Discovery of MK-1084: An Orally Bioavailable and Low-Dose KRASG12C Inhibitor.

Oncogenic mutations in the RAS gene account for 30% of all human tumors; more than 60% of which present as KRAS mutations at the hotspot codon 12. After decades of intense pursuit, a covalent inhibition strategy has enabled selective targeting of this previously "undruggable" target. Herein, we disclose our journey toward the discovery of MK-1084, an orally bioavailable and low-dose KRASG12C covalent inhibitor currently in phase I clinical trials (NCT05067283). We leveraged structure-based drug design to identify a macrocyclic core structure, and hypothesis-driven optimization of biopharmaceutical properties to further improve metabolic stability and tolerability.

Broad Survey of Selectivity in the Heterogeneous Hydrogenation of Heterocycles.

A broad survey of heterogeneous hydrogenation catalysts has been conducted for the reduction of heterocycles commonly found in pharmaceuticals. The comparative reactivity of these substrates is reported as a function of catalyst, temperature, and hydrogen pressure. This analysis provided several catalysts with complementary reactivity between substrates. We then explored a series of bisheterocyclic substrates that provided an intramolecular competition of heterocycle hydrogenation reactivity. In several cases, complete selectivity could be achieved for reduction of one heterocycle and isolated yields are reported. A general trend in reactivity is inferred in which quinoline is the most reactive, followed by pyrazine, then pyrrole and with pyridine being the least reactive.

Acoustically Driven Magnon-Phonon Coupling in a Layered Antiferromagnet.

Harnessing the causal relationships between mechanical and magnetic properties of Van der Waals materials presents a wealth of untapped opportunity for scientific and technological advancement, from precision sensing to novel memories. This can, however, only be exploited if the means exist to efficiently interface with the magnetoelastic interaction. Here, we demonstrate acoustically driven spin-wave resonance in a crystalline antiferromagnet, chromium trichloride, via surface acoustic wave irradiation. The resulting magnon-phonon coupling is found to depend strongly on sample temperature and external magnetic field orientation, and displays a high sensitivity to extremely weak magnetic anisotropy fields in the few mT range. Our work demonstrates a natural pairing between power-efficient strain-wave technology and the excellent mechanical properties of Van der Waals materials, representing a foothold toward widespread future adoption of dynamic magnetoacoustics.

Interspecies exciton interactions lead to enhanced nonlinearity of dipolar excitons and polaritons in MoS2 homobilayers.

Nonlinear interactions between excitons strongly coupled to light are key for accessing quantum many-body phenomena in polariton systems. Atomically-thin two-dimensional semiconductors provide an attractive platform for strong light-matter coupling owing to many controllable excitonic degrees of freedom. Among these, the recently emerged exciton hybridization opens access to unexplored excitonic species, with a promise of enhanced interactions. Here, we employ hybridized interlayer excitons (hIX) in bilayer MoS2 to achieve highly nonlinear excitonic and polaritonic effects. Such interlayer excitons possess an out-of-plane electric dipole as well as an unusually large oscillator strength allowing observation of dipolar polaritons (dipolaritons) in bilayers in optical microcavities. Compared to excitons and polaritons in MoS2 monolayers, both hIX and dipolaritons exhibit ≈ 8 times higher nonlinearity, which is further strongly enhanced when hIX and intralayer excitons, sharing the same valence band, are excited simultaneously. This provides access to an unusual nonlinear regime which we describe theoretically as a mixed effect of Pauli exclusion and exciton-exciton interactions enabled through charge tunnelling. The presented insight into many-body interactions provides new tools for accessing few-polariton quantum correlations.

Early Use of Iloprost in Nonfreezing Cold Injury.

Nonfreezing cold injury (NFCI) is caused by prolonged exposure to cold, usually wet conditions and represents a separate pathological entity from frostbite. The pathophysiology of NFCI is characterized by vasoconstriction and microcirculatory disturbance. Iloprost, a synthetic prostaglandin analogue with vasodilatory properties is a recognized adjuvant treatment in frostbite; however, its role in NFCI is unclear. We present a case of a 29-y-old man with severe NFCI to both forefeet after prolonged immersion in cold seawater. Initial treatment with passive rewarming, analgesia and aspirin was initiated. Infusion of iloprost was used within 24 h from presentation and was well tolerated. This resulted in reduced tissue loss compared to the apparent tissue damage documented during the initial assessment. Delayed surgical intervention allowed minor debridement and minor toe amputations, maintaining the patient's ability to ambulate. This case demonstrates the safe use of iloprost in acute NFCI and highlights the importance of delayed surgical intervention in patients presenting with severe NFCI.

Does Bail Reform Decarcerate Mental Illness? Public Health Challenges for a Large County Jail System.

Although bail reform reduces jail census, whether or not its effects extend to incarcerated individuals with mental illness is unknown. Using a novel high-sensitivity measure of serious mental illness (SMI) from jail-based electronic health records, we conducted an interrupted time series analysis assessing the impact of Illinois bail reform on total jail registrations and the nested subset with SMI ± co-occurring substance use disorder (SUD). Compared with a decline in total jail registrations, admission of individuals with SMI ± SUD showed no decline. Consequently, the proportion of admissions involving SMI increased between 2015 and 2019 from 26% to 35%. Intentional efforts involving cooperation by the health, social services, and justice sectors are needed to translate the impact of bail reform onto the population experiencing SMI.

Prevalence and risk factors for opioid related mortality among probation clients in an American city.

INTRODUCTION: Substance use disorder researchers and treatment professionals have long recognized that risk of opioid-related mortality (ORM) is elevated after release from jail and prison. However, there are gaps in knowledge around ORM among people on probation and the relationship of ORM to drug testing and treatment referral while under supervision. Understanding this relationship is critical for probation officers who are often tasked with referring clients to treatment and monitoring compliance with treatment, without having a clinical background. In this cross-sectional study we estimate the prevalence and risk factors for ORM in a large, urban probation department. METHODS: We joined mortality records and probation records for 2018 and 2019 to determine the rate of ORM for the probation population. We stratified ORM rates by risk factors, including demographics, drug testing results, and treatment placements. RESULTS: Individuals on probation were fifteen times more likely to die from ORM (361 per 100,000) than the general county population (23 per 100,000), largely driven by fentanyl (detected in 86.8% of deaths). Risk was elevated for clients over age 45 (838 per 100,000; 95% CI [655-1057]), clients with at least one positive drug test for opioids (1995 per 100,000; 95% CI [1419-2727]) or cocaine (1200 per 100,000; 95% CI [841-1661]), and clients with previous placements in drug treatment (692 per 100,000; 95% CI [503-929]). Positive urine tests for opioids were associated with 80 times greater risk of ORM than the general population. Although Black clients experienced ORM in greater numbers, white clients had relatively greater ORM risk. CONCLUSIONS: Elevated risk for ORM among the probation population justifies urgent and data-driven partnerships between public health and community corrections to train probation staff; to identify high-risk clients for evidence-based treatment and overdose prevention strategies; and to institute policies to support and sustain these activities.

Comprehensive Strategies to Bicyclic Prolines: Applications in the Synthesis of Potent Arginase Inhibitors.

Comprehensive synthetic strategies afforded a diverse set of structurally unique bicyclic proline-containing arginase inhibitors with a high degree of three-dimensionality. The analogs that favored the Cγ-exo conformation of the proline improved the arginase potency over the initial lead. The novel synthetic strategies reported here not only enable access to previously unknown stereochemically complex proline derivatives but also provide a foundation for the future synthesis of bicyclic proline analogs, which incorporate inherent three-dimensional character into building blocks, medicine, and catalysts and could have a profound impact on the conformation of proline-containing peptides and macrocycles.

Structure-Based Discovery of Proline-Derived Arginase Inhibitors with Improved Oral Bioavailability for Immuno-Oncology.

Recent data suggest that the inhibition of arginase (ARG) has therapeutic potential for the treatment of a number of indications ranging from pulmonary and vascular disease to cancer. Thus, high demand exists for selective small molecule ARG inhibitors with favorable druglike properties and good oral bioavailability. In light of the significant challenges associated with the unique physicochemical properties of previously disclosed ARG inhibitors, we use structure-based drug design combined with a focused optimization strategy to discover a class of boronic acids featuring a privileged proline scaffold with superior potency and oral bioavailability. These compounds, exemplified by inhibitors 4a, 18, and 27, demonstrated a favorable overall profile, and 4a was well tolerated following multiple days of dosing at concentrations that exceed those required for serum arginase inhibition and concomitant arginine elevation in a syngeneic mouse carcinoma model.

Association Between Treatment Progression, Disease Refractoriness, and Burden of Illness Among Hospitalized Patients With Status Epilepticus.

Importance: Status epilepticus (SE) is associated with poor clinical outcomes and high cost. Increased levels of refractory SE require treatment with additional medications and carry increased morbidity and mortality, but the associations between SE refractoriness, clinical outcomes, and cost remain poorly characterized. Objective: To examine differences in clinical outcomes and costs associated with hospitalization for SE of varying refractoriness. Design, Setting, and Participants: A cross-sectional study of 43 988 US hospitalizations from January 1, 2016 to December 31, 2018, was conducted, including patients with primary or secondary International Statistical Classification of Diseases, Tenth Revision, diagnosis specifying "with status epilepticus." Exposure: Patients were categorized by administration of antiseizure drugs given during hospitalization. Low refractoriness denoted treatment with none or 1 intravenous antiseizure drug. Moderate refractoriness denoted treatment with more than 1 intravenous antiseizure drug. High refractoriness denoted treatment with 1 or more intravenous antiseizure drug, more than 1 intravenous anesthetic, and intensive care unit admission. Main Outcomes and Measures: Outcomes included discharge disposition, hospital length of stay, intensive care unit length of stay, hospital-acquired conditions, and cost (total and per diem). Results: Among 43 988 hospitalizations for SE, 22 851 patients (51.9%) were male; mean age was 49.9 years (95% CI, 49.7-50.1 years). There were 14 694 admissions (33.4%) for low refractory, 10 140 (23.1%) for moderate refractory, and 19 154 (43.5%) for highly refractory SE. In-hospital mortality was 11.2% overall, with the highest rates among patients with highly (18.9%) compared with moderate (6.3%) and low (4.6%) refractory SE (P < .001 for all comparisons). Median hospital length of stay was 5 days (interquartile range [IQR], 2-10 days) with greater length of stay in highly (8 days; IQR, 4-15 days) compared with moderate (4 days; IQR, 2-8 days) and low (3 days; IQR, 2-5 days) refractory SE (P < .001 for all comparisons). Patients with highly refractory SE also had greater hospital costs, with median costs of $25 105 (mean [SD], $41 858 [$59 063]) in the high, $10 592 (mean [SD], $18 328 [$30 776]) in the moderate, and $6812 (mean [SD], $11 532 [$17 228]) in the low refractory cohorts (P < .001 for all comparisons). Conclusions and Relevance: Status epilepticus apparently continues to be associated with a large burden on patients and the US health system, with high mortality and costs that increase with disease refractoriness. Interventions that prevent SE from progressing to a more refractory state may have the potential to improve outcomes and lower costs associated with this neurologic condition.

Discovery and Optimization of Rationally Designed Bicyclic Inhibitors of Human Arginase to Enhance Cancer Immunotherapy.

The action of arginase, a metalloenzyme responsible for the hydrolysis of arginine to urea and ornithine, is hypothesized to suppress immune-cell activity within the tumor microenvironment, and thus its inhibition may constitute a means by which to potentiate the efficacy of immunotherapeutics such as anti-PD-1 checkpoint inhibitors. Taking inspiration from reported enzyme-inhibitor cocrystal structures, we designed and synthesized novel inhibitors of human arginase possessing a fused 5,5-bicyclic ring system. The prototypical member of this class, 3, when dosed orally, successfully demonstrated serum arginase inhibition and concomitant arginine elevation in a syngeneic mouse carcinoma model, despite modest oral bioavailability. Structure-based design strategies to improve the bioavailability of this class, including scaffold modification, fluorination, and installation of active-transport recognition motifs were explored.

Manipulating molecules with strong coupling: harvesting triplet excitons in organic exciton microcavities.

Exciton-polaritons are quasiparticles with mixed photon and exciton character that demonstrate rich quantum phenomena, novel optoelectronic devices and the potential to modify chemical properties of materials. Organic materials are of current interest as active materials for their ability to sustain exciton-polaritons even at room temperature. However, within organic optoelectronic devices, it is often the 'dark' spin-1 triplet excitons that dominate operation. These triplets have been largely ignored in treatments of polaritons, which instead only consider the role of states that directly and strongly interact with light. Here we demonstrate that these 'dark' states can also play a major role in polariton dynamics, observing polariton population transferred directly from the triplet manifold via triplet-triplet annihilation. The process leads to polariton emission that is longer-lived (>µs) even than exciton emission in bare films. This enhancement is directly linked to spin-2 triplet-pair states, which are formed in films and microcavities by singlet fission or triplet-triplet annihilation. Such high-spin multiexciton states are generally non-emissive and cannot directly couple to light, yet the formation of polaritons creates for them entirely new radiative decay pathways. This is possible due to weak mixing between singlet and triplet-pair manifolds, which - in the strong coupling regime - enables direct interaction between the bright polariton states and those that are formally non-emissive. Our observations offer the enticing possibility of using polaritons to harvest or manipulate population from states that are formally dark.

Chemotherapy versus surgery for initial treatment in advanced ovarian epithelial cancer.

BACKGROUND: Epithelial ovarian cancer presents at an advanced stage in the majority of women. These women require surgery and chemotherapy for optimal treatment. Conventional treatment has been to perform surgery first and then give chemotherapy. However, there may be advantages to using chemotherapy before surgery. OBJECTIVES: To assess whether there is an advantage to treating women with advanced epithelial ovarian cancer with chemotherapy before debulking surgery (neoadjuvant chemotherapy (NACT)) compared with conventional treatment where chemotherapy follows debulking surgery (primary debulking surgery (PDS)). SEARCH METHODS: We searched the following databases on 11 February 2019: CENTRAL, Embase via Ovid, MEDLINE (Silver Platter/Ovid), PDQ and MetaRegister. We also checked the reference lists of relevant papers that were identified to search for further studies. The main investigators of relevant trials were contacted for further information. SELECTION CRITERIA: Randomised controlled trials (RCTs) of women with advanced epithelial ovarian cancer (Federation of International Gynaecologists and Obstetricians (FIGO) stage III/IV) who were randomly allocated to treatment groups that compared platinum-based chemotherapy before cytoreductive surgery with platinum-based chemotherapy following cytoreductive surgery. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed risk of bias in each included trial. MAIN RESULTS: We found 1952 potential titles, with a most recent search date of February 2019, of which five RCTs of varying quality and size met the inclusion criteria. These studies assessed a total of 1713 women with stage IIIc/IV ovarian cancer randomised to NACT followed by interval debulking surgery (IDS) or PDS followed by chemotherapy. We pooled results of the three studies where data were available and found little or no difference with regard to overall survival (OS) (1521 women; hazard ratio (HR) 1.06; 95% confidence interval (CI) 0.94 to 1.19, I2 = 0%; moderate-certainty evidence) or progression-free survival in four trials where we were able to pool data (1631 women; HR 1.02; 95% CI 0.92 to 1.13, I2 = 0%; moderate-certainty evidence). Adverse events, surgical morbidity and quality of life (QoL) outcomes were poorly and incompletely reported across studies. There may be clinically meaningful differences in favour of NACT compared to PDS with regard to serious adverse effects (SAE grade 3+). These data suggest that NACT may reduce the risk of need for blood transfusion (risk ratio (RR) 0.80; 95% CI 0.64 to 0.99; four studies,1085 women; low-certainty evidence), venous thromboembolism (RR 0.28; 95% CI 0.09 to 0.90; four studies, 1490 women; low-certainty evidence), infection (RR 0.30; 95% CI 0.16 to 0.56; four studies, 1490 women; moderate-certainty evidence), compared to PDS. NACT probably reduces the need for stoma formation (RR 0.43, 95% CI 0.26 to 0.72; two studies, 581 women; moderate-certainty evidence) and bowel resection (RR 0.49, 95% CI 0.26 to 0.92; three studies, 1213 women; moderate-certainty evidence), as well as reducing postoperative mortality (RR 0.18; 95% CI 0.06 to 0.54:five studies, 1571 women; moderate-certainty evidence). QoL on the EORTC QLQ-C30 scale produced inconsistent and imprecise results in two studies (MD -1.34, 95% CI -2.36 to -0.32; participants = 307; very low-certainty evidence) and use of the QLQC-30 and QLQC-Ov28 in another study (MD 7.60, 95% CI 1.89 to 13.31; participants = 217; very low-certainty evidence) meant that little could be inferred. AUTHORS' CONCLUSIONS: The available moderate-certainty evidence suggests there is little or no difference in primary survival outcomes between PDS and NACT. NACT may reduce the risk of serious adverse events, especially those around the time of surgery, and the need for bowel resection and stoma formation. These data will inform women and clinicians and allow treatment to be tailored to the person, taking into account surgical resectability, age, histology, stage and performance status. Data from an unpublished study and ongoing studies are awaited.

Mindfulness-Based Relapse Prevention in a Jail Drug Treatment Program.

BACKGROUND: More than half of prisoners in the United States are estimated to suffer from a substance use disorder. Mindfulness involves attention to the present moment, and nonjudgmental acceptance of sensations, thoughts, and emotional states. Mindfulness-based relapse prevention (MBRP) following substance use disorder treatment has been shown to reduce substance use. OBJECTIVE: We sought to adapt and test MBRP for a jail substance use disorder treatment setting. METHODS: We enrolled successive cohorts of incarcerated men participating in a drug treatment program in a large urban jail (n = 189) into six weekly sessions of either MBRP or an comparison communication skills intervention, between 2013 and 2015. MBRP was delivered by a culturally competent African-American trainer. Pre- and post-test measures included mindfulness, anxiety, posttraumatic stress disorder (PTSD), and drug craving. RESULTS: At baseline, measures of mindfulness were significantly inversely correlated with anxiety, PTSD symptoms and drug cravings. Anxiety, PTSD symptoms and cravings declined significantly in both treatment arms, and mindfulness increased. Comparison of the two study arms using maximum likelihood estimation suggested a small but significantly greater increase in mindfulness in the treatment arm. Conclusions/Importance. An attention control trial of a mindfulness intervention, delivered by a culturally competent trainer, is feasible in a jail setting.

Epidermal growth factor receptor blockers for the treatment of ovarian cancer.

BACKGROUND: This is an update of a previously published version of the review (Issue 10, 2011).Epithelial ovarian cancer (EOC) is the seventh most common cause of cancer death among women worldwide. Treatment consists of a combination of surgical debulking and platinum-based chemotherapy. Between 55% and 75% of women who respond to first-line therapy experience relapse within two years. Second-line chemotherapy is palliative and aims to reduce symptoms and prolong survival. Improved understanding about the molecular basis of EOC has led to the development of novel agents, such as epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors and anti-EGFR antibodies. OBJECTIVES: To compare the effectiveness and harmful effects of interventions that target the epidermal growth factor receptor in the treatment of epithelial ovarian cancer (EOC). SEARCH METHODS: We searched the Cochrane Gynaecological Cancer Group Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL; 2010, Issue 4), MEDLINE, and Embase up to October 2010. We also searched registers of clinical trials, abstracts of scientific meetings, and reference lists of included studies, and we contacted experts in the field. This update includes further searches up to September 2017. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing anti-EGFR agents with or without conventional chemotherapy versus conventional chemotherapy alone or no treatment in women with histologically proven EOC. DATA COLLECTION AND ANALYSIS: Two review authors independently abstracted data, assessed risk of bias, and performed GRADE assessment. MAIN RESULTS: From 6105 references obtained through the literature search and an additional 15 references derived from grey literature searches, we identified seven RCTs that met our inclusion criteria and included 1725 participants. Trial results show that after first-line chemotherapy is provided, maintenance treatment with erlotinib (EGFR tyrosine kinase inhibitor (TKI)) probably makes little or no difference in overall survival (hazard ratio (HR) 0.99, 95% confidence interval (CI) 0.81 to 1.20; one study; 835 participants; low-certainty evidence) and may make little or no difference in progression-free survival (HR 1.05, 95% CI 0.90 to 1.23; one study; 835 participants; very low-certainty evidence). Less than 50% of participants provided quality of life data, and study authors reported these results incompletely. The certainty of evidence is very low, but treatment may reduce quality of life compared to observation.Treatment with an EGFR TKI (vandetanib) for women with relapsed EOC may make little or no difference in overall survival (HR 1.25, 95% CI 0.80 to 1.95; one study; 129 participants; low-certainty evidence) and may make little or no difference in progression-free survival (HR 0.99, 95% CI 0.69 to 1.42; one study; 129 participants; very low-certainty evidence). In treating patients with relapse, giving EGFR TKI may slightly increase some toxicities, such as severe rash (risk ratio (RR) 13.63, 95% CI 0.78 to 236.87; one study; 125 participants; very low-certainty evidence). Quality of life data were not available for meta-analysis.Anti-EGFR antibody treatment in relapsed EOC may or may not make a difference to overall survival (HR 0.93, 95% CI 0.74 to 1.18; four studies; 658 participants; moderate-certainty evidence) and may or may not have any effect on progression-free survival (HR 0.90, 95% CI 0.70 to 1.16; four studies; 658 participants; low-certainty evidence). Anti-EGFR antibody treatment may or may not increase side effects, including severe nausea and/or vomiting (RR 1.27, 95% CI 0.56 to 2.89; three studies; 503 participants; low-certainty evidence), severe fatigue (RR 1.06, 95% CI 0.66 to 1.73; I² = 0%; four studies; 652 participants; low-certainty evidence), and hypokalaemia (RR 2.01, 95% CI 0.80 to 5.06; I² = 0%; three studies; 522 participants; low-certainty evidence). Severe diarrhoea rates were heterogeneous across studies (RR 2.87, 95% CI 0.59 to 13.89; four studies; 652 participants; low-certainty evidence), and subgroup analysis revealed that severe diarrhoea was more likely with pertuzumab (RR 6.37, 95% CI 1.89 to 21.45; I² = 0%; three studies; 432 participants; low-certainty evidence) than with seribantumab treatment (RR 0.38, 95% CI 0.07 to 2.23; I² = 0%; one study; 220 participants; very low-certainty evidence). Quality of life data were incompletely reported, and we were unable to combine them in a meta-analysis. AUTHORS' CONCLUSIONS: Current evidence suggests that an anti-EGFR single-agent biological treatment (EGFR TKI or anti-EGFR antibody) makes little or no difference to survival, either as maintenance treatment after first-line chemotherapy or in association with chemotherapy in recurrent cancer. Anti-EGFR therapy may increase some side effects and may or may not reduce quality of life.

A Next Generation Synthesis of BACE1 Inhibitor Verubecestat (MK-8931).

The development of a commercial manufacturing route to verubecestat (MK-8931) is described, highlights of which include the application of a continuous processing step to outcompete fast proton transfer in a Mannich-type ketimine addition, a copper-catalyzed amidation reaction, and an optimized guanidinylation procedure to form the key iminothiadiazine dioxide core.

Untargeted Metabotyping Lolium perenne Reveals Population-Level Variation in Plant Flavonoids and Alkaloids.

Metabolomics provides a powerful platform to characterize plants at the biochemical level, allowing a search for underlying genes and associations with higher level complex traits such as yield and nutritional value. Efficient and reliable methods to characterize metabolic variation in economically important species are considered of high value to the evaluation and prioritization of germplasm and breeding lines. In this investigation, a large-scale metabolomic survey was performed on a collection of diverse perennial ryegrass (Lolium perenne L.) plants. A total of 2,708 data files, derived from liquid chromatography coupled to high resolution mass spectrometry (LCMS), were selected to assess the effectiveness and efficiency of applying high throughput metabolomics to survey chemical diversity in plant populations. The data set was generated from 23 ryegrass populations, with 3-25 genotypes per population, and five clonal replicates per genotype. We demonstrate an integrated approach to rapidly mine and analyze metabolic variation from this large, multi-batch LCMS data set. After performing quality control, statistical data mining and peak annotation, a wide range of variation for flavonoid glycosides and plant alkaloids was discovered among the populations. Structural variation of flavonoids occurs both in aglycone structures and acetylated/malonylated/feruloylated sugar moieties. The discovery of comprehensive metabolic variation among the plant populations offers opportunities to probe into the genetic basis of the variation, and provides a valuable resource to gain insight into biochemical functions and to relate metabolic variation with higher level traits in the species.

Assessing Implicit Cognition Among Patients Lost to Follow-up for HIV Care: A Preliminary Study.

OBJECTIVE: While a growing body of research indicates that implicit cognitive processes play an important role in a range of health behaviors, the assessment of these impulsive, associative mental processes among patients living with HIV has received little attention. This preliminary study explored how multidimensional scaling (MDS) could be used to assess implicit cognitive processes among patients lost to follow-up for HIV care and develop interventions to improve their engagement. METHOD: The sample consisted of 33 patients who were identified as lost to follow up for HIV care at two urban hospitals. Participants were randomly assigned to either the MDS assessment program or control group. All participants underwent measures designed to gauge behavioral change intentions and treatment motivation. Assessment group participants were interviewed to determine their reactions to the assessment program. RESULTS: The MDS assessment program identified cognitive processes and their relationship to treatment-related behaviors among assessment group participants. Assessment group participants reported significantly greater behavior change intentions than those in the control group (p =.02; Cohen's d = 0.84). CONCLUSION: MDS shows promise as a tool to identify implicit cognitive processes related to treatment-related behaviors. Assessments based on MDS could serve as the basis for patient-centered clinical interventions designed to improve treatment adherence and HIV care engagement in general.

Intramolecular Hydrogen Transfer Reactions Catalyzed by Pentamethylcyclopentadienyl Rhodium and Cobalt Olefin Complexes: Mechanistic Studies.

The mechanism of intramolecular transfer dehydrogenation catalyzed by [Cp*M(VTMS)2] (1, M=Rh, 2, M=Co, Cp* = C5Me5, VTMS = vinyltrimethylsilane) complexes has been studied using vinyl silane protected alcohols as substrates. Deuterium-labeled substrates have been synthesized and the regioselectivity of H/D transfers investigated using 1H and 2H NMR spectroscopy. The labeling studies establish a regioselective pathway consisting of alkene directed α C-H activation, 2,1 alkene insertion, and finally ß-hydride elimination to give silyl enol ether products.

Prison Meditation Movements and Mass Incarceration.

By some estimates, more than half of inmates held in jails and prisons in the United States have a substance use disorder. Treatments involving the teaching of meditation and other contemplative practices have been developed for a variety of physical and mental disorders, including drug and alcohol addiction. At the same time, an expanding volunteer movement across the country has been bringing meditation and yoga into jails and prisons. This review first examines the experimental research on one such approach-mindfulness meditation as a treatment for drug and alcohol addiction, as well as the research on mindfulness in incarcerated settings. We argue that to make a substantial impact on recidivism, such programs must mirror volunteer programs which emphasize interdependency and non-duality between the "helper" and the "helped," and the building of meditation communities both inside and outside of prison.