Cerebrospinal Creatine Kinase BB Isoenzyme: A Biomarker for Predicting Outcome After Cardiac Arrest.

BACKGROUND: Cerebrospinal fluid creatine kinase BB isoenzyme (CSF CK-BB) after cardiac arrest (CA) has been shown to have a high positive predictive value for poor neurological outcome, but it has not been evaluated in the setting of targeted temperature management (TTM) and modern CA care. We aimed to evaluate CSF CK-BB as a prognostic biomarker after CA. METHODS: We performed a retrospective cohort study of patients with CA admitted between 2010 and 2020 to a three-hospital health system who remained comatose and had CSF CK-BB assayed between 36 and 84 h after CA. We examined the proportion of patients at hospital discharge who achieved favorable or intermediate neurological outcome, defined as Cerebral Performance Category score of 1-3, compared with those with poor outcome (Cerebral Performance Category score 4-5) for various CSF CK-BB thresholds. We also evaluated additive value of bilateral absence of somatosensory evoked potentials (SSEPs). RESULTS: Among 214 eligible patients, the mean age was 54.7 ± 4.8 years, 72% of patients were male, 33% were nonwhite, 17% had shockable rhythm, 90% were out-of-hospital CA, and 83% received TTM. A total of 19 (9%) awakened. CSF CK-BB ≥ 230 U/L predicted a poor outcome at hospital discharge, with a specificity of 100% (95% confidence interval [CI] 82-100%) and sensitivity of 69% (95% CI 62-76%). When combined with bilaterally absent N20 response on SSEP, specificity remained 100% while sensitivity increased to 80% (95% CI 73-85%). Discordant CK-BB and SSEP findings were seen in 13 (9%) patients. CONCLUSIONS: Cerebrospinal fluid creatine kinase BB isoenzyme levels accurately predicted poor neurological outcome among CA survivors treated with TTM. The CSF CK-BB cutoff of 230 U/L optimizes sensitivity to 69% while maintaining a specificity of 100%. CSF CK-BB could be a useful addition to multimodal neurological prognostication after CA.

Correction: An un-forgotten classic: the nitro-Mannich reaction between nitrones and silyl nitronates catalysed by B(C6F5)3.

[This corrects the article DOI: 10.1039/D3SC05672D.].

Acute Appendicitis in the Setting of Infectious Mononucleosis: A Case Report.

Infectious mononucleosis (IM) is a viral illness caused by the Epstein-Barr virus that typically manifests with pharyngitis, lymphadenopathy, and fatigue. In rare cases, IM can cause acute appendicitis. We present the case of an 18-year-old female who arrived at the emergency department with worsening abdominal pain and an ongoing cough. Initial imaging showed a questionably dilated appendix, and a follow-up examination revealed cervical lymphadenopathy. She later returned to the ED with severe abdominal pain, clinical signs of acute appendicitis, and a positive monospot test, which led to an appendectomy. This case illustrates the need for complete history taking and thorough physical examination in patients with acute appendicitis, as their condition may be due to an atypical underlying cause.

Histopathologic Features of Mucosal Head and Neck Cancer Cachexia.

Objective: Determine the histopathologic features that correlate with head and neck cancer (HNC) cachexia. Methods: A single-institution, retrospective study was performed on adults with HPV-negative, mucosal squamous cell carcinoma of the aerodigestive tract undergoing resection and free flap reconstruction from 2014 to 2019. Patients with distant metastases were excluded. Demographics, comorbidities, preoperative nutrition, and surgical pathology reports were collected. Comparisons of histopathologic features and cachexia severity were made. Results: The study included 222 predominantly male (64.9%) patients aged 61.3 ± 11.8 years. Cachexia was identified in 57.2% patients, and 18.5% were severe (≥15% weight loss). No differences in demographics were identified between the groups. Compared to control, patients with severe cachexia had lower serum hemoglobin (p=0.048) and albumin (p < 0.001), larger tumor diameter (p < 0.001), greater depth of invasion (p < 0.001), and elevated proportions of pT4 disease (p < 0.001), pN2-N3 disease (p=0.001), lymphovascular invasion (p=0.009), and extranodal extension (p=0.014). Multivariate logistic regression identified tumor size (OR [95% CI] = 1.36 [1.08-1.73]), oral cavity tumor (OR [95% CI] = 0.30 [0.11-0.84]), and nodal burden (OR [95% CI] = 1.16 [0.98-1.38]) as significant histopathologic contributors of cancer cachexia. Conclusions: Larger, more invasive tumors with nodal metastases and aggressive histologic features are associated with greater cachexia severity in mucosal HNC.

Urine Epidermal Growth Factor and Kidney Function Decline in Middle-Aged Adults.

Rationale & Objective: The diagnosis and prognostication of chronic kidney disease (CKD) largely rely on glomerular measures that may not reflect tubular damage. We investigated the associations of urine kidney tubule biomarkers with estimated glomerular filtration rate (eGFR) change among middle-aged adults, when chronic diseases typically emerge. Study Design: An observational cohort study. Setting & Participants: A total of 1,145 participants of the Coronary Artery Risk Development in Young Adults (CARDIA) study without CKD, hypertension, or cardiovascular disease at the year 20 visit. Exposures: Seven different biomarkers of tubular health: urine epidermal growth factor (EGF), alpha-1-microglobulin (α1m), interleukin-18, kidney injury molecule-1, monocyte chemoattractant protein-1, uromodulin, and chitinase-3-like protein 1. Outcomes: Ten-year eGFR change and incident reduced eGFR (new onset of eGFR < 60 mL/min/1.73 m2). Analytical Approach: We examined associations of tubular health biomarkers with 10-year eGFR change and incident reduced eGFR with linear mixed models and interval-censored proportional hazards regression models, respectively. Both minimally and fully adjusted models were controlled for urine creatinine levels. Results: The mean age of participants was 44.8 ± 3.7 years, with 39% African American and 56% female. The average 10-year change in eGFR was -18.6 mL/min/1.73 m2 (95% CI, -19.4 to -17.8). In contrast to the other tubular biomarkers, which showed conflicting results, EGF demonstrated strong, consistent associations with both kidney outcomes. Each 1-standard deviation (SD) higher EGF was associated with a 2.37 mL/min/1.73 m2 (95% CI, 0.64-4.10) smaller 10-year decrease in eGFR and a 42% (95% CI, 4%-64%) lower risk of incident reduced eGFR in the fully adjusted model. Limitations: Observational design, measurements of eGFR were done only at 5-year intervals during follow-up. Conclusions: In middle-aged, community-dwelling adults without hypertension, cardiovascular disease or CKD, higher urine EGF concentrations are associated with slower eGFR decline, whereas other kidney tubule biomarkers lacked a consistent association with kidney function decline.

Current measures of chronic kidney disease (CKD) rely on markers of glomerular health and function. This approach inadequately captures the role of kidney tubule health, a known histopathological predictor of CKD development. We investigated associations of 7 biomarkers of kidney tubule health with 10-year estimated glomerular filtration rate (eGFR) change and incident reduced eGFR. Among 7 biomarkers, only epidermal growth factor showed persistent and inverse associations with both 10-year eGFR change and incident reduced eGFR. These findings suggest that epidermal growth factor has an association with kidney function changes and might play a protective role in kidney disease development.

Total Synthesis of a Peptide Diatom Sex Pheromone Bearing a Sulfated Aspartic Acid.

The peptide sex-inducing pheromone SIP+ (1) bearing an unusual sulfated aspartic acid residue induces sexual reproduction in diatom populations. Herein, we report the first total synthesis of SIP+ using both a sulfated building block approach and a solid-phase peptide synthesis (SPPS)-compatible late-stage sulfation strategy to assemble the natural product. The modular approaches provide concise routes to useful quantities of the natural product for future structure activity relationship studies examining the role of SIP+ in diatom biology.

Machine learning-based cluster analysis identifies four unique phenotypes of patients with degenerative cervical myelopathy with distinct clinical profiles and long-term functional and neurological outcomes.

BACKGROUND: Degenerative cervical myelopathy (DCM), the predominant cause of spinal cord dysfunction among adults, exhibits diverse interrelated symptoms and significant heterogeneity in clinical presentation. This study sought to use machine learning-based clustering algorithms to identify distinct patient clinical profiles and functional trajectories following surgical intervention. METHODS: In this study, we applied k-means and latent profile analysis (LPA) to identify patient phenotypes, using aggregated data from three major DCM trials. The combination of Nurick score, NDI (neck disability index), neck pain, as well as motor and sensory scores facilitated clustering. Goodness-of-fit indices were used to determine the optimal cluster number. ANOVA and post hoc Tukey's test assessed outcome differences, while multinomial logistic regression identified significant predictors of group membership. FINDINGS: A total of 1047 patients with DCM (mean [SD] age: 56.80 [11.39] years, 411 [39%] females) had complete one year outcome assessment post-surgery. Latent profile analysis identified four DCM phenotypes: "severe multimodal impairment" (n = 286), "minimal impairment" (n = 116), "motor-dominant" (n = 88) and "pain-dominant" (n = 557) groups. Each phenotype exhibited a unique symptom profile and distinct functional recovery trajectories. The "severe multimodal impairment group", comprising frail elderly patients, demonstrated the worst overall outcomes at one year (SF-36 PCS mean [SD]: 40.01 [9.75]; SF-36 MCS mean [SD], 46.08 [11.50]) but experienced substantial neurological recovery post-surgery (ΔmJOA mean [SD]: 3.83 [2.98]). Applying the k-means algorithm yielded a similar four-class solution. A higher frailty score and positive smoking status predicted membership in the "severe multimodal impairment" group (OR 1.47 [95% CI 1.07-2.02] and 1.58 [95% CI 1.25-1.99, respectively]), while undergoing anterior surgery and a longer symptom duration were associated with the "pain-dominant" group (OR 2.0 [95% CI 1.06-3.80] and 3.1 [95% CI 1.38-6.89], respectively). INTERPRETATION: Unsupervised learning on multiple clinical metrics predicted distinct patient phenotypes. Symptom clustering offers a valuable framework to identify DCM subpopulations, surpassing single patient reported outcome measures like the mJOA. FUNDING: No funding was received for the present work. The original studies were funded by AO Spine North America.

Associations between urinary rare Earth elements with renal function: Findings from a cross-sectional study in Guangxi, China.

BACKGROUND: With increased applications of rare earth elements (REEs) across various industries, evaluating the relationship between REEs exposure and potential health effects has become a public concern. In vivo experiments have established that REEs impact renal function. However, relevant epidemiological evidence on this relationship remains scarce. The objective of this study is to examine the impact of exposure to REEs on renal function. METHODS: In this cross-sectional study, 1052 participants were recruited from Guangxi, China. We measured urinary concentrations of 12 REEs using an inductively coupled plasma-mass spectrometer (ICP-MS). Multiple linear regression models were developed to explore the relationship between a single REEs exposure and the estimated glomerular filtration rate (eGFR), a marker of renal function. Weighted quantile sum (WQS) regression and Bayesian kernel machine regression (BKMR) were used to examine the combined effects of REE co-exposure on eGFR. RESULTS: In the multiple linear regression analysis, increasing the concentrations of lanthanum (La, ß: 8.22, 95% CI: 5.67-10.77), cerium (Ce, ß:6.61, 95% CI: 3.80-9.43), praseodymium (Pr, ß: 8.46, 95% CI: 5.85-11.07), neodymium (Nd, ß:8.75, 95% CI: 6.10-11.41), and dysprosium (Dy, ß:7.38, 95% CI: 4.85-9.91) significantly increased the eGFR. In the WQS regression model, the WQS index was significantly associated with eGFR (ß: 4.03, 95% CI: 2.46-5.60), with Pr having the strongest correlation with eGFR. Similar results were obtained in the BKMR model. Additionally, interactions between Pr and La, and Pr and Nd were observed. CONCLUSIONS: Co-exposure to REEs is positively associated with elevated eGFR. Pr is likely to have the most significant influence on increased eGFRs and this might be exacerbated when interacting with La and Nd. Mixed exposure to low doses of REEs had a protective effect on renal function, which can provide some evidence for the exposure threshold of REEs in the environment. TRIAL REGISTRATION: The study has been approved by the Guangxi Medical University Medical Ethics Committee (#20170206-1), and all participants provided written informed consent.

Measurement properties of the Inclusion Body Myositis Functional Rating Scale.

OBJECTIVES: To evaluate the validity, reliability, responsiveness and meaningful change threshold of the Inclusion Body Myositis (IBM) Functional Rating Scale (FRS). METHODS: Data from a large 20-month multicentre, randomised, double-blind, placebo-controlled trial in IBM were used. Convergent validity was tested using Spearman correlation with other health outcomes. Discriminant (known groups) validity was assessed using standardised effect sizes (SES). Internal consistency was tested using Cronbach's alpha. Intrarater reliability in stable patients and equivalence of face-to-face and telephone administration were tested using intraclass correlation coefficients (ICCs) and Bland-Altman plots. Responsiveness was assessed using standardised response mean (SRM). A receiver operator characteristic (ROC) curve anchor-based approach was used to determine clinically meaningful IBMFRS change. RESULTS: Among the 150 patients, mean (SD) IBMFRS total score was 27.4 (4.6). Convergent validity was supported by medium to large correlations (rs modulus: 0.42-0.79) and discriminant validity by moderate to large group differences (SES=0.51-1.59). Internal consistency was adequate (overall Cronbach's alpha: 0.79). Test-retest reliability (ICCs=0.84-0.87) and reliability of telephone versus face-to-face administration (ICCs=0.93-0.95) were excellent, with Bland-Altman plots showing good agreement. Responsiveness in the worsened group defined by various external constructs was large at both 12 (SRM=-0.76 to -1.49) and 20 months (SRM=-1.12 to -1.57). In ROC curve analysis, a drop in at least two IBMFRS total score points was shown to represent a meaningful decline. CONCLUSIONS: When administered by trained raters, the IBMFRS is a reliable, valid and responsive tool that can be used to evaluate the impact of IBM and its treatment on physical function, with a 2-point reduction representing meaningful decline. TRIAL REGISTRATION NUMBER: NCT02753530.

Understanding Limitations in Electrochemical Conversion to CO at Low CO2 Concentrations.

Low-temperature electrochemical CO2 reduction has demonstrated high selectivity for CO when devices are operated with pure CO2 streams. However, there is currently a dearth of knowledge for systems operating below 30% CO2, a regime interesting for coupling electrochemical devices with CO2 point sources. Here we examine the influence of ionomer chemistry and cell operating conditions on the CO selectivity at low CO2 concentrations. Utilizing advanced electrochemical diagnostics, values for cathode catalyst layer ionic resistance and electrocatalyst capacitance as a function of relative humidity (RH) were extracted and correlated with selectivity and catalyst utilization. Staying above 20% CO2 concentration with at least a 50% cathode RH resulted in >95% CO/H2 selectivity regardless of the ionomer chemistry. At 10% CO2, however, >95% CO/H2 selectivity was only obtained at 95% RH under scenarios where the resulting electrode morphology enabled high catalyst utilization.

Creating a digital approach for promoting physical activity in pediatric pulmonary hypertension: A framework for future interventions.

Children with pulmonary hypertension (PH) often demonstrate limited exercise capacity. Data support exercise as an effective nonpharmacologic intervention among adults with PH. However, data on exercise training in children and adolescents are limited, and characteristics of the optimal exercise program in pediatric PH have not been identified. Exercise programs may have multiple targets, including muscle deficits which are associated with exercise limitations in both adult and pediatric PH. Wearable accelerometer sensors measure physical activity volume and intensity in the naturalistic setting and can facilitate near continuous data transfer and bidirectional communication between patients and the study team when paired with informatics tools during exercise interventions. To address the knowledge gaps in exercise training in pediatric PH, we designed a prospective, single arm, nonrandomized pilot study to determine feasibility and preliminary estimates of efficacy of a 16-week home exercise intervention, targeting lower extremity muscle mass and enriched by wearable mobile health technology. The exercIse Training in pulmONary hypertEnsion (iTONE) trial includes (1) semistructured exercise prescriptions tailored to the participant's baseline level of activity and access to resources; (2) interval goal setting fostering self-efficacy; (3) real time monitoring of activity via wearable devices; (4) a digital platform enabling communication and feedback between participant and study team; (5) multiple avenues to assess participant safety. This pilot intervention will provide information on the digital infrastructure needed to conduct home-based exercise interventions in PH and will generate important preliminary data on the effect of exercise interventions in youth with chronic cardiorespiratory conditions to power larger studies in the future.

Epithelial cells maintain memory of prior infection with Streptococcus pneumoniae through di-methylation of histone H3.

Epithelial cells are the first point of contact for bacteria entering the respiratory tract. Streptococcus pneumoniae is an obligate human pathobiont of the nasal mucosa, carried asymptomatically but also the cause of severe pneumoniae. The role of the epithelium in maintaining homeostatic interactions or mounting an inflammatory response to invasive S. pneumoniae is currently poorly understood. However, studies have shown that chromatin modifications, at the histone level, induced by bacterial pathogens interfere with the host transcriptional program and promote infection. Here, we uncover a histone modification induced by S. pneumoniae infection maintained for at least 9 days upon clearance of bacteria with antibiotics. Di-methylation of histone H3 on lysine 4 (H3K4me2) is induced in an active manner by bacterial attachment to host cells. We show that infection establishes a unique epigenetic program affecting the transcriptional response of epithelial cells, rendering them more permissive upon secondary infection. Our results establish H3K4me2 as a unique modification induced by infection, distinct from H3K4me3 or me1, which localizes to enhancer regions genome-wide. Therefore, this study reveals evidence that bacterial infection leaves a memory in epithelial cells after bacterial clearance, in an epigenomic mark, thereby altering cellular responses to subsequent infections and promoting infection.

Indoor environmental quality in WELL-certified and LEED-certified buildings.

International building certification systems, such as the WELL and Leadership in Energy and Environmental Design (LEED) standards, play a pivotal role in the design of healthy and sustainable buildings. While LEED adopts a holistic approach to designing healthy and sustainable buildings, the WELL standard has a strong emphasis on human health, comfort, and well-being. Although prior research has revealed inconsistent results for occupant satisfaction in office buildings with WELL certification compared to buildings without WELL certification, or are certified using another certification system (e.g., LEED), most of these comparisons tend to lack methodological rigor. This study used a statistical procedure to match and compare 1634 occupant surveys from LEED-certified buildings to 1634 surveys from WELL-certified buildings. Six important architectural and experiential parameters were matched, masking their influence on the outcome. Overall building and workspace satisfaction was high in both WELL-certified buildings (94% and 87%) and LEED-certified (73% and 71%). We found that there is a 39% higher probability of finding occupants who are more satisfied in WELL-certified buildings compared to LEED-certified buildings, indicating occupant satisfaction is higher in buildings with WELL certification. Although we were unable to pinpoint the reason for higher occupant satisfaction in WELL-certified buildings, the results consistently showed that perceived indoor environmental quality was enhanced across all parameters except for the amount of space.

Cocoa and Polyphenol-Rich Cocoa Fractions Fail to Improve Acute Colonic Inflammation in Dextran Sulfate Sodium-Treated Mice.

SCOPE: A study is conducted to determine the anti-inflammatory effects of cocoa and polyphenol-rich cocoa fractions in the dextran sulfate sodium (DSS)-induced mouse model of acute colonic inflammation. METHODS AND RESULTS: Male C57BL/6J mice are treated with dietary cocoa powder, an extractable cocoa polyphenol fraction, or a non-extractable cocoa polyphenol fraction for 2 weeks prior to treatment with 2.5% DSS in the drinking water for 7 days to induce colonic inflammation. Cocoa treatment continues during the DSS period. Cocoa and/or cocoa fractions exacerbate DSS-induced weight loss and fail to mitigate DSS-induced colon shortening but do improve splenomegaly. Cocoa/cocoa fraction treatment fails to mitigate DSS-induced mRNA and protein markers of inflammation. Principal component analysis shows overlap between cocoa or cocoa fraction-treated mice and DSS-induced controls, but separation from mice not treated with DSS. CONCLUSION: The results suggest cocoa and cocoa polyphenols may not be useful in mitigating acute colonic inflammation.

A versatile functional interaction between electrically silent KV subunits and KV7 potassium channels.

Voltage-gated K+ (KV) channels govern K+ ion flux across cell membranes in response to changes in membrane potential. They are formed by the assembly of four subunits, typically from the same family. Electrically silent KV channels (KVS), however, are unable to conduct currents on their own. It has been assumed that these KVS must obligatorily assemble with subunits from the KV2 family into heterotetrameric channels, thereby giving rise to currents distinct from those of homomeric KV2 channels. Herein, we show that KVS subunits indeed also modulate the activity, biophysical properties and surface expression of recombinant KV7 isoforms in a subunit-specific manner. Employing co-immunoprecipitation, and proximity labelling, we unveil the spatial coexistence of KVS and KV7 within a single protein complex. Electrophysiological experiments further indicate functional interaction and probably heterotetramer formation. Finally, single-cell transcriptomic analyses identify native cell types in which this KVS and KV7 interaction may occur. Our findings demonstrate that KV cross-family interaction is much more versatile than previously thought-possibly serving nature to shape potassium conductance to the needs of individual cell types.

Characterization of ribosome stalling and no-go mRNA decay stimulated by the Fragile X protein, FMRP.

Loss of functional fragile X mental retardation protein (FMRP) causes fragile X syndrome (FXS) and is the leading monogenic cause of autism spectrum disorders and intellectual disability. FMRP is most notably a translational repressor and is thought to inhibit translation elongation by stalling ribosomes as FMRP-bound polyribosomes from brain tissue are resistant to puromycin and nuclease treatment. Here, we present data showing that the C-terminal non-canonical RNA-binding domain of FMRP is essential and sufficient to induce puromycin-resistant mRNA•ribosome complexes. Given that stalled ribosomes can stimulate ribosome collisions and no-go mRNA decay (NGD), we tested the ability of FMRP to drive NGD of its target transcripts in neuroblastoma cells. Indeed, FMRP and ribosomal proteins, but not poly(A)-binding protein, were enriched in isolated nuclease-resistant disomes compared to controls. Using siRNA knockdown and RNA-seq, we identified 16 putative FMRP-mediated NGD substrates, many of which encode proteins involved in neuronal development and function. Increased mRNA stability of 4 putative substrates was also observed when either FMRP was depleted or NGD was prevented via RNAi. Taken together, these data support that FMRP stalls ribosomes but only stimulates NGD of a small select set of transcripts, revealing a minor role of FMRP that would be misregulated in FXS.