Mechanistic Investigation of Ni-Catalyzed Reductive Cross-Coupling of Alkenyl and Benzyl Electrophiles.

Mechanistic investigations of the Ni-catalyzed asymmetric reductive alkenylation of N-hydroxyphthalimide (NHP) esters and benzylic chlorides are reported. Investigations of the redox properties of the Ni-bis(oxazoline) catalyst, the reaction kinetics, and mode of electrophile activation show divergent mechanisms for these two related transformations. Notably, the mechanism of C(sp3) activation changes from a Ni-mediated process when benzyl chlorides and Mn0 are used to a reductant-mediated process that is gated by a Lewis acid when NHP esters and tetrakis(dimethylamino)ethylene is used. Kinetic experiments show that changing the identity of the Lewis acid can be used to tune the rate of NHP ester reduction. Spectroscopic studies support a NiII-alkenyl oxidative addition complex as the catalyst resting state. DFT calculations suggest an enantiodetermining radical capture step and elucidate the origin of enantioinduction for this Ni-BOX catalyst.

Enantioselective Synthesis of N-Benzylic Heterocycles by Ni/Photoredox Dual Catalysis.

An asymmetric cross-coupling of α-N-heterocyclic trifluoroborates with aryl bromides using Ni/photoredox dual catalysis has been developed. This C(sp2)-C(sp3) cross-coupling provides access to pharmaceutically relevant chiral N-benzylic heterocycles in good to excellent enantioselectivity when bioxazolines (BiOX) are used as the chiral ligand. High-throughput experimentation significantly streamlined reaction development by identifying BiOX ligands for further investigation and by allowing for rapid optimization of conditions for new trifluoroborate salts.

The CKD Stress Scale: Development and identification of patients at risk.

AIMS: Develop a novel chronic kidney disease (CKD)-specific stress scale and examine associations with patient characteristics. MATERIALS AND METHODS: Adults with CKD stages 1 - 5 enrolled in a cross-sectional survey. Eight questions assessed patients' thoughts and feelings of stress related to CKD (CKD Stress Scale). Patients also reported their knowledge of CKD, barriers to CKD health, and demographics. The scale was evaluated using exploratory factor analysis and Cronbach's alpha. Associations were examined via linear regression. RESULTS: 245 participant enrolled with a mean age of 60 years and a mean estimated glomerular filtration rate (eGFR) of 34 mL/min/1.73m2; 49% were women (match percentage in Table 1), 74% White, 14% African American. A one-factor model of CKD Stress exhibited high internal consistency (α = 0.89). In bivariate analyses, higher CKD Stress was associated with lower eGFR, younger age, African American race (compared to White), and having a high school education or some college (compared to college degree or higher). Adjusting for these characteristics, as well as income and knowledge about CKD, only lower eGFR (b = -0.01; 95% CI [-0.01, -0.001]), younger age (b = -0.01; 95% CI [-0.01, -0.003]), African American race (b = 0.35, 95% CI [0.10, 0.60]), and receiving a high school education or some college (b = 0.20, 95% CI [0.01, 0.39]) were independently associated with more CKD-specific stress. Concurrent validity was supported by associations between stress and perceived barriers to care. CONCLUSION: Our CKD Stress Scale exhibits excellent internal reliability and identified where future educational interventions may benefit from tailoring for at-risk patients.

Surrogate Satisfaction with Decision Making After Intracerebral Hemorrhage.

BACKGROUND/OBJECTIVE: Surrogate decision makers for patients with intracerebral hemorrhage (ICH) are frequently asked to make difficult decisions on use of life-sustaining treatments. We explored ICH surrogate satisfaction with decision making and experience of decision regret using validated measures in a prospective multicenter study. METHODS: Cases of non-traumatic ICH were enrolled from three hospitals (September 2015-December 2016), and surrogate decision makers were invited to complete a self-administered survey. The primary outcome was the 10-item decision-making subscale of the Family Satisfaction in the Intensive Care Unit scale (FSICU-DM, range 0-100, higher is greater satisfaction), and the secondary outcome was the decision regret scale (range 0-100, higher is greater regret). Linear regression models were used to assess the association between satisfaction with decision making and pre-specified covariates using manual backward selection. RESULTS: A total of 73 surrogates were approached for participation (in person or mail), with 48 surrogates returning a completed survey (median surrogate age 60.5 years, 63% female, 77% white). Patients had a median age of 72.5, 54% were female, with a median admission Glasgow coma scale of 10, in-hospital mortality of 31%, and 56% with an in-hospital DNR order. Physicians commonly made treatment recommendation (> 50%) regarding brain surgery or transitions to comfort measures, but rarely made recommendations (< 20%) regarding DNR orders. Surrogate satisfaction with decision making was generally high (median FSICU-DM 85, IQR 57.5-95). Factors associated with higher satisfaction on multivariable analysis included greater use of shared decision making (P < 0.0001), younger patient age (p = 0.02), ICH score of 3 or higher (p = 0.03), and surrogate relationship (spouse vs. other, p = 0.02). Timing of DNR orders was not associated with satisfaction (P > 0.25). Decision regret scores were generally low (median 12.5, IQR 0-31.3). CONCLUSIONS: Considering the severity and abruptness of ICH, it is reassuring that surrogate satisfaction with decision making was generally high and regret was generally low. However, more work is needed to define the appropriate outcome measures and optimal methods of recruitment for studies of surrogate decision makers of ICH patients.

Synthesis strategies for non-symmetric, photochromic diarylethenes.

Diarylethenes (DAEs) represent an important class of photochromes with notable characteristics, like thermally irreversible photoisomerization and high fatigue resistance. Structural diversification of the DAE scaffold has enabled further refinement of photochromic properties and realization of new applications, ranging from advanced materials to tools for studying biological systems. In particular, methods for synthesizing non-symmetric DAE scaffolds, which are typically more challenging to synthesize than their symmetric counterparts, have grown over the past 20 years. These developments are surveyed in this review, with discussion of how access to these compounds has contributed to the improvement of photochromic properties and paved the way for exploring new applications of DAEs. First, non-symmetric DAE structures are classified and their uses and applications are overviewed. Subsequent sections discuss the main strategies that have been used to access non-symmetric DAEs with examples illustrating the impact of non-symmetric DAEs in the growing field of light-controlled molecular systems.

Development and usability testing of Understanding Stroke, a tailored life-sustaining treatment decision support tool for stroke surrogate decision makers.

BACKGROUND: Surrogate decision makers of stroke patients are often unprepared to make critical decisions on life-sustaining treatments. We describe the development process and key features for the Understanding Stroke web-based decision support tool. METHODS: We used multiple strategies to develop a patient-centered, tailored decision aid. We began by forming a Patient and Family Advisory Council to provide continuous input to our multidisciplinary team on the development of the tool. Additionally, focus groups consisting of nurses, therapists, social workers, physicians, stroke survivors, and family members reviewed key elements of the tool, including prognostic information, graphical displays, and values clarification exercise. To design the values clarification exercise, we asked focus groups to provide feedback on a list of important activities of daily living. An ordinal prognostic model was developed for ischemic stroke and intracerebral hemorrhage using data taken from the Virtual International Stroke Trials Archive Plus, and incorporated into the tool. RESULTS: Focus group participants recommended making numeric prognostic information optional due to possible emotional distress. Pie charts were generally favored by participants for graphical presentation of prognostic information, though a horizontal stacked bar chart was also added due to its prevalence in stroke literature. Plain language descriptions of the modified Rankin Scale were created to accompany the prognostic information. A values clarification exercise was developed consisting of a list of 13 situations that may make an individual consider comfort measures only. The final version of the web based tool (which can be viewed on tablets) included the following sections: general introduction to stroke, outcomes (prognostic information and recovery), in-hospital and life-sustaining treatments, decision making and values clarification, post-hospital care, tips for talking to the health care team, and a summary report. Preliminary usability testing received generally favorable feedback. CONCLUSION: We developed Understanding Stroke, a tailored decision support tool for surrogate decision makers of stroke patients. The tool was well received and will be formally pilot tested in a group of stroke surrogate decision makers. TRIAL REGISTRATION: ClinicalTrials.gov ( NCT03427645 ).

Emotional Experiences and Coping Strategies of Family Members of Critically Ill Patients.

BACKGROUND: Two out of three family members experience symptoms of posttraumatic stress, depression, or anxiety lasting for months after the ICU stay. Interventions aimed at mitigating these symptoms have been unsuccessful. RESEARCH QUESTION: To understand the emotional experiences of family members of critically ill patients and to identify coping strategies used by family members during the ICU stay. STUDY DESIGN: and Methods: As part of a mixed methods study to understand sources of distress among ICU family members, semistructured interviews were conducted with ICU family members. Family members completed surveys at the time of interview and at 90 days to assess for symptoms of depression, anxiety, and posttraumatic stress. RESULTS: Semistructured interviews and baseline surveys were conducted with 40 ICU family members; 78% of participants (n = 31) completed follow-up surveys at 90 days. At the time of interview, 65% of family members had symptoms of depression, anxiety, or posttraumatic stress. At 90 days, 48% of surveyed family members had symptoms of psychological distress. Three primary emotions were identified among ICU family members: sadness, anger, and fear. A diverse array of coping strategies was used by family members, including problem-solving, information seeking, avoidance/escape, self-reliance, support seeking, and accommodation. INTERPRETATION: This study emphasizes similarities in emotions but diversity in coping strategies used by family members in the ICU. Understanding the relationship between ICU experiences, emotional responses, and long-term psychological outcomes may guide targeted interventions to improve mental health outcomes of ICU family members.

Surrogate Decision Makers' Perspectives on Family Members' Prognosis after Intracerebral Hemorrhage.

BACKGROUND: Surrogate communication with providers about prognosis in the setting of acute critical illness can impact both patient treatment decisions and surrogate outcomes. OBJECTIVES: To examine surrogate decision maker perspectives on provider prognostic communication after intracerebral hemorrhage (ICH). DESIGN: Semistructured interviews were conducted and analyzed qualitatively for key themes. SETTING/SUBJECTS: Surrogate decision makers for individuals admitted with ICH were enrolled from five acute care hospitals. RESULTS: Fifty-two surrogates participated (mean age = 54, 60% women, 58% non-Hispanic white, 13% African American, 21% Hispanic). Patient status at interview was hospitalized (17%), in rehabilitation/nursing facility (37%), deceased (38%), hospice (4%), or home (6%). Nineteen percent of surrogates reported receiving discordant prognoses, leading to distress or frustration in eight cases (15%) and a change in decision for potentially life-saving brain surgery in three cases (6%). Surrogates were surprised or confused by providers' use of varied terminology for the diagnosis (17%) (e.g., "stroke" vs. "brain hemorrhage" or "brain bleed") and some interpreted "stroke" as having a more negative connotation. Surrogates reported that physicians expressed uncertainty in prognosis in 37%; with physician certainty in 56%. Surrogate reactions to uncertainty were mixed, with some surrogates expressing a negative emotional response (e.g., anxiety) and others reporting understanding or acceptance of uncertainty. CONCLUSIONS: Current practice of prognostic communication in acute critical illness has many gaps, leading to distress for surrogates and variability in critical treatment decisions. Further work is needed to limit surrogate distress and improve the quality of treatment decisions.