Single-cell trajectory detection uncovers progression and regulatory coordination in human B cell development.

Tissue regeneration is an orchestrated progression of cells from an immature state to a mature one, conventionally represented as distinctive cell subsets. A continuum of transitional cell states exists between these discrete stages. We combine the depth of single-cell mass cytometry and an algorithm developed to leverage this continuum by aligning single cells of a given lineage onto a unified trajectory that accurately predicts the developmental path de novo. Applied to human B cell lymphopoiesis, the algorithm (termed Wanderlust) constructed trajectories spanning from hematopoietic stem cells through to naive B cells. This trajectory revealed nascent fractions of B cell progenitors and aligned them with developmentally cued regulatory signaling including IL-7/STAT5 and cellular events such as immunoglobulin rearrangement, highlighting checkpoints across which regulatory signals are rewired paralleling changes in cellular state. This study provides a comprehensive analysis of human B lymphopoiesis, laying a foundation to apply this approach to other tissues and "corrupted" developmental processes including cancer.

AI-based pathology predicts origins for cancers of unknown primary.

Cancer of unknown primary (CUP) origin is an enigmatic group of diagnoses in which the primary anatomical site of tumour origin cannot be determined1,2. This poses a considerable challenge, as modern therapeutics are predominantly specific to the primary tumour3. Recent research has focused on using genomics and transcriptomics to identify the origin of a tumour4-9. However, genomic testing is not always performed and lacks clinical penetration in low-resource settings. Here, to overcome these challenges, we present a deep-learning-based algorithm-Tumour Origin Assessment via Deep Learning (TOAD)-that can provide a differential diagnosis for the origin of the primary tumour using routinely acquired histology slides. We used whole-slide images of tumours with known primary origins to train a model that simultaneously identifies the tumour as primary or metastatic and predicts its site of origin. On our held-out test set of tumours with known primary origins, the model achieved a top-1 accuracy of 0.83 and a top-3 accuracy of 0.96, whereas on our external test set it achieved top-1 and top-3 accuracies of 0.80 and 0.93, respectively. We further curated a dataset of 317 cases of CUP for which a differential diagnosis was assigned. Our model predictions resulted in concordance for 61% of cases and a top-3 agreement of 82%. TOAD can be used as an assistive tool to assign a differential diagnosis to complicated cases of metastatic tumours and CUPs and could be used in conjunction with or in lieu of ancillary tests and extensive diagnostic work-ups to reduce the occurrence of CUP.

CD39 Is Expressed on Functional Effector and Tissue-resident Memory CD8+ T Cells.

The ecto-ATPase CD39 is expressed on exhausted CD8+ T cells in chronic viral infection and has been proposed as a marker of tumor-specific CD8+ T cells in cancer, but the role of CD39 in an effector and memory T cell response has not been clearly defined. We report that CD39 is expressed on Ag-specific CD8+ short-lived effector cells, while it's co-ectoenzyme, CD73, is found on memory precursor effector cells (MPECs) in vivo. Inhibition of CD39 enzymatic activity during in vitro T cell priming enhances MPEC differentiation in vivo after transfer and infection. The enriched MPEC phenotype is associated with enhanced tissue resident memory T cell (TRM cell) establishment in the brain and salivary gland following an acute intranasal viral infection, suggesting that CD39 ATPase activity plays a role in memory CD8+ T cell differentiation. We also show that CD39 is expressed on human and murine TRM cells across several nonlymphoid tissues and melanoma, whereas CD73 is expressed on both circulating and resident memory subsets in mice. In contrast to exhausted CD39+ T cells in chronic infection, CD39+ TRM cells are fully functional when stimulated ex vivo with cognate Ag, further expanding the identity of CD39 beyond a T cell exhaustion marker.

Mechanistic details of CRISPR-associated transposon recruitment and integration revealed by cryo-EM.

CRISPR-associated transposons (CASTs) are Tn7-like elements that are capable of RNA-guided DNA integration. Although structural data are known for nearly all core transposition components, the transposase component, TnsB, remains uncharacterized. Using cryo-electron microscopy (cryo-EM) structure determination, we reveal the conformation of TnsB during transposon integration for the type V-K CAST system from Scytonema hofmanni (ShCAST). Our structure of TnsB is a tetramer, revealing strong mechanistic relationships with the overall architecture of RNaseH transposases/integrases in general, and in particular the MuA transposase from bacteriophage Mu. However, key structural differences in the C-terminal domains indicate that TnsB's tetrameric architecture is stabilized by a different set of protein-protein interactions compared with MuA. We describe the base-specific interactions along the TnsB binding site, which explain how different CAST elements can function on cognate mobile elements independent of one another. We observe that melting of the 5' nontransferred strand of the transposon end is a structural feature stabilized by TnsB and furthermore is crucial for donor-DNA integration. Although not observed in the TnsB strand-transfer complex, the C-terminal end of TnsB serves a crucial role in transposase recruitment to the target site. The C-terminal end of TnsB adopts a short, structured 15-residue "hook" that decorates TnsC filaments. Unlike full-length TnsB, C-terminal fragments do not appear to stimulate filament disassembly using two different assays, suggesting that additional interactions between TnsB and TnsC are required for redistributing TnsC to appropriate targets. The structural information presented here will help guide future work in modifying these important systems as programmable gene integration tools.

Early-Life Social Determinants of SCA6 Age at Onset, Severity, and Progression.

SCA6 patients with the same size CAG repeat allele can vary significantly in age at onset (AAO) and clinical progression. The specific external factors affecting SCA6 have yet to be investigated. We assessed the effect of early life events on AAO, severity, and progression in SCA6 patients using a social determinant of health approach. We performed a survey of biological and social factors in SCA6 patients enrolled in the SCA6 Network at the University of Chicago. AAO of ataxia symptoms and patient-reported outcome measure (PROM) of ataxia were used as primary outcome measures. Least absolute shrinkage and selection operation (LASSO) regressions were used to identify which early life factors are predictive of SCA6 AAO, severity, and progression. Multiple linear regression models were then used to assess the degree to which these determinants influence SCA6 health outcomes. A total of 105 participants with genetically confirmed SCA6 completed the assessments. SCA6 participants with maternal difficulty during pregnancy, active participation in school sports, and/or longer CAG repeats were determined to have earlier AAO. We found a 13.44-year earlier AAO for those with maternal difficulty in pregnancy than those without (p = 0.008) and a 12.31-year earlier AAO for those active in school sports than those who were not (p < 0.001). Higher education attainment was associated with decreased SCA6 severity and slower progression. Early life biological and social factors can have a strong influence on the SCA6 disease course, indicating that non-genetic factors can contribute significantly to SCA6 health outcomes.

A Comparative Biochemical and Pathological Evaluation of Brain Samples from Knock-In Murine Models of Gaucher Disease.

Gaucher disease (GD) is a lysosomal storage disorder stemming from biallelic mutations in GBA1, characterized by glucocerebrosidase dysfunction and glucocerebroside and glucosylsphingosine accumulation. Since phenotypes of murine models of GD often differ from those in patients, the careful characterization of Gba1 mutant mice is necessary to establish their ability to model GD. We performed side-by-side comparative biochemical and pathologic analyses of four murine Gba1 models with genotypes L444P/L444P (p.L483P/p.L483P), L444P/null, D409H/D409H (p.D448H/p.D448H) and D409H/null, along with matched wildtype mice, all with the same genetic background and cage conditions. All mutant mice exhibited significantly lower glucocerebrosidase activity (p < 0.0001) and higher glucosylsphingosine levels than wildtype, with the lowest glucocerebrosidase and the highest glucosylsphingosine levels in mice carrying a null allele. Although glucocerebrosidase activity in L444P and D409H mice was similar, D409H mice showed more lipid accumulation. No Gaucher or storage-like cells were detected in any of the Gba1 mutant mice. Quantification of neuroinflammation, dopaminergic neuronal loss, alpha-synuclein levels and motor behavior revealed no significant findings, even in aged animals. Thus, while the models may have utility for testing the effect of different therapies on enzymatic activity, they did not recapitulate the pathological phenotype of patients with GD, and better models are needed.

Weight stigma from romantic partners: Its relations with maladaptive and adaptive coping and depressive symptoms.

Social devaluation of being overweight is common in daily life, but little is known about the weight stigma in romantic relationships. The present study investigated the roles of maladaptive and adaptive coping strategies in the relation between the experience of weight stigma in romantic relationships and depressive symptoms in men and women, respectively. Analyses of gender differences and structural equation modeling yielded several findings. First, while men and women experienced similar levels of weight stigma from their romantic partners, women were more likely to use exercise avoidance, disengagement coping, and reappraisal coping strategies, and to exhibit more depressive symptoms than men. Second, men who experienced weight stigma tended to cope with it through exercise avoidance and disengagement coping, which were related to greater depressive symptoms. Men also coped with weight stigma adaptively via reappraisal coping, which was additionally associated with more positive affect. Third, the relation between the experience of weight stigma and depressive symptoms in women was only explained by using disengagement coping. These findings extend the understanding of weight stigma to a specific context and provide some insight that future interventions to reduce the impacts of weight stigma should be tailored accordingly for men and women.

Advantages and disadvantages of digital mental health initiatives in Nigeria - a qualitative interview study.

BACKGROUND: The impact of COVID-19 and its mitigation measures have exacerbated the global mental health crisis. Digital mental health interventions (DMHIs) may have the potential to address health system gaps and global health inequalities in low- and middle-income countries (LMICs). AIMS: This thesis aims to map the current state of DMHIs in Nigeria and illustrate their progress, limitations, and challenges. METHODS: Twenty interviews were conducted with researchers, healthcare providers, and digital health experts. Interviews were recorded and transcribed. Then data were coded and analyzed using thematic analysis. RESULTS: The majority of DMHIs in Nigeria are private mental health service delivery platforms that connect directly to mental health professionals. The target audience encompasses all mental health conditions and ages. Advantages of DMHIs include increasing efficiency, accessibility, addressing stigma, and filling the mental health service gap. Disadvantages include skepticism, limitations of applicability, lack of accessibility to internet and technology, lack of sustainability and infrastructure, and lack of funding and policies. CONCLUSION: The lessons learned in the Nigerian context can inform the delivery of DMHIs in other low-resource settings. Future research should examine user and provider feedback of DMHIs to allow for comparative analysis, more conclusive and replicable results to inform DMHI design and implementation.

Carboxylic Acids as Adaptive Functional Groups in Metallaphotoredox Catalysis.

The development of palladium-catalyzed cross-coupling methods for the activation of C(sp2)-Br bonds facilitated access to arene-rich molecules, enabling a concomitant increase in the prevalence of this structural motif in drug molecules in recent decades. Today, there is a growing appreciation of the value of incorporating saturated C(sp3)-rich scaffolds into pharmaceutically active molecules as a means to achieve improved solubility and physiological stability, providing the impetus to develop new coupling strategies to access these challenging motifs in the most straightforward way possible. As an alternative to classical two-electron chemistry, redox chemistry can enable access to elusive transformations, most recently, by interfacing abundant first-row transition-metal catalysis with photoredox catalysis. As such, the functionalization of ubiquitous and versatile functional handles such as (aliphatic) carboxylic acids via metallaphotoredox catalysis has emerged as a valuable field of research over the past eight years.In this Account, we will outline recent progress in the development of methodologies that employ aliphatic and (hetero)aromatic carboxylic acids as adaptive functional groups. Whereas recent decarboxylative functionalization methodologies often necessitate preactivated aliphatic carboxylic acids in the form of redox-active esters or as ligands for hypervalent iodine reagents, methods that enable the direct use of the native carboxylic acid functionality are highly desired and have been accomplished through metallaphotoredox protocols. As such, we found that bench-stable aliphatic carboxylic acids can undergo diverse transformations, such as alkylation, arylation, amination, and trifluoromethylation, by leveraging metallaphotoredox catalysis with prevalent first-row transition metals such as nickel and copper. Likewise, abundant aryl carboxylic acids are now able to undergo halogenation and borylation, enabling new entry points for traditional, primarily palladium- or copper-catalyzed cross-coupling strategies. Given the breadth of the functional group tolerance of the employed reaction conditions, the late-stage functionalization of abundant carboxylic acids toward desired targets has become a standard tool in reaction design, enabling the synthesis of various diversified drug molecules. The rapid rise of this field has positively inspired pharmaceutical discovery and will be further accelerated by novel reaction development. The achievement of generality through reaction optimization campaigns allows for future breakthroughs that can render protocols more reliable and applicable for industry. This article is intended to highlight, in particular, (i) the employment of aliphatic and (hetero)aryl carboxylic acids as powerful late-stage adaptive functional handles in drug discovery and (ii) the need for the further development of still-elusive and selective transformations.We strongly believe that access to native functionalities such as carboxylic acids as adaptive handles will further inspire researchers across the world to investigate new methodologies for complex molecular targets.

Challenges and opportunities for early career medical professionals in cardiovascular magnetic resonance (CMR) imaging: a white paper from the Society for Cardiovascular Magnetic Resonance.

The early career professionals in the field of Cardiovascular Magnetic Resonance (CMR) face unique challenges and hurdles while establishing their careers in the field. The Society for Cardiovascular Magnetic Resonance (SCMR) has expanded the role of the early career section within the society to foster the careers of future CMR leaders. This paper aims to describe the obstacles and available opportunities for the early career CMR professionals worldwide. Societal opportunities and actions targeted at the professional advancement of the early career CMR imagers are needed to ensure continuous growth of CMR as an imaging modality globally.

Prevalence of Polypharmacy in Patients With Vestibular and Balance Complaints.

OBJECTIVES: To determine the prevalence of polypharmacy in patients presenting with dizziness to a tertiary neurotology clinic and analyze the association between polypharmacy and clinical characteristics. DESIGN: Retrospective, cross-sectional review. Demographics, symptoms, diagnoses, medications, audiometry, dizziness handicap index (DHI) scores, and cognitive failure questionnaire (CFQ) scores were extracted from charts of patients seen as new patients from September 1, 2019, to March 31, 2020, with a primary complaint of dizziness. RESULTS: A total of 382 patients were included. More than two-thirds of the patients (n = 265, 69.4%) met criteria for polypharmacy (≥5 medications), of which most (n = 249, 94.0%) were prescribed a potentially ototoxic drug. Approximately 10% of patients were taking five or more ototoxic medications (oto-polypharmacy). Polypharmacy was correlated to age and was more common for patients with diabetes, hypertension, other cardiovascular comorbidities, and depression (odds ratio [OR], 3.73-6.67; p < 0.05). Polypharmacy was twice as likely in patients with mild to moderate hearing loss (OR 2.02 [1.24-3.29] and OR 2.13 [1.06-4.27], respectively; p < 0.05) and ~1.5× more likely in patients who had moderate to severe DHI scores (OR 1.65 [1.05-2.59] and OR 1.63 [1.00-2.65], respectively; p < 0.05). Patients with polypharmacy also had higher CFQ scores compared to those without polypharmacy (CFQ 32.5 [19.0-48.0] versus CFQ 25.0 [13.0-40.0]; p = 0.002. Oto-polypharmacy was more common for patients with lightheadedness as a dizziness descriptor (OR 3.16 [1.56-6.41]; p < 0.01). However, oto-polypharmacy was only more common for patients with mild to moderate hearing loss (OR 2.69 [1.33-5.45] and OR 2.86 [1.31-6.20], respectively; p < 0.01) and severe DHI scores (2.31 [1.12-4.77], p = 0.02). CONCLUSIONS: The prevalence of polypharmacy in patients with vestibular disorders is high. Some of the medications that patients are on are also potentially ototoxic at variable degrees. Polypharmacy is more common when lightheadedness is one of the dizziness descriptors and seems to be associated with worse scores on patient-reported outcome measures (DHI, CFQ). Medication reconciliation and multidisciplinary involvement could help to better address polypharmacy in this patient population. However, further investigation is needed to elucidate polypharmacy's role in symptom presentation, vestibular testing results, and therapeutic strategies.

A self-amplifying mRNA SARS-CoV-2 vaccine candidate induces safe and robust protective immunity in preclinical models.

RNA vaccines have demonstrated efficacy against SARS-CoV-2 in humans, and the technology is being leveraged for rapid emergency response. In this report, we assessed immunogenicity and, for the first time, toxicity, biodistribution, and protective efficacy in preclinical models of a two-dose self-amplifying messenger RNA (SAM) vaccine, encoding a prefusion-stabilized spike antigen of SARS-CoV-2 Wuhan-Hu-1 strain and delivered by lipid nanoparticles (LNPs). In mice, one immunization with the SAM vaccine elicited a robust spike-specific antibody response, which was further boosted by a second immunization, and effectively neutralized the matched SARS-CoV-2 Wuhan strain as well as B.1.1.7 (Alpha), B.1.351 (Beta) and B.1.617.2 (Delta) variants. High frequencies of spike-specific germinal center B, Th0/Th1 CD4, and CD8 T cell responses were observed in mice. Local tolerance, potential systemic toxicity, and biodistribution of the vaccine were characterized in rats. In hamsters, the vaccine candidate was well-tolerated, markedly reduced viral load in the upper and lower airways, and protected animals against disease in a dose-dependent manner, with no evidence of disease enhancement following SARS-CoV-2 challenge. Therefore, the SARS-CoV-2 SAM (LNP) vaccine candidate has a favorable safety profile, elicits robust protective immune responses against multiple SARS-CoV-2 variants, and has been advanced to phase 1 clinical evaluation (NCT04758962).

You are how you speak: The roles of vocal pitch and semantic cues in shaping social perceptions.

Social perceptions of speakers are influenced by their voice information, including vocal characteristics and semantic content. Our study investigated how individuals' warmth- and competence-related perceptions of speakers were affected by vocal pitch levels (i.e., high/low) and three kinds of semantic cues (i.e., prosocial, antisocial, and neutral) simultaneously. We have three key findings. First, antisocial cues negatively affected social perceptions, regardless of speakers' gender. However, prosocial cues did not have positive impacts on evaluations of speakers because ratings were similar between prosocial cues and neutral cues. Second, female vocal pitch mattered for warmth-related perceptions but not for competence-related perceptions. The role of semantic cues should be additionally considered when investigating the impact of male vocal pitch on these perceptions. For example, higher-pitched men in prosocial contexts were perceived as warmer, while low-pitched men in antisocial contexts were judged as more competent. Third, the connection between vocal pitch and two kinds of perceptions showed an opposite trend, in which high pitch was related to more warmth but less competence, while the low pitch was associated with less warmth but more competence. These findings extend the understanding of the role of vocal pitch in the formation of stereotypes of strangers in different semantic contexts.

Changes in Physical Inactivity Among US Adults Overall and by Sociodemographic Characteristics, Behavioral Risk Factor Surveillance System, 2020 Versus 2018.

The COVID-19 pandemic may have disrupted people's work-life patterns and access to places to be physically active. Behavioral Risk Factor Surveillance System data were analyzed to assess changes in self-reported leisure-time physical inactivity. The results showed that prevalence of inactivity among US adults decreased 0.7 percentage points (95% CI: -1.2 to -0.3), from 24.5% in 2018 to 23.8% in 2020, and the greatest decreases were observed among rural-dwelling women, rural-dwelling men, and non-Hispanic White women. These findings highlight a need to understand and address factors that lead to differential changes in leisure-time physical inactivity across subpopulations during public health emergencies.

Retrospective investigation of perioperative risk factors for immediate postoperative corneal erosions in dogs undergoing phacoemulsification.

OBJECTIVE: To characterize the incidence, contributing risk factors, and healing characteristics of immediate postoperative corneal erosions (IPCE) in dogs undergoing routine phacoemulsification. ANIMALS STUDIED: Medical records of 313 canine eyes (159 dogs) undergoing routine phacoemulsification surgery. PROCEDURES: Medical records of dogs undergoing planned cataract surgery at UW Veterinary Care were retrospectively reviewed. Patient-related variables including age, skull conformation, diabetes status, and cataract stage at the time of surgery were recorded. Intraoperative variables per eye were also recorded including surgical technique, surgeon expertise level, average phacoemulsification power, and phacoemulsification time. Diagnosis of IPCE ≤ 24 h after completion of surgery and time to IPCE healing were recorded where follow-up data were available. RESULTS: Immediate postoperative corneal erosions were observed in 48/313 (15.3%) operated eyes. The presence of diabetes mellitus or brachycephalic skull conformation, preoperative Schirmer tear test (STT) value, surgical technique and surgeon experience level, phacoemulsification time, and absolute phacoemulsification time were not statistically significant risk factors for IPCE. Average phacoemulsification power was associated with IPCE (RR 1.52, p = .001). Time to IPCE healing was similar in diabetic and non-diabetic dogs (median [IQR] 8 [6-11] days and 8 [6-15] days, respectively). Diabetes mellitus, brachycephaly, and phacoemulsification parameters were not associated with IPCE healing at 7 or 14 days postoperatively. CONCLUSIONS: Higher average phacoemulsification power may be associated with the development of IPCE in canine eyes. The presence of diabetes mellitus or brachycephaly are not risk factors for the development of IPCE, nor are they factors that influence IPCE healing.

Combination phacoemulsification and pars plana vitrectomy for retinal reattachment surgery in the Siberian Husky breed.

OBJECTIVE: To report the success rate and complications of combined phacoemulsification and pars plana vitrectomy (PPV) for treatment of cataracts and retinal detachment in the Siberian Husky breed. ANIMALS STUDIED: Client-owned Siberian Husky dogs that underwent combined phacoemulsification and PPV at two veterinary referral centers. PROCEDURE: Retrospective study of 16 Siberian Husky dogs that underwent combined phacoemulsification and PPV with a minimum 3-month postoperative follow-up. Signalment and preoperative ophthalmic examination findings, intraoperative findings, and postoperative visual status and complications were recorded. Functional success was defined as the maintenance or restoration of vision. RESULTS: Seventeen eyes of 16 dogs were evaluated. Immediate postoperative anatomic success was achieved in all 17 eyes (100%), with functional success through the last known follow-up examination achieved in 88.2% of operated eyes (15/17). The most common postoperative complication was silicone oil migration into the anterior chamber (AC-SiO migration), occurring in 47.1% of eyes (8/17), followed by corneal endothelial decompensation and glaucoma each occurring in 17.6% of eyes (3/17). CONCLUSIONS: Combined phacoemulsification and PPV is a viable option in Siberian Husky dogs with cataracts and preoperative retinal detachment. Visual success was achieved in 88.2% of eyes, with the most common postoperative complication being AC-SiO migration.

Longitudinal Links Between Parental Failure Mindsets, Helicopter Parenting, and Fixed Mindset of Intelligence in Adolescents.

Evidence for the prospective associations among parental failure mindset, helicopter parenting, and children's intelligence mindset is lacking. This three-wave longitudinal study (12 months apart between waves) addressed this research gap by testing whether perceived maternal helicopter parenting mediated the link between perceived maternal failure mindset and intelligence mindset. Participants included 525 Chinese adolescents (47.2% girls, Mage = 15.41 years, SD = 0.22). Random-intercept cross-lagged analysis suggests that mothers with stronger failure-is-debilitating mindsets are more likely to engage in helicopter parenting, which may in turn contribute to stronger endorsements of a fixed mindset of intelligence in their adolescent children. The relation between maternal helicopter parenting and children's intelligence mindset appeared to be reciprocal, i.e., children's fixed mindset may elicit more helicopter parenting over time.

Decarboxylative Borylation and Cross-Coupling of (Hetero)aryl Acids Enabled by Copper Charge Transfer Catalysis.

We report a copper-catalyzed strategy for arylboronic ester synthesis that exploits photoinduced ligand-to-metal charge transfer (LMCT) to convert (hetero)aryl acids into aryl radicals amenable to ambient-temperature borylation. This near-UV process occurs under mild conditions, requires no prefunctionalization of the native acid, and operates broadly across diverse aryl, heteroaryl, and pharmaceutical substrates. We also report a one-pot procedure for decarboxylative cross-coupling that merges catalytic LMCT borylation and palladium-catalyzed Suzuki-Miyaura arylation, vinylation, or alkylation with organobromides to access a range of value-added products. The utility of these protocols is highlighted through the development of a heteroselective double-decarboxylative C(sp2)-C(sp2) coupling sequence, pairing copper-catalyzed LMCT borylation and halogenation processes of two distinct acids (including pharmaceutical substrates) with subsequent Suzuki-Miyaura cross-coupling.

A Unified Approach to Decarboxylative Halogenation of (Hetero)aryl Carboxylic Acids.

Aryl halides are a fundamental motif in synthetic chemistry, playing a critical role in metal-mediated cross-coupling reactions and serving as important scaffolds in drug discovery. Although thermal decarboxylative functionalization of aryl carboxylic acids has been extensively explored, the scope of existing halodecarboxylation methods remains limited, and there currently exists no unified strategy that provides access to any type of aryl halide from an aryl carboxylic acid precursor. Herein, we report a general catalytic method for direct decarboxylative halogenation of (hetero)aryl carboxylic acids via ligand-to-metal charge transfer. This strategy accommodates an exceptionally broad scope of substrates. We leverage an aryl radical intermediate toward divergent functionalization pathways: (1) atom transfer to access bromo- or iodo(hetero)arenes or (2) radical capture by copper and subsequent reductive elimination to generate chloro- or fluoro(hetero)arenes. The proposed ligand-to-metal charge transfer mechanism is supported through an array of spectroscopic studies.

Characterization of initial/early histologic features of proliferative leukoplakia and correlation with malignant transformation: a multicenter study.

The aim of this multicenter retrospective study is to characterize the histopathologic features of initial/early biopsies of proliferative leukoplakia (PL; also known as proliferative verrucous leukoplakia), and to analyze the correlation between histopathologic features and malignant transformation (MT). Patients with a clinical diagnosis of PL who have at least one biopsy and one follow-up visit were included in this study. Initial/early biopsy specimens were reviewed. The biopsies were evaluated for the presence of squamous cell carcinoma (SCCa), oral epithelial dysplasia (OED), and atypical verrucous hyperplasia (AVH). Cases that lacked unequivocal features of dysplasia were termed "hyperkeratosis/parakeratosis not reactive (HkNR)". Pearson chi-square test and Wilcoxon test were used for statistical analysis. There were 86 early/initial biopsies from 59 patients; 74.6% were females. Most of the cases had a smooth/homogenous (34.8%) or fissured appearance (32.6%), and only 13.0% had a verrucous appearance. The most common biopsy site was the gingiva/alveolar mucosa (40.8%) and buccal mucosa (25.0%). The most common histologic diagnosis was OED (53.5%) followed by HkNR (31.4%). Of note, two-thirds of HkNR cases showed only hyperkeratosis and epithelial atrophy. A lymphocytic band was seen in 34.8% of OED cases and 29.6% of HkNR cases, mostly associated with epithelial atrophy. Twenty-eight patients (47.5%) developed carcinoma and 28.9% of early/initial biopsy sites underwent MT. The mortality rate was 11.9%. Our findings show that one-third of cases of PL do not show OED with most exhibiting hyperkeratosis and epithelial atrophy, but MT nevertheless occurred at such sites in 3.7% of cases.