Multi-omics analysis in IgM monoclonal gammopathies reveals epigenetic influence on oncogenesis via DNA methylation.

Currently, the role of DNA methylation in the IgM-monoclonal gammopathy disease spectrum remains poorly understood. In the present study, a multi-omics prospective analysis was conducted integrating DNA methylation, RNA-seq and WES data in 34 subjects [23 WM, 6 IgM-MGUS, 5 normal controls]. Analysis was focused on defining differences between IgM-gammopathies (WM/IgM-MGUS) compared to controls, and specifically between WM and IgM-MGUS. Between groups, genome-wide DNA methylation analysis demonstrated a significant number of differentially methylated regions which were annotated according to genomic region. Next, integration of RNA-seq data was performed to identify potentially epigenetically deregulated pathways. We found that pathways involved in cell cycle, metabolism, cytokine/immune signaling, cytoskeleton, tumor microenvironment, and intracellular signaling were differentially activated and potentially epigenetically regulated. Importantly, there was a positive enrichment of CXCR4 signaling pathway along with several interleukin (IL-6, IL-8, IL15) signaling pathways in WM compared to IgM-MGUS. Further assessment of known tumor suppressor genes and oncogenes uncovered differential promoter methylation of several targets with concordant change in gene expression, including CCND1 and CD79B. Overall, this report defines how aberrant DNA methylation in IgM-gammopathies may play a critical role in the epigenetic control of oncogenesis and key cellular functions.

Prevalence of and Risks for Bacterial Infections in Hospitalized Children With Bronchiolitis.

BACKGROUND AND OBJECTIVES: Viral bronchiolitis is a common pediatric illness. Treatment is supportive; however, some children have concurrent serious bacterial infections (cSBIs) requiring antibiotics. Identifying children with cSBI is challenging and may lead to unnecessary treatment. Improved understanding of the prevalence of and risk factors for cSBI are needed to guide treatment. We sought to determine the prevalence of cSBI and identify factors associated with cSBI in children hospitalized with bronchiolitis. METHODS: We performed a retrospective cohort study of children <2 years old hospitalized with bronchiolitis at a free-standing children's hospital from 2012 to 2019 identified by International Classification of Diseases codes. cSBI was defined as bacteremia, urinary tract infection, meningitis, or pneumonia. Risk factors for cSBI were identified using logistic regression. RESULTS: We identified 7871 admissions for bronchiolitis. At least 1 cSBI occurred in 4.2% of these admissions; with 3.5% meeting our bacterial pneumonia definition, 0.4% bacteremia, 0.3% urinary tract infection, and 0.02% meningitis. cSBI were more likely to occur in children with invasive mechanical ventilation (odds ratio [OR] 2.53, 95% confidence interval [CI] 1.78-3.63), a C-reactive protein ≥4 mg/dL (OR 2.20, 95% CI 1.47-3.32), a concurrent complex chronic condition (OR 1.67, 95% CI 1.22-2.25) or admission to the PICU (OR 1.46, 95% CI 1.02-2.07). CONCLUSIONS: cSBI is uncommon among children hospitalized with bronchiolitis, with pneumonia being the most common cSBI. Invasive mechanical ventilation, elevated C-reactive protein, presence of complex chronic conditions, and PICU admission were associated with an increased risk of cSBI.

Multiomic analysis identifies a high-risk signature that predicts early clinical failure in DLBCL.

Recent genetic and molecular classification of DLBCL has advanced our knowledge of disease biology, yet were not designed to predict early events and guide anticipatory selection of novel therapies. To address this unmet need, we used an integrative multiomic approach to identify a signature at diagnosis that will identify DLBCL at high risk of early clinical failure. Tumor biopsies from 444 newly diagnosed DLBCL were analyzed by WES and RNAseq. A combination of weighted gene correlation network analysis and differential gene expression analysis was used to identify a signature associated with high risk of early clinical failure independent of IPI and COO. Further analysis revealed the signature was associated with metabolic reprogramming and identified cases with a depleted immune microenvironment. Finally, WES data was integrated into the signature and we found that inclusion of ARID1A mutations resulted in identification of 45% of cases with an early clinical failure which was validated in external DLBCL cohorts. This novel and integrative approach is the first to identify a signature at diagnosis, in a real-world cohort of DLBCL, that identifies patients at high risk for early clinical failure and may have significant implications for design of therapeutic options.

Association between adverse events after COVID-19 vaccination and anti-SARS-CoV-2 antibody concentrations, the Netherlands, May 2021 to November 2022: a population-based prospective cohort study.

BackgroundNon-severe adverse events (AE) including pain at injection site or fever are common after COVID-19 vaccination.AimTo describe determinants of AE after COVID-19 vaccination and investigate the association between AE and pre- and post-vaccination antibody concentrations.MethodsParticipants of an ongoing prospective cohort study (VASCO) completed a questionnaire on AE within 2 months after vaccination and provided 6 monthly serum samples during May 2021-November 2022. Logistic regression analyses were performed to investigate AE determinants after mRNA vaccination, including pre-vaccination Ig antibody concentrations against the SARS-CoV-2 spike protein receptor binding domain. Multivariable linear regression was performed in SARS-CoV-2-naive participants to assess the association between AE and log-transformed antibody concentrations 3-8 weeks after mRNA vaccination.ResultsWe received 47,947 completed AE questionnaires by 28,032 participants. In 42% and 34% of questionnaires, injection site and systemic AE were reported, respectively. In 2.2% of questionnaires, participants sought medical attention. AE were reported more frequently by women, younger participants (< 60 years), participants with medical risk conditions and Spikevax recipients (vs Comirnaty). Higher pre-vaccination antibody concentrations were associated with higher incidence of systemic AE after the second and third dose, but not with injection site AE or AE for which medical attention was sought. Any AE after the third dose was associated with higher post-vaccination antibody concentrations (geometric mean concentration ratio: 1.38; 95% CI: 1.23-1.54).ConclusionsOur study suggests that high pre-vaccination antibody levels are associated with AE, and experiencing AE may be a marker for higher antibody response to vaccination.

The link between early adolescents' gender discrimination and gender attitudes about peers: Does gender similarity matter?

Gender is one of the most salient social identities, particularly during early adolescence. However, factors related to adolescents' gender attitudes remain underexamined. We examined links between adolescents' gender discrimination, felt-gender similarity, and intergroup gender attitudes. Participants were 270 adolescents in the United States (Mage = 12.95 years, SD = 1.33; 47.4% adolescent girls; 63.7% White, 12.2% Latinx, 10.7% Black, 4.1% Asian, 5.6% multiracial, and 3% indigenous). Path analyses showed that gender discrimination negatively predicted adolescents' attitudes towards own- and other-gender peers. Felt own-gender similarity positively predicted own-gender attitudes as expected, but other-gender similarity did not predict other-gender attitudes. Further, own- and other-gender similarity did not interact to predict adolescents' gender attitudes. However, adolescents' attitudes towards other-gender peers were more negatively impacted by gender discrimination for those who felt highly similar to own-gender peers than for those with average or low own-gender similarity. Findings inform potential strategies to improve adolescents' gender attitudes.

Longitudinal Change in Appearance-Related Social Media Consciousness and Depressive Symptoms: A Within-Person Analysis during Early-to-Middle Adolescence.

Online appearance preoccupation may put adolescents at risk of developing mental health challenges, perhaps especially during early-to-middle adolescence. A random intercept cross-lagged panel model assessed within-person associations between appearance-related social media consciousness and depressive symptoms over three time-points with three months between waves. The sample (n = 1594) included U.S. adolescents aged 11-15 (Mage = 13; 47% girls, 46% boys, 7% another gender; 37% Latine, 33% White, 18% Black, 7% Asian). Within-person increases in appearance-related social media consciousness were associated with subsequent increases in depressive symptoms, but not vice versa. There was no evidence of gender differences and results were robust to controlling for both time on social media and offline self-objectification. Thus, online appearance concerns precede mental health challenges during early and middle adolescence.

Monkeypox Virus Infections After 2 Preexposure Doses of JYNNEOS Vaccine - United States, May 2022-May 2024.

Two doses of JYNNEOS vaccine are effective in preventing many mpox cases and can reduce the severity of symptoms in infected persons. However, infections among fully vaccinated persons can occur. During May 2022-May 2024, a total of 271 mpox cases among fully vaccinated persons were reported to CDC from 27 U.S. jurisdictions. These reported infections are estimated to have occurred in <1% of fully vaccinated persons. Compared with cases among unvaccinated persons, infections among fully vaccinated persons were more likely to occur among non-Hispanic White men aged 30-39 years, were associated with increased numbers of sexual partners, and resulted in less severe disease (p<0.001). Among infections in fully vaccinated persons with complete data, infections after vaccination were reported more commonly after receipt of heterologous (subcutaneous and intradermal) (46%) or homologous subcutaneous (32%) JYNNEOS vaccination than after homologous intradermal (22%) vaccination. Disparate time intervals from vaccination to infection among fully vaccinated persons suggest that immunity is not waning. The median interval between the second vaccine dose and illness onset was longer for cases among persons who had received 2 intradermal doses (median = 363 days; IQR = 221-444 days) compared with cases in persons who had received 2 subcutaneous doses (median = 263 days; IQR = 47-334 days) (p<0.001). The implications of this finding are not known; however, these data should increase confidence in the effectiveness of vaccine doses that were administered intradermally, the preferred method of administration during the peak of the outbreak when vaccine supply was limited. Persons recommended to receive the JYNNEOS vaccine should receive 2 doses, irrespective of the route of administration, and at this time, additional doses are not recommended for the affected population.

Epidemiology of heat-related illness in dogs under UK emergency veterinary care in 2022.

BACKGROUND: Dogs are exposed to increasing environmental risk for developing heat-related illness (HRI), with 2022 recorded as the hottest year to date in the UK and most of Europe. METHODS: This study used VetCompass data to report the incidence risk, event fatality rate and canine risk factors for HRI in dogs presenting to Vets Now emergency care practices in the UK during 2022. RESULTS: From the clinical records of 167,751 dogs under care at Vets Now emergency clinics in 2022, 384 HRI events were identified. The 2022 incidence risk of HRI within the Vets Now caseload was 0.23% (95% confidence interval [CI]: 0.21%‒0.25%), with an event fatality rate of 26.56% (95% CI: 21.66%-32.25%). Multivariable analysis identified breed, age and sex/neuter status as risk factors for HRI. Brachycephalic dogs had 4.21 times the odds of HRI compared to mesocephalic dogs (95% CI: 3.22‒5.49, p < 0.001). LIMITATIONS: The clinical data used in this study were not primarily recorded for research and had some substantial levels of missing data (especially patient bodyweight). CONCLUSION: In order to protect canine welfare, improved long-term mitigation strategies are urgently needed to minimise HRI risk and associated fatality in UK dogs.

Spectinamide MBX-4888A exhibits favorable lesion and tissue distribution and promotes treatment shortening in advanced murine models of tuberculosis.

The spectinamides are novel, narrow-spectrum semisynthetic analogs of spectinomycin, modified to avoid intrinsic efflux by Mycobacterium tuberculosis . Spectinamides, including lead MBX-4888A (Lee-1810), exhibit promising therapeutic profiles in mice, as single drugs and as partner agents with other anti-tuberculosis antibiotics including rifampin and/or pyrazinamide. To demonstrate that this translates to more effective cure, we first confirmed the role of rifampin, with or without pyrazinamide, as essential to achieve effective bactericidal responses and sterilizing cure in the current standard of care regimen in chronically infected C3HeB/FeJ mice compared to BALB/c mice. Thus, demonstrating added value in testing clinically relevant regimens in murine models of increasing pathologic complexity. Next we show that MBX-4888A, given by injection with the front-line standard of care regimen, is treatment shortening in multiple murine tuberculosis infection models. The positive treatment responses to MBX-4888A combination therapy in multiple mouse models including mice exhibiting advanced pulmonary disease can be attributed to favorable distribution in tissues and lesions, retention in caseum, along with favorable effects with rifampin and pyrazinamide under conditions achieved in necrotic lesions. This study also provides an additional data point regarding the safety and tolerability of spectinamide MBX-4888A in long-term murine efficacy studies.

Add-on testing: stability assessment of 63 biochemical analytes in centrifuged and capped samples stored at 16 °C.

OBJECTIVES: Integration of add-on testing in high-scale automated clinical laboratories constitute a valuable instrument not only for the clinicians and the general patient care, but also for the laboratory itself. Knowledge on sample quality and analytical stability upon storage is necessary to be able to offer add-on testing. The objectives of this study were to examine the analytical stability of 63 biochemical analytes in plasma and urine samples stored at 16 °C. METHODS: Samples were collected by professional laboratory technicians, analyzed at automated analyzers and stored in their primary, capped tube without separator for 10, 12, 16, 20 or 24 h at 16 °C. Stability was assessed by inspecting mean concentration of samples at baseline and examining if (A) mean concentration over time violated limits of bias, or if (B) individual sample concentrations violated limits of total error. RESULTS: The majority of the 63 analytes were stable for up to 24 h of storage. Few of the analytes were only suitable for add-on testing for 4, 6, 10, 12, 16 or 20 h of storage. One analyte, P-lactate dehydrogenase, was not found suitable for add-on testing when stored at 16 °C. CONCLUSIONS: Due to the increasing number of intelligent solutions for high-scale clinical laboratories, add-on testing has come to stay. Loss of stability could not be demonstrated for the majority of analytes after 10, 12, 16, 20 or 24 h of storage. This feature of analytical stability suggests that add-on testing is an acceptable tool for these analytes.

Comparison of different interposition techniques after surgical resection of tarsal coalitions in children: a systematic review.

In the surgical treatment of tarsal coalitions, it is unclear whether interposition material should be used to prevent recurrence. The aim of this review was to systematically examine the results of different interposition tissues after surgical resection of tarsal coalitions in children. A systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Two independent investigators systematically searched electronic databases (PubMed, Embase, Cochrane) and included original articles reporting outcomes of tarsal coalition resection. The quality of included studies was assessed using the Methodological Index for Non-Randomized Studies (MINORS) criteria. Out of 294 articles, 21 studies examining 436 patients (581 feet), were included. The mean age was 12.2 years (range 7-18). There were 153 talocalcaneal, 425 calcaneonavicular, 2 naviculocuboidal, and 1 naviculocuneiform coalitions. The mean follow-up time was 58 months (range 12-276). In 96 feet, solely resection was performed. Resection and interposition were performed with muscle/tendon (n = 178), fat graft (n = 176), other material (n = 36), or a combination of interposition techniques (n = 95). Eighteen studies reported on recurrence, which was found in 45 of 485 feet (9%). The highest recurrence (17%) was described after muscle/tendon interposition for calcaneonavicular coalitions. However, a statistical comparison could not be performed. The included studies were diverse and the scientific quality was generally low (MINORS mean 7, range 3-20). Coalition resection with various interposition techniques results in low recurrence rates. It is unclear which interposition material shows the best results.

Mobility, functionality and functional mobility: A review and application for canine veterinary patients.

Mobility is an essential aspect of a dog's daily life. It is defined as the ability to move freely and easily and deviations from an animals' normal mobility capabilities are often an indicator of disease, injury or pain. When a dog's mobility is compromised, often functionality (ability to perform activities of daily living [ADL]), is also impeded, which can diminish an animal's quality of life. Given this, it is necessary to understand the extent to which conditions impact a dog's physiological ability to move around their environment to carry out ADL, a concept termed functional mobility. In contrast to human medicine, validated measures of canine functional mobility are currently limited. The aim of this review is to summarise the extent to which canine mobility and functionality are associated with various diseases and how mobility and functional mobility are currently assessed within veterinary medicine. Future work should focus on developing a standardised method of assessing functional mobility in dogs, which can contextualise how a wide range of conditions impact a dog's daily life. However, for a true functional mobility assessment to be developed, a greater understanding of what activities dogs do on a daily basis and movements underpinning these activities must first be established.

Mtb-Selective 5-Aminomethyl Oxazolidinone Prodrugs: Robust Potency and Potential Liabilities.

Linezolid is a drug with proven human antitubercular activity whose use is limited to highly drug-resistant patients because of its toxicity. This toxicity is related to its mechanism of action─linezolid inhibits protein synthesis in both bacteria and eukaryotic mitochondria. A highly selective and potent series of oxazolidinones, bearing a 5-aminomethyl moiety (in place of the typical 5-acetamidomethyl moiety of linezolid), was identified. Linezolid-resistant mutants were cross-resistant to these molecules but not vice versa. Resistance to the 5-aminomethyl molecules mapped to an N-acetyl transferase (Rv0133) and these mutants remained fully linezolid susceptible. Purified Rv0133 was shown to catalyze the transformation of the 5-aminomethyl oxazolidinones to their corresponding N-acetylated metabolites, and this transformation was also observed in live cells of Mycobacterium tuberculosis. Mammalian mitochondria, which lack an appropriate N-acetyltransferase to activate these prodrugs, were not susceptible to inhibition with the 5-aminomethyl analogues. Several compounds that were more potent than linezolid were taken into C3HeB/FeJ mice and were shown to be highly efficacious, and one of these (9) was additionally taken into marmosets and found to be highly active. Penetration of these 5-aminomethyl oxazolidinone prodrugs into caseum was excellent. Unfortunately, these compounds were rapidly converted into the corresponding 5-alcohols by mammalian metabolism which retained antimycobacterial activity but resulted in substantial mitotoxicity.

The Role of Feminism and Gender in Endorsement of Hookup Culture among Emerging Adults.

Hookup culture has transformed the sexual behavior of emerging adults. Feminism, a movement that has advocated for liberating women from sexual repression, may be associated with hookup endorsement attitudes. This study explores the associations among multiple dimensions of feminism, gender, and hookup culture endorsement. Participants included 318 emerging adults (46% women; Mage = 22.2 years; 51% White, 27% Asian, 5% Hispanic/Latinx, 9% Black, 1% Middle Eastern, 1% American Indian, 6% Multiracial) from five Anglophone countries (62% U.S., 23% United Kingdom, 9% Canada, 5% Australia, 1% New Zealand), who completed the Feminist Beliefs and Behavior Scale and Endorsement of Hookup Culture Index via an anonymous, online survey. Participants were categorized according to their feminist identity label (feminist, non-feminist) and feminist belief system (hold feminist beliefs, hold non-feminist beliefs). A series of ANCOVAs was conducted, revealing that women who identified as feminist and/or held feminist beliefs reported significantly higher endorsement of hookup culture compared to non-feminist women with non-feminist beliefs. Neither dimension of feminism predicted hookup culture endorsement in men. When comparing feminist-identifying women and men, the gender disparity in hookup culture endorsement was eliminated. Together, these findings highlight how social movements, such as feminism, may be associated with young women's attitudes towards hookups, and may ultimately shape their sexual experiences.

Revisiting poly(vinyl chloride) reactivity in the context of chemical recycling.

Poly(vinyl chloride) (PVC) is one of the highest production volume polymers due to its many applications, and it is one of the least recycled due to its chemical structure and frequent formulation with additives. Developing efficient PVC recycling techniques would enable PVC waste to be reused or repurposed in other processes. Within this context, the literature on PVC modification offers considerable insight into versatile reaction pathways, potentially inspiring new approaches for repurposing PVC waste into value-added products. This perspective provides an overview of PVC functionalization through a lens of chemical recycling, discussing various PVC reactivity trends and their applications with a critical assessment and future outlook of their recycling implications.

Electrographic monitoring for seizure detection in the neonatal unit: current status and future direction.

Neonatal neurocritical intensive care is dedicated to safeguarding the newborn brain by prioritising clinical practices that promote early identification, diagnosis and treatment of brain injuries. The most common newborn neurological emergency is neonatal seizures, which may also be the initial clinical indication of neurological disease. A high seizure burden in the newborn period independently contributes to increased mortality and morbidity. The majority of seizures in newborns are subclinical (without clinical presentation), and hence identification may be difficult. Neuromonitoring techniques most frequently used to monitor brain wave activity include conventional electroencephalography (cEEG) or amplitude-integrated EEG (aEEG). cEEG with video is the gold standard for diagnosing and treating seizures. Many neonatal units do not have access to cEEG, and frequently those that do, have little access to real-time interpretation of monitoring. IMPACT: EEG monitoring is of no benefit to an infant without expert interpretation. Whilst EEG is a reliable cot-side tool and of diagnostic and prognostic use, both conventional EEG and amplitude-integrated EEG have strengths and limitations, including sensitivity to seizure activity and ease of interpretation. Automated seizure detection requires a sensitive and specific algorithm that can interpret EEG in real-time and identify seizures, including their intensity and duration.

Antibiotic route and outcomes for children hospitalized with pneumonia.

BACKGROUND: Emerging evidence suggests that initial oral and intravenous (IV) antibiotics have similar efficacy in pediatric community-acquired pneumonia (CAP), but further data are needed. OBJECTIVE: We determined the association between hospital-level initial oral antibiotic rates and outcomes in pediatric CAP. DESIGNS, SETTINGS AND PARTICIPANTS: This retrospective cohort study included children hospitalized with CAP at 43 hospitals in the Pediatric Health Information System (2016-2022). Hospitals were grouped by whether initial antibiotics were given orally in a high, moderate, or low proportion of patients. MAIN OUTCOME AND MEASURES: Regression models examined associations between high versus low oral-utilizing hospitals and length of stay (LOS, primary outcome), intensive care unit (ICU) transfers, escalated respiratory care, complicated CAP, cost, readmissions, and emergency department (ED) revisits. RESULTS: Initial oral antibiotics were used in 16% (interquartile range: 10%-20%) of 30,207 encounters, ranging from 1% to 68% across hospitals. Comparing high versus low oral-utilizing hospitals (oral rate: 32% [27%-47%] and 10% [9%-11%], respectively), there were no differences in LOS, intensive care unit, complicated CAP, cost, or ED revisits. Escalated respiratory care occurred in 1.3% and 0.5% of high and low oral-utilizing hospitals, respectively (relative ratio [RR]: 2.96 [1.12, 7.81]), and readmissions occurred in 1.5% and 0.8% (RR: 1.68 [1.31, 2.17]). Initial oral antibiotics varied across hospitals without a difference in LOS. While high oral-utilizing hospitals had higher escalated respiratory care and readmission rates, these were rare, the clinical significance of these small differences is uncertain, and there were no differences in other clinically relevant outcomes. This suggests some children may benefit from initial IV antibiotics, but most would probably do well with oral antibiotics.

Effectiveness of Omicron XBB.1.5 vaccine against infection with SARS-CoV-2 Omicron XBB and JN.1 variants, prospective cohort study, the Netherlands, October 2023 to January 2024.

We estimated vaccine effectiveness (VE) of SARS-CoV-2 Omicron XBB.1.5 vaccination against self-reported infection between 9 October 2023 and 9 January 2024 in 23,895 XBB.1.5 vaccine-eligible adults who had previously received at least one booster. VE was 41% (95% CI: 23-55) in 18-59-year-olds and 50% (95% CI: 44-56) in 60-85-year-olds. Sequencing data suggest lower protection against the BA.2.86 (including JN.1) variant from recent prior infection (OR = 2.8; 95% CI:1.2-6.5) and, not statistically significant, from XBB.1.5 vaccination (OR = 1.5; 95% CI:0.8-2.6).

IQGAP1 and NWASP promote human cancer cell dissemination and metastasis by regulating ß1-integrin via FAK and MRTF/SRF.

Attachment of circulating tumor cells to the endothelial cells (ECs) lining blood vessels is a critical step in cancer metastatic colonization, which leads to metastatic outgrowth. Breast and prostate cancers are common malignancies in women and men, respectively. Here, we observe that ß1-integrin is required for human prostate and breast cancer cell adhesion to ECs under shear-stress conditions in vitro and to lung blood vessel ECs in vivo. We identify IQGAP1 and neural Wiskott-Aldrich syndrome protein (NWASP) as regulators of ß1-integrin transcription and protein expression in prostate and breast cancer cells. IQGAP1 and NWASP depletion in cancer cells decreases adhesion to ECs in vitro and retention in the lung vasculature and metastatic lung nodule formation in vivo. Mechanistically, NWASP and IQGAP1 act downstream of Cdc42 to increase ß1-integrin expression both via extracellular signal-regulated kinase (ERK)/focal adhesion kinase signaling at the protein level and by myocardin-related transcription factor/serum response factor (SRF) transcriptionally. Our results identify IQGAP1 and NWASP as potential therapeutic targets to reduce early metastatic dissemination.