Site-selective and versatile aromatic C-H functionalization by thianthrenation.

Direct C-H functionalization can quickly increase useful structural and functional molecular complexity1-3. Site selectivity can sometimes be achieved through appropriate directing groups or substitution patterns1-4-in the absence of such functionality, most aromatic C-H functionalization reactions provide more than one product isomer for most substrates1,4,5. Development of a C-H functionalization reaction that proceeds with high positional selectivity and installs a functional group that can serve as a synthetic linchpin for further functionalization would provide access to a large variety of well-defined arene derivatives. Here we report a highly selective aromatic C-H functionalization reaction that does not require a particular directing group or substitution pattern to achieve selectivity, and provides functionalized arenes that can participate in various transformations. We introduce a persistent sulfur-based radical to functionalize complex arenes with high selectivity and obtain thianthrenium salts that are ready to engage in different transformations, via both transition-metal and photoredox catalysis. This transformation differs fundamentally from all previous aromatic C-H functionalization reactions in that it provides direct access to a large number of derivatives of complex small molecules, quickly generating functional diversity with selectivity that is not achievable by other methods.

Lead and generator dysfunction in children and adolescents with epicardial pacemaker and implantable cardioverter defibrillator systems: The challenge of early recognition.

BACKGROUND: A major issue of cardiac implantable electronic device therapy in pediatric patients is the high incidence of lead dysfunctions and associated reinterventions. This study aims to analyze the timing and mode of generator and lead dysfunction. METHODS: Retrospective single-center analysis of 283 children and young adults with an epicardial pacemaker or implantable cardioverter defibrillator therapy from 1998 to 2018. RESULTS: Mean age at implant was 6.1 years (SD ± 5.8 years) and median follow-up 6.4 years (IQR, 3.4-10.4 years) with a total of 1998.1 patient-years of cardiac device therapy. A total of 120 lead-related complications were observed in 82 patients (29.0%). They were detected by device interrogation (n = 86), symptoms (n = 13), intraoperative findings (n = 7), routine chest radiography (n = 5), routine ECG (n = 4), patient alert sound by device (n = 3), and physical examination (n = 2). It was possible to find the date of the event on the device memory in 21 out of 120 lead dysfunctions (18%) with a median time interval between occurrence and detection of 1.3 months (IQR, 0.2-5.0 months). Moreover, 20 generator-related complications were found in 13 patients. CONCLUSIONS: Early recognition of lead and generator dysfunction remains challenging in pediatric patients. As symptoms are relatively rare conditions in the context of PM and ICD dysfunction, close patient monitoring is mandatory, even in asymptomatic patients with a good clinical course. To further improve the safety of pediatric pacing systems, more durable epicardial electrodes are desirable.

Use of implantable cardioverter-defibrillator in children supported with ventricular assist device: An analysis of data from the EUROMACS registry.

BACKGROUND: Data on the use and outcome of children on ventricular assist device (VAD) support provided with an implantable cardioverter-defibrillator (ICD) remains poor. METHODS: A retrospective analysis of the EUROMACS database on children supported with VAD < 19 years of age from January 1, 2009 to April 1, 2020. Patients with missing data on status of ICD, missing baseline and/or follow up information were excluded. The primary independent variable of interest was the concomitant presence or absence of an ICD at the time of VAD placement. Kaplan-Meier survival analysis was performed to evaluate survival differences between children on VAD with and without an ICD. RESULTS: Out of 303 patients provided with a VAD, 7% (7♀, 15♂) had an ICD implanted and formed the study group. Median age was 14 years, median weight was 43.5 kg, and median BSA was 1.39. Median Intermacs stage was 2 (range: 1-7). Seventeen patients (77%) were transplanted, 4 (18%) died while on support, and 1 (5%) was weaned from device after myocardial recovery. Median time on support was 68 days compared to 361 days in the control group (p: 0.01). Three patients underwent device exchange due to thrombus formation in the pump. There was no difference in survival between groups (p = 0.342). CONCLUSION: The presence of ICD in pediatric patients supported with a VAD is low (7%). Children on VAD support provided with an ICD do not have a survival benefit compared to children without an ICD.

Inducibility of atrioventricular nodal reentrant tachycardia and ectopic atrial tachycardia in children under general anesthesia.

BACKGROUND: In children, invasive electrophysiological studies (EPS) and radiofrequency catheter ablations (RFA) of supraventricular tachycardia (SVT) are often performed under general anesthesia. Atrioventricular nodal reentrant tachycardia (AVNRT) and ectopic atrial tachycardia (EAT) must be inducible during EPS as reliable diagnosis and subsequent therapy are not possible in sinus rhythm. This study aims to assess the problem of noninducible AVNRT and EAT under general anesthesia. METHODS AND RESULTS: Anesthesia protocols of 166 patients undergoing EPS were retrospectively analyzed. 122 AVNRT patients were compared to 22 whose tachycardia was not inducible but probably due to an AVNRT mechanism. Another 16 patients with inducible EAT were compared to 6 whose EAT appeared on surface ECG but not during EPS. Demographic characteristics were similar among all groups. Inducibility did not differ (p = .42) between AVNRT patients with inhalational anesthesia (sevoflurane and/or nitrous oxide) and patients with intravenous anesthesia (propofol with/without remifentanil). The EAT group exhibited lower inducibility under intravenous anesthesia (64%) than under inhalational (88%), however without significance (p = .35). CONCLUSION: Tachycardia induction succeeds with similar frequency under both inhalational and intravenous general anesthesia in children with AVNRT. In children with EAT, inhalational anesthesia is associated with a trend towards better inducibility.

Trifluoromethyl Thianthrenium Triflate: A Readily Available Trifluoromethylating Reagent with Formal CF3+, CF3•, and CF3- Reactivity.

Here we report the synthesis and application of trifluoromethyl thianthrenium triflate (TT-CF3+OTf-) as a novel trifluoromethylating reagent, which is conveniently accessible in a single step from thianthrene and triflic anhydride. We demonstrate the use of TT-CF3+OTf- in electrophilic, radical, and nucleophilic trifluoromethylation reactions.

High Site Selectivity in Electrophilic Aromatic Substitutions: Mechanism of C-H Thianthrenation.

The introduction of thianthrene as a linchpin has proven to be a versatile strategy for the C-H functionalization of aromatic compounds, featuring a broad scope and fast diversification. The synthesis of aryl thianthrenium salts has displayed an unusually high para regioselectivity, notably superior to those observed in halogenation or borylation reactions for various substrates. We report an experimental and computational study on the mechanism of aromatic C-H thianthrenation reactions, with an emphasis on the elucidation of the reactive species and the nature of the exquisite site selectivity. Mechanisms involving a direct attack of arene to the isolated O-trifluoracetylthianthrene S-oxide (TT+-TFA) or to the thianthrene dication (TT2+) via electron transfer under acidic conditions are identified. A reversible interconversion of the different Wheland-type intermediates before a subsequent, irreversible deprotonation is proposed to be responsible for the exceptional para selectivity of the reaction.

Beyond the visible spectrum - applying 3D multispectral full-body imaging to the VirtoScan system.

Multispectral photography offers a wide range of applications for forensic investigations. It is commonly used to detect latent evidence and to enhance the visibility of findings. Additionally, three-dimensional (3D) full-body documentation has become much easier and more affordable in recent years. However, the benefits of performing 3D imaging beyond the visible (VIS) spectrum are not well known, and the technique has not been widely used in forensic medical investigations. A multicamera setup was used to employ multispectral photogrammetry between 365 and 960 nm in postmortem investigations. The multicamera setup included four modified digital cameras, ultraviolet (UV) and near-infrared (NIR) light sources and supplemental lens filters. Full-body documentation was performed in conjunction with the use of a medical X-ray computed tomography (CT) scanner to automate the imaging procedure. Textured 3D models based on multispectral datasets from four example cases were reconstructed successfully. The level of detail and overall quality of the 3D reconstructions varied depending on the spectral range of the image data. Generally, the NIR datasets showed enhanced visibility of vein patterns and specific injuries, whereas the UV-induced datasets highlighted foreign substances on the skin. Three-dimensional multispectral full-body imaging enables the detection of latent evidence that is invisible to the naked eye and allows visualization, documentation and analysis of evidence beyond the VIS spectrum.

Late-Stage Heteroarylation of Hetero(aryl)sulfonium Salts Activated by α-Amino Alkyl Radicals.

We report a late-stage heteroarylation of aryl sulfonium salts through activation with α-amino alkyl radicals in a mechanistically distinct approach from previously reported halogen-atom transfer (XAT). The new mode of activation of aryl sulfonium salts proceeds in the absence of light and photoredox catalysts, engaging a wide range of hetarenes. Furthermore, we demonstrate the applicability of this methodology in synthetically useful cross-coupling transformations.

Tau directs intracellular trafficking by regulating the forces exerted by kinesin and dynein teams.

Organelles, proteins, and mRNA are transported bidirectionally along microtubules by plus-end directed kinesin and minus-end directed dynein motors. Microtubules are decorated by microtubule-associated proteins (MAPs) that organize the cytoskeleton, regulate microtubule dynamics and modulate the interaction between motor proteins and microtubules to direct intracellular transport. Tau is a neuronal MAP that stabilizes axonal microtubules and crosslinks them into bundles. Dysregulation of tau leads to a range of neurodegenerative diseases known as tauopathies including Alzheimer's disease (AD). Tau reduces the processivity of kinesin and dynein by acting as an obstacle on the microtubule. Single-molecule assays indicate that kinesin-1 is more strongly inhibited than kinesin-2 or dynein, suggesting tau might act to spatially modulate the activity of specific motors. To investigate the role of tau in regulating bidirectional transport, we isolated phagosomes driven by kinesin-1, kinesin-2, and dynein and reconstituted their motility along microtubules. We find that tau biases bidirectional motility towards the microtubule minus-end in a dose-dependent manner. Optical trapping measurements show that tau increases the magnitude and frequency of forces exerted by dynein through inhibiting opposing kinesin motors. Mathematical modeling indicates that tau controls the directional bias of intracellular cargoes through differentially tuning the processivity of kinesin-1, kinesin-2, and dynein. Taken together, these results demonstrate that tau modulates motility in a motor-specific manner to direct intracellular transport, and suggests that dysregulation of tau might contribute to neurodegeneration by disrupting the balance of plus- and minus-end directed transport.

Obstacles to HBV functional cure: Late presentation in HIV and its impact on HBV seroconversion in HIV/HBV coinfection.

Several cohorts have shown that long-term tenofovir-containing combination antiretroviral therapy (cART) leads to higher HBsAg seroclearance rates in HIV/HBV coinfected patients vs HBV-monoinfected patients under tenofovir disoproxil fumarate (TDF)-based therapy. We have analysed data on determinants of HBsAg loss in a retrospective multicentric cohort of 359 HIV/HBV coinfected patients. Median CD4 T-cell count at baseline was 359/ul (321-404), CDC stage was C in 20% (n = 70). Most patients (68%) were ART-naïve when TDF- or tenofovir alafenamide (TAF)-containing cART was initiated (baseline). After a median follow-up of 11 years HBsAg loss had occurred in 66/359 (18%) patients. However, patients with stage CDC C (P ≤ .001), lower CD4 gain (P = .043) and not receiving TDF/FTC (P = .008) were less likely to lose HBsAg. Long-term TDF-containing cART appears to achieve higher rates of HBsAg seroclearance compared to published data for HBV monoinfected subjects. However, late presentation for HIV and poor immune recovery significantly impair HBV seroconversion rates.

Has Increased Rollout of Direct Acting Antiviral Therapy Decreased the Burden of Late Presentation and Advanced Liver Disease in Patients Starting Hepatitis C Virus Therapy in Germany?

GOALS AND BACKGROUND: International guidelines recommend prioritized treatment initiation in hepatitis C virus (HCV)-infected patients with advanced liver disease. We aimed to evaluate whether the widespread usage of direct acting antivirals (DAAs) has led to a decrease in late presentation for care. STUDY: Data derived from the multicenter German Hepatitis C Cohort (GECCO) was analyzed. Treatment naive HCV-infected patients initiating DAA-based treatment between January 2014 and September 2017 were included. Advanced liver disease was defined by aspartate aminotransferase to platelet ratio index score ≥1.5, METAVIR≥F3, or FibroScan ≥9.5 kPa. Period prevalence and risk factors for late presentation were evaluated. RESULTS: Six hundred fifty-three HCV-monoinfected and 210 HIV/HCV-coinfected patients (mean age, 48.6±12.7 y; 65.5% male) were included. Overall 32.5% of patients had advanced liver disease. In 2014 39.4% of patients presented with advanced liver disease, decreasing to 30.1%, 34.4%, and 26.4% in the years 2015, 2016, and 2017 (P=0.057), respectively. Patients with and without advanced liver disease differed in age (P<0.0001), CD4 ≤350/µL (P=0.027), genotype (P=0.005), transmission route (P=0.047), body mass index (P<0.001), and time since diagnosis (P=0.007). In the multivariable binary logistic regression analysis GT3, age above 45 years and being diagnosed >2 years ago were positively and HCV transmission through men who have sex with men was negatively associated with advanced liver disease. CONCLUSIONS: Overall 32.5% of patients presented with advanced liver disease. We observed a trend toward a lower proportion of patients starting treatment late.GT3, age, years since HCV diagnosis and HCV transmission route were identified as risk factors for presentation with advanced liver disease.

Early recurrence after pulmonary vein isolation is associated with inferior long-term outcomes: Insights from a retrospective cohort study.

AIMS: The aim of this retrospective cohort study was to assess the influence of early recurrence (ER) after pulmonary vein isolation (PVI) for paroxysmal atrial fibrillation (AF) on long-term outcomes and to identify clinical variables associated with ER. METHODS: We retrospectively collected clinical and procedural data from 1285 patients with paroxysmal AF who underwent PVI from 2011 to 2016. Kaplan-Meier, receiver operating characteristic (ROC) curve, logistic and Cox regression analyses were performed to analyze the influence of ER on long-term outcomes. RESULTS: ER was observed in 13% of patients. Kaplan-Meier analyses showed significantly different outcomes in 1285 patients with and without ER (49% vs 74%, log rank P < .01) and in 286 patients in the subgroup that underwent reablation (44% vs 79%, log rank P < .01). The hazard ratio (HR) of ER was 1.7 within 48 hours (5% of patients), 2.7 within 1 month (5%), 3.0 within 2 months (2%), and 6.4 within 3 months (1%) for late recurrence (LR), P < .01. ROC analysis (area under the curve [AUC] = 0.79) resulted in 70.3% sensitivity and 74.2% specificity for a 14-day blanking period, and 53.1% sensitivity and 85.5% specificity for a 30-day blanking period. Female patients (odds ratio [OR] 1.69, P < .01) and those with diabetes (OR 1.95, P = .01) were at higher risk for ER. CONCLUSIONS: ER is observed in a substantial number of patients with paroxysmal AF after PVI and has a continuous direct effect on LR according to the timing of ER. Randomized trials are required to assess the safety and effects of reablations in a shortened blanking period on long-term outcomes.

Radiofrequency catheter ablation for supraventricular tachycardia in a paediatric population: characteristics of tachycardia mechanisms in a subpopulation with early onset.

BACKGROUND: In children, the first episode of supraventricular tachycardia occurs at various ages. The aim of this study is to describe age-specific tachycardia mechanisms, clinical findings, and outcome in a contemporary cohort of paediatric patients with supraventricular tachycardia. METHODS: Retrospective analysis of 531 consecutive patients with structurally normal hearts under the age of 18 years who underwent invasive electrophysiological study for supraventricular tachycardia. The study population was divided into two groups, early-onset group (n = 57) and late-onset group (n = 474), according to the age of the occurrence of the first tachycardia before or after the age of 12 months. RESULTS: Accessory pathway-mediated tachycardia was more common (82.5 versus 50.1%, p < 0.001) and the proportion of left-sided accessory pathways was more pronounced (74.5 versus 53.7%, p = 0.01) in the early-onset group than in the late-onset group. The antegrade and retrograde refractory periods of the accessory pathways were similar in both groups, but pre-excitation was more common in the early-onset group (50.9 versus 31.9%, p = 0.007). Typical atrioventricular nodal re-entrant tachycardia was more common (36.7 versus 7.0%, p < 0.001) in the late-onset group. There was no difference among the two groups regarding overall outcome. CONCLUSION: Accessory pathway-mediated re-entrant tachycardia is the most common mechanism of recurrent supraventricular tachycardia in infants with structurally normal hearts who are later referred to an electrophysiological study. These pathways often cause pre-excitation and tend to be located on the left side whereas their refractory period is not different from that of patients with late-onset tachycardia.

Force-Dependent Unbinding Rate of Molecular Motors from Stationary Optical Trap Data.

Molecular motors walk along filaments until they detach stochastically with a force-dependent unbinding rate. Here, we show how this unbinding rate can be obtained from the analysis of experimental data of molecular motors moving in stationary optical traps. Two complementary methods are presented, based on the analysis of the distribution for the unbinding forces and of the motor's force traces. In the first method, analytically derived force distributions for slip bonds, slip-ideal bonds, and catch bonds are used to fit the cumulative distributions of the unbinding forces. The second method is based on the statistical analysis of the observed force traces. We validate both methods with stochastic simulations and apply them to experimental data for kinesin-1.

Decoding Biomineralization: Interaction of a Mad10-Derived Peptide with Magnetite Thin Films.

Protein-surface interactions play a pivotal role in processes as diverse as biomineralization, biofouling, and the cellular response to medical implants. In biomineralization processes, biomacromolecules control mineral deposition and architecture via complex and often unknown mechanisms. For studying these mechanisms, the formation of magnetite nanoparticles in magnetotactic bacteria has become an excellent model system. Most interestingly, nanoparticle morphologies have been discovered that defy crystallographic rules (e.g., in the species Desulfamplus magnetovallimortis strain BW-1). In certain conditions, this strain mineralizes bullet-shaped magnetite nanoparticles, which exhibit defined (111) crystal faces and are elongated along the [100] direction. We hypothesize that surface-specific protein interactions break the nanoparticle symmetry, inhibiting the growth of certain crystal faces and thereby favoring the growth of others. Screening the genome of BW-1, we identified Mad10 (Magnetosome-associated deep-branching) as a potential magnetite-binding protein. Using atomic force microscope (AFM)-based single-molecule force spectroscopy, we show that a Mad10-derived peptide, which represents the most conserved region of Mad10, binds strongly to (100)- and (111)-oriented single-crystalline magnetite thin films. The peptide-magnetite interaction is thus material- but not crystal-face-specific. It is characterized by broad rupture force distributions that do not depend on the retraction speed of the AFM cantilever. To account for these experimental findings, we introduce a three-state model that incorporates fast rebinding. The model suggests that the peptide-surface interaction is strong in the absence of load, which is a direct result of this fast rebinding process. Overall, our study sheds light on the kinetic nature of peptide-surface interactions and introduces a new magnetite-binding peptide with potential use as a functional coating for magnetite nanoparticles in biotechnological and biomedical applications.

Regio- and Stereoselective Thianthrenation of Olefins To Access Versatile Alkenyl Electrophiles.

Herein, we report a regioselective alkenyl electrophile synthesis from unactivated olefins that is based on a direct and regioselective C-H thianthrenation reaction. The selectivity is proposed to arise from an unusual inverse-electron-demand hetero-Diels-Alder reaction. The alkenyl sulfonium salts can serve as electrophiles in palladium- and ruthenium-catalyzed cross-coupling reactions to make alkenyl C-C, C-Cl, C-Br, and C-SCF3 bonds with stereoretention.

Site-Selective Late-Stage Aromatic [18 F]Fluorination via Aryl Sulfonium Salts.

Site-selective functionalization of C-H bonds in small complex molecules is a long-standing challenge in organic chemistry. Herein, we report a broadly applicable and site-selective aromatic C-H dibenzothiophenylation reaction. The conceptual advantage of this transformation is further demonstrated through the two-step C-H [18 F]fluorination of a series of marketed small-molecule drugs.

C-N Cross-Couplings for Site-Selective Late-Stage Diversification via Aryl Sulfonium Salts.

We report diverse C-N cross-coupling reactions of aryl thianthrenium salts that are formed site-selectively by direct C-H functionalization. The scope of N-nucleophiles ranges from primary and secondary alkyl and aryl amines to various N-containing heterocycles, and the overall transformation is applicable to late-stage functionalization of complex, drug-like small molecules.

Risk factors for remaining liver injury in patients with virological elimination of chronic hepatitis C.

BACKGROUND AND AIMS: Disease activity, but also demographics, lifestyle, and comorbidities, may influence alanine aminotransferase (ALT) levels in hepatitis C virus (HCV)-infected patients. Direct-acting antiviral agents (DAA) achieve virological cure in > 90 % of patients, regardless of HCV genotype and fibrosis stage. This allows assessing determinants for ALT levels before and after elimination of HCV. METHODS: Our prospective cohort included HCV- and HIV/HCV-infected patients treated with DAA at 9 German centers (GECCO cohort). We analyzed all consecutive patients with sustained virological response (SVR) at week 12 (SVR12) and/or 24. Normal ALT was defined as ≤ 35 U/L, regardless of sex. RESULTS: At baseline, 1477 out of 1774 patients (83 %) had ALT > 35 U/L, and 297 (17 %) had ALT ≤ 35 U/L. Baseline ALT > 35 U/L was independently associated with male sex, higher body mass index (BMI), liver cirrhosis, and not being on opioid substitution. After SVR, > 80 % of patients normalized ALT, and even patients with low baseline ALT further reduced ALT levels. However, ALT remained > 35 U/L in 15 % (221/1477) after SVR12. By multivariate analysis, ALT > 35 U/L at SVR12 was associated with male sex, higher BMI, liver cirrhosis, baseline ALT, HCV genotype 2, and younger age. Obesity, cirrhosis, and ALT were also independent factors associated with ALT > 15 U/L at SVR12 in patients with normal ALT at baseline. CONCLUSIONS: Male sex, advanced liver fibrosis, and obesity are main risk factors for the lack of ALT normalization and/or ALT decline after SVR, indicative of fatty liver disease as a relevant comorbidity in hepatitis C.

Site-Selective C-H Oxygenation via Aryl Sulfonium Salts.

Herein, we report a two-step process forming arene C-O bonds in excellent site-selectivity at a late-stage. The C-O bond formation is achieved by selective introduction of a thianthrenium group, which is then converted into C-O bonds using photoredox chemistry. Electron-rich, -poor and -neutral arenes as well as complex drug-like small molecules are successfully transformed into both phenols and various ethers. The sequence differs conceptually from all previous arene oxygenation reactions in that oxygen functionality can be incorporated into complex small molecules at a late stage site-selectively, which has not been shown via aryl halides.