Serum IgG4 Concentration is a Potential Predictive Biomarker in Glucocorticoid Treatment for Idiopathic Retroperitoneal Fibrosis

Objectives: To evaluate the management and outcome of idiopathic retroperitoneal fibrosis (iRPF) in Japan, and identify its clinical biomarker. Methods: We retrospectively analyzed 129 patients with iRPF treated between January 2008 and May 2018 at 12 university and related hospitals. Patients treated with glucocorticoid were analyzed to identify a predictive biomarker. These patients were classified into three groups according to overall effectiveness (no change: NC, complete response: CR and partial response groups: PR), and each parameter was compared statistically.Results: Male-female ratio was 5: 1, and median age at diagnosis was 69 (33-86) years. Smoking history was reported in 59.6% of the patients. As treatment, 95 patients received glucocorticoid therapy with an overall response rate of 84%. As a result, serum concentration of IgG4 was significantly decreased in NC group compared with the other two groups (56.6mg/dL vs 255mg/dL, 206mg/dL, P=0.0059 and 0.0078). ROC analysis was performed between the non-responder (NC) and responder groups (CR+PR) to identify the cut-off value of serum IgG4 as a predictive marker. As a result, AUC was 0.793 and the values of sensitivity and specificity were 0.85 and 0.64, respectively, under the cut-off values of 67.6mg/dL. Conclusions: In the majority of iRPF patients, glucocorticoid therapy resulted in a favorable response. Pre-treatment serum IgG4 concentration may have potential as a predictive biomarker of steroid treatment.

Molecular Characterization and Prognostication of Large Cell Neuroendocrine Carcinoma and Large Cell Carcinoma

PurposeLarge cell neuroendocrine carcinoma (LCNEC) and classic large cell carcinoma (LCC) are two distinct entities with different histological and biological characteristics. However, the mutational profiles and the clinical behavior of the two subtypes of lung cancer remain to be explored.Patients and MethodsPathological diagnoses of all screened patients were finally confirmed by three or four experienced pathologists. Patients with uncertain pathological diagnoses were excluded. Finally, we genetically profiled ten patients with LCNEC and seven with LCC. ALL patients were subjected to next-generation sequencing (NGS) test, which included nine patients sequenced with a 139-gene panel and eight patients with a 425-gene panel. Including only intersected mutations from these two panels, survival analysis was further conducted.ResultsBoth LCNEC and LCC showed high prevalence in male patients, with no clear association with smoking history. Potential targetable mutations in KRAS and RET were detected in the study cohort. However, LCNEC and LCC showed distinct mutational profiles with an enrichment of RB1/TP53 co-mutations in a subset of LCNEC patients. SMARCA4 and KEAP1 mutations were exclusively found in LCC patients, and RICTOR, BRAF, ROS1 and TET2 mutations were only detected in LCNEC. LCC patients in the cohort had shorter survival compared to LCNEC patients (p=0.006). Survival analysis revealed an association between SMARCA4 mutations and poor outcome in the study cohort and in the LCC subset. Mutations in BRAF were associated with a trend of increased survival in the study cohort, as well as in the LCNEC subset. Finally, TET2 mutations were associated with poor outcome in the LCNEC cohort.ConclusionLCC and LCNEC were both heterogeneous diseases with limited treatment options. Our study identified potential targetable mutations and prognostic biomarkers that might provide more therapeutic options and improve individualized patient care.

Deep Learning Based Long Term Mortality Prediction in the National Lung Screening Trial

In this study, the long-term mortality in the National Lung Screening Trial (NLST) was investigated using a deep learning-based method. Binary classification of the non-lung-cancer mortality (i.e. cardiovascular and respiratory mortality) was performed using neural network models centered around a 3D-ResNet. The models were trained on a participant age, gender, and smoking history matched cohort. Utilising both the 3D CT scan and clinical information, the models can achieve an AUC of 0.73 which outperforms humans at cardiovascular mortality prediction. By interpreting the trained models with 3D saliency maps, we examined the features on the CT scans that correspond to the mortality signal. The saliency maps can potentially assist the clinicians' and radiologists' to identify regions of concern on the image that may indicate the need to adopt preventative healthcare management strategies to prolong the patients' life expectancy.

Characteristics and Outcomes of MI with Non-obstructive Coronary Arteries in a South-east Asian Cohort

Background: MI with non-obstructive coronary arteries (MINOCA) is caused by a heterogenous group of conditions with clinically significant sequelae. Aim: This study aimed to compare the clinical characteristics and prognosis of MINOCA with MI with obstructive coronary artery disease (MICAD). Methods: Data on patients with a first presentation of MI between 2011 and 2014 were extracted from the Singapore Cardiac Longitudinal Outcomes Database and patients were classified as having either MINOCA or MICAD. The primary outcomes were all-cause mortality (ACM) and major adverse cardiac events (MACE), defined as a composite of ACM, recurrent MI, heart failure hospitalisation and stroke. Results: Of the 4,124 patients who were included in this study, 159 (3.9%) were diagnosed with MINOCA. They were more likely to be women, present with a non-ST-elevation MI, have a higher left ventricular ejection fraction and less likely to have diabetes, previous stroke or smoking history. Over a mean follow-up duration of 4.5 years, MINOCA patients had a lower incidence of ACM (10.1% versus 16.5%) and MACE (20.8% versus 35.5%) compared with MICAD. On multivariable analysis, patients with MINOCA had a lower risk of ACM (HR 0.42; 95% CI [0.21–0.82]) and MACE (HR 0.42; 95% CI [0.26–0.69]). Within the MINOCA group, older age, higher creatinine, a ST-elevation MI presentation, and the absence of antiplatelet use predicted ACM and MACE. Conclusion: While patients with MINOCA had better clinical outcomes compared with MICAD patients, MINOCA is not a benign entity, with one in five patients experiencing an adverse cardiovascular event in the long term.

Cross-sectional Analysis of Risk Factors for Surgical Site Infection Secondary to Spinal Internal Fixation via the Posterior Approach

Backgroud: The aim of this study was to investigate the risk factors related to surgical site infection (SSI) secondary to spinal internal fixation via the posterior approach.Methods: Patients who had undergone spinal internal fixation via the posterior approach at the spinal center of our hospital from January 2004 to December 2019 were selected in this cross-sectional study. Information about age, sex, body mass index (BMI), fused segment, hemoglobin concentration, serum albumin concentration, surgical duration, surgery beginning time, allogeneic blood transfusion, combined diabetes, peak blood glucose 72 h postoperatively ≥12 mmol/L, smoking history, and blood loss were included. The factors related to SSI were analyzed using univariate and multivariate analyses. P < 0.05 was considered to indicate statistical significance.Results: Among the 4,350 patients, 66 had SSI, with an infection prevalence of 1.5%. The subjects included 37 men and 29 women (age range, 22–84 y; average age, 47.4 ± 12.8 y). Univariate analysis showed that sex, BMI, fused segment, surgery beginning time, allogeneic blood transfusion, and smoking history were not correlated to infection (P > 0.05). However, age >60 y, surgical duration >3 h, serum albumin concentration <30 g/L, hemoglobin concentration <80 g/L, combined diabetes, peak blood glucose 72 h postoperatively ≥12 mmol/L, and blood loss >1,000 mL were correlated with infection (P < 0.05). Multivariate logistic regression analysis demonstrated that age >60 y, surgical duration >3 h, hemoglobin concentration <80 g/L, serum albumin concentration <30 g/L, combined diabetes, and blood loss >1,000 mL were significantly correlated with SSI secondary to spinal internal fixation via the posterior approach.Conclusion: This study provides information on SSI secondary to spinal internal fixation via the posterior approach. We found that age >60 y, surgical duration >3 h, hemoglobin concentration <80 g/L, serum albumin concentration <30 g/L, combined diabetes, and blood loss >1,000 mL are directly correlated with SSI secondary to spinal internal fixation via the posterior approach. These findings may contribute to discussions and actions that may help to reduce SSI secondary to spinal internal fixation via the posterior approach in the short or medium term.

Sex-Specific Prevalence, Demographic Characteristics, and Risk Factors of Tinnitus in the Hispanic Community Health Study/Study of Latinos

Purpose: The aim of this study was to determine the prevalence of any and chronic tinnitus among female and male individuals from varied Hispanic/Latino backgrounds and to estimate associations between risk factors for chronic tinnitus. Method: Our analysis used cross-sectional baseline data collected from 2008 to 2011 from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). Prevalence estimates and multivariable logistic regression were conducted using survey methodology. Participants included 15,768 adults (8,229 women and 7,539 men) aged 18–76 years. The primary outcome of interest was chronic tinnitus, defined as self-reported tinnitus lasting ≥ 5 min at a time and at least once per week. We hypothesized that after adjusting for covariates, the risk factors of depressed and anxious symptoms, smoking history, hypertension, and noise exposure history would be associated with higher odds of chronic tinnitus. Results: Unstratified prevalence for any tinnitus was 32.9%, and for chronic tinnitus, it was 12.1%. Sex-stratified results demonstrated that 2,995 female individuals (36.4%) and 2,187 male individuals (29.0%) reported any tinnitus, and of these, 1,043 female individuals (12.7%) and 870 male individuals (11.5%) reported chronic tinnitus. In the fully adjusted model, depressed and anxious symptoms as well as recreational noise exposure were associated with higher odds of chronic tinnitus in female individuals (odds ratios [ ORs ] = 1.06, confidence interval [CI; 1.04, 1.07]; 1.02, CI [1.01, 1.04]; and 1.40, CI [1.20, 1.62]) and in male individuals ( OR s = 1.06, CI [1.03, 1.08]; 1.05, CI [1.02, 1.08]; and 1.30, CI [1.05, 1.65]). Current smoking was a risk factor for chronic tinnitus in male individuals ( OR = 1.53, CI [1.16, 2.02]). Conclusions: Prevalence of any and chronic tinnitus in the HCHS/SOL baseline cohort is higher than that reported in previous studies, particularly among female individuals. Understanding risk factors associated with tinnitus is important for the development of culturally and linguistically appropriate public health programs that consider sex differences and promote lifestyle modifications known to lower the odds of experiencing tinnitus.

Lung function and atherosclerosis: a cross-sectional study of multimorbidity in rural Uganda

Background Chronic obstructive pulmonary disease (COPD) is a leading cause of global mortality. In high-income settings, the presence of cardiovascular disease among people with COPD increases mortality and complicates longitudinal disease management. An estimated 26 million people are living with COPD in sub-Saharan Africa, where risk factors for co-occurring pulmonary and cardiovascular disease may differ from high-income settings but remain uncharacterized. As non-communicable diseases have become the leading cause of death in sub-Saharan Africa, defining multimorbidity in this setting is critical to inform the required scale-up of existing healthcare infrastructure. Methods We measured lung function and carotid intima media thickness (cIMT) among participants in the UGANDAC Study. Study participants were over 40 years old and equally divided into people living with HIV (PLWH) and an age- and sex-similar, HIV-uninfected control population. We fit multivariable linear regression models to characterize the relationship between lung function (forced expiratory volume in one second, FEV1) and pre-clinical atherosclerosis (cIMT), and evaluated for effect modification by age, sex, smoking history, HIV, and socioeconomic status. Results Of 265 participants, median age was 52 years, 125 (47%) were women, and 140 (53%) were PLWH. Most participants who met criteria for COPD were PLWH (13/17, 76%). Median cIMT was 0.67 mm (IQR: 0.60 to 0.74), which did not differ by HIV serostatus. In models adjusted for age, sex, socioeconomic status, smoking, and HIV, lower FEV1 was associated with increased cIMT (β = 0.006 per 200 mL FEV1 decrease; 95% CI 0.002 to 0.011, p = 0.01). There was no evidence that age, sex, HIV serostatus, smoking, or socioeconomic status modified the relationship between FEV1 and cIMT. Conclusions Impaired lung function was associated with increased cIMT, a measure of pre-clinical atherosclerosis, among adults with and without HIV in rural Uganda. Future work should explore how co-occurring lung and cardiovascular disease might share risk factors and contribute to health outcomes in sub-Saharan Africa.

Differences in Clinical Characteristics Between Delta Variant and Wild-Type SARS-CoV-2 Infected Patients

Background: As delta variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) prevailed in the current coronavirus disease 2019 (COVID-19) pandemic, its clinical characteristics with the difference from those of wild-type strains have been little studied.Methods: We reported one cohort of 341 wild-type patients with COVID-19 admitted at Wuhan, China in 2020 and the other cohort of 336 delta variant patients with COVID-19 admitted at Yangzhou, China in 2021, with comparisons of their demographic information, medical history, clinical manifestation, and hematological data. Furthermore, within the delta variant cohort, patients with none, partial, and full vaccination were also compared to assess vaccine effectiveness.Findings: For a total of 677 patients with COVID-19 included in this study, their median age was 53.0 years [interquartile range (IQR): 38.0–66.0] and 46.8% were men. No difference was found in age, gender, and percentage of patients with the leading comorbidity between wild-type and delta variant cohorts, but delta variant cohort showed a lessened time interval between disease onset to hospitalization, a reduced portion of patients with smoking history, and a lowered frequency of clinical symptoms. For hematological parameters, most values demonstrated significant differences between wild-type and delta variant cohorts, while full vaccination rather than partial vaccination alleviated the disease condition. This reflected the viremic effect of delta variant when vaccination succeeds or fails to protect.Interpretation: Delta variant of SARS-CoV-2 may cause severe disease profiles, but timely diagnosis and full vaccination could protect patients with COVID-19 from worsened disease progression.

Prospective study evaluating dynamic changes of cell-free HPV DNA in locoregional viral-associated oropharyngeal cancer treated with induction chemotherapy and response-adaptive treatment

Background Human papillomavirus (HPV)-associated oropharyngeal cancer (OPC) has a favorable prognosis which has led to efforts to de-intensify treatment. Response-adaptive de-escalated treatment is promising, however improved biomarkers are needed. Quantitative cell-free HPV-DNA (cfHPV-DNA) in plasma represents an attractive non-invasive biomarker for grading treatment response and post-treatment surveillance. This prospective study evaluates dynamic changes in cfHPV-DNA during induction therapy, definitive (chemo)radiotherapy, and post-treatment surveillance in the context of risk and response-adaptive treatment for HPV + OPC. Methods Patients with locoregional HPV + OPC are stratified into two cohorts: High risk (HR) (T4, N3, $$\ge$$ ≥ 20 pack-year smoking history (PYH), or non-HPV16 subtype); Low risk (LR) (all other patients). All patients receive induction chemotherapy with three cycles of carboplatin and paclitaxel. LR with ≥ 50% response receive treatment on the single-modality arm (minimally-invasive surgery or radiation alone to 50 Gy). HR with ≥ 50% response or LR with ≥ 30% and < 50% response receive treatment on the intermediate de-escalation arm (chemoradiation to 50 Gy with cisplatin). All other patients receive treatment on the regular dose arm with chemoradiation to 70 Gy with concurrent cisplatin. Plasma cfHPV-DNA is assessed during induction, (chemo)radiation, and post-treatment surveillance. The primary endpoint is correlation of quantitative cfHPV-DNA with radiographic response. Discussion A de-escalation treatment paradigm that reduces toxicity without compromising survival outcomes is urgently needed for HPV + OPC. Response to induction chemotherapy is predictive and prognostic and can select candidates for de-escalated definitive therapy. Assessment of quantitative cfHPV-DNA in the context of response-adaptive treatment of represents a promising reliable and convenient biomarker-driven strategy to guide personalized treatment in HPV + OPC. Trial registration This trial is registered with ClinicalTrials.gov on October 1st, 2020 with Identifier: NCT04572100.