Identification of a ß-arrestin-biased negative allosteric modulator for the ß2-adrenergic receptor.

Catecholamine-stimulated ß2-adrenergic receptor (ß2AR) signaling via the canonical Gs-adenylyl cyclase-cAMP-PKA pathway regulates numerous physiological functions, including the therapeutic effects of exogenous ß-agonists in the treatment of airway disease. ß2AR signaling is tightly regulated by GRKs and ß-arrestins, which together promote ß2AR desensitization and internalization as well as downstream signaling, often antithetical to the canonical pathway. Thus, the ability to bias ß2AR signaling toward the Gs pathway while avoiding ß-arrestin-mediated effects may provide a strategy to improve the functional consequences of ß2AR activation. Since attempts to develop Gs-biased agonists and allosteric modulators for the ß2AR have been largely unsuccessful, here we screened small molecule libraries for allosteric modulators that selectively inhibit ß-arrestin recruitment to the receptor. This screen identified several compounds that met this profile, and, of these, a difluorophenyl quinazoline (DFPQ) derivative was found to be a selective negative allosteric modulator of ß-arrestin recruitment to the ß2AR while having no effect on ß2AR coupling to Gs. DFPQ effectively inhibits agonist-promoted phosphorylation and internalization of the ß2AR and protects against the functional desensitization of ß-agonist mediated regulation in cell and tissue models. The effects of DFPQ were also specific to the ß2AR with minimal effects on the ß1AR. Modeling, mutagenesis, and medicinal chemistry studies support DFPQ derivatives binding to an intracellular membrane-facing region of the ß2AR, including residues within transmembrane domains 3 and 4 and intracellular loop 2. DFPQ thus represents a class of biased allosteric modulators that targets an allosteric site of the ß2AR.

Rigorous Screened Interactions for Realistic Correlated Electron Systems.

We derive a widely applicable first-principles approach for determining two-body, static effective interactions for low-energy Hamiltonians with quantitative accuracy. The algebraic construction rigorously conserves all instantaneous two-point correlation functions in a chosen model space at the level of the random phase approximation, improving upon the traditional uncontrolled static approximations. Applied to screened interactions within a quantum embedding framework, we demonstrate these faithfully describe the relaxation of local subspaces via downfolding high-energy physics in molecular systems, as well as enabling a systematically improvable description of the long-range plasmonic contributions in extended graphene.

Autologous cell immunotherapy (IGV-001) with IGF-1R antisense oligonucleotide in newly diagnosed glioblastoma patients.

Standard-of-care first-line therapy for patients with newly diagnosed glioblastoma (ndGBM) is maximal safe surgical resection, then concurrent radiotherapy and temozolomide, followed by maintenance temozolomide. IGV-001, the first product of the Goldspire™ platform, is a first-in-class autologous immunotherapeutic product that combines personalized whole tumor-derived cells with an antisense oligonucleotide (IMV-001) in implantable biodiffusion chambers, with the intent to induce a tumor-specific immune response in patients with ndGBM. Here, we describe the design and rationale of a randomized, double-blind, phase IIb trial evaluating IGV-001 compared with placebo, both followed by standard-of-care treatment in patients with ndGBM. The primary end point is progression-free survival, and key secondary end points include overall survival and safety.

Glioblastoma (GBM) is a fast-growing brain tumor that happens in about half of all gliomas. Surgery is the first treatment for patients with newly diagnosed GBM, followed by the usual radiation and chemotherapy pills named temozolomide. Temozolomide pills are then given as a long-term treatment. The outcome for the patient with newly diagnosed GBM remains poor. IGV-001 is specially made for each patient. The tumor cells are removed during surgery and mixed in the laboratory with a small DNA, IMV-001. This mix is the IGV-001 therapy that is designed to give antitumor immunity against GBM. IGV-001 is put into small biodiffusion chambers that are irradiated to stop the growth of any tumor cells in the chambers. In the phase IIb study, patients with newly diagnosed GBM are chosen and assigned to either the IGV-001 or the placebo group. A placebo does not contain any active ingredients. The small biodiffusion chambers containing either IGV-001 or placebo are surgically placed into the belly for 48 to 52 h and then removed. Patients then receive the usual radiation and chemotherapy treatment. Patients must be adults aged between 18 and 70 years. Patients also should be able to care for themselves overall, but may be unable to work or have lower ability to function. Patients with tumors on both sides of the brain are not eligible. The main point of this study is to see if IGV-001 helps patients live longer without making the illness worse compared with placebo. Clinical Trial Registration: NCT04485949 (ClinicalTrials.gov).

A "moment-conserving" reformulation of GW theory.

We show how to construct an effective Hamiltonian whose dimension scales linearly with system size, and whose eigenvalues systematically approximate the excitation energies of GW theory. This is achieved by rigorously expanding the self-energy in order to exactly conserve a desired number of frequency-independent moments of the self-energy dynamics. Recasting GW in this way admits a low-scaling O[N4] approach to build and solve this Hamiltonian, with a proposal to reduce this further to O[N3]. This relies on exposing a novel recursive framework for the density response moments of the random phase approximation, where the efficient calculation of its starting point mirrors the low-scaling approaches to compute RPA correlation energies. The frequency integration of GW, which distinguishes so many different GW variants, can be performed without approximation directly in this moment representation. Furthermore, the solution to the Dyson equation can be performed exactly, avoiding analytic continuation, diagonal approximations, or iterative solutions to the quasiparticle equation, with the full-frequency spectrum obtained from the complete solution of this effective static Hamiltonian. We show how this approach converges rapidly with respect to the order of the conserved self-energy moments and is applied across the GW100 benchmark dataset to obtain accurate GW spectra in comparison to traditional implementations. We also show the ability to systematically converge all-electron full-frequency spectra and high-energy features beyond frontier excitations, as well as avoiding discontinuities in the spectrum, which afflict many other GW approaches.

The forensic assessment of dissociation: Distinguishing real from the unreal.

Because a wide range of disorders incorporate dissociative symptoms, evaluators should be familiar with evidence-based approaches to evaluating dissociation claims in the clinical and forensic context. This article provides specific guidelines for practitioners when conducting a forensic assessment of individuals who report dissociative symptoms. We review the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition disorders that include dissociation as a symptom, highlight how to distinguish genuine versus atypical symptoms of dissociative identity disorder, and summarize strengths and weaknesses of structured assessments in the evaluation of dissociative claims.

Using multiple agreement methods for continuous repeated measures data: a tutorial for practitioners.

BACKGROUND: Studies of agreement examine the distance between readings made by different devices or observers measuring the same quantity. If the values generated by each device are close together most of the time then we conclude that the devices agree. Several different agreement methods have been described in the literature, in the linear mixed modelling framework, for use when there are time-matched repeated measurements within subjects. METHODS: We provide a tutorial to help guide practitioners when choosing among different methods of assessing agreement based on a linear mixed model assumption. We illustrate the use of five methods in a head-to-head comparison using real data from a study involving Chronic Obstructive Pulmonary Disease (COPD) patients and matched repeated respiratory rate observations. The methods used were the concordance correlation coefficient, limits of agreement, total deviation index, coverage probability, and coefficient of individual agreement. RESULTS: The five methods generated similar conclusions about the agreement between devices in the COPD example; however, some methods emphasized different aspects of the between-device comparison, and the interpretation was clearer for some methods compared to others. CONCLUSIONS: Five different methods used to assess agreement have been compared in the same setting to facilitate understanding and encourage the use of multiple agreement methods in practice. Although there are similarities between the methods, each method has its own strengths and weaknesses which are important for researchers to be aware of. We suggest that researchers consider using the coverage probability method alongside a graphical display of the raw data in method comparison studies. In the case of disagreement between devices, it is important to look beyond the overall summary agreement indices and consider the underlying causes. Summarising the data graphically and examining model parameters can both help with this.

Jail diversion: a practical primer.

The United States has the highest incarceration rate in the world. With a substantial number of inmates diagnosed with mental illness, substance use, or both, various diversion strategies have been developed to help decrease and avoid criminalization of individuals with mental illness. This article focuses primarily on the first three Sequential Intercept Model intercept points as related to jail diversion and reviews types of diversion programs, research outcomes for diversion programs, and important components that contribute to successful diversion.

The Cal-DSH diversion guidelines.

The Cal-DSH Diversion Guidelines provide 10 general guidelines that jurisdictions should consider when developing diversion programs for individuals with a serious mental illness (SMI) who become involved in the criminal justice system. Screening for SMI in a jail setting is reviewed. In addition, important treatment interventions for SMI and substance use disorders are highlighted with the need to address criminogenic risk factors highlighted.

Theory and implementation of a novel stochastic approach to coupled cluster.

We present a detailed discussion of our novel diagrammatic coupled cluster Monte Carlo (diagCCMC) [Scott et al. J. Phys. Chem. Lett. 10, 925 (2019)]. The diagCCMC algorithm performs an imaginary-time propagation of the similarity-transformed coupled cluster Schrödinger equation. Imaginary-time updates are computed by the stochastic sampling of the coupled cluster vector function: each term is evaluated as a randomly realized diagram in the connected expansion of the similarity-transformed Hamiltonian. We highlight similarities and differences between deterministic and stochastic linked coupled cluster theory when the latter is re-expressed as a sampling of the diagrammatic expansion and discuss details of our implementation that allow for a walker-less realization of the stochastic sampling. Finally, we demonstrate that in the presence of locality, our algorithm can obtain a fixed errorbar per electron while only requiring an asymptotic computational effort that scales quartically with system size, independent of the truncation level in coupled cluster theory. The algorithm only requires an asymptotic memory cost scaling linearly, as demonstrated previously. These scaling reductions require no ad hoc modifications to the approach.

Nuclear/cytoplasmic transport defects in BBS6 underlie congenital heart disease through perturbation of a chromatin remodeling protein.

Mutations in BBS6 cause two clinically distinct syndromes, Bardet-Biedl syndrome (BBS), a syndrome caused by defects in cilia transport and function, as well as McKusick-Kaufman syndrome, a genetic disorder characterized by congenital heart defects. Congenital heart defects are rare in BBS, and McKusick-Kaufman syndrome patients do not develop retinitis pigmentosa. Therefore, the McKusick-Kaufman syndrome allele may highlight cellular functions of BBS6 distinct from the presently understood functions in the cilia. In support, we find that the McKusick-Kaufman syndrome disease-associated allele, BBS6H84Y; A242S, maintains cilia function. We demonstrate that BBS6 is actively transported between the cytoplasm and nucleus, and that BBS6H84Y; A242S, is defective in this transport. We developed a transgenic zebrafish with inducible bbs6 to identify novel binding partners of BBS6, and we find interaction with the SWI/SNF chromatin remodeling protein Smarcc1a (SMARCC1 in humans). We demonstrate that through this interaction, BBS6 modulates the sub-cellular localization of SMARCC1 and find, by transcriptional profiling, similar transcriptional changes following smarcc1a and bbs6 manipulation. Our work identifies a new function for BBS6 in nuclear-cytoplasmic transport, and provides insight into the disease mechanism underlying the congenital heart defects in McKusick-Kaufman syndrome patients.

Meta-analysis of the impact of alpha-glucosidase inhibitors on incident diabetes and cardiovascular outcomes.

BACKGROUND: Alpha-glucosidase inhibitors (AGIs) have been shown to reduce incident type 2 diabetes but their impact on cardiovascular (CV) disease remains controversial. We sought to identify the overall impact of AGIs with respect to incident type 2 diabetes in individuals with impaired glucose tolerance (IGT), and CV outcomes in those with IGT or type 2 diabetes. METHODS: We used PubMed and SCOPUS to identify randomized controlled trials reporting the incidence of type 2 diabetes and/or CV outcomes that had compared AGIs with placebo in populations with IGT or type 2 diabetes, with or without established CV disease. Eligible studies were required to have ≥ 500 participants and/or ≥ 100 endpoints of interest. Meta-analyses of available trial data were performed using random effects models to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for incident type 2 diabetes and CV outcomes. RESULTS: Of ten trials identified, three met our inclusion criteria for incident type 2 diabetes and four were eligible for CV outcomes. The overall HR (95% CI) comparing AGI with placebo for incident type 2 diabetes was 0.77 (0.67-0.88), p < 0.0001, and for CV outcomes was 0.98 (0.89-1.10), p = 0.85. There was little to no heterogeneity between studies, with I2 values of 0.03% (p = 0.43) and 0% (p = 0.79) for the two outcomes respectively. CONCLUSIONS: Allocation of people with IGT to an AGI significantly reduced their risk of incident type 2 diabetes by 23%, whereas in those with IGT or type 2 diabetes the impact on CV outcomes was neutral.

Gabapentin Enacarbil Extended-Release for Alcohol Use Disorder: A Randomized, Double-Blind, Placebo-Controlled, Multisite Trial Assessing Efficacy and Safety.

BACKGROUND: Several single-site alcohol treatment clinical trials have demonstrated efficacy for immediate-release (IR) gabapentin in reducing drinking outcomes among individuals with alcohol dependence. The purpose of this study was to conduct a large, multisite clinical trial of gabapentin enacarbil extended-release (GE-XR) (HORIZANT® ), a gabapentin prodrug formulation, to determine its safety and efficacy in treating alcohol use disorder (AUD). METHODS: Men and women (n = 346) who met DSM-5 criteria for at least moderate AUD were recruited across 10 U.S. clinical sites. Participants received double-blind GE-XR (600 mg twice a day) or placebo and a computerized behavioral intervention (Take Control) for 6 months. Efficacy analyses were prespecified for the last 4 weeks of the treatment period. RESULTS: The GE-XR and placebo groups did not differ significantly on the primary outcome measure, percentage of subjects with no heavy drinking days (28.3 vs. 21.5, respectively, p = 0.157). Similarly, no clinical benefit was found for other drinking measures (percent subjects abstinent, percent days abstinent, percent heavy drinking days, drinks per week, drinks per drinking day), alcohol craving, alcohol-related consequences, sleep problems, smoking, and depression/anxiety symptoms. Common side-effects were fatigue, dizziness, and somnolence. A population pharmacokinetics analysis revealed that patients had lower gabapentin exposure levels compared with those in other studies using a similar dose but for other indications. CONCLUSIONS: Overall, GE-XR at 600 mg twice a day did not reduce alcohol consumption or craving in individuals with AUD. It is possible that, unlike the IR formulation of gabapentin, which showed efficacy in smaller Phase 2 trials at a higher dose, GE-XR is not effective in treating AUD, at least not at doses approved by the U.S. Food and Drug Administration for treating other medical conditions.

Clinical trial of L-Carnitine and valproic acid in spinal muscular atrophy type I.

INTRODUCTION: The aim of this study was to determine the safety and therapeutic potential of L-carnitine and valproic acid (VPA) in infants with spinal muscular atrophy (SMA). METHODS: Our investigation was an open-label phase 2 multicenter trial of L-carnitine and VPA in infants with SMA type I with retrospective comparison to an untreated, matched cohort. Primary outcomes were: safety and adverse events; secondary outcomes were survival, time to death/>16 hours/day of ventilator support; motor outcomes; and maximum ulnar compound motor action potential amplitude. RESULTS: A total of 245 AEs were observed in 35 of the 37 treated subjects (95%). Respiratory events accounted for 49% of all adverse events, resulting in 14 deaths. Survival was not significantly different between treated and untreated cohorts. DISCUSSION: This trial provides evidence that, in infants with SMA type I, L-carnitine/VPA is ineffective at altering survival. The substantial proportion of infants reaching end-points within 6 months of enrollment underscores the urgent need for pre-symptomatic treatment in SMA type I. Muscle Nerve 57: 193-199, 2018.

Randomized Controlled Trial of Two Alcohol-based Preparations for Surgical Site Antisepsis in Colorectal Surgery.

OBJECTIVE: To compare 2 alcohol-based, dual-action skin preparations for surgical site infection (SSI) prevention in elective colorectal surgery. BACKGROUND: Colorectal surgery is associated with the highest SSI rate among elective surgical procedures. Although evidence indicates that alcohol-based skin preparations are superior in SSI prevention, it is not clear if different alcohol-based preparations are equivalent in clean-contaminated colorectal procedures. METHODS: We performed a blinded, randomized, noninferiority trial comparing iodine povacrylex-alcohol (IPA) and chlorhexidine-alcohol for elective, clean-contaminated colorectal surgery. The primary outcome was the presence or absence of SSI, defined as superficial or deep SSI, within 30 days postdischarge. A 6.6% noninferiority margin was chosen. RESULTS: Between January 2011 and January 2015, 802 patients were randomized with 788 patients included in the intent to treat analysis (396 IPA and 392 chlorhexidine-alcohol). The difference in overall SSI rate between IPA (18.7%) and chlorhexidine-alcohol (15.9%) was 2.8% (P = 0.30). The upper bound of the 2.5% confidence interval of this difference was 8.9%, which is greater than the prespecified noninferiority margin of 6.6%. Other endpoints, including individual SSI types, time to SSI diagnosis, and length of stay were not different between the 2 arms. CONCLUSIONS: In patients undergoing elective, clean contaminated colorectal surgery, the use of IPA failed to meet criterion for noninferiority for overall SSI prevention compared with chlorhexidine-alcohol. Photodocumentation of wounds and rigorous tracking of outcomes up to 30 days postdischarge contributed to high fidelity to current standard SSI descriptions and wound classifications.

A height-for-age growth reference for children with achondroplasia: Expanded applications and comparison with original reference data.

The height-for-age (HA) reference currently used for children with achondroplasia is not adaptable for electronic records or calculation of HA Z-scores. We report new HA curves and tables of mean and standard deviation (SD) HA, for calculating Z-scores, from birth-16 years in achondroplasia. Mixed longitudinal data were abstracted from medical records of achondroplasia patients from a single clinical practice (CIS, 1967-2004). Gender-specific height percentiles (5, 25, 50, 75, 95th) were estimated across the age continuum, using a 2 month window per time point smoothed by a quadratic smoothing algorithm. HA curves were constructed for 0-36 months and 2-16 years to optimize resolution for younger children. Mean monthly height (SD) was tabulated. These novel HA curves were compared to reference data currently in use for children with achondroplasia. 293 subjects (162 male/131 female) contributed 1,005 and 932 height measures, with greater data paucity with age. Mean HA tracked with original achondroplasia norms, particularly through mid-childhood (2-9 years), but with no evidence of a pubertal growth spurt. Standard deviation of height at each month interval increased from birth through 16 years. Birth length was lower in achondroplasia than average stature and, as expected, height deficits increased with age. A new HA reference is available for longitudinal growth assessment in achondroplasia, taking advantage of statistical modeling techniques and allowing for Z-score calculations. This is an important contribution to clinical care and research endeavors for the achondroplasia population.

Stochastic coupled cluster theory: Efficient sampling of the coupled cluster expansion.

We consider the sampling of the coupled cluster expansion within stochastic coupled cluster theory. Observing the limitations of previous approaches due to the inherently non-linear behavior of a coupled cluster wavefunction representation, we propose new approaches based on an intuitive, well-defined condition for sampling weights and on sampling the expansion in cluster operators of different excitation levels. We term these modifications even and truncated selections, respectively. Utilising both approaches demonstrates dramatically improved calculation stability as well as reduced computational and memory costs. These modifications are particularly effective at higher truncation levels owing to the large number of terms within the cluster expansion that can be neglected, as demonstrated by the reduction of the number of terms to be sampled when truncating at triple excitations by 77% and hextuple excitations by 98%.

Psychiatric education in the correctional setting: challenges and opportunities.

As the need for mental healthcare services within correctional settings in the US increases, so does the need for a mental health workforce that is motivated to work within such systems. One potentially effective method by which to increase the number of psychiatrists working in jails, prisons, and parole clinics is to provide exposure to these environments during their training. Correctional settings can serve as unique training sites for medical students and psychiatric residents and fellows. Such training experiences can provide a host of benefits to both trainees and staff within the correctional mental health system. Alongside many potential benefits exist substantial potential barriers to coordinating correctional training experiences, including both programme directors' and residents' concerns regarding safety and enjoyment and negative perceptions of inmate and prisoner patients. The establishment of academic affiliations with correctional institutions and didactic instruction on commonly encountered clinical issues with inmate populations may be methods of diffusing these concerns. Improving residents' and fellows' training experiences offers a hope for increasing the attractiveness of a career in correctional psychiatry.

Precision and cost considerations for two-stage sampling in a panelized forest inventory design.

Due to the relatively high cost of measuring sample plots in forest inventories, considerable attention is given to sampling and plot designs during the forest inventory planning phase. A two-stage design can be efficient from a field work perspective as spatially proximate plots are grouped into work zones. A comparison between subsampling with units of unequal size (SUUS) and a simple random sample (SRS) design in a panelized framework assessed the statistical and economic implications of using the SUUS design for a case study in the Northeastern USA. The sampling errors for estimates of forest land area and biomass were approximately 1.5-2.2 times larger with SUUS prior to completion of the inventory cycle. Considerable sampling error reductions were realized by using the zones within a post-stratified sampling paradigm; however, post-stratification of plots in the SRS design always provided smaller sampling errors in comparison. Cost differences between the two designs indicated the SUUS design could reduce the field work expense by 2-7 %. The results also suggest the SUUS design may provide substantial economic advantage for tropical forest inventories, where remote areas, poor access, and lower wages are typically encountered.

17α-Ethynylestradiol-3-sulfate treatment of severe blood loss in rats.

BACKGROUND: From 2001-2011, >80% of potentially survivable United States battlefield deaths were due to severe hemorrhage. We subjected male rats to acute severe blood loss, administered a single dose of 17α-ethynylestradiol-3-sulfate (EE-3-SO4) without resuscitative fluids, and measured survival and also mean arterial pressures (MAP). METHODS: After controlled removal of 60% circulating blood volume (10-11 mL) over approximately 45 min, rats received EE-3-SO4 at 0 (vehicle controls), 0.1, 0.3, 1.0, or 3.0 mg/kg in 40 µL/100 g BW saline intravenously. MAP was recorded for 40 min after drug administration and survival was recorded for 6 h. RESULTS: The dose response curve was bell shaped with optimum survival at 1 mg/kg EE-3-SO4. Median survival times of rats receiving 1 mg/kg (360 min) were approximately 6 times that of the control group (57 min): P = 0.0001. The number of animals alive at 6 h was 16 of 20 (80%) in the 1 mg/kg group versus 0 of 20 (0%) in the control group. Early increases in MAP correlated with longer survival times. CONCLUSIONS: Administration of a single dose of 1 mg/kg EE-3-SO4 in 0.4 mL/kg of saline after controlled severe hemorrhage increased survival in rats by 6-fold. Partial recovery of blood pressure values correlated with longer survival time. These results, coupled with similar findings in a companion study in minipigs, support the further product development of EE-3-SO4 for: (1) severe hemorrhage when standard resuscitative fluids are not available, and (2) situations in which prolonged transportation periods are required for definitive treatment of the injured.