The histone variant macroH2A1.1 regulates RNA polymerase II-paused genes within defined chromatin interaction landscapes.

The histone variant macroH2A1.1 plays a role in cancer development and metastasis. To determine the underlying molecular mechanisms, we mapped the genome-wide localization of endogenous macroH2A1.1 in the human breast cancer cell line MDA-MB-231. We demonstrate that macroH2A1.1 specifically binds to active promoters and enhancers in addition to facultative heterochromatin. Selective knock down of macroH2A1.1 deregulates the expression of hundreds of highly active genes. Depending on the chromatin landscape, macroH2A1.1 acts through two distinct molecular mechanisms. The first mitigates excessive transcription by binding over domains including the promoter and the gene body. The second stimulates expression of RNA polymerase II (Pol II)-paused genes, including genes regulating mammary tumor cell migration. In contrast to the first mechanism, macroH2A1.1 specifically associates with the transcription start site of Pol II-paused genes. These processes occur in a predefined local 3D genome landscape, but do not require rewiring of enhancer-promoter contacts. We thus propose that macroH2A1.1 serves as a transcriptional modulator with a potential role in assisting the conversion of promoter-locked Pol II into a productive, elongating Pol II.

Concurrent CDX2 cis-deregulation and UBTF::ATXN7L3 fusion define a novel high-risk subtype of B-cell ALL.

Oncogenic alterations underlying B-cell acute lymphoblastic leukemia (B-ALL) in adults remain incompletely elucidated. To uncover novel oncogenic drivers, we performed RNA sequencing and whole-genome analyses in a large cohort of unresolved B-ALL. We identified a novel subtype characterized by a distinct gene expression signature and the unique association of 2 genomic microdeletions. The 17q21.31 microdeletion resulted in a UBTF::ATXN7L3 fusion transcript encoding a chimeric protein. The 13q12.2 deletion resulted in monoallelic ectopic expression of the homeobox transcription factor CDX2, located 138 kb in cis from the deletion. Using 4C-sequencing and CRISPR interference experiments, we elucidated the mechanism of CDX2 cis-deregulation, involving PAN3 enhancer hijacking. CDX2/UBTF ALL (n = 26) harbored a distinct pattern of additional alterations including 1q gain and CXCR4 activating mutations. Within adult patients with Ph- B-ALL enrolled in GRAALL trials, patients with CDX2/UBTF ALL (n = 17/723, 2.4%) were young (median age, 31 years) and dramatically enriched in females (male/female ratio, 0.2, P = .002). They commonly presented with a pro-B phenotype ALL and moderate blast cell infiltration. They had poor response to treatment including a higher risk of failure to first induction course (19% vs 3%, P = .017) and higher post-induction minimal residual disease (MRD) levels (MRD ≥ 10-4, 93% vs 46%, P < .001). This early resistance to treatment translated into a significantly higher cumulative incidence of relapse (75.0% vs 32.4%, P = .004) in univariate and multivariate analyses. In conclusion, we discovered a novel B-ALL entity defined by the unique combination of CDX2 cis-deregulation and UBTF::ATXN7L3 fusion, representing a high-risk disease in young adults.

Systematic analysis of electronic barrier heights and widths for concerted proton transfer in cyclic hydrogen bonded clusters: (HF)n, (HCl)n and (H2O)n where n = 3, 4, 5.

The MP2 and CCSD(T) methods are paired with correlation consistent basis sets as large as aug-cc-pVQZ to optimize the structures of the cyclic minima for (HF)n, (HCl)n and (H2O)n where n = 3-5, as well as the corresponding transition states (TSs) for concerted proton transfer (CPT). MP2 and CCSD(T) harmonic vibrational frequencies confirm the nature of each minimum and TS. Both conventional and explicitly correlated CCSD(T) computations are employed to assess the electronic dissociation energies and barrier heights for CPT near the complete basis (CBS) limit for all 9 clusters. Results for (HF)n are consistent with prior studies identifying Cnh and Dnh point group symmetry for the minima and TSs, respectively. Our computations also confirm that CPT proceeds through Cs TS structures for the C1 minima of (H2O)3 and (H2O)5, whereas the process goes through a TS with D2d symmetry for the S4 global minimum of (H2O)4. This work corroborates earlier findings that the minima for (HCl)3, (HCl)4 and (HCl)5 have C3h, S4 and C1 point group symmetry, respectively, and that the Cnh structures are not minima for n = 4 and 5. Moreover, our computations show the TSs for CPT in (HCl)3, (HCl)4 and (HCl)5 have D3h, D2d, and C2 point group symmetry, respectively. At the CCSD(T) CBS limit, (HF)4 and (HF)5 have the smallest electronic barrier heights for CPT (≈15 kcal mol-1 for both), followed by the HF trimer (≈21 kcal mol-1). The barriers are appreciably higher for the other clusters (around 27 kcal mol-1 for (H2O)4 and (HCl)3; roughly 30 kcal mol-1 for (H2O)3, (H2O)5 and (HCl)4; up to 38 kcal mol-1 for (HCl)5). At the CBS limit, MP2 significantly underestimates the CCSD(T) barrier heights (e.g., by ca. 2, 4 and 7 kcal mol-1 for the pentamers of HF, H2O and HCl, respectively), whereas CCSD overestimates these barriers by roughly the same magnitude. Scaling the barrier heights and dissociation energies by the number of fragments in the cluster reveals strong linear relationships between the two quantities and with the magnitudes of the imaginary vibrational frequency for the TSs.

A Novel Approach to Evaluating Cardiac Surgery Providers: An Alternative to the RAMR.

OBJECTIVE: We propose an alternative to the Risk Adjusted Mortality Rate (RAMR), about which we identify four serious concerns. We apply our method to cardiac surgery. DESIGN: We present a methodology that uses the upper and lower tail probabilities (UTP/LTP) of the binomial distribution to screen for poor/high performing providers. STUDY SETTING: The New York State Department of Health (NYS DOH) publicly releases data on all cardiac surgery patients in the state. We download cardiac surgery data from the NYS DOH website for the years 2011 through 2013. The state's objective is to identify poorly performing hospitals and surgeons and thereby reduce deaths. NYS employs the RAMR. RESULTS: The UTP/LTP approach agrees with the RAMR in its classification of all 132 surgeons and all 40 hospitals. However, performance is a continuous construct and strict categorization can lead to failure to identify marginal providers. CONCLUSIONS: Our methodology addresses all four concerns regarding the RAMR. The UTP/LTP approach avoids inappropriate hypothesis testing and is consistent with standard statistical theory and practice in its approach to case volume. It does not require confidence intervals and it applies to all providers regardless of case volume.

Predicting photosynthetic capacity in tobacco using shortwave infrared spectral reflectance.

Plateauing yield and stressful environmental conditions necessitate selecting crops for superior physiological traits with untapped potential to enhance crop performance. Plant productivity is often limited by carbon fixation rates that could be improved by increasing maximum photosynthetic carboxylation capacity (Vcmax). However, Vcmax measurements using gas exchange and biochemical assays are slow and laborious, prohibiting selection in breeding programs. Rapid hyperspectral reflectance measurements show potential for predicting Vcmax using regression models. While several hyperspectral models have been developed, contributions from different spectral regions to predictions of Vcmax have not been clearly identified or linked to biochemical variation contributing to Vcmax. In this study, hyperspectral reflectance data from 350-2500 nm were used to build partial least squares regression models predicting in vivo and in vitro Vcmax. Wild-type and transgenic tobacco plants with antisense reductions in Rubisco content were used to alter Vcmax independent from chlorophyll, carbon, and nitrogen content. Different spectral regions were used to independently build partial least squares regression models and identify key regions linked to Vcmax and other leaf traits. The greatest Vcmax prediction accuracy used a portion of the shortwave infrared region from 2070 nm to 2470 nm, where the inclusion of fewer spectral regions resulted in more accurate models.

Using Data Analytics to Improve Hospital Quality Performance.

EXECUTIVE SUMMARY: The objective of this study was to build a unified quality performance model for hospitals using publicly available data. We obtained data from the New York State Department of Health's Statewide Planning and Research Cooperative System database for our model, which had three outcome measures that we wished to make smaller (deaths, readmissions, average length of stay). Because this was a performance model rather than an economic efficiency model, we excluded costs, which are affected significantly by local economic conditions. We included four site characteristics. With our data envelopment analysis model structure, we used logistic regression to analyze the output. We extracted data for 2,233,214 discharges in 2014 from 183 hospitals in the state. We found that 20.8% of the facilities were on the quality performance frontier-20.6% of the not-for-profit facilities and 21.4% of the other facilities. Hospitals with more discharges performed better with respect to mortality, readmission, and average length of stay. We found no difference in performance between not-for-profit hospitals and others. We concluded that 79.2% of hospitals could improve their quality of care. As an upper bound, if all hospitals increased each quality factor performance to 100%, there would have been 11,722 (24.8%) fewer deaths, 17,840 (15.8%) fewer readmissions, and the statewide average length of stay would have been 0.71 days (13.5%) less.

Dissociation Energy of the H2O···HF Dimer.

Even though (H2O)2 and (HF)2 are arguably the most thoroughly characterized prototypes for hydrogen bonding, their heterogeneous analogue H2O···HF has received relatively little attention. Here we report that the experimental dissociation energy ( D0) of this important paradigm for heterogeneous hydrogen bonding is too large by 2 kcal mol-1 or 30% relative to our computed value of 6.3 kcal mol-1. For reference, computational procedures similar to those employed here to compute D0 (large basis set CCSD(T) computations with anharmonic corrections from second-order vibrational perturbation theory) provide results within 0.1 kcal mol-1 of the experimental values for (H2O)2 and (HF)2. Near the CCSD(T) complete basis set limit, the electronic dissociation energy for H2O···HF is ∼4 kcal mol-1 larger than those for (H2O)2 and (HF)2 (∼9 kcal mol-1 for the heterogeneous dimer vs ∼5 kcal mol-1 for the homogeneous dimers). Results reported here from symmetry-adapted perturbation theory computations suggest that this large difference is primarily due to the induction contribution to the interaction energy.

Communication: Gas phase vibrational spectroscopy of the azide-water complex.

The vibrational spectra of the azide-water complex, N3 -(H2O), and its fully deuterated isotopologue are studied using infrared photodissociation (IRPD) spectroscopy (800-3800 cm-1) and high-level ab initio computations. The IRPD spectrum of the H2-tagged complex exhibits four fundamental transitions at 3705, 3084, 2003, and 1660 cm-1, which are assigned to the free OH stretching, the hydrogen-bonded O-H stretching, the antisymmetric N3 stretching, and the water bending mode, respectively. The IRPD spectrum is consistent with a planar, singly hydrogen-bonded structure according to an MP2 and CCSD(T) anharmonic analysis via generalized second-order vibrational perturbation theory. The red-shift of the hydrogen-bonded OH stretching fundamental of 623 cm-1 associated with this structure is computed within 6 cm-1 (or 1%) and is used to estimate the proton affinity of azide (1410 kJ mol-1). Born-Oppenheimer molecular dynamics simulations show that large amplitude motions are responsible for the observed band broadening at cryogenic temperature. Temperature-dependent (6-300 K) IR multiphoton dissociation spectra of the untagged complex are also presented and discussed in the context of spectral diffusion observed in the condensed phase.

Extraordinary Mechanism of the Diels-Alder Reaction: Investigation of Stereochemistry, Charge Transfer, Charge Polarization, and Biradicaloid Formation.

The Diels-Alder reaction between 1,3-butadiene and ethene is investigated from far-out in the entrance channel to the very last step in the exit channel thus passing two bifurcation points and extending the range of the reaction valley studied with URVA (Unified Reaction Valley Approach) by 300% compared to previous studies. For the first time, the pre- and postchemical steps of the reaction are analyzed at the same level of theory as the actual chemical processes utilizing the path curvature and its decomposition into internal coordinate or curvilinear coordinate components. A first smaller charge transfer to the dienophile facilitates the rotation of gauche butadiene into its cis form. The actual chemical processes are initiated by a second larger charge transfer to the dienophile that facilitates pyramidalization of the reacting carbon centers, bond equalization, and biradicaloid formation of the reactants. The transition state is aromatically stabilized and moved by five path units into the entrance channel in line with the Hammond-Leffler postulate. The pseudorotation of the boat form into the halfchair of cyclohexene is analyzed. Predictions are made for the Diels-Alder reaction based on a 11-phase mechanism obtained by the URVA analysis.

A Reaction Valley Investigation of the Cycloaddition of 1,3-Dipoles with the Dipolarophiles Ethene and Acetylene: Solution of a Mechanistic Puzzle.

The reaction mechanism of the cycloaddition of 10 1,3-dipoles with the two dipolarphiles ethene and acetylene is investigated and compared using the Unified Reaction Valley Approach in a new form, which is based on a dual-level strategy, an accurate description of the reaction valley far out into the van der Waals region, and a comparative analysis of the electronic properties of the reaction complex. A detailed one-to-one comparison of 20 different 1,3-dipolar cycloadditions is performed, and unknown mechanistic features are revealed. There are significant differences in the reaction mechanisms for the two dipolarophiles that result from the van der Waals complex formation in the entrance channel of the cycloadditions. Hydrogen bonding between the 1,3-dipoles and acetylene is generally stronger, which leads to higher reaction barriers in the acetylene case, but which also facilitates to overcome the problem of a reduced charge transfer from 1,3-dipole to acetylene. Mechanistic differences are found in the prechemical and chemical reaction regions with regard to reactant orientation, preparation for the reaction, charge transfer, charge polarization, rehybridization, and bond formation. It is shown that similarities in the reaction barriers as determined by CCSD(T)-F12/aug-cc-pVTZ calculations result from a fortuitous cancellation of different electronic effects. In general, a caveat must be made with regard to oversimplified descriptions of the reaction mechanism based on orbital theory or energy decomposition schemes.

The Effectiveness of Functional Family Therapy in Reducing Adolescent Mental Health Risk and Family Adjustment Difficulties in an Irish Context.

To evaluate the effectiveness of Functional Family Therapy (FFT) 42 cases were randomized to FFT and 55 to a waiting-list control group. Minimization procedures controlled the effects of potentially confounding baseline variables. Cases were treated by a team of five therapists who implemented FFT with a moderate degree of fidelity. Rates of clinical recovery were significantly higher in the FFT group than in the control group. Compared to the comparison group, parents in the FFT group reported significantly greater improvement in adolescent problems on the Strengths and Difficulties Questionnaire (SDQ) and both parents and adolescents reported improvements in family adjustment on the Systemic Clinical Outcomes and Routine Evaluation (SCORE). In addition, 93% of youth and families in the treatment condition completed FFT. Improvements shown immediately after treatment were sustained at 3-month follow-up. Results provide a current demonstration of FFT's effectiveness for youth with behavior problems in community-based settings, expand our understanding of the range of positive outcomes of FFT to include mental health risk and family-defined problem severity and impact, and suggests that it is an effective intervention when implemented in an Irish context.

Development of clinical practice guidelines.

Clinical practice guidelines (CPGs) are intended to improve mental, behavioral, and physical health by promoting clinical practices that are based on the best available evidence. The American Psychological Association (APA) is committed to generating patient-focused CPGs that are scientifically sound, clinically useful, and informative for psychologists, other health professionals, training programs, policy makers, and the public. The Institute of Medicine (IOM) 2011 standards for generating CPGs represent current best practices in the field. These standards involve multidisciplinary guideline development panels charged with generating recommendations based on comprehensive systematic reviews of the evidence. The IOM standards will guide the APA as it generates CPGs that can be used to inform the general public and the practice community regarding the benefits and harms of various treatment options. CPG recommendations are advisory rather than compulsory. When used appropriately, high-quality guidelines can facilitate shared decision making and identify gaps in knowledge.

The development and evolution of family therapy research: its impact on practice, current status, and future directions.

Science has always been a central part of family therapy. Research by early pioneers focused on studying the efficacy of both couple and family interventions from a systemic perspective. Today we know more now than ever before about the processes of diverse families and the therapeutic outcomes of family therapy practices. Despite the acknowledged importance of family therapy research, there are still questions about its impact on "real life" practice. Despite all the flaws of each, research and practice are critical interacting elements of a dialectic relationship: High-quality practice combines reliable scientific knowledge with individual clinical judgment made by family therapists in the context of their dynamic transactions with a family or couple. Future research can help uncover the mechanisms we have yet to know and test the ones we have identified while the dynamic interaction of research and practice that can lead to further innovations and developments central to the future of family therapy.

Spinal magnetic stimulation to treat chronic back pain: a feasibility study in veterans.

Aim: Chronic low back pain represents a significant societal problem leading to increased healthcare costs and quality of life. This study was designed to evaluate the feasibility and effectiveness of non-invasive spinal electromagnetic simulation (SEMS) to treat nonspecific chronic low back pain (CLBP). Methods: A single-site prospective study was conducted to evaluate SEMS in reducing pain and improving disability. A total of 17 patients received SEMS two to three sessions a week. The Numeric Rating Scale and the Modified Oswestry Disability Questionnaire were used to assess pain and disability. Results: Participants receiving SEMS exhibited statistically significant reductions in pain and disability. Conclusion: Current results suggest that non-invasive SEMS can be an effective treatment in reducing pain and improving disability associated with CLBP.

Using Data Analytics to Improve Nursing Home Quality.

BACKGROUND: There exists an array of quality performance measures for nursing homes. They can confuse consumers, administrators, and government regulators. Our methodology provides a unified multidimensional evaluation. OBJECTIVE: To present a methodology to perform a multidimensional assessment of each nursing home within any specified group of nursing homes to aid policy makers, administrators, and consumers with a clear, easy-to-interpret evaluation of a nursing home quality performance. METHODS: We use data envelopment analysis (DEA) to integrate several quality measures into a comprehensive benchmarking model. We present statewide results comparing DEA performance scores with the Five-Star rating using data from New York State (NYS) Department of Health. RESULTS: In total, 212 of the 526 nursing homes performed as well as possible. Public nursing homes are most likely to lie on the frontier and have the highest average performance scores. The relationship between the DEA-based performance scores and the NYS Five-Star quality ratings is very weak. CONCLUSION: DEA is a comprehensive methodology for measuring nursing home quality. The DEA factor performance scores provide detailed information for individual nursing homes, enabling administrators to benchmark their facility's quality performance and to focus quality improvement efforts more effectively.

Patient outcomes associated with subcutaneous C1INH prophylaxis for hereditary angioedema: a retrospective analysis.

BACKGROUND: Real-world data on subcutaneous C1INH (C1INH[SC]) usage and patient-level impacts on hereditary angioedema (HAE)-related outcomes and quality of life (QoL) are both lacking and challenging to generate using conventional study methodologies. Using a hybrid study design involving patient interviews supplemented by retrospective medical chart data review, we conducted a real-world assessment of the impact of C1INH(SC) prophylaxis on HAE attack patterns, QoL, and on-demand medication use. METHODS: The study was conducted at seven US sites and included 36 adults with HAE who had been treated with C1INH(SC) long-term prophylaxis following ≥ 12 months of on-demand management only. Patients underwent 30-min interviews, facilitated and analyzed by a trained qualitative research specialist. Medical records were reviewed for 12 months before (pre-index) and after (post-index) initiation of C1INH(SC). Using interview data with descriptive terms converted to numerical values, we compared pre- versus post-index attack frequency, severity, and rescue medication usage. RESULTS: Mean (SD) annualized attack frequency per patient decreased 82.0%, from 38.8 (38.8) attacks/year pre-index to 7.0 (15.3) attacks/year (P < 0.001); the median number of attacks decreased by 97.0% (30 pre-index to 1 post-index). For 20 patients, the annualized attack rate after starting C1INH(SC) prophylaxis was ≤ 1 attack/year; 12 of these patients reported 0 attacks. Mean (SD) attack severity (scale: 0 = none/mild to 4 = very severe) decreased from 2.3 (0.7) pre-index to 0.9 (0.9) post-index (P < 0.001). Mean/median rescue medication use decreased by 77.2%/96.3%. Improved QoL was narratively described for many domains. CONCLUSIONS: These real-world findings indicate that long-term prophylaxis with C1INH(SC) markedly improves important factors that contribute to the goal of achieving total disease control and normalization of patients' lives, including fewer and less severe attacks, less rescue medication usage, and improved QoL.

Synthesis and Characterization of Stimuli-Responsive Polymer Brushes in Nanofluidic Channels.

Nanochannels with controllable gating behavior are attractive features in a wide range of nanofluidic applications including viral detection, particle sorting, and flow regulation. Here, we use selective sidewall functionalization of nanochannels with a polyelectrolyte brush to investigate the channel gating response to variations in solution pH and ionic strength. The conformational and structural changes of the interfacial brush layer within the channels are interrogated by specular and off-specular neutron reflectometry. Simultaneous fits of the specular and off-specular signals, using a dynamical theory model and a fitting optimization protocol, enable detailed characterization of the brush conformations and corresponding channel geometry under different solution conditions. Our results indicate a collapsed brush state under basic pH, equivalent to an open gate, and an expanded brush state representing a partially closed gate upon decreasing the pH and salt concentration. These findings open new possibilities in noninvasive in situ characterization of tunable nanofluidics and lab-on-chip devices with advanced designs and improved functionality.

Guidelines for classifying evidence-based treatments in couple and family therapy.

Guidelines for Evidence-Based Treatments in Family Therapy are intended to help guide clinicians, researchers, and policy makers in identifying specific clinical interventions and treatment programs for couples and families that have scientifically based evidence to support their efficacy. In contrast to criteria, which simply identify treatments that "work" and have been employed in the evaluation of other psychotherapies, these guidelines propose a three-tiered levels-of-evidence-based model that moves from "evidence-informed," to "evidence-based," to "evidence-based and ready for dissemination and transportation within diverse community settings." Each level reflects an interaction between the specificity of the intervention, the strength and readth of the outcomes, and the quality of the studies that form the evidence. These guidelines uniquely promote a clinically based "matrix" approach in which the empirical support is evaluated according to various dimensions including strength of the outcomes, the applicability across cultural contexts, and demonstration of specific change mechanisms. The guidelines are offered not only as a basis for understanding the evidence for diverse clinical approaches in couple and family therapy within the systemic tradition of the field, but also as an alternative aspirational model for evaluating all psychotherapies.

Leaf temperature impacts canopy water use efficiency independent of changes in leaf level water use efficiency.

Canopy water use efficiency (above-ground biomass over lifetime water loss, WUEcanopy) can influence yield in wheat and other crops. Breeding for WUEcanopy is difficult because it is influenced by many component traits. For example, intrinsic water use efficiency (WUEi), the ratio of net carbon assimilation (Anet) over stomatal conductance, contributes to WUEcanopy and can be estimated from carbon isotope discrimination (Δ). However, Δ is not sensitive to differences in the water vapor pressure deficit between the air and leaf (VPDleaf). Alternatively, measurements of instantaneous leaf water use efficiency (WUEleaf) are defined as Anet over transpiration and can be determined with gas exchange, but the dynamic nature of field conditions are not represented. Specifically, fluctuations in canopy temperature lead to changes in VPDleaf that impact transpiration but not Anet. This alters WUEleaf and in turn affects WUEcanopy. To test this relationship, WUEcanopy was measured in conjunction with WUEi, WUEcanopy, and canopy temperature under well-watered and water-limited conditions in two drought-tolerant wheat cultivars that differ in canopy architecture. In this experiment, boundary layer conductance was low and significant changes in leaf temperature occurred between cultivars and treatments that correlated with WUEcanopy likely because of the effect of canopy temperature on VPDleaf driving T. However, deviations between WUEi, WUEleaf, and WUEcanopy were present because measurements made at the leaf level do not account for variations in leaf temperature. This uncoupled the relationship of measured WUEleaf and WUEi from WUEcanopy and emphasizes the importance of canopy temperature on carbon uptake and transpired water loss.

Age-related and disease locus-specific mechanisms contribute to early remodelling of chromatin structure in Huntington's disease mice.

Temporal dynamics and mechanisms underlying epigenetic changes in Huntington's disease (HD), a neurodegenerative disease primarily affecting the striatum, remain unclear. Using a slowly progressing knockin mouse model, we profile the HD striatal chromatin landscape at two early disease stages. Data integration with cell type-specific striatal enhancer and transcriptomic databases demonstrates acceleration of age-related epigenetic remodelling and transcriptional changes at neuronal- and glial-specific genes from prodromal stage, before the onset of motor deficits. We also find that 3D chromatin architecture, while generally preserved at neuronal enhancers, is altered at the disease locus. Specifically, we find that the HD mutation, a CAG expansion in the Htt gene, locally impairs the spatial chromatin organization and proximal gene regulation. Thus, our data provide evidence for two early and distinct mechanisms underlying chromatin structure changes in the HD striatum, correlating with transcriptional changes: the HD mutation globally accelerates age-dependent epigenetic and transcriptional reprogramming of brain cell identities, and locally affects 3D chromatin organization.