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Simple Summary: Endometrial cancer disrupts various internal functions, which may be reflected across several blood markers or biomarkers. The precise ratios of these biomarkers could be useful for endometrial cancer diagnosis, prognosis, and treatment decisions. Our study aimed to observe whether a panel of blood markers (red blood cells, white blood cells, platelets, inflammatory markers) managed to distinguish between two endometrial entities (neoplasia versus hyperplasia). Background: Endometrial cancer is associated with changes in blood cell counts and with high levels of inflammatory markers, thus reflecting the tumor's impact on various biological processes and suggesting their potential as biomarkers for endometrial cancer diagnosis, prognosis, and treatment response. The neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, and monocyte-to-lymphocyte ratio in peripheral blood sampled preoperatively from patients have been reported to be independently associated with the prognosis of different types of malignancies. Objectives: This study aimed to compare several blood markers—red blood cells, white blood cells, platelet parameters, neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, monocyte-to-lymphocyte ratio, C-reactive protein, and fibrinogen—in patients with benign or malignant endometrial tumors. Material and methods: Our retrospective study included 670 patients (192 diagnosed with endometrial cancer and 478 with endometrial hyperplasia), and we compared the serological parameters discussed above with those sampled the day before surgery. Results: Analysis of complete blood count indices revealed no significant differences in red blood cell or total white blood cell parameters between the endometrial cancer group and the endometrial hyperplasia group. However, a distinct pattern emerged in the white blood cell differential. The endometrial cancer group showed a statistically significant decrease in lymphocyte count compared with the endometrial hyperplasia group. In contrast, the endometrial cancer group showed significantly higher mean platelet counts and increased mean platelet volume compared with controls. Furthermore, the endometrial cancer group demonstrated a marked inflammatory response, as evidenced by significantly elevated levels of C-reactive protein, fibrinogen, neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, and monocyte-to-lymphocyte ratio compared with the endometrial hyperplasia group. Conclusions: The current research revealed statistically significant differences in multiple serological biomarkers between the two groups. These findings support the initial hypothesis regarding the potential utility of these biomarkers in endometrial cancer diagnosis, prognosis, and treatment response, highlighting the existence of biomarkers affordable for analysis under any health system, regardless of the country's level of development. [ABSTRACT FROM AUTHOR]

Simple Summary: We developed an attention-based whole slide image (WSI)-level classification deep learning model employing surgically and endoscopically resected specimens to predict LNM in T1 CRC. Our AI model with H&E-stained WSIs and without annotations showed good performance power with the validation of an independent cohort in a single center. The area under the curve of our model was 0.781–0.824, higher than that of previous artificial intelligence (AI) studies with only WSIs. Our AI model, which showed the highest sensitivity (92.9%), reduced unnecessary additional surgery by 14.2% more than using the current JSCCR guidelines (68.3% vs. 82.5%). This revealed the feasibility of using an AI model with only H&E-stained WSIs to predict LNM in T1 CRC. According to the current guidelines, additional surgery is performed for endoscopically resected specimens of early colorectal cancer (CRC) with a high risk of lymph node metastasis (LNM). However, the rate of LNM is 2.1–25.0% in cases treated endoscopically followed by surgery, indicating a high rate of unnecessary surgeries. Therefore, this study aimed to develop an artificial intelligence (AI) model using H&E-stained whole slide images (WSIs) without handcrafted features employing surgically and endoscopically resected specimens to predict LNM in T1 CRC. To validate with an independent cohort, we developed a model with four versions comprising various combinations of training and test sets using H&E-stained WSIs from endoscopically (400 patients) and surgically resected specimens (881 patients): Version 1, Train and Test: surgical specimens; Version 2, Train and Test: endoscopic and surgically resected specimens; Version 3, Train: endoscopic and surgical specimens and Test: surgical specimens; Version 4, Train: endoscopic and surgical specimens and Test: endoscopic specimens. The area under the curve (AUC) of the receiver operating characteristic curve was used to determine the accuracy of the AI model for predicting LNM with a 5-fold cross-validation in the training set. Our AI model with H&E-stained WSIs and without annotations showed good performance power with the validation of an independent cohort in a single center. The AUC of our model was 0.758–0.830 in the training set and 0.781–0.824 in the test set, higher than that of previous AI studies with only WSI. Moreover, the AI model with Version 4, which showed the highest sensitivity (92.9%), reduced unnecessary additional surgery by 14.2% more than using the current guidelines (68.3% vs. 82.5%). This revealed the feasibility of using an AI model with only H&E-stained WSIs to predict LNM in T1 CRC. [ABSTRACT FROM AUTHOR]

Simple Summary: Prostate cancer is a commonly diagnosed cancer in men with varying outcomes following treatment. This study focuses on a specific feature observed in some prostate cancers called a histologically overt stromal response (HOST-response), which involves changes in the tissue surrounding the cancer cells. Our research used data from patients who had undergone surgery for prostate cancer to explore how this stromal response impacted their recovery without the cancer returning. We found that the presence of a HOST-response is linked to a higher chance of the cancer coming back sooner. These findings suggest that monitoring for this feature could help identify patients who might benefit from additional treatments after surgery, which could potentially improve their outcomes. The results of this study could guide future clinical trials aiming to refine treatment strategies for prostate cancer patients exhibiting a HOST-response. Purpose: Given the variable clinical course of prostate cancer and the limitations of current prognostic factors, this study was conducted to investigate the impact of a histologically overt stromal response (HOST-response) to prostate cancer on clinical outcomes after radical prostatectomy. Methods: This retrospective analysis utilized The Cancer Genome Atlas (TCGA) to evaluate data from individuals with a confirmed diagnosis of prostate cancer who underwent radical prostatectomy and had available pathology slides. These slides were assessed for the presence of a HOST-response, similar to desmoplasia. The primary endpoint was progression-free survival (PFS). A multivariable competing risk regression analysis was used to assess whether a significant association existed between HOST-response and PFS, adjusting for known prostate cancer prognostic factors. Results: Among the 348 patients analyzed, 166 (47.70%) demonstrated a HOST-response. After a median follow-up of 37.87 months (IQR: 21.20, 65.50), the presence of a HOST-response was significantly associated with a shorter PFS (SDHR, 2.10; 95% CI, 1.26 to 3.50; p = 0.004), after adjusting for covariates. Conclusions: HOST-response in prostate cancer patients treated with radical prostatectomy is significantly associated with reduced PFS, suggesting a potential benefit from adjuvant therapy and highlighting the need for further investigation in a prospective randomized clinical trial. [ABSTRACT FROM AUTHOR]

Simple Summary: Selecting and developing effective therapies for distinct epithelial ovarian cancer subtypes necessitates tumor models that accurately recapitulate the individual characteristics and microenvironmental interactions. Patient-derived tumor models offer a promising approach by preserving the tumor's integrity, providing a platform for personalized treatment strategies. Zebrafish embryos could be a useful tool for quickly testing potential treatments in parallel. In this research article, we aimed to evaluate the model using a real-world case study and compare results with existing in vitro and in vivo models. A patient-derived cell line from a low-grade serous ovarian cancer with a KRAS mutation was engrafted in zebrafish embryos. Xenografts were assigned to a five-day treatment with trametinib and/or luminespib, targeting two complementary pathways that have previously shown efficacy in other cancer models of this cell line. The zebrafish model offers several options to analyze the response of the tumor to drug exposure. Here, we evaluated both cell growth and cell death, which showed a significant positive tumor response upon treatment that was amplified further by combining the drugs. Ovarian cancer (OC) is an umbrella term for cancerous malignancies affecting the ovaries, yet treatment options for all subtypes are predominantly derived from high-grade serous ovarian cancer, the largest subgroup. The concept of "functional precision medicine" involves gaining personalized insights on therapy choice, based on direct exposure of patient tissues to drugs. This especially holds promise for rare subtypes like low-grade serous ovarian cancer (LGSOC). This study aims to establish an in vivo model for LGSOC using zebrafish embryos, comparing treatment responses previously observed in mouse PDX models, cell lines and 3D tumor models. To address this goal, a well-characterized patient-derived LGSOC cell line with the KRAS mutation c.35 G>T (p.(Gly12Val)) was used. Fluorescently labeled tumor cells were injected into the perivitelline space of 2 days' post-fertilization zebrafish embryos. At 1 day post-injection, xenografts were assessed for tumor size, followed by random allocation into treatment groups with trametinib, luminespib and trametinib + luminespib. Subsequently, xenografts were euthanized and analyzed for apoptosis and proliferation by confocal microscopy. Tumor cells formed compact tumor masses (n = 84) in vivo, with clear Ki67 staining, indicating proliferation. Zebrafish xenografts exhibited sensitivity to trametinib and luminespib, individually or combined, within a two-week period, establishing them as a rapid and complementary tool to existing in vitro and in vivo models for evaluating targeted therapies in LGSOC. [ABSTRACT FROM AUTHOR]

An assessment of the projected changes in precipitation extremes for the 21st century is presented here for Greece and its individual administrative regions. The analysis relies on an ensemble of high-resolution Regional Climate Model (RCM) simulations following various Representative Concentration Pathways (RCP2.6, RCP4.5, and RCP8.5). The simulated changes in future annual total precipitation (PRTOT) under the examined scenarios are generally negative but statistically non-robust, except towards the end of the century (2071–2100) over high-altitude mountainous regions in Western Greece, Peloponnese, and Crete under RCP8.5. The pattern of change in the number of very heavy precipitation days (R20) is linked to the respective pattern of the PRTOT change with a statistically robust decrease of up to −5 days per year only over parts of the high-altitude mountainous regions in Western Greece, Peloponnese, and Crete for 2071–2100 under RCP8.5. Contrasting the future tendency for decrease in total precipitation and R20, the changes in the intensity of precipitation extremes show a tendency for intensification. However, these change patterns are non-robust for all periods and scenarios. Statistical significance is indicated for the highest 1-day precipitation amount in a year (Rx1day) for the administrative regions of Thessaly, Central Greece, Ionian Islands, and North Aegean under RCP8.5 in 2071–2100. The changes in the contribution of the wettest day per year to the annual total precipitation (RxTratio) are mainly positive but non-robust for most of Greece and all scenarios in the period 2021–2050, becoming more positive and robust in 2071–2100 for RCP8.5. This work highlights the necessity of taking into consideration high-resolution multi-model RCM estimates in future precipitation extremes with various scenarios, for assessing their potential impact on flood episodes and the strategic planning of structure resilience at national and regional level under the anticipated human-induced future climate change. [ABSTRACT FROM AUTHOR]

Simple Summary: Checkpoint-inhibitor-associated diabetes mellitus is a severely morbid immune-related adverse event that occurs from immunotherapy treatment during cancer therapy. Many patients and clinicians opt to discontinue therapy after this adverse event occurs while others choose to resume treatment. There are currently no data to inform this decision in terms of risks and benefits to the patient. This study aims to determine future risk for immune-related adverse events and cancer outcomes in patients who make this decision after experiencing diabetes mellitus. Immune checkpoint inhibitor (CPI)-induced diabetes mellitus (CPI-DM) is a rare immune-related adverse event (irAE). Patients and providers fear that continuing CPIs puts patients at risk for additional irAEs and thus may discontinue therapy. Currently, there are little data to inform this decision. Therefore, this study aims to elucidate whether discontinuing CPIs after diagnosis of CPI-DM impacts the development of future irAEs and cancer outcomes such as progression and death. Patients who developed CPI-DM during cancer treatment at UCSF from 1 July 2015 to 5 July 2023 were analyzed for cancer outcomes and irAE development. Fisher's exact tests, Student t-tests, Kaplan–Meier methods, and Cox regression were used as appropriate. Of the 43 patients with CPI-DM, 20 (47%) resumed CPIs within 90 days of the irAE, 4 (9%) patients restarted after 90 days, and 19 (44%) patients never restarted. Subsequent irAEs were diagnosed in 9 of 24 (38%) who resumed CPIs and 3 of 19 (16%) who discontinued CPIs (p = 0.17). There was no significant difference in death (p = 0.74) or cancer progression (p = 0.55) between these two groups. While our single-institution study did not show worse cancer outcomes after discontinuing CPIs, many variables can impact outcomes, which our study was not adequately powered to evaluate. A nuanced approach is needed to decide whether to continue CPI treatment after a severe irAE like CPI-DM. [ABSTRACT FROM AUTHOR]

Simple Summary: Osteosarcoma is one of the most lethal bone tumors worldwide. Immune checkpoint blockades have achieved significant success in solid tumors; however, their role in osteosarcoma remains obscure. Therefore, we aim to explore the clinical significance of soluble immune checkpoint-related proteins in osteosarcoma in this study. We identified four soluble immune checkpoint-related proteins as predictors of progress-free survival and lung metastasis-free survival of osteosarcoma patients. Our findings indicated that soluble immune checkpoint-related proteins could be promising biomarkers for the outcomes and immunotherapy of osteosarcoma. Background: The immune checkpoint blockade remains obscure in osteosarcoma (OS). We aim to explore the clinical significance of soluble immune checkpoint (ICK)-related proteins in OS. Methods: We profiled 14 soluble ICK-related proteins (BTLA, GITR, HVEM, IDO, LAG-3, PD-1, PD-L1, PD-L2, TIM-3, CD28, CD80, CD137, CD27, and CTLA-4) in the plasma of 76 OS patients and matched controls. We evaluated the associations between the biomarkers and the risk of OS using unconditional multivariate logistic regression. The multivariate Cox model was utilized to develop the prediction model of OS. Immune subtypes were established from the identified biomarkers. Transcriptional data from GEO were analyzed to elucidate potential mechanisms. Results: We found that sTIM3, sCD137, sIDO, and sCTLA4 were significantly correlated with OS risk (all p < 0.05). sBTLA, sPDL2, and sCD27 were significantly associated with the risk of lung metastasis, whereas sBTLA and sTIM3 were associated with the risk of disease progression. We also established an immune subtype based on sBTLA, sPD1, sTIM3, and sPDL2. Patients in the sICK-type2 subtype had significantly decreased progression-free survival (PFS) and lung metastasis-free survival (LMFS) than those in the sICK-type1 subtype (log-rank p = 2.8 × 10−2, 1.7 × 10−2, respectively). Interestingly, we found that the trend of LMFS and PFS in the subtypes of corresponding ICK genes' expression was opposite to the results in the blood (log-rank p = 2.6 × 10−4, 9.5 × 10−4, respectively). Conclusion: Four soluble ICK-related proteins were associated with the survival of OS patients. Soluble ICK-related proteins could be promising biomarkers for the outcomes and immunotherapy of OS patients, though more research is warranted. [ABSTRACT FROM AUTHOR]

(1) Background: A missing bilateral maxillary lateral incisor (MBMLI) causes aesthetic and functional problems and a multidisciplinary approach is required for treatment. This study aimed to compare the changes in the mesiodistal axial angulations of the maxillary canines and central incisors with orthodontic treatment of MBMLI. (2) Methods: A total of 56 patients with MBMLI were included in the study, and three groups were formed: the control group (Group 1, n = 20) with untreated ideal occlusion and the space opening (Group 2, n = 20) and space closure (Group 3, n = 16) groups as treated study groups. The mesiodistal angulations between the long axes of the maxillary right canine (tooth no 13), right central incisor (tooth no 11), left central incisor (tooth no 21) and maxillary left canine (tooth no 23), and the bicondylar plane, were measured on the panoramic radiographs taken pre (T0) and post treatment (T1). p < 0.05 was accepted for statistical significance. (3) Results: At T0, while there was no significant difference between the mesiodistal angulations of the right–left maxillary canines and central incisors in all groups (p > 0.05), the mesiodistal angulations of the canines in the Group 1 were significantly higher than the study groups (p < 0.05). With treatment, while the mesiodistal angulation of the canines increased in Group 2, it decreased in Group 3 (p < 0.05). On the other hand, the mesiodistal angulation of the central incisors decreased in Group 2 and did not change in Group 3 (p > 0.05). At T1, the mesiodistal angulation of the canines was found to be lower in Group 3 than in Groups 1 and 2, while the angulation of the central incisors was found to be lower in Group 2 compared to Group 1 (p < 0.05). (4) Conclusions: In the orthodontic treatment of MBMLIs, changes in the mesiodistal angulations of the maxillary canine and central incisors should be taken into account for satisfactory outcomes. It was concluded that there should be a tendency to select the space closure method in which normal mesiodistal angulations are obtained in maxillary central incisors for aesthetics and planned incisor position, and also at a low cost. [ABSTRACT FROM AUTHOR]

Simple Summary: Persistent infection with high-risk HPV is the main cause of cervical cancer. However, the changes in epigenetics and viral load (VL) during persistent HPV infection are not well understood. This study selected individuals with a persistent HPV infection but without developing high-grade cervical lesions, analyzed the changes in PAX1/JAM3 methylation and VL according to the duration of HPV infection, and found that in women with HPV infections persisting for more than 3 years, there is a notable increase in the methylation levels of PAX1/JAM3, which could be used as cumulative evidence of persistent HPV infection before the occurrence of precancerous lesions. HPV infection persisting for more than 3 years is more likely to be associated with vaginal lesions, and HPV VL could be used as an indicative biomarker for concurrent cervical–vaginal lesions, which might be helpful to provide a clinical perspective for monitoring and intervention of individuals with persistent HPV infection. The relationship of PAX1/JAM3 methylation as well as HPV viral load (VL) with cervical lesions has been reported, but their role in persistent HPV infection without cervical high-grade lesions has not been fully elucidated. A total of 231 females diagnosed with persistent HPV infection and pathologically confirmed absence of high-grade cervical lesions were selected from the Colposcopy Outpatient Clinic of Peking University People's Hospital, from March 2023 to December 2023. They were categorized into two groups based on the duration of HPV infection: the HPV persistent less than 3 years group and the more than 3 years group. PAX1/JAM3 methylation and HPV VL were determined by real-time PCR and BioPerfectus Multiplex Real-Time (BMRT)-HPV reports type-specific VL/10,000 cells, respectively. The average age of individuals with HPV infection lasting more than 3 years was higher compared to those with less than 3 years (48.9 vs. 45.1 years), with a statistically significant difference. Among the participants, 81.8% (189/231) had no previous screening. The methylation levels of JAM3 and PAX1 were significantly higher in individuals with HPV infection persisting for more than 3 years compared to those with less than 3 years, with a statistically significant difference (p < 0.05). There was a significant correlation between PAX1 and JAM3 methylation (p < 0.001), which could be used as cumulative evidence of HPV infection duration before the occurrence of precancerous lesions. The incidence of vaginal intraepithelial lesions was higher in individuals with HPV infection persisting for more than 3 years compared to those with less than 3 years, and HPV VL can be used as an indicative biomarker for concurrent cervical–vaginal lesions, especially for HPV other than 16/18 genotypes. [ABSTRACT FROM AUTHOR]

Simple Summary: Allogeneic stem cell transplantation (allo-SCT) represents the only potentially curative treatment for high-risk acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), but up to 50% of patients relapse after allo-SCT. The salvage therapy after disease recurrence is not standardized, and the outcome remains unfavorable. Therefore, there is a growing interest in determining the most effective approach to manage the post-transplant phase with the goal of promptly detecting disease recurrence or preventing it. In this context, we conducted a retrospective study to assess the overall survival (OS) of patients with relapsed AML or MDS after allo-SCT with the aim of acquiring useful information for identifying the best prospective therapeutic strategy. The OS was evaluated according to the type of therapy, whether it included donor lymphocyte infusion (DLI), the timing of administration, and whether it occurred during an overt hematological relapse or in a preemptive setting. Background: Disease relapse after allogeneic stem cell transplantation (allo-SCT) is the main challenge for curing acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). We investigated the overall survival (OS) after allo-SCT relapse according to different therapeutic approaches. Methods: We analyzed 134 patients who relapsed after allo-SCT performed between 2015 and 2021 at Saint-Antoine University Hospital, Paris and Spedali Civili di Brescia, Brescia. Of these, 103 (77%) were treated, comprising 69/103 (67%) who received therapy in overt relapse and 34/103 (33%) who were treated in a pre-emptive manner when molecular/cytogenetics recurrence or mixed chimerism occurred. The treatment was donor lymphocyte infusion (DLI)-based for 40/103 (39%) patients. Results: The 1-, 2-, and 5-year OS of patients treated with DLI (n = 40) was 67%, 34%, and 34%, respectively, for those treated preventively (n = 20) and 43%, 20%, and 20%, respectively, for those treated in overt relapse (n = 20) (p < 0.01). The 1-, 2-, and 5-year OS of patients treated without DLI (n = 63) was 54%, 40%, and 26%, respectively, for those treated preventively (n = 14) and 17%, 5%, and 0%, respectively, for those treated in overt relapse (n = 49) (p < 0.01). Conclusions: Relapse treatment with a pre-emptive strategy was associated with improved outcomes, particularly when DLI was employed. [ABSTRACT FROM AUTHOR]

We have explored the exponential surface brightness profile (SBP) of stellar disks, a topic extensively discussed by many authors yet seldom integrated with the study of correlations between black holes, bulges, and entire disks. Building upon our prior work in the statistical mechanics of disk-shaped systems and aligning with methodologies from other research, we analyze the influence of the central body. This analysis reveals analytical relationships among black holes, bulges, and the entire stellar disk. Additionally, we incorporate a specific angular momentum distribution (SAMD) that aligns more closely with observational data, showing that for the self-gravitating disk, with the same surface density, a reduction in its spin results in only a slight decrease in its radius, whereas with the same SAMD, an increment in its spin significantly limits its extent. A key feature of our model is its prediction that the surface density profile of an isolated disk will invariably exhibit downbending at a sufficient distance, a hypothesis that future observations can test. Our refined equations provide a notably improved fit for SBPs, particularly in the central regions of stellar disks. While our findings underscore the significance of statistical mechanics in comprehending spiral galaxy structures, they also highlight areas in our approach that warrant further discussion and exploration. [ABSTRACT FROM AUTHOR]

Background: Anti-glaucoma eye drops have been investigated due to their production of fibrotic changes on the conjunctival surface, undermining the functioning of the upper lacrimal drainage system. We aimed to assess whether these effects may impair the effectiveness of endoscopic endonasal dacryocystorhinostomy (EE-DCR). Methods: This is a single-center observational retrospective study on EE-DCR via a posterior approach. Resolution of epiphora and dacryocystitis were analyzed after 1 (T1) and 6-months (T2) from surgery. Surgical success was defined as anatomical (patency at irrigation, no recurring dacryocystitis) or complete (zeroing of Munk score). Results: Twenty patients (32 sides) were enrolled. Preoperatively, 93.75% (n = 30/32) presented severe (Munk 3–4) epiphora and 68.75% (n = 22/32) recurrent dacryocystitis. At T1, 50.0% (n = 16/32) were referred with residual epiphora (Munk ≥ 1) and 18.75% (n = 6/32) dacryocystitis. At T2, 31.25% (n = 10/32) still complained of epiphora (Munk ≥ 1) and 6.25% (n = 2/32) dacryocystitis. Difference of outcomes at aggregate and paired timepoints (except for T1 versus T2) resulted in statistical significance (p < 0.05). At T2, 22 (68.75%) complete, 8 (25.0%) anatomical successes and 2 (6.25%) surgical failures were observed. Conclusions: Despite the chronic uptake of anti-glaucoma eye drops, EE-DCR guaranteed high rates of clinical relief from epiphora and remarkable decreases in the rates of recurrent dacryocystitis. [ABSTRACT FROM AUTHOR]

Background: Distal surface caries (DSC) has been associated with partially erupted impacted third molars. The purpose of this study was to compare the rates of DSC between populations that had undergone different third molar management strategies. Methods: Radiographs that had been taken during routine examinations of 1012, 251 and 250 patients in Manchester, Bucharest and Amsterdam, respectively, were evaluated. The following parameters were assessed: the state of the distal surface in the second mandibular molar, loss of periodontal support, impaction type of the third molar, contact point localization, and patients' genders, ages and their cumulative history of dental health. Results: The rate of DSC in the second mandibular molar was 63.9%, 19.9% and 26.0% in the Manchester, Bucharest and Amsterdam populations, respectively. A loss of lamina dura of ≥2 mm, increased percentages of decayed, missing or filled teeth and male gender were risk factors in all three populations. All assessed parameters apart from the site of the mandible reached statistical significance in the Manchester sample (p < 0.001). The DSC rate was cumulative with increasing age in the Manchester population, in which third molars were strategically retained. Conclusions: The UK population, treated according to strict guidelines that limit the removal of third molars, had a statistically significant higher DSC prevalence rate (p < 0.001) than the Romanian or Dutch populations. The active surgical management of mandibular third molars seems to have the potential to reduce the DSC rate in the adjacent second molar. [ABSTRACT FROM AUTHOR]

Simple Summary: For effective cancer treatment, it is important to scrutinize individual driver gene mutations. In this study, we investigated whether analyzing gene mutations in primary breast cancer based on ctDNA could be a biomarker of prognosis using plasma from 95 patients with primary breast cancer. The key finding was that TP53 and/or BRCA1 mutation-positive groups had poor recurrence-free survival in the TNBC patients compared to TP53 and BRCA1 mutation-negative groups. This result indicates that TP53 and/or BRCA1 mutations on ctDNA could be useful prognostic markers in TNBC patients. Precise biomarkers for predicting the therapeutic efficacy of molecularly targeted drugs are limited at the protein level; thus, it has been important to broadly scrutinize individual cancer driver gene mutations for effective cancer treatments. Multiplex cancer genome profiling can comprehensively identify gene mutations that are therapeutic targets using next-generation sequencing (NGS). In addition, circulating tumor DNA (ctDNA) is a DNA fragment released into the blood by tumor cell-derived cell death or apoptosis. Liquid biopsy with ctDNA is a novel clinical test for identifying genetic mutations in an entire population noninvasively, in real-time, and heterogeneously. Although there are several reports on ctDNA, fewer have evaluated ctDNA with NGS before an initial treatment for breast cancer patients. Therefore, we examined whether analyzing tumor-associated gene mutations in primary breast cancer based on ctDNA could serve as a biomarker for prognosis and optimal treatment selection. Ninety-five primary breast cancer patients treated at our department from January 2017 to October 2020 were included. Pretreatment plasma samples were subjected to NGS analysis of ctDNA, and correlations with patients' clinicopathological characteristics were evaluated. Fifty-nine (62.1%) patients were positive for ctDNA. ctDNA tended to be positive in hormone receptor-negative, and TP53 (34%), BRCA1 (20%), and BRCA2 (17%) gene mutations were more frequent. Regarding recurrence-free survival, the prognosis was poor in the TP53 and/or BRCA1 mutation-positive groups, especially in triple-negative breast cancer (TNBC) patients. In conclusion, the results of this study indicate that ctDNA with liquid biopsy could identify the poor prognosis group before treatment among TNBC patients and for those for whom optimal treatment selection is desirable; additionally, optimal treatment could be selected according to the ctDNA analysis results. [ABSTRACT FROM AUTHOR]

Simple Summary: Convincing data have indicated that human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC) is associated with much better locoregional control and survival than its HPV-unrelated counterparts. It is also worth noting that the distant metastases (DM) rate does not differ between HPV-related and HPV-unrelated OPSCC. Recently, the analysis of HPV in liquid biopsy (circulating tumor-related HPV DNA, ctHPV) has gained significant prognostic importance. Little is known about the importance of viral load (VL) levels of ctHPV16 in OPSCC on survival. Meanwhile, our results provide comprehensive data that the pretreatment ctHPV16 VL in liquid biopsy may be a biomarker of the risk of DM. Background: There are definite reasons to implement molecular diagnostics based on the measurement of human papillomavirus (HPV) DNA in liquid biopsy into clinical practice. It is a quick, repeatable, and health-safe test for cancer biomarkers in the blood. In this study, we investigated whether the circulating tumor-related HPV16 (ctHPV16) viral load (VL) in patients with oropharyngeal squamous cell carcinoma (OPSCC) was important for determining the risk of locoregional recurrence-free survival (LRFS), metastasis-free survival (MFS), and overall survival (OS). Methods: This study included 91 patients with ctHPV16-positive OPSCC who had been treated with radical radiotherapy and chemotherapy. The VL was measured using quantitative PCR (qPCR) and a probe specific for HPV16. Based on 10 years of follow-up, the 2-, 3-, 5-, and 9-year LRFS, MFS, and OS were estimated. Results: The 5-year actuarial LRFS, MFS, and OS rates of patients with ctHPV16-positive/OPSCC were 88%, 90%, and 81%, respectively. The VL was significantly higher in patients who subsequently developed distant metastases (DM) than in those who did not (VL 4.09 vs. 3.25; p = 0.009). In a Cox proportional hazards regression model for MFS, a higher ctHPV16 VL appeared to be a significant independent prognostic factor for the occurrence of DM (HR 2.22, p = 0.015). The ROC curve revealed a cutoff value of 3.556 for VL (p = 0.00001). Conclusions: A high VL before treatment indicates patients with a significant risk of DM, and should be used in OPSCC treatment stratification. [ABSTRACT FROM AUTHOR]

In the realm of quality assurance, the significance of statistical measurement studies cannot be overstated, particularly when it comes to quantifying the diverse sources of variation in measurement processes. However, the complexity intensifies when addressing 3D topography data. This research introduces an intuitive similarity-based framework tailored for conducting measurement studies on 3D topography data, aiming to precisely quantify distinct sources of variation through the astute application of similarity evaluation techniques. In the proposed framework, we investigate the mean and variance of the similarity between 3D surface topography measurements to reveal the uniformity of the surface topography measurements and statistical reproducibility of the similarity evaluation procedure, respectively. The efficacy of our framework is vividly demonstrated through its application to measurements derived from additive-fabricated specimens. We considered four metal specimens with 20 segmented windows in total. The topography measurements were obtained by three operators using two scanning systems. We find that the repeatability variation of the topography measurements and the reproducibility variation in the measurements induced by operators are relatively smaller compared with the variation in the measurements induced by optical scanners. We also notice that the variation in the surface geometry of different surfaces is much larger in magnitude compared with the repeatability variation in the topography measurements. Our findings are consistent with the physical intuition and previous research. The ensuing experimental studies yield compelling evidence, affirming that our devised methods are adept at providing profound insights into the multifaceted sources of variation inherent in processes utilizing 3D surface topography data. This innovative framework not only showcases its applicability but also underlines its potential to significantly contribute to the field of quality assurance. By offering a systematic approach to measuring and comprehending variation in 3D topography data, it stands poised to become an indispensable tool in diverse quality assurance contexts. [ABSTRACT FROM AUTHOR]

Background: this study aims to assess the effect of embryo transfer (ET) performance parameters of a technical nature on IVF outcome. Methods: A total of 1417 ETs from a single IVF center were included in this prospective observational study. The parameters investigated were as follows: the presence of cervical mucus post catheter withdrawal, the presence of blood, catheter reload, the employment of a tenaculum and stylet, catheter resistance as experienced by the physician and patient discomfort. Results: When ET performance parameters were associated with clinical outcomes on a singular level, none of the ET parameters presented with any statistical significance. The evaluation of covariates indicated that the number and the quality of transferred embryos, as well as maternal age, exerted a statistically significant effect on clinical outcomes. In a multivariate analysis, only the presence of mucus along with significant catheter resistance presented with statistical significance; however, when adjusting for covariates, this combination showed no statistically significant effect on clinical outcomes. Conclusions: the results indicate that the time-consuming process of recording and analyzing ET performance parameters fails to offer any additional value in predicting the cycle's outcome, while factors like embryo quality and number, as well as maternal age, seem to be the sole robust predictive factors of an IVF cycle. [ABSTRACT FROM AUTHOR]

Three-dimensional (3D) deformity assessment and leg realignment planning is emerging. The aim of this study was to (1) validate a novel 3D planning modality that incorporates the weight-bearing (WB) state (3D WB) by comparing it to existing modalities (3D non-weight-bearing (NWB), 2D WB) and (2) evaluate the influence of the modality (2D vs. 3D) and the WB condition on the measurements. Three different planning and deformity measurement protocols were analyzed in 19 legs that underwent medial open-wedge high tibial osteotomy (HTO): (1) a 3D WB protocol, after 2D/3D registration of 3D CT models onto the long-leg radiograph (LLR) (3D WB), (2) a 3D NWB protocol based on the 3D surface models obtained in the supine position (3D NWB), and (3) a 2D WB protocol based on the LLR (2D WB). The hip–knee–ankle angle (HKA), joint line convergence angle (JLCA), and the achieved surgical correction were measured for each modality and patient. All the measurement protocols demonstrated excellent intermodal agreement for the achieved surgical correction, with an ICC of 0.90 (95% CI: 0.76–0.96)) (p < 0.001). Surgical correction had a higher mean absolute difference compared to the 3D opening angle (OA) when measured with the WB protocols (3D WB: 2.7 ± 1.8°, 3D NWB: 1.9 ± 1.3°, 2D WB: 2.2 ± 1.3°), but it did not show statistical significance. The novel planning modality (3D WB) demonstrated excellent agreement when measuring the surgical correction after HTO compared to existing modalities. [ABSTRACT FROM AUTHOR]

Objective: This study aims to identify content variables that theoretical research suggests should be considered as strategic approaches to facilitate science communication with the public and to assess their practical effects on user engagement metrics. Methods: Data were collected from the official Chinese TikTok account (Douyin) of the Nutrition Research Institute of China National Cereals, Oils and Foodstuffs Corporation, China's largest state-owned food processing conglomerate. Dependent variables included likes, shares, comments, subscription increases. Independent variables encompassed explanation of jargon (metaphor, personification, science visualization), communication remarks (conclusion presence, recommendation presence), and content themes. Descriptive analysis and negative binomial regression were employed, with statistical significance set at 0.05. Results: First, subscription increases were positively associated with personification (p < 0.05, 0.024) and science visualization (p < 0.01, 0.000). Second, a positive relationship existed between comments and communicator recommendations (p < 0.01, 0.000), while presenting conclusions negatively correlated with shares (p < 0.05, 0.012). Conclusions: Different strategies yielded improvements in various engagement metrics. This can provide practical guidance for communicators, emphasizing the need to balance scholarly presentation with sustaining appealing statistics. [ABSTRACT FROM AUTHOR]

Simple Summary: Cholangiocarcinoma (CCA) accounts for approximately 15% of primary liver cancers. CCA has a poor prognosis and, thus, more effective systemic treatments are needed. We tested opaganib and upamostat, drugs that target sphingosine kinase 2 and multiple serine proteases, primarily trypsins, which are highly expressed in CCA tumors. This study demonstrates the results of inhibiting these novel targets with these drugs individually and in combination in a patient-derived CCA xenograft mouse model. Upamostat is an orally available small-molecule serine protease inhibitor that is a highly potent inhibitor of trypsin 1, trypsin 2, trypsin 3 (PRSS1/2/3), and the urokinase-type plasminogen activator (uPA). These enzymes are expressed in many cancers, especially during tissue remodeling and subsequent tumor cell invasion. Opaganib (ABC294640), a novel, orally available small molecule is a selective inhibitor of the phosphorylation of sphingosine to sphingosine-1-phosphate (S-1-P) by sphingosine kinase 2 (SPHK2). Both sphingosine kinase 1 (SPHK1) and SPHK2 are known to regulate the proliferation-inducing compound S-1-P. However, SPHK2 is more critical in cancer pathogenesis. The goal of this project was to investigate the potential antitumor effects of upamostat and opaganib, individually and in combination, on cholangiocarcinoma (CCA) xenografts in nude mice. PAX165, a patient-derived xenograft (PDX) from a surgically resected CCA, expresses substantial levels of SPHK2, PRSS1, PRSS2, and PRSS3. Four groups of 18 mice each were treated with upamostat, opaganib, both, or vehicle. Mouse weights and PAX165 tumor volumes were measured. Tumor volumes in the upamostat, opaganib, and upamostat plus opaganib groups were significantly decreased compared to the control group. [ABSTRACT FROM AUTHOR]

Simple Summary: Bladder cancer (BCa) is a major urologic malignancy with a high potential for death-threatening complications. Successful treatment relies on timely diagnostics and prediction of clinical outcomes. Molecular markers can be helpful for earlier diagnosis and for making treatment decisions. The biomarker landscape for BCa is not satisfactory yet. The discovery of novel diagnostic indicators for making treatment decisions is critical. Biological fluids are the most convenient and reliable source of these molecules. Circular RNAs (CircRNAs), special non-coding RNAs with a stable structure that are formed by a unique backsplicing process, recently became popular candidates for biomarkers in cancer biology. CircRNAs are widely distributed within the body including biological fluids. Their biological functions include gene regulation via sponging microRNAs, another type of small regulatory RNA. Our study characterized the circRNA hsa_circ_0139697 (circSTAG(16–25)) derived from exons 16 to 25 of STAG2, a gene known to play an important role in BCa biology that can serve as a biomarker predicting recurrence. We found that circSTAG2(16–25) could promote the proliferation, migration, and invasion of BCa cells by binding miR-145-5p, which causes the upregulation of the potential onco-gene TAGLN2. In addition, circSTAG(16–25) can serve as a biomarker for recurrence prediction. The current study aimed to elucidate the regulatory mechanisms of the circRNA hsa_circ_0139697 (circSTAG2(16–25)) in BCa and to consider the opportunity of using circSTAG2(16–25) isolated from BCa patient urine as a marker for disease development prediction. The selection of this circRNA was determined by the special role of its parental gene STAG2 in BCa biology. The circRNA hsa_circ_0139697 was chosen from 25 STAG2 circRNAs due to its differential expression in the urine of BCa patients and healthy volunteers. Higher levels of circSTAG2(16–25) were detected in urine samples obtained from patients with recurrent tumors. A higher expression of circSTAG2(16–25) was also detected in more tumorigenic BCa cell lines. The overexpression of circSTAG2(16–25) in BCa cells induced the elevation of proliferation, motility, and invasion. To study the mechanisms of circSTAG2(16–25) activity, we confirmed that circSTAG2(16–25) can bind miR-145-5p in vitro as was predicted by bioinformatic search. miR-145-5p was shown to suppress some genes that promoted BCa progression. One of these genes, TAGLN2, encodes the protein Transgelin 2, which plays a role in BCa cell motility and invasion. Therefore, the possible mechanism of action of circSTAG2(16–25) could be sponging the tumor suppressor miR-145-5p, which results in activation of TAGLN2. In addition, circSTAG2(16–25) might be considered as a potential biomarker for recurrence prediction. [ABSTRACT FROM AUTHOR]

The false discovery rate (FDR) is a widely used metric of statistical significance for genomic data analyses that involve multiple hypothesis testing. Power and sample size considerations are important in planning studies that perform these types of genomic data analyses. Here, we propose a three-rectangle approximation of a p-value histogram to derive a formula to compute the statistical power and sample size for analyses that involve the FDR. We also introduce the R package FDRsamplesize2, which incorporates these and other power calculation formulas to compute power for a broad variety of studies not covered by other FDR power calculation software. A few illustrative examples are provided. The FDRsamplesize2 package is available on CRAN. [ABSTRACT FROM AUTHOR]

The process of sorting or categorizing objects or information about these objects into clusters according to certain criteria is a fundamental procedure in data analysis. Where it is feasible to determine the distance metric for any pair of objects, the significance and reliability of the separation can be evaluated by calculating the separation/segregation power (SP) index proposed herein. The latter index is the ratio of the average inter distance to the average intra distance, independent of the scale parameter. Here, the calculated SP value is compared to its statistical distribution obtained by a simulation study for a given partition under the homogeneity null hypothesis to draw a conclusion using standard statistical procedures. The proposed concept is illustrated using three examples representing different types of objects under study. Some general considerations are given regarding the nature of the SP distribution under the null hypothesis and its dependence on the number of divisions and the amount of data within them. A detailed modus operandi (working method) for analyzing a metric data partition is also offered. [ABSTRACT FROM AUTHOR]

Aim: The aim of our study was to investigate skin conditions when wearing and removing a novel wireless non-adhesive cardiorespiratory monitoring device for neonates (Bambi-Belt) compared to standard adhesive electrodes. Study Design: This was a prospective study including preterm neonates requiring cardiorespiratory monitoring. Besides standard electrodes, the infants wore a Bambi Belt for 10 consecutive days. Their skin conditions were assessed using Trans Epidermal Water Loss (TEWL) and the Neonatal Skin Condition Score (NSCS) after daily belt and standard electrode removal. The ∆TEWL was calculated as the difference between the TEWL at the device's location (Bambi-Belt/standard electrode) and the adjacent control skin location, with a higher ∆TEWL indicating skin damage. Results: A total of 15 infants (gestational age (GA): 24.1–35.6 wk) were analyzed. The ΔTEWL significantly increased directly after electrode removal (10.95 ± 9.98 g/m2/h) compared to belt removal (5.18 ± 6.71 g/m2/h; F: 8.73, p = 0.004) and after the washout period (3.72 ± 5.46 g/m2/h vs. 1.86 ± 3.35 g/m2/h; F: 2.84, p = 0.09), although the latter did not reach statistical significance. The TEWL was not influenced by prolonged belt wearing. No significant differences in the NSCS score were found between the belt and electrode (OR: 0.69, 95% CI [0.17, 2.88], p = 0.6). Conclusion: A new wireless non-adhesive device for neonatal cardiorespiratory monitoring was well tolerated in preterm infants and may be less damaging during prolonged wearing. [ABSTRACT FROM AUTHOR]

Simple Summary: LET-optimized pencil beam scanning (PBS) proton treatment plans have the potential to improve patient outcomes. Dose-escalated x-ray conformal therapy has improved the prostate cancer 5-year freedom from biochemical progression (FFBP) but has also increased gastrointestinal and genitourinary toxicities; toxicities can be reduced by escalating dose via a simultaneously-integrated boost (SIB) to the intraprostatic tumor (IPT). These techniques can be applied with greater precision using protons, which have shown high overall 5-year FFBP and low toxicities, although improvement in FFBP is needed for high-risk patients. Relative biological effectiveness (RBE) of 1.1 is uniformly assumed for proton treatment planning, although an increasing number of studies show that RBE increases with linear energy transfer (LETd). We show improvement with PBS LET-optimized plans over single-field optimized (SFO), or IPT-SIB plans through increased target volume LETd, RBE, and target-to-organs-at-risk (OAR) dose ratios (TODRs). This study also highlights the necessity of developing disease-specific LET-dependent RBE models. Purpose: To demonstrate the feasibility of improving prostate cancer patient outcomes with PBS proton LETd optimization. Methods: SFO, IPT-SIB, and LET-optimized plans were created for 12 patients, and generalized-tissue and disease-specific LET-dependent RBE models were applied. The mean LETd in several structures was determined and used to calculate mean RBEs. LETd- and dose–volume histograms (LVHs/DVHs) are shown. TODRs were defined based on clinical dose goals and compared between plans. The impact of robust perturbations on LETd, TODRs, and DVH spread was evaluated. Results: LETd optimization achieved statistically significant increased target volume LETd of ~4 keV/µm compared to SFO and IPT-SIB LETd of ~2 keV/µm while mitigating OAR LETd increases. A disease-specific RBE model predicted target volume RBEs > 1.5 for LET-optimized plans, up to 18% higher than for SFO plans. LET-optimized target LVHs/DVHs showed a large increase not present in OARs. All RBE models showed a statistically significant increase in TODRs from SFO to IPT-SIB to LET-optimized plans. RBE = 1.1 does not accurately represent TODRs when using LETd optimization. Robust evaluations demonstrated a trade-off between increased mean target LETd and decreased DVH spread. Conclusion: The demonstration of improved TODRs provided via LETd optimization shows potential for improved patient outcomes. [ABSTRACT FROM AUTHOR]

Simple Summary: Non-small cell lung cancer accounts for most lung cancer. In recent years, immunotherapy, especially with PD1/PDL1 inhibitors such as pembrolizumab, has emerged as an important treatment modality. The exploration of new avenues such as tumor biomarker analysis has proven beneficial in determining treatment responsiveness. Various studies have shown a positive association between distinct tumor characteristics and the response to pembrolizumab. In this study, we established that the presence of higher proportions of viable tumor cells and increased tumor-infiltrating lymphocytes in non-small cell lung cancer show favorable responses to treatment with pembrolizumab. Pembrolizumab, a widely used immune checkpoint inhibitor (ICI), has revolutionized the treatment of non-small cell lung cancer (NSCLC). Identifying unique tumor characteristics in patients likely to respond to pembrolizumab could help the clinical adjudication and development of a personalized therapeutic strategy. In this retrospective study, we reviewed the clinical data and pathological features of 84 NSCLC patients treated with pembrolizumab. We examined the correlation between the clinical and demographic characteristics and the tumor histopathologic features obtained before immunotherapy. The response to pembrolizumab therapy was evaluated via the Response Evaluation Criteria in Solid Tumors (RECIST). The clinical data and cancer tissue characteristics were assessed and compared among three groups according to the following RECIST: the responsive group (RG), the stable disease group (SD), and the progressive disease group (PD), where the RG comprised patients with either a complete response (CR) or a partial response (PR). The overall survival rate of the RG group was significantly higher than the SD and PD groups. In addition, the percentage of pre-treatment viable tumor cell content in the RG and SD groups was significantly higher. At the same time, the extracellular stroma proportion was significantly lower than that of the PD group. The number of tumor-infiltrating lymphocytes (TILs) in the RG group was significantly higher than in the PD group. There were no significant differences in tumor necrosis, the stroma composition, PD-L1 expression level (TPS 1–49% vs. ≥50%), and treatment response. In conclusion, our population of NSCLC patients who experienced positive treatment responses to pembrolizumab therapy had a better prognosis compared to patients with either SD or PD. Moreover, the relative proportions of viable tumor cells to tumor-associated lymphocytes were associated with responsiveness to treatment. It is expected that larger prospective clinical studies will further validate these findings. [ABSTRACT FROM AUTHOR]

Rapid intensification (RI) and eyewall replacement cycles (ERCs) frequently occur in intense tropical cyclones (TCs), often causing rapid, significant changes in intensity and structure. In some TCs, RI and ERCs can occur concurrently or within a short period of one another. This study investigates whether there is a link between RI and ERCs by conducting a statistical analysis of TCs that occurred in the North Atlantic basin from 2015 to 2020. The HURDAT2 dataset was used to detect RI events, while the Morphed Integrated Microwave Imagery archive by the Cooperative Institute for Meteorological Satellite Studies was used to detect ERC events. Three sets of data were constructed from this analysis: TCs with paired RI/ERC events that occurred within 24 h of each other, TCs with RI only, and TCs with ERCs only. Statistics selected for analysis within the constructed datasets were mean duration of phenomena, mean rate of intensification, and mean peak intensity. We performed t-tests to determine the statistical significance of results. The results of this study show that TCs with these paired RI/ERC events often intensified at a faster rate, intensified for longer, and ended up stronger than TCs that only experienced RI or ERCs in isolation. [ABSTRACT FROM AUTHOR]

Simple Summary: Patients with symptomatic Benign Prostatic Hyperplasia (BPH) showed upregulated gene expression of biological pathways associated with T cell activation and suppression of a key transcription factor HOXB13, which is associated with transcription and epigenetic regulation of prostate cancer (PCa). In contrast, patients with BPH who later developed PCa showed significantly reduced inflammation and revealed activation of several transcription factors related to PCa, including HOXB13, AR, FOXA1 and SIM2. It may be clinically beneficial for urologists to be able to distinguish between men with BPH who are at a higher risk of developing PCa in the future based on their molecular subtype. Our objective was to identify variations in gene expression that could help elucidate the pathways for the development of prostate cancer (PCa) in men with Benign Prostatic Hyperplasia (BPH). We included 98 men with BPH, a positive prostate MRI (Prostate Imaging Reporting and Data System; PIRADS ≥ 4), and a negative biopsy from November 2014 to January 2018. RNA sequencing (RNA-Seq) was performed on tissue cores from the MRI lesion and a geographically distant region (two regions per patient). All patients were followed for at least three years to identify who went on to develop PCa. We compared the gene expressions of those who did not develop PCa ("BPH-only") vs. those who did ("BPH/PCa"). Then, we identified the subset of men with BPH who had the highest American Urological Association (AUA) symptom scores ("symptomatic BPH") and compared their gene expression to the BPH/PCa group. At a median follow-up of 47.5 months, 15 men had developed PCa while 83 did not. We compared gene expressions of 14 men with symptomatic BPH (AUAss ≥ 18) vs. 15 with BPH/PCa. We found two clusters of genes, suggesting the two groups had distinctive molecular features. Differential analysis revealed genes that were upregulated in BPH-only and downregulated in BPH/PCa, and vice versa. Symptomatic BPH men had upregulation of T-cell activation markers (TCR, CD3, ZAP70, IL-2 and IFN-γ and chemokine receptors, CXCL9/10) expression. In contrast, men with BPH/PCa had upregulation of NKX3-1 and HOXB13 transcription factors associated with luminal epithelial progenitors but depleted of immune cells, suggesting a cell-autonomous role in immune evasion. Symptomatic BPH with immune-enriched landscapes may support anti-tumor immunity. RNA sequencing of benign prostate biopsy tissue showing upregulation of NKX3-1 and HOXB13 with the absence of T-cells might help in identifying men at higher risk of future PCa development, which may be useful in determining ongoing PCa screening. [ABSTRACT FROM AUTHOR]

The paper makes a case that the current discussions on replicability and the abuse of significance testing have overlooked a more general contributor to the untrustworthiness of published empirical evidence, which is the uninformed and recipe-like implementation of statistical modeling and inference. It is argued that this contributes to the untrustworthiness problem in several different ways, including [a] statistical misspecification, [b] unwarranted evidential interpretations of frequentist inference results, and [c] questionable modeling strategies that rely on curve-fitting. What is more, the alternative proposals to replace or modify frequentist testing, including [i] replacing p-values with observed confidence intervals and effects sizes, and [ii] redefining statistical significance, will not address the untrustworthiness of evidence problem since they are equally vulnerable to [a]–[c]. The paper calls for distinguishing between unduly data-dependant 'statistical results', such as a point estimate, a p-value, and accept/reject H 0 , from 'evidence for or against inferential claims'. The post-data severity (SEV) evaluation of the accept/reject H 0 results, converts them into evidence for or against germane inferential claims. These claims can be used to address/elucidate several foundational issues, including (i) statistical vs. substantive significance, (ii) the large n problem, and (iii) the replicability of evidence. Also, the SEV perspective sheds light on the impertinence of the proposed alternatives [i]–[iii], and oppugns [iii] the alleged arbitrariness of framing H 0 and H 1 which is often exploited to undermine the credibility of frequentist testing. [ABSTRACT FROM AUTHOR]

Retinal vein occlusion (RVO) results in ischemia followed by an inflammatory response. Both processes affect tissue temperature in opposite directions. Here, we evaluate the effect of RVO on the ocular surface temperature (OST) profile. Subjects with RVO were prospectively recruited. Healthy subjects without any ocular disease served as controls. The OST was determined using the Therm-App thermal imaging camera, and image processing software was employed to compute the mean temperature values of the medial canthus, lateral canthus, and cornea. We obtained thermographic images from 30 RVO subjects (30 eyes) and 148 controls (148 eyes). A univariate analysis found that eyes with RVO had significantly elevated OSTs compared to the controls (mean difference of 0.6 ± 0.3 Celsius, p < 0.05). However, this distinction between the groups lost statistical significance upon adjusting for possible confounders, including patient and environmental factors. These findings were confirmed with a post hoc case–control matched comparison. In conclusion, RVO does not seem to affect the OST. This might be due to the balance between inflammatory thermogenesis and heat constriction from ischemia in RVO. It is also possible that, in our cohort, the RVO pathophysiological processes involved were localized and did not extend to the anterior segment. Patient and environmental factors must be considered when interpreting the OST. [ABSTRACT FROM AUTHOR]

In the realm of bioinformatics, Multiple Sequence Alignment (MSA) is a pivotal technique used to optimize the alignment of multiple biological sequences, guided by specific scoring criteria. Existing approaches addressing the MSA challenge tend to specialize in distinct biological features, leading to variability in alignment outcomes for the same set of sequences. Consequently, this paper proposes an enhanced evolutionary-based approach that simplifies the sequence alignment problem without considering the sequences in the non-dominated solution. Our method employs a multi-objective optimization technique that uniquely excludes non-dominated solution sets, effectively mitigating computational complexities. Utilizing the Sum of Pairs and the Total Conserved Column as primary objective functions, our approach offers a novel perspective. We adopt an integer coding approach to enhance the computational efficiency, representing chromosomes with sets of integers during the alignment process. Using the SABmark and BAliBASE datasets, extensive experimentation is conducted to compare our method with existing ones. The results affirm the superior solution quality achieved by our approach compared to its predecessors. Furthermore, via the Wilcoxon signed-rank test, a statistical analysis underscores the statistical significance of our model's improvement (p < 0.05). This comprehensive approach holds promise for advancing Multiple Sequence Alignment in bioinformatics. [ABSTRACT FROM AUTHOR]

Protein structure prediction continues to pose multiple challenges despite outstanding progress that is largely attributable to the use of novel machine learning techniques. One of the widely used representations of local 3D structure—protein blocks (PBs)—can be treated in a similar way to secondary structure classes. Here, we present a new approach for predicting local conformation in terms of PB classes solely from amino acid sequences. We apply the RMSD metric to ensure unambiguous future 3D protein structure recovery. The selection of statistically assessed features is a key component of the proposed method. We suggest that ML input features should be created from the statistically significant predictors that are derived from the amino acids' physicochemical properties and the resolved structures' statistics. The statistical significance of the suggested features was assessed using a stepwise regression analysis that permitted the evaluation of the contribution and statistical significance of each predictor. We used the set of 380 statistically significant predictors as a learning model for the regression neural network that was trained using the PISCES30 dataset. When using the same dataset and metrics for benchmarking, our method outperformed all other methods reported in the literature for the CB513 nonredundant dataset (for the PBs, Q16 = 81.01%, and for the DSSP, Q3 = 85.99% and Q8 = 79.35%). [ABSTRACT FROM AUTHOR]

The aim of this study was to retrospectively evaluate the effectiveness of corrective osteotomies in lower limb axis disorders at different levels of non-idiopathic (post traumatic, developmental, post-septic) etiology. A total of 50 patients were divided into three groups: A—thigh segment alignment disorder (24 patients); B—tibia segment alignment disorder (18 patients); C—thigh and tibia segment alignment disorder (8 patients). Radiological evaluation of digital lower limb postural X-ray was performed laterally and for AP, and included mLPFA, mLDFA, MAD, CORA coronal and sagittal plane parameters for the femur segment and mMPTA, mLDTA, MAD, CORA coronal and sagittal plane for the tibia segment. Clinical assessment was based on the LLFI. The mean follow-up was 55.8 months (12–86). Improvements in the radiological parameters and statistical significance were achieved for all measurements in all groups (p < 0.05). The most common plane of deformation was the coronal plane (varus/valgus), followed by the transverse (rotational) and sagittal planes (procurvatum/recurvatum). In this study, we examined 29 post-traumatic deformities and 21 other etiologies. Improvements in the LLFI score performance after corrective osteotomies were observed in all three groups. Corrective osteotomies are a safe and useful but challenging method of preserving joints in cases of post-traumatic, developmental or post-septic lower limb alignment disorders. [ABSTRACT FROM AUTHOR]

This prospective study aimed to evaluate the impact of Visian Implantable Collamer Lens (ICL) V4c implantation on retinal and choroidal morphology in patients with high myopia. A total of 97 eyes from 52 high myopic patients who underwent ICL V4c implantation were followed up for 12 months. Preoperative and postoperative evaluations included comprehensive ophthalmic assessments and enhanced depth imaging optical coherence tomography (EDI-OCT) to analyze changes in central retinal thickness (CRT), retinal volume (CRV), choroidal thickness (ChT), total choroidal area (TCA), luminal area (LA), and choroidal vascular index (CVI). Repeated measures mixed-effects models were used for comparing pre- and postoperative measurement variables and exploring relationships among age, axial length (AL), spherical equivalent refraction (SER), and postoperative retinal and choroidal changes, with statistical significance set at p < 0.05. Follow-up assessments were conducted at various time points, with participation rates ranging from 21% to 98%. Baseline characteristics showed a median age of 26.7 years, −10.14 diopters of SER, and an AL of 27.44 mm. Throughout the 12-month follow-up, CRT and 3.0 mm CRV consistently increased compared to the baseline, with statistically significant rises observed at postoperative day 1, week 1, and month 12. Most ChT measurements, including subfoveal ChT, declined over the 12 months, except at postoperative 6 months. Horizontal and vertical TCA and LA values significantly increased throughout the follow-up, except for month 6. After surgery, both horizontal and vertical CVI parameters exhibited an increase compared to the baseline, with some changes reaching statistical significance. Correlation analysis performed by repeated measures mixed-effects models showed that no relationship was found between age, AL, and SER and changes in postoperative retinal parameters and CVI parameters. However, postoperative changes in ChT and choroidal area parameters showed a negative correlation with AL and a positive correlation with SER. Our research demonstrated that ICL V4c implantation resulted in noteworthy alterations in retinal and choroidal morphology over a 1-year follow-up period. Moreover, in patients with high myopia, individuals with longer AL and higher degrees of myopia exhibited more pronounced postoperative changes in the choroid and retina. Further studies with extended follow-up durations are necessary to comprehensively understand the long-term effects of ICL implantation on retinal and choroidal morphology and function. [ABSTRACT FROM AUTHOR]

Simple Summary: Helicobacter pylori infection is known to be a major risk factor for gastric cancer, which continues to be a huge health burden worldwide, especially in Mongolia. There is a complicated interaction between host genetics, environmental factors, and bacterial virulence determinants in the etiology of this cancer. The virulence factors produced by this bacterium are among the most important contributors to the onset of gastric cancer. This study provides an accessible introduction to the relationship between H. pylori infection and gastric cancer and focuses on elucidating the impact of H. pylori's varying virulence factors on a set of virulence-associated genes at the level of gene presence or absence and single nucleotide polymorphisms from a genome-wide H. pylori perspective on gastric disease progression. Current results provide the basis for gastric progression depending on bacterial factors and help to find new insights into the prevention and treatment of gastric cancer. Background: The prevalence of gastric cancer in Mongolia, in East Asia, remains the highest in the world. However, most Helicobacter pylori strains in Mongolia have a less virulent Western-type CagA. We aimed to determine how H. pylori genomic variation affected gastric diseases, especially gastric cancer, based on comprehensive genome analysis. Methods: We identified a set of 274 virulence-associated genes in H. pylori, including virulence factor and outer membrane protein (OMP) genes, the type four secretion system gene cluster, and 13 well-known virulence gene genotypes in 223 H. pylori strains and their associations with gastric cancer and other gastric diseases. We conducted a genome-wide association study on 158 H. pylori strains (15 gastric cancer and 143 non-gastric cancer strains). Results: Out of 274 genes, we found 13 genes were variable depending on disease outcome, especially iron regulating OMP genes. H. pylori strains from Mongolia were divided into two main subgroups: subgroup (Sg1) with high risk and Sg2 with low risk for gastric cancer. The general characteristics of Sg1 strains are that they possess more virulence genotype genes. We found nine non-synonymous single nucleotide polymorphisms in seven genes that are linked with gastric cancer strains. Conclusions: Highly virulent H. pylori strains may adapt through host-influenced genomic variations, potentially impacting gastric carcinogenesis. [ABSTRACT FROM AUTHOR]

Machine learning methods have been a standard approach to select features that are associated with an outcome and to build a prediction model when the number of candidate features is large. LASSO is one of the most popular approaches to this end. The LASSO approach selects features with large regression estimates, rather than based on statistical significance, that are associated with the outcome by imposing an L 1 -norm penalty to overcome the high dimensionality of the candidate features. As a result, LASSO may select insignificant features while possibly missing significant ones. Furthermore, from our experience, LASSO has been found to select too many features. By selecting features that are not associated with the outcome, we may have to spend more cost to collect and manage them in the future use of a fitted prediction model. Using the combination of L 1 - and L 2 -norm penalties, elastic net (EN) tends to select even more features than LASSO. The overly selected features that are not associated with the outcome act like white noise, so that the fitted prediction model may lose prediction accuracy. In this paper, we propose to use standard regression methods, without any penalizing approach, combined with a stepwise variable selection procedure to overcome these issues. Unlike LASSO and EN, this method selects features based on statistical significance. Through extensive simulations, we show that this maximum likelihood estimation-based method selects a very small number of features while maintaining a high prediction power, whereas LASSO and EN make a large number of false selections to result in loss of prediction accuracy. Contrary to LASSO and EN, the regression methods combined with a stepwise variable selection method is a standard statistical method, so that any biostatistician can use it to analyze high-dimensional data, even without advanced bioinformatics knowledge. [ABSTRACT FROM AUTHOR]

The possibility of neutrinos moving at faster-than-light speeds can be modeled using terms in the Lagrangian that violate Lorentz symmetry, but the question of whether m 2 < 0 and v > c tachyonic neutrinos exist is an empirical question. It remains unresolved despite evidence from cosmic ray and other data that the electron neutrino has an effective m ν 2 ≈ − 0.25 eV 2 , which would require that one or more mass states is also tachyonic. In 2013, the 3 + 3 model of the neutrino masses, which includes one tachyonic mass state, was proposed based on supernova SN 1987A neutrino data. Here, we update evidence for tachyonic electron neutrinos and the 3 + 3 model and discuss one test which could prove conclusive. The update of earlier evidence includes many new elements, including new data which make the earlier cosmic ray evidence more robust, new results on cosmic ray composition, the ankle of the spectrum, leptonic cosmic ray data, and the statistical significance of finding the three large neutrino masses stipulated in the 3 + 3 model. Barring a galactic supernova, which occur only around twice a century, a decisive test of the 3 + 3 model could involve observing an extragalactic supernova neutrino burst, that is, a cluster of neutrinos in a specific time window well beyond what chance would predict. Even though existing searches for such bursts have yielded only upper limits on the extragalactic supernova frequency within a certain distance, it is shown that the choice of a one-day window for possible neutrino clusters in time might be far more sensitive. A search using a one-day time window could be conducted using existing data, and if a signal is found it would confirm the 3 + 3 model. Of course, the absence of any day-long neutrino burst would not disprove the model, since it could mean only that the nearest supernova during the period when detectors were active was simply too far to be detected. Finally, apart from testing the 3 + 3 model, an alternative type of search is suggested using existing hadronic cosmic ray data (from the IceCube Collaboration) that might verify the tachyonic neutrino hypothesis. [ABSTRACT FROM AUTHOR]

The detection of pain in persons with advanced dementia is challenging due to their inability to verbally articulate the pain they are experiencing. Pain Assessment in Advanced Dementia (PAINAD) is an observer-rated pain assessment tool developed based on non-verbal expressions of pain for persons with severe dementia. This study aimed to perform construct validation of PAINAD for pain assessment in persons with severe dementia in Malaysia. This was a prospective cross-sectional study conducted from 27 April 2022 to 28 October 2022 in eight public hospitals in Malaysia. The PAINAD scale was the index test, and the Discomfort Scale—Dementia of the Alzheimer Type (DS-DAT) and Nurse-Reported Pain Scale (NRPS) were the reference tests for construct and concurrent validity assessment. Pain assessment for the study subjects was performed by two raters concurrently at rest and during activity. The PAINAD score was determined by the first rater, whereas the DS-DAT and NRPS were assessed by the second rater, and they were blinded to each other's findings to prevent bias. PAINAD showed good positive correlations ranging from 0.325 to 0.715 with DS-DAT and NRPS at rest and during activity, with a p-value of <0.05. It also demonstrated statistically significant differences when comparing pain scores at rest and during activity, pre- and post-intervention. In conclusion, the PAINAD scale is a reliable observer-rated pain assessment tool for persons with severe dementia in Malaysia. It is also sensitive to changes in the pain level during activity and at rest, pre- and post-intervention. [ABSTRACT FROM AUTHOR]

Endoscopic submucosal dissection (ESD) in colorectal lesions is demanding, and a significant rate of non-curative procedures is expected. We aimed to assess the rate of residual lesion after a piecemeal ESD resection, or after an en bloc resection but with positive horizontal margins (local-risk resection—LocRR), for colorectal benign neoplasia. A retrospective multicenter analysis of consecutive colorectal ESDs was performed. Patients with LocRR ESDs for the treatment of benign colorectal lesions with at least one follow-up endoscopy were included. A cohort of en bloc resected lesions, with negative margins, was used as the control. A total of 2255 colorectal ESDs were reviewed; 352 of the ESDs were "non-curative". Among them, 209 were LocRR: 133 high-grade dysplasia and 76 low-grade dysplasia. Ten cases were excluded due to missing data. A total of 146 consecutive curative resections were retrieved for comparison. Compared to the "curative group", LocRRs were observed in lengthier procedures, with larger lesions, and in non-granular LSTs. Recurrence was higher in the LocRR group (16/199, 8% vs. 1/146, 0.7%; p = 0.002). However, statistical significance was lost when considering only en bloc resections with positive horizontal margins (p = 0.068). In conclusion, a higher rate of residual lesion was found after a piecemeal ESD resection, but not after an en bloc resection with positive horizontal margins. [ABSTRACT FROM AUTHOR]

Simple Summary: HSP60, a mitochondrial chaperone, can promote or inhibit cancer progression. Patients with colorectal cancer (CRC) were examined for HSP60 expression using the TNM classification. Patients with differentiated and p53-mutated CRC expressed high levels of HSP60. Compared with patients with high HSP60 expression, those with low expression had event-free and disease-specific survival hazard ratios of 1.42 and 1.69, respectively. TNM class and HSP60 expression affected survival, especially in late/advanced stages. The expression of the HSPD1 gene, which encodes HSP60, exhibited the same pattern as the protein. The hazard ratios for overall and relapse-free survival were 1.80 and 1.87, respectively, for patients with reduced HSPD1 expression. Low HSPD1 expression and advanced malignancy worsen CRC prognosis. This study suggests that HSPD1/HSP60 may be a useful biomarker for refined survival prediction in late-stage and advanced-stage CRC, allowing for individualized therapy. The role of heat shock protein 60 (HSP60), a mitochondrial chaperone, in tumor progression or its anti-tumor effects remains controversial. This study aimed to confirm the possibility of using HSP60 as a prognostic marker in patients with colorectal cancer (CRC), considering TNM classification for precise prediction. HSP60 expression increased with differentiation and p53 mutations in patients. However, compared to patients with high HSP60 expression, patients with low HSP60 expression had event-free survival and disease-specific survival hazard ratios (HRs) of 1.42 and 1.69, respectively. Moreover, when the survival rate was analyzed by combining TNM classification and HSP60 expression, the prognosis was poor, particularly when HSP60 expression was low in the late/advanced stage. This pattern was also observed with HSP family D member 1, HSPD1, the gene that encodes HSP60. Low HSPD1 expression was linked to lower overall survival and relapse-free survival rates, with HRs of 1.80 and 1.87, respectively. When TNM classification and HSPD1 expression were considered, CRC patients with low HSPD1 expression and advanced malignancy had a poorer prognosis than those with high HSPD1 expression. Thus, HSPD1/HSP60 can be a useful biomarker for a sophisticated survival prediction in late- and advanced-stage CRC, allowing the design of individualized treatment strategies. [ABSTRACT FROM AUTHOR]

Simple Summary: Pemetrexed, a multi-target anti-folate agent, is the treatment choice for advanced or metastatic thymoma at the second or later line setting. Thymoma patients occasionally show an exceptionally durable and deep response to pemetrexed treatment. Recent studies using next-generation sequencing have identified some genomic aberrations in such patients, but the mechanism underlying their sensitivity to pemetrexed remains unclear. This study explores certain somatic single-nucleotide variants or copy number variations (CNVs) in exceptional responders to pemetrexed treatment. To elucidate any genomic changes, we performed whole-exome sequencing in patients with advanced thymomas treated with pemetrexed. We found no differences between the exceptional and typical responders, but the highest number of whole arm gain or the loss of chromosomal CNVs was observed in an exceptional responder to pemetrexed. Our study provides additional genomic findings on thymomas and chemosensitivity. Background: Pemetrexed is used for the chemotherapy of advanced thymoma. Exceptional responses of thymoma to pemetrexed treatment are not frequently observed. The underlying genetic mechanism of the exceptional responses remains unclear. We used whole-exome sequencing to explore the specific genomic aberrations that lead to an extreme and durable response. Methods: Whole-exome sequencing using NovaSeq6000 (150 bp paired-end sequencing) was performed on nine formalin-fixed paraffin-embedded tissues from patients with advanced thymomas treated with pemetrexed (two exceptional responders and seven typical responders). Results: We identified 284 somatic single-nucleotide variants (SNVs; 272 missense, 8 missense/splice-site, 3 stop-gain, and 1 stop-gain/splice-site), 34 insertions and deletions (Indels; 33 frameshift and one splice region), and 21 copy number variations (CNVs; 15 gains and six losses). No difference in the number of SNVs variants and distribution of deleterious Indels was observed between the exceptional and typical responders. Interestingly, arm-level chromosomal CNVs (15 gains and six losses) were detected in four patients, including an exceptional responder. The highest number of arm-level CNVs was observed in an exceptional responder. Conclusion: Exceptional responders to pemetrexed for metastatic thymomas may be characterized by arm-level CNVs. Further, whole-genome and RNA sequencing studies should be performed. [ABSTRACT FROM AUTHOR]

This study investigated the effects of a modified rice bran arabinoxylan compound (RBAC) as a dietary supplement on the gut microbiota of healthy adults. Ten volunteers supplemented their diet with 1 g of RBAC for six weeks and 3 g of RBAC for another six weeks, with a three-week washout period. Faecal samples were collected every 3 weeks over 21 weeks. Microbiota from faecal samples were profiled using 16S rRNA sequencing. Assessment of alpha and beta microbiota diversity was performed using the QIIME2 platform. The results revealed that alpha and beta diversity were not associated with the experimental phase, interventional period, RBAC dosage, or time. However, the statistical significance of the participant was detected in alpha (p < 0.002) and beta (weighted unifrac, p = 0.001) diversity. Explanatory factors, including diet and lifestyle, were significantly associated with alpha (p < 0.05) and beta (p < 0.01) diversity. The individual beta diversity of six participants significantly changed (p < 0.05) during the interventional period. Seven participants showed statistically significant taxonomic changes (ANCOM W ≥ 5). These results classified four participants as responders to RBAC supplementation, with a further two participants as likely responders. In conclusion, the gut microbiome is highly individualised and modulated by RBAC as a dietary supplement, dependent on lifestyle and dietary intake. [ABSTRACT FROM AUTHOR]

The horizontal storm structure surrounding 92,512 lightning-ignited wildfires is examined in the mid to eastern sections of the United States from 2003 to 2015 using Vaisala's National Lightning Detection Network (NLDN), NCEP's Stage IV gauge-corrected radar precipitation mosaic, and the US Forest Service's Fire Occurrence Database. Though lightning flash density peaks strongly around fire ignitions on the instantaneous 1 km scale, on the hourly 10 km scale, both the lightning and precipitation peaks are typically offset from fire ignitions. Lightning density is higher, and precipitation is lower around ignition points compared to non-ignition points. The average spatial distribution of total lightning flashes around fire ignitions is symmetrical, while that of precipitation and positive flashes is not. Though regression is consistent with the claim that positive flashes have a stronger association with ignition than negative flashes, the statistical significance is ambiguous and is contradicted by an unchanging positive flash fraction in the vicinity of wildfires. [ABSTRACT FROM AUTHOR]

Background: Patellofemoral anatomy has not been well characterized. Applying deep learning to automatically measure knee anatomy can provide a better understanding of anatomy, which can be a key factor in improving outcomes. Methods: 483 total patients with knee CT imaging (April 2017–May 2022) from 6 centers were selected from a cohort scheduled for knee arthroplasty and a cohort with healthy knee anatomy. A total of 7 patellofemoral landmarks were annotated on 14,652 images and approved by a senior musculoskeletal radiologist. A two-stage deep learning model was trained to predict landmark coordinates using a modified ResNet50 architecture initialized with self-supervised learning pretrained weights on RadImageNet. Landmark predictions were evaluated with mean absolute error, and derived patellofemoral measurements were analyzed with Bland–Altman plots. Statistical significance of measurements was assessed by paired t-tests. Results: Mean absolute error between predicted and ground truth landmark coordinates was 0.20/0.26 cm in the healthy/arthroplasty cohort. Four knee parameters were calculated, including transepicondylar axis length, transepicondylar-posterior femur axis angle, trochlear medial asymmetry, and sulcus angle. There were no statistically significant parameter differences (p > 0.05) between predicted and ground truth measurements in both cohorts, except for the healthy cohort sulcus angle. Conclusion: Our model accurately identifies key trochlear landmarks with ~0.20–0.26 cm accuracy and produces human-comparable measurements on both healthy and pathological knees. This work represents the first deep learning regression model for automated patellofemoral annotation trained on both physiologic and pathologic CT imaging at this scale. This novel model can enhance our ability to analyze the anatomy of the patellofemoral compartment at scale. [ABSTRACT FROM AUTHOR]

Background: The present study reports on the outcomes of our mono-institutional experience of Helical Tomotherapy (HT)-based SRT for brain metastases. The use of this linac is less frequently reported for this kind of treatment. Methods: This retrospective study displays a series of patients treated with HT-SRT. The eligibility of using SRT for brain metastases was defined by a Karnofsky performance status of >70, a life expectancy of >6 months, and controlled extra-cranial disease; no SRT was allowed in the case of a number of brain metastases larger than 10. All the cases were discussed by a multidisciplinary board. Toxicity assessments were performed based on CTCAE v5.0. Survival endpoints were assessed using the Kaplan–Meier method, and univariate and multivariate analyses were carried out to identify any potential predictive factor for an improved outcome. Results: Sixty-four lesions in 37 patients were treated using HT-SRT with a median total dose of 30 Gy in five fractions. The median follow-up was 7 months, and the 1- and 2-year LC rates were both 92.5%. The IPFS rates were and 56.75% and 51.35%. The OS rates were 54% and 40%. The UA showed better IPFS rates significantly related to male sex (p = 0.049), a BED12 of ≥42 Gy (p = 0.006), and controlled extracranial disease (p = 0.03); in the MA, a favorable trend towards LC (p = 0.11) and higher BED (p = 0.11) schedules maintained a correlation with improved IPFS rates, although statistical significance was not reached. Conclusions: HT-based SRT for brain metastases showed safety and efficacy in our monoinstiutional experience. Higher RT doses showed statistical significance for improved outcomes of LC and OS. [ABSTRACT FROM AUTHOR]

Simple Summary: Surgery of locally advanced rectal cancer involving the anal sphinkter or recurrent anal cancer demands reliable surgical margins resulting in local defects. Skin-soft tissue reconstruction after extended or extralevator approaches to abdominoperineal resection for lower gastrointestinal tract cancers or inflammatory tumors has been described mainly with muscle flaps such as the vertical rectus abdominis muscle flap. In this article, we demonstrate our tailored approach with the use of bilateral adipo-fasciocutaneous perforator flaps of the inferior gluteal artery in a VY manner after surgery in 29 cases. The relatively simple surgical technique and postoperative course are presented. Surgery was performed with a minimally invasive abdominal approach combined with open perineal extralevator abdominoperineal resection and immediate flap reconstruction by a plastic surgeon. The rate of early perineal complication after plastic reconstruction was 19.0%, requiring local revision due to local infection. The use of bilateral adipo-fasciocutaneous perforator flaps of the inferior gluteal artery is a reliable, rapid, and safe option for pelvic floor reconstruction with minimal donor site morbidity. Background: Extralevator abdominoperineal excision (ELAPE) is a relatively new surgical technique for low rectal cancers, enabling a more radical approach than conventional abdominoperineal excision (APE) with a potentially better oncological outcome. To date, no standard exists for reconstruction after extended or extralevator approaches of abdominoperineal (ELAPE) resection for lower gastrointestinal cancer or inflammatory tumors. In the recent literature, techniques with myocutaneous flaps, such as the VY gluteal flap, the pedicled gracilis flap, or the pedicled rectus abdominis flaps (VRAM) are primarily described. We propose a tailored concept with the use of bilateral adipo-fasciocutaneous inferior gluteal artery perforator (IGAP) advancement flaps in VY fashion after ELAPE surgery procedures. This retrospective cohort study analyzes the feasibility of this concept and is, to our knowledge, one of the largest published series of IGAP flaps in the context of primary closure after ELAPE procedures. Methods: In a retrospective cohort analysis, we evaluated all the consecutive patients with rectal resections from Jan 2017 to Sep 2021. All the patients with abdominoperineal resection were included in the study evaluation. The primary endpoint of the study was the proportion of plastic reconstruction and inpatient discharge. Results: Out of a total of 560 patients with rectal resections, 101 consecutive patients with ELAPE met the inclusion criteria and were included in the study evaluation. The primary direct defect closure was performed in 72 patients (71.3%). In 29 patients (28.7%), the defect was closed with primary unilateral or bilateral IGAP flaps in VY fashion. The patients' mean age was 59.4 years with a range of 25–85 years. In 84 patients, the indication of the operation was lower rectal cancer or anal cancer recurrence, and non-oncological resections were performed in 17 patients. Surgery was performed in a minimally invasive abdominal approach in combination with open perineal extralevatoric abdominoperineal resection (ELAPE) and immediate IGAP flap reconstruction. The rate of perineal early complications after plastic reconstruction was 19.0%, which needed local revision due to local infection. All these interventions were conducted under general anesthesia (Clavien–Dindo IIIb). The mean length of the hospital stay was 14.4 days after ELAPE, ranging from 3 to 53 days. Conclusions: Since radical resection with a broad margin is the standard choice in primary, sphincter-infiltrating rectal cancer and recurrent anal cancer surgery in combination with ELAPE, the choice technique for pelvic floor reconstruction is under debate and there is no consensus. Using IGAP flaps is a reliable, technical, easy, and safe option, especially in wider defects on the pelvic floor with minimal donor site morbidity and an acceptable complication (no flap necrosis) rate. The data for hernia incidence in the long term are not known. [ABSTRACT FROM AUTHOR]

Although comprehensive school-wide interventions targeting bullying have proven effective, many schools, particularly those in low-to-middle income countries like Pakistan, lack the necessary resources to implement them. As a result, implementing cost-effective antibullying bystander programs that train students to become peer advocates is a promising approach for intervening in bullying incidents. Peer training in antibullying intervention involves training students to take on leadership roles and advocate for antibullying initiatives within their school communities. The aim of this study was to design, implement, and evaluate a peer-training module that was subsequently implemented in four schools (N = 38, boys = 26, girls = 12) in Pakistan. The aim was to raise awareness and prepare a team of peer mentors to effectively implement antibullying policies in educational institutions. Pre-post tests and participant feedback were used to evaluate the effectiveness of the peer-training program in increasing knowledge and awareness of bullying and the role of bystanders among trained peer mentors. To determine the impact of the peer mentor training on improving the school environment, data were also collected from students (N = 219, boys = 152, girls = 67) before and after the implementation of the program. The pilot implementation of the peer-training module was considered successful, indicating that the training was effective in improving the knowledge of peer mentors and could be used in a similar way in future cases. The results also showed a significant improvement in the development of prosocial bystanders. However, although improvements were observed in other aspects of the school environment, these did not reach statistical significance. The discussion section includes recommendations and explanations for differences based on gender and urban–rural factors. Suggestions are also made to improve the results for future applications. [ABSTRACT FROM AUTHOR]

Currently, composite resins have become the material of choice for the restoration of posterior teeth. Although bulk-fill resins represent a tempting alternative due to their lower complexity and faster use, some dentists are reluctant to use this material. The objective is to compare the performance of bulk-fill resins and conventional resins in direct restorations of posterior teeth based on the literature. The databases that were used to carry out the research were PubMed/MEDLINE, Embase, the Cochrane Library and the WOS. This umbrella literature review complies with PRISMA standards and assesses the quality of studies using the AMSTAR 2 tool. With the application of the criteria of the AMSTAR 2 tool, the reviews were considered low to moderate. The overall meta-analysis, although without statistical significance, favours mostly the use of conventional resin, as it is about five times more likely to obtain a favourable result than bulk-fill resin. Bulk-fill resins result in a simplification of the clinical process of posterior direct restorations, which is an advantage. The performance in terms of several properties of bulk-fill resins and conventional resins showed that they present similar behaviour. [ABSTRACT FROM AUTHOR]

Introduction: In public health, machine learning algorithms have been used to predict or diagnose chronic epidemiological disorders such as diabetes mellitus, which has reached epidemic proportions due to its widespread occurrence around the world. Diabetes is just one of several diseases for which machine learning techniques can be used in the diagnosis, prognosis, and assessment procedures. Methodology: In this paper, we propose a new approach for boosting the classification of diabetes based on a new metaheuristic optimization algorithm. The proposed approach proposes a new feature selection algorithm based on a dynamic Al-Biruni earth radius and dipper-throated optimization algorithm (DBERDTO). The selected features are then classified using a random forest classifier with its parameters optimized using the proposed DBERDTO. Results: The proposed methodology is evaluated and compared with recent optimization methods and machine learning models to prove its efficiency and superiority. The overall accuracy of diabetes classification achieved by the proposed approach is 98.6%. On the other hand, statistical tests have been conducted to assess the significance and the statistical difference of the proposed approach based on the analysis of variance (ANOVA) and Wilcoxon signed-rank tests. Conclusions: The results of these tests confirmed the superiority of the proposed approach compared to the other classification and optimization methods. [ABSTRACT FROM AUTHOR]

This study aimed to perform a systematic review and meta-analysis to compare pre-shaped implants on a patient-specific 3D-printed (3DP) model to manual free-hand shaping (MFS) for orbital wall reconstruction. The PRISMA protocol was followed in this study, and the review was registered in the PROSPERO database (CRD42021261594). A search was conducted in MEDLINE (PubMed), Embase, Cochrane Library, Clinicaltrials.gov, Google Scholar, and the grey literature. Ten articles were included, and six outcomes were analyzed. In total, 281 patients were in the 3DP group and 283 were in the MFS group. The studies had an overall high risk of bias. 3DP models resulted in a better accuracy of fit, anatomical angle reproduction, and defect area coverage. The correction of orbital volume was also superior with statistical significance. There was a higher percentage of the correction of enophthalmos and diplopia in the 3DP group. Intraoperative bleeding and hospital stay were reduced in the 3DP group. The meta-analysis of operative time showed a reduction in the average operative time by 23.58 min (95% CI: −43.98 to −3.19), which was statistically significant (t(6) = −2.8299, p = 0.0300). The 3DP models appear advantageous for an accurate orbital wall reconstruction, with fewer complications than those for conventional free-hand-shaped implants. [ABSTRACT FROM AUTHOR]