Neighborhood Walkability Is Associated With Lower Burden of Cardiovascular Risk Factors Among Cancer Patients.

Background: Modifiable cardiovascular risk factors constitute a significant cause of cardiovascular disease and mortality among patients with cancer. Recent studies suggest a potential link between neighborhood walkability and favorable cardiovascular risk factor profiles in the general population. Objectives: This study aimed to investigate whether neighborhood walkability is correlated with favorable cardiovascular risk factor profiles among patients with a history of cancer. Methods: We conducted a cross-sectional study using data from the Houston Methodist Learning Health System Outpatient Registry (2016-2022) comprising 1,171,768 adults aged 18 years and older. Neighborhood walkability was determined using the 2019 Walk Score and divided into 4 categories. Patients with a history of cancer were identified through International Classification of Diseases-10th Revision-Clinical Modification codes (C00-C96). We examined the prevalence and association between modifiable cardiovascular risk factors (hypertension, diabetes, smoking, dyslipidemia, and obesity) and neighborhood walkability categories in cancer patients. Results: The study included 121,109 patients with a history of cancer; 56.7% were female patients, and 68.8% were non-Hispanic Whites, with a mean age of 67.3 years. The prevalence of modifiable cardiovascular risk factors was lower among participants residing in the most walkable neighborhoods compared with those in the least walkable neighborhoods (76.7% and 86.0%, respectively). Patients with a history of cancer living in very walkable neighborhoods were 16% less likely to have any risk factor compared with car-dependent-all errands neighborhoods (adjusted OR: 0.84, 95% CI: 0.78-0.92). Sensitivity analyses considering the timing of events yielded similar results. Conclusions: Our findings demonstrate an association between neighborhood walkability and the burden of modifiable cardiovascular risk factors among patients with a medical history of cancer. Investments in walkable neighborhoods may present a viable opportunity for mitigating the growing burden of modifiable cardiovascular risk factors among patients with a history of cancer.

Molecular characterization of the salivary adenoid cystic carcinoma immune landscape by anatomic subsites.

Adenoid cystic carcinoma (AdCC) is a slow-growing salivary gland malignancy that relapses frequently. AdCCs of the submandibular gland exhibit unique differences in prognosis and treatment response to adjuvant radiotherapy compared to other sites, yet the role of tumor anatomic subsite on gene expression and tumor immune microenvironment (TIME) composition remains unclear. We used 87 samples, including 48 samples (27 AdCC and 21 normal salivary gland tissue samples) from 4 publicly available AdCC RNA sequencing datasets, a validation set of 33 minor gland AdCCs, and 39 samples from an in-house cohort (30 AdCC and 9 normal salivary gland samples). RNA sequencing data were used for single sample gene set enrichment analysis and TIME deconvolution. Quantitative PCR and multiplex immunofluorescence were performed on the in-house cohort. Wilcoxon rank-sum, nonparametric equality-of-medians tests and linear regression models were used to evaluate tumor subsite differences. AdCCs of different anatomic subsites including parotid, submandibular, sublingual, and minor salivary glands differed with respect to expression of several key tumorigenic pathways. Among the three major salivary glands, the reactive oxygen species (ROS)/nuclear factor erythroid 2-related factor 2 (NRF2) pathway signature was significantly underexpressed in AdCC of submandibular compared to parotid and sublingual glands while this association was not observed among normal glands. Additionally, the NRF2 pathway, whose expression was associated with favorable overall survival, was overexpressed in AdCCs of parotid gland compared to minor and submandibular glands. The TIME deconvolution identified differences in CD4+ T cell populations between AdCC of major and minor glands and natural killer (NK) cells among AdCC of minor, submandibular, and parotid glands while plasma cells were enriched in normal submandibular glands compared to other normal gland controls. Our data reveal key molecular differences in AdCC of different anatomic subsites. The ROS and NRF2 pathways are underexpressed in submandibular and minor AdCCs compared to parotid gland AdCCs, and NRF2 pathway expression is associated with favorable overall survival. The CD4+ T, NK, and plasma cell populations also vary by tumor subsites, suggesting that the observed submandibular AdCC tumor-intrinsic pathway differences may be responsible for influencing the TIME composition and survival differences.

A Mathematical Model for Fibrous Dysplasia: The Role of the Flow of Mutant Cells.

Fibrous dysplasia (FD) is a mosaic non-inheritable genetic disorder of the skeleton in which normal bone is replaced by structurally unsound fibro-osseous tissue. There is no curative treatment for FD, partly because its pathophysiology is not yet fully known. We present a simple mathematical model of the disease incorporating its basic known biology, to gain insight on the dynamics of the involved bone-cell populations, and shed light on its pathophysiology. We develop an analytical study of the model and study its basic properties. The existence and stability of steady states are studied, an analysis of sensitivity on the model parameters is done, and different numerical simulations provide findings in agreement with the analytical results. We discuss the model dynamics match with known facts on the disease, and how some open questions could be addressed using the model.

Use of digital patient decision-support tools for atrial fibrillation treatments: a systematic review and meta-analysis.

OBJECTIVES: To assess the effects of digital patient decision-support tools for atrial fibrillation (AF) treatment decisions in adults with AF. STUDY DESIGN: Systematic review and meta-analysis. ELIGIBILITY CRITERIA: Eligible randomised controlled trials (RCTs) evaluated digital patient decision-support tools for AF treatment decisions in adults with AF. INFORMATION SOURCES: We searched MEDLINE, EMBASE and Scopus from 2005 to 2023.Risk-of-bias (RoB) assessment: We assessed RoB using the Cochrane Risk of Bias Tool 2 for RCTs and cluster RCT and the ROBINS-I tool for quasi-experimental studies. SYNTHESIS OF RESULTS: We used random effects meta-analysis to synthesise decisional conflict and patient knowledge outcomes reported in RCTs. We performed narrative synthesis for all outcomes. The main outcomes of interest were decisional conflict and patient knowledge. RESULTS: 13 articles, reporting on 11 studies (4 RCTs, 1 cluster RCT and 6 quasi-experimental) met the inclusion criteria. There were 2714 participants across all studies (2372 in RCTs), of which 26% were women and the mean age was 71 years. Socioeconomically disadvantaged groups were poorly represented in the included studies. Seven studies (n=2508) focused on non-valvular AF and the mean CHAD2DS2-VASc across studies was 3.2 and for HAS-BLED 1.9. All tools focused on decisions regarding thromboembolic stroke prevention and most enabled calculation of individualised stroke risk. Tools were heterogeneous in features and functions; four tools were patient decision aids. The readability of content was reported in one study. Meta-analyses showed a reduction in decisional conflict (4 RCTs (n=2167); standardised mean difference -0.19; 95% CI -0.30 to -0.08; p=0.001; I2=26.5%; moderate certainty evidence) corresponding to a decrease in 12.4 units on a scale of 0 to 100 (95% CI -19.5 to -5.2) and improvement in patient knowledge (2 RCTs (n=1057); risk difference 0.72, 95% CI 0.68, 0.76, p<0.001; I2=0%; low certainty evidence) favouring digital patient decision-support tools compared with usual care. Four of the 11 tools were publicly available and 3 had been implemented in healthcare delivery. CONCLUSIONS: In the context of stroke prevention in AF, digital patient decision-support tools likely reduce decisional conflict and may result in little to no change in patient knowledge, compared with usual care. Future studies should leverage digital capabilities for increased personalisation and interactivity of the tools, with better consideration of health literacy and equity aspects. Additional robust trials and implementation studies are warranted. PROSPERO REGISTRATION NUMBER: CRD42020218025.

Metabolomics of IgE-Mediated Food Allergy and Oral Immunotherapy Outcomes based on Metabolomic Profiling.

Background: The immunometabolic mechanisms underlying variable responses to oral immunotherapy (OIT) in patients with IgE-mediated food allergy are unknown. Objective: To identify novel pathways associated with tolerance in food allergy, we used metabolomic profiling to find pathways important for food allergy in multi-ethnic cohorts and responses to OIT. Methods: Untargeted plasma metabolomics data were generated from the VDAART healthy infant cohort (N=384), a Costa Rican cohort of children with asthma (N=1040), and a peanut OIT trial (N=20) evaluating sustained unresponsiveness (SU, protection that lasts after therapy) versus transient desensitization (TD, protection that ends immediately afterwards). Generalized linear regression modeling and pathway enrichment analysis identified metabolites associated with food allergy and OIT outcomes. Results: Compared with unaffected children, those with food allergy were more likely to have metabolomic profiles with altered histidines and increased bile acids. Eicosanoids (e.g., arachidonic acid derivatives) (q=2.4×10 -20 ) and linoleic acid derivatives (q=3.8×10 -5 ) pathways decreased over time on OIT. Comparing SU versus TD revealed differing concentrations of bile acids (q=4.1×10 -8 ), eicosanoids (q=7.9×10 -7 ), and histidine pathways (q=0.015). In particular, the bile acid lithocholate (4.97[1.93,16.14], p=0.0027), the eicosanoid leukotriene B4 (3.21[1.38,8.38], p=0.01), and the histidine metabolite urocanic acid (22.13[3.98,194.67], p=0.0015) were higher in SU. Conclusions: We observed distinct profiles of bile acids, histidines, and eicosanoids that vary among patients with food allergy, over time on OIT and between SU and TD. Participants with SU had higher levels of metabolites such as lithocholate and urocanic acid, which have immunomodulatory roles in key T-cell subsets, suggesting potential mechanisms of tolerance in immunotherapy. Key Messages: - Compared with unaffected controls, children with food allergy demonstrated higher levels of bile acids and distinct histidine/urocanic acid profiles, suggesting a potential role of these metabolites in food allergy. - In participants receiving oral immunotherapy for food allergy, those who were able to maintain tolerance-even after stopping therapyhad lower overall levels of bile acid and histidine metabolites, with the exception of lithocholic acid and urocanic acid, two metabolites that have roles in T cell differentiation that may increase the likelihood of remission in immunotherapy. Capsule summary: This is the first study of plasma metabolomic profiles of responses to OIT in individuals with IgE-mediated food allergy. Identification of immunomodulatory metabolites in allergic tolerance may help identify mechanisms of tolerance and guide future therapeutic development.

Pediatric Device Clinical Trials Activity: 1999-2022.

OBJECTIVES: This study assessed the state of pediatric medical device (PMD) development by comparing PMD clinical trials to pediatric trials evaluating drugs and biologics, from 1999 to 2022. METHODS: The site https://www.clinicaltrials.gov was used to identify and quantify both PMD clinical trials and pediatric trials for drugs and biologics. Clinical specialty was also assessed. The institutions included were the 7 children's hospitals primarily affiliated with the Food and Drug Administration (FDA) Pediatric Device Consortia (PDC) grant program between 2018 and 2023. For a national comparison, an additional search assessed PMD trials across all US medical institutions. RESULTS: A total of 243 PMD clinical trials were identified at the FDA-PDC institutions on the basis of the year of initiation; the average number of PMD trials initiated per year per institution was 1.5 from 1999 to 2022. However, PMD trials significantly increased during the period 2014 to 2022 compared with 1999 to 2013 (P < .001); the rate of initiation of drug and biologic pediatric trials demonstrated no significant differences between these time periods. A national survey of all institutions initiating PMD trials, and drugs and biologics trials, identified 1885 PMD trials out of a total 12 943. A comparable trend was noted in the national survey with initiation of PMD trials increasing significantly from 2014 to 2022 (P < .001), compared with 1999 to 2013, whereas the rate of initiation of drug and biologic trials during these periods did not demonstrate a significant change. CONCLUSIONS: Although pediatric clinical trial initiation for drugs and biologics remained stable from 1999 to 2022, the rate of new PMD trials significantly increased during the period 2014 to 2022 at FDA-PDC institutions and nationally.

NAPRT silencing in FH-deficient renal cell carcinoma confers therapeutic vulnerabilities via NAD+ depletion.

Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is caused by loss of function mutations in fumarate hydratase (FH) and results in an aggressive subtype of renal cell carcinoma with limited treatment options. Loss of FH leads to accumulation of fumarate, an oncometabolite that disrupts multiple cellular processes and drives tumor progression. High levels of fumarate inhibit alpha ketoglutarate-dependent dioxygenases, including the ten eleven translocation (TET) enzymes and can lead to global DNA hypermethylation. Here, we report patterns of hypermethylation in FH-mutant cell lines and tumor samples are associated with silencing of nicotinate phosphoribosyl transferase (NAPRT), a rate-limiting enzyme in the Preiss-Handler pathway of NAD+ biosynthesis in a subset of HLRCC cases. NAPRT is hypermethylated at a CpG island in the promoter in cell line models and patient samples, resulting in loss of NAPRT expression. We find that FH-deficient RCC models with loss of NAPRT expression, as well as other oncometabolite-producing cancer models that silence NAPRT, are extremely sensitive to nicotinamide phosphoribosyl transferase inhibitors (NAMPTis). NAPRT silencing was also associated with synergistic tumor cell killing with poly(ADP)-ribose polymerase inhibitors (PARPis) and NAMPTis, which was associated with effects on PAR-mediated DNA repair. Overall, our findings indicate that NAPRT-silencing can be targeted in oncometabolite-producing cancers and elucidates how oncometabolite associated hypermethylation can impact diverse cellular processes and leads to therapeutically relevant vulnerabilities in cancer cells. Implications: NAPRT is a novel biomarker for targeting NAD+ metabolism in FH-deficient HLRCCs with NAMPTis alone and targeting DNA repair processes with the combination of NAMPTis and PARPis.

Gynecologic infection rates after ablation treatment for cervical intraepithelial neoplasia grade 2 and higher (CIN2+): Secondary analysis of a non-inferiority randomized trial.

Although concerns have been raised regarding potential infection and morbidity in women undergoing ablation treatment for cervical precancer in low- and middle-income countries (LMIC), there is extremely limited data to substantiate this claim. This is a secondary analysis of a randomized non-inferiority trial (id: NCT03084081) that compares the efficacy and safety of three ablation treatments for biopsy-confirmed cervical intraepithelial neoplasia grade 2 or higher (CIN2+): CO2 gas-based cryotherapy, non-gas cryotherapy, and thermal ablation (TA). Here, we present findings regarding the incidence of sexually transmitted infections (STI) and vaginitis post-treatment. Samples were collected at enrollment and again at 6 weeks post-treatment and assessed for STIs (Chlamydia trachomatis (CT), Neisseria gonorrhea (NG), and Trichomonas vaginalis (TV)) and vaginitis (Bacterial vaginosis (BV) and/or Candida albicans (Candida)). This analysis reflects 864 women with baseline and 6-week follow-up data. None of the ablative treatments put women at increased risk for STIs (CT, NG, TV) or vaginitis (BV, Candida). While most women adhered to post-treatment recommendations (97%) and no difference by treatment arm was observed, the incidence of STIs at follow-up in women that did not adhere with a given recommendation was higher compared to their adherent counterparts. The incidence of gynecologic infection did not increase with any of the ablation treatments from baseline to the six-week follow-up. Non-gas cryotherapy and TA emerge as safe alternatives to gas-based cryotherapy with respect to gynecologic infection rates.

The cerebellum modulates thirst.

The cerebellum, a phylogenetically ancient brain region, has long been considered strictly a motor control structure. Recent studies have implicated the cerebellum in cognition, sensation, emotion and autonomic function, making it an important target for further investigation. Here, we show that cerebellar Purkinje neurons in mice are activated by the hormone asprosin, leading to enhanced thirst, and that optogenetic or chemogenetic activation of Purkinje neurons induces rapid manifestation of water drinking. Purkinje neuron-specific asprosin receptor (Ptprd) deletion results in reduced water intake without affecting food intake and abolishes asprosin's dipsogenic effect. Purkinje neuron-mediated motor learning and coordination were unaffected by these manipulations, indicating independent control of two divergent functions by Purkinje neurons. Our results show that the cerebellum is a thirst-modulating brain area and that asprosin-Ptprd signaling may be a potential therapeutic target for the management of thirst disorders.

Acute activation of hemichannels by ethanol leads to Ca2+-dependent gliotransmitter release in astrocytes.

Multiple studies have demonstrated that acute ethanol consumption alters brain function and cognition. Nevertheless, the mechanisms underlying this phenomenon remain poorly understood. Astrocyte-mediated gliotransmission is crucial for hippocampal plasticity, and recently, the opening of hemichannels has been found to play a relevant role in this process. Hemichannels are plasma membrane channels composed of six connexins or seven pannexins, respectively, that oligomerize around a central pore. They serve as ionic and molecular exchange conduits between the cytoplasm and extracellular milieu, allowing the release of various paracrine substances, such as ATP, D-serine, and glutamate, and the entry of ions and other substances, such as Ca2+ and glucose. The persistent and exacerbated opening of hemichannels has been associated with the pathogenesis and progression of several brain diseases for at least three mechanisms. The uncontrolled activity of these channels could favor the collapse of ionic gradients and osmotic balance, the release of toxic levels of ATP or glutamate, cell swelling and plasma membrane breakdown and intracellular Ca2+ overload. Here, we evaluated whether acute ethanol exposure affects the activity of astrocyte hemichannels and the possible repercussions of this phenomenon on cytoplasmatic Ca2+ signaling and gliotransmitter release. Acute ethanol exposure triggered the rapid activation of connexin43 and pannexin1 hemichannels in astrocytes, as measured by time-lapse recordings of ethidium uptake. This heightened activity derived from a rapid rise in [Ca2+]i linked to extracellular Ca2+ influx and IP3-evoked Ca2+ release from intracellular Ca2+ stores. Relevantly, the acute ethanol-induced activation of hemichannels contributed to a persistent secondary increase in [Ca2+]i. The [Ca2+]i-dependent activation of hemichannels elicited by ethanol caused the increased release of ATP and glutamate in astroglial cultures and brain slices. Our findings offer fresh perspectives on the potential mechanisms behind acute alcohol-induced brain abnormalities and propose targeting connexin43 and pannexin1 hemichannels in astrocytes as a promising avenue to prevent deleterious consequences of alcohol consumption.

Conductive extracellular matrix derived/chitosan methacrylate/ graphene oxide-pegylated hybrid hydrogel for cell expansion.

Electrical stimulation has emerged as a cornerstone technique in the rapidly evolving field of biomedical engineering, particularly within the realms of tissue engineering and regenerative medicine. It facilitates cell growth, proliferation, and differentiation, thereby advancing the development of accurate tissue models and enhancing drug-testing methodologies. Conductive hydrogels, which enable the conduction of microcurrents in 3D in vitro cultures, are central to this advancement. The integration of high-electroconductive nanomaterials, such as graphene oxide (GO), into hydrogels has revolutionized their mechanical and conductivity properties. Here, we introduce a novel electrostimulation assay utilizing a hybrid hydrogel composed of methacryloyl-modified small intestine submucosa (SIS) dECM (SISMA), chitosan methacrylate (ChiMA), and GO-polyethylene glycol (GO-PEG) in a 3D in vitro culture within a hypoxic environment of umbilical cord blood cells (UCBCs). Results not only demonstrate significant cell proliferation within 3D constructs exposed to microcurrents and early growth factors but also highlight the hybrid hydrogel's physiochemical prowess through comprehensive rheological, morphological, and conductivity analyses. Further experiments will focus on identifying the regulatory pathways of cells subjected to electrical stimulation.

Neutralizing the threat: harnessing broadly neutralizing antibodies against HIV-1 for treatment and prevention.

Broadly neutralizing antibodies (bnAbs) targeting the human immunodeficiency virus-1 (HIV-1) have played a crucial role in elucidating and characterizing neutralization-sensitive sites on the HIV-1 envelope spike and in informing vaccine development. Continual advancements in identifying more potent bnAbs, along with their capacity to trigger antibody-mediated effector functions, coupled with modifications to extend their half-life, position them as promising candidates for both HIV-1 treatment and prevention. While current pharmacological interventions have made significant progress in managing HIV-1 infection and enhancing quality of life, no definitive cure or vaccines have been developed thus far. Standard treatments involve daily oral anti-retroviral therapy, which, despite its efficacy, can lead to notable long-term side effects. Recent clinical trial data have demonstrated encouraging therapeutic and preventive potential for bnAb therapies in both HIV-1-infected individuals and those without the infection. This review provides an overview of the advancements in HIV-1-specific bnAbs and discusses the insights gathered from recent clinical trials regarding their application in treating and preventing HIV-1 infection.

Mitochondrial Structure, Dynamics, and Physiology: Light Microscopy to Disentangle the Network.

Mitochondria serve as energetic and signaling hubs of the cell: This function results from the complex interplay between their structure, function, dynamics, interactions, and molecular organization. The ability to observe and quantify these properties often represents the puzzle piece critical for deciphering the mechanisms behind mitochondrial function and dysfunction. Fluorescence microscopy addresses this critical need and has become increasingly powerful with the advent of superresolution methods and context-sensitive fluorescent probes. In this review, we delve into advanced light microscopy methods and analyses for studying mitochondrial ultrastructure, dynamics, and physiology, and highlight notable discoveries they enabled.

PUPpy: a primer design pipeline for substrain-level microbial detection and absolute quantification.

Characterizing microbial communities at high resolution and with absolute quantification is crucial to unravel the complexity and diversity of microbial ecosystems. This can be achieved with PCR assays, which enable highly selective detection and absolute quantification of microbial DNA. However, a major challenge that has hindered PCR applications in microbiome research is the design of highly specific primer sets that exclusively amplify intended targets. Here, we introduce Phylogenetically Unique Primers in python (PUPpy), a fully automated pipeline to design microbe- and group-specific primers within a given microbial community. PUPpy can be executed from a user-friendly graphical user interface, or two simple terminal commands, and it only requires coding sequence files of the community members as input. PUPpy-designed primers enable the detection of individual microbes and quantification of absolute microbial abundance in defined communities below the strain level. We experimentally evaluated the performance of PUPpy-designed primers using two bacterial communities as benchmarks. Each community comprises 10 members, exhibiting a range of genetic similarities that spanned from different phyla to substrains. PUPpy-designed primers also enable the detection of groups of bacteria in an undefined community, such as the detection of a gut bacterial family in a complex stool microbiota sample. Taxon-specific primers designed with PUPpy showed 100% specificity to their intended targets, without unintended amplification, in each community tested. Lastly, we show the absolute quantification of microbial abundance using PUPpy-designed primers in droplet digital PCR, benchmarked against 16S rRNA and shotgun sequencing. Our data shows that PUPpy-designed microbe-specific primers can be used to quantify substrain-level absolute counts, providing more resolved and accurate quantification in defined communities than short-read 16S rRNA and shotgun sequencing. IMPORTANCE: Profiling microbial communities at high resolution and with absolute quantification is essential to uncover hidden ecological interactions within microbial ecosystems. Nevertheless, achieving resolved and quantitative investigations has been elusive due to methodological limitations in distinguishing and quantifying highly related microbes. Here, we describe Phylogenetically Unique Primers in python (PUPpy), an automated computational pipeline to design taxon-specific primers within defined microbial communities. Taxon-specific primers can be used to selectively detect and quantify individual microbes and larger taxa within a microbial community. PUPpy achieves substrain-level specificity without the need for computationally intensive databases and prioritizes user-friendliness by enabling both terminal and graphical user interface applications. Altogether, PUPpy enables fast, inexpensive, and highly accurate perspectives into microbial ecosystems, supporting the characterization of bacterial communities in both in vitro and complex microbiota settings.

Safety and Pharmacokinetics of a Combined Antioxidant Therapy against Myocardial Reperfusion Injury: A Phase I Randomized Clinical Trial in Healthy Humans.

Myocardial reperfusion injury (MRI) accounts for up to 50% of the final size in acute myocardial infarction and other conditions associated with ischemia-reperfusion. Currently, there is still no therapy to prevent MRI, but it is well known that oxidative stress has a key role in its mechanism. We previously reduced MRI in rats through a combined antioxidant therapy (CAT) of ascorbic acid, N-acetylcysteine, and deferoxamine. This study determines the safety and pharmacokinetics of CAT in a Phase I clinical trial. Healthy subjects (n = 18) were randomized 2:1 to CAT or placebo (NaCl 0.9% i.v.). Two different doses/infusion rates of CATs were tested in a single 90-minute intravenous infusion. Blood samples were collected at specific times for 180 minutes to measure plasma drug concentrations (ascorbic acid, N-acetylcysteine, and deferoxamine) and oxidative stress biomarkers. Adverse events were registered during infusion and followed for 30 days. Both CAT1 and CAT2 significantly increased the CAT drug concentrations compared to placebo (P < .05). Most of the pharmacokinetic parameters were similar between CAT1 and CAT2. In total, 6 adverse events were reported, all nonserious and observed in CAT1. The ferric-reducing ability of plasma (an antioxidant biomarker) increased in both CAT groups compared to placebo (P < .001). The CAT is safe in humans and a potential treatment for patients with acute myocardial infarction undergoing reperfusion therapy.

Endoscopic Endonasal Approach to the Ventral Petroclival Fissure: Anatomical Findings and Surgical Techniques.

Objective The endoscopic endonasal approach has emerged as an excellent option for the treatment of lesions involving the petroclival fissure (PCF). Here, we investigate the surgical anatomy of the ventral PCF and its application in endoscopic endonasal surgery. Methods Sixteen head specimens were used to investigate the anatomical features of PCF and relevant technical nuances in translacerum, extreme medial, and contralateral transmaxillary (CTM) approaches. Two representative endoscopic endonasal surgeries involving the PCF were selected to illustrate the clinical application. Results From the endoscopic endonasal view, the ventral PCF is presented as a lazy L sign, which is divided into two distinct segments: (1) upper (or petrosphenoidal) segment, which extends vertically from the foramen lacerum inferiorly to the junction of the petrosal process of sphenoid bone and petrous apex superiorly, and (2) lower (or petroclival) segment, which extends inferolaterally from the foramen lacerum to the ventral jugular foramen. Approaching both segments of the ventral PCF first requires full exposure of the foramen lacerum, followed either by exposure of the anterior wall of cavernous sinus and paraclival internal carotid artery for upper segment access, or transection of pterygosphenoidal fissure and Eustachian tube mobilization for lower segment access. Combined with a CTM approach, the lateral extension of the surgical access can be improved for both upper and lower segment PCF approaches. Conclusion This study provides a detailed investigation of the microsurgical anatomy of the ventral part of PCF, relevant surgical approaches, and technical nuances that may facilitate its safe exposure intraoperatively.

Global Perspective on COVID-19 Therapies, Cardiovascular Outcomes, and Implications for Long COVID: A State-of-the-Art Review.

The COVID-19 pandemic has resulted in many therapies, of which many are repurposed and used for other diseases in the last decade such in Influenza and Ebola. We intend to provide a robust foundation for cardiovascular outcomes of the therapies to better understand the rationale for the clinical trials that were conducted during the COVID-19 pandemic, and to gain more clarity on the steps moving forward should the repurposing provide clinical benefit in pandemic situations. With this state-of-the-art review, we aim to improve the understanding of the cardiovascular involvement of the therapies prior to, during, and after the COVID-19 pandemic to provide meaningful findings to the cardiovascular specialists and clinical trials for therapies, moving on from the period of pandemic urgency.

Clinical and structural damage outcomes in axial spondyloarthritis patients receiving NSAIDs or advanced therapies: a description of a real-life cohort.

Introduction: This study aims to describe the clinical characteristics, disease activity, and structural damage in patients with axial spondyloarthritis (axSpA) who receive chronic treatment with nonsteroideal anti-inflammatory drugs (NSAIDs) or advanced therapies in a clinical setting. Methods: Cross-sectional study on axSpA patients consecutively recruited from the outpatient clinic of a tertiary hospital. We collected data on clinical and demographic characteristics, as well as treatment patterns involving NSAIDs and advanced therapies. Structural damage was assessed using mSASSS. Results: Overall, data from 193 axSpA patients (83% ankylosing spondylitis) were gathered, with a mean disease duration of 21.4 years. Of these, 85 patients (44%) were exclusively taking NSAIDs, while 108 (56%) were receiving advanced therapies, with TNF inhibitors being the predominant choice (93 out of 108, 86.1%). Among patients using NSAIDs, 64.7% followed an on-demand dosing regimen, while only 17.6% used full doses. Disease activity was low, with a mean BASDAI of 3.1 and a mean ASDAS-CRP of 1.8. In comparison to patients under chronic NSAID treatment, those taking advanced therapies were primarily male (69.4% versus 51.8%, p = 0.025) and significantly younger (mean age of 49 versus 53.9 years, p = 0.033). Additionally, patients on advanced therapies exhibited lower ASDAS-CRP (p = 0.046), although CRP serum levels and BASDAI scores did not differ between the two groups. In the multivariable analysis, therapy (NSAID versus biological treatment) was not independently associated with ASDAS-CRP, BASDAI or mSASSS. Conclusion: This cross-sectional analysis of a real-world cohort of axSpA patients shows positive clinical and radiological outcomes for both NSAIDs and advanced therapies.

From hit to vial: Precision discovery and development of an imidazopyrimidine TLR7/8 agonist adjuvant formulation.

Vaccination can help prevent infection and can also be used to treat cancer, allergy, and potentially even drug overdose. Adjuvants enhance vaccine responses, but currently, the path to their advancement and development is incremental. We used a phenotypic small-molecule screen using THP-1 cells to identify nuclear factor-κB (NF-κB)-activating molecules followed by counterscreening lead target libraries with a quantitative tumor necrosis factor immunoassay using primary human peripheral blood mononuclear cells. Screening on primary cells identified an imidazopyrimidine, dubbed PVP-037. Moreover, while PVP-037 did not overtly activate THP-1 cells, it demonstrated broad innate immune activation, including NF-κB and cytokine induction from primary human leukocytes in vitro as well as enhancement of influenza and SARS-CoV-2 antigen-specific humoral responses in mice. Several de novo synthesis structural enhancements iteratively improved PVP-037's in vitro efficacy, potency, species-specific activity, and in vivo adjuvanticity. Overall, we identified imidazopyrimidine Toll-like receptor-7/8 adjuvants that act in synergy with oil-in-water emulsion to enhance immune responses.