difference Fourier syntheses. These ions were proximal to lysine and arginine residues at the surface of the proteins while a pair of strong ion binding sites were seen to fall exactly in the active site clefts of both RNase B molecules in the asymmetric unit.

Objective: Guidelines on apology and disclosure after adverse events and errors have been in place for over 5 years. This study examines whether patients consider recommended responses to be appropriate and desirable, and whether clinicians' actions after adverse events are consistent with recommendations.Methods: Patients who believed that something had gone wrong during their cancer care were identified. During in-depth interviews, patients described the event, clinicians' responses, and their reactions.Results: 78 patients were interviewed. Patients' valued apology and expressions of remorse, empathy and caring, explanation, acknowledgement of responsibility, and efforts to prevent recurrences, but these key elements were often missing. For many patients, actions and evidence of clinician learning were most important.Conclusion: Patients' reports of apology and disclosure when they believe something has gone wrong in their care suggest that clinicians' responses continue to fall short of expectations.Practice Implications: Clinicians preparing to talk with patients after an adverse event or medical error should be aware that patients expect their actions to be congruent with their words of apology and caring. Healthcare systems need to support clinicians throughout the disclosure process, and facilitate both system and individual learning to prevent recurrences. [ABSTRACT FROM AUTHOR]

Enzymatic cleavage of amyloid-β protein precursor (AβPP) produces amyloid-β (Aβ) peptides which form the insoluble cortical plaques characteristic of Alzheimer's disease (AD). AβPP is post-transcriptionally processed into three major isoforms with differential cellular and tissue expression patterns. Changes in AβPP isoform expression may be indicative of disease pathogenesis in AD, but accurately measuring AβPP gene isoforms has been difficult to standardize, reproduce, and interpret. In light of this, we developed a set of isoform specific absolute quantification real time PCR standards that allow for quantification of transcript copy numbers for total AβPP and all three major isoforms (AβPP695, AβPP751, and AβPP770) in addition to glyceraldehyde-3-dehydrogenase (GAPDH) and examined expression patterns in superior frontal gyrus (SFG) and cerebellar samples from patients with (n = 12) and without AD (n = 10). Both total AβPP and AβPP695 transcripts were significantly decreased in SFG of patients with AD compared to control (p = 0.037 and p = 0.034, respectively). AβPP751 and AβPP770 transcripts numbers were not significantly different between AD and control (p > 0.15). There was trend for decreased percentage AβPP695 (p = 0.051) and increased percentage AβPP770 (p = 0.013) expression in SFG of patients with AD. GAPDH transcripts levels were also decreased significantly in the SFG of patients with AD compared to control (p = 0.005). Decreasing total AβPP and AβPP695 copy number was associated with increased plaque burden and decreased cognitive function. In this study we describe a simple procedure for measuring AβPP isoform transcripts by real-time PCR and confirm previous studies showing altered AβPP isoform expression patterns in AD. [ABSTRACT FROM AUTHOR]

Health messages on television and other mass media have the potential to significantly influence the public's health-related knowledge and behaviors, but little is known about people's ability to comprehend such messages. To investigate whether people understood the spoken information in media messages about cancer prevention and screening, we recruited 44 adults from 3 sites to view 6 messages aired on television and the internet. Participants were asked to paraphrase main points and selected phrases. Qualitative analysis methods were used to identify what content was correctly and accurately recalled and paraphrased, and to describe misunderstandings and misconceptions. While most participants accurately recalled and paraphrased the gist of the messages used here, overgeneralization (e.g., believing preventative behaviors to be more protective than stated), loss of details (e.g., misremembering the recommended age for screening), and confusion or misunderstandings around specific concepts (e.g., interpreting "early stage" as the stage in one's life rather than cancer stage) were common. Variability in the public's ability to understand spoken media messages may limit the effectiveness of both pubic health campaigns and provider-patient communication. Additional research is needed to identify message characteristics that enhance understandability and improve comprehension of spoken media messages about cancer. [ABSTRACT FROM AUTHOR]

Because of recent studies showing strong prevention benefit and acceptable psychosocial outcomes, more women may be considering prophylactic mastectomy. A growing literature shows some positive psychosocial outcomes for women with bilateral prophylactic mastectomy, but less is known about women with contralateral prophylactic mastectomy. Several surveys have shown that a large majority of women with prophylactic mastectomy report satisfaction with their decisions to have the procedure when asked in a quantitative, closed-ended format. We sought to explore the nuances of women's satisfaction with the procedure using a qualitative, open-ended format. We included open-ended questions as part of a mailed survey on psychosocial outcomes of prophylactic mastectomy. The research team coded and analyzed these responses using qualitative methods. We used simple descriptive statistics to compare the demographics of the entire survey sample to those women who answered the open-ended questions; the responses to the open- and closed-ended satisfaction questions, and the responses of women with bilateral and contralateral prophylactic mastectomy. Seventy-one percent of women with prophylactic mastectomy responded to the survey and 48% provided open-ended responses about psychosocial outcomes. Women's open-ended responses regarding psychosocial outcomes could be coded into one of three general categories--positive, negative, and disparate. In the subgroup of women with both open- and closed-ended responses, over 70% of women providing negative and disparate comments to the open-ended question simultaneously indicated satisfaction on a closed-ended question. Negative and disparate open-ended responses were twice as common among women with bilateral prophylactic mastectomy (52%) than women with contralateral prophylactic mastectomy (26%). These findings suggest that even among women who report general satisfaction with their decision to have prophylactic mastectomy via closed-ended survey questions, lingering negative psychosocial outcomes can remain, particularly among women with bilateral prophylactic mastectomy. This dichotomy could be an important factor to discuss in counseling women considering the procedure. [ABSTRACT FROM AUTHOR]

Rationale: There is a need for a brief, validated patient self-report instrument to assess the extent to which patients with chronic illness receive care that aligns with the Chronic Care Model-measuring care that is patient-centered, proactive, planned and includes collaborative goal setting; problem-solving and follow-up support.Sample: A total of 283 adults reporting one or more chronic illness from a large integrated health care delivery system were studied.Methods: Participants completed the 20-item Patient Assessment of Chronic Illness Care (PACIC) as well as measures of demographic factors, a patient activation scale, and subscales from a primary care assessment instrument so that we could evaluate measurement performance, construct, and concurrent validity of the PACIC.Results: The PACIC consists of 5 scales and an overall summary score, each having good internal consistency for brief scales. As predicted, the PACIC was only slightly correlated with age and gender, and unrelated to education. Contrary to prediction, it was only slightly correlated (r = 0.13) with number of chronic conditions. The PACIC demonstrated moderate test-retest reliability (r = 0.58 during the course of 3 months) and was correlated moderately, as predicted (r = 0.32-0.60, median = 0.50, P < 0.001) to measures of primary care and patient activation.Discussion: The PACIC appears to be a practical instrument that is reliable and has face, construct, and concurrent validity. The resulting questionnaire is in the public domain, and recommendations for its use in research and quality improvement are outlined. [ABSTRACT FROM AUTHOR]

3D-framework Prussian blue analogues (PBAs) are appealing as a cost-effective, sustainable cathodes for Na-ion batteries. However, the aqueous-based synthesis of PBAs inherently introduces three different forms of water molecules (surface, interstitial and crystal) into the structure. Removal of water molecules causes phase transformation from monoclinic (M) to rhombohedral (R). This work presents the effects of water molecules on the structure before the phase transformation temperature, employing two promising PBA cathodes, Na 2 Fe[Fe(CN) 6 ]·1.69H 2 O and Na 2 Mn[Fe(CN) 6 ]·1.76H 2 O. Specifically, the water molecules impact the molecular interactions at the local structure and the electrochemical properties. This work has performed calculations on low-vacancy Na 2 M[Fe(CN) 6 ] PBAs (where M = Mn, Fe, Co, Ni and Cu) to understand the dehydration energy. Employing in situ high-temperature X-ray diffraction and Raman spectroscopy, this work observes that water removal induces negative thermal expansion and stronger interactions between C≡N and Na ions, resulting in biphasic reactions with sluggish kinetics. Additionally, water molecules play a role in maintaining the open 3D tunnels and facilitating a solid-solution like insertion of Na ions. Calculated phonon-Raman spectra provide insights into cyanide group deformations, revealing the interactions between water molecules, alkali-ions, and transition-metal ions. This study enhances the understanding of the relationship among electronic, vibrational, and electrochemical properties., (© 2024 Wiley‐VCH GmbH.)

Play behavior has been extensively studied across species, but its direct role in social relationships remains unclear. Here we use an "isolation versus separation" protocol to identify behaviors associated with relationship renewal in adolescent female rats. Members of a dyad that had been separated for 24 hr, without isolation from other peers, initially increased investigative behaviors relative to nonseparated peers; however, in contrast with social isolation, separation by itself did not increase rough-and-tumble play. The data suggest that increased play following isolation depends on general motivations, rather than a "peer-specific" drive to renew relationships with an individual. This is consistent with a role of play in more general social learning rather than reestablishing bonds or expectations. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

A rechargeable battery that employs a Li metal anode requires that Li be plated in a uniform fashion during charging. In "anode-free" configurations, this plating will occur on the surface of the Cu current collector (CC) during the initial cycle and in any subsequent cycle where the capacity of the cell is fully accessed. Experimental measurements have shown that the plating of Li on Cu can be inhomogeneous, which can lower the efficiency of plating and foster the formation of Li dendrites. The present study employs a combination of first-principles calculations and sessile drop experiments to characterize the thermodynamics and adhesive ( i.e. , wetting) properties of interfaces involving Li and other phases present on or near the CC. Interfaces between Li and Cu, Cu 2 O, and Li 2 O are considered. The calculations predict that both Cu and Cu 2 O surfaces are lithiophilic. However, sessile drop measurements reveal that Li wetting occurs readily only on pristine Cu. This apparent discrepancy is explained by the occurrence of a spontaneous conversion reaction, 2 Li + Cu 2 O → Li 2 O + 2 Cu, that generates Li 2 O as one of its products. Calculations and sessile drop measurements show that Li does not wet (newly formed) Li 2 O. Hence, Li that is deposited on a Cu CC where surface oxide species are present will encounter a compositionally heterogeneous substrate comprising lithiophillic (Cu) and lithiophobic (Li 2 O) regions. These initial heterogeneities have the potential to influence the longer-term behavior of the anode under cycling. In sum, the present study provides insights into the early stage processes associated with Li plating in anode-free batteries and describes mechanisms that contribute to inefficiencies in their operation.

Understanding how natural aging impacts rodent performance in translational behavior tests is critical to teasing apart impairments due to age-related decline from neurodegenerative disorder modeling. Reduced neuropilin and tolloid-like 1 (NETO1), an accessory protein of ionotropic glutamate receptors involved in synaptic plasticity, was associated with Alzheimer's disease, yet aging effects on Neto1 remain unclear. For these reasons, our goal was to characterize how Neto1 expression corresponded with social, repetitive, and spatial learning behaviors and stress response across the C57BL/6J mouse lifespan. We measured social preferences in three-chamber tests, and motor stereotypies by marble burying. Cognitive flexibility is typically assessed in the Morris water maze (MWM), wherein C57BL/6J mice exhibit deficits with age. However, fatigue or locomotor impairment may confound interpretation of MWM performance. Therefore, we used a less arduous water T-maze (WTM) to compare spatial learning flexibility in 2, 9-15, and 24-month-old male and female mice to test the hypothesis that deficits would emerge with age. In both sexes, 9-15-month-olds made more chamber entries during social preference tests, while 2-month-olds did less social sniffing than aged mice. No age or sex differences emerged in marble burying or serum corticosterone measurements. In 24-month-olds hippocampal Neto1was increased relative to 2-month-olds, and male cognitive flexibility was strong, while spatial learning and reversal learning of 24-month-old females was impaired in WTM irrespective of Neto1 expression. The WTM is a useful alternative assessment for cognitive flexibility deficits in aged mice, and the role of hippocampal Neto1 in promoting social sniffing is of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

The vision of the learning health system (LHS), conceptualized 15 years ago, is for the rapid generation, use, and spread of high-quality evidence that yields better health experiences, outcomes, efficiencies, and equity in everyday practice settings across communities. However, despite the emergence of many useful LHS frameworks and examples to guide adoption, large gaps remain in the speed and consistency with which evidence is generated and used across the range of settings from the bedside to the policy table. Gaps in progress are not surprising, however, given the tensions that predictably arise when key stakeholders-researchers, health systems, and funders-comingle in these efforts. This commentary examines eight core tensions that naturally arise and offers practical actions that stakeholders can take to address these tensions and speed LHS adoption. The urgency for attenuating these tensions and accelerating health system improvements has never been higher. Timeliness, rigor, and prioritization can be aligned across stakeholders, but only if all partners are intentional about the operational and cultural challenges that exist., (© 2023 The Authors. Learning Health Systems published by Wiley Periodicals LLC on behalf of University of Michigan.)

We present a stable and systematically improvable quantum Monte Carlo (QMC) approach to calculating excited-state energies, which we implement using our fast randomized iteration method for the full configuration interaction problem (FCI-FRI). Unlike previous excited-state quantum Monte Carlo methods, our approach, which is based on an asymmetric variant of subspace iteration, avoids the use of dot products of random vectors and instead relies upon trial vectors to maintain orthogonality and estimate eigenvalues. By leveraging recent advances, we apply our method to calculate ground- and excited-state energies of challenging molecular systems in large active spaces, including the carbon dimer with 8 electrons in 108 orbitals (8e,108o), an oxo-Mn(salen) transition metal complex (28e,28o), ozone (18e,87o), and butadiene (22e,82o). In the majority of these test cases, our approach yields total excited-state energies that agree with those from state-of-the-art methods─including heat-bath CI, the density matrix renormalization group approach, and FCIQMC─to within sub-milliHartree accuracy. In all cases, estimated excitation energies agree to within about 0.1 eV.

Introduction: Over the past decade, numerous efforts have encouraged the realization of the learning health system (LHS) in the United States. Despite these efforts, and promising aims of the LHS, the full potential and value of research conducted within LHSs have yet to be realized. New technology coupled with a catalyzing global pandemic have spurred momentum. In addition, the LHS has lacked a consistent framework within which "best evidence" can be identified. Positive deviance analysis, itself reinvigorated by recent advances in health information technology (IT) and ubiquitous adoption of electronic health records (EHRs), may finally provide a framework through which LHSs can be operationalized and optimized., Methods: We describe the synergy between positive deviance and the LHS and how they may be integrated to achieve a continuous cycle of health system improvement., Results: As we describe below, the positive deviance approach focuses on learning from high-performing teams and organizations., Conclusion: Such learning can be enabled by EHRs and health IT, providing a lens into how digital clinical interventions are successfully developed and deployed., Competing Interests: This work was not supported by grant funding. The authors report the following disclosures. Kristen Azar has received funding from the National Institute of Health (NIH), Janssen Scientific Affairs, and the Patient‐Centered Outcomes Research Institute (PCORI) Mark J. Pletcher has received research grants from the PCORI. Alice R. Pressman has received funding from the NIH. All the other authors declare that they have no conflicts of interest., (© 2022 The Authors. Learning Health Systems published by Wiley Periodicals LLC on behalf of University of Michigan.)

Applying theories of emotion to understanding the regulation of aversive parenting, we used microanalytic observational methods to test whether transient changes in a mother's negative emotional reactivity predict changes over time in key parameters of her moment-to-moment aversive behavior: its intensity, variability, persistence, and connection to difficult child inputs. At multiple times over 2 years, 319 divorcing mothers and their 5- to 12-year-old children were observed as they discussed mutual disagreements. Sequences of talk-turns were recorded and coded for affect and content. Relative to days when a mother was low in negative emotional reactivity, on days when she was high she displayed more intensely aversive behavior, more variable aversiveness, more transitions from average to high or low aversiveness, tendencies to remain aversive longer following spikes in her aversiveness, and difficulty maintaining low aversiveness following drops in her aversiveness. As her negative emotional reactivity increased, she went from being relatively unaffected by children's difficult behavior to being aversively reactive; from ceasing aversive sequences increasingly quickly to ceasing aversive sequences increasingly slowly; from deviating more from her nonreactive low-aversive parenting to deviating less from her reactive high-aversive parenting. Independent of stable individual differences in mothers and children, transient variations in mothers' emotional reactivity may correspond to key moment-to-moment parameters of aversive parenting, even when interactions are relatively noncontentious. The data provide a viable account of how initially transient, context-specific reactivity could initiate moment-to-moment changes in aversive patterns that in some families influence problematic family trajectories over time. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

While an extensive literature has demonstrated that the selective serotonin reuptake inhibitor (SSRI) antidepressant fluoxetine, disrupts aggressive behavior in male Betta splendens the behavioral mechanisms underlying this disruption remain unknown. To elucidate the behavioral mechanism underlying fluoxetine, male fish were acutely exposed to a 10 μmol (0.0034578 μg/L) concentration of fluoxetine for 25 days using an ABA design. Male Betta splendens are naturally aggressive fish with well-studied and patterned behavioral responses. Importantly, aggressive behavior in this species can be conditionally primed allowing for examination of motivational components of behavior in addition to motor performance. The present study focused on using female fish as an ecologically relevant prime for eliciting aggressive behavior as a means of examining the motivational and motoric effects of fluoxetine. We found that male courtship with a female was strongly correlated with aggressive responding against a mirror. However, despite the strong correlation male fish were not found to have different levels of aggression or changes in aggressive responding when compared to males not primed with a female. Also, latency was not different between the no female prime and female prime males for either the excitatory mirror condition or inhibitory white wall condition, of which the fish had no preference. However, fluoxetine was found to have profound effects on all males in the study regardless of prime type, with increases in latency for the mirror and white wall and decreases in aggressive responding to the mirror. These results support the hypothesis that fluoxetine impairs aggressive motivation and movement in Betta splendens., (Published by Elsevier B.V.)

The inherent atomistic precision of synthetic chemistry enables bottom-up structural control over quantum bits, or qubits, for quantum technologies. Tuning paramagnetic molecular qubits that feature optical-spin initialization and readout is a crucial step toward designing bespoke qubits for applications in quantum sensing, networking, and computing. Here, we demonstrate that the electronic structure that enables optical-spin initialization and readout for S = 1, Cr(aryl) 4 , where aryl = 2,4-dimethylphenyl ( 1 ), o -tolyl ( 2 ), and 2,3-dimethylphenyl ( 3 ), is readily translated into Cr(alkyl) 4 compounds, where alkyl = 2,2,2-triphenylethyl ( 4 ), (trimethylsilyl)methyl ( 5 ), and cyclohexyl ( 6 ). The small ground state zero field splitting values (<5 GHz) for 1 - 6 allowed for coherent spin manipulation at X-band microwave frequency, enabling temperature-, concentration-, and orientation-dependent investigations of the spin dynamics. Electronic absorption and emission spectroscopy confirmed the desired electronic structures for 4 - 6 , which exhibit photoluminescence from 897 to 923 nm, while theoretical calculations elucidated the varied bonding interactions of the aryl and alkyl Cr 4+ compounds. The combined experimental and theoretical comparison of Cr(aryl) 4 and Cr(alkyl) 4 systems illustrates the impact of the ligand field on both the ground state spin structure and excited state manifold, laying the groundwork for the design of structurally precise optically addressable molecular qubits.

Although divorce is typically stressful for mothers, the formation of post-divorce dating relationships can help to ease this stress. Unfortunately, research has yet to empirically consider children's post-divorce adjustment for mothers' wellbeing leading up to and during mothers' post-divorce dating. This study addresses the following questions: 1) How do children's problem behaviors predict mothers' depressive symptoms following divorce? 2) How do children's problem behaviors predict the quality of mothers' dating relationships and the rapport between children and mothers' dating partners? 3) How do children's problem behaviors, the quality of mothers' dating relationships, child-dating partner rapport, and length of mothers' dating simultaneously impact mothers' depressive symptoms? Data for this study comes from a longitudinal investigation of recently divorced mothers and their children ( N = 232). Hierarchical linear models revealed that mothers experienced more depressive symptoms when their children exhibited more internalizing behaviors. Children's internalizing behaviors were negatively associated with the quality of mothers' dating relationships. When examining these variables simultaneously, increases in children's internalizing behaviors and decreases in relationship quality predicted increases in mothers' depressive symptoms. Promoting family-level adjustment appears best for mothers' wellbeing following divorce. Other implications for post-divorce adjustment are discussed., Competing Interests: Compliance with Ethical Standards The authors decline that they have no conflict of interest.

Background: Traditional research approaches do not promote timely implementation of evidence-based innovations (EBIs) to benefit patients. Embedding research within health systems can accelerate EBI implementation by blending rigorous methods with practical considerations in real-world settings. A state-of-the-art (SOTA) conference was convened in February 2019 with five workgroups that addressed five facets of embedded research and its potential to impact healthcare. This article reports on results from the workgroup focused on how embedded research programs can be implemented into heath systems for greatest impact., Methods: Based on a pre-conference survey, participants indicating interest in accelerating implementation were invited to participate in the SOTA workgroup. Workgroup participants (N = 26) developed recommendations using consensus-building methods. Ideas were grouped by thematic clusters and voted on to identify top recommendations. A summary was presented to the full SOTA membership. Following the conference, the workgroup facilitators (LJD, CDH, NR) summarized workgroup findings, member-checked with workgroup members, and were used to develop recommendations., Results: The workgroup developed 12 recommendations to optimize impact of embedded researchers within health systems. The group highlighted the tension between "ROI vs. R01" goals-where health systems focus on achieving return on their investments (ROI) while embedded researchers focus on obtaining research funding (R01). Recommendations are targeted to three key stakeholder groups: researchers, funders, and health systems. Consensus for an ideal foundation to support optimal embedded research is one that (1) maximizes learning; (2) aligns goals across all 3 stakeholders; and (3) implements EBIs in a consistent and timely fashion., Conclusions: Four cases illustrate a variety of ways that embedded research can be structured and conducted within systems, by demonstrating key embedded research values to enable collaborations with academic affiliates to generate actionable knowledge and meaningfully accelerate implementation of EBIs to benefit patients., Implications: Embedded research approaches have potential for transforming health systems and impacting patient health. Accelerating embedded research should be a focused priority for funding agencies to maximize a collective return on investment., (Published by Elsevier Inc.)

Behaving like atomically precise two-dimensional quantum wells with non-negligible dielectric contrast, the layered hybrid organic-inorganic lead halide perovskites (HOIPs) have strong electronic interactions leading to tightly bound excitons with binding energies on the order of 500 meV. These strong interactions suggest the possibility of larger excitonic complexes like trions and biexcitons, which are hard to study numerically due to the complexity of the layered HOIPs. Here, we propose and parametrize a model Hamiltonian for excitonic complexes in layered HOIPs and we study the correlated eigenfunctions of trions and biexcitons using a combination of diffusion Monte Carlo and very large variational calculations with explicitly correlated Gaussian basis functions. Binding energies and spatial structures of these complexes are presented as a function of the layer thickness. The trion and biexciton of the thinnest layered HOIP have binding energies of 35 and 44 meV, respectively, whereas a single exfoliated layer is predicted to have trions and biexcitons with equal binding energies of 48 meV. We compare our findings to available experimental data and to that of other quasi-two-dimensional materials.

Gestational diabetes mellitus (GDM) was associated with greater autism risk in epidemiological studies. Disrupted leptin signaling may contribute to their coincidence, as it is found in both disorders. Given this we examined leptin receptor (Lepr) deficient (BKS.Cg-Dock7 m +/+ Lepr db /J diabetic (db)) heterozygous (db/+) mice for autism-relevant behaviors. BKS db/+ females are lean with normal blood glucose, but they develop GDM while pregnant. We hypothesized BKS db/+ offspring might exhibit physiological and behavior traits consistent with autism. Adolescent body weight, fasting blood glucose, serum corticosterone, social preferences, self-grooming, marble burying, social dominance and cognitive flexibility of BKS db/+ mice was compared to C57BLKS/J (BKS) and C57BL/6J (BL6) mice. Male db/+ weighed more and had higher blood glucose and corticosterone relative to BL6, but not BKS mice. Also, male db/+ lacked social interaction preference, explored arenas less, and buried more marbles than BL6, but not BKS males. Male and female db/+ were more dominant and made more mistakes in water T-mazes locating a sunken platform after its position was reversed than BL6, but not BKS mice. Overall BKS db/+, particularly males, exhibited some autism-like social deficits and restrictive-repetitive behaviors relative to BL6, but BKS strain contributions to BKS db/+ behaviors were evident. Since BKS db/+ and BKS behavioral and physiological phenotypes are already so similar, it will be difficult to use these models in studies designed to detect contributions of fetal GDM exposures to offspring behaviors., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Opportunities to advance science increasingly arise through investigations embedded within routine clinical practice in the form of learning health systems. Such activities challenge conventional approaches to research regulation that have not caught up with those opportunities, often imposing burdens generalized from riskier research. We analyze the rules and conventions in the US, demonstrating how even those rules are compatible with a much more flexible approach to participant risk, institutional oversight, participant consent, and disclosure for low-risk learning activities in all jurisdictions., (Published by Elsevier Inc.)

Introduction: Despite the proliferation of pragmatic clinical trials (PCTs) conducted in health care delivery settings, we know relatively little about how practicing clinicians perceive their potential roles in such research. Empirical evidence and practical guidance concerning clinician engagement in research is needed to inform the design and successful implementation of PCTs., Methods: We conducted a two-phase qualitative study to better understand how and to what extent practicing clinicians should be involved in PCTs and to develop guidance for researchers on engaging front-line clinicians in PCTs. In phase one, clinicians who spend the majority of their time providing direct patient care participated in 90-min focus groups. In phase two, we conducted key informant interviews with PCT research teams and clinicians participating in the ADAPTABLE (Aspirin Dosing: A Patient-centric Trial Assessing Benefits and Long-Term Effectiveness) trial., Results: Thirty-four physicians, nurses, and other care providers from four health care delivery organizations participated in focus groups. Focus group participants stressed the importance of engaging clinicians early in the PCT planning process to identify clinically relevant study questions, provide input on study design, and customize study protocols to fit unique clinic workflows. We conducted 18 interviews with principal investigators, project managers, and clinicians involved in the ADAPTABLE trial across six clinical data research networks. Study team members described trying multiple approaches to optimize in-clinic recruitment and enrollment of eligible patients. Successful strategies involved several key factors related to research team interactions with eligible patients, clinicians, and clinic staff., Conclusions: More active involvement by a range of clinical stakeholders in PCT planning may help researchers avoid common barriers to trial implementation. We propose a "medium-touch" approach to involving clinicians in PCT recruitment and enrollment that focuses clinician effort where it is most critical-to reassure eligible patients that trial participation is a safe alternative for them., Competing Interests: The authors have no conflicts of interest to declare., (© 2020 The Authors. Learning Health Systems published by Wiley Periodicals LLC on behalf of University of Michigan.)

We present three modifications to our recently introduced fast randomized iteration method for full configuration interaction (FCI-FRI) and investigate their effects on the method's performance for Ne, H 2 O, and N 2 . The initiator approximation, originally developed for full configuration interaction quantum Monte Carlo, significantly reduces statistical error in FCI-FRI when few samples are used in compression operations, enabling its application to larger chemical systems. The semistochastic extension, which involves exactly preserving a fixed subset of elements in each compression, improves statistical efficiency in some cases but reduces it in others. We also developed a new approach to sampling excitations that yields consistent improvements in statistical efficiency and reductions in computational cost. We discuss possible strategies based on our findings for improving the performance of stochastic quantum chemistry methods more generally.

We introduce a family of methods for the full configuration interaction problem in quantum chemistry, based on the fast randomized iteration (FRI) framework [Lim, L.-H.; Weare, J. SIAM Rev. 2017 , 59 , 547; DOI: 10.1137/15M1040827 ]. These methods, which we term "FCI-FRI", stochastically impose sparsity during iterations of the power method and can be viewed as a generalization of full configuration interaction quantum Monte Carlo (FCIQMC) without walkers. In addition to the multinomial scheme commonly used to sample excitations in FCIQMC, we present a systematic scheme where excitations are not sampled independently. Performing ground-state calculations on five small molecules at fixed cost, we find that the systematic FCI-FRI scheme is 11-45 times more statistically efficient than the multinomial FCI-FRI scheme, which is in turn 1.4-178 times more statistically efficient than the original FCIQMC algorithm.

The 25th annual conference of the Health Care Systems Research Network (HCSRN) was held April 10-12 in Portland, Oregon, attracting 420 attendees. The HCSRN, a consortium of 18 community-based research organizations embedded in or affiliated with large health care delivery systems, has hosted annual research conferences since 1994. The primary objective of the conference is to convene researchers, project staff, funders, and other stakeholders to share latest scientific findings and cultivate new partnerships among research teams, patients, and clinicians. Collaboration is the cornerstone of the HCSRN's success; the conference serves as a catalyst for a variety of collaborative ventures as well as tactics and approaches to more effective and efficient research. This year's program included 70 distinct scientific presentations, plus nearly 100 posters, and spanned diverse content offerings that mirrored the diversity of the HCSRN and its collaborators. Plenary sessions imparted insights on ways that data science and approaches to collaborative design in health care can speed the translation of research into practice., Competing Interests: Conflicts of Interest None.

In 2016, the U.S. National Institutes of Health (NIH) announced a new policy requiring single institutional review board (sIRB) review for multisite studies. However, adherence to the new policy requires the separation of regulatory institutional review board (IRB) work per Federal guidance from site-specific local compliance concerns. In particular, genomic research is subject to a wide range of state laws, institutional requirements, and local population preferences. In this qualitative study, we explored the anticipated needs of genomics researchers and IRB administrators around implementing the policy. We observed multiple uncertainties, particularly about intersite communication processes, sIRB selection processes, and roles of the reviewing IRB and local sites regarding local context information relevant to genomics. Optimal implementation of the NIH policy may require additional guidance for researchers and IRB administrators.

Even though it is well known that quality, safety, and patient-centeredness of health care can be improved, leveraging the organizational apparatus of a care delivery environment to render improvement in a consistent and comprehensive manner has proven difficult. The Health Care Systems Research Network (HCSRN), which began as the HMO Research Network, emerged from a desire to improve health and study problems in health care in a systematic and collaborative way, spurring the delivery of true evidence-informed medicine. The HCSRN has honed network-wide data resources, a collaborative culture, and shared infrastructure, enabling multicenter health care research that is often more difficult for researchers working in less integrated settings and across organizational boundaries. The HCSRN's 25-year track record confers both an opportunity and obligation to share what we have learned through our research. Considering the quarter-century since the HCSRN was established, we describe three evolving areas-health data, new health care models, and diversified research teams that must be thoughtfully harnessed to realize a transformed health care ecosystem that generates and learns with research., Competing Interests: Sarah Greene, MPH, is the Executive Director of the Health Care Systems Research Network. Paul Wallace, MD, serves as the Executive Editor of eGEMs and is a senior scholar at AcademyHealth. Andrew F. Nelson is a senior advisor for research at HealthPartners.

Introduction: A randomized trial demonstrated benefit from thymectomy in nonthymomatous acetylcholine receptor (AChR)-antibody positive myasthenia gravis (MG). Uncontrolled observational and histologic studies suggest thymectomy may not be efficacious in anti-muscle-specific kinase (MuSK)-MG., Methods: The therapeutic impact of thymectomy was evaluated from data collected for a multicenter, retrospective blinded review of rituximab in MuSK-MG., Results: Baseline characteristics were similar between thymectomy (n = 26) and nonthymectomy (n = 29) groups, including treatment with rituximab (42% vs. 45%). At last visit, 35% of thymectomy subjects reached the primary endpoint, a Myasthenia Gravis Foundation of America (MGFA) post-intervention status (PIS) score of minimal manifestations (MM) or better, compared with 55% of controls (P = 0.17). After controlling for age at onset of MG, rituximab, prednisone, and intravenous immunoglobulin/plasma exchange treatment, thymectomy was not associated with greater likelihood of favorable clinical outcome (odds ratio = 0.43, 95% confidence interval 0.12-1.53, P = 0.19)., Discussion: Thymectomy was not associated with additional clinical improvement in this multicenter cohort of MuSK-MG patients. Muscle Nerve 59:404-410, 2019., (© 2019 Wiley Periodicals, Inc.)

The Cancer Research Network (CRN) is a consortium of 12 research groups, each affiliated with a nonprofit integrated health care delivery system, that was first funded in 1998. The overall goal of the CRN is to support and facilitate collaborative cancer research within its component delivery systems. This paper describes the CRN's 20-year experience and evolution. The network combined its members' scientific capabilities and data resources to create an infrastructure that has ultimately supported over 275 projects. Insights about the strengths and limitations of electronic health data for research, approaches to optimizing multidisciplinary collaboration, and the role of a health services research infrastructure to complement traditional clinical trials and large observational datasets are described, along with recommendations for other research consortia., Competing Interests: The authors have no competing interests to declare.

Although it is well-established how nutrients, growth factors, and hormones impact functional β-cell mass (BCM), the influence of the central nervous system in this regard, and especially in the context of islet immune modulation, has been understudied. Here we investigated the expression and activity of pancreatic islet α7 nicotinic acetylcholine receptor (α7nAChR) in islet anti-inflammatory and prosurvival signaling. Systemic administration of α7nAChR agonists in mice improved glucose tolerance and curtailed streptozotocin-induced hyperglycemia by retaining BCM, in part through maintaining Pdx1 and MafA expression and reducing apoptosis. α7nAChR activation of mouse islets ex vivo led to reduced inflammatory drive through a JAK2-STAT3 pathway that couples with CREB/Irs2/Akt survival signaling. Because the vagus nerve conveys anti-inflammatory signals to immune cells of the spleen and other nonneural tissues in the viscera by activating α7nAChR agonists, our study suggests a novel role for β-cell α7nAChR that functions to maintain β-cell survival and mass homeostasis through modulating islet cytokine and phosphatidylinositol 3-kinase-dependent signaling pathways. Exploiting these pathways may have therapeutic potential for the treatment of autoimmune diabetes., (© 2018 Gupta et al.)

The 24th annual conference of the Health Care Systems Research Network (HCSRN, formerly the HMO Research Network), held April 11-13, 2018, in Minneapolis, Minnesota, attracted 357 attendees. The HCSRN is a consortium of 18 community-based research organizations embedded in or affiliated with large health care delivery systems. Its annual research conference, held since 1994, is a unique venue that brings diverse stakeholders (eg, research teams, clinicians, patients, funders) together to explore a range of health research topics and scientific findings, with a unifying goal of connecting applied research to real-world care delivery for the betterment of individual and community health. The 2018 conference was hosted by Minneapolis-based HealthPartners Institute and organized around 3 tracks: Research & Results, Practical Application, and Data Science & Informatics. Themes of the 4 plenary, 7 panel, 36 oral abstract, and 111 poster presentations included the learning health system, the opioid epidemic, health disparities, high costs of care, informing population health policy with evidence, and how to use storytelling to present data to inspire change, among others., Competing Interests: Conflicts of Interest None.

The Patient-Centered Outcomes Research Institute (PCORI) in Washington, DC, has catalyzed a meaningful shift in the composition of research project teams since its initial research funding cycle in 2011. Despite the influx of funding in the research community for patient-centered research, research on how to effectively engage patients and stakeholders in the research process is still relatively nascent. Kaiser Permanente Washington Health Research Institute (KPWHRI) in Seattle, WA, was an early recipient of PCORI research funding and, as of December 2017, has received 8 PCORI research awards totaling nearly $15 million. Anticipating the pivotal importance of PCORI's patient-focused approach, KPWHRI developed a set of 8 principles to guide how research teams should work with patients and other stakeholders to simultaneously achieve research aims and embrace this new paradigm in how research teams collaborate. With a goal of assisting other research teams, this article describes the genesis of the KPWHRI principles, their relevance to patient- and stakeholder-engaged research, and how these principles were brought to life in the context of a specific PCORI-funded project on surveillance imaging in women after a breast cancer diagnosis.

We introduce the "tensor-train split-operator Fourier transform" (TT-SOFT) method for simulations of multidimensional nonadiabatic quantum dynamics. TT-SOFT is essentially the grid-based SOFT method implemented in dynamically adaptive tensor-train representations. In the same spirit of all matrix product states, the tensor-train format enables the representation, propagation, and computation of observables of multidimensional wave functions in terms of the grid-based wavepacket tensor components, bypassing the need of actually computing the wave function in its full-rank tensor product grid space. We demonstrate the accuracy and efficiency of the TT-SOFT method as applied to propagation of 24-dimensional wave packets, describing the S 1 /S 2 interconversion dynamics of pyrazine after UV photoexcitation to the S 2 state. Our results show that the TT-SOFT method is a powerful computational approach for simulations of quantum dynamics of polyatomic systems since it avoids the exponential scaling problem of full-rank grid-based representations.