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Strained cyclic organic molecules, such as arynes, cyclic alkynes and cyclic allenes, have intrigued chemists for more than a century with their unusual structures and high chemical reactivity 1 . The considerable ring strain (30–50 kilocalories per mole) 2 , 3 that characterizes these transient intermediates imparts high reactivity in many reactions, including cycloadditions and nucleophilic trappings, often generating structurally complex products 4 . Although strategies to control absolute stereochemistry in these reactions have been reported using stoichiometric chiral reagents 5 , 6 , catalytic asymmetric variants to generate enantioenriched products have remained difficult to achieve. Here we report the interception of racemic cyclic allene intermediates in a catalytic asymmetric reaction and provide evidence for two distinct mechanisms that control absolute stereochemistry in such transformations: kinetic differentiation of allene enantiomers and desymmetrization of intermediate π-allylnickel complexes. Computational studies implicate a catalytic mechanism involving initial kinetic differentiation of the cyclic allene enantiomers through stereoselective olefin insertion, loss of the resultant stereochemical information, and subsequent introduction of absolute stereochemistry through desymmetrization of an intermediate π-allylnickel complex. These results reveal reactivity that is available to cyclic allenes beyond the traditional cycloadditions and nucleophilic trappings previously reported, thus expanding the types of product accessible from this class of intermediates. Additionally, our computational studies suggest two potential strategies for stereocontrol in reactions of cyclic allenes. Combined, these results lay the foundation for the development of catalytic asymmetric reactions involving these classically avoided strained intermediates. Asymmetric nickel catalysis is used to intercept transient cyclic allene intermediates to achieve stereocontrol.

Background Obstructive sleep apnea (OSA) and insomnia are commonly co-occurring conditions that amplify morbidity and complicates the management of affected patients. Unfortunately, previous research provides limited guidance as to what constitutes the best and most practical management approach for this comorbid patient group. Some preliminary studies show that when cognitive behavioral insomnia therapy (CBT-I) is combined with standard OSA therapies for these patients, outcomes are improved. However, the dearth of trained providers capable of delivering CBT-I has long served as a pragmatic barrier to the widespread use of this therapy in clinical practice. The emergence of sophisticated online CBT-I (OCBT-I) programs could improve access, showing promising reductions in insomnia severity. Given its putative scalability and apparent efficacy, some have argued OCBT-I should represent a 1st-stage intervention in a broader stepped care model that allocates more intensive and less assessable therapist-delivered CBT-I (TCBT-I) only to those who show an inadequate response to lower intensity OCBT-I. However, the efficacy of OCBT-I as a 1st-stage therapy within a broader stepped care management strategy for insomnia comorbid with OSA has yet to be tested with comorbid OSA/insomnia patients. Methods/design This dual-site randomized clinical trial will use a Sequential Multiple Assignment Randomized Trial (SMART) design to test a stepped care model relative to standard positive airway pressure (PAP) therapy and determine if (1) augmentation of PAP therapy with OCBT-I improves short-term outcomes of comorbid OSA/insomnia and (2) providing a higher intensity 2nd-stage CBT-I to patients who show sub-optimal short-term outcomes with OCBT-I+PAP improves short and longer-term outcomes. After completing baseline assessment, the comorbid OSA/insomnia patients enrolled will be randomized to a 1st-stage therapy that includes usual care PAP + OCBT-I or UC (usual care PAP + sleep hygiene education). Insomnia will be reassessed after 8 weeks. OCBT-I recipients who meet “remission” criteria (defined as an Insomnia Severity Index score < 10) will continue PAP but will not be offered any additional insomnia intervention and will complete study outcome measures again after an additional 8 weeks and at 3 and 6 month follow-ups. OCBT-I recipients classified as “unremitted” after 8 weeks of treatment will be re-randomized to a 2nd-stage treatment consisting of continued, extended access to OCBT-I or a switch to TCBT-I. Those receiving the 2nd-stage intervention as well as the UC group will be reassessed after another 8 weeks and at 3- and 6-month follow-up time points. The primary outcome will be insomnia remission. Secondary outcomes will include subjective and objective sleep data, including sleep time, sleep efficiency, fatigue ratings, PAP adherence, sleepiness ratings, sleep/wake functioning ratings, and objective daytime alertness. Discussion This study will provide new information about optimal interventions for patients with comorbid OSA and insomnia to inform future clinical decision-making processes. Trial registration ClinicalTrials.gov, NCT03109210 , registered on April 12, 2017, prospectively registered.

Introduction Many patients have difficulties achieving hypnotic discontinuation due to anxiety that arises when they knowingly reduce their hypnotic dose or withhold it entirely. This study is testing a blinded tapering approach designed to reduce patients’ anxiety during the hypnotic tapering process. Methods Thus far, a sample of 44 (M age = 59.1±14.1 yrs.; 61.4% women) users of benzodiazepine (BZD) or newer generation benzodiazepine receptor agonists (BZRA) have enrolled in this trial and completed a 3-month post-tapering follow-up. Following baseline assessments that included completion of the insomnia severity index (ISI), these enrollees completed 4 sessions of cognitive behavioral insomnia therapy (CBTI). Subsequently they were randomized to one of two 10-week, tapering protocols wherein their medication dosage was reduced by 25% every two weeks either in a blinded or open-label manner. Medication usage was assessed and ISI scores were obtained at the end of the tapering phase and at a 3-month follow-up. Results A linear mixed model analysis showed only an effect for time in study on ISI scores with both tapering groups showing a significant (F = 36.89; p = .0001) decline in these scores from baseline through the 3-month follow-up. By the 3-month follow-up, a slightly, albeit non-significantly, higher proportion of the blinded tapering group (76.2%) were no longer using their BZD/BZRA hypnotics than in the open label group (60.9%). However, there was a significantly higher BZD/BZRA discontinuation rate by the 3-month follow-up among those who achieved ISI score-determined insomnia remission than among unremitted participants both for the sample as a whole (85% vs. 54.2%; p = .05) and for the open label group (88.9% vs. 42.9%; p = .0397) considered separately. This difference between remitted and unremitted participants was not seen in the blinded tapering group. Conclusion Early findings in this trial suggest a slight advantage to blinded over open label hypnotic tapering in achieving hypnotic discontinuation. Moreover, insomnia remission may not be essential for hypnotic discontinuation when blinded tapering is conducted. Support (if any) National Institute of Drug Abuse, Grant # 1R01DA047341-01A1

Introduction Many patients have difficulties achieving hypnotic discontinuation due to anxiety that arises when they knowingly reduce their hypnotic dose or withhold it entirely. This study tested a blinded tapering approach to reduce patients’ anxiety and help them discontinue their hypnotics. Methods The study sample included 78 (M age = 55.2 ± 12.8 yrs.; 65.4% women) users of benzodiazepine and benzodiazepine receptor agonists. Following baseline assessments, enrollees first completed 4 sessions of cognitive behavioral insomnia therapy (CBTI). Subsequently they were randomized to one of three 20-week, double-blinded tapering protocols wherein their medication dosage either remained unchanged (CTRL) or was reduced by 25% or 10% every two weeks. At the end of the 20-week period the study blind was eliminated and those who completed one of the two blinded tapering protocols entered a 3-month follow-up period, whereas CTRL participants were offered an open label taper before completing the follow-up. Results Among those who completed one of the blinded tapering protocols, 92.9% totally discontinued their medication use by the end of the 20-week tapering phase, whereas 77.3% in the CTRL group discontinued hypnotic use by the end of their open label tapering. At follow-up 72.1% of those who completed blinded tapering remained medication free whereas only 52% of those who underwent open-label tapering remained medication free. Comparisons at follow-up showed those who received the open-label taper continued to use hypnotics on average 2.06 nights/week compared to .051 times per week for the blinded taper group (p = .042). The average weekly diazepam equivalent dose of medication used by the open label tapering group was 11.29 mg whereas the weekly dose for the blinded tapering group was 3.22 (p = .069). Conclusion CBTI combined with blinded hypnotic tapering is a promising treatment approach for helping hypnotic users overcome their medication dependence. Support (if any) National Institute of Drug Abuse, Grant # R34 DA042329-01

Introduction Prior studies have shown that CBTI improves patient reported outcomes including daytime fatigue, mood status and quality of life, yet there are limited data concerning the effects of therapy on objective measures of daytime function. The current study tested the effects of CBTI on measures derived from the psychomotor vigilance test (PVT) in a sample of patients with comorbid insomnia disorder and sleep apnea. Methods Patients with insomnia and comorbid OSA, who were prescribed PAP therapy (N =155; Mage= 56.8±12.5 yrs.; 58.1% women) were randomized to digital CBTI (dCBTI) or Sleep Hygiene (CTRL). They completed PVT at baseline and after 8 weeks of treatment. Patients in the dCBTI arm who reached remission were offered no additional insomnia treatment, whereas those who did not were randomly assigned to 8 weeks of continued access to dCBTI or to a therapist delivered CBTI. Patients again completed the PVT after this second 8-week treatment phase. PVT outcome measures included mean reaction time, attentional lapses and efficiency scores. Linear mixed models were used to compare the PVT measures of patients receiving either of the CBTI treatment sequences with those assigned to the CTRL. Results Analyses showed significant group x time interactions for PVT attentional lapses (F = 3.04; p < .05) and for efficiency scores (F= 4.06; p< .025). Those who received either of the CBTI treatment sequences showed a greater reduction in attentional lapses and greater improvement in their efficiency scores from baseline to the post-treatment assessments than did those assigned the CTRL. Conclusion Findings indicate that CBTI improves objective indices of daytime cognitive functioning among those with comorbid apnea and insomnia disorder. Further tests of CBTI’s effects on these and other measures of cognitive functioning are warranted in other samples of insomnia patients who do and do not have medical, psychiatric and sleep disorder comorbidities. Support (if any) Funding support from the National Heart, Lung and Blood Institute, Grant # 1R01HL130559-01A1.

Abstract Study Objectives It is common to provide insomnia patients a second treatment when the initial treatment fails, but little is known about optimal treatment sequences for different patient types. This study examined whether pre-treatment characteristics/traits predict optimal treatment sequences for insomnia patients. Methods A community sample of 211 adults (132 women; Mage = 45.6 ± 14.9 years) with insomnia were recruited. Patients were first treated with behavioral therapy (BT) or zolpidem (Zol). Non-remitting BT recipients were randomized to a second treatment with either Zol or cognitive therapy; non-remitting Zol recipients underwent BT or Trazodone as a second treatment. Remission rates were assessed at the end of the first and second 6-week treatments. We then compared the remission rates of dichotomous groups formed on the basis of gender, age, pretreatment scores on SF36 and Multidimensional Fatigue Scale, the presence/absence of psychiatric/medical comorbidities or pain disorders, and mean subjective sleep duration and efficiency within and across treatment sequences. Results Lower remission rates were noted for those: with a pain disorder, poor mental health perceptions, high MFI fatigue scores, and lower sleep times and efficiencies. Patients with a pain disorder responded best to the BT-to-Zol sequence, whereas patients with more mental impairment, severe fatigue, short sleep, and low sleep efficiency responded poorly to treatment starting with BT. Conclusions Pain, fatigue, poor mental health status, and subjective sleep duration and efficiency all affect response to different insomnia treatment sequences. Findings may guide clinicians in matching insomnia treatments to their patients. Clinical Trial Registration ClinicalTrials.gov Identifier: NCT01651442, Protocol version 4, April 20, 2011, registered June 26, 2012, https://clinicaltrials.gov/ct2/show/NCT01651442?rslt=With&type=Intr&cond=Insomnia&cntry=US&state=US%3ACO&city=Denver&age=12&draw=2&rank=1.

Background: Hospitalized patients are at an increased risk of invasive infection with Staphylococcus aureus when colonized with the bacteria on admission. Rates of methicillin-resistant Staphylococcus aureus (MRSA) bacteremia are directly correlated with overall patient acuity, placing patients in intensive care areas at greatest risk. Universal decolonization with nasal antibiotic ointments has been shown to reduce the incidence of invasive MRSA in critically ill patients; however, debate remains regarding the long-term efficacy of this strategy and the possibility of developing antimicrobial resistance. An alcohol-based nasal antimicrobial may be an effective alternative. This study evaluated the effectiveness of a twice daily alcohol-based product in reducing the rate of MRSA bacteremia in an academic tertiary-care adult intensive care setting. Methods: Our study was an observational design with retrospective and prospective cohorts each consisting of 61 critical care beds. The baseline incidence of MRSA bacteremia was determined from a 7-month period preceding the implementation of the nasal antimicrobial. At implementation, each admission received an electronic order for an alcohol-based nasal antiseptic that was applied twice daily during the intensive care stay. The primary outcome was the incidence of MRSA bacteremia in each group. MRSA bacteremia was defined by the CDC NHSN criteria after review by an infection prevention nurse. The 2 test was used to compare the rates between the 2 groups, and P < .005 was considered significant. Results: The study periods contained similar patient days, with 12,475 in the retrospective group and 12,733 in the prospective group. The rate of MRSA bacteremia in the retrospective cohort was 0.2404 compared to 0 in the prospective cohort. This rate change was statistically significant, with P < .0001. Conclusions: The alcohol-based nasal antiseptic was effective in reducing healthcare-onset MRSA bacteremia in this intensive care population. This approach may be a safe and effective alternative to nasal antibiotic ointment that avoids antibiotic resistance risks. Funding: None Disclosures: None

Study Objectives: Cognitive behavioral therapy for insomnia (CBTI) has been paired with supervised medication tapering to help hypnotic-dependent individuals discontinue their hypnotics. This study examined the hypothesis that higher participant adherence to behavioral recommendations of CBTI will predict lower odds of using sleep medications 3 months after completion of a combined CBTI/sleep medication tapering protocol. Methods: Fifty-eight individuals who used sedative hypnotics completed four CBTI sessions followed by sleep medication tapering. Logistic regression was used to examine the association of stability of time in bed and stability of rise time (measured as the within-person standard deviation) at completion of CBTI with two outcomes at 3-month follow-up: use of sedative hypnotics and use of any medication/substance for sleep. Results: Participants with more stability in their rise time after CBTI than at baseline (ie, a decrease in their within-person standard deviation) had 69.5% lower odds of using sedative hypnotics at follow-up (odds ratio = 0.305, 95% confidence interval = 0.095–0.979, P = .046) than individuals who had no change or a decrease in the stability of their rise time. Results were similar for time in bed: participants with more stability in their time in bed after CBTI than at baseline had 83.2% lower odds of using sedative hypnotics (odds ratio = 0.168, 95% confidence interval = 0.049–0.580, P = .005). Increase in stability of rise time and stability of time in bed was also associated with reduced odds of using any medication/substance for sleep at follow-up. Conclusions: Participants who implement behavioral recommendations of CBTI appear to have more success with discontinuing use of sleep medications. Clinical Trial Registration: Registry: ClinicalTrials.gov; Name: The Role of Tapering Pace and Selected Traits on Hypnotic Discontinuation; URL: https://clinicaltrials.gov/ct2/show/NCT02831894 ; Identifier: NCT02831894. Citation: Edinger JD, Wamboldt FS, Johnson RL, et al. Adherence to behavioral recommendations of cognitive behavioral therapy for insomnia predicts medication use after a structured medication taper. J Clin Sleep Med . 2023;19(8):1495–1503.

Introduction Hypnotic users commonly make unsuccessful attempts to discontinue their hypnotics. This study tested a blinded tapering approach to reduce anxiety and help patients discontinue their hypnotics. Methods This study enrolled 78 (M age = 55.2 ± 12.8 yrs.; 65.4% women) users of benzodiazepine and benzodiazepine receptor agonists. Enrollees completed baseline measures including the Insomnia Severity Index (ISI). They then completed 4 sessions of cognitive behavioral insomnia therapy (CBTI). Subsequently they were randomized to one of three 20-week, double-blinded tapering protocols wherein their medication dosage was either reduced by 25% or 10% every two weeks, or remained unchanged (CTRL). During tapering, all enrollees were seen biweekly by the study physician for support and guidance. At the end of the 20-week period the study blind was eliminated and those who completed one of the two blinded tapering protocols entered a 3-month follow-up period, whereas CTRL participants are offered an open label taper before completing the follow-up. Results Baseline ISI scores (ISI=18.07±0.58) showed that the total sample entered the trial with moderately severe insomnia complaints despite almost nightly hypnotic use. These scores declined into the mild range after CBTI (10.19±0.53) and tapering (9.62±.63) and approached the normative range by follow-up (7.59±1.05). Of the 45 who completed one of the blinded tapering protocols to date, 39 (86.7%) totally discontinued their medication use by the end of the 20-week tapering phase whereas 12 (75%) of 16 in the CTRL group discontinued hypnotic use by the end of their open label tapering. At follow-up 22 of 30 (73.3%) who completed blinded tapering remained medication free whereas only 5 of 14 (35.7%) in the CTRL group who underwent open-label tapering remained medication free. Conclusion CBTI combined with blinded hypnotic tapering seems a promising treatment approach to help hypnotic users overcome their medication dependence and improve insomnia symptoms. Support (If Any) National Institute of Drug Abuse, Grant # R34 DA042329-01