Fulvenallenyl Radical (C7H5·)-Mediated Gas-Phase Synthesis of Bicyclic Aromatic C10H8 Isomers: Can Fulvenallenyl Efficiently React with Closed-Shell Hydrocarbons?

To understand the reactivity of resonantly stabilized radicals, often found in relevant concentrations in gaseous environments, it is important to determine their main reaction pathways. Here, it is investigated whether the fulvenallenyl radical (C7H5·) reacts preferentially with closed-shell molecules or radicals. Electronic structure calculations on the C10H9 potential energy surface accessed by the reactions of C7H5· with methylacetylene (CH3CCH) and allene (H2CCCH2) were combined with RRKM-ME calculations of temperature- and pressure-dependent rate constants using the automated EStokTP software suite and kinetic modeling to assess the reactivity of C7H5· with closed-shell unsaturated hydrocarbons. Experimentally, the reactions were attempted in a chemical microreactor heated to 998 ± 10 K by preparing fulvenallenyl radicals via pyrolysis of trichloromethylbenzene (C7H5Cl3) and seeding the radicals in methylacetylene or allene carrier gas, with product identification by means of photoionization mass spectrometry. The measured photoionization efficiency curve of m/z = 128 was assigned to a linear combination of the reference curves of two C10H8 isomers, azulene (minor) and naphthalene (major), presumably resulting from the C7H5· plus C3H4 reactions. However, the calculations demonstrated that these reactions are too slow, and kinetic modeling of processes in the reactor allowed us to conclude that the observation of naphthalene and azulene is due to the C7H5· plus C3H3· reaction, where propargyl is produced by direct hydrogen atom abstraction by chlorine (Cl) atoms from allene or methylacetylene and Cl stem from the pyrolysis of C7H5Cl3. Modeling results under the copyrolysis conditions of toluene and methylacetylene in high-temperature shock tube experiments confirmed the prevalence of the fulvenallenyl reaction with propargyl over its reactions with C3H4 even when the concentrations of allene and methylacetylene largely exceed that of propargyl. Overall, the reactions of fulvenallenyl with both allene and methylacetylene were found to be noncompetitive in the formation of naphthalene and azulene thus attesting the inefficiency of the fulvenallenyl radical reactions with the prototype closed-shell hydrocarbon species. In the meantime, the new reaction pathways revealed, including H-assisted isomerizations between C10H8 isomers and decomposition reactions of various C10H9 isomers, emerge as relevant and are recommended for inclusion in combustion kinetic models for naphthalene formation.

Design, in silico Evaluation, and Determination of Antitumor Activity of Potential Inhibitors Against Protein Kinases: Application to BCR-ABL Tyrosine Kinase.

Despite significant progress made over the past two decades in the treatment of chronic myeloid leukemia (CML), there is still an unmet need for effective and safe agents to treat patients with resistance and intolerance to the drugs used in clinic. In this work, we designed 2-arylaminopyrimidine amides of isoxazole-3-carboxylic acid, assessed in silico their inhibitory potential against Bcr-Abl tyrosine kinase, and determined their antitumor activity in K562 (CML), HL-60 (acute promyelocytic leukemia), and HeLa (cervical cancer) cells. Based on the analysis of computational and experimental data, three compounds with the antitumor activity against K562 and HL-60 cells were identified. The lead compound efficiently suppressed the growth of these cells, as evidenced by the low IC50 values of 2.8 ± 0.8 µM (K562) and 3.5 ± 0.2 µM (HL-60). The obtained compounds represent promising basic structures for the design of novel, effective, and safe anticancer drugs able to inhibit the catalytic activity of Bcr-Abl kinase by blocking the ATP-binding site of the enzyme.

Diabetic Ketoacidosis and Adverse Outcomes Among Pregnant Individuals With Pregestational Diabetes in the United States, 2010-2020.

OBJECTIVE: To assess the frequency of, risk factors for, and adverse outcomes associated with diabetic ketoacidosis (DKA) at delivery hospitalization among individuals with pregestational diabetes (type 1 and 2 diabetes mellitus) and secondarily to evaluate the frequency of and risk factors for antepartum and postpartum hospitalizations for DKA. METHODS: We conducted a serial, cross-sectional study using the Agency for Healthcare Research and Quality's Healthcare Cost and Utilization Project Nationwide Readmissions Database from 2010 to 2020 of pregnant individuals with pregestational diabetes hospitalized for delivery. The exposures were 1) sociodemographic and clinical risk factors for DKA and 2) DKA. The outcomes were DKA at delivery hospitalization, maternal morbidity (nontransfusion severe maternal morbidity (SMM), critical care procedures, cardiac complications, acute renal failure, and transfusion), and adverse pregnancy outcomes (preterm birth, hypertensive disorders of pregnancy, and cesarean delivery) and secondarily DKA at antepartum and postpartum hospitalizations. RESULTS: Of 392,796 deliveries in individuals with pregestational diabetes (27.2% type 1 diabetes, 72.8% type 2 diabetes), there were 4,778 cases of DKA at delivery hospitalization (89.1% type 1 diabetes, 10.9% type 2 diabetes). The frequency of DKA at delivery hospitalization was 1.2% (4.0% with type 1 diabetes, 0.2% with type 2 diabetes), and the mean annual percentage change was 10.8% (95% CI, 8.2-13.2%). Diabetic ketoacidosis at delivery hospitalization was significantly more likely among those who had type 1 diabetes compared with those with type 2 diabetes, who were younger in age, who delivered at larger and metropolitan hospitals, and who had Medicaid insurance, lower income, multiple gestations, and prior psychiatric illness. Diabetic ketoacidosis during the delivery hospitalization was associated with an increased risk of nontransfusion SMM (20.8% vs 2.4%, adjusted odds ratio [aOR] 8.18, 95% CI, 7.20-9.29), critical care procedures (7.3% vs 0.4%, aOR 15.83, 95% CI, 12.59-19.90), cardiac complications (7.8% vs 0.8%, aOR 8.87, 95% CI, 7.32-10.76), acute renal failure (12.3% vs 0.7%, aOR 9.78, 95% CI, 8.16-11.72), and transfusion (6.2% vs 2.2%, aOR 2.27, 95% CI, 1.87-2.75), as well as preterm birth (31.9% vs 13.5%, aOR 2.41, 95% CI, 2.17-2.69) and hypertensive disorders of pregnancy (37.4% vs 28.1%, aOR 1.11, 95% CI, 1.00-1.23). In secondary analyses, the overall frequency of antepartum DKA was 3.1%, and the mean annual percentage change was 4.1% (95% CI, 0.3-8.6%); the overall frequency of postpartum DKA was 0.4%, and the mean annual percentage change was 3.5% (95% CI, -1.6% to 9.6%). Of 3,092 antepartum hospitalizations among individuals with DKA, 15.7% (n=485) had a recurrent case of DKA at delivery hospitalization. Of 1,419 postpartum hospitalizations among individuals with DKA, 20.0% (n=285) previously had DKA at delivery hospitalization. The above risk factors for DKA at delivery hospitalization were similar for DKA at antepartum and postpartum hospitalizations. CONCLUSION: The frequency of DKA at delivery hospitalization and antepartum hospitalizations for DKA increased between 2010 and 2020 among deliveries in individuals with pregestational diabetes in the United States. Diabetic ketoacidosis is associated with an increased risk of maternal morbidity and adverse pregnancy outcomes. Risk factors for DKA at delivery were similar to those for DKA during the antepartum and postpartum periods.

Cross polarization stability in multidimensional NMR spectroscopy of biological solids.

Magic-angle spinning (MAS) solid-state nuclear magnetic resonance (SSNMR) spectroscopy is a powerful and versatile technique for probing structure and dynamics in large, insoluble biological systems at atomic resolution. With many recent advances in instrumentation and polarization methods, technology development in SSNMR remains an active area of research and presents opportunities to further improve data collection, processing, and analysis of samples with low sensitivity and complex tertiary and quaternary structures. SSNMR spectra are often collected as multidimensional data, requiring stable experimental conditions to minimize signal fluctuations (t1 noise). In this work, we examine the factors adversely affecting signal stability as well as strategies used to mitigate them, considering laboratory environmental requirements, configuration of amplifiers, and pulse sequence parameter selection. We show that Thermopad® temperature variable attenuators (TVAs) can partially compensate for the changes in amplifier output power as a function of temperature and thereby ameliorate one significant source of instability for some spectrometers and pulse sequences. We also consider the selection of tangent ramped cross polarization (CP) waveform shapes, to balance the requirements of sensitivity and instrumental stability. These findings collectively enable improved stability and overall performance for CP-based multidimensional spectra of microcrystalline, membrane, and fibrous proteins performed at multiple magnetic field strengths.

A Rocky Road: Bladder Stones in the Augmented Exstrophy-Epispadias Complex Patient.

OBJECTIVES: To determine the rate of stone formation amongst patients of the exstrophy-epispadias complex with augmentation cystoplasty. We hypothesize that bowel segment choice influences the rate of stone formation after bladder augmentation and the rate of complications from bladder stone surgery. METHODS: An IRB approved institutional database of 1512 exstrophy-epispadias patients was reviewed retrospectively. Patients that had a history of bladder augmentation and were seen at our institution between 2003 and 2023 were included. RESULTS: Out of 259 patients, bladder stones developed in 21.6% (56), of which the bowel segment used was colon in 147 patients and ileum in 100. Stones formed in 19% of colon augments compared to 29% ileal augments, however this was not statistically significant (p=0.07). The most common primary stone component was dahllite, followed by struvite for all augments. The median time to stone treatment after augmentation was 4.14 years (0.75-31). 74% of patients had a recurrence that required a second surgery. The median time from first to second surgery and second to third surgery was 1.4 years and 2.22 years, respectively. Bladder stone surgery complications occurred in 14% of patients, vesicocutaneous fistula being the most common, and complications did not differ by augment type. Median follow up after first stone intervention was 6.07 years (0-19.5). CONCLUSION: The treatment of bladder stones in the exstrophy-epispadias complex remains challenging. Interventions to prevent recurrence are crucial as the majority of patients will require two or more stone surgeries in their lifetime.

Puncture Cube Patient-Mounted Navigation System versus Freehand Method for CT-Guided Needle Placement: Study on a Neoprene Covered Elliptical Cylinder Gelatin Phantom.

PURPOSE: The study aims to show how the "Puncture Cube" (PC) (Medical Templates, Egg, Switzerland) compares to the freehand method (FHM) for CT-guided punctures. METHODS: The PC is a patient-mounted disassemblable cube consisting of an upper and lower template with multiple holes each to predefine puncture trajectory. A total of 80 punctures (FHM in-plane, FHM off-plane, PC in-plane, PC off-plane) was performed by 4 radiologists on a target 9.1 cm below surface level of a neoprene covered elliptical cylinder gelatin phantom. The PC was never disassembled. Evaluated parameters were procedure time, number of CT-scans, euclidean distance (ED) and normal distance (ND). Respective parameters of FHM and PC were compared using the Wilcoxon signed-rank test and Levene test with significance levels of 5%. RESULTS: PC achieved smaller ED and ND values after initial needle insertion without corrections for both in-plane and off-plane punctures (P > 0.05). Variance of initial NDs was off-plane significantly larger for FHM. Final ED after needle path corrections was smaller for FHM both in- and off-plane (P < 0.05). Final off-plane ND was significantly lower for FHM with no significant difference in final in-plane ND. FHM off-plane punctures were significantly faster. There was no significant difference in CT-scans between both methods. CONCLUSION: Utilizing the PC may improve initial needle positioning and safety especially off-plane. However, better final needle positioning after correction with the greater freedom of movement method may suggest need for disassembly of the cube.

Modification of χ_{c1}(3872) and ψ(2S) Production in pPb Collisions at sqrt[s_{NN}]=8.16 TeV.

The LHCb Collaboration measures production of the exotic hadron χ_{c1}(3872) in proton-nucleus collisions for the first time. Comparison with the charmonium state ψ(2S) suggests that the exotic χ_{c1}(3872) experiences different dynamics in the nuclear medium than conventional hadrons, and comparison with data from proton-proton collisions indicates that the presence of the nucleus may modify χ_{c1}(3872) production rates. This is the first measurement of the nuclear modification factor of an exotic hadron.

Monitoring of controlled ovarian stimulation in IVF.

Since the inception of in vitro fertilization (IVF), monitoring of controlled ovarian stimulation (COS) has traditionally involved numerous appointments for ultrasound and laboratory testing to guide medication use and dosing, determine trigger timing, and allow for measures to reduce the risk of ovarian hyperstimulation syndrome (OHSS). Recent advances in the field of assisted reproductive technology (ART) have called into question the timing and frequency of COS monitoring appointments, as discussed in this commentary.

Cell wall integrity modulates HOOKLESS1 and PHYTOCHROME INTERACTING FACTOR4 expression controlling apical hook formation.

Formation of the apical hook in etiolated dicot seedlings results from differential growth in the hypocotyl apex and is tightly controlled by environmental cues and hormones, among which auxin and gibberellins (GAs) play an important role. Cell expansion is tightly regulated by the cell wall, but whether and how feedback from this structure contributes to hook development is still unclear. Here, we show that etiolated seedlings of the Arabidopsis (Arabidopsis thaliana) quasimodo2-1 (qua2) mutant, defective in pectin biosynthesis, display severe defects in apical hook formation and maintenance, accompanied by loss of asymmetric auxin maxima and of differential cell expansion. Moreover, qua2 seedlings show reduced expression of HOOKLESS 1 (HLS1) and PHYTOCHROME INTERACTING FACTOR 4 (PIF4), which are positive regulators of hook formation. Treatment of wild-type seedlings with the cellulose inhibitor isoxaben (isx) also prevents hook development and represses HLS1 and PIF4 expression. Exogenous GAs, loss of DELLA proteins or HLS1 overexpression partially restore hook development in qua2 and isx-treated seedlings. Interestingly, increased agar concentration in the medium restores, both in qua2 and isx-treated seedlings, hook formation, asymmetric auxin maxima and PIF4 and HLS1 expression. Analysis of plants expressing a FRET-based GA sensor indicate that isx reduces accumulation of GAs in the apical hook region in a turgor-dependent manner. Lack of the cell wall integrity sensor THESEUS 1, which modulates turgor loss point, restores hook formation in qua2 and isx-treated seedlings. We propose that turgor-dependent signals link changes in cell wall integrity to the PIF4-HLS1 signalling module to control differential cell elongation during hook formation.

Myeloid progenitor dysregulation fuels immunosuppressive macrophages in tumors.

Monocyte-derived macrophages (mo-macs) drive immunosuppression in the tumor microenvironment (TME) and tumor-enhanced myelopoiesis in the bone marrow (BM) fuels these populations. Here, we performed paired transcriptome and chromatin analysis over the continuum of BM myeloid progenitors, circulating monocytes, and tumor-infiltrating mo-macs in mice and in patients with lung cancer to identify myeloid progenitor programs that fuel pro-tumorigenic mo-macs. Analyzing chromatin accessibility and histone mark changes, we show that lung tumors prime accessibility for Nfe2l2 (NRF2) in BM myeloid progenitors as a cytoprotective response to oxidative stress. NRF2 activity is sustained and increased during monocyte differentiation into mo-macs in the lung TME to regulate oxidative stress, in turn promoting metabolic adaptation, resistance to cell death, and contributing to immunosuppressive phenotype. NRF2 genetic deletion and pharmacological inhibition significantly reduced mo-macs' survival and immunosuppression in the TME, enabling NK and T cell therapeutic antitumor immunity and synergizing with checkpoint blockade strategies. Altogether, our study identifies a targetable epigenetic node of myeloid progenitor dysregulation that sustains immunoregulatory mo-macs in the TME.

Single cell view of tumor microenvironment gradients in pleural mesothelioma.

Immunotherapies have shown great promise in pleural mesothelioma (PM), yet most patients still do not achieve significant clinical response, highlighting the importance of improving understanding of the tumor microenvironment (TME). Here, we utilized high-throughput, single-cell RNA-sequencing to de novo identify 54 expression programs and construct a comprehensive cellular catalogue of the PM TME. We found four cancer-intrinsic programs associated with poor disease outcome and a novel fetal-like, endothelial cell population that likely responds to VEGF signaling and promotes angiogenesis. Throughout cellular compartments, we observe substantial difference in the TME associated with a cancer-intrinsic sarcomatoid signature, including enrichment in fetal-like endothelial cells, CXCL9+ macrophages, cytotoxic, exhausted, and regulatory T cells, which we validated using imaging and bulk deconvolution analyses on independent cohorts. Finally, we show, both computationally and experimentally, that NKG2A-HLA-E interaction between NK and tumor cells represents an important new therapeutic axis in PM, especially for epithelioid cases.

Aspects of acceptance: building a shared conceptual understanding.

Many contemplatives, scientists, and clinicians have pointed to the value of responding to life's difficulties by accepting experiences as they are. A growing body of research also suggests that acceptance contributes to effective coping with adversity, reduced stress, and improved emotional well-being. Yet within the scientific literature, there is little consensus on what acceptance means or how it should be measured. This makes it nearly impossible to synthesize empirical work on acceptance into a cohesive scientific understanding. Our goal in this paper is to clarify four facets of acceptance that are commonly referenced in research: acknowledging, allowing, non-judging, and non-attachment. We do not propose a specific definition of acceptance or even a set of privileged facets that must be included in future frameworks. We instead offer a vocabulary to facilitate productive communication among researchers that will, in turn, enable a more definitive scientific understanding of this important construct to emerge. After defining and explaining these aspects of acceptance, we further clarify these constructs in two ways. First, we illustrate how the four aspects are dissociable from one another. Second, we analyze their correspondence to related constructs from Acceptance and Commitment Therapy (ACT). Finally, we provide a concept worksheet that scholars can utilize to precisely operationalize acceptance in their own work.

Stomal Stenosis After Continent Urinary Diversion in Bladder Exstrophy: Risk Factors and Management.

OBJECTIVE: To identify risk factors for stenosis and compare management strategies for stenosis etiology and to examine the efficacy of each approach. Patients with classic bladder exstrophy (CBE), a rare genitourinary malformation, may require construction of a continent urinary stoma (CUS) if incontinence persists. Stomal stenosis is a challenging complication as it is common, progressive and recurrent. METHODS: CBE patients who underwent CUS were retrospectively reviewed for risk factors for stenosis including stoma type, prior midline laparotomy number, and umbilicoplasty suture material. Stenosis etiology and management strategies were further reviewed. RESULTS: A total of 260 CBE patients underwent CUS creation. Stenosis developed in 65 patients (25.0%) at a median interval of 1.9 years. Etiology included scar contracture (n=41), keloid (n=17), and hypertrophic scar (n=7). Multifilament suture was the only variable associated with an increased risk of stenosis compared to monofilament suture (p=0.009). Almost all patients required surgical intervention. Most scar contractures underwent stomal incision with success in 100%. Hypertrophic scars and keloids responded best to excision with local tissue rearrangement (66.7%). At last follow-up, all patients achieved success. CONCLUSION: Stomal stenosis is common and challenging for the reconstructive surgeon. Strategies to prevent and effectively manage this are greatly desired. Use of multifilament suture for the umbilicoplasty increased stenosis perhaps from a greater inflammatory response and scarring, while monofilament suture may reduce its incidence. Stomal incision for treating scar contractures, and excision with local tissue rearrangement for hypertrophic scars and keloids may improve successful primary surgical intervention.

Overfeeding copper during rearing affects the liver function and fertility of replacement dairy heifers.

BACKGROUND: Oversupply of dietary copper (Cu) is common among UK dairy herds, but studies on the long-term outcomes of this oversupply are scarce. METHODS: A longitudinal study was undertaken to determine the long-term implications when 80 Holstein‒Friesian heifers with a mean (±standard error) age of 4.1 ± 0.1 months and a mean liveweight of 137 ± 2.4 kg were fed a recommended (R; 16 mg/kg dry matter [DM]) or high (H; 32 mg/kg DM) dietary Cu concentration until 6 weeks prior to calving. RESULTS: Hepatic Cu concentrations in both treatment groups were elevated into the ranges used to diagnose chronic Cu toxicity in cattle at 6.9 months of age (798 ± 46.4 mg/kg DM for H vs. 643 ± 35.4 mg/kg DM for R), with associated evidence of liver damage. Hepatic Cu concentrations then returned to normality but remained higher (p < 0.001) for heifers fed H than for those fed R and were associated with a reduced (p = 0.044) conception rate to first and second services (73.7 ± 8.05% for H vs. 91.2 ± 7.68% for R). LIMITATION: This retrospective analysis identified pre-study liver damage, which may have affected results. CONCLUSIONS: Supplying Cu in excess of requirements resulted in liver damage and reduced conception rates.

Functional and Structural Properties of Cytoplasmic Tropomyosin Isoforms Tpm1.8 and Tpm1.9.

The actin cytoskeleton is one of the most important players in cell motility, adhesion, division, and functioning. The regulation of specific microfilament formation largely determines cellular functions. The main actin-binding protein in animal cells is tropomyosin (Tpm). The unique structural and functional diversity of microfilaments is achieved through the diversity of Tpm isoforms. In our work, we studied the properties of the cytoplasmic isoforms Tpm1.8 and Tpm1.9. The results showed that these isoforms are highly thermostable and differ in the stability of their central and C-terminal fragments. The properties of these isoforms were largely determined by the 6th exons. Thus, the strength of the end-to-end interactions, as well as the affinity of the Tpm molecule for F-actin, differed between the Tpm1.8 and Tpm1.9 isoforms. They were determined by whether an alternative internal exon, 6a or 6b, was included in the Tpm isoform structure. The strong interactions of the Tpm1.8 and Tpm1.9 isoforms with F-actin led to the formation of rigid actin filaments, the stiffness of which was measured using an optical trap. It is quite possible that the structural and functional features of the Tpm isoforms largely determine the appearance of these isoforms in the rigid actin structures of the cell cortex.

National Beef Quality Audit-2022: in-plant assessments of quality and yield determining carcass characteristics of fed steers and heifers.

The National Beef Quality Audit - 2022 serves as a benchmark of the current fed steer and heifer population of the U.S. beef industry and allows comparison to previous audits as a method of monitoring industry progress. In-plant cooler assessments and collections of beef carcass data took place from July 2021 to November 2022. During in-plant evaluations, 10% of 1-d production was surveyed for quality and yield indicating characteristics of fed beef carcasses (n = 9,746 beef carcasses). Distributions of sex classes among sampled carcasses were steer (65.0%) and heifer (35.0%), whereas distributions of breed type were native (87.7%), dairy (11.3%), and Bos indicus (0.9%). Mean values were observed for USDA Yield Grades (YG; 3.3), USDA Quality Grade (QG; Choice16), marbling score (Small98), ribeye area (91.0 cm2), adjusted fat thickness (1.49 cm), hot carcass weight (401.9 kg), and KPH (2.5%). Mean overall maturity was A66, with a mean lean maturity of A56 and mean skeletal maturity of A72. There were 28.1% of carcasses identified for use in a USDA-certified beef G-Schedule Program. Defects, such as dark cutting and blood splash, were observed at 1.8% and 0.5%, respectively. Distributions of USDA YG were YG 1 (8.2%), YG 2 (30.7%), YG 3 (40.2%), YG 4 (16.6%), and YG 5 (4.3%). USDA QGs were observed at 7.5% Prime, 69.2% Choice, 16.4% Select, and 6.8% other. The results of this study provide an updated look at the current grading trends of beef carcasses in the United States to drive progress in the fed beef industry.

Duration of triple antithrombotic therapy and clinical outcomes after percutaneous coronary intervention in atrial fibrillation.

BACKGROUND: Triple antithrombotic therapy (TAT) with aspirin, a P2Y12 inhibitor, and oral anticoagulation in patients with atrial fibrillation (AF) undergoing percutaneous coronary intervention (PCI) raises concerns about increased bleeding. Regimens incorporating more potent P2Y12 inhibitors over clopidogrel have not been investigated adequately. RESEARCH DESIGN AND METHODS: A retrospective observational study was performed on 387 patients with AF receiving TAT for 1 month (n = 236) or ≤1 week (n = 151) after PCI. Major and clinically relevant non-major bleeding and major adverse cardiac and cerebrovascular events (MACCE) were assessed up to 30 days post-procedure. RESULTS: Bleeding was less frequent with ≤1 week versus 1 month of TAT (3.3 vs 9.3%; p = 0.025) while MACCE were similar (4.6 vs 4.7%; p = 0.998). No differences in bleeding or MACCE were observed between ticagrelor/prasugrel and clopidogrel regimens. For patients receiving ≤1 week of TAT, no excess of MACCE was seen in the subgroup given no further aspirin post-PCI compared with those given aspirin for up to 1 week (3.6 vs 5.2%). CONCLUSIONS: TAT post-PCI for ≤1 week was associated with less bleeding despite greater use of ticagrelor/prasugrel but similar MACCE versus 1-month TAT. These findings support further studies on safety and efficacy of dual therapy with ticagrelor/prasugrel immediately after PCI.

Determining the Minimal Clinically Important Difference (MCID) and Responsiveness of the Chinese Version of Zurich Chronic Middle Ear Inventory (ZCMEI-21-Chn): A Prospective Multicenter Study.

OBJECTIVES: This study aimed to establish the minimal clinically important difference (MCID) and assess the responsiveness of the Chinese version of Zurich Chronic Middle Ear Inventory (ZCMEI-21-Chn). STUDY DESIGN: Prospective multicenter study. SETTING: Four Chinese tertiary referral centers admitting patients nationwide. PATIENTS: 230 adult patients with chronic otitis media (COM) undergoing tympanoplasty. INTERVENTION: Patients were required to complete the ZCMEI-21-Chn to measure health-related quality of life both preoperatively and postoperatively. An anchor-based method was used to determine the MCID of the derivative cohort by including the Global Rating of Change Questionnaire as an anchor. The generalizability and consistency with functional outcomes of the MCID estimates were externally examined in a validation cohort using a receiver operating characteristic curve analysis. RESULTS: A total of 161 and 69 patients were included in the derivative and validation cohort. The mean preoperative and postoperative ZCMEI-21-Chn total scores were 28.4 (standard deviation [SD] 14.5) and 17.5 (SD 12.6). The mean change in ZCMEI-21-Chn score was 10.9 (SD 14.3, p < 0.001). The MCIDs of the ZCMEI-21-Chn for improvement and deterioration were estimated at 13 (SD 13.0) and -7 (SD 12.9), accordingly. For patients who have reported an improved health-related quality of life, a cutoff value of 15.6 dB HL for elevation of the air-conducted hearing threshold was noticed. However, change of clinical importance judged according to MCID and Japan Otological Society criteria disagreed with each other, notably with a Cohen's kappa ( κ ) of 0.14 ( p = 0.21) in the validation cohort. CONCLUSION: This study is the first to establish the MCID of a COM-specific questionnaire in Chinese. For the COM population undergoing surgical intervention, MCID values of 13 for improvement and -7 for deterioration are recommended. The results were externally validated to be generalizable to nationwide usage, yet distinguishable from the audiological criteria. The availability of the MCID greatly adds to the clinical utility of the ZCMEI-21-Chn by enabling a clinically meaningful interpretation of its score changes.

A Pd-catalyzed route to carborane-fused boron heterocycles.

Due to the expanding applications of icosahedral carboranes in medicinal and materials chemistry research, their functionalizations have become one of the central themes in boron-rich cluster chemistry. Although several strategies for incorporating nitrogen-containing nucleophiles on a single boron vertex of the icosahedral carboranes (C2B10H12) have been developed, methods for preparing clusters with vicinal B-N moieties are still lacking. The steric bulk of icosahedral carboranes and disparate electronic and steric nature of the N-containing groups have rendered the vicinal diamination challenging. In this article, we show how a developed Pd-catalyzed process is used to incorporate an array of NH-heterocycles, anilines, and heteroanilines with various electronic and steric profiles onto the vicinal boron vertices of a meta-carborane cluster via sequential or one-pot fashion. Importantly, oxidative cyclizations of the cross-coupling products with indoles and pyrroles appended to boron vertices generate a previously unknown class of all-boron-vertex bound carborane-fused six- and seven-membered ring heterocycles. Photophysical studies of the meta-carborane-fused heterocycles show that these structures can exhibit luminescence with high quantum yields and are amenable to further manipulations.