Sociodemographic characteristics and longitudinal progression of multimorbidity: A multistate modelling analysis of a large primary care records dataset in England.

BACKGROUND: Multimorbidity, characterised by the coexistence of multiple chronic conditions in an individual, is a rising public health concern. While much of the existing research has focused on cross-sectional patterns of multimorbidity, there remains a need to better understand the longitudinal accumulation of diseases. This includes examining the associations between important sociodemographic characteristics and the rate of progression of chronic conditions. METHODS AND FINDINGS: We utilised electronic primary care records from 13.48 million participants in England, drawn from the Clinical Practice Research Datalink (CPRD Aurum), spanning from 2005 to 2020 with a median follow-up of 4.71 years (IQR: 1.78, 11.28). The study focused on 5 important chronic conditions: cardiovascular disease (CVD), type 2 diabetes (T2D), chronic kidney disease (CKD), heart failure (HF), and mental health (MH) conditions. Key sociodemographic characteristics considered include ethnicity, social and material deprivation, gender, and age. We employed a flexible spline-based parametric multistate model to investigate the associations between these sociodemographic characteristics and the rate of different disease transitions throughout multimorbidity development. Our findings reveal distinct association patterns across different disease transition types. Deprivation, gender, and age generally demonstrated stronger associations with disease diagnosis compared to ethnic group differences. Notably, the impact of these factors tended to attenuate with an increase in the number of preexisting conditions, especially for deprivation, gender, and age. For example, the hazard ratio (HR) (95% CI; p-value) for the association of deprivation with T2D diagnosis (comparing the most deprived quintile to the least deprived) is 1.76 ([1.74, 1.78]; p < 0.001) for those with no preexisting conditions and decreases to 0.95 ([0.75, 1.21]; p = 0.69) with 4 preexisting conditions. Furthermore, the impact of deprivation, gender, and age was typically more pronounced when transitioning from an MH condition. For instance, the HR (95% CI; p-value) for the association of deprivation with T2D diagnosis when transitioning from MH is 2.03 ([1.95, 2.12], p < 0.001), compared to transitions from CVD 1.50 ([1.43, 1.58], p < 0.001), CKD 1.37 ([1.30, 1.44], p < 0.001), and HF 1.55 ([1.34, 1.79], p < 0.001). A primary limitation of our study is that potential diagnostic inaccuracies in primary care records, such as underdiagnosis, overdiagnosis, or ascertainment bias of chronic conditions, could influence our results. CONCLUSIONS: Our results indicate that early phases of multimorbidity development could warrant increased attention. The potential importance of earlier detection and intervention of chronic conditions is underscored, particularly for MH conditions and higher-risk populations. These insights may have important implications for the management of multimorbidity.

Bone mesenchymal stem cell-derived extracellular vesicles inhibit DAPK1-mediated inflammation by delivering miR-191 to macrophages.

Alveolar macrophage activation and apoptosis are vital contributors to sepsis-associated acute lung injury (ALI). However, the mechanisms of alveolar macrophage activation are yet to be clarified. Death-associated protein kinase 1 (DAPK1) is one of the potential candidates that play crucial roles in regulating alveolar macrophage inflammation. Herein, we found that primary human bone mesenchymal stem cell (BMSC)-derived extracellular vesicles (EVs) antagonize LPS-induced inflammation in the THP-1 human macrophage-like cell line. Mechanistically, LPS stimulation elevates the expression of DAPK1 and the inflammation markers in THP-1 cells, while BMSC-derived EVs inhibit the expression of DAPK1 and inflammation through delivering miR-191, which can target the 3'-UTR of the DAPK1 mRNA and therefore suppress its translation. The importance of DAPK1 in the activation of THP-1 is also stressed in this study. Our findings provide evidence that BMSC-derived EVs regulate the alveolar macrophage inflammation and highlight BMSC-derived EVs as a potential vehicle to deliver biomacromolecules to macrophages.

[Prostatitis studies in China from 2000 to 2020: A Knowledge Atlas-based study on the development trend of contemporary disciplines].

OBJECTIVE: To review and analyze the trend of researches on prostatitis in China in the past two decades. METHODS: We searched the core collection of China National Knowledge Infrastructure (CNKI) for studies on prostatitis, and analyzed the data obtained using Excel, Citespace and VOSviewer. RESULTS: Totally, 1 216 original articles were identified, with 3 271 keywords, ≥3-time high-frequency keywords accounting for 12.9%, with "", "", "chronic prostatitis", "prostatitis", and "" as the top 5 ones, each with a centrality higher than 300. Major prostatitis-related studies focused on the 8 keywords, namely, prostatitis, prostatic fluid, rats, prostate, syndromes, efficacy observation, compound (in traditional Chinese medicine, TCM), and therapeutic application. The included literature involved 2 808 authors, with 402 involved more than twice and most of them in a scattered manner. The major topics of prostatitis studies varied in the past two decades, focusing on TCM therapies, promotion of blood circulation and stasis and comprehensive nursing in 2000－2001, on animal models, CD4+ lymphocytes and other experimental molecules in 2007－2010, on urodynamics, risk factors and specific antigens in 2013－2016, and on literature information resources in 2016. CONCLUSIONS: The immune mechanism remains a hot topic in the future researches on prostatitis. In terms of treatment of the disease, TCM has a potential value, and more practice and studies are required for an optimal combination of TCM and Western medicine. Strengthened collaborative efforts are needed to establish an authoritative source channel for the keywords, and incorporate it into the national standard system, and above all, to integrate the prostatitis study into multi-disciplinary researches, eliminate academic barriers, encourage collaborative innovation with multiple parties, and promote the exchanges and development in this field.

Iliac Vein Stenting for Chronic Proximal Venous Outflow Obstruction in a Predominantly Asian-American Cohort.

BACKGROUND: We investigated the outcome of vein stenting placement for chronic proximal venous outflow obstruction (PVOO) in a predominantly Asian-American cohort to improve patient selection, enhance technical approach, and better define quality measurements of this emerging vascular intervention. METHODS: A total of 462 consecutive patients, 73% Asian American (n = 336), who underwent iliac vein stenting for chronic PVOO from October 2013 to July 2016 were reviewed. Postoperative outcomes at five follow-up visits were assessed. Wilcoxon-Mann-Whitney and Kruskal-Wallis tests were run for demographic and operative variables. Ordered logistic regressions were run for the outcome at each time point, and Chi-squared tests as well as Fisher's exact tests were used for categorical variables. RESULTS: Follow-up was maintained in 90% of patients, with a mean follow-up time of 695 days. Asian-American patients were more likely to present with varicose veins (77.4% vs. 54.8%, P < 0.001), and non-Asian patients were more likely to present with active ulceration (26.2% vs. 5.1%, P < 0.001). Asian-American patients were more likely to have bilateral stents placed (61.6% vs. 50%, P = 0.026) and were less likely to have reinterventions (11.3% vs. 27.8%, P < 0.001), a history of deep vein thrombosis (8.3% vs. 29.4%, P < 0.001), or intraoperative findings of chronic postphlebitic changes (17.6% vs. 33.3%, P < 0.001). Kruskal-Wallis tests were significant for improvement in patients of all the Clinical, Etiology, Anatomy, Pathophysiology classes at 30 days (P = 0.041), 90 days (P = 0.045), 6 months (P = 0.041), and 1 year (P < 0.01). The Asian-American population had improved but comparatively lower follow-up scores at the 30-day mark (48% significantly improved or better vs. 63%, P = 0.008) but higher follow-up scores at the >1 year mark (80% significantly improved or better vs. 59%, P < 0.001). CONCLUSIONS: Asian-American patients undergoing vein stent placement for chronic PVOO had comparatively worse outcomes than non-Asian patients at 30 days and better outcomes after one year. These patient groups had different outcomes postoperatively and outcomes which evolve differently over time.

Low baseline awareness of gastric cancer risk factors amongst at-risk multiracial/ethnic populations in New York City: results of a targeted, culturally sensitive pilot gastric cancer community outreach program.

Background and Aims: There are limited efforts to address modifiable risk factors for gastric cancer (GC) among racial/ethnic groups at higher GC risk, which may reflect decreased public awareness of risk factors. Our primary aim was to assess baseline awareness of GC risk factors and attitudes/potential barriers for uptake of a GC screening program among high-risk individuals.Methods: Participants attended a linguistically and culturally targeted GC educational program in East Harlem (EH)/Bronx and Chinatown communities in New York City. Demographic information and relevant behavioral/lifestyle habits were collected. Participants' ability to identify GC risk factors and attitudes/barriers surrounding GC screening were assessed before and after the program.Results: Of the 168 included participants, most were female with 77% above age 70. Nearly half of participants in the EH/Bronx programs identified themselves as black and 63% as Hispanic/Latino; 93% of the Chinatown participants identified as Chinese. Among EH/Bronx participants, the majority correctly identified older age, smoking, alcohol, H. pylori, family history, race/ethnicity, excess salt, and preserved foods as risk factors. Among Chinatown participants, the majority correctly identified smoking, alcohol, race/ethnicity, and excess salt, although only 53% and 57.8% correctly identified H. pylori and preserved foods, respectively; the majority incorrectly answered that older age was not a major risk factor. The majority in both groups failed to identify male gender as higher risk and incorrectly identified stress and obesity as major risk factors. Participants were more concerned about the potential findings on GC screening tests than the risks and costs or having to take time off work.Conclusion: Among multiracial/ethnic groups of individuals presumably at higher risk for GC, we identified several gaps in baseline knowledge of both modifiable and non-modifiable GC risk factors. Culturally and linguistically appropriate educational interventions may be a worthwhile adjunctive intervention within the context of a targeted GC screening program.

[Biofeedback therapy for chronic prostatitis: Application and consideration].

Studies of biological feedback (BF) for the treatment of chronic prostatitis (CP) are occasionally reported have exhibited some related problems. This article presents an evaluation of the published literature on the BF treatment of CP at home and abroad in the aspects of instrument, method, application, effect, function, and mechanism. UROSTYMTM and MyoTrac are often employed and their operating paths are basically the same. NIH prostate symptom scores, urinary function, pain, sexual function, immune function, prostate fluid, and other indicators are generally used for the analysis of the effects of BF alone or in combination with other therapies on CP and its related symptoms. Either BF alone or BF combined with other therapies can promote urination, reduce pain, improve the quality of life, attenuate inflammation, improve sexual function, adjust immunity, and lessen physical and chemical stimulation. However, the relevant literature is of low quantity and quality, the reported studies are not standardized, and exploration of the action mechanisms is neglected.

Swept-source optical coherence tomography imaging of macular retinal and choroidal structures in healthy eyes.

BACKGROUND: To report the thickness of the retina, retinal ganglion cell (RGC)-related layers, and choroid in healthy subjects using swept source optical coherence tomography (SS-OCT). METHODS: One hundred and forty-six healthy volunteers were consecutively recruited for this prospective observational study. Thickness of retina, RGC-related layers, and choroid in the standard early treatment of diabetic retinopathy study (ETDRS) grid were automatically measured using one SS-OCT (DRI OCT-1, Topcon, Japan). The IOL Master (Carl Zeiss Meditec, Germany) was used to measure axial length (AL). RESULTS: Thicknesses of the average macular ganglion cell complex (GCC) and ganglion cell-inner plexiform layer (GCIPL) were 105.3±9.7 and 78.5±6.2 um respectively. Neither of them was significantly related with sex, age, or AL. Both showed strong correlations with retinal thickness (r=0.793, p=0.000; r=0.813, p=0.000, respectively) and with similar topographic distributions within the retina. The thicknesses of retina and GCC/GCIPL in the inner sectors were significantly higher than in the outer sectors of the EDTRS area, while in the same region of the macula, the choroid exhibited completely different patterns of topographic variation. Men had 7.8 um thicker retina and 34.9 um thicker choroid than women after adjustment for age and AL (all p<0.05). Age and AL could significantly influence the choroidal thickness but not the retina (all p<0.05). CONCLUSION: Thickness of GCC/GCIPL in healthy Chinese individuals is not dramatically different across gender, age, and AL groups in terms of ETDRS grid, but sex is critical for retinal and choroidal thickness. Choroidal structure (but not retinal) can be significantly influenced by age and AL.

Exploring the Application of Metagenomic Next-Generation Sequencing in the Diagnosis of Unexplained Pulmonary Infection.

Background: Pulmonary infections are significant global health burdens, and conventional diagnostic methods (culture and polymerase chain reaction), are often limited by slow results and low sensitivity. Metagenomic next-generation sequencing (mNGS) offers a rapid, comprehensive alternative for identifying diverse pathogens, including rare and mixed infections. Thus, we assessed the diagnostic performance of mNGS in pulmonary infections, compared the findings with those of traditional pathogen detection methods, and explored its potential to enhance clinical diagnostics and patient care. Methods: We collected samples from 125 immunocompromised patients diagnosed with pulmonary infection at the Department of Respiratory Medicine of Shenzhen Longgang Central Hospital from March 2020 to July 2022. We compared the rate of pathogen positivity and pathogen distribution between conventional pathogen detection methods and mNGS using samples including sputum, blood, and bronchoalveolar lavage fluid. Results: Among the 125 cases of unexplained pulmonary infection, 82 (65.6%) and 40 (32.0%) tested positive for pathogens using mNGS and routine culture, respectively (P < 0.05). Both methods of pathogen detection were positive in 28 (22.4%) cases (complete match, 9; complete mismatch, 13; partial match, 6). However, 43.2% of cases only tested positive using mNGS, 9.4% only tested positive using routine tests, and 24.8% tested negative using both methods. A viral infection was present in 55.2% of cases. The detection rate of mycobacteria using mNGS (12.8%) was higher than that using conventional pathogen detection methods (5.6%). Conclusion: mNGS technology enhances pathogen detection in unexplained pulmonary infections, enabling targeted antimicrobial therapy and consequently helping to reduce broad-spectrum antibiotic use, aligning treatments more closely with the causative pathogens. Thus, mNGS offers significant clinical value by improving treatment efficacy and potentially reducing antibiotic resistance in pulmonary infection cases.

Polydopamine@ZIFs with enhanced electrochemiluminescence quenching performance for mycotoxin detection.

Quench-type electrochemiluminescence (ECL) immunosensors are appealing for detecting small molecule contaminants in signal-on mode, for which efficient ECL quenchers are highly desirable. Here, the classical quencher of polydopamine (PDA) was transformed into a unique structure by introducing zeolite imidazole frameworks (ZIFs). Besides the inherent energy transfer quenching effect on ECL, the resulting PDA@ZIFs exhibits a high scavenging property against electrogenerated coreactant-radicals and inhibits the formation of excited luminophore. A quench-type ECL immunosensor for ochratoxin A (OTA) was developed using the PDA@ZIFs as a quencher and the g-C3N4 as a luminophore. The immunosensor showed a good response towards the OTA with a linear range of 10.0 fg/mL-1.0 ng/mL and a detection limit of 4.8 fg/mL. Acceptable recoveries of 85.7 to 109.2 % were achieved for the detection of OTA in spiked foods. This work offers valuable insight for improving the performance of quench-typed ECL biosensors.

Salvage surgery for recurrent or residual hypopharyngeal squamous cell carcinoma: A systematic review.

BACKGROUND: This systematic review aggregates the data of studies that include site-specific analyses of patients undergoing salvage surgery for residual or recurrent hypopharyngeal squamous cell carcinoma. METHODS: The primary outcomes are disease-free, disease-specific, and overall survival (DFS, DSS, and OS, respectively). Secondary outcomes include complications and postoperative feeding requirements. RESULTS: Fifteen studies met the inclusion criteria with a total of 442 patients. Two-year DFS is reported from 30.0 to 50.0% and 5-year DFS ranges from 15.0 to 57.1%. Five-year DSS ranges from 28.0 to 57.1%. Two-year OS ranges from 38.8 to 52.0% and 5-year OS ranges from 15.5 to 57.1%. Complications include pharyngocutaneous fistula (0.0-71.4%), carotid artery rupture (2.9-13.3%), and stomal stenosis (4.2-20.0%). Complete oral feeding achieved following surgery ranges from 61.9 to 100.0%, while complete gastrostomy tube dependence ranges from 0.0 to 28.6%. CONCLUSIONS: Salvage surgery for residual or recurrent hypopharyngeal squamous cell carcinoma has a relatively high complication rate and should be offered to patients with the understanding of a guarded prognosis.

Effect analysis of 847 nasopharyngeal carcinoma cases treated with intensity modulated radiation: Experience and suggestions.

OBJECTIVES: To identify the failure patterns and prognostic factors of nonmetastatic nasopharyngeal carcinoma (NPC) in the intensity-modulated radiotherapy (IMRT) era. METHODS: Data on 847 patients with newly diagnosed, non-disseminated NPC treated by IMRT between 2012 and 2016 were retrospectively reviewed. Survival outcome, failure patterns and prognosis factors were analyzed. RESULTS: The 5-year local relapse-free survival, nodal relapse-free survival, distant metastasis-free survival, disease-free survival, and overall survival rates were 94.3%, 95.3%, 84.8%, 76.5% and 85.7%, respectively. The major local recurrence sites were the nasopharynx (91.5%, 43/47) and skull base (68.1%, 32/47); 39 patients had in-field failures, four had marginal failures, and four had out-field failures. Level IIb (62.2%, 23/37) was the most frequent regional recurrence site, followed by IIa (35.1%, 13/37) and retropharyngeal region (32.4%, 12/37); 35 cases had in-field failure alone, one had out-field failure alone, and one had both in- and out-field failure. TNM stage was the most significant factor for prognosis prediction. 402 (47.5%) patients had acute adverse events of grade 3 or 4; leukopenia (31.5%) and mucositis (26.7%) was the most common hematological and non-hematological event, respectively. Late complications were slight or moderate damages; xerostomia (647/847, 76.4%) and hearing impairment (422/847, 49.8%) remained the most troublesome. CONCLUSION: NPC patients treated with IMRT obtained satisfactory survival outcomes. The key failure pattern was distant metastasis. The main pattern of local-regional failure was in-field failure. Screening high risk patients with distant metastases and optimizing radiotherapy targets should be studied.

Utility of TTMV-HPV DNA in resolving indeterminate findings during oropharyngeal cancer surveillance.

OBJECTIVES: Clinical and imaging examinations frequently have indeterminate results during cancer surveillance, which can lead to overtreatment and cause psychological and financial harm to the patient. This study addresses the critical need to enhance diagnostic precision and decision-making in the management of HPV-associated oropharyngeal cancer. This study evaluated the utility of tumor tissue-modified viral (TTMV)-HPV DNA to resolve indeterminate disease status following definitive treatment for HPV-associated oropharyngeal cancer. MATERIALS AND METHODS: In this retrospective cohort, patients treated for HPV-associated oropharyngeal cancer at eight U.S. institutions and who received one or more TTMV-HPV DNA tests during post-treatment surveillance between February 2020 and January 2022 were included. RESULTS: Among 543 patients, 210 patients (38.7%; 210/543) experienced one or more clinically indeterminate findings (CIFs) during surveillance, with 503 CIFs recorded. Of those patients with an "indeterminate" disease status at a point during surveillance, 79 were associated with contemporaneous TTMV-HPV DNA testing. TTMV-HPV DNA testing demonstrated high accuracy (97.5%; 77/79) in correctly determining recurrence status. Patients whose disease status was "indeterminate" at the time of a positive TTMV-HPV DNA test were clinically confirmed to recur faster than those whose disease status was "no evidence of disease." Only 3% of patients (17/543) experienced indeterminate TTMV-HPV DNA tests during surveillance. Discordance between TTMV-HPV DNA tests and clinical results was minimal, with only 0.6% (3/543) of patients showing positive tests without recurrence. CONCLUSION: Our findings support the utility of circulating TTMV-HPV DNA in resolving indeterminate disease status and informing the subsequent clinical course.

Barriers, Facilitators, and Sustainers in Tai Ji Quan Practice: A Mixed-Methods RE-AIM Assessment of College Students Versus the General Population.

BACKGROUND: Tai Ji Quan (TJQ) has broad appeal to people of all ages and backgrounds. This study aimed to examine a variety of individual and environmental factors in the dissemination of TJQ to diverse practicing communities in China. METHODS: A mixed-methods approach was utilized in the research design. Quantitative data were collected via an online survey using a national sample (N = 737), whereas qualitative data came from focus groups and in-depth interviews. Analysis was performed along the RE-AIM dimensions of reach, efficacy, adoption, implementation, and maintenance. RESULTS: We divided TJQ experience into 4 distinct categories (nonlearners, current learners, quitters, and retainers) and observed significant patterns of variation along lines of occupation groups and age cohorts. A significant male/female difference was detected in TJQ experience among college students but not the general public, and having practicing family members was an important predictor of personal TJQ history. Varied TJQ experience has a significant impact on perceptions of TJQ's miscellaneous values as well as level of satisfaction with its health outcomes. CONCLUSIONS: Both individual (personal) and environmental (settings) factors are important in shaping personal decisions in TJQ engagement. An ecological approach coordinating individual factors and settings resources is essential in promoting TJQ to the general population.

M2b macrophages protect against doxorubicin induced cardiotoxicity via alternating autophagy in cardiomyocytes.

OBJECTIVE: Doxorubicin (DOX) is an anthracycline antibiotic which is widely used for the treatment of various cancers, while the dose-related cardiotoxicity limits its potential therapeutic application. The underlying mechanism of DOX induced cardiotoxicity is complex and remains elusive. Our previous studies have shown that M2b macrophage plays an important role in reducing inflammation due to ischemic reperfusion injury in the myocardium. The purpose of this study was to investigate the potential protective role of M2b macrophages in DOX induced cardiotoxicity. METHODS: In vivo, we conducted DOX induced cardiac injury in C57BL/6 mice and treated them with M2b macrophages. Then, the mice were examined by echocardiography. The heart specimens were harvested for histological examination, transmission electron microscope analysis, and autophagy molecules evaluation. In vitro, HL-1 cardiac cell lines treated with DOX were cocultured with or without M2b macrophages. Then, Autophagy related genes and protein expression were assessed by real-time quantitative PCR and western blot; cell proliferation was assessed by cell counting kit-8. RESULTS: We found that M2b macrophages can improve cardiac function and alleviate cardiac injury in DOX induced cardiac injury mice. M2b macrophages can enhance cardiac autophagy levels both in vivo and in vitro in DOX induced cardiac injury model. In addition, this protective effect can be blocked by an autophagy inhibitor. CONCLUSION: Our study shows that M2b macrophages can help attenuate the DOX induced cardiotoxicity by regulating the autophagy level of cardiomyocytes.

High-throughput metagenomics analysis in early and precise diagnosis of eosinophilic meningoencephalitis complicated with respiratory failure: A case report.

RATIONALE: Human infection with Angiostrongylus cantonensis is uncommon and has only been sporadically reported in the literature. Patients infected with A cantonensis usually have a delayed diagnosis and sometimes a poor prognosis. PATIENT CONCERNS: A 70-year-old woman presented to the respiratory department with complaints of headache, chest pain, myalgia, fatigue, and anorexia for 7 days. DIAGNOSES: Complete blood count showed eosinophilia. The serum was tested showing a positive finding of A cantonensis antibody. Cerebrospinal fluid was tested using high-throughput metagenomics analysis and 16 reads for A cantonensis were mapped. The patient was diagnosed with A cantonensis infection. INTERVENTIONS: The patient received a 7-day course of albendazole and 4-day course of prednisone. OUTCOMES: When discharged from the hospital, the patient still suffered from fatigue and poor memory. Aminotransferase levels were high due to albendazole's liver toxicity. In a post-discharge follow-up about 1 month later she had recovered completely both physically and mentally, and peripheral eosinophil count and aminotransferase levels were both normal. LESSONS: Because the direct identification of parasites is difficult, high-throughput metagenomics analysis may provide a reliable alternative tool for the diagnoses of infection with A cantonensis. When albendazole is prescribed, caution must be taken with respect to its liver toxicity.

Performance of Liquid Biopsy for Diagnosis and Surveillance of Human Papillomavirus-Associated Oropharyngeal Cancer.

Importance: There is growing interest in the use of circulating plasma tumor human papillomavirus (HPV) DNA for diagnosis and surveillance of patients with HPV-associated oropharyngeal squamous cell carcinoma (OPSCC). Recent advances in the assays, combining the identification of circulating HPV tumor DNA and tumor DNA fragment analysis (tumor tissue-modified viral [TTMV]-HPV DNA), have been shown to be highly accurate. However, use of these newer techniques has been limited to small cohort studies and clinical trials. Objective: To establish the clinical efficacy of plasma TTMV-HPV DNA testing in the diagnosis and surveillance of HPV-associated OPSCC in a contemporary clinical setting. Design, Setting, and Participants: This retrospective observational cohort study included patients with OPSCC who underwent TTMV-HPV DNA testing between April 2020 and September 2022 during the course of routine clinical care. For the diagnosis cohort, patients with at least 1 TTMV-HPV DNA measurement prior to initiation of primary therapy were included. Patients were included in the surveillance cohort if they had at least 1 TTMV-HPV DNA test performed after completion of definitive or salvage therapy. Main Outcomes and Measures: Per-test performance metrics, including sensitivity, specificity, positive predictive value, and negative predictive value, for TTMV-HPV DNA testing. Results: Of 399 patients included in the analysis, 163 were in the diagnostic cohort (median [IQR] age, 63 [56-68.5] years; 142 [87.1%] male), and 290 were in the surveillance cohort (median [IQR] age, 63 [57-70] years; 237 [81.7%] male). Of the 163 patients in the diagnostic cohort, 152 (93.3%) had HPV-associated OPSCC while 11 (6.7%) had HPV-negative OPSCC. The TTMV-HPV DNA sensitivity in pretreatment diagnosis was 91.5% (95% CI, 85.8%-95.4% [139 of 152 tests]), and the specificity was 100% (95% CI, 71.5%-100% [11 of 11 tests]). In the surveillance cohort, 591 tests conducted in 290 patients were evaluated. A total of 23 patients had molecularly confirmed pathologic recurrences. The TTMV-HPV DNA test demonstrated sensitivity of 88.4% (95% CI, 74.9%-96.1% [38 of 43 tests]) and specificity of 100% (95% CI, 99.3%-100% [548 of 548 tests]) in detecting the recurrences. Positive predictive value was 100% (95% CI, 90.7%-100% [38 of 38 tests]), and negative predictive value was 99.1% (95% CI, 97.9%-99.7% [548 of 553 tests]). The median (range) lead time from positive TTMV-HPV DNA test to pathologic confirmation was 47 (0-507) days. Conclusions and Relevance: This cohort study demonstrated that when evaluated in a clinical setting, the TTMV-HPV DNA assay demonstrated 100% specificity in both diagnosis and surveillance. However, the sensitivity was 91.5% for the diagnosis cohort and 88.4% for the surveillance cohort, signifying that nearly 1 in 10 negative tests among patients with HPV-associated OPSCC was a false negative. Additional research is required to validate the assay's performance and, if validated, then further research into the implementation of this assay into standard clinical practice guidelines will be required.

Negative Predictive Value of Circulating Tumor Tissue Modified Viral (TTMV)-HPV DNA for HPV-driven Oropharyngeal Cancer Surveillance.

PURPOSE: Human papillomavirus (HPV) is causally linked to oropharyngeal squamous cell carcinoma (OPSCC). Consensus guidelines recommend clinical exams and imaging in decreasing frequency as part of posttreatment surveillance for recurrence. Plasma tumor tissue modified viral (TTMV)-HPV DNA testing has emerged as a biomarker which can inform disease status during surveillance. EXPERIMENTAL DESIGN: This retrospective observational cohort study involved 543 patients who completed curative-intent therapy for HPV-associated OPSCC between February 2020 and January 2022 at eight U.S. cancer care institutions. We determined the negative predictive value (NPV) of TTMV-HPV DNA for recurrence when matched to physician-reported clinical outcome data (median follow-up time: 27.9 months; range: 4.5-154). RESULTS: The cohort included mostly men with a median age of 61 who had locoregionally advanced disease. HPV status was determined by p16 positivity in 87% of patients, with a positive HPV PCR/ISH among 55%; while pretreatment TTMV-HPV DNA status was unknown for most (79%) patients. Patients had a mean of 2.6 tests and almost half had three or more TTMV-HPV DNA results during surveillance. The per-test and per-patient sensitivity of the assay was 92.5% [95% confidence interval (CI): 87.5-97.5] and 87.3% (95% CI: 79.1-95.5), respectively. The NPV for the assay was 99.4% (95% CI: 98.9-99.8) and 98.4% (95% CI: 97.3-99.5), respectively. CONCLUSIONS: TTMV-HPV DNA surveillance testing yields few false negative results and few missed recurrences. These data could inform decisions on when to pursue reimaging following first disease restaging and could inform future surveillance practice. Additional study of how pretreatment TTMV-HPV DNA status impacts sensitivity for recurrence is needed.

Prediction and control of focal seizure spread: Random walk with restart on heterogeneous brain networks.

Whole-brain models offer a promising method of predicting seizure spread, which is critical for successful surgical treatment of focal epilepsy. Existing methods are largely based on structural connectome, which ignores the effects of heterogeneity within the regional excitability of brains. In this study we used a whole-brain model to show that heterogeneity in nodal excitability had a significant impact on seizure propagation in the networks and compromised the prediction accuracy with structural connections. We then addressed this problem with an algorithm based on random walk with restart on graphs. We demonstrated that by establishing a relationship between the restarting probability and the excitability for each node, this algorithm could significantly improve the seizure spread prediction accuracy in heterogeneous networks and was more robust against the extent of heterogeneity. We also strategized surgical seizure control as a process to identify and remove the key nodes (connections) responsible for the early spread of seizures from the focal region. Compared to strategies based on structural connections, virtual surgery with a strategy based on a modified random walk with extended restart generated outcomes with a high success rate while maintaining low damage to the brain by removing fewer anatomical connections. These findings may have potential applications in developing personalized surgery strategies for epilepsy.

Erratum: lncRNA FTX promotes asthma progression by sponging miR-590-5p and upregulating JAK2.

[This corrects the article on p. 8833 in vol. 13, PMID: 34539998.].

Bilateral internal thoracic artery coronary grafting: risks and benefits in elderly patients.

AIMS: Whether bilateral internal thoracic artery (BITA) grafting benefits elderly patients in coronary artery bypass grafting (CABG) remains unclear since they tend to have a limited life expectancy and severe comorbidities. We aim to evaluate the outcomes of BITA vs. single internal thoracic artery (SITA) grafting in elderly patients. METHODS AND RESULTS: A meta-analysis was performed by database searching until May 2021. Studies comparing BITA and SITA grafting among elderly patients were included. One randomized controlled trial, nine propensity score matching, and six unmatched studies were identified, with a total of 18 146 patients (7422 received BITA grafting and 10 724 received SITA grafting). Compared with SITA grafting, BITA grafting had a higher risk of deep sternal wound infection (DSWI) [odds ratio: 1.67; 95% confidence interval (CI): 1.22-2.28], and this risk could not be significantly reduced by the skeletonization technique. Meanwhile, BITA grafting was associated with a higher long-term survival [hazard ratio: 0.83; 95% CI: 0.77-0.90], except for the octogenarian subgroup. Reconstructed Kaplan-Meier survival curves revealed 4-year, 8-year, and 12-year overall survival rates of 85.5%, 66.7%, and 45.3%, respectively, in the BITA group and 79.3%, 58.6%, and 34.9%, respectively, in the SITA group. No significant difference was observed in early mortality, perioperative myocardial infarction, perioperative cerebral vascular accidents, or re-exploration for bleeding. CONCLUSION: Compared with SITA grafting, BITA grafting could provide a long-term survival benefit for elderly patients, although this benefit remained uncertain in octogenarians. Meanwhile, elderly patients who received BITA were associated with a higher risk of DSWI and such a risk could not be eliminated by the skeletonization technique.