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The observation of post-transition-state dynamic effects in the context of metal-based transformation is rare. To date, there has been no reported case of a dynamic effect for the widely employed class of palladium-mediated coupling reactions. We performed an experimental and computational study of the trifluoromethylation of Pd (II) F, which is a key step in the Pd (0) /Pd (II) -catalyzed trifluoromethylation of aryl halides or acid fluorides. Our experiments show that the cis / trans speciation of the formed Pd (II) CF 3 is highly solvent- and transmetalation reagent-dependent. We employed GFN2-xTB- and B3LYP-D3-based molecular dynamics trajectory calculations (with and without explicit solvation) along with high-level QM calculations and found that depending on the medium, different transmetalation mechanisms appear to be operative. A statistically representative number of Born-Oppenheimer molecular dynamics (MD) simulations suggest that in benzene, a difluorocarbene is generated in the transmetalation with R 3 SiCF 3 , which subsequently recombines with the Pd via two distinct pathways, leading to either the cis - or trans- Pd (II) CF 3 . Conversely, GFN2-xTB simulations in MeCN suggest that in polar/coordinating solvents an ion-pair mechanism is dominant. A CF 3 anion is initially liberated and then rebinds with the Pd (II) cation to give a cis - or trans- Pd (II) . In both scenarios, a single transmetalation transition state gives rise to both cis - and trans -species directly, owing to bifurcation after the transition state. The potential subsequent cis - to trans isomerization of the Pd (II) CF 3 was also studied and found to be strongly inhibited by free phosphine, which in turn was experimentally identified to be liberated through displacement by a polar/coordinating solvent from the cis -Pd (II) CF 3 complex. The simulations also revealed how the variation of the Pd-coordination sphere results in divergent product selectivities., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Published by American Chemical Society.)

Recommendations for pneumococcal vaccination in adults have been updated in the hopes not only of preventing more cases of invasive pneumococcal disease but also of making the recommendations simpler and easier to follow., (Copyright © 2022 The Cleveland Clinic Foundation. All Rights Reserved.)

Background: Alcohol septal ablation (ASA) is an accepted treatment for medically refractory hypertrophic obstructive cardiomyopathy (HOCM). The procedural and medium-term outcomes have been reassuring. The iatrogenic targeted septal infarction has raised theoretical concerns about risk of arrhythmia and long-term survival. In this study, we describe the long-term survival in a large cohort of patients from a single referral center and the iterative improvement in procedural technique since its inception., Methods: This cohort includes 580 consecutive patients who underwent 664 ASA procedures between the years 1999 and 2015. Procedural details and outcomes are described. Long-term survival is compared with expected survival of demographically similar controls., Results: Fifty-four percent were women and 85% were Caucasian. At the time of ablation, mean age was 57 ± 15 years, septal thickness was 2.1 ± 0.5 cm, and left ventricular outflow tract (LVOT) gradient was 72 ± 40 mm Hg at rest and 102 ± 58 mm Hg with Valsalva provocation. Mean follow-up was 8.0 ± 4.3 years. LVOT gradient reduction >50% was achieved in 94% of patients with reduction in New York Heart Association functional class scores and increase in exercise treadmill duration. Procedural mortality was 0.9%. Over the 16-year period, survival estimates at 1, 5, 10, and 15 years were 98%, 92%, 84%, and 81%, respectively, which are comparable to demographically similar controls. The standardized mortality ratio was 0.84 (95% confidence interval, 0.66-1.06); P=.09., Conclusions: ASA appears to be a safe and effective treatment for symptomatic HOCM refractory to medical therapy with long-term survival comparable to a demographically similar United States population.

Downstream intermediates are crucial for the reactivity and selectivity of aminocatalytic reactions. We present an analysis of the stereopreference in aminocatalytic downstream intermediates, which reveals an inconspicuous mechanism of chiral recognition between the catalyst and the rest of the molecule. We delineate a stereoelectronic model to rationalize the mode of chiral transmission. We also exploit it for the resolution of chiral lactols relevant in organic synthesis as well as in the flavor and fragrance industry.

Upon treatment with a combination of HFIP and an organic sulfonic acid, alkenes behave as Brønsted bases and protonate to give carbocations which can be trapped by electron-rich arenes. The reaction constitutes a Friedel-Crafts hydroarylation which proceeds with Markovnikov selectivity and is orthogonal to traditional metal-catalyzed processes. Intermolecular transfer hydrogenation and hydrothiolation under analogous conditions are also demonstrated.

Visual kinetic analyses extract meaningful mechanistic information from experimental data using the naked-eye comparison of appropriately modified progress reaction profiles. Basic kinetic information is obtained easily and quickly from just a few experiments. Therefore, these methods are valuable tools for all chemists working in process chemistry, synthesis or catalysis with an interest in mechanistic studies. This minireview describes the visual kinetic analyses developed in the last fifteen years and provides answers to the most common queries of new users. Furthermore, a video tutorial is attached detailing the implementation of both VTNA and RPKA.

Herein we report a combined experimental and computational investigation of the acid catalyzed cyclocondensation reaction between styrenyl homoallylic alcohols and salicylaldehyde to form furanochromanes. We disclose a previously unreported isomerisation of the 'unnatural' trans -fused products to the diastereomeric 'natural' cis -fused congeners. Notwithstanding the appeal of assuming this corresponds to endo to exo isomerisation of Diels-Alder (D-A) adducts via concerted retro-cycloaddition/cycloaddition reactions of an in situ generated ortho -quinone methide with the styrenyl alkene, our combined Hammett/DFT study reveals a stepwise Prins-like process via discrete benzylic carbocation intermediates for all but the most electron deficient styrenes. As these reactions fortuitously lie at the intersection of these two mechanistic manifolds, it allows us to propose an experimentally determined indicative ρ + value of ca. -3 as marking this nexus between a stepwise Prins-type pathway and a concerted cycloaddition reaction. This value should prove useful for categorising other reactions formally involving ' ortho -quinomethides', without the need for the extensive computation performed here. Logical optimisation of the reaction based upon the mechanistic insight led to the use of HFIP as an additive which enables exclusive formation of 'natural' cis -fused products with a ∼100-fold reaction rate increase and improved scope.

Background: In nonrandomized, open-label studies, a transcatheter interatrial shunt device (IASD, Corvia Medical) was associated with lower pulmonary capillary wedge pressure (PCWP), fewer symptoms, and greater quality of life and exercise capacity in patients with heart failure (HF) and midrange or preserved ejection fraction (EF ≥40%). We conducted the first randomized sham-controlled trial to evaluate the IASD in HF with EF ≥40%., Methods: REDUCE LAP-HF I (Reduce Elevated Left Atrial Pressure in Patients With Heart Failure) was a phase 2, randomized, parallel-group, blinded multicenter trial in patients with New York Heart Association class III or ambulatory class IV HF, EF ≥40%, exercise PCWP ≥25 mm Hg, and PCWP-right atrial pressure gradient ≥5 mm Hg. Participants were randomized (1:1) to the IASD versus a sham procedure (femoral venous access with intracardiac echocardiography but no IASD placement). The participants and investigators assessing the participants during follow-up were blinded to treatment assignment. The primary effectiveness end point was exercise PCWP at 1 month. The primary safety end point was major adverse cardiac, cerebrovascular, and renal events at 1 month. PCWP during exercise was compared between treatment groups using a mixed-effects repeated measures model analysis of covariance that included data from all available stages of exercise., Results: A total of 94 patients were enrolled, of whom 44 met inclusion/exclusion criteria and were randomized to the IASD (n=22) and control (n=22) groups. Mean age was 70±9 years, and 50% were female. At 1 month, the IASD resulted in a greater reduction in PCWP compared with sham control ( P =0.028 accounting for all stages of exercise). Peak PCWP decreased by 3.5±6.4 mm Hg in the treatment group versus 0.5±5.0 mm Hg in the control group ( P =0.14). There were no peri-procedural or 1-month major adverse cardiac, cerebrovascular, and renal events in the IASD group and 1 event (worsening renal function) in the control group ( P =1.0)., Conclusions: In patients with HF and EF ≥40%, IASD treatment reduces PCWP during exercise. Whether this mechanistic effect will translate into sustained improvements in symptoms and outcomes requires further evaluation., Clinical Trial Registration: URL: https://clinicaltrials.gov. Unique identifier: NCT02600234., (© 2017 American Heart Association, Inc.)

Background: July 2011 saw the implementation of the newest duty hour restrictions, further limiting the working hours of first year residents and necessitating a variety of adaptations on the part of residency programs. The present study sought to characterize the perceived impact of these restrictions on residency program personnel using a multi-specialty and multi-site approach., Methods: We developed and administered a survey to internal medicine and general surgery residency programs at three academic medical centers within an urban region. The survey combined quantitative and qualitative components to gain a broader understanding of the impact of the newest regulations. Quantitative responses were compared between Internal Medicine and General Surgery programs with Student t-tests. Other comparisons were performed using ANOVA or Kruskal-Wallis testing as appropriate. For all comparisons, the threshold for significance was set at 0.01. Two independent reviewers coded all qualitative data and assigned one or more themes based on content. Descriptive statistics were calculated and the diversity of themes identified. No between-group comparisons were conducted with the qualitative data., Results: We found significant differences in the overall perceptions of duty hour restrictions across specialty (internal medicine more positive than general surgery) and across position (first year residents more positive than senior residents and faculty). Notably, individuals who trained at osteopathic medical schools reported significantly more negative views of the duty hour restrictions than those who had trained at allopathic or international medical schools, suggesting an influence of undergraduate medical training. The complementary qualitative data offered insights into the perceived strengths and weaknesses of the duty hour restrictions, as well as actionable suggestions that could help to improve residency program function., Conclusion: This study characterizes responses to the new duty hour restrictions from a variety of perspectives. Our findings show that individual (type of undergraduate medical education, role in graduate medical education) and program-wide (e.g., specialty) factors contribute to participant satisfaction with DHR. This research highlights the value of a mixed methods approach in the study of duty hour restrictions, with our qualitative arm yielding rich data that complemented and expanded upon the insights derived from the quantitative data.

Objectives: The purpose of this study was to examine the effects of alcohol septal ablation (ASA) on ventricular arrhythmias among patients with obstructive hypertrophic cardiomyopathy (HCM), as measured by appropriate implantable cardioverter-defibrillator (ICD) discharges., Background: Alcohol septal ablation is an effective therapy for patients with symptomatic HCM. However, concern has been raised that ASA may be proarrhythmic secondary to the iatrogenic scar created during the procedure. The impact of ASA on ventricular arrhythmias has not been well described., Methods: This prospective study included 123 consecutive patients with obstructive HCM who underwent ASA and had an ICD implanted for primary prevention of sudden cardiac death (SCD). The ICDs were implanted based on commonly accepted risk factors for SCD in the HCM population. Data from ICD interrogations during routine follow-up were collected., Results: Nine appropriate ICD shocks were recorded over a mean follow-up of 2.9 years in the cohort, which had a mean of 1.5 +/- 0.9 risk factors for SCD. Using Kaplan-Meier survival analysis, the estimated annual event rate was 2.8% over 3-year follow-up. There were no significant differences in the incidence of risk factors between patients who did and did not receive appropriate shocks., Conclusions: The annual rate of appropriate ICD discharges after ASA is low and less than that reported previously for primary prevention of SCD in HCM. This suggests that ASA is not proarrhythmic. Traditional SCD risk factors did not predict ICD shocks in this cohort.

Background: Nonsurgical septal reduction therapy (NSRT) has been shown to improve left ventricular outflow tract (LVOT) gradients, decrease septal thickness, and improve symptoms in patients with hypertrophic obstructive cardiomyopathy (HOCM). The major complication of this procedure has been the development of complete heart block (CHB) requiring permanent pacemaker implantation, which has been reported in up to 33% of patients in early studies. Since this procedure was first reported, there have been refinements in the technique such as the use of echocardiographic contrast material to localize the site of infarction, slower injection of alcohol, as well as improvement in balloon technology., Hypothesis: We sought to determine the results of NSRT using echocardiographic contrast localization, slow injection of alcohol, and short balloon length. We theorized that the incidence CHB would be lower than earlier reported results using these refined techniques., Methods: We performed 50 NSRT procedures on 46 patients using echocardiographic contrast localization, slow alcohol injection, and currently available balloons. Patients had an echocardiogram before, immediately after NSRT, and at 3 months, and a treadmill test before and at 3 months after NSRT. In the hospital, patients were observed for the development of CHB or other complications, and infarct size was determined by serial creatine kinase (CK) measurements., Results: There was a decrease in the LVOT gradient from 84.2 (+/- 30.8) mmHg at baseline, to 18.5 (+/- 14.8) mmHg immediately after NSRT (p < 0.001). At 3 months, the gradient was not statistically different at 22.7 (+/- 22.2) mmHg 0.27). The septal thickness decreased from 2.21 (+/- 0.66) cm at baseline, to 1.67 (+/- 0.51) cm at 3 months (p < 0.001). New York Heart Association symptom class improved from 3.2 (+/- 0.4) at baseline, to 1.1 (+/- 0.6) at 3 months (p < 0.001). Mean treadmill time in 30 patients was 235 (+/- 142) s at baseline, to 367 (+/- 159) s at 3 months (p < 0.001). Of the 50 procedures, 45 were performed in patients without a previously placed permanent pacemaker or intracardiac cardioverter defibrillator, only 3 (6.7%) of the 45 developed complete heart blocks required permanent pacing. While only three patients in the series had a preexisting left bundle-branch block (LBBB), two of the three patients who required a permanent pacemaker had an LBBB before the prcoedure., Conclusion: Using contrast echocardiographic localization, slow injection of alcohol, and shorter balloon catheters, there continues to be excellent improvement in LVOT gradients, septal thickness, and symptoms, with a reduced incidence of CHB requiring permanent pacemaker implantation. Left bundle-branch block appears to be a strong predictor for the development of CHB after NSRT.

The spike timing in rhythmically active interneurons in the mammalian spinal locomotor network varies from cycle to cycle. We tested the contribution from passive membrane properties to this variable firing pattern, by measuring the reliability of spike timing, P, in interneurons in the isolated neonatal rat spinal cord, using intracellular injection of sinusoidal command currents of different frequencies (0.325-31.25 Hz). P is a measure of the precision of spike timing. In general, P was low at low frequencies and amplitudes (P = 0-0.6; 0-1.875 Hz; 0-30 pA), and high at high frequencies and amplitudes (P = 0.8-1; 3.125-31.25 Hz; 30-200 pA). The exact relationship between P and amplitude was difficult to describe because of the well-known low-pass properties of the membrane, which resulted in amplitude attenuation of high-frequency compared with low-frequency command currents. To formalize the analysis we used a leaky integrate and fire (LIF) model with a noise term added. The LIF model was able to reproduce the experimentally observed properties of P as well as the low-pass properties of the membrane. The LIF model enabled us to use the mathematical theory of nonlinear oscillators to analyze the relationship between amplitude, frequency, and P. This was done by systematically calculating the rotational number, N, defined as the number of spikes divided by the number of periods of the command current, for a large number of frequencies and amplitudes. These calculations led to a phase portrait based on the amplitude of the command current versus the frequency-containing areas [Arnold tongues (ATs)] with the same rotational number. The largest ATs in the phase portrait were those where N was a whole integer, and the largest areas in the ATs were seen for middle to high (>3 Hz) frequencies and middle to high amplitudes (50-120 pA). This corresponded to the amplitude- and frequency-evoked increase in P. The model predicted that P would be high when a cell responded with an integer and constant N. This prediction was confirmed by comparing N and P in real experiments. Fitting the result of the LIF model to the experimental data enabled us to estimate the standard deviation of the internal neuronal noise and to use these data to simulate the relationship between N and P in the model. This simulation demonstrated a good correspondence between the theoretical and experimental values. Our data demonstrate that interneurons can respond with a high reliability of spike timing, but only by combining fast and slow oscillations is it possible to obtain a high reliability of firing during rhythmic locomotor movements. Theoretical analysis of the rotation number provided new insights into the mechanism for obtaining reliable spike timing.