Catalytic asymmetric cationic shifts of aliphatic hydrocarbons.

Asymmetric catalysis is an advanced area of chemical synthesis, but the handling of abundantly available, purely aliphatic hydrocarbons has proven to be challenging. Typically, heteroatoms or aromatic substructures are required in the substrates and reagents to facilitate an efficient interaction with the chiral catalyst. Confined acids have recently been introduced as tools for homogenous asymmetric catalysis, specifically to enable the processing of small unbiased substrates1. However, asymmetric reactions in which both substrate and product are purely aliphatic hydrocarbons have not previously been catalysed by such super strong and confined acids. We describe here an imidodiphosphorimidate-catalysed asymmetric Wagner-Meerwein shift of aliphatic alkenyl cycloalkanes to cycloalkenes with excellent regio- and enantioselectivity. Despite their long history and high relevance for chemical synthesis and biosynthesis, Wagner-Meerwein reactions utilizing purely aliphatic hydrocarbons, such as those originally reported by Wagner and Meerwein, had previously eluded asymmetric catalysis.

The alpha7 integrin subunit in astrocytes promotes endothelial blood-brain barrier integrity.

The blood-brain barrier (BBB) is a vascular endothelial cell boundary that partitions the circulation from the central nervous system to promote normal brain health. We have a limited understanding of how the BBB is formed during development and maintained in adulthood. We used quantitative transcriptional profiling to investigate whether specific adhesion molecules are involved in BBB functions, with an emphasis on understanding how astrocytes interact with endothelial cells. Our results reveal a striking enrichment of multiple genes encoding laminin subunits as well as the laminin receptor gene Itga7, which encodes the alpha7 integrin subunit, in astrocytes. Genetic ablation of Itga7 in mice led to aberrant BBB permeability and progressive neurological pathologies. Itga7-/- mice also showed a reduction in laminin protein expression in parenchymal basement membranes. Blood vessels in the Itga7-/- brain showed separation from surrounding astrocytes and had reduced expression of the tight junction proteins claudin 5 and ZO-1. We propose that the alpha7 integrin subunit in astrocytes via adhesion to laminins promotes endothelial cell junction integrity, all of which is required to properly form and maintain a functional BBB.

Cytoplasmic control of intranuclear polarity by human cytomegalovirus.

Despite its size and rigidity, the cell nucleus can be moved or reorganized by cytoskeletal filaments under various conditions (for example, during viral infection)1-11. Moreover, whereas chromatin organizes into non-random domains12, extensive heterogeneity at the single-cell level13 means that precisely how and why nuclei reorganize remains an area of intense investigation. Here we describe convolutional neural network-based automated cell classification and analysis pipelines, which revealed the extent to which human cytomegalovirus generates nuclear polarity through a virus-assembled microtubule-organizing centre. Acetylation of tubulin enables microtubules emanating from this centre to rotate the nucleus by engaging cytoplasmically exposed dynein-binding domains in the outer nuclear membrane protein nesprin-2G, which polarizes the inner nuclear membrane protein SUN1. This in turn creates intranuclear polarity in emerin, and thereby controls nuclear actin filaments that spatially segregate viral DNA from inactive histones and host DNA, maximizing virus replication. Our findings demonstrate the extent to which viruses can control the nucleus from the cytoplasm.

HLA Allele-Restricted Immune-Mediated Adverse Drug Reactions: Framework for Genetic Prediction.

Human leukocyte antigen (HLA) is a hallmark genetic marker for the prediction of certain immune-mediated adverse drug reactions (ADRs). Numerous basic and clinical research studies have provided the evidence base to push forward the clinical implementation of HLA testing for the prevention of such ADRs in susceptible patients. This review explores current translational progress in using HLA as a key susceptibility factor for immune ADRs and highlights gaps in our knowledge. Furthermore, relevant findings of HLA-mediated drug-specific T cell activation are covered, focusing on cellular approaches to link genetic associations to drug-HLA binding as a complementary approach to understand disease pathogenesis.

Quantum Chemical Interrogation of Reactions Promoted by Dirhodium Tetracarboxylate Catalysts─Mechanism, Selectivity, and Nonstatistical Dynamic Effects.

ConspectusRh2L4 catalysts have risen in popularity in the world of organic synthesis, being used to accomplish a variety of reactions, including C-H insertion and cyclopropanation, and often doing so with high levels of stereocontrol. While the mechanisms and origins of selectivity for such reactions have been examined with computational quantum chemistry for decades, only recently have detailed pictures of the dynamic behavior of reacting Rh2L4-complexed molecules become accessible. Our computational studies on Rh2L4 catalyzed reactions are described here, with a focus on C-H insertion reactions of Rh2L4-carbenes. Several issues complicate the modeling of these reactions, each providing an opportunity for greater understanding and each revealing issues that should be incorporated into future rational design efforts. First, the fundamental mechanism of C-H insertion is discussed. While early quantum chemical studies pointed to transition structures with 3-center [C-H-C] substructures and asynchronous hydride transfer/C-C bond formation, recent examples of reactions with particularly flat potential energy surfaces and even discrete zwitterionic intermediates have been found. These reactions are associated with systems bearing π-donating groups at the site of hydride transfer, allowing for an intermediate with a carbocation substructure at that site to be selectively stabilized. Second, the possible importance of solvent coordination at the Rh atom distal to the carbene is discussed. While effects on reactivity and selectivity were found to be small, they turn out not to be negligible in some cases. Third, it is shown that, in contrast to many other transition metal promoted reactions, many Rh2L4 catalyzed reactions likely involve dissociation of the Rh2L4 catalyst before key chemical steps leading to products. When to expect dissociation is associated with specific features of substrates and the product-forming reactions in question. Often, dissociation precedes transition structures for pericyclic reactions that involve electrons that would otherwise bind to Rh2L4. Finally, the importance of nonstatistical dynamic effects, characterized through ab initio molecular dynamics studies, in some Rh2L4 catalyzed reactions is discussed. These are reactions where transition structures are shown to be followed by flat regions, very shallow minima, and/or pathways that bifurcate, all allowing for trajectories from a single transition state to form multiple different products. The likelihood of encountering such a situation is shown to be associated again with the likelihood of formation of zwitterionic structures along reaction paths, but ones for which pathways to multiple products are expected to be associated with very low or no barriers. The connection between these features and reduced yields of desired products are highlighted, as are the means by which some Rh2L4 catalysts modulate dynamic behavior to produce particular products in high yield.

Activation of Human CD8+ T Cells with Nitroso Dapsone-Modified HLA-B*13:01-Binding Peptides.

Previous studies have shown that cysteine-reactive drug metabolites bind covalently with protein to activate patient T cells. However, the nature of the antigenic determinants that interact with HLA and whether T cell stimulatory peptides contain the bound drug metabolite has not been defined. Because susceptibility to dapsone hypersensitivity is associated with the expression of HLA-B*13:01, we have designed and synthesized nitroso dapsone-modified, HLA-B*13:01 binding peptides and explored their immunogenicity using T cells from hypersensitive human patients. Cysteine-containing 9-mer peptides with high binding affinity to HLA-B*13:01 were designed (AQDCEAAAL [Pep1], AQDACEAAL [Pep2], and AQDAEACAL [Pep3]), and the cysteine residue was modified with nitroso dapsone. CD8+ T cell clones were generated and characterized in terms of phenotype, function, and cross-reactivity. Autologous APCs and C1R cells expressing HLA-B*13:01 were used to determine HLA restriction. Mass spectrometry confirmed that nitroso dapsone-peptides were modified at the appropriate site and were free of soluble dapsone and nitroso dapsone. APC HLA-B*13:01-restricted nitroso dapsone-modified Pep1- (n = 124) and Pep3-responsive (n = 48) CD8+ clones were generated. Clones proliferated and secreted effector molecules with graded concentrations of nitroso dapsone-modified Pep1 or Pep3. They also displayed reactivity against soluble nitroso dapsone, which forms adducts in situ, but not with the unmodified peptide or dapsone. Cross-reactivity was observed between nitroso dapsone-modified peptides with cysteine residues in different positions in the peptide sequence. These data characterize a drug metabolite hapten CD8+ T cell response in an HLA risk allele-restricted form of drug hypersensitivity and provide a framework for structural analysis of hapten HLA binding interactions.

Running Wild through Dirhodium Tetracarboxylate-Catalyzed Combined CH(C)-Functionalization/Cope Rearrangement Landscapes: Does Post-Transition-State Dynamic Mismatching Influence Product Distributions?

A special type of C-H functionalization can be achieved through C-H insertion combined with Cope rearrangement (CHCR) in the presence of dirhodium catalysts. This type of reaction was studied using density functional theory and ab initio molecular dynamics simulations, the results of which pointed to the dynamic origins of low yields observed in some experiments. These studies not only reveal intimate details of the complex reaction network underpinning CHCR reactions but also further cement the generality of the importance of nonstatistical dynamic effects in controlling Rh2L4-promoted reactions.

Combined Computational and Experimental Study Reveals Complex Mechanistic Landscape of Brønsted Acid-Catalyzed Silane-Dependent P═O Reduction.

The reaction mechanism of Brønsted acid-catalyzed silane-dependent P═O reduction has been elucidated through combined computational and experimental methods. Due to its remarkable chemo- and stereoselective nature, the Brønsted acid/silane reduction system has been widely employed in organophosphine-catalyzed transformations involving P(V)/P(III) redox cycle. However, the full mechanistic profile of this type of P═O reduction has yet to be clearly established to date. Supported by both DFT and experimental studies, our research reveals that the reaction likely proceeds through mechanisms other than the widely accepted "dual activation mode by silyl ester" or "acid-mediated direct P═O activation" mechanism. We propose that although the reduction mechanisms may vary with the substitution patterns of silane species, Brønsted acid generally activates the silane rather than the P═O group in transition structures. The proposed activation mode differs significantly from that associated with traditional Brønsted acid-catalyzed C═O reduction. The uniqueness of P═O reduction originates from the dominant Si/O═P orbital interactions in transition structures rather than the P/H-Si interactions. The comprehensive mechanistic landscape provided by us will serve as a guidance for the rational design and development of more efficient P═O reduction systems as well as novel organophosphine-catalyzed reactions involving P(V)/P(III) redox cycle.

Sunitinib inhibits STAT3 phosphorylation in cardiac muscle and prevents cardiomyopathy in the mdx mouse model of Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is a fatal X-linked genetic disorder affecting approximately 1 in 5000 male births worldwide. DMD is caused by mutations in the dystrophin gene. Dystrophin is essential for maintaining muscle cell membrane integrity and stability by linking the cytoskeleton to the extracellular matrix, which protects myofibers from contraction-induced damage. Loss of dystrophin leads to mechanically induced skeletal and cardiac muscle damage. Although the disease is not evident in DMD patients at birth, muscular dystrophy rapidly progresses and results in respiratory and cardiac muscle failure as early as the teenage years. Premature death in DMD patients is due to cardiac arrhythmias and left ventricular dysfunction. Currently, there is no effective treatment for DMD-related cardiac failure. Recently, we have shown that a Food and Drug Administration-approved small molecule, sunitinib, a multi-targeted tyrosine kinase inhibitor can mitigate skeletal muscle disease through an increase in myogenic capacity, cell membrane integrity, and improvement of skeletal muscle function via regulation of STAT3-related signaling pathway. Chronic activation of STAT3 has been shown to promote cardiac hypertrophy and failure. In this study, we examined the effects of long-term sunitinib treatment on cardiac pathology and function. Our results showed sunitinib treatment reduced STAT3 phosphorylation in the heart muscle of mdx mice, improved cardiac electrical function, increased cardiac output and stroke volume, decreased ventricular hypertrophy, reduced cardiomyocytes membrane damage, fibrotic tissue deposition and slightly decreased cardiac inflammation. Together, our studies support the idea that sunitinib could serve as a novel treatment to slow cardiomyopathy progression in DMD. One Sentence Summary In this study, we determined if sunitinib, a Food and Drug Administration-approved drug, could reduce the pathology and improve cardiac function in an animal model for DMD.

Glycolysis: An early marker for vancomycin-specific T-cell activation.

BACKGROUND: Vancomycin, a glycopeptide antibiotic used for Gram-positive bacterial infections, has been linked with drug reaction with eosinophilia and systemic symptoms (DRESS) in HLA-A*32:01-expressing individuals. This is associated with activation of T lymphocytes, for which glycolysis has been isolated as a fuel pathway following antigenic stimulation. However, the metabolic processes that underpin drug-reactive T-cell activation are currently undefined and may shed light on the energetic conditions needed for the elicitation of drug hypersensitivity or tolerogenic pathways. Here, we sought to characterise the immunological and metabolic pathways involved in drug-specific T-cell activation within the context of DRESS pathogenesis using vancomycin as model compound and drug-reactive T-cell clones (TCCs) generated from healthy donors and vancomycin-hypersensitive patients. METHODS: CD4+ and CD8+ vancomycin-responsive TCCs were generated by serial dilution. The Seahorse XFe96 Analyzer was used to measure the extracellular acidification rate (ECAR) as an indicator of glycolytic function. Additionally, T-cell proliferation and cytokine release (IFN-γ) assay were utilised to correlate the bioenergetic characteristics of T-cell activation with in vitro assays. RESULTS: Model T-cell stimulants induced non-specific T-cell activation, characterised by immediate augmentation of ECAR and rate of ATP production (JATPglyc). There was a dose-dependent and drug-specific glycolytic shift when vancomycin-reactive TCCs were exposed to the drug. Vancomycin-reactive TCCs did not exhibit T-cell cross-reactivity with structurally similar compounds within proliferative and cytokine readouts. However, cross-reactivity was observed when analysing energetic responses; TCCs with prior specificity for vancomycin were also found to exhibit glycolytic switching after exposure to teicoplanin. Glycolytic activation of TCC was HLA restricted, as exposure to HLA blockade attenuated the glycolytic induction. CONCLUSION: These studies describe the glycolytic shift of CD4+ and CD8+ T cells following vancomycin exposure. Since similar glycolytic switching is observed with teicoplanin, which did not activate T cells, it is possible the master switch for T-cell activation is located upstream of metabolic signalling.

Insight into neofunctionalization of 2,3-oxidosqualene cyclases in B,C-ring-opened triterpene biosynthesis in quinoa.

Bioactive triterpenes feature complex fused-ring structures, primarily shaped by the first-committed enzyme, 2,3-oxidosqualene cyclases (OSCs) in plant triterpene biosynthesis. Triterpenes with B,C-ring-opened skeletons are extremely rare with unknown formation mechanisms, harbouring unchartered chemistry and biology. Here, through mining the genome of Chenopodium quinoa followed by functional characterization, we identified a stress-responsive and neofunctionalized OSC capable of generating B,C-ring-opened triterpenes, including camelliol A and B and the novel (-)-quinoxide A as wax components of the specialized epidermal bladder cells, namely the quinoxide synthase (CqQS). Protein structure analysis followed by site-directed mutagenesis identified key variable amino acid sites underlying functional interconversion between pentacyclic ß-amyrin synthase (CqbAS1) and B,C-ring-opened triterpene synthase CqQS. Mutation of one key residue (N612K) in even evolutionarily distant Arabidopsis ß-amyrin synthase could generate quinoxides, indicating a conserved mechanism for B,C-ring-opened triterpene formation in plants. Quantum computation combined with docking experiments further suggests that conformations of conserved W613 and F413 of CqQS might be key to selectively stabilizing intermediate carbocations towards B,C-ring-opened triterpene formation. Our findings shed light on quinoa triterpene skeletal diversity and mechanisms underlying B,C-ring-opened triterpene biosynthesis, opening avenues towards accessing their chemistry and biology and paving the way for quinoa trait engineering and quality improvement.

Characterization of metabolic alterations of chronic lymphocytic leukemia in the lymph node microenvironment.

Altered metabolism is a hallmark of both cell division and cancer. Chronic lymphocytic leukemia (CLL) cells circulate between peripheral blood (PB) and lymph nodes (LNs), where they receive proliferative and prosurvival signals from surrounding cells. However, insight into the metabolism of LN CLL and how this may relate to therapeutic response is lacking. To obtain insight into CLL LN metabolism, we applied a 2-tiered strategy. First, we sampled PB from 8 patients at baseline and after 3-month ibrutinib (IBR) treatment, which forces egress of CLL cells from LNs. Second, we applied in vitro B-cell receptor (BCR) or CD40 stimulation to mimic the LN microenvironment and performed metabolomic and transcriptomic analyses. The combined analyses indicated prominent changes in purine, glucose, and glutamate metabolism occurring in the LNs. CD40 signaling mostly regulated amino acid metabolism, tricarboxylic acid cycle (TCA), and energy production. BCR signaling preferably engaged glucose and glycerol metabolism and several biosynthesis routes. Pathway analyses demonstrated opposite effects of in vitro stimulation vs IBR treatment. In agreement, the metabolic regulator MYC and its target genes were induced after BCR/CD40 stimulation and suppressed by IBR. Next, 13C fluxomics performed on CD40/BCR-stimulated cells confirmed a strong contribution of glutamine as fuel for the TCA cycle, whereas glucose was mainly converted into lactate and ribose-5-phosphate. Finally, inhibition of glutamine import with V9302 attenuated CD40/BCR-induced resistance to venetoclax. Together, these data provide insight into crucial metabolic changes driven by the CLL LN microenvironment. The prominent use of amino acids as fuel for the TCA cycle suggests new therapeutic vulnerabilities.

A dedicated risk prediction model of 1-year mortality following endovascular aortic aneurysm repair involving the renal-mesenteric arteries.

OBJECTIVE: Treatment goals of prophylactic endovascular aortic repair of complex aneurysms involving the renal-mesenteric arteries (complex endovascular aortic repair [cEVAR]) include achieving both technical success and long-term survival benefit. Mortality within the first year after cEVAR likely indicates treatment failure owing to associated costs and procedural complexity. Notably, no validated clinical decision aid tools exist that reliably predict mortality after cEVAR. The purpose of this study was to derive and validate a preoperative prediction model of 1-year mortality after elective cEVAR. METHODS: All elective cEVARs including fenestrated, branched, and/or chimney procedures for aortic disease extent confined proximally to Ishimaru landing zones 6 to 9 in the Society for Vascular Surgery Vascular Quality Initiative were identified (January 2012 to August 2023). Patients (n = 4053) were randomly divided into training (n = 3039) and validation (n = 1014) datasets. A logistic regression model for 1-year mortality was created and internally validated by bootstrapping the AUC and calibration intercept and slope, and by using the model to predict 1-year mortality in the validation dataset. Independent predictors were assigned an integer score, based on model beta-coefficients, to generate a simplified scoring system to categorize patient risk. RESULTS: The overall crude 1-year mortality rate after elective cEVAR was 11.3% (n = 456/4053). Independent preoperative predictors of 1-year mortality included chronic obstructive pulmonary disease, chronic renal insufficiency (creatinine >1.8 mg/dL or dialysis dependence), hemoglobin <12 g/dL, decreasing body mass index, congestive heart failure, increasing age, American Society of Anesthesiologists class ≥IV, current tobacco use, history of peripheral vascular intervention, and increasing extent of aortic disease. The 1-year mortality rate varied from 4% among the 23% of patients classified as low risk to 23% for the 24% classified as high risk. Performance of the model in validation was comparable with performance in the training data. The internally validated scoring system classified patients roughly into quartiles of risk (low, low/medium, medium/high and high), with 52% of patients categorized as medium/high to high risk, which had corresponding 1-year mortality rates of 11% and 23%, respectively. Aneurysm diameter was below Society for Vascular Surgery recommended treatment thresholds (<5.0 cm in females, <5.5 cm in males) in 17% of patients (n = 679/3961), 41% of whom were categorized as medium/high or high risk. This subgroup had significantly increased in-hospital complication rates (18% vs 12%; P = .02) and 1-year mortality (13% vs 5%; P < .0001) compared with patients in the low- or low/medium-risk groups with guideline-compliant aneurysm diameters (≥5.0 cm in females, ≥5.5 cm in males). CONCLUSIONS: This validated preoperative prediction model for 1-year mortality after cEVAR incorporates physiological, functional, and anatomical variables. This novel and simplified scoring system can effectively discriminate mortality risk and, when applied prospectively, may facilitate improved preoperative decision-making, complex aneurysm care delivery, and resource allocation.

Current Medicare reimbursement for complex endovascular aortic repair is inadequate based on results from a multi-institutional cost analysis.

OBJECTIVE: Complex endovascular juxta-, para- and suprarenal abdominal aortic aneurysm repair (comEVAR) is frequently accomplished with commercially available fenestrated (FEVAR) devices or off-label use of aortoiliac devices with parallel branch stents (chEVAR). We sought to evaluate the implantable vascular device costs incurred with these procedures as compared with standard Medicare reimbursement to determine the financial viability of comEVAR in the modern era. METHODS: Five geographically distinct institutions with high-volume, complex aortic centers were included. Implantable aortoiliac and branch stent device cost data from 25 consecutive, recent, comEVAR in the treatment of juxta-, para-, and suprarenal aortic aneurysms at each center were analyzed. Cases of rupture, thoracic aneurysms, reinterventions, and physician-modified EVAR were excluded, as were ancillary costs from nonimplantable equipment. Data from all institutions were combined and stratified into an overall cost group and two, individual cost groups: FEVAR or chEVAR. These groups were compared, and each respective group was then compared with weighted Medicare reimbursement for Diagnosis-Related Group codes 268/269. Median device costs were obtained from an independent purchasing consortium of >3000 medical centers, yielding true median cost-to-institution data rather than speculative, administrative projections or estimates. RESULTS: A total of 125 cases were analyzed: 70 FEVAR and 53 chEVAR. Two cases of combined FEVAR/chEVAR were included in total cost analysis, but excluded from direct FEVAR vs chEVAR comparison. Median Medicare reimbursement was calculated as $35,755 per case. Combined average implantable device cost for all analyzed cases was $28,470 per case, or 80% of the median reimbursement ($28,470/$35,755). Average FEVAR device cost per case ($26,499) was significantly lower than average chEVAR cost per case ($32,122; P < .002). Device cost was 74% ($26,499/$35,755) of total reimbursement for FEVAR and 90% ($32,122/$35,755) for chEVAR. CONCLUSIONS: Results from this multi-institutional analysis show that implantable device cost alone represents the vast majority of weighted total Medicare reimbursement per case with comEVAR, and that chEVAR is significantly more costly than FEVAR. Inadequate Medicare reimbursement for these cases puts high-volume, high-complexity aortic centers at a distinct financial disadvantage. In the interest of optimizing patient care, these data suggest a reconsideration of previously established, outdated, Diagnosis-Related Group coding and Medicare reimbursement for comEVAR.

Patients with naproxen-induced liver injury display T-cell memory responses toward an oxidative (S)-O-desmethyl naproxen metabolite but not the acyl glucuronide.

BACKGROUND: Exposure to nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen (IBU) and naproxen (NAP) is associated with idiosyncratic drug-induced liver injury (DILI). Carboxylate bioactivation into reactive metabolites (e.g., acyl glucuronides, AG) and resulting T-cell activation is hypothesized as causal for this adverse event. However, conclusive evidence supporting this is lacking. METHODS: In this work, we identify CD4+ and CD8+ T-cell hepatic infiltration in a biopsy from an IBU DILI patient. Lymphocyte transformation test and IFN-γ ELIspot, conducted on peripheral blood mononuclear cells (PBMCs) of patients with NAP-DILI, were used to explore drug-specific T-cell activation. T-cell clones (TCC) were generated and tested for drug specificity, phenotype/function, and pathways of T-cell activation. Cells were exposed to NAP, its oxidative metabolite 6-O-desmethyl NAP (DM-NAP), its AG or synthesized NAP-AG human-serum albumin adducts (NAP-AG adduct). RESULTS: CD4+ and CD8+ T-cells from patients expressing a range of different Vß receptors were stimulated to proliferate and secrete IFN-γ and IL-22 when exposed to DM-NAP, but not NAP, NAP-AG or the NAP-AG adduct. Activation of the CD4+ TCC was HLA-DQ-restricted and dependent on antigen presenting cells (APC); most TCC were activated with DM-NAP-pulsed APC, while fixation of APC blocked the T-cell response. Cross-reactivity was not observed with structurally-related drugs. CONCLUSION: Our results confirm hepatic T-cell infiltrations in NSAID-induced DILI, and show a T-cell memory response toward DM-NAP indicating an immune-mediated basis for the adverse event. Whilst bioactivation at the carboxylate group is widely hypothesized to be pathogenic for NSAID associated DILI, we found no evidence of this with NAP.

Immunological Drug-Drug Interactions Affect the Efficacy and Safety of Immune Checkpoint Inhibitor Therapies.

With the rapid expansion in the development and clinical utility of immune checkpoint inhibitors (ICIs) for oncology, the continual evaluation of the safety profile of such agents is imperative. The safety profile of ICIs as monotherapy is dominated by immune-related adverse events, which can be considered as an extension of the mechanism of action of these immunomodulatory drugs. Further to this, an emerging theme is that ICI treatment can significantly impact upon the tolerability of coadministered medications. Numerous reports in literature indicate that ICIs may alter the immunological perception of coadministered drugs, resulting in undesirable reactions to a variety of concomitant medications. These reactions can be severe in manifestation, including hepatotoxicity and Stevens-Johnson Syndrome (SJS)/toxic epidermal necrolysis (TEN), but may also have detrimental impact on malignancy control. To minimize the impact of such drug-drug interactions on patients, it is imperative to identify medications that may cause these reactions, understand the underlying mechanisms, consider the timing and dosing of comedication, and explore alternative medications with comparable efficacies. Improving our understanding of how concomitant medications affect the safety and efficacy of ICIs can allow for potential culprit drugs to be identified/removed/desensitized. This approach will allow the continuation of ICI therapy that may have been discontinued otherwise, thereby improving malignant control and patient and drug development outcomes.

Endovascular Salvage of Type Ia and Ib Endoleaks Using a Physician-Modified Fenestrated/Branched Endograft and an Iliac Branch Device Via Unilateral Transfemoral Arterial Access.

PURPOSE: This study aims to explore the feasibility and effectiveness of a unilateral transfemoral access endovascular salvage technique for complex abdominal aortic aneurysms with concurrent type Ia and Ib endoleaks following previous endovascular repair. CASE REPORT: A 69-year-old female with multiple comorbidities presented with an extent IV thoracoabdominal aortic aneurysm complicated by type Ia and Ib endoleaks and chronically occluded left iliac endoprosthesis after prior endovascular repair. Given the patient's medical complexities, open explant repair was deemed high risk. The case was successfully managed using a physician-modified fenestrated/branched endograft (PM-F/BEVAR) and an iliac branch device (IBD) deployed through a single percutaneous transfemoral access. CONCLUSION: The presented case demonstrates the safety and efficacy of PM-F/BEVAR with concomitant IBD deployment via unilateral transfemoral access. This innovative approach allows endovascular salvage in cases with restricted iliofemoral access and avoids the complexities associated with upper extremity or aortic arch manipulation. While acknowledging the technical challenges, this technique offers a viable alternative for salvaging failed endovascular repairs, emphasizing the importance of real-time modifications in achieving successful outcomes. Further studies and long-term follow-up are warranted to validate the broader applicability and durability of this approach in the management of complex abdominal aortic aneurysms with multiple endoleaks. CLINICAL IMPACT: Although not the conventional approach, unilateral transfemoral access can be utilized to implant either a physician-modified fenestrated aortic endograft or an iliac branch device. Such an approach avoids complicating issues related to upper extremity access. This innovative technique may be necessary when there is a failed prior EVAR in the setting of significant contralateral iliofemoral occlusive disease. Doing both procedures in the same setting to resolve a type Ia and Ib endoleak is feasible as demonstrated in this case report. Expanding the endovascular armamentarium to address EVAR failure will be increasingly useful in the future, especially given the morbidity profile of EVAR explantation.

Cobalt-Catalyzed Deacylative Ipso-C-C Bond Functionalization: An Approach toward Indole-Acyloins and Its Photophysical Studies.

Selective functionalization of the indole-C3-C bond with aromatic/heteroaromatic 1,2-diketones has been uncovered for the first time. Cobalt catalyst was found to be an effective catalyst for this unusual transformation. This ipso-C-C bond functionalization occurred in the presence of easily available weakly coordinating groups such as ketone and ester. One of the salient features of this methodology is the in situ generation of water from hexafluoro-2-propanol which acts as a reactant for the removal of the pivaloyl/ester group in a deacylative manner. The plausible mechanism has been supported by DFT calculations. Moreover, photophysical studies show the potential utility of indole-C3-acyloin and indolo-fused carbazole, which could be used in photovoltaic and optoelectronic application.

Early bolus epinephrine administration during pediatric cardiopulmonary resuscitation for bradycardia with poor perfusion: an ICU-resuscitation study.

BACKGROUND: Half of pediatric in-hospital cardiopulmonary resuscitation (CPR) events have an initial rhythm of non-pulseless bradycardia with poor perfusion. Our study objectives were to leverage granular data from the ICU-RESUScitation (ICU-RESUS) trial to: (1) determine the association of early epinephrine administration with survival outcomes in children receiving CPR for bradycardia with poor perfusion; and (2) describe the incidence and time course of the development of pulselessness. METHODS: Prespecified secondary analysis of ICU-RESUS, a multicenter cluster randomized trial of children (< 19 years) receiving CPR in 18 intensive care units in the United States. Index events (October 2016-March 2021) lasting ≥ 2 min with a documented initial rhythm of bradycardia with poor perfusion were included. Associations between early epinephrine (first 2 min of CPR) and outcomes were evaluated with Poisson multivariable regression controlling for a priori pre-arrest characteristics. Among patients with arterial lines, intra-arrest blood pressure waveforms were reviewed to determine presence of a pulse during CPR interruptions. The temporal nature of progression to pulselessness was described and outcomes were compared between patients according to subsequent pulselessness status. RESULTS: Of 452 eligible subjects, 322 (71%) received early epinephrine. The early epinephrine group had higher pre-arrest severity of illness and vasoactive-inotrope scores. Early epinephrine was not associated with survival to discharge (aRR 0.97, 95%CI 0.82, 1.14) or survival with favorable neurologic outcome (aRR 0.99, 95%CI 0.82, 1.18). Among 186 patients with invasive blood pressure waveforms, 118 (63%) had at least 1 period of pulselessness during the first 10 min of CPR; 86 (46%) by 2 min and 100 (54%) by 3 min. Sustained return of spontaneous circulation was highest after bradycardia with poor perfusion (84%) compared to bradycardia with poor perfusion progressing to pulselessness (43%) and bradycardia with poor perfusion progressing to pulselessness followed by return to bradycardia with poor perfusion (62%) (p < 0.001). CONCLUSIONS: In this cohort of pediatric CPR events with an initial rhythm of bradycardia with poor perfusion, we failed to identify an association between early bolus epinephrine and outcomes when controlling for illness severity. Most children receiving CPR for bradycardia with poor perfusion developed subsequent pulselessness, 46% within 2 min of CPR onset.

Discrimination, gender dysphoria, drinking to cope, and alcohol harms in the UK trans and non-binary community.

Transgender (trans) and non-binary people may be at increased risk of alcohol harms, but little is known about motives for drinking in this community. This study explored the relationship between risk of alcohol dependence, experience of alcohol harms, drinking motives, dysphoria, and discrimination within a United Kingdom sample of trans and non-binary people with a lifetime history of alcohol use. A cross-sectional survey was co-produced with community stakeholders and administered to a purposive sample of trans and non-binary people from 1 February until 31 March 2022. A total of 462 respondents were included-159 identified as non-binary and/or genderqueer (identities outside the man/woman binary), 135 solely as women, 63 solely as men, 15 as another gender identity, 90 selected multiple identities. Higher levels of reported discrimination were associated with higher risk of dependence and more reported harms from drinking. Coping motives, enhancement motives, and drinking to manage dysphoria were associated with higher Alcohol Use Disorders Identification Test scores. Social, coping, and enhancement motives alongside discrimination and drinking to have sex were associated with harms. The relationship between discrimination and risk of dependence was mediated by coping motives and drinking to manage dysphoria. Further to these associations, we suggest that reducing discrimination against trans and non-binary communities might reduce alcohol harms in this population. Interventions should target enhancement motives, coping motives and gender dysphoria. Social and enhancement functions of alcohol could be replaced by alcohol free supportive social spaces.