Intercepting fleeting cyclic allenes with asymmetric nickel catalysis.

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 reactivity1. 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 products4. Although strategies to control absolute stereochemistry in these reactions have been reported using stoichiometric chiral reagents5,6, 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.

Stereocontrolled Radical Thiophosphorylation.

The first practical, fully stereoselective P(V)-radical hydrophosphorylation is presented herein by using simple, limonene-derived reagent systems. A set of reagents have been developed that upon radical initiation react smoothly with olefins and other radical acceptors to generate P-chiral products, which can be further diversified (with conventional 2e- chemistry) to a range of underexplored bioisosteric building blocks. The reactions have a wide scope with excellent chemoselectivity, and the unexpected stereochemical outcome has been supported computationally and experimentally. Initial ADME studies are suggestive of the promising properties of this rarely explored chemical space.

COVID-19 on the Navajo Nation: experiences of Diné families of children with asthma.

OBJECTIVE: The first case of COVID-19 on the Navajo Nation (NN) was found on March 17, 2020. Even with strong public health efforts, NN saw the highest per capita infection rate in the US during May of 2020 with 2450/100,000. To determine the impact of COVID-19 on families of children with asthma on the NN, families participating in the NHLBI funded Community Asthma Program were contacted to see if they would share their experiences. METHODS: Sixty-six of 193 families (34%) were interviewed.Results: The average age of the child with asthma was 13.5 (SD = 3.9) and 33% were female. Most Diné children with asthma in our study did not contract COVID-19. However, the pandemic had a significant impact on them and their families. Many family members contracted COVID-19, some children lost family members, and half of interviewed parents reported a decline in their child's mental health. Twenty-five percent of families sought the help of a traditional healer. Many accessed medical care through telehealth and most were able to obtain asthma medications when needed.Conclusions: Despite significant challenges, our research indicated resilience among Navajo families.

A symmetry-driven approach toward the total synthesis of dodecahedrane.

Herein, we describe our progress toward the total synthesis of dodecahedrane, a complex and highly symmetrical hydrocarbon that bears twelve fused rings arranged in a cage-like architecture. Central to our approach is a late-stage [2+2+2+2+2] polyene cyclization cascade, which is expected to construct five new bonds and ten new rings in a single transformation. Toward this end, we describe efforts to synthesize key monomeric fragments, along with successful dimerization studies using a pinacol coupling approach. Subsequent studies include an attempted olefin metathesis rearrangement cascade in addition to a successful intramolecular photochemical [2+2] reaction. Although attempts to elaborate the photocycloaddition product were unsuccessful, our studies provide access to complex dimeric scaffolds and are expected to help guide our future total synthesis studies.

Chemoselective Electrosynthesis Using Rapid Alternating Polarity.

Challenges in the selective manipulation of functional groups (chemoselectivity) in organic synthesis have historically been overcome either by using reagents/catalysts that tunably interact with a substrate or through modification to shield undesired sites of reactivity (protecting groups). Although electrochemistry offers precise redox control to achieve unique chemoselectivity, this approach often becomes challenging in the presence of multiple redox-active functionalities. Historically, electrosynthesis has been performed almost solely by using direct current (DC). In contrast, applying alternating current (AC) has been known to change reaction outcomes considerably on an analytical scale but has rarely been strategically exploited for use in complex preparative organic synthesis. Here we show how a square waveform employed to deliver electric current-rapid alternating polarity (rAP)-enables control over reaction outcomes in the chemoselective reduction of carbonyl compounds, one of the most widely used reaction manifolds. The reactivity observed cannot be recapitulated using DC electrolysis or chemical reagents. The synthetic value brought by this new method for controlling chemoselectivity is vividly demonstrated in the context of classical reactivity problems such as chiral auxiliary removal and cutting-edge medicinal chemistry topics such as the synthesis of PROTACs.

A direct HDAC4-MAP kinase crosstalk activates muscle atrophy program.

Prolonged deficits in neural input activate pathological muscle remodeling, leading to atrophy. In denervated muscle, activation of the atrophy program requires HDAC4, a potent repressor of the master muscle transcription factor MEF2. However, the signaling mechanism that connects HDAC4, a protein deacetylase, to the atrophy machinery remains unknown. Here, we identify the AP1 transcription factor as a critical target of HDAC4 in neurogenic muscle atrophy. In denervated muscle, HDAC4 activates AP1-dependent transcription, whereas AP1 inactivation recapitulates HDAC4 deficiency and blunts the muscle atrophy program. We show that HDAC4 activates AP1 independently of its canonical transcriptional repressor activity. Surprisingly, HDAC4 stimulates AP1 activity by activating the MAP kinase cascade. We present evidence that HDAC4 binds and promotes the deacetylation and activation of a key MAP3 kinase, MEKK2. Our findings establish an HDAC4-MAPK-AP1 signaling axis essential for neurogenic muscle atrophy and uncover a direct crosstalk between acetylation- and phosphorylation-dependent signaling cascades.

Synthesis of Fused Indolines by Interrupted Fischer Indolization in a Microfluidic Reactor.

This study describes our development of a microfluidic reaction scheme for the synthesis of fused indoline ring systems found in several bioactive compounds. We have utilized a continuous-flow microfluidic reactor for the reaction of hydrazines with latent aldehydes through the interrupted Fischer indolization reaction to form fused indoline and azaindoline products. We have identified optimal conditions and evaluated the scope of this microfluidic reaction using various hydrazine and latent aldehyde surrogates. This green chemistry approach can be of general utility to rapidly produce indoline scaffolds and intermediates in a continuous manner.

Understanding and Interrupting the Fischer Azaindolization Reaction.

Experimental and computational studies pertaining to the Fischer azaindolization reaction are reported. These studies explain why pyridylhydrazines are poorly reactive in Fischer indolization reactions, in addition to the origin of hydrazine substituent effects. Additionally, an interrupted variant of Fischer azaindolization methodology is disclosed, which provides a synthetic entryway into fused azaindoline scaffolds.

Generation and regioselective trapping of a 3,4-piperidyne for the synthesis of functionalized heterocycles.

We report the generation of the first 3,4-piperidyne and its use as a building block for the synthesis of annulated piperidines. Experimental and computational studies of this intermediate are disclosed, along with comparisons to the well-known 3,4-pyridyne. The distortion/interaction model is used to explain the observed regioselectivities.

Adherence to behavioral recommendations of cognitive behavioral therapy for insomnia predicts medication use after a structured medication taper.

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.

An assessment of the relation between metal contaminated sediment and freshwater mussel populations in the Big River, Missouri.

The Big River in southeast Missouri drains the largest historical lead mining area in the United States. Ongoing releases of metal contaminated sediments into this river are well documented and are suspected of suppressing freshwater mussel populations. We characterized the spatial extent of metal contaminated sediments and evaluated its relationship with mussel populations in the Big River. Mussels and sediments were collected at 34 sites with potential metal effects and 3 reference sites. Analysis of sediment samples showed that lead (Pb) and zinc (Zn) concentrations were 1.5 to 65 times greater than background concentrations in the reach extending 168 km downstream from Pb mining releases. Mussel abundance decreased acutely downstream from these releases where sediment Pb concentrations were highest and increased gradually as Pb sediment concentrations attenuated downstream. We compared current species richness with historical survey data from three reference rivers with similar physical habitat characteristics and human effects, but without Pb-contaminated sediment. Big River species richness was on average about one-half that expected based on reference stream populations and was 70-75 % lower in reaches with high median Pb concentrations. Sediment Zn and cadmium, and particularly Pb, had significant negative correlations with species richness and abundance. The association of sediment Pb concentrations with mussel community metrics in otherwise high-quality habitat indicates that Pb toxicity is likely responsible for depressed mussel populations observed within the Big River. We used concentration-response regressions of mussel density verses sediment Pb to determine that the Big River mussel community is adversely affected when sediment Pb concentrations are above 166 ppm, the concentration associated with 50 % decreases in mussel density. Based on this assessment of metals concentrations sediment and mussel fauna, our findings indicate that sediment in approximately 140 km of the Big River with suitable habitat has a toxic effect to mussels.

Effect of Psychological and Medication Therapies for Insomnia on Daytime Functions: A Randomized Clinical Trial.

Importance: Daytime functional impairments are the primary reasons for patients with insomnia to seek treatment, yet little is known about what the optimal treatment is for improving daytime functions and how best to proceed with treatment for patients whose insomnia has not remitted. Objectives: To compare the efficacy of behavioral therapy (BT) and zolpidem as initial therapies for improving daytime functions among patients with insomnia and evaluate the added value of a second treatment for patients whose insomnia has not remitted. Design, Setting, and Participants: In this sequential multiple-assignment randomized clinical trial conducted at institutions in Canada and the US, 211 adults with chronic insomnia disorder were enrolled between May 1, 2012, and December 31, 2015, and followed up for 12 months. Statistical analyses were performed on an intention-to-treat basis in April and October 2023. Interventions: Participants were randomly assigned to either BT or zolpidem as first-stage therapy, and those whose insomnia had not remitted received a second-stage psychological therapy (BT or cognitive therapy) or medication therapy (zolpidem or trazodone). Main Outcomes and Measures: Study outcomes were daytime symptoms of insomnia, including mood disturbances, fatigue, functional impairments of insomnia, and scores on the 36-item Short-Form Health Survey (SF-36) physical and mental health components. Results: Among 211 adults with insomnia (132 women [63%]; mean [SD] age, 45.6 [14.9] years), 104 were allocated to BT and 107 to zolpidem at the first stage. First-stage treatment with BT or zolpidem yielded significant and equivalent benefits for most of the daytime outcomes, including depressive symptoms (Beck Depression Inventory-II mean score change, -3.5 [95% CI, -4.7 to -2.3] vs -4.3 [95% CI, -5.7 to -2.9]), fatigue (Multidimensional Fatigue Inventory mean score change, -4.7 [95% CI, -7.3 to -2.2] vs -5.2 [95% CI, -7.9 to -2.5]), functional impairments (Work and Social Adjustment Scale mean score change, -5.0 [95% CI, -6.7 to -3.3] vs -5.1 [95% CI, -7.2 to -2.9]), and mental health (SF-36 mental health subscale mean score change, 3.5 [95% CI, 1.9-5.1] vs 2.5 [95% CI, 0.4-4.5]), while BT produced larger improvements for anxiety symptoms relative to zolpidem (State-Trait Anxiety Inventory mean score change, -4.1 [95% CI, -5.8 to -2.4] vs -1.2 [95% CI, -3.0 to 0.5]; P = .02; Cohen d = 0.55). Second-stage therapy produced additional improvements for the 2 conditions starting with zolpidem at posttreatment in fatigue (Multidimensional Fatigue Inventory mean score change: zolpidem plus BT, -3.8 [95% CI, -7.1 to -0.4]; zolpidem plus trazodone, -3.7 [95% CI, -6.3 to -1.1]), functional impairments (Work and Social Adjustment Scale mean score change: zolpidem plus BT, -3.7 [95% CI, -6.4 to -1.0]; zolpidem plus trazodone, -3.3 [95% CI, -5.9 to -0.7]) and mental health (SF-36 mental health subscale mean score change: zolpidem plus BT, 5.3 [95% CI, 2.7-7.9]; zolpidem plus trazodone, 2.0 [95% CI, 0.1-4.0]). Treatment benefits achieved at posttreatment were well maintained throughout the 12-month follow-up, and additional improvements were noted for patients receiving the BT treatment sequences. Conclusions and Relevance: In this randomized clinical trial of adults with insomnia disorder, BT and zolpidem produced improvements for various daytime symptoms of insomnia that were no different between treatments. Adding a second treatment offered an added value with further improvements of daytime functions. Trial Registration: ClinicalTrials.gov Identifier: NCT01651442.

Association between insomnia patients' pre-treatment characteristics and their responses to distinctive treatment sequences.

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.

Stepped care management of insomnia co-occurring with sleep apnea: the AIR study protocol.

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.

HDACs in skeletal muscle remodeling and neuromuscular disease.

Skeletal muscle is made of heterogeneous myofibers with different contractile and metabolic properties. The diverse functionality of myofibers enables skeletal muscle to carry out different tasks from maintaining body posture to performing active movements. In addition to motility, skeletal muscle, which constitutes 40% of body mass, is also a key target of insulin action and performs an essential function in glucose metabolism. Adult skeletal muscle is a highly adaptive organ system and can undergo specific changes in contractile and metabolic properties to meet different functional demands. This plasticity of myofibers reflects a highly coordinated change in gene expression program that is controlled by neural activity. The capacity for on-demand remodeling confers skeletal muscle the remarkable adaptability important for animal survival; its dysregulation, however, could contribute to muscle and metabolic diseases. How neural activity dictates transcriptional programming to modify muscle functionality and diversity is a fundamental issue. Recent studies have identified members of class IIa HDACs as important effectors in both physiological and pathological muscle remodeling. By way of modifying myofiber properties, pharmacological manipulation of IIa HDACs activity could have potential therapeutic utility in the treatment of muscle disorders.

The Asthma Toolkit Bootcamp to Improve Rural Primary Care for Pediatric Asthma.

BACKGROUND: Children with asthma living in rural areas receive most of their care from primary care providers who have variable knowledge of evidence-based guideline management. OBJECTIVE: To test the capacity of the Asthma Toolkit Bootcamp program to improve primary care provider guidelines adherence and reduce health care utilization in rural children with asthma. METHODS: The Asthma Toolkit Bootcamp program provided intensive training in National Heart, Lung, and Blood Institute guidelines-based asthma care, evaluated within a RE-AIM implementation science framework. All primary care practices serving pediatric patients in rural La Plata County, Colorado, received (1) online instruction, (2) full-day training, and (3) follow-up, in-practice training 1 month later. Training focused on spirometry use, severity and control assessment, medication management, asthma action plan utilization, and adoption of a standardized visit protocol. RESULTS: RE-AIM evaluation determined successful enrollment of practices in La Plata County (Reach) and provider uptake of evidence-based practices including spirometry (Adoption). Pediatric asthma patients receiving spirometry increased from 22% pretraining to 86% posttraining; severity assessment from 47% to 88%; and action plans from 40% to 86%. Significant improvements in health care utilization were observed among trained practices including a 10% decrease in emergency department visits, 35% decrease in hospital admissions, and 29% decrease in oral corticosteroid prescriptions (Effectiveness). Comparison practices showed no significant reductions in health care utilization. Participating providers reported that having the training in their own community, intense practice, a team-based approach, and cost-free materials including the spirometer and patient education materials were particularly helpful. CONCLUSIONS: The Asthma Toolkit Bootcamp improved pediatric asthma care given by rural providers and reduced health care utilization among their patients.

Intimate Partner Violence and Adult Asthma Morbidity: A Population-Based Study.

BACKGROUND: The etiologies for difficult-to-control asthma are complex and incompletely understood. Intimate partner violence (IPV) is a pervasive problem and may play a role in difficult-to-control asthma. IPV is associated with increased prevalence of asthma. There are no prior studies evaluating IPV's association with adult asthma exacerbations. OBJECTIVE: This study hypothesized that IPV exposure would be associated with increased asthma exacerbations, higher symptom burden, and poorer asthma control among adults. METHODS: Analyses are based on 2634 adults who participated in the 2005 Behavioral Risk Factor Surveillance System survey, reported active asthma, and completed the asthma and IPV questions. We used multivariate logistic regression to examine the association of IPV with asthma morbidity outcomes while controlling for the following potential confounders: sex, race, education, health care coverage, smoking status, age, and body mass index. RESULTS: The prevalence of IPV was 32.4%. IPV was associated with increased odds of an asthma exacerbation (adjusted odds ratio [AOR] = 1.75, 95% confidence interval [CI] = 1.26-2.43), higher symptom burden (AOR = 2.33, 95% CI = 1.53-3.55), and lack of asthma control (AOR = 2.23, 95% CI = 1.22-4.09) when using composite measures for these outcomes. When using single-item measures for outcomes, IPV was also associated with increased asthma-related emergency department or urgent care visits (AOR = 2.35, 95% CI = 1.56-3.54), other urgent provider visits (AOR = 1.84, 95% CI = 1.28-2.64), perceived asthma attacks (AOR = 1.53, 95% CI = 1.12-2.09), limitations (AOR = 2.07, 95% CI = 1.49-2.89), daytime symptoms (AOR = 1.92, 95% CI = 1.35-2.72), and nocturnal awakenings (AOR = 1.88, 95% CI = 1.32-2.69). CONCLUSIONS: IPV is prevalent in adult asthmatics and consistently and significantly associated with worsened adult asthma morbidity, even after adjusting for key confounders. Further research is needed to more fully understand the mechanisms underlying these relationships.

Effectiveness of Sequential Psychological and Medication Therapies for Insomnia Disorder: A Randomized Clinical Trial.

Importance: Despite evidence of efficacious psychological and pharmacologic therapies for insomnia, there is little information about what first-line treatment should be and how best to proceed when initial treatment fails. Objective: To evaluate the comparative efficacy of 4 treatment sequences involving psychological and medication therapies for insomnia and examine the moderating effect of psychiatric disorders on insomnia outcomes. Design, Setting, and Participants: In a sequential multiple-assignment randomized trial, patients were assigned to first-stage therapy involving either behavioral therapy (BT; n = 104) or zolpidem (zolpidem; n = 107), and patients who did not remit received a second treatment involving either medication (zolpidem or trazodone) or psychological therapy (BT or cognitive therapy [CT]). The study took place at Institut Universitaire en Santé Mentale de Québec, Université Laval, Québec City, Québec, Canada, and at National Jewish Health, Denver, Colorado, and enrollment of patients took place from August 2012 through July 2017. Main Outcomes and Measures: The primary end points were the treatment response and remission rates, defined by the Insomnia Severity Index total score. Results: Patients included 211 adults (132 women; mean [SD] age, 45.6 [14.9] years) with a chronic insomnia disorder, including 74 patients with a comorbid anxiety or mood disorder. First-stage therapy with BT or zolpidem produced equivalent weighted percentages of responders (BT, 45.5%; zolpidem, 49.7%; OR, 1.18; 95% CI, 0.60-2.33) and remitters (BT, 38.03%; zolpidem, 30.3%; OR, 1.41; 95% CI, 0.75-2.65). Second-stage therapy produced significant increases in responders for the 2 conditions, starting with BT (BT to zolpidem, 40.6% to 62.7%; OR, 2.46; 95% CI, 1.14-5.30; BT to CT, 50.1% to 68.2%; OR, 2.09; 95% CI, 1.01-4.35) but no significant change following zolpidem treatment. Significant increase in percentage of remitters was observed in 2 of 4 therapy sequences (BT to zolpidem, 38.1% to 55.9%; OR, 2.06; 95% CI, 1.04-4.11; zolpidem to trazodone, 31.4% to 49.4%; OR, 2.13; 95% CI, 0.91-5.00). Although response/remission rates were lower among patients with psychiatric comorbidity, treatment sequences that involved BT followed by CT or zolpidem followed by trazodone yielded better outcomes for patients with comorbid insomnia. Response and remission rates were well sustained through the 12-month follow-up. Conclusions and Relevance: Behavioral therapy and zolpidem medication produced equivalent response and remission rates. Adding a second treatment produced an added value for those whose insomnia failed to remit with initial therapies. Trial Registration: ClinicalTrials.gov Identifier: NCT01651442.

Dual Neutral Sphingomyelinase-2/Acetylcholinesterase Inhibitors for the Treatment of Alzheimer's Disease.

We report the discovery of a novel class of compounds that function as dual inhibitors of the enzymes neutral sphingomyelinase-2 (nSMase2) and acetylcholinesterase (AChE). Inhibition of these enzymes provides a unique strategy to suppress the propagation of tau pathology in the treatment of Alzheimer's disease (AD). We describe the key SAR elements that affect relative nSMase2 and/or AChE inhibitor effects and potency, in addition to the identification of two analogs that suppress the release of tau-bearing exosomes in vitro and in vivo. Identification of these novel dual nSMase2/AChE inhibitors represents a new therapeutic approach to AD and has the potential to lead to the development of truly disease-modifying therapeutics.

Timing of antimicrobial prophylaxis and the risk of surgical site infections: results from the Trial to Reduce Antimicrobial Prophylaxis Errors.

OBJECTIVE: The objective of this study is to determine the optimal timing for surgical antimicrobial prophylaxis (AMP). SUMMARY BACKGROUND DATA: National AMP guidelines should be supported by evidence from large contemporary data sets. METHODS: Twenty-nine hospitals prospectively obtained information on AMP from 4472 randomly selected cardiac, hip/knee arthroplasty, and hysterectomy cases. Surgical site infections (SSIs) were ascertained through routine surveillance, using National Nosocomial Infections Surveillance system methodology. The association between the prophylaxis timing and the occurrence of SSI was assessed using conditional logistic regression (conditioning on hospital). RESULTS: One-hundred thirteen SSI were detected in 109 patients. SSI risk increased incrementally as the interval of time between antibiotic infusion and the incision increased (overall association between timing and infection risk P = 0.04). When antibiotics requiring long infusion times (vancomycin and fluoroquinolones) were excluded, the infection risk following administration of antibiotic within 30 minutes prior to incision was 1.6% compared with 2.4% associated with administration of antibiotic between 31 to 60 minutes prior to surgery (OR: 1.74; 95% confidence interval, 0.98-3.04). The infection risk increased as the time interval between preoperative antibiotic and incision increased or if the antibiotic was first infused after incision. Intraoperative redosing (performed in only 21% of long operations) appeared to reduce SSI risk in operations lasting more than 4 hours (OR of 3.08 with no redosing; 95% confidence interval 0.74-12.90), but only when the preoperative dose was given correctly. CONCLUSIONS: These data from a large multicenter collaborative study confirm and extend previous observations and show a consistent relationship between the timing of AMP and SSI risk with a trend toward lower risk occurring when AMP with cephalosporins and other antibiotics with short infusion times were given within 30 minutes prior to incision.