Semi-supervised auto-segmentation method for pelvic organ-at-risk in magnetic resonance images based on deep-learning.

BACKGROUND AND PURPOSE: In radiotherapy, magnetic resonance (MR) imaging has higher contrast for soft tissues compared to computed tomography (CT) scanning and does not emit radiation. However, manual annotation of the deep learning-based automatic organ-at-risk (OAR) delineation algorithms is expensive, making the collection of large-high-quality annotated datasets a challenge. Therefore, we proposed the low-cost semi-supervised OAR segmentation method using small pelvic MR image annotations. METHODS: We trained a deep learning-based segmentation model using 116 sets of MR images from 116 patients. The bladder, femoral heads, rectum, and small intestine were selected as OAR regions. To generate the training set, we utilized a semi-supervised method and ensemble learning techniques. Additionally, we employed a post-processing algorithm to correct the self-annotation data. Both 2D and 3D auto-segmentation networks were evaluated for their performance. Furthermore, we evaluated the performance of semi-supervised method for 50 labeled data and only 10 labeled data. RESULTS: The Dice similarity coefficient (DSC) of the bladder, femoral heads, rectum and small intestine between segmentation results and reference masks is 0.954, 0.984, 0.908, 0.852 only using self-annotation and post-processing methods of 2D segmentation model. The DSC of corresponding OARs is 0.871, 0.975, 0.975, 0.783, 0.724 using 3D segmentation network, 0.896, 0.984, 0.890, 0.828 using 2D segmentation network and common supervised method. CONCLUSION: The outcomes of our study demonstrate that it is possible to train a multi-OAR segmentation model using small annotation samples and additional unlabeled data. To effectively annotate the dataset, ensemble learning and post-processing methods were employed. Additionally, when dealing with anisotropy and limited sample sizes, the 2D model outperformed the 3D model in terms of performance.

A score for predicting invasive pulmonary aspergillosis in immunocompetent critically ill patients.

BACKGROUND: Delayed treatment leads to increased mortality in critically ill patients with invasive pulmonary aspergillosis (IPA). We aimed to develop and validate a prediction score based on novel biomarkers and clinical risk factors to identify IPA in immunocompetent patients in the intensive care unit (ICU). METHODS: A retrospective study was conducted to collect medical information and novel biomarkers upon ICU admission. Risk factors adopted for the final prediction score were identified using multivariate logistic regression analysis. RESULTS: We retrospectively collected 1841 critical ill patients between January 2018 and August 2022. Patients with IPA had higher C-reactive protein-to-albumin ratio (CAR), neutrophil-to-lymphocyte ratio, systemic immune-inflammation index and lower prognostic nutritional index (PNI). Chronic obstructive pulmonary disease (COPD), continuous renal replacement therapy (CRRT), high dose of corticosteroids, broad-spectrum antibiotics, blood galactomannan (GM) positivity and high CAR were independent risk factors for IPA and were entered into the final prediction score. The score had good discrimination, with the area under receiver operating characteristic curve of 0.816 and 0.780 for the training and validation cohorts, respectively, and good calibration. CONCLUSION: A score based on six clinical and novel immunological biomarkers showed promising predictive value for antifungal treatment in immunocompetent ICU patients.

Associations Between Reproductive Factors and the Risk of Adult-Onset Asthma: A Prospective Cohort Study of European Ancestry.

BACKGROUND: Multiple studies showed sex discrepancies in the prevalence, incidence, and disease control of asthma. The relationships between different reproductive factors and the risk of asthma in females remain uncertain. DESIGN: A prospective cohort study recruited 239,701 female participants from the UK Biobank. The Cox proportional hazard model and multiple adjusted restricted cubic splines were used to evaluate the association between each reproductive factor and the risk of adult-onset asthma. KEY RESULTS: We observed that the association of age at menarche and age of menopause with adult-onset asthma risk presented as U-shaped, with multiple adjusted HRs for age at menarche being 1.129 (95% CI, 1.038-1.228) for ≤ 11 years old and 1.157 (95% CI, 1.058-1.265) for ≥ 15 years old referenced to 13 years old, and for age at menopause being 1.368 (1.237-1.512) for ≤ 46 years old and 1.152 (1.026-1.294) for ≥ 55 years old referenced to 50-52 years old. Early age at first live birth (≤ 20 years old), a greater number of miscarriages (≥ 2) or stillbirths (≥ 2), more children (≥ 4), and shorter reproductive years (≤ 32 years) were associated with elevated risk of asthma. In addition, history of hysterectomy or oophorectomy was associated with increased risk of adult-onset asthma, particularly in those with simultaneous hysterectomy and oophorectomy (HR, 1.239; 95% CI, 1.063-1.445). For exogenous sex hormones, hormone replacement therapy (HR, 1.482; 95% CI, 1.394-1.574) was identified to be associated with elevated risk of adult-onset asthma. CONCLUSIONS: This study not only demonstrated significant associations between multiple reproductive factors and the risk of adult-onset asthma in a female's later life, but also found that history of hysterectomy or oophorectomy, as well as hormone replacement therapy, was linked to an elevated incidence of adult-onset asthma. Our findings highlighted the significance of reproductive factors in the development of asthma in female populations.

A prediction model for acute respiratory distress syndrome in immunocompetent adults with adenovirus-associated Pneumonia: a multicenter retrospective analysis.

BACKGROUND: In recent years, the number of human adenovirus (HAdV)-related pneumonia cases has increased in immunocompetent adults. Acute respiratory distress syndrome (ARDS) in these patients is the predominant cause of HADV-associated fatality rates. This study aimed to identify early risk factors to predict early HAdV-related ARDS. METHODS: Data from immunocompetent adults with HAdV pneumonia between June 2018 and May 2022 in ten tertiary general hospitals in central China was analyzed retrospectively. Patients were categorized into the ARDS group based on the Berlin definition. The prediction model of HAdV-related ARDS was developed using multivariate stepwise logistic regression and visualized using a nomogram. RESULTS: Of 102 patients with adenovirus pneumonia, 41 (40.2%) developed ARDS. Overall, most patients were male (94.1%), the median age was 38.0 years. Multivariate logistic regression showed that dyspnea, SOFA (Sequential Organ Failure Assessment) score, lactate dehydrogenase (LDH) and mechanical ventilation status were independent risk factors for this development, which has a high mortality rate (41.5%). Incorporating these factors, we established a nomogram with good concordance statistics of 0.904 (95% CI 0.844-0.963) which may help to predict early HAdV-related ARDS. CONCLUSION: A nomogram with good accuracy in the early prediction of ARDS in patients with HAdV-associated pneumonia may could contribute to the early management and effective treatment of severe HAdV infection.

Association of air pollution, genetic risk, and lifestyle with incident adult-onset asthma: A prospective cohort study.

BACKGROUND: Numerous studies have explored the association of air pollution with asthma but have yielded conflicting results. The exact role of air pollution in the incidence of adult-onset asthma and whether this effect is modified by genetic risk, lifestyle, or their interaction remain uncertain. METHODS: We conducted a prospective cohort study on 298,738 participants (aged 37-73 years) registered in the UK Biobank. Cox proportional hazard models were used to evaluate the association of air pollution, including particulate matter (PM2.5, PMcoarse, and PM10), nitrogen dioxide (NO2), and nitrogen oxides (NOx), with asthma incidence. We constructed genetic risk and lifestyle scores, assessed whether the impact of air pollution on adult-onset asthma risk was modified by genetic susceptibility or lifestyle factors, and evaluated the identified interactions. RESULTS: We found that each interquartile range increase in annual concentrations of PM2.5, NO2, and NOx was related to 1.04 (95% confidence interval [CI]: 1.01, 1.08), 1.04 (95% CI: 1.00, 1.08), and 1.03 (95% CI: 1.00, 1.06) times the risk of adult-onset asthma, respectively. The size of the effect of air pollution was greater among subpopulations with low genetic risk or unfavorable lifestyles. We also identified an additive interaction effect of air pollution with lifestyle factors, but not with genetic risk, on the risk of adult-onset asthma. CONCLUSION: Our analyses show that air pollution increases the risk of adult-onset asthma, but that the size of the effect is modified by lifestyle and genetic risk. These findings emphasize the need for integrated interventions for environmental pollution by the government as well as adherence to healthy lifestyles to prevent adult-onset asthma.

Delayed neutrophil apoptosis may enhance NET formation in ARDS.

BACKGROUND: Acute respiratory distress syndrome (ARDS) is a neutrophil-associated disease. Delayed neutrophil apoptosis and increased levels of neutrophil extracellular traps (NETs) have been described in ARDS. We aimed to investigate the relationship between these phenomena and their potential as inflammation drivers. We hypothesized that delayed neutrophil apoptosis might enhance NET formation in ARDS. METHOD: Our research was carried out in three aspects: clinical research, animal experiments, and in vitro experiments. First, we compared the difference between neutrophil apoptosis and NET levels in healthy controls and patients with ARDS and analyzed the correlation between neutrophil apoptosis and NET levels in ARDS. Then, we conducted animal experiments to verify the effect of neutrophil apoptosis on NET formation in Lipopolysaccharide-induced acute lung injury (LPS-ALI) mice. Furthermore, this study explored the relationship between neutrophil apoptosis and NETs at the cellular level. Apoptosis was assessed using morphological analysis, flow cytometry, and western blotting. NET formation was determined using immunofluorescence, PicoGreen assay, SYTOX Green staining, and western blotting. RESULTS: ARDS neutrophils lived longer because of delayed apoptosis, and the cyclin-dependent kinase inhibitor, AT7519, reversed this phenomenon both in ARDS neutrophils and neutrophils in bronchoalveolar lavage fluid (BALF) of LPS-ALI mice. Neutrophils in a medium containing pro-survival factors (LPS or GM-CSF) form more NETs, which can also be reversed by AT7519. Tissue damage can be reduced by promoting neutrophil apoptosis. CONCLUSIONS: Neutrophils with extended lifespan in ARDS usually enhance NET formation, which aggravates inflammation. Enhancing neutrophil apoptosis in ARDS can reduce the formation of NETs, inhibit inflammation, and consequently alleviate ARDS.

NETs promote ALI/ARDS inflammation by regulating alveolar macrophage polarization.

Neutrophils activated during acute lung injury (ALI) form neutrophil extracellular traps (NETs) to capture pathogens. However, excessive NETs can cause severe inflammatory reactions. Macrophages are classified as M1 macrophages with proinflammatory effects or M2 macrophages with anti-inflammatory effects. During ALI, alveolar macrophages (AMs) polarize to the M1 phenotype. This study tested the hypothesis that NETs may aggravate ALI or acute respiratory distress syndrome (ARDS) inflammation by promoting alveolar macrophage polarization to the M1 type. Our research was carried out in three aspects: clinical research, animal experiments and in vitro experiments. We determined that NET levels in ARDS patients were positively correlated with M1-like macrophage polarization. NET formation was detected in murine ALI tissue and associated with increased M1 markers and decreased M2 markers in BALF and lung tissue. Treatment with NET inhibitors significantly inhibitor NETs generation, downregulated M1 markers and upregulated M2 markers. Regardless of LPS pre-stimulation, significant secretion of proinflammatory cytokines and upregulated M1 markers were detected from bone marrow-derived macrophages (M0 and M2) cocultured with high concentrations of NETs; conversely, M2 markers were downregulated. In conclusion, NETs promote ARDS inflammation during the acute phase by promoting macrophage polarization to the M1 phenotype. We propose that NETs play an important role in the interaction between neutrophils and macrophages during the early acute phase of ALI.

PKR suppress NLRP3-pyroptosis pathway in lipopolysaccharide-induced acute lung injury model of mice.

To explore the effect of double-stranded RNA-dependent kinase (PKR) in acute lung injury (ALI) and resultant acute respiratory distress syndrome (ARDS). A mouse model of lipopolysaccharide (LPS)-induced ALI was used to evaluate the levels of phosphorylated (p)-PKR and NLRP3 in lung tissue, and the protective effects of a PKR inhibitor on lung injury. And in vitro, macrophages were incubated with LPS, with or without PKR inhibitor pre-treatment. It was observed that the levels of p-PKR protein and NLRP3 protein were significantly increased compared with those in control tissues after LPS administration. Meanwhile, treatment with PKR inhibitor decreased inflammation, injury score, wet/dry weight ratio, bronchoalveolar lavage fluid (BALF) protein levels, neutrophil count in BALF, myeloperoxidase activity and expression of high-mobility group box1(HMGB1) and interleukin(IL)-1ß in the lungs of LPS-challenged mice. In vitro, we demonstrated that the levels of p-PKR and NLRP3, and cell mortality rate were increased in macrophages which were incubated with LPS compared with those without LPS administration, and PKR inhibitor significantly suppressed the level of NLRP3, caspase-1, HMGB1 and IL-1ß. These results indicate that PKR plays a key role in ALI through NLRP3-pyrotosis pathway and pharmacological inhibition of PKR may have potential therapeutic effects in the treatment of patients with ALI and ARDS.

New 8-Hydroxybriaranes from the Gorgonian Coral Junceella fragilis (Ellisellidae).

Three new 8-hydroxybriaranes-fragilides R-T (1-3) were obtained from a sea whip gorgonian coral Junceella fragilis. The structures of briaranes 1-3 were elucidated by using spectroscopic methods, including 1D (1H and 13C NMR), 2D (COSY, HSQC, HMBC, and NOESY experiments) NMR studies, and (+)-HRESIMS. Fragilides S and T (2 and 3) are the only briaranes known to possess 8α-hydroxy and 17ß-methyl groups, respectively. Briarane 2 exerted an inhibition effect on iNOS release from RAW264.7; a macrophage cell line that originated from a mouse monocyte macrophage, stimulated with lipopolysaccharides.

New 1,4-Dienonesteroids from the Octocoral Dendronephthya sp.

Two new steroids, dendronesterones D (1) and E (2), featuring with 1,4-dienone moiety, along with three known steroids, methyl 3-oxochola-4,22-diene-24-oate (3), 5α,8α-epidioxy-24(S)- methylcholesta-6,22-dien-3ß-ol (4), and 5α,8α-epidioxy-24(S)-methylcholesta-6,9(11),22-trien-3ß-ol (5), were isolated from an octocoral Dendronephthya sp. The structures of steroids 1 and 2 were elucidated by using spectroscopic methods and steroid 1 was found to exhibit significant in vitro anti-inflammatory activity in lipopolysaccharides (LPS)-induced RAW264.7 macrophage cells by inhibiting the expression of the iNOS protein.

Identification of an anti-lipopolysacchride factor possessing both antiviral and antibacterial activity from the red claw crayfish Cherax quadricarinatus.

It is well-known that anti-lipopolysacchride factors (ALFs) are involved in the recognition and elimination of invading pathogens. In this study, the full-length ALF cDNA sequence of the red claw crayfish Cherax quadricarinatus (termed CqALF) was cloned from a suppression subtractive hybridization library constructed using red claw crayfish hematopoietic tissue cell (Hpt cell) cultures following challenge with white spot syndrome virus (WSSV). The full-length cDNA sequence of CqALF was 863 bp, and the open reading frame encoded 123 amino acids with a signal peptide in the N-terminus and a conserved LPS-binding domain. Unlike most ALFs, which are highly expressed in haemocytes, high expression levels of CqALF were detected in epithelium, the stomach and eyestalks, while lower expression was detected in Hpt, nerves, the heart, muscle tissue, gonads, haemocytes, intestines, gills and the hepatopancreas. To further explore the biological activities of CqALF, mature recombinant CqALF protein (rCqALF) was expressed and purified using a eukaryotic expression system, and an antimicrobial activity test was carried out. rCqALF clearly exerted antiviral activity, as evidenced by the severe disruption of the envelope of intact WSSV virions following co-incubation of virions with rCqALF. Additionally, pre-incubation of WSSV with rCqALF resulted in both a significant reduction in WSSV replication in red claw crayfish Hpt cell cultures and an increased survival rate among animals. Furthermore, rCqALF was effective against both Gram-negative bacteria and Gram-positive bacteria, particularly Shigella flexneri and Staphylococcus aureus. A membrane integrity assay suggested that rCqALF was unlikely to disrupt bacterial membrane integrity compared to cecropin P1. Taken together, these data suggest that CqALF may play an important role in immune defence in the crustacean C. quadricarinatus.

Synthetic CT generation for pelvic cases based on deep learning in multi-center datasets.

BACKGROUND AND PURPOSE: To investigate the feasibility of synthesizing computed tomography (CT) images from magnetic resonance (MR) images in multi-center datasets using generative adversarial networks (GANs) for rectal cancer MR-only radiotherapy. MATERIALS AND METHODS: Conventional T2-weighted MR and CT images were acquired from 90 rectal cancer patients at Peking University People's Hospital and 19 patients in public datasets. This study proposed a new model combining contrastive learning loss and consistency regularization loss to enhance the generalization of model for multi-center pelvic MRI-to-CT synthesis. The CT-to-sCT image similarity was evaluated by computing the mean absolute error (MAE), peak signal-to-noise ratio (SNRpeak), structural similarity index (SSIM) and Generalization Performance (GP). The dosimetric accuracy of synthetic CT was verified against CT-based dose distributions for the photon plan. Relative dose differences in the planning target volume and organs at risk were computed. RESULTS: Our model presented excellent generalization with a GP of 0.911 on unseen datasets and outperformed the plain CycleGAN, where MAE decreased from 47.129 to 42.344, SNRpeak improved from 25.167 to 26.979, SSIM increased from 0.978 to 0.992. The dosimetric analysis demonstrated that most of the relative differences in dose and volume histogram (DVH) indicators between synthetic CT and real CT were less than 1%. CONCLUSION: The proposed model can generate accurate synthetic CT in multi-center datasets from T2w-MR images. Most dosimetric differences were within clinically acceptable criteria for photon radiotherapy, demonstrating the feasibility of an MRI-only workflow for patients with rectal cancer.

Ambient air pollution, lifestyle, and genetic predisposition on all-cause and cause-specific mortality: A prospective cohort study.

BACKGROUND: Although it is widely acknowledged that long-term exposure to ambient air pollution is closely related to the risk of mortality, there were inconsistencies in terms of cause-specific mortality and it is still unknown whether lifestyle and genetic susceptibility could modify the association. METHODS: This population-based prospective cohort study involved 461,112 participants from the UK Biobank. The land-use regression model was used to estimate the concentrations of particulate matter (PM2.5, PMcoarse, PM10), and nitrogen oxides (NO2 and NOx). The association between air pollution and mortality was evaluated using Cox proportional hazard models. Furthermore, a lifestyle score incorporated with smoking status, physical activity, alcohol consumption, and diet behaviors, and polygenic risk score using 12 genetic variants, were developed to assess the modifying effect of air pollution on mortality outcomes. RESULTS: During a median follow-up of 14.0 years, 33,903 deaths were recorded, including 17,083 (2835; 14,248), 6970, 2429, and 1287 deaths due to cancer (lung cancer, non-lung cancer), cardiovascular disease (CVD), respiratory and digestive disease, respectively. Each interquartile range (IQR) increase in PM2.5, NO2 and NOx was associated with 7 %, 6 % and 5 % higher risk of all-cause mortality, respectively. Specifically, for cause-specific mortality, each IQR increase in PM2.5, NO2 and NOx was also linked to mortality due to cancer (lung cancer and non-lung cancer), CVD, respiratory and digestive disease. Furthermore, additive and multiplicative interactions were identified between high ambient air pollution and unhealthy lifestyle on mortality. In addition, associations between air pollution and mortality were modified by lifestyle behaviors. CONCLUSION: Long-term exposure to air pollutants increased the risk of all-cause and cause-specific mortality, which was modified by lifestyle behaviors. In addition, we also revealed a synergistically detrimental effect between air pollution and an unhealthy lifestyle, suggesting the significance of joint air pollution management and adherence to a healthy lifestyle on public health.

Gut Microbiome-Based Therapeutics in Critically Ill Adult Patients-A Narrative Review.

The gut microbiota plays a crucial role in the human microenvironment. Dysbiosis of the gut microbiota is a common pathophysiological phenomenon in critically ill patients. Therefore, utilizing intestinal microbiota to prevent complications and improve the prognosis of critically ill patients is a possible therapeutic direction. The gut microbiome-based therapeutics approach focuses on improving intestinal microbiota homeostasis by modulating its diversity, or treating critical illness by altering the metabolites of intestinal microbiota. There is growing evidence that fecal microbiota transplantation (FMT), selective digestive decontamination (SDD), and microbiota-derived therapies are all effective treatments for critical illness. However, different treatments are appropriate for different conditions, and more evidence is needed to support the selection of optimal gut microbiota-related treatments for different diseases. This narrative review summarizes the curative effects and limitations of microbiome-based therapeutics in different critically ill adult patients, aiming to provide possible directions for gut microbiome-based therapeutics for critically ill patients such as ventilator-associated pneumonia, sepsis, acute respiratory distress syndrome, and COVID-19, etc.

Serum Krebs von den Lungen-6 is associated with in-Hospital mortality of patients with severe Community-Acquired Pneumonia: A retrospective cohort study.

BACKGROUND: Currently, no ideal biomarker can accurately stratify the risk of patients with severe community-acquired pneumonia (SCAP). This study aimed to evaluate the role of serum Krebs von den Lungen-6 (sKL-6) in predicting in-hospital mortality in adults with SCAP. METHODS: In this retrospective cohort study, 249 severe pneumonia adult patients were recruited between 6 May 2021 to 30 April 2023 in Xiangya Hospital of Central South University. The sKL-6 level within 48 h of admission was measured, and the primary outcome assessed was in-hospital mortality. Multivariable logistic regression analysis was performed to calculate adjusted odds ratios (OR) with 95% confidence intervals (CI). Survival curves were plotted and subgroup analyses were conducted, stratified by relevant covariates. RESULTS: A total of 249 patients were included in the study,with 124 patients having normal sKL-6 levels, and 125 patients having abnormal sKL-6 levels. The overall in-hospital mortality rate was 28.9% (72 out of 249 patients). Univariate and multivariate logistic regression analysis revealed that the patients with abnormal sKL-6 levels had a higher risk of in-hospital mortality compared to those with normal sKL-6 levels, both in the total SCAP patient population (OR: 5.38, 95%CI: 2.41-12.01, P < 0.001) and the non-COVID-19 SCAP patients subgroup (OR: 8.12, 95%CI: 3.16-20.84, P < 0.001). Subgroup and interaction analyses confirmed the stability of the relationship between sKL-6 levels and in-hospital mortality(P for interaction > 0.05). Kaplan-Meier survival curves showed that patients with abnormal sKL-6 levels had a higher in-hospital mortality rate than those with normal sKL-6 levels (P < 0.05). However, the results of restricted cubic spline plots(RCS) analysis demonstrated a nonlinear association between sKL-6 levels (as a continuous variable) and in-hospital mortality in patients with SCAP. Similar results were observed in non-COVID-19 SCAP patients. Furthermore, the receiver operating characteristic curve (ROC) analysis revealed that sKL-6 had superior predictive performance compared to existing biomarkers (e.g., APACHE-II, SOFA, BUN/Cr, PCT, and D-dimer) for in-hospital mortality in non-COVID-19 SCAP patients. CONCLUSION: sKL-6 is a practical and useful biomarker for predicting in-hospital mortality in patients with SCAP.

Comparison of clinical, laboratory and radiological characteristics between Chlamydia psittaci and adenovirus pneumonias: a multicenter retrospective study.

OBJECTIVES: Pneumonia caused by Chlamydia psittaci is a significant global public health issue. Symptom onset and laboratory characteristics may be confused with those of other respiratory viral infections, including adenovirus pneumonia. We aimed to determine differences in clinical presentations and establish a simple nomogram to differentiate C. psittaci and adenovirus pneumonias. METHODS: We conducted a multicenter retrospective study in 10 tertiary general hospitals to compare patients with either C. psittaci (n = 78) or adenovirus (n = 102) pneumonia. A multivariable logistic regression model was used to identify risk factors of C. psittaci pneumonia that were used to establish a nomogram. RESULTS: C. psittaci and adenovirus pneumonia showed certain similar clinical symptoms, including fever, dyspnea, and fatigue, but differed in other characteristics. The multivariate logistic regression showed that age, sex, nervous system symptoms, lymphocyte count, C-reactive protein level, and bilateral lung lesions were risk factors for C. psittaci pneumonia. After incorporating these six factors, the established nomogram achieved a good concordance value (0.949 [95% CI 0.917-0.982]) in differentiating the types of pneumonia, with well-fitting calibration curves. CONCLUSION: Despite having similar clinical features, the variables of age, sex, nervous system symptoms, lymphocytes, C-reactive protein levels, and bilateral lung lesions were combined into a clinically useful nomogram for the rapid and early differentiation of C. psittaci pneumonia from adenovirus pneumonia. This nomogram may help improve treatments and clinical outcomes.

Association of telomere length with risk of lung cancer: A large prospective cohort study from the UK Biobank.

OBJECTIVES: Leukocyte telomere length (LTL) is associated with a wide variety of diseases, including cancer. However, findings regarding the association between LTL and the risk for lung cancer have been inconclusive and inconsistent across previous observational studies. METHODS: This prospective cohort study included data from 425,146 participants 37-73 years of age housed in the UK Biobank. Quantitative polymerase chain reaction (qPCR) was used to measure LTL in baseline DNA samples. A multivariate Cox proportional hazards model was used to evaluate the relationship between LTL and the risk for lung cancer. RESULTS: An increase in LTL per interquartile range (IQR) was associated with a 9% increase in the risk for lung cancer (hazard ratio [HR] 1.09 [95% confidence interval (CI) 1.03-1.16]). Participants in the highest LTL quintile exhibited an approximately 25% elevated risk for developing lung cancer (HR 1.25 [95% CI 1.09-1.45]) compared with those in the lowest quintile. The relationship between per IQR increase in LTL and elevated risk for lung cancer was greater in the histological subtype of adenocarcinoma (HR 1.30 [95% CI 1.18-1.43]), female sex (HR 1.16 [95% CI 1.06-1.26]), non-smokers (HR 1.45 [95% CI 1.23-1.71]), and individuals with high genetic risk for lung cancer (HR 1.18 [95% CI 1.03-1.34]), respectively. Surprisingly, a per IQR increase in LTL was associated with increased risks for both lung adenocarcinoma (HR 1.56 [95% CI 1.24-1.96]) and squamous cell carcinoma (HR 2.01 [95% CI 1.13-3.56]) in never smokers. CONCLUSIONS: Longer LTL was associated with an elevated risk for lung cancer, particularly for adenocarcinoma and squamous cell carcinoma in never smokers. The results suggest the potential of telomeres as non-invasive biomarkers for the early screening of lung cancer, particularly in non-smokers, who are typically overlooked.

A scoring system based on novel biomarkers and clinical risk factors to predict invasive candidiasis in immunocompetent critically ill patients.

Background: Delayed diagnosis further increases the mortality of invasive candidiasis (IC) in intensive care unit (ICU) patients. This study aimed to develop and validate a score based on novel serological biomarkers and clinical risk factors for predicting IC in immunocompetent ICU patients. Methods: We retrospectively collected clinical data and novel serological markers on admission to ICU. Multivariate logistic regression was used to identify the risk factors associated with IC, which were adopted to establish a scoring system. Results: Patients with IC had a higher C-reactive protein-to-albumin ratio (CAR) and neutrophil-to-lymphocyte ratio (NLR) and lower prognostic nutritional index than those without IC. The NLR, CAR, sepsis, total parenteral nutrition, 1,3-ß-D-glucan (BDG)-positivity, and Sequential Organ Failure Assessment score were identified as independent risk factors for IC by multivariate logistic regression analysis and entered into the final scoring system. The area under receiver operating characteristic curve of the score were 0.883 and 0.892, respectively, in the development and validation cohort, higher than Candida score (0.883 vs.0.730, p < 0.001). Conclusion: We established a parsimonious score based on NLR, CAR, BDG-positivity, and clinical risk factors, which can accurately identify IC in ICU patients to give treatment on time and reduce mortality.

Associations Between Sex-Specific Reproductive Factors and Risk of New-Onset Lung Cancer Among Female Patients.

BACKGROUND: Several characteristics distinguish lung cancer in female patients from that in male patients, with adenocarcinoma being more prevalent in female patients and occurring more frequently in female patients who do not smoke. Uncertainty surrounds the relationship between female-specific reproductive factors and lung cancer risk. RESEARCH QUESTION: Are sex-specific reproductive factors associated with risk of lung cancer in different genetic risk groups and histologic types? STUDY DESIGN AND METHODS: A Cox proportional hazard model was used to evaluate the association between multiple reproductive factors and the risk of lung cancer developing in a prospective cohort study involving 273,190 female individuals from the UK Biobank. Subgroup analyses stratified by age, smoking status, BMI, genetic risk, and histologic subtype were conducted to emphasize the modification effects further. RESULTS: A total of 1,182 cases of lung cancer in female patients were recorded over a median follow-up period of 12.0 years in the cohort study. In multivariable-adjusted models, early menarche (age ≤ 11 years: hazard ratio [HR], 1.22; 95% CI, 1.03-1.46), early menopause (age ≤ 46 years: HR, 1.49; 95% CI, 1.19-1.86), a shorter reproductive span (≤ 32 years: HR, 1.42; 95% CI, 1.18-1.71; and 33-35 years: HR, 1.24; 95% CI, 1.00-1.53), and early age at first birth (age ≤ 20 years: HR, 1.63; 95% CI, 1.33-2.01) were associated with a higher risk of lung cancer. Stratified analysis revealed that several reproductive factors, including early age at menopause, shortened reproductive span, and early age at first birth, showed a substantially stronger relationship with an elevated risk of lung cancer, particularly of lung adenocarcinoma, in populations with high genetic risk and more detrimental behaviors. INTERPRETATION: Early age at menopause, a shortened reproductive life span, and early age at first birth were associated with higher risks of lung cancer, particularly of lung adenocarcinoma, in a subpopulation with higher genetic susceptibility and detrimental behaviors. The evidence provided by this study emphasizes the significance of screening for multiple reproductive factors to prevent lung cancer among female individuals.

The Application of Awake-Prone Positioning Among Non-intubated Patients With COVID-19-Related ARDS: A Narrative Review.

The coronavirus disease (COVID-19) pandemic has significantly increased the number of patients with acute respiratory distress syndrome (ARDS), necessitating respiratory support. This strain on intensive care unit (ICU) resources forces clinicians to limit the use of mechanical ventilation by seeking novel therapeutic strategies. Awake-prone positioning appears to be a safe and tolerable intervention for non-intubated patients with hypoxemic respiratory failure. Meanwhile, several observational studies and meta-analyses have reported the early use of prone positioning in awake patients with COVID-19-related ARDS (C-ARDS) for improving oxygenation levels and preventing ICU transfers. Indeed, some international guidelines have recommended the early application of awake-prone positioning in patients with hypoxemic respiratory failure attributable to C-ARDS. However, its effectiveness in reducing intubation rate, mortality, applied timing, and optimal duration is unclear. High-quality evidence of awake-prone positioning for hypoxemic patients with COVID-19 is still lacking. Therefore, this article provides an update on the current state of published literature about the physiological rationale, effect, timing, duration, and populations that might benefit from awake proning. Moreover, the risks and adverse effects of awake-prone positioning were also investigated. This work will guide future studies and aid clinicians in deciding on better treatment plans.