PURPOSE: Recent papers suggested a correlation between the risk of distant metastasis (DM) and dose outside the PTV, though conclusions in different publications conflicted. This study resolves these conflicts and provides a compelling explanation of prognostic factors. MATERIALS AND METHODS: A dataset of 478 NSCLC patients treated with SBRT (IMRT or VMAT) was analyzed. We developed a deep learning model for DM prediction and explainable AI was used to identify the most significant prognostic factors. Subsequently, the prognostic power of the extracted features and clinical details were analyzed using conventional statistical methods. RESULTS: Treatment technique, tumor features, and dosiomic features in a 3 cm wide ring around the PTV (PTV3cm) were identified as the strongest predictors of DM. The Hazard Ratio (HR) for Dmean,PTV3cm was significantly above 1 (p < 0.001). There was no significance of the PTV3cm dose after treatment technique stratification. However, the dose in PTV3cm was found to be a highly significant DM predictor (HR > 1, p = 0.004) when analyzing only VMAT patients with small and spherical tumors (i.e., sphericity > 0.5). CONCLUSIONS: The main reason for conflicting conclusions in previous papers was inconsistent datasets and insufficient consideration of confounding variables. No causal correlation between the risk of DM and dose outside the PTV was found. However, the mean dose to PTV3cm can be a significant predictor of DM in small spherical targets treated with VMAT, which might clinically imply considering larger PTV margins for smaller, more spherical tumors (e.g., if IGTV > 2 cm, then margin ≤ 7 mm, else margin > 7 mm).

• MeSH
• Radiotherapy Dosage * MeSH
• Deep Learning * MeSH
• Middle Aged MeSH
• Humans MeSH
• Neoplasm Metastasis MeSH
• Lung Neoplasms * pathology   radiotherapy   MeSH
• Carcinoma, Non-Small-Cell Lung * radiotherapy   pathology   MeSH
• Radiotherapy Planning, Computer-Assisted methods   MeSH
• Prognosis MeSH
• Radiosurgery * methods   MeSH
• Radiotherapy, Intensity-Modulated methods   MeSH
• Aged MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

BACKGROUND: Patients with bipolar disorder (BD) and major depressive disorder (MDD) exhibit depressive episodes with similar symptoms despite having different and poorly understood underlying neurobiology, often leading to misdiagnosis and improper treatment. This exploratory study examined whole-brain functional connectivity (FC) using FC multivariate pattern analysis (fc-MVPA) to identify the FC patterns with the greatest ability to distinguish between currently depressed patients with BD type I (BD I) and those with MDD. METHODOLOGY: In a cross-sectional design, 41 BD I, 40 MDD patients and 63 control participants completed resting state functional magnetic resonance imaging scans. Data-driven fc-MVPA, as implemented in the CONN toolbox, was used to identify clusters with differential FC patterns between BD patients and MDD patients. The identified cluster was used as a seed in a post hoc seed-based analysis (SBA) to reveal associated connectivity patterns, followed by a secondary ROI-to-ROI analysis to characterize differences in connectivity between these patterns among BD I patients, MDD patients and controls. RESULTS: FC-MVPA identified one cluster located in the right frontal pole (RFP). The subsequent SBA revealed greater FC between the RFP and posterior cingulate cortex (PCC) and between the RFP and the left inferior/middle temporal gyrus (LI/MTG) and lower FC between the RFP and the left precentral gyrus (LPCG), left lingual gyrus/occipital cortex (LLG/OCC) and right occipital cortex (ROCC) in MDD patients than in BD patients. Compared with the controls, ROI-to-ROI analysis revealed lower FC between the RFP and the PCC and greater FC between the RFP and the LPCG, LLG/OCC and ROCC in BD patients; in MDD patients, the analysis revealed lower FC between the RFP and the LLG/OCC and ROCC and greater FC between the RFP and the LI/MTG. CONCLUSIONS: Differences in the RFP FC patterns between currently depressed patients with BD and those with MDD suggest potential neuroimaging markers that should be further examined. Specifically, BD patients exhibit increased FC between the RFP and the motor and visual networks, which is associated with psychomotor symptoms and heightened compensatory frontoparietal FC to counter distractibility. In contrast, MDD patients exhibit increased FC between the RFP and the default mode network, corresponding to sustained self-focus and rumination.

• MeSH
• Bipolar Disorder * physiopathology   diagnostic imaging   MeSH
• Depressive Disorder, Major * physiopathology   diagnostic imaging   MeSH
• Adult MeSH
• Connectome methods   MeSH
• Middle Aged MeSH
• Humans MeSH
• Magnetic Resonance Imaging * methods   MeSH
• Brain Mapping methods   MeSH
• Brain physiopathology   diagnostic imaging   MeSH
• Multivariate Analysis MeSH
• Nerve Net diagnostic imaging   physiopathology   MeSH
• Neural Pathways physiopathology   diagnostic imaging   MeSH
• Cross-Sectional Studies MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

We present a novel system that leverages curators in the loop to develop a dataset and model for detecting structure features and functional annotations at residue-level from standard publication text. Our approach involves the integration of data from multiple resources, including PDBe, EuropePMC, PubMedCentral, and PubMed, combined with annotation guidelines from UniProt, and LitSuggest and HuggingFace models as tools in the annotation process. A team of seven annotators manually curated ten articles for named entities, which we utilized to train a starting PubmedBert model from HuggingFace. Using a human-in-the-loop annotation system, we iteratively developed the best model with commendable performance metrics of 0.90 for precision, 0.92 for recall, and 0.91 for F1-measure. Our proposed system showcases a successful synergy of machine learning techniques and human expertise in curating a dataset for residue-level functional annotations and protein structure features. The results demonstrate the potential for broader applications in protein research, bridging the gap between advanced machine learning models and the indispensable insights of domain experts.

• MeSH
• Databases, Protein MeSH
• Humans MeSH
• Proteins * chemistry   MeSH
• Machine Learning * MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Dataset MeSH

Colorectal cancer (CRC) is a leading global cause of illness and death. There is a need for identification of better prognostic markers beyond traditional clinical variables like grade and stage. Previous research revealed that abnormal expression of cytokeratin 7 (CK7) and loss of the intestinal-specific Special AT-rich sequence-binding protein 2 (SATB2) are linked to poor CRC prognosis. This study aimed to explore these markers' prognostic significance alongside two extraintestinal mucins (MUC5AC, MUC6), claudin 18, and MUC4 in 285 CRC cases using immunohistochemistry on tissue microarrays (TMAs). CK7 expression and SATB2-loss were associated with MUC5AC, MUC6, and claudin 18 positivity. These findings suggest a distinct "non-intestinal" immunohistochemical profile in CRC, often right-sided, SATB2-low, with atypical expression of CK7 and non-colorectal mucins (MUC5AC, MUC6). Strong MUC4 expression negatively impacted cancer-specific survival (hazard ratio = 2.7, p = 0.044). Genetic analysis via next-generation sequencing (NGS) in CK7 + CRCs and those with high MUC4 expression revealed prevalent mutations in TP53, APC, BRAF, KRAS, PIK3CA, FBXW7, and SMAD4, consistent with known CRC mutation patterns. NGS also identified druggable variants in BRAF, PIK3CA, and KRAS. CK7 + tumors showed intriguingly common (31.6%) BRAF V600E mutations corelating with poor prognosis, compared to the frequency described in the literature and databases. Further research on larger cohorts with a non-colorectal immunophenotype and high MUC4 expression is needed.

• MeSH
• Adult MeSH
• Phenotype MeSH
• Class I Phosphatidylinositol 3-Kinases genetics   metabolism   MeSH
• Immunohistochemistry * MeSH
• Keratin-7 metabolism   genetics   MeSH
• Colorectal Neoplasms * genetics   pathology   metabolism   mortality   MeSH
• Middle Aged MeSH
• Humans MeSH
• Mucin-4 genetics   metabolism   MeSH
• Mucin 5AC genetics   metabolism   MeSH
• Mucin-6 genetics   metabolism   MeSH
• Mutation MeSH
• Biomarkers, Tumor * genetics   metabolism   MeSH
• Prognosis MeSH
• Proto-Oncogene Proteins B-raf genetics   MeSH
• Proto-Oncogene Proteins p21(ras) genetics   MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Transcription Factors MeSH
• Matrix Attachment Region Binding Proteins * genetics   metabolism   MeSH
• High-Throughput Nucleotide Sequencing MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

OBJECTIVE: To investigate the impact of ageing on survival outcomes in Bacillus Calmette-Guérin (BCG) treated non-muscle invasive bladder cancer (NMIBC) patients and its synergy with adequate BCG treatment. METHOD: Patients with NMIBC who received BCG treatment from 2001 to 2020 were divided into group 1 (< = 70 years) and group 2 (> 70 years). Overall Survival (OS), Cancer-Specific Survival (CSS), Recurrence-Free Survival (RFS), and Progression-Free Survival (PFS) were analyzed using the Kaplan-Meier method. Multivariable Cox regression analysis was used to adjust potential confounding factors and to estimate Hazard Ratio (HR) and 95% Confidence Interval (CI). Subgroup analysis was performed according to adequate versus inadequate BCG treatment. RESULTS: Overall, 2602 NMIBC patients were included: 1051 (40.4%) and 1551 (59.6%) in groups 1 and 2, respectively. At median follow-up of 11.0 years, group 1 (< = 70 years) was associated with better OS, CSS, and RFS, but not PFS as compared to group 2 (> 70 years). At subgroup analysis, patients in group 1 treated with adequate BCG showed better OS, CSS, RFS, and PFS as compared with inadequate BCG treatment in group 2, while patients in group 2 receiving adequate BCG treatment had 41% less progression than those treated with inadequate BCG from the same group. CONCLUSIONS: Being younger (< = 70 years) was associated with better OS, CSS, and RFS, but not PFS. Older patients (> 70 years) who received adequate BCG treatment had similar PFS as those younger with adequate BCG treatment.

• MeSH
• Adjuvants, Immunologic * therapeutic use   MeSH
• Administration, Intravesical MeSH
• BCG Vaccine * therapeutic use   MeSH
• Neoplasm Invasiveness * MeSH
• Middle Aged MeSH
• Humans MeSH
• Survival Rate MeSH
• Non-Muscle Invasive Bladder Neoplasms MeSH
• Urinary Bladder Neoplasms * drug therapy   pathology   therapy   mortality   MeSH
• Retrospective Studies MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Age Factors MeSH
• Treatment Outcome MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

BACKGROUND: Surgical site infection (SSI) is the most consistently reported complication of cranioplasty. No material showed a categorical superiority in the incidence of infection. Porous polyethylene (PE) is considered a low risk material regarding SSI. However, the literature data are very limited. Thus, our objective was to verify the assumed low incidence of SSI after PE cranioplasty in patients at high risk of SSI. The primary objective was the infection rate, while secondary objectives were implant exposure, revision and cosmetic results. METHOD: Patients who underwent three-dimensional (3D) personalized PE cranioplasty in the period 2014-2023 were evaluated prospectively. Only patients with an increased risk of SSI, and a satisfactory clinical conditions were included in the study. RESULTS: Thirty procedures were performed in 30 patients. Cranioplasty was performed 23 times after hemispheric decompressive craniectomy, five times after limited size craniotomy and two times after bifrontal decompressive craniectomy. Risk factors for the development of infection were 18 previous SSIs, 16 previous repeated revision surgeries, four intraoperatively opened frontal sinuses and two times radiotherapy. Neither infection nor implant exposure was detected in any patient. All patients were satisfied with the aesthetic result. In two cases, a revision was performed due to postoperative epidural hematoma. CONCLUSIONS: Three-dimensional personalized PE cranioplasty is associated with an extremely low incidence of SSI even in high-risk patients. However, our conclusions can only be confirmed in larger studies.

• MeSH
• Decompressive Craniectomy adverse effects   methods   MeSH
• Adult MeSH
• Surgical Wound Infection * epidemiology   etiology   MeSH
• Craniotomy adverse effects   methods   MeSH
• Skull surgery   MeSH
• Middle Aged MeSH
• Humans MeSH
• Polyethylene MeSH
• Porosity MeSH
• Prospective Studies MeSH
• Risk Factors MeSH
• Aged MeSH
• Plastic Surgery Procedures * methods   adverse effects   MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

BACKGROUND: The 6-minute walking test (6WT) has previously shown to be reliable and valid outcome measure in patients undergoing surgery for degenerative lumbar disorders (DLD). A role of 6WT in conservatively treated patients undergoing epidural steroid injection (ESI) remains unclear. METHODS: About 50 patients with DLD, scheduled for ESI were assessed by the smartphone-based 6WT and common paper-based patient-reported outcome measures (PROMs), including the Core Outcome Measures Index [COMI] back, Oswestry Disability Index (ODI) and Short Form Survey (SF-12). Pearson correlation coefficient (PCC) was used to define the relationship between 6WT and PROMs. Reliability of the 6WT was determined by intraclass correlation coefficient (ICC). Age- and sex-adjusted objective functional impairment (OFI) z-scores were calculated for each patient. RESULTS: A total of 50 patients (mean age 52 years, SD 13; 25% female), including 35 patients (70%) with lumbar disc herniation and 15 patients (30%) with lumbar spinal stenosis were included. The mean 6-minute walking distance (6WD) was 454.1 m (SD 89.1); the age- and sex-adjusted mean OFI z-score was -2.1 (SD 4.0). A total of 17 (34%) patients had mild, 8 (16%) moderate, and 4 (8%) severe OFI, while 21 (42%) had 6WT results within the normal population range (no OFI). The PCCs between the 6WD and VAS back pain were r=-0.30, ODI r=-0.43, COMI back r=-0.36, and PCS-12 r=0.51 (all p<.05). The ICC of the 6WT was β=0.92. CONCLUSIONS: This external validation in a patient cohort with DLD, which was managed conservatively, confirms the reliability and content validity of the 6WT with similar PCCs with PROMs compared to the original surgical cohort. The results confirm the 6WT as a valid and useful tool for assessing OFI in patients with DLD and a broad range of functional restrictions in an outpatient setting.

• Publication type
• Journal Article MeSH

BACKGROUND: Improved prediction of prognosis among lung cancer patients could facilitate better clinical management. We aimed to study the prognostic significance of circulating proteins at the time of lung cancer diagnosis, among patients with and without smoking history. METHODS: We measured 91 proteins using the Olink Immune-Oncology panel in plasma samples that were collected at diagnosis from 244 never smoking and 742 ever smoking patients with stage I-IIIA non-small cell lung cancer (NSCLC). Patients were recruited from nine centres in Russian Federation, Poland, Serbia, Czechia, and Romania, between 2007-2016 and were prospectively followed through 2020. We used multivariable Survey-weighted Cox models to assess the relationship between overall survival and levels of proteins by adjusting for smoking, age at diagnosis, sex, education, alcohol intake, histology, and stage. RESULTS: The 5-year survival rate was higher among never than ever smoking patients (63.1% vs. 46.6%, P<0.001). In age- and sex-adjusted survival analysis, 23 proteins were nominally associated with overall survival, but after adjustment for potential confounders and correcting for multiple testing, none of the proteins showed a significant association with overall survival. In stratified analysis by smoking status, IL8 [hazard ratio (HR) per standard deviation (SD): 1.40, 95% confidence interval (CI): 1.18-1.65, P=1×10-4] and hepatocyte growth factor (HGF) (HR: 1.45, 95% CI: 1.18-1.79, P=5×10-4) were associated with survival among never smokers, but no protein was found associated with survival among ever smokers. Integrating proteins into the models with clinical risk factors did not improve the predictive performance of NSCLC prognosis [C-index of 0.63 (clinical) vs. 0.64 (clinical + proteins) for ever smokers, P=0.20; C-index of 0.68 (clinical) vs. 0.72 (clinical + proteins) for never smokers, P=0.28]. CONCLUSIONS: We found limited evidence of a potential for circulating immune- and cancer-related protein markers in lung cancer prognosis. Whereas some specific proteins appear to be uniquely associated with lung cancer survival in never smokers.

• Publication type
• Journal Article MeSH

Background/Objectives: For locally applied, locally acting generic drug products, comparison to an originator product based on systemic exposure is usually not feasible due to low plasma concentrations and inadequate reflection of local exposure at the site of action. Where a validated PD model exists, a comparative clinical study can be performed in healthy subjects; where no surrogate endpoint is available, patients with the relevant indication need to be enrolled, with all the associated factors which could result in lack of sensitivity. Even though the need for alternative in vitro approaches has been acknowledged by both industry and regulatory bodies, the complexity of in vivo drug delivery processes makes the development of guidance documents particularly difficult. Our objective was to present in vitro approaches less classically used and to address in vivo relevance of the selected tests. Methods: This article analyses current regulatory approaches in Europe and the U.S., and highlights the key advantages of in vitro tests in terms of their sensitivity, reliability, reproducibility and in vivo relevance using locally applied flurbiprofen in various formulations. Results: The in vitro esophageal retention (IVOR) model demonstrates that the first 6-10 min after application of different flurbiprofen formulations is important for their comparison and also offers the best correlation with in vivo data using the partial area under the concentration-time curves (pAUCs). Rheological evaluations further demonstrated that the mucoadhesive properties of the gel spray formulation are based on interaction with mucin. Conclusions: Designing a relevant in vitro test requires adequate evaluation of the complexity of the drug substance, drug product, dosing conditions and delivery processes.

• Publication type
• Journal Article MeSH

OBJECTIVES: Due to Albendazole's relatively low efficacy and bioavailability, Echinococcosis has proven a challenge to manage successfully, with several studies investigating ways to improve the outcome, mainly showing mixed results. We, therefore, aimed to evaluate whether Sulfonated Graphene Oxide (S-GO), as nanocarriers, could improve the mentioned outcome. METHODS: Echinococcus protoscoleces were divided into four groups based on the agent they received, which comprised control, S-GO, Albendazole, and Albendazole-loaded S-GO (S-GO-Albendazole). Then, the Bax and Bcl-2 gene expression levels and the number of surviving protoscoleces in each group were determined. RESULTS: Bax gene expression increased by 121% in the 50 μg/ml concentration of the S-GO-Albendazole, while Bcl-2 gene expression decreased by 64%. Moreover, S-GO-Albendazole was approximately 18% more effective at neutralizing protoscoleces than Albendazole and 14% and 31% more effective at improving the expression of the mentioned genes, respectively (p < 0.05). In addition, the number of surviving protoscoleces after exposure to the mentioned concentration reduced by approximately 99%. CONCLUSIONS: S-GO, despite not having significant lethality on protoscoleces, significantly increased the lethality of Albendazole and, therefore, is a suitable nanocarrier. However, we recommend conducting in vivo and clinical studies to more accurately determine this nanocomplex's potential and side effects.

• Publication type
• Journal Article MeSH