Citations

AbstractThe sliding filament theory explains skeletal muscle fibre force change as a function of length based on the overlap of actin and myosin filaments. Although this length‐tension (LT) relationship has been well investigated in animal models, it is not known whether this microscopic sarcomere LT property can be scaled up five orders of magnitude to explain the LT behaviour of a long human muscle such as the gracilis. The goal of this study is to validate the sarcomere LT curve in humans based on human filament length combined with in vivo experimental data. Intraoperative measurements of maximal tetanic force and muscle‐tendon unit length at four different joint configurations (JC) were obtained from 19 patients undergoing free functioning muscle transfer surgery. With physiologically measured fibre length and estimated sarcomere shortening resulting from tendon compliance, we show that 79.7% variance in isometric force data is explained by a simple human sarcomere LT model. This study demonstrates that the human whole muscle LT relationship can be modelled by the sliding filament theory given patient‐specific fibre length, filament length, tendon compliance and sarcomere shortening. imageKey points Whole human gracilis muscle isometric length‐tension relationships were measured in the operating room. Grouped whole muscle raw length‐tension curves showed no obvious form. The width of each experimental length‐tension curve was highly variable across subjects and used to predict fibre length (serial sarcomere number). After whole muscle length‐tension curves were normalized to each patient's serial sarcomere number, the whole human muscle length‐tension curve was well predicted by the sliding filament theory.

Abstract Rationale: MUC5B and MUC5AC are neighboring genes on chromosome 11p15 that encode the two predominant mucins secreted in the respiratory airways. Increased airway mucin concentrations and an imbalance between these two mucins drive COPD symptoms and the development of airflow obstruction or COPD, but the epigenomic regulation of this loci has not been characterized in the airways. Methods: We isolated DNA from bronchial airway brushings of 72 participants with >20 pack-years smoking history from the Subpopulations and Intermediate Outcomes Measures in COPD Study (SPIROMICS). 36 participants had GOLD-based moderate-to-severe COPD (FEV1/FVC<0.70, FEV1<80%) and 36 were without or with mild COPD. We used the Illumina Infinium Methylation EPIC BeadChip Array to assess proportion of DNA methylation (β) spanning 689,937 CpG sites. We evaluated proportional DNA methylation (β) at 96 CpG loci within a 103kB region using matrixQTL for cis-expression quantitative trait methylation (eQTM: 10kB flanks relative to MUC5AC/MUC5B) integrating bulk RNA-seq data and mQTL models integrating gene sequencing data to identify DNA variation associated with proportion eQTM methylation. Models included age, sex, BMI, clinical site, current smoking vs past smoking, total pack-years, three ancestral components of ancestry, chipset, and position. Results: We identified a top eQTM, cg00524486, marginally associated with MUC5B expression (coefficient estimate=8.75, punadjusted=0.0014, pFDR=0.065, Figure 1B). This eQTM was associated with CT scan parametric response mapping-based functional small airways disease (PRM-fSAD, beta coefficient[β]=3.64, p=0.011). We tested for DNA variation associated with methylation of this top eQTM which identified two methylation quantitative trait loci (mQTL: rs885454 [β=0.044, minor allele frequency[MAF]=0.09, pFDR=0.01], rs868902 [β=0.020, MAF=0.43, pFDR=0.08, Figure 1A) associated with cg00524486 methylation, of which the more frequent mQTL, rs868902, was marginally associated with PRM-fSAD (p=0.07) in the larger SPIROMICS cohort with MUC5B DNA sequencing data. Conclusions: This preliminary multi-omic study of the lower airway epithelium demonstrates that the expression of MUC5B is epigenetically regulated by neighboring CpG probe methylation (eQTM) represented by DNA variation (mQTL). These studies require further confirmation in a larger dataset of airway samples and support a role for epigenetic variation as a biologic contributor and biomarker of early COPD pathogenesis.

Abstract Rationale Hyperchloremia, characterized by elevated chloride levels (>110 mEq/L) in the blood, frequently occurs in critically ill patients following aggressive fluid resuscitation with chloride-rich solutions. It is associated with metabolic acidosis, leading to negative clinical outcomes such as higher morbidity and mortality. However, the impact of hyperchloremia on the duration of mechanical ventilation remains unclear. This study evaluates the correlation between hyperchloremia and the duration of mechanical ventilation in critically ill patients. Methods A retrospective analysis was conducted on intensive care unit patients admitted between 2018 and 2023 who required mechanical ventilation. Patients were categorized into hyperchloremic (serum chloride >110 mEq/L) and non-hyperchloremic groups. The hyperchloremic group was further subdivided into those with metabolic acidosis (pH <7.35) and those without acidosis (pH >7.35). The primary outcome measured was the duration of mechanical ventilation across these groups. Results The study included 7,333 patients, 408 in the hyperchloremic group and 6,926 in the non-hyperchloremic group. Patients with hyperchloremia experienced significantly longer ventilation durations, with an average of 5.9 days compared to 2.6 days in the non-hyperchloremic group (p < 0.01). Among the hyperchloremic subgroups, those with metabolic acidosis had a mean ventilation duration of 4.9 days compared to 6.2 days in those without acidosis (p = 0.7), suggesting no apparent significant influence of acid-base status on ventilation duration. Discussion The study found that hyperchloremia correlates with longer ventilation duration (4.9-6.2 days vs. 2.6 days), independent of pH. While metabolic acidosis might impair respiratory function and increase ventilatory needs, evidence is mixed. Hyperchloremic metabolic acidosis can alter respiratory regulation, causing issues like tachypnea, ventilator dyssynchrony, and the need for sedation, complicating weaning from ventilation. However, hyperchloremia does not always impair respiratory muscle function. The study is limited by its retrospective nature, making causal conclusions difficult. However, the study suggests that better electrolyte management may reduce ventilation duration and improve patient outcomes. Conclusion This study demonstrates a significant association between hyperchloremia and prolonged mechanical ventilation, independent of pH status. The findings suggest that hyperchloremia may either be a marker of severe illness or aggressive resuscitation and directly contribute to prolonged ventilatory support. These findings offer hope for improved patient outcomes, as they suggest that chloride management strategies, including chloride-sparing resuscitation, could potentially reduce mechanical ventilation duration in critically ill patients.

Abstract Rationale: We have previously shown reduced total IgG, IgG subclasses, and levels/function of pneumococcal-specific antibodies are associated with increased risk for exacerbations of COPD (ECOPD). The binding of IgG to its receptor, the Fc receptor for IgG (FcγR) on immune cells, has a critical role in determining antibody levels and function. In addition to our research demonstrating that IgG heavy chain gene (IGHG) variants are associated with ECOPD, single nucleotide variants (SNVs) in genes encoding FcγR (FCGR1-3, which encode receptor subtypes FcγRI, FcγRIIa/b/c, and FcγRIIIa/b) may also result in antibody deficiency and increased exacerbation risk. Due to technical challenges in accurately identifying SNVs in FCGR, this region has not been well-characterized. The limited data that exist are from people of European descent, and prior studies have not included African American participants. We therefore sought to investigate the hypothesis that distinct SNVs in genes encoding FcγR are associated with disease severity and history of exacerbations in African American people with COPD. Methods: We developed a novel pipeline to identify SNVs in the coding (CDS) regions of chromosome 1 using short-read whole genome sequence data. The pipeline was benchmarked using paired long-read samples from Genome in a Bottle. SNVs were called within CDS regions and analyzed in a meta-analysis of self-reported African American participants in SPIROMICS and COPDGene (n=3063). Genetic variants were tested for association with COPD severity (GOLD spirometry stage 1-2 vs 3-4) as well as COPD exacerbations, adjusting for age, sex and principal components controlling for population structure. Results: Eight SNVs were significantly associated with frequent ECOPD (≥2 in one year) in the meta-analysis of African American COPDGene and SPIROMICS participants (Table). Seven of these 8 SNVs were found in FCGR3; 4 in the activating FCGR3A subtype, and 3 in FCGR3B. Seven of 11 SNVs associated with COPD severity were in FCGR3 (4 in FCGR3A; 3 in FCGR3B). One SNV (rs371849) was associated with both frequent exacerbations (P=0.002) and COPD severity (P=0.044). Conclusions: We used a cutting-edge variant calling pipeline to identify multiple SNVs in FCGR, primarily involving FcγRIII receptor subtypes, associated with COPD severity and exacerbations in African American participants in SPIROMICS and COPDGene. FcγRIII variants are known to cause impaired antibody levels and function in people of European descent. The structural and functional importance of newly recognized variants in African American cohorts require further study, as they may represent immunogenetic risk factors for antibody deficiency and exacerbations.

Abstract Rationale: The D'Nerva Targeted Lung Denervation (TLD) System uses radiofrequency energy delivered bronchoscopically to the main bronchi to disrupt parasympathetic nerve innervation to the lung. AIRFLOW-3 clinical trial was a randomized, double blind, sham controlled study to determine the impact of TLD on COPD exacerbations. Methods: AIRFLOW-3 patients had symptomatic COPD (CAT ≥10) with moderate to very severe airflow obstruction (GOLD stage II-IV: 25% ≤ FEV1 ≤ 80% predicted, FEV1/FVC<0.70) and GOLD E status (≥2 moderate or ≥1 severe exacerbation in the prior 12 months) despite optimal medical therapy. The primary endpoint was a time-to-first event comparison of the probability of subjects having a moderate or severe exacerbation, between the Treatment arm (TLD + optimal medical therapy) and the Sham Control arm (optimal medical therapy). Results: 388 patients were randomized 1:1 at 32 clinical sites across the US, EU, and UK. Patients were 67.8 (SD 7.1) years of age, ex-smokers with a 46.7 (22.0) pack-year smoking history, and 41.0 (11.8) post bronchodilator FEV1% pred. SGRQ-C and CAT scores were 62.5 (17.0) and 23.6 (6.3), respectively. Over 90% of patients were on triple therapy (LAMA+LABA+ICS) at baseline and through 1 year of follow up. 42% of patients had prior-year COPD hospitalization(s). There was no difference between groups in the analysis of the primary endpoint. At 1 year, the sham arm exhibited a statistical decline in lung function (decrease in FEV1 and FVC) and worsening of gas trapping (increase in RV). Lung function and gas trapping were stable in the treatment arm. The treatment arm exhibited a statistically significant improvement in dyspnea at one year compared to sham (mMRC, and TDI). These observations led to the identification of a subgroup of TLD treatment responders corresponding to an airway predominant phenotype (lung hyperinflation in the absence of significant emphysema) that demonstrated clinically and statistically significant improvements in lung function and exacerbation frequency and severity (Table). Conclusions: The AIRFLOW-3 clinical trial failed to meet its prespecified primary endpoint. Post-hoc analysis of this robust dataset led to the identification of a responder profile that achieved significant and sustained improvements in lung function, and exacerbation reduction. A future clinical study is being designed to confirm these findings.

Abstract RATIONALE: The diagnosis of Pulmonary Embolism (PE) is associated with high mortality and morbidity. In patients with cancer, high-risk pulmonary emboli further escalate these risks. Ensuring access to the necessary resources for appropriate intervention is crucial for improving patient outcomes. However, the resource-intensive nature of managing multiple life-threatening conditions can create barriers for certain demographic populations, leading to disparities in outcomes. To address this issue, we explored mortality trends among diverse groups based on gender, ethnicity, and geographical background in the United States from 1999-2000. METHODS: We obtained mortality data from death certificate queries in the Centers for Disease Control and Prevention Wide-range Online Data for Epidemiologic Research database. Queries included all decedents with the underlying cause of death being PE (I26) in patients with a diagnosis of cancer (C00 – C97). Age-adjusted mortality rates (AAMR) per 100,000 people were compared across demographic populations, and 95% Confidence Intervals were standardized to the year 2000. Log-linear regression models were utilized to assess temporal mortality shifts and calculate annual percentage change (APC) from 1999 to 2020. RESULTS: A total of 179483 PE-related deaths was reported in patients with cancer. The AAMR increased from 2.14 [2.08-2.19] in 1999 to 3.05 [3.00-3.11] in 2020. The cumulative AAMR was 2.42 [2.41-2.43] with an average APC of +1.56% (p<0.001). The mortality rate accelerated following the year 2016, with the years prior having an APC of +0.69%, (p<0.001) and the years following having an APC +5.33% (p<0.001). A higher mortality was observed in males (AAMR 2.71 [2.69-2.73]) than females (2.20 [2.18-2.21]), in rural communities (AAMR 2.50 [2.47-2.53]) compared to urban communities (AAMR 2.38 [2.37-2.40]), and in non-Hispanic (AAMR 2.48 [2.47-2.49]) populations over Hispanic populations (AAMR 1.45 [1.42-1.48]). Mortality was highest in the Black population (AAMR 3.65 [3.60-3.69]), followed by White population (AAMR 2.33 [2.32-2.34]), American Natives (AAMR 1.43 [1.33-1.54]), and Asian (AAMR 1.04 [1.00-1.08]). Geographically, Midwest (AAMR 2.58 [2.56-2.61]) had the highest mortality while the South (AAMR 2.26 [2.24-2.28]) had the lowest mortality. CONCLUSIONS: We identified significant disparities in mortality related to pulmonary embolism (PE) among cancer patients across different demographic populations. Further investigation into these healthcare inequities is essential for addressing the disparities affecting various groups.

The NCCN Guidelines for Multiple Myeloma (MM) provide recommendations for diagnosis, initial workup, treatment, follow-up, and supportive care for patients with MM. These NCCN Guidelines Insights highlight the important updates and changes specific to systemic therapy for patients with newly diagnosed as well as previously treated MM included in Version 1.2025 of the NCCN Guidelines for MM.

Gastric cancer is the fifth leading cause of cancer-related deaths worldwide. Over 95% of gastric cancers are adenocarcinomas, which are typically classified based on anatomic location and histologic type. Gastric cancer generally carries a poor prognosis because it is often diagnosed at an advanced stage. Systemic therapy can provide palliation, improve survival, and enhance the quality of life in patients with locally advanced or metastatic disease. The implementation of biomarker testing has had a significant impact on clinical practice and patient care. Targeted therapies have demonstrated encouraging results in clinical trials for the treatment of patients with locally advanced or metastatic disease. This selection from the NCCN Clinical Practice Guidelines in Oncology for Gastric Cancer highlights recommendations for biomarker testing and discusses updates for the treatment of advanced disease, including peritoneal carcinoma as only disease and unresectable locally advanced, recurrent, or metastatic disease.