High-income ZIP codes in New York City demonstrate higher case rates during off-peak COVID-19 waves.

Introduction: Our study explores how New York City (NYC) communities of various socioeconomic strata were uniquely impacted by the COVID-19 pandemic. Methods: New York City ZIP codes were stratified into three bins by median income: high-income, middle-income, and low-income. Case, hospitalization, and death rates obtained from NYCHealth were compared for the period between March 2020 and April 2022. Results: COVID-19 transmission rates among high-income populations during off-peak waves were higher than transmission rates among low-income populations. Hospitalization rates among low-income populations were higher during off-peak waves despite a lower transmission rate. Death rates during both off-peak and peak waves were higher for low-income ZIP codes. Discussion: This study presents evidence that while high-income areas had higher transmission rates during off-peak periods, low-income areas suffered greater adverse outcomes in terms of hospitalization and death rates. The importance of this study is that it focuses on the social inequalities that were amplified by the pandemic.

The Impact of L4-5 Minimally Invasive Transforaminal Lumbar Interbody Fusion on Two-year Adjacent-Level Parameters.

OBJECTIVE: This study evaluates the impact of L4-5 minimally invasive surgery (MIS)-TLIF on adjacent-level parameters. METHODS: This is a retrospective study performed on consecutive patients between January 2015-December 2019. The index- and adjacent-level segmental lordosis (SL) and disc angle (DA) were measured. Patient-reported outcomes (PROs) were collected preoperatively and at 3-24 months postoperatively. Factors influencing changes in adjacent-level parameters and the occurrence of adjacent segment degeneration (ASDeg) were assessed. RESULTS: One hundred and seventeen adult patients, averaging 65.5 years of age and slight preponderance of female (56.4%), were analyzed. L4-5 SL decreased at 2 years (p<0.05), but L4-5 DA significantly increased at all timepoints (p<0.05). While L3-4 SL and DA significantly decreased at all timepoints (p<0.05), L5-S1 SL decreased at 3 and 12 months (p<0.05) and L5-S1 DA only significantly decreased at 2 years (p<0.05). All PROs improved significantly (p<0.0001). The ASDeg rate was 19.7% at 2.2 years. Cephalad and caudal ASDeg rates were 12.0% and 10.3%, respectively. Eight patients (6.8%) required adjacent-level reoperations, mainly at L3-4 (6 cases). The use of expandable cage significantly reduced the odds of caudal ASDeg (OR 0.15, p=0.037), but had no significant effect on cephalad ASDeg.. CONCLUSIONS: L4-5 MIS-TLIF had a more consistent effect on L3-4 than L5-S1. Although adjacent-level SL and DA decreased over time, their association with ASDeg appears limited, suggesting a multifactorial etiology. L4-5 MIS-TLIF provides demonstrable clinical benefits with lasting PRO improvements and low adjacent-level reoperations.

A multi-biomarker micronucleus assay using imaging flow cytometry.

Genetic toxicity testing assesses the potential of compounds to cause DNA damage. There are many genetic toxicology screening assays designed to assess the DNA damaging potential of chemicals in early drug development aiding the identification of promising drugs that have low-risk potential for causing genetic damage contributing to cancer risk in humans. Despite this, in vitro tests generate a high number of misleading positives, the consequences of which can lead to unnecessary animal testing and/or the abandonment of promising drug candidates. Understanding chemical Mode of Action (MoA) is vital to identifying the true genotoxic potential of substances and, therefore, the risk translation into the clinic. Here we demonstrate a simple, robust protocol for staining fixed, human-lymphoblast p53 proficient TK6 cells with antibodies against É£H2AX, p53 and pH3S28 along with DRAQ5™ DNA staining that enables analysis of un-lysed cells via microscopy approaches such as imaging flow cytometry. Here, we used the Cytek® Amnis® ImageStream®X Mk II which provides a high-throughput acquisition platform with the sensitivity of flow cytometry and spatial morphological information associated with microscopy. Using the ImageStream manufacturer's software (IDEAS® 6.2), a masking strategy was developed to automatically detect and quantify micronucleus events (MN) and characterise biomarker populations. The gating strategy developed enables the generation of a template capable of automatically batch processing data files quantifying cell-cycle, MN, É£H2AX, p53 and pH3 populations simultaneously. In this way, we demonstrate how a multiplex system enables DNA damage assessment alongside MN identification using un-lysed cells on the imaging flow cytometry platform. As a proof-of-concept, we use the tool chemicals carbendazim and methyl methanesulphonate (MMS) to demonstrate the assay's ability to correctly identify clastogenic or aneugenic MoAs using the biomarker profiles established.

Upper Limb Function in People With Upper and Lower Limb Loss 8 Years Postinjury: The Armed Services Trauma Outcome Study (ADVANCE) Cohort Study.

OBJECTIVE: Upper limb (UL) disability in people with UL amputation/s is well reported in the literature, less so for people with lower limb amputation/s. This study aimed to compare UL disability in injured (major trauma) and uninjured UK military personnel, with particular focus on people with upper and lower limb amputation/s. METHODS: A volunteer sample of injured (n = 579) and uninjured (n = 566) UK military personnel who served in a combat role in the Afghanistan war were frequency matched on age, sex, service, rank, regiment, role, and deployment period and recruited to the Armed Services Trauma Rehabilitation Outcome (ADVANCE) longitudinal cohort study. Participants completed the Disability of the Arm, Shoulder, and Hand (DASH) questionnaire, scored from 0 (no disability) to 100 (maximum disability) 8 years postinjury. Mann-Whitney U and Kruskal Wallis tests were used to compared DASH scores between groups. An ordinal model was used to assess the effect of injury and amputation on DASH scores. RESULTS: DASH scores were higher in the group with injuries compared to the group without injuries (3.33 vs 0.00) and higher in people with lower limb loss compared to the group without injuries (0.83 vs 0.00), although this was not statistically significant. In the adjusted ordinal model, the odds of having a higher DASH score was 1.70 (95% CI = 1.18-2.47) times higher for people with lower limb loss compared to the group without injuries. DASH score was not significantly different between people with major and partial UL loss (15.42 vs 12.92). The odds of having a higher DASH score was 8.30 (95% CI = 5.07-13.60) times higher for people with UL loss compared to the uninjured group. CONCLUSION: People with lower limb loss have increased odds of having more UL disability than the uninjured population 8 years postinjury. People with major and partial UL loss have similar UL disability. The ADVANCE study will continue to follow this population for the next 20 years. IMPACT: For the first time, potential for greater upper limb disability has been shown in people with lower limb loss long-term, likely resulting from daily biomechanical compensations such as weight-bearing, balance, and power generation. This population may benefit from prophylactic upper limb rehabilitation, strength, and technique.

Recruitment of FBXO22 for targeted degradation of NSD2.

Targeted protein degradation (TPD) is an emerging therapeutic strategy that would benefit from new chemical entities with which to recruit a wider variety of ubiquitin E3 ligases to target proteins for proteasomal degradation. Here we describe a TPD strategy involving the recruitment of FBXO22 to induce degradation of the histone methyltransferase and oncogene NSD2. UNC8732 facilitates FBXO22-mediated degradation of NSD2 in acute lymphoblastic leukemia cells harboring the NSD2 gain-of-function mutation p.E1099K, resulting in growth suppression, apoptosis and reversal of drug resistance. The primary amine of UNC8732 is metabolized to an aldehyde species, which engages C326 of FBXO22 to recruit the SCFFBXO22 Cullin complex. We further demonstrate that a previously reported alkyl amine-containing degrader targeting XIAP is similarly dependent on SCFFBXO22. Overall, we present a potent NSD2 degrader for the exploration of NSD2 disease phenotypes and a new FBXO22-recruitment strategy for TPD.

Renal autocrine neuropeptide FF (NPFF) signaling regulates blood pressure.

The kidney and brain play critical roles in the regulation of blood pressure. Neuropeptide FF (NPFF), originally isolated from the bovine brain, has been suggested to contribute to the pathogenesis of hypertension. However, the roles of NPFF and its receptors, NPFF-R1 and NPFF-R2, in the regulation of blood pressure, via the kidney, are not known. In this study, we found that the transcripts and proteins of NPFF and its receptors, NPFF-R1 and NPFF-R2, were expressed in mouse and human renal proximal tubules (RPTs). In mouse RPT cells (RPTCs), NPFF, but not RF-amide-related peptide-2 (RFRP-2), decreased the forskolin-stimulated cAMP production in a concentration- and time-dependent manner. Furthermore, dopamine D1-like receptors colocalized and co-immunoprecipitated with NPFF-R1 and NPFF-R2 in human RPTCs. The increase in cAMP production in human RPTCs caused by fenoldopam, a D1-like receptor agonist, was attenuated by NPFF, indicating an antagonistic interaction between NPFF and D1-like receptors. The renal subcapsular infusion of NPFF in C57BL/6 mice decreased renal sodium excretion and increased blood pressure. The NPFF-mediated increase in blood pressure was prevented by RF-9, an antagonist of NPFF receptors. Taken together, our findings suggest that autocrine NPFF and its receptors in the kidney regulate blood pressure, but the mechanisms remain to be determined.

Associations between hypopharyngeal defect closure and quality of life in long-term total laryngectomy survivors.

BACKGROUND: Few studies have examined health-related quality of life (HRQOL) outcomes in long-term total laryngectomy survivors in relation to the type of hypopharyngeal defect. METHODS: A cross-sectional study was performed in long-term total laryngectomy survivors, treated between 2000 and 2020. The primary outcome was HRQOL, assessed using the FACE-Q Head and Neck Cancer Module, in relation to the type of hypopharyngeal closure (primary closure, partial or circumferential reconstruction). RESULTS: Seventy-nine survivors were included with a median follow-up of 92.1 months (IQR 75.6-140.2 months). Patients requiring partial hypopharyngeal reconstruction (n = 18) scored significantly worse than patients with primary closure (n = 51) on 4 of 13 FACE-Q domains: functional domains of eating (p = 0.03), speech (p = 0.05), and swallowing (p = 0.03), and the psychological domain of speaking-related distress (p = 0.02). No statistically significant differences were found between the circumferential hypopharyngeal defect reconstruction group (n = 10). Stricture occurrence was the only clinical factor associated with worse eating, speaking, swallowing, eating-related distress, and cancer worry in multivariable analyses. CONCLUSION: Several functional and psychological domains were significantly worse following partial hypopharyngeal reconstruction than in patients who received primary closure. Efforts to reduce stricture rates to enhance reconstructive outcomes following total laryngectomy merit further research.

Mutations in the Staphylococcus aureus Global Regulator CodY Confer Tolerance to an Interspecies Redox-Active Antimicrobial.

Bacteria often exist in multispecies communities where interactions among different species can modify individual fitness and behavior. Although many competitive interactions have been characterized, molecular adaptations that can counter this antagonism and preserve or increase fitness remain underexplored. Here, we characterize the adaptation of Staphylococcus aureus to pyocyanin, a redox-active interspecies antimicrobial produced by Pseudomonas aeruginosa , a co-infecting pathogen frequently isolated from wound and chronic lung infections with S. aureus . Using experimental evolution, we identified mutations in a conserved global transcriptional regulator, CodY, that confer tolerance to pyocyanin and thereby enhance survival of S. aureus . The transcriptional response of a pyocyanin tolerant CodY mutant to pyocyanin indicated a two-pronged defensive response compared to the wild type. Firstly, the CodY mutant strongly suppressed metabolism, by downregulating pathways associated with core metabolism, especially translation-associated genes, upon exposure to pyocyanin. Metabolic suppression via ATP depletion was sufficient to provide comparable protection against pyocyanin to the wild-type strain. Secondly, while both the wild-type and CodY mutant strains upregulated oxidative stress response pathways, the CodY mutant overexpressed multiple stress response genes compared to the wild type. We determined that catalase overexpression was critical to pyocyanin tolerance as its absence eliminated tolerance in the CodY mutant and overexpression of catalase was sufficient to impart tolerance to the wild-type strain. Together, these results suggest that both transcriptional responses likely contribute to pyocyanin tolerance in the CodY mutant. Our data thus provide new mechanistic insight into adaptation toward interbacterial antagonism via altered regulation that facilitates multifaceted protective cellular responses.

Current patterns of care and outcomes for dermatofibrosarcoma protuberans: An international multi-institutional collaborative.

BACKGROUND: Dermatofibrosarcoma protuberans (DFSP) is a cutaneous sarcoma with an infiltrative growth pattern that makes it challenging to clear margins. High quality data regarding DFSP natural history, management, and outcomes are limited. METHODS: Data were retrospectively collected for adult DFSP patients who underwent resection at 10 institutions in eight countries. Demographics, tumor characteristics, treatment strategies, and outcomes were analyzed. RESULTS: Analysis included 347 patients consisting of young (median, 42 years), White (76.2%), males (54.2%) with truncal lesions (57.3%). The majority (76.8%) were symptomatic at presentation. Preoperative imaging was used in 55.9% of cases. Diagnosis was established with excisional biopsy in 50.9% versus incisional biopsy in 25.0% of cases. Despite planned margins of >1.0 cm in 67.4% of cases, only 69.0% of patients achieved R0 resection. Twenty-two percent of patients underwent at least one re-excision. R0 resection was achieved at a second procedure in 80.2% and a third procedure in 86.2%. Ultimately, R0 resection was feasible in 89.5% of all patients. Fibrosarcomatous transformation (FST) was observed in 12.6%. In total, 6.6% (N = 23) recurred (17 local, six distant). Of the six distant recurrences, 50.0% had FST. With a median follow-up of 47.0 months, disease-specific survival rate was 98.8%. In multivariable analysis, R0 margins at index resection were associated with wider circumferential margins and non-FST histology. CONCLUSIONS: In this international, multicenter collaborative, DFSP practice patterns were heterogeneous but achieved favorable recurrence rates and survival. Multiple excisions to clear margins remain commonplace and can inform future efforts to optimize margin selection.

Validity of Ultra-Short-Term Heart Rate Variability Derived from Femoral Arterial Pulse Waveform in a British Military Cohort.

Various non-electrocardiogram (ECG) based methods are considered reliable sources of heart rate variability (HRV) measurement. However, the ultra-short recording of a femoral arterial waveform has never been validated against the gold-standard ECG-based 300s HRV and was the aim of this study.A validity study was conducted using a sample from the first follow-up of the longitudinal ADVANCE study UK. The participants were adult servicemen (n = 100); similar in age, rank, and deployment period (Afghanistan 2003-2014). The femoral arterial waveforms (14s) from the pulse wave velocity (PWV) assessment, and ECG (300s) were recorded at rest in the supine position using the Vicorder™ and Bittium Faros™ devices, respectively, in the same session. HRV analysis was performed using Kubios Premium. Resting heart rate (HR) and root mean square of successive differences (RMSSD) were reported. The Bland-Altman %plots were constructed to explore the PWV-ECG agreement in HRV measurement. A further exploratory analysis was conducted across methods and durations.The participants' mean age was 38.0 ± 5.3 years. Both PWV-derived HR (r = 0.85) and RMSSD (rs=0.84) showed strong correlations with their 300s-ECG counterparts (p < 0.001). Mean HR was significantly higher with ECG than PWV (mean bias: -12.71 ± 7.73%, 95%CI: -14.25%, -11.18%). In contrast, the difference in RMSSD between the two methods was non-significant [mean bias: -2.90 ± 37.82% (95%CI: -10.40%, 4.60%)] indicating good agreement. An exploratory analysis of 14s ECG-vs-300s ECG measurement revealed strong agreement in both RMSSD and HR.The 14s PWV-derived RMSSD strongly agrees with the gold-standard (300s-ECG-based) RMSSD at rest. Conversely, HR appears method sensitive.

Phylogenetically diverse bacterial species produce histamine.

Histamine is an important biogenic amine known to impact a variety of patho-physiological processes ranging from allergic reactions, gut-mediated anti-inflammatory responses, and neurotransmitter activity. Histamine is found both endogenously within specialized host cells and exogenously in microbes. Exogenous histamine is produced through the decarboxylation of the amino acid L-histidine by bacterial-derived histidine decarboxylase enzymes. To investigate how widespread histamine production is across bacterial species, we examined 102,018 annotated genomes in the Integrated Microbial Genomes Database and identified 3,679 bacterial genomes (3.6 %) which possess the enzymatic machinery to generate histamine. These bacteria belonged to 10 phyla: Bacillota, Bacteroidota, Actinomycetota, Pseudomonadota, Lentisphaerota, Fusobacteriota, Armatimonadota, Cyanobacteriota, Thermodesulfobacteriota, and Verrucomicrobiota. The majority of the identified bacteria were terrestrial or aquatic in origin, although several bacteria originated in the human gut microbiota. We used liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based targeted metabolomics to confirm our genome discoveries correlated with L-histidine-to-histamine conversion in a chemically defined bacterial growth medium by a cohort of select environmental and human gut bacteria. We found that environmental microbes Vibrio harveyi, Pseudomonas fluorescens and Streptomyces griseus generated considerable levels of histamine (788 - 8,730 ng/mL). Interestingly, we found higher concentrations of histamine produced by gut-associated Fusobacterium varium, Clostridium perfringens, Limosilactobacillus reuteri and Morganella morganii (8,510--82,400 ng/mL). This work expands our knowledge of histamine production by diverse microbes.

Regulating interparticle proximity in plasmonic nanosphere aggregates to enhance photoacoustic response and photothermal stability.

Designing plasmonic nanoparticles for biomedical photoacoustic (PA) imaging involves tailoring material properties at the nanometer scale. A key in developing plasmonic PA contrast nanoagents is to engineer their enhanced optical responses in the near-infrared wavelength range, as well as heat transfer properties and photostability. This study introduces anisotropic plasmonic nanosphere aggregates with close interparticle proximity as photostable and efficient contrast agent for PA imaging. Silver (Ag), among plasmonic metals, is particularly attractive due to its strongest optical response and highest heat conductivity. Our results demonstrate that close interparticle proximity in silver nanoaggregates (AgNAs), spatially confined within a polymer shell layer, leads to blackbody-like optical absorption, resulting in robust PA signals through efficient pulsed heat generation and transfer. Additionally, our AgNAs exhibit a high photodamage threshold highlighting their potential to outperform conventional plasmonic contrast agents for high-contrast PA imaging over multiple imaging sessions. Furthermore, we demonstrate the capability of the AgNAs for molecular PA cancer imaging in vivo by incorporating a tumor-targeting peptide moiety.

Assessing the quality of artificial intelligence-generated patient counseling for rhinosinusitis.

KEY POINTS: GPT-4 generated moderate quality information in response to questions regarding sinusitis and surgery. GPT-4 generated significantly higher quality responses to questions regarding treatment of sinusitis. Future studies exploring quality of GPT responses should seek to limit bias and use validated instruments.

An acidic pH environment converts necroptosis to apoptosis.

Cardiac ischemia results in anaerobic metabolism and lactic acid accumulation and with time, intracellular and extracellular acidosis. Ischemia and subsequent reperfusion injury (IRI) lead to various forms of programmed cell death. Necroptosis is a major form of programmed necrosis that worsens cardiac function directly and also promotes inflammation by the release of cellular contents. Potential effects of increasing acidosis on programmed cell death and their specific components have not been well studied. While apoptosis is caspase-dependent, in contrast, necroptosis is mediated by the receptor-interacting protein kinases 1 and 3 (RIPK1/3). In our study, we observed that at physiological pH = 7.4, caspase-8 inhibition did not prevent TNFα-induced cell death in mouse cardiac vascular endothelial cells (MVECs) but promoted necroptotic cell death. As expected, necroptosis was blocked by RIPK1 inhibition. However, at pH = 6.5, TNFα induced an apoptosis-like pattern which was inhibited by caspase-8 inhibition. Interestingly phosphorylation of necroptotic molecules RIPK1, RIPK3, and mixed lineage kinase domain-like protein (MLKL) was enhanced in an acidic pH environment. However, RIPK3 and MLKL phosphorylation was self-limited which may have limited their participation in necroptosis. In addition, an acidic pH promoted apoptosis-inducing factor (AIF) cleavage and nuclear translocation. AIF RNA silencing inhibited cell death, supporting the role of AIF in this cell death. In summary, our study demonstrated that the pH of the micro-environment during inflammation can bias cell death pathways by altering the function of necroptosis-related molecules and promoting AIF-mediated cell death. Further insights into the mechanisms by which an acidic cellular micro-environment influences these and perhaps other forms of regulated cell death, may lead to therapeutic strategies to attenuate IRI.

Her Legacy Lives On: Celebrating the Women Behind Head and Neck Eponyms.

This article profiles 6 notable female scientists who have had eponyms named after them, highlighting their significant contributions to various medical fields and whose scientific endeavors have influenced our practice and understanding of otolaryngology. We discuss Lucja Frey Gottesman and her description of Frey's syndrome; Margaret Dix and the Dix-Hallpike test; Lotte Strauss and her work defining Churg-Strauss disease; Dorothy Reed Mendenhall's discovery of Reed-Sternberg cells in Hodgkin's lymphoma; Edith Louise Potter defining Potter sequence in utero; Denise Louis-Bar originally characterizing the condition now known as ataxia-telangiectasia or Louis-Bar syndrome. Despite the challenges these women faced as pioneering female physicians as well as personal and political turmoil, their contributions greatly advanced the fields of otolaryngology, neurology, neuropathology, perinatology, and pediatric pathology. We aim to honor their stories and medical legacies.

Identification and treatment of midaortic syndrome in an adult patient with orthostatic tachycardia and hypertension: A case report.

Anatomical cardiovascular etiologies are less frequently investigated and identified in cases of orthostatic intolerance, which can have a profound impact on a patient's functional status. Here, we present a 26-year-old female with a recent diagnosis of hyperadrenergic postural orthostatic tachycardia and hypertension who was found to have diminished pedal pulses. Workup revealed an underlying midaortic syndrome that was then surgically corrected with resolution of symptoms. We discuss the epidemiology, presentation, and management of this rare condition, as well as its role in our patient's symptomatology.

Factors predictive of recurrence, metastasis and death in node-negative penile squamous cell carcinoma: A retrospective multicentre cohort study.

BACKGROUND: Penile squamous cell carcinoma (PSCC) carries significant morbidity and mortality. Literature is limited regarding prognostic factors, especially prognostic factors for development of metastasis. OBJECTIVES: To identify independent prognostic factors associated with poor outcomes, defined as local recurrence (LR), metastasis and disease-specific death (DSD) in clinically node-negative PSCC undergoing local therapy. METHODS: Thirty-two-year Retrospective Multicenter Cohort Study of 265 patients with histologically diagnosed PSCC at three tertiary care centres. Predictive models based on patient or tumour characteristics were developed. RESULTS: Local recurrence occurred in 56 patients, metastasis in 52 patients and DSD in 40 patients. In multivariable models, the following five factors were independent prognostic factors based on subhazard ratio (SHR): history of balanitis (LR SHR: 2.3; 95% CI 1.2-4.2), poor differentiation (metastasis SHR 1.9; 95% CI 1.0-3.6), invasion into the corpora (metastasis SHR: 3.0; 95% CI 1.5-5.8 and DSD SHR: 4.5; 95% CI 1.7-12.1), perineural invasion (PNI) (metastasis SHR: 2.8; 95% CI 1.4-5.5 and DSD SHR: 3.5; 95% CI, 1.6-7.8) and a history of phimosis (DSD SHR: 2.5; 95% CI 1.2-5.3). The 5-year cumulative incidence of metastasis was higher for tumours with PNI [cumulative incidence function (CIF) = 55%, 95% CI 38-75 vs. CIF 15%, 95% CI 11-22], corporal invasion (CIF: 35%, 95% CI 26-47 vs. 12%, 95% CI 7-19) and poorly differentiated tumours (CIF = 46%, 95% CI 31-64 vs. CIF 15%, 95% CI 11-22). CONCLUSIONS: History of balanitis, history of phimosis, PNI, corporal invasion and poor differentiation are independent risk factors associated with poor outcomes. Since poor differentiation and PNI currently constitute only T1b disease, prognostic staging can likely be improved.

A case-control study: epigenetic age acceleration in psoriasis.

Psoriasis (PsO) is a chronic inflammatory skin condition, often accompanied by psoriatic arthritis (PsA) and linked to various comorbidities and increased mortality rates. This study aimed to explore the relationship between PsO and accelerated biological aging, specifically focusing on epigenetic DNA methylation clocks. Using a matched case-control design, 20 PsO cases were selected along with age, race, and sex-matched 20 controls without PsO from the Skin Disease Biorepository at Brown Dermatology, Inc, Providence, Rhode Island. Blood samples retrieved from both groups were analyzed for DNA methylation, and epigenetic ages were calculated using DNA methylation clocks, including Horvath, Hannum, Pheno, SkinBlood, and Grim ages. Generalized estimation equations were employed to test the differences in epigenetic and chronological ages between PsO cases and controls, as well as within various subgroups in comparison to their respective controls. There were no statistically significant differences in epigenetic ages between PsO cases and controls. However, notably, PsO cases with PsA demonstrated an accelerated PhenoAge, compared to their matched controls. This study represents a pioneering investigation into the potential link between PsO and epigenetic aging, shedding light on the possibility of accelerated epigenetic aging in PsA, possibly associated with heightened inflammatory burden. These findings emphasize the systemic impact of PsA on the aging process, prompting the need for deeper exploration into autoimmune pathways, inflammation, and epigenetic modifications underlying PsO pathogenesis and aging mechanisms. Larger-scale studies with diverse populations are imperative to discern PsO subgroups experiencing accelerated biological aging and decipher the intricate interplay between PsO, inflammation, and aging pathways.

Long-lasting, biochemically modified mRNA, and its frameshifted recombinant spike proteins in human tissues and circulation after COVID-19 vaccination.

According to the CDC, both Pfizer and Moderna COVID-19 vaccines contain nucleoside-modified messenger RNA (mRNA) encoding the viral spike glycoprotein of severe acute respiratory syndrome caused by corona virus (SARS-CoV-2), administered via intramuscular injections. Despite their worldwide use, very little is known about how nucleoside modifications in mRNA sequences affect their breakdown, transcription and protein synthesis. It was hoped that resident and circulating immune cells attracted to the injection site make copies of the spike protein while the injected mRNA degrades within a few days. It was also originally estimated that recombinant spike proteins generated by mRNA vaccines would persist in the body for a few weeks. In reality, clinical studies now report that modified SARS-CoV-2 mRNA routinely persist up to a month from injection and can be detected in cardiac and skeletal muscle at sites of inflammation and fibrosis, while the recombinant spike protein may persist a little over half a year in blood. Vaccination with 1-methylΨ (pseudouridine enriched) mRNA can elicit cellular immunity to peptide antigens produced by +1 ribosomal frameshifting in major histocompatibility complex-diverse people. The translation of 1-methylΨ mRNA using liquid chromatography tandem mass spectrometry identified nine peptides derived from the mRNA +1 frame. These products impact on off-target host T cell immunity that include increased production of new B cell antigens with far reaching clinical consequences. As an example, a highly significant increase in heart muscle 18-flourodeoxyglucose uptake was detected in vaccinated patients up to half a year (180 days). This review article focuses on medical biochemistry, proteomics and deutenomics principles that explain the persisting spike phenomenon in circulation with organ-related functional damage even in asymptomatic individuals. Proline and hydroxyproline residues emerge as prominent deuterium (heavy hydrogen) binding sites in structural proteins with robust isotopic stability that resists not only enzymatic breakdown, but virtually all (non)-enzymatic cleavage mechanisms known in chemistry.