Measuring functional connectivity in frequency-domain helps to better characterize brain function.

Resting-state functional connectivity (FC) is widely used in multivariate pattern analysis of functional magnetic resonance imaging (fMRI), including identifying the locations of putative brain functional borders, predicting individual phenotypes, and diagnosing clinical mental diseases. However, limited attention has been paid to the analysis of functional interactions from a frequency perspective. In this study, by contrasting coherence-based and correlation-based FC with two machine learning tasks, we observed that measuring FC in the frequency domain helped to identify finer functional subregions and achieve better pattern discrimination capability relative to the temporal correlation. This study has proven the feasibility of coherence in the analysis of fMRI, and the results indicate that modeling functional interactions in the frequency domain may provide richer information than that in the time domain, which may provide a new perspective on the analysis of functional neuroimaging.

Validation Study of the Newly Proposed Refined Diagnostic Criteria for Malignant Phyllodes Tumor With 136 Borderline and Malignant Phyllodes Tumor Cases.

The World Health Organization (WHO) diagnostic criteria for malignant phyllodes tumor (MPT) may miss a significant number of MPTs with metastatic potential. New refined diagnostic criteria (Refined Criteria) for MPT were recently proposed. The aim of this study is to validate the Refined Criteria. This validation study included 136 borderline (borderline phyllodes tumor [BoPT]) and MPT cases that were not included in the initial study. We evaluated tumor classifications based on both the Refined Criteria and the WHO criteria. The Refined Criteria defines MPT when these criteria are met (1) stromal overgrowth with ≥ 1 feature(s) of marked stromal cellularity, marked stromal cytologic atypia, or ≥10 mitoses per 10 high-power fields (10 mitoses/10 HPFs) or (2) marked stromal cellularity with ≥1 feature(s) of marked stromal cytologic atypia, ≥10 mitoses/10 HPFs or permeative border. The WHO criteria require all 5 morphologic features (stromal overgrowth, permeative border, marked stromal cellularity, marked stromal cytologic atypia, and ≥10 mitoses/10 HPFs) for an MPT diagnosis. Using the Refined Criteria, none of the 61 BoPTs developed metastasis and 40.0% of the 75 MPTs developed metastases; local recurrence was seen in 11.5% BoPTs and 25.3% MPTs. Using the WHO criteria, 9.6% of the 94 BoPTs developed metastases and 50.0% of the 42 MPTs developed metastases; 14.9% of the BoPTs had local recurrence and 28.6% of the MPTs had local recurrence. Nine (30.0%) of the 30 tumors that developed distant metastases were diagnosed as BoPTs by the WHO criteria. When we combined the 75 MPTs from this validation cohort with the 65 MPT cases from the published data using the Refined Criteria, 50 (35.7%) of the 140 MPTs developed metastases, whereas 8 cases with metastases were <5 cm. In the univariate analysis with log-rank test, stromal overgrowth, marked stromal cellularity, marked stromal cytologic atypia, ≥10 mitoses/10 HPFs, presence of heterologous components other than liposarcomatous component, and presence of stromal necrosis were significantly associated with the risk of metastasis (all with P < 0.05). In multivariate analysis with Cox proportional hazard regression, stromal overgrowth and marked stromal cellularity were significantly associated with metastasis (both with P < 0.001). The Refined Criteria are superior to the WHO criteria in predicting the clinical outcomes of BoPTs and MPTs. Using the Refined Criteria, 35.7% of 140 patients with MPT developed metastases, whereas none (0%) of the patients with BoPT developed metastases. Patients with MPT have a high metastatic rate; these patients may benefit from systemic chemotherapy or targeted therapies. In contrast, patients with BoPT may be managed with complete local excision alone without chemotherapy.

Changes in expression of breast cancer tumor biomarkers between primary tumors and corresponding metastatic sites: common patterns and relationships with survival.

PURPOSE: In metastatic breast cancer, differences in expression patterns of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2) between the primary tumor (PT) and metastatic site (MET) have been reported. However, there is limited understanding of the relationship of tumor subtype discordance and overall survival (OS). We evaluated patterns of ER/PR/HER2 in PTs and corresponding METs and assessed the relationship between these patterns and OS. METHODS: Patients diagnosed at our center with metastatic breast cancer (2011-2020) were included. ER/PR were stratified as < 1%/1-10%/ > 10% by immunohistochemistry and HER2 as positive/negative by immunohistochemistry/FISH. Tumor subtypes were classified as ER or PR + /HER2-, HER2+ , or triple-negative. Biomarker discordance data from PTs to METs were analyzed for expression patterns. OS was assessed. RESULTS: Of 254 patients, 41 (16.1%) had synchronous and 213 (83.9%) had metachronous METs. Category change of ER/PR/HER2 expression was observed in 56 (22.0%), 117 (40.5%), and 30 (11.8%) patients, respectively. Tumor subtype changed in 56 (22.0%) patients. We identified a difference between PT and MET from ER > 10% to ER < 1% (n = 28,16.2% p < 0.01); PR > 10% to PR < 1% (n = 54,48.2%, p < 0.001); PR > 10% to PR 1-10% (n = 18,16.1%, p < 0.001), and ER or PR+/HER2- to triple-negative (n = 19,13.0%, p = 0.03). In log-rank analysis, change from an ER or PR+/HER2- (5-year OS 88.6%) PT to a HER2+(67.5%) or triple-negative (54.6%) MET was associated with decreased survival (p < 0.01); however, in multivariate analysis, discordant biomarker expression was not associated with decreased survival (p > 0.05). CONCLUSION: Tumor expression of ER/PR/HER2 can differ between the PT and MET. Loss of ER/PR expression is common and may be related to worse survival. Routine assessment of MET tumor markers could inform prognosis and therapeutic decision-making.

Continuous Glucose Monitoring Metrics and Hemoglobin A1c Relationship in Patients with Type 2 Diabetes Treated by Hemodialysis.

Background:There is a need for accurate glycemic control metrics in patients with diabetes and end-stage kidney disease (ESKD). Hence, we assessed the relationship of continuous glucose monitoring (CGM) metrics and laboratory-measured hemoglobin A1c (HbA1c) in patients with type 2 diabetes (T2D) treated by hemodialysis. Methods: This prospective observational study included adults (age 18-80 years) with T2D (HbA1c 5%-12%), treated by hemodialysis (for at least 90 days). Participants used a Dexcom G6 Pro CGM for 10 days. Correlation analyses between CGM metrics [mean glucose, glucose management indicator (GMI), and time-in-range (TIR 70-180 mg/dL)] and HbA1c were performed. Results: Among 59 participants (mean age was 57.7 ± 9.3 years, 58% were female, 86% were non-Hispanic blacks), the CGM mean glucose level was 188.9 ± 45 mg/dL (95% CI: 177.2, 200.7), the mean HbA1c and GMI were 7.1% ± 1.3% and 7.8% ± 1.1%, respectively (difference 0.74% ± 0.95). GMI had a strong negative correlation with TIR 70-180 mg/dL (r = -0.96). The correlation between GMI and HbA1c (r = 0.68) was moderate. Up to 29% of participants had a discordance between HbA1c and GMI of <0.5%, with 22% having a discordance between 0.5% and 1%, and 49% having a discordance of >1%. Conclusions: In patients with diabetes and ESKD treated by hemodialysis, the GMI has a strong correlation with TIR, while HbA1c underestimated the average glucose and GMI. Given the limitations of HbA1c in this population, GMI or mean glucose and TIR may be considered as more appropriate glucose control markers.

Effects of vaginal progesterone and placebo on preterm birth and antenatal outcomes in women with singleton pregnancies and short cervix on ultrasound: a meta-analysis.

Background: Vaginal progesterone in preterm birth and adverse outcomes caused by cervical insufficiency remains controversial. To address it, the effect of vaginal progesterone on preterm delivery and perinatal outcome of single pregnancy women with short cervix (less than 25 mm) was systematically evaluated by meta-analysis. Methods: "Vaginal progesterone," "placebo," "ultrasound," "cervix," "singleton pregnancy," "preterm birth," and "antenatal outcomes" were entered to screen clinical studies PubMed, Embase, and the Chinese Biomedical Literature Database (CBM). The study population consisted of women with singleton pregnancies and a short cervix on ultrasound, and were assigned into the progesterone group (n = 1,368) and the placebo group (n = 1,373). Treatment began after the patient was diagnosed with short cervix until delivery. Neonatal survival rate, Neonatal Intensive Care Unit (NICU) admission rate, respiratory distress syndrome (RDS), intraventricular hemorrhage (IVH), neonatal mortality, and birth weight <1,500 g were analyzed. Results: A total of 8 articles, totaling 2,741 study subjects, were enrolled. The progesterone group exhibited an obvious reduced rate of preterm birth at <34 weeks (OR = 0.67, 95% CI: 0.53∼0.84; Z = 3.53, P = 0.004), preterm birth at <32 weeks (OR = 0.46, 95% CI: 0.28∼0.77; Z = 2.99, P = 0.003), NICU admission rate (OR = 0.45, 95% CI: 0.30∼0.66; Z = 0.15, P < 0.0001), RDS rate (OR = 0.42, 95% CI: 0.28∼0.63; Z = 4.25, P < 0.0001), IVH incidence rate (OR = 0.40, 95% CI: 0.17∼0.95; Z = 2.08, P = 0.04), neonatal mortality (OR = 0.25, 95% CI: 0.13∼0.46; Z = 4.39, P < 0.0001), and proportion of neonates with birth weight < 1,500 g (OR = 0.45, 95% CI: 0.32∼0.64; Z = 4.50, P < 0.0001). Conclusion: Vaginal progesterone lowered the incidences of preterm birth and adverse pregnancy outcomes in women with singleton pregnancies and a short cervix.

Effects of long-term closed and socially isolating spaceflight analog environment on default mode network connectivity as indicated by fMRI.

Long-term manned spaceflight and extraterrestrial planet settlement become the focus of space powers. However, the potential influence of closed and socially isolating spaceflight on the brain function remains unclear. A 180-day controlled ecological life support system integrated experiment was conducted, establishing a spaceflight analog environment to explore the effect of long-term socially isolating living. Three crewmembers were enrolled and underwent resting-state fMRI scanning before and after the experiment. We performed both seed-based and network-based analyses to investigate the functional connectivity (FC) changes of the default mode network (DMN), considering its key role in multiple higher-order cognitive functions. Compared with normal controls, the leader of crewmembers exhibited significantly reduced within-DMN and between-DMN FC after the experiment, while two others exhibited opposite trends. Moreover, individual differences of FC changes were further supported by evidence from behavioral analyses. The findings may shed new light on the development of psychological protection for space exploration.

Continuous Glucose Monitoring-Guided Insulin Administration in Long-Term Care Facilities: A Randomized Clinical Trial.

OBJECTIVES: To evaluate the efficacy of real-time continuous glucose monitoring (rt-CGM) in adjusting insulin therapy in long-term care facilities (LTCF). DESIGN: Prospective randomized clinical trial. SETTINGS AND PARTICIPANTS: Insulin-treated patients with type 2 diabetes (T2D) admitted to LTCF. METHODS: Participants in the standard of care wore a blinded CGM with treatment adjusted based on point-of-care capillary glucose results before meals and bedtime (POC group). Participants in the intervention (CGM group) wore a Dexcom G6 CGM with treatment adjusted based on daily CGM profile. Treatment adjustment was performed by the LTCF medical team, with a duration of intervention up to 60 days. The primary endpoint was difference in time in range (TIR 70-180 mg/dL) between treatment groups. RESULTS: Among 100 participants (age 74.73 ± 11 years, 80% admitted for subacute rehabilitation and 20% for nursing home care), there were no significant differences in baseline clinical characteristics between groups, and CGM data were compared for a median of 17 days. There were no differences in TIR (53.38% ± 30.16% vs 48.81% ± 28.03%, P = .40), mean daily mean CGM glucose (184.10 ± 43.4 mg/dL vs 190.0 ± 45.82 mg/dL, P = .71), or the percentage of time below range (TBR) <70 mg/dL (0.83% ± 2.59% vs 1.18% ± 3.54%, P = .51), or TBR <54 mg/dL (0.23% ± 0.85% vs 0.56% ± 2.24%, P = .88) between rt-CGM and POC groups. CONCLUSIONS AND IMPLICATIONS: The use of rtCGM is safe and effective in guiding insulin therapy in patients with T2D in LTCF resulting in a similar improvement in glycemic control compared to POC-guided insulin adjustment.

Frequency-specific segregation and integration of human cerebral cortex: An intrinsic functional atlas.

The cognitive and behavioral functions of the human brain are supported by its frequency multiplexing mechanism. However, there is limited understanding of the dynamics of the functional network topology. This study aims to investigate the frequency-specific topology of the functional human brain using 7T rs-fMRI data. Frequency-specific parcellations were first performed, revealing frequency-dependent dynamics within the frontoparietal control, parietal memory, and visual networks. An intrinsic functional atlas containing 456 parcels was proposed and validated using stereo-EEG. Graph theory analysis suggested that, in addition to the task-positive vs. task-negative organization observed in static networks, there was a cognitive control system additionally from a frequency perspective. The reproducibility and plausibility of the identified hub sets were confirmed through 3T fMRI analysis, and their artificial removal had distinct effects on network topology. These results indicate a more intricate and subtle dynamics of the functional human brain and emphasize the significance of accurate topography.

Key inflammatory markers in bronchoalveolar lavage predict bronchiectasis progression in young children with CF.

INTRODUCTION: Inflammation appears early in cystic fibrosis (CF) pathogenesis, with specific elevated inflammatory markers in bronchoalveolar lavage fluid (BALF) correlating with structural lung disease. Our aim was to identify markers of airway inflammation able to predict bronchiectasis progression over two years with high sensitivity and specificity. METHODS: Children with CF with two chest computed tomography (CT) scans and bronchoscopies at a two-year interval were included (n= 10 at 1 and 3 years and n= 27 at 3 and 5 years). Chest CTs were scored for increase in bronchiectasis (Δ%Bx), using the PRAGMA-CF score. BALF collected with the first CT scan were analyzed for neutrophil% (n= 36), myeloperoxidase (MPO) (n= 25), neutrophil elastase (NE) (n= 26), and with a protein array for inflammatory and fibrotic markers (n= 26). RESULTS: MPO, neutrophil%, and inducible T-cell costimulator ligand (ICOSLG), but not clinical characteristics, correlated significantly with Δ%Bx. Evaluation of neutrophil%, NE, MPO, interleukin-8 (IL-8), ICOSLG, and hepatocyte growth factor (HGF), for predicting an increase of > 0.5% of Δ%Bx in two years, showed that IL-8 had the best sensitivity (82%) and specificity (73%). Neutrophil%, ICOSLG and HGF had sensitivities of 85, 82, and 82% and specificities of 59, 67 and 60%, respectively. The odds ratio for risk of >0.5% Δ%Bx was higher for IL-8 (12.4) than for neutrophil%, ICOSLG, and HGF (5.9, 5.3, and 6.7, respectively). Sensitivity and specificity were lower for NE and MPO). CONCLUSIONS: High levels of IL-8, neutrophil%, ICOSGL and HGF in BALF may be good predictors for progression of bronchiectasis in young children with CF.

Latent Class Proportional Hazards Regression with Heterogeneous Survival Data.

Heterogeneous survival data are commonly present in chronic disease studies. Delineating meaningful disease subtypes directly linked to a survival outcome can generate useful scientific implications. In this work, we develop a latent class proportional hazards (PH) regression framework to address such an interest. We propose mixture proportional hazards modeling, which flexibly accommodates class-specific covariate effects while allowing for the baseline hazard function to vary across latent classes. Adapting the strategy of nonparametric maximum likelihood estimation, we derive an Expectation-Maximization (E-M) algorithm to estimate the proposed model. We establish the theoretical properties of the resulting estimators. Extensive simulation studies are conducted, demonstrating satisfactory finite-sample performance of the proposed method as well as the predictive benefit from accounting for the heterogeneity across latent classes. We further illustrate the practical utility of the proposed method through an application to a mild cognitive impairment (MCI) cohort in the Uniform Data Set.

Assessment of Glycemic Control by Continuous Glucose Monitoring, Hemoglobin A1c, Fructosamine, and Glycated Albumin in Patients With End-Stage Kidney Disease and Burnt-Out Diabetes.

OBJECTIVE: Patients with diabetes and end-stage kidney disease (ESKD) may experience "burnt-out diabetes," defined as having an HbA1c value <6.5% without antidiabetic therapy for >6 months. We aim to assess glycemic control by continuous glucose monitoring (Dexcom G6 CGM) metrics and glycemic markers in ESKD patients on hemodialysis with burnt-out diabetes. RESEARCH DESIGN AND METHODS: In this pilot prospective study, glycemic control was assessed by continuous glucose monitoring (CGM), HbA1c measures, and glycated albumin and fructosamine measurements in patients with burnt-out diabetes (n = 20) and without a history of diabetes (n = 20). RESULTS: Patients with burnt-out diabetes had higher CGM-measured daily glucose levels, lower percent time in the range 70-180 mg/dL, higher percent time above range (>250 mg/dL), and longer duration of hyperglycemia >180 mg/dL (hours/day) compared with patients without diabetes (all P < 0.01). HbA1c and fructosamine levels were similar; however, patients with burnt-out diabetes had higher levels of glycated albumin than did patients without diabetes. CONCLUSIONS: The use of CGM demonstrated that patients with burnt-out diabetes have significant undiagnosed hyperglycemia. CGM and glycated albumin provide better assessment of glycemic control than do values of HbA1c and fructosamine in patients with ESKD.

Exploring the causal relationship between periodontitis and gut microbiome: Unveiling the oral-gut and gut-oral axes through bidirectional Mendelian randomization.

AIM: This Mendelian randomization (MR) study was performed to explore the potential bidirectional causal relationship between the gut microbiome (GM) and periodontitis. MATERIALS AND METHODS: We used genetic instruments from the genome-wide association study of European descent for periodontitis from the GeneLifestyle Interactions in Dental Endpoints (GLIDE) consortium (17,353 cases and 28,210 controls) and the FinnGen consortium (4434 cases and 259,234 controls) to investigate the causal relationship with GM (the MiBioGen consortium, 18,340 samples), and vice versa. Several MR techniques, which include inverse variance weighting (IVW), MR-Egger, weighted median, simple mode and weighted mode approaches, were employed to investigate the causal relationship between the exposures and the outcomes. Cochran's Q-test was performed to detect heterogeneity. The MR-Egger regression intercept and MR pleiotropy residual sum and outlier test (MR-PRESSO) were conducted to test potential horizontal pleiotropy. Leave-one-out sensitivity analyses were used to assess the stabilities of single nucleotide polymorphisms (SNPs). Finally, the IVW results from the two databases were analysed using meta-analysis. RESULTS: We confirmed three potential causal relationships between GM taxa and periodontitis at the genus level. Among them, the genera Alistipes and Holdemanella were genetically associated with an increased risk of periodontitis. In reverse, periodontitis may lead to a decreased abundance of the genus Ruminococcaceae UCG014. CONCLUSIONS: The demonstration of a causal link between GM and periodontitis provides compelling evidence, highlighting the interconnectivity and interdependence of the gut-oral and oral-gut axes.

Development of lycopene-based whole-cell biosensors for the visual detection of trace explosives and heavy metals.

Residual explosives in conflicting zones have caused irreversible damage to human safety and the environment. Whole-cell biosensors can to detect remnants of buried explosives, such as 2,4-dinitrotoluene (DNT), a stable and highly volatile compound in explosives. However, all the reported whole-cell biosensors utilize fluorescence or luminescence as the biological markers, making their detection difficult in real minefields. Here, we presented a lycopene-based whole-cell biosensor in Escherichia coli to output visible signals in response to DNT, which can help in the visual detection of buried explosives. To construct the whole-cell biosensor, the DNT-responsive promoter yqjF was used as the sensing element, and the lycopene synthetic gene cassette crtEBI was served as the reporting element. Then, the metabolic flux for lycopene production was enhanced to improve the output signal of the whole-cell biosensor, and a terminator was utilized to reduce the background interference. The optimized biosensor LSZ05 could perceive at least 1 mg/L DNT. The DNT-specificity and robust performance of the biosensor under different environmental factors were confirmed. Our results showed that converting the biosensor into a lyophilized powder was an effective storage method. The biosensor LSZ05 could effectively detect DNT in two kinds of soil samples. The lycopene-based whole-cell biosensor could also be used to visually detect heavy metals. Our findings laid the foundation for visually detecting buried explosives in minefields, which was a valuable supplement to the reported biosensors. The methods used for optimizing the lycopene-based whole-cell biosensor, including the improvement of the output signal and reduction of background interference, were quite effective.

Influence of METTL3 knockdown on PDLSC osteogenesis in E. coli LPS-induced inflammation.

OBJECTIVE: This study aimed to investigate the effect of METTL3 knockdown on osteogenic differentiation of human periodontal ligament stem cells (PDLSCs) in the weak inflammation microenvironments, as well as the underlying mechanisms. MATERIALS AND METHODS: PDLSCs were stimulated by lipopolysaccharide from Escherichia coli (E. coli LPS), followed by quantification of METTL3. METTL3 expression was assessed using RT-qPCR and Western blot analysis in periodontitis. METTL3 knockdown PDLSCs were stimulated with or without E. coli LPS. The evaluation included proinflammatory cytokines, osteogenic markers, ALP activity, and mineralized nodules. Bioinformatics analysis and Western blot determined the association between METTL3 and the PI3K/Akt pathway. RESULTS: METTL3 was overexpressed in periodontitis. METTL3 knockdown in PDLSCs reduced proinflammatory cytokines, osteogenic markers, ALP activity, and mineralized nodules in both environments. Bioinformatics analysis suggested a link between METTL3 and the PI3K/Akt pathway. METTL3 knockdown inhibited PI3K/Akt signaling pathway activation. CONCLUSION: METTL3 knockdown might inhibit osteogenesis in PDLSCs through the inactivation of PI3K/Akt signaling pathway. Concomitant findings might shed novel light on the roles and potential mechanisms of METTL3 in the LPS-stimulated inflammatory microenvironments of PDLSCs.

Pulmonary exacerbations in early cystic fibrosis lung disease are marked by strong modulation of CD3 and PD-1 on luminal T cells.

Background: In chronic cystic fibrosis (CF) lung disease, neutrophilic inflammation and T-cell inhibition occur concomitantly, partly due to neutrophil-mediated release of the T-cell inhibitory enzyme Arg1. However, the onset of this tonic inhibition of T cells, and the impact of pulmonary exacerbations (PEs) on this process, remain unknown. Methods: Children with CF aged 0-5 years were enrolled in a longitudinal, single-center cohort study. Blood (n = 35) and bronchoalveolar lavage (BAL) fluid (n = 18) were collected at stable outpatient clinic visits or inpatient PE hospitalizations and analyzed by flow cytometry (for immune cell presence and phenotype) and 20-plex chemiluminescence assay (for immune mediators). Patients were categorized by PE history into (i) no prior PE, (ii) past history of PE prior to stable visit, or (iii) current PE. Results: PEs were associated with increased concentration of both pro- and anti-inflammatory mediators in BAL, and increased neutrophil frequency and G-CSF in circulation. PE BAL samples showed a trend toward an increased frequency of hyperexocytic "GRIM" neutrophils, which we previously identified in chronic CF. Interestingly, expression levels of the T-cell receptor associated molecule CD3 and of the inhibitory programmed death-1 (PD-1) receptor were respectively decreased and increased on T cells from BAL compared to blood in all patients. When categorized by PE status, CD3 and PD-1 expression on blood T cells did not differ among patients, while CD3 expression was decreased, and PD-1 expression was increased on BAL T cells from patients with current PE. Conclusions: Our findings suggest that airway T cells are engaged during early-life PEs, prior to the onset of chronic neutrophilic inflammation in CF. In addition, increased blood neutrophil frequency and a trend toward increased BAL frequency of hyperexocytic neutrophils suggest that childhood PEs may progressively shift the balance of CF airway immunity towards neutrophil dominance.

Comprehensive Clinical-Pathologic Assessment of Malignant Phyllodes Tumors: Proposing Refined Diagnostic Criteria.

The latest World Health Organization classification of breast tumors recommends diagnosing malignant phyllodes tumors (MPTs) when all 5 morphologic features are present: permeative borders, marked stromal cellularity, marked stromal cytologic atypia, ≥10 mitoses per 10 high-power fields (HPF), and stromal overgrowth. We assessed the performance of this recommendation to capture MPTs and features predictive of distant metastasis in a multi-institutional retrospective study. Of 65 MPTs, most cases had at least focally permeative borders (58, 89%), with marked stromal cellularity in 40 (61.5%), marked atypia in 38 (58.5%), ≥10 mitoses per 10 HPF in 50 (77%), and stromal overgrowth in 56 (86%). Distant metastases were observed in 20 (31%) patients (median follow-up 24.5 mo, 1 to 204). Only 13 of 65 (20%) cases had all 5 morphologic features, while only 7 of 20 (35%) cases with distant metastases had all 5 features. In univariate analysis, only marked stromal atypia ( P =0.004) and cellularity ( P =0.017) were associated with decreased distant metastasis-free survival. In multivariate Cox regression, the combination of stromal overgrowth, marked stromal cellularity, and atypia (C-index 0.721, 95% CI: 0.578, 0.863) was associated with decreased distant metastasis-free survival. The current World Health Organization recommendation will miss a significant number of MPTs with distant metastases. We propose refined diagnostic criteria for MPTs: (1) stromal overgrowth combined with ≥1 feature(s) (marked cellularity, marked atypia, or ≥10 mitoses per 10 HPF), or (2) in the absence of stromal overgrowth, marked cellularity combined with ≥1 feature(s) (permeative borders, marked atypia, or ≥10 mitoses per 10 HPF).

Airway macrophages display decreased expression of receptors mediating and regulating scavenging in early cystic fibrosis lung disease.

Background: Cystic fibrosis (CF) airway disease is characterized by chronic inflammation, featuring neutrophil influx to the lumen. Airway macrophages (AMs) can promote both inflammation and resolution, and are thus critical to maintaining and restoring homeostasis. CF AM functions, specifically scavenging activity and resolution of inflammation, have been shown to be impaired, yet underlying processes remain unknown. We hypothesized that impaired CF AM function results from an altered expression of receptors that mediate or regulate scavenging, and set out to investigate changes in expression of these markers during the early stages of CF lung disease. Methods: Bronchoalveolar lavage fluid (BALF) was collected from 50 children with CF aged 1, 3 or 5 years. BALF cells were analyzed using flow cytometry. Expression levels of surface markers on AMs were expressed as median fluorescence intensities (MFI) or percentage of AMs positive for these markers. The effect of age and neutrophilic inflammation, among other variables, on marker expression was assessed with a multivariate linear regression model. Results: AM expression of scavenger receptor CD163 decreased with age (p = 0.016) and was negatively correlated with BALF %neutrophils (r = -0.34, p = 0.016). AM expression of immune checkpoint molecule SIRPα also decreased with age (p = 0.0006), but did not correlate with BALF %neutrophils. Percentage of AMs expressing lipid scavenger CD36 was low overall (mean 20.1% ± 16.5) and did not correlate with other factors. Conversely, expression of immune checkpoint PD-1 was observed on the majority of AMs (mean PD-1pos 72.9% ± 11.8), but it, too, was not affected by age or BALF %neutrophils. Compared to matched blood monocytes, AMs had a higher expression of CD16, CD91, and PD-1, and a lower expression of CD163, SIRPα and CD36. Conclusion: In BALF of preschool children with CF, higher age and/or increased neutrophilic inflammation coincided with decreased expression of scavenger receptors on AMs. Expression of scavenging receptors and regulators showed a distinctly different pattern in AMs compared to blood monocytes. These findings suggest AM capacity to counter inflammation and promote homeostasis reduces during initiation of CF airway disease and highlight new avenues of investigation into impaired CF AM function.

A Randomized Controlled Trial Comparing the Efficacy and Safety of IDegLira Versus Basal-Bolus in Patients With Poorly Controlled Type 2 Diabetes and Very High HbA1c ≥9-15%: DUAL HIGH Trial.

OBJECTIVE: In participants with type 2 diabetes (T2D) and HbA1c >9.0-10.0%, guidelines recommend treatment with basal-bolus insulin. RESEARCH DESIGN AND METHODS: This randomized trial compared the efficacy and safety of insulin degludec and liraglutide (IDegLira) and basal-bolus among participants with high HbA1c ≥9.0-15.0%, previously treated with 2 or 3 oral agents and/or basal insulin, allocated (1:1) to basal-bolus (n = 73) or IDegLira (n = 72). The primary end point was noninferiority (0.4%) in HbA1c reduction between groups. RESULTS: Among 145 participants (HbA1c 10.8% ± 1.3), there was no statistically significant difference in HbA1c reduction (3.18% ± 2.29 vs. 3.00% ± 1.79, P = 0.65; estimated treatment difference (ETD) 0.18%, 95% CI -0.59, 0.94) between the IDegLira and basal-bolus groups. IDegLira resulted in significantly lower rates of hypoglycemia <70 mg/dL (26% vs. 48%, P = 0.008; odds ratio 0.39, 95% CI 0.19, 0.78), and less weight gain (1.24 ± 8.33 vs. 5.84 ± 6.18 kg, P = 0.001; ETD -4.60, 95% CI -7.33, -1.87). CONCLUSIONS: In participants with T2D and HbA1c ≥9.0-15.0%, IDegLira resulted in similar HbA1c reduction, less hypoglycemia, and less weight gain compared with the basal-bolus regimen.

Diabetic retinopathy in African-Americans with end-stage kidney disease: a cross-sectional study on prevalence and impact on quality of life.

INTRODUCTION: The prevalence, severity, and quality of life (QoL) impact of diabetic retinopathy (DR) among African-Americans (AAs) with end-stage kidney disease (ESKD) undergoing dialysis are unknown. RESEARCH DESIGN AND METHODS: A cross-sectional study was conducted on 93 AA adults with diabetes and ESKD. The diagnosis of DR was based on a review of medical records and/or a positive photograph with a portable hand-held device reviewed by both artificial intelligence software and a retinal specialist. QoL, physical disability social determinants of health (SDoHs) were assessed by standardized questionnaires. RESULTS: The prevalence of DR was 75%, with 33% of participants having mild, 9.6% moderate and 57.4% severe DR. A total of 43% had normal visual acuity; 45% had moderate visual impairment; and 12% had severe visual impairment. We found a high burden of disease, multiple SDoH challenges, and low QoL and general health among patients with ESKD. The presence of DR had no significant impact on physical health and QoL compared with participants without DR. CONCLUSIONS: DR is present in 75% of AA patients with diabetes and ESKD on haemodialysis. ESKD has a significant burden on general health and QoL; however, DR has a minor additional impact on the overall physical health and QoL in people with ESKD.

Globally Adaptive Longitudinal Quantile Regression with High Dimensional Compositional Covariates.

In this work, we propose a longitudinal quantile regression framework that enables a robust characterization of heterogeneous covariate-response associations in the presence of high-dimensional compositional covariates and repeated measurements of both response and covariates. We develop a globally adaptive penalization procedure, which can consistently identify covariate sparsity patterns across a continuum set of quantile levels. The proposed estimation procedure properly aggregates longitudinal observations over time, and ensures the satisfaction of the sum-zero coefficient constraint that is needed for proper interpretation of the effects of compositional covariates. We establish the oracle rate of uniform convergence and weak convergence of the resulting estimators, and further justify the proposed uniform selector of the tuning parameter in terms of achieving global model selection consistency. We derive an efficient algorithm by incorporating existing R packages to facilitate stable and fast computation. Our extensive simulation studies confirm the theoretical findings. We apply the proposed method to a longitudinal study of cystic fibrosis children where the association between gut microbiome and other diet-related biomarkers is of interest.