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Purpose: Analysis of autofluorescence holds promise for brain tumor delineation and diagnosis. Therefore, we investigated the potential of a commercial confocal laser scanning endomicroscopy (CLE) system for clinical imaging of brain tumors., Methods: A clinical CLE system with fiber probe and 488 nm laser excitation was used to acquire images of tissue autofluorescence. Fresh samples were obtained from routine surgeries (glioblastoma n = 6, meningioma n = 6, brain metastases n = 10, pituitary adenoma n = 2, non-tumor from surgery for the treatment of pharmacoresistant epilepsy n = 2). Additionally, in situ intraoperative label-free CLE was performed in three cases. The autofluorescence images were visually inspected for feature identification and quantification. For reference, tissue cryosections were prepared and further analyzed by label-free multiphoton microscopy and HE histology., Results: Label-free CLE enabled the acquisition of autofluorescence images for all cases. Autofluorescent structures were assigned to the cytoplasmic compartment of cells, elastin fibers, psammoma bodies and blood vessels by comparison to references. Sparse punctuated autofluorescence was identified in most images across all cases, while dense punctuated autofluorescence was most frequent in glioblastomas. Autofluorescent cells were observed in higher abundancies in images of non-tumor samples. Diffuse autofluorescence, fibers and round fluorescent structures were predominantly found in tumor tissues., Conclusion: Label-free CLE imaging through an approved clinical device was able to visualize the characteristic autofluorescence patterns of human brain tumors and non-tumor brain tissue ex vivo and in situ. Therefore, this approach offers the possibility to obtain intraoperative diagnostic information before resection, importantly independent of any kind of marker or label., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Purpose: Raman spectroscopy (RS) is a promising method for brain tumor detection. Near-infrared autofluorescence (AF) acquired during RS provides additional useful information for tumor identification and was investigated in comparison with RS for delineating brain tumors in situ., Methods: Raman spectra were acquired together with AF in situ within the solid tumor and at the tumor border during routine brain tumor surgeries (218 spectra; glioma WHO II-III, n = 6; GBM, n = 10; metastases, n = 10; meningioma, n = 3). Tissue classification for tumor identification in situ was trained on ex vivo data (375 spectra; glioma/GBM patients, n = 20; metastases, n = 11; meningioma, n = 13; and epileptic hippocampi, n = 4)., Results: Both in situ and ex vivo data showed that AF intensity in brain tumors was lower than that in border regions and normal brain tissue. Moreover, a positive correlation was observed between the AF intensity and the intensity of the Raman band corresponding to lipids at 1437 cm - 1 , while a negative correlation was found with the intensity of the protein band at 1260 cm - 1 . The classification of in situ AF and RS datasets matched the surgeon's evaluation of tissue type, with correct rates of 0.83 and 0.84, respectively. Similar correct rates were achieved in comparison to histopathology of tissue biopsies resected in selected measurement positions (AF: 0.80, RS: 0.83)., Conclusions: Spectroscopy was successfully integrated into existing neurosurgical workflows, and in situ spectroscopic data could be classified based on ex vivo data. RS confirmed its ability to detect brain tumors, while AF emerged as a competitive method for intraoperative tumor delineation., Competing Interests: Declarations. Ethical approval: All procedures involving humans were performed in accordance with the Helsinki Declaration. The study was approved by the Ethics Commission of the TU Dresden (study n. EK 323,122,008 and EK 24012019). Mouse brains were obtained from the Heart Center Dresden. No animals were additionally killed in the sense of the 3R in animal protection, but brains from other experiments were used (study n. DD24-5131/338/26); brain explantation took place after regular mouse killing and had no influence on the planning or execution of animal experiments. Consent to participate: Informed consent was obtained from all individual participants included in the study. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background: Coagulation plays a crucial role in innate immune response to invasive infections. Coagulative biomarkers might predict clinical outcomes differently, depending on etiology., Methods: A retrospective study was conducted during a 79-month period, recruiting 90 patients with meningitis or bloodstream infection caused by Neisseria meningitidis (n = 47) or Streptococcus pneumoniae (n = 43), median age 19 and 58 years, respectively. Biomarkers were assessed within 24 hours., Results: For N. meningitidis: in univariate analysis, increasing D-dimer was associated with in-hospital mortality (odds ratio [OR] 1.360; 95% confidence interval [CI], 1.063-1.889); in multivariate regression, increasing D-dimer was predictive (OR 1.037; 95% CI, 1.001-1.074) of the composite outcome (in-hospital mortality or amputations or hearing loss or neurological sequelae); protein C showed a clear trend toward lower levels in nonsurvivors (26% vs 48%) and in patients with the composite outcome (32% vs 51%); activated partial thromboplastin time (aPTT) was significantly prolonged in nonsurvivors (51.3 vs 35.3 seconds, P = .003), confirmed in univariate analysis (OR 1.122; 95% CI, 1.031-1.253). For S. pneumoniae: antithrombin was significantly lower in nonsurvivors (70% vs 81%, P = .038), confirmed in univariate analysis (OR 0.961; 95% CI, 0.921-0.997). For overall population: in multivariate regression, increasing age was associated with mortality (OR 1.043; 95% CI, 1.010-1.077), and S. pneumoniae etiology with the composite outcome (OR 6.024; 95% CI, 1.798-20.180)., Conclusions: For invasive infections caused by N. meningitidis, D-dimer is a biomarker capable of predicting unfavorable clinical outcomes; a potential role is suggested for aPTT prolongation and protein C decrease, and, in case of S. pneumoniae infections, for antithrombin decrease., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Enhanced recovery after surgery (ERAS) is an established pathway to improve short-term outcomes in colorectal surgery. It is unclear whether the efficacy, feasibility, and safety of the ERAS protocol are similar in older and younger patients. The study examined adherence to the ERAS protocol and identified factors leading to deviations in older patients., Materials and Methods: Patients undergoing colorectal resection were prospectively included in the ERAS protocol between 2019 and 2022. The cohort was stratified according to age and ERAS adherence score. The patients were compared regarding clinical short-term follow-up (30 days). Univariate and multivariate analyses were performed using the statistical program R (version 4.1.2)., Results: During the study period, 414 patients were recruited, including 132 patients (31.9 %) aged ≥75 years. The cohort of older adults showed significantly higher American Society of Anesthesiologists (ASA) scores III/IV (57.8 % vs. 81.8 %; p < 0.001) and more frequently malignant diseases (45.9 % vs. 64.1 %; p < 0.001), but a lower body mass index (26.7 vs. 24.4; p < 0.001). Furthermore, older adults achieved significantly lower adherence to the ERAS protocol in the postoperative phase (84.6 % vs. 80.1 %; p = 0.003) and experienced a longer median length of hospital stay (6 vs. 8 days; p < 0.001). The differences identified were increased change of body weight on postoperative day 1, delayed removal of a urinary catheter, and shorter duration of mobilization on postoperative days 2 and 3 (p < 0.05). However, in the multivariate analysis, emergency and open surgery as well as severe complications, but not age, were elicited as independent predictive factors for lower adherence to the ERAS protocol postoperatively., Discussion: Adherence to the postoperative ERAS requirements appears to be lower in older patients, although age alone was not an independent factor in our multivariate analysis and therefore not responsible for a lower adherence to the postoperative ERAS protocol after colorectal resection. This difference underlines the importance of interdisciplinary teamwork in daily practice to achieve optimal postoperative results, especially in older adults., Competing Interests: Declaration of Competing Interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Introduction: Standardisation has the potential to serve as a measure to mitigate complication rates. The objective was to assess the impact of standardisation by implementing a colorectal bundle (CB), which comprises nine elements, on the complication rates in left-sided colorectal resections., Patients and Methods: This prospective, multicentre, observational, cohort trial was conducted in Switzerland at nine participating hospitals. During the control period, each patient was treated in accordance with the local standard protocol at their respective hospital. In the CB period, all patients were treated in accordance with the CB. The primary endpoint was the Comprehensive Complication Index (CCI) at 30 days., Results: A total of 1141 patients were included (723 in the No CB group and 418 in the CB group). Median age was 66 years and 50.6% were female. Median CCI before and after CB implementation was 0.0 (Interquartile Range [IQR]: 0.0-20.9). A hurdle model approach was used for the analysis. The CB was not associated with the presence or severity of complications. Older age (Odds Ratio [OR] 1.02, 95% Confidence Intervall [CI]: 1.00-1.03), surgery for malignancy (OR 1.34, 95% CI: 1.01-1.92), emergency surgery (OR 2.19, 95% CI: 1.31-3.41), elevated nutritional risk score (OR 1.13, 95% CI: 1.01-1.24) and Body-Mass Index (OR 1.04, 95% CI: 1.00-1.06) were associated with higher odds of postoperative complications. In a supplementary per-protocol analysis, for each additional item of the CB fulfilled, the odds of anastomotic leakage (AL) were 24% lower (OR 0.76, 95% CI: 0.64-0.93)., Conclusions: Dedicated teams can establish high quality colorectal services in a network of hospitals with a joint standard. The study can serve as a model for other healthcare settings to conduct and implement quality improvement programs. The consistent implementation of the CB items can reduce the occurrence of AL., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Glioblastoma (GBM) stands as the most prevalent and aggressive form of adult gliomas. Despite the implementation of intensive therapeutic approaches involving surgery, radiation, and chemotherapy, Glioblastoma Stem Cells contribute to tumor recurrence and poor prognosis. The induction of Glioblastoma Stem Cells differentiation by manipulating the transcriptional machinery has emerged as a promising strategy for GBM treatment. Here, we explored an innovative approach by investigating the role of the depolarized resting membrane potential (RMP) observed in patient-derived GBM sphereforming cell (GSCs), which allows them to maintain a stemness profile when they reside in the G0 phase of the cell cycle., Methods: We conducted molecular biology and electrophysiological experiments, both in vitro and in vivo, to examine the functional expression of the voltage-gated sodium channel (Na v ) in GSCs, particularly focusing on its cell cycle-dependent functional expression. Na v activity was pharmacologically manipulated, and its effects on GSCs behavior were assessed by live imaging cell cycle analysis, self-renewal assays, and chemosensitivity assays. Mechanistic insights into the role of Na v in regulating GBM stemness were investigated through pathway analysis in vitro and through tumor proliferation assay in vivo., Results: We demonstrated that Na v is functionally expressed by GSCs mainly during the G0 phase of the cell cycle, suggesting its pivotal role in modulating the RMP. The pharmacological blockade of Na v made GBM cells more susceptible to temozolomide (TMZ), a standard drug for this type of tumor, by inducing cell cycle re-entry from G0 phase to G1/S transition. Additionally, inhibition of Na v substantially influenced the self-renewal and multipotency features of GSCs, concomitantly enhancing their degree of differentiation. Finally, our data suggested that Na v positively regulates GBM stemness by depolarizing the RMP and suppressing the ERK signaling pathway. Of note, in vivo proliferation assessment confirmed the increased susceptibility to TMZ following pharmacological blockade of Na v ., Conclusions: This insight positions Na v as a promising prognostic biomarker and therapeutic target for GBM patients, particularly in conjunction with temozolomide treatment., (© 2024. The Author(s).)

Glioblastoma (GBM) is the most common malignant primary brain cancer that, despite recent advances in the understanding of its pathogenesis, remains incurable. GBM contains a subpopulation of cells with stem cell-like properties called cancer stem cells (CSCs). Several studies have demonstrated that CSCs are resistant to conventional chemotherapy and radiation thus representing important targets for novel anti-cancer therapies. Proton sensing receptors expressed by CSCs could represent important factors involved in the adaptation of tumours to the extracellular environment. Accordingly, the expression of acid-sensing ion channels (ASICs), proton-gated sodium channels mainly expressed in the neurons of peripheral (PNS) and central nervous system (CNS), has been demonstrated in several tumours and linked to an increase in cell migration and proliferation. In this paper we report that the ASIC3 isoform, usually absent in the CNS and present in the PNS, is enriched in human GBM CSCs while poorly expressed in the healthy human brain. We propose here a novel therapeutic strategy based on the pharmacological activation of ASIC3, which induces a significant GBM CSCs damage while being non-toxic for neurons. This approach might offer a promising and appealing new translational pathway for the treatment of glioblastoma., (© 2024. The Author(s).)

Background: The DV-QoL is a 17-item questionnaire measuring health-related quality of life in patients affected by symptomatic diverticular disease, covering four domains: physical symptoms, concerns, feelings, and behavioral changes. Given the lack of a diverticulitis-specific questionnaire to be used for German-speaking patients, we prospectively validated the German version of the DV-QoL., Methods: German-speaking patients with CT-confirmed history of recurrent diverticular disease admitted to a Swiss surgical department completed the German version of the DV-QoL, along with short form-36 (SF-36) and the Gastrointestinal Quality of Life Index (GIQLI). Reliability was examined using exploratory and confirmatory factor analysis, a Martin-Loef test, and Cronbach's alpha. For convergent validity testing, correlations were calculated with the GIQLI and SF-36. Discriminant validity tests included age and gender., Results: We included 121 patients, of whom 77 were admissions for elective surgery and 44 presented with acute diverticulitis treated conservatively. The DV-QoL's total score showed good correlations with the GIQLI (r = - 0.77) and its subscales (r = - 0.76 to - 0.45), as well as with the SF-36's subscales (r = - 0.30 to - 0.57). No relationships were found with age or gender (p < 0.05). The Cronbach's alpha coefficient was 0.89 over all items and 0.69, 0.90, 0.78, and 0.77 for the four separated domains (physical symptoms, cognitions/concerns, feelings, and behavioral changes, respectively). A nonsignificant Martin-Loef test indicated unidimensionality (p = 1), further supported by the exploratory factor analysis, which showed an item information sharing of 65%., Conclusion: The German DV-QoL questionnaire can be used as a valid and reliable disease-specific measure for quality of life in patients with recurrent diverticular disease., (© 2024. Springer Nature Switzerland AG.)

In patients with cerebellar ataxia (CA), symptoms related to oculomotor dysfunction significantly affect quality of life (QoL). This study aimed to analyze the literature on patient-related outcome measures (PROMs) assessing QoL impacts of vestibular and cerebellar oculomotor abnormalities in patients with CA to identify the strengths and limitations of existing scales and highlight any areas of unmet need. A systematic review was conducted (Medline, Embase) of English-language original articles reporting on QoL measures in patients with vertigo, dizziness or CA. Pre-specified parameters were retrieved, including diseases studied, scales applied and conclusions drawn. Our search yielded 3671 articles of which 467 studies (n = 111,606 participants) were deemed relevant. The most frequently studied disease entities were (a) non-specific dizziness/gait imbalance (114 studies; 54,581 participants), (b) vestibular schwannomas (66; 15,360), and (c) vestibular disorders not further specified (66; 10,259). The Dizziness Handicap Inventory (DHI) was the most frequently used PROM to assess QoL (n = 91,851), followed by the Penn Acoustic Neuroma Quality-of-Life Scale (n = 12,027) and the Activities-Specific Balance Confidence Scale (n = 2'471). QoL-scores capturing symptoms related to oculomotor abnormalities in CA were rare, focused on visual impairments (e.g., National-Eye-Institute Visual Function Questionnaire, Oscillopsia Functional Impact, oscillopsia severity score) and were unvalidated. The DHI remains the most widely used and versatile scale for evaluating dizziness. A lack of well-established PROMs for assessing the impact of oculomotor-related symptoms on QoL in CA was noted, emphasizing the need for developing and validating a new QoL-score dedicated to the oculomotor domain for individuals with CA., (© 2024. The Author(s).)

Background: Infrared (IR) spectroscopy allows intraoperative, optical brain tumor diagnosis. Here, we explored it as a translational technology for the identification of aggressive meningioma types according to both, the WHO CNS grading system and the methylation classes (MC)., Methods: Frozen sections of 47 meningioma were examined by IR spectroscopic imaging and different classification approaches were compared to discern samples according to WHO grade or MC., Results: IR spectroscopic differences were more pronounced between WHO grade 2 and 3 than between MC intermediate and MC malignant, although similar spectral ranges were affected. Aggressive types of meningioma exhibited reduced bands of carbohydrates (at 1024 cm -1 ) and nucleic acids (at 1080 cm -1 ), along with increased bands of phospholipids (at 1240 and 1450 cm -1 ). While linear discriminant analysis was able to discern spectra of WHO grade 2 and 3 meningiomas (AUC 0.89), it failed for MC (AUC 0.66). However, neural network classifiers were effective for classification according to both WHO grade (AUC 0.91) and MC (AUC 0.83), resulting in the correct classification of 20/23 meningiomas of the test set., Conclusions: IR spectroscopy proved capable of extracting information about the malignancy of meningiomas, not only according to the WHO grade, but also for a diagnostic system based on molecular tumor characteristics. In future clinical use, physicians could assess the goodness of the classification by considering classification probabilities and cross-measurement validation. This might enhance the overall accuracy and clinical utility, reinforcing the potential of IR spectroscopy in advancing precision medicine for meningioma characterization., Competing Interests: None., (© The Author(s) 2024. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Introduction: Despite the advances in the medical management, especially biologics, there are still clear indications for operative management of IBD. For Crohn's disease, surgical therapy plays an important role after failure of medical management and for treatment of complications. In recent years, however, there has been a change in the treatment philosophy of patients with isolated involvement of the ileocecal region, and for selected patients, primary surgical resection appears to be an equivalent treatment alternative to therapy with biologics. In ulcerative colitis, surgery offers the only curative option. In severe acute colitis, surgery is indicated when conservative treatment is not effective and/or when there is a risk of colonic perforation. Indications for elective surgery are failure of conservative therapy and malignant transformation. The ileoanal J-pouch reconstruction is the standard procedure after restorative proctocolectomy with excellent functional long-term results. The increasing complexity of indications and minimally invasive surgical techniques, as well as the demanding perioperative treatment, led to an increasing specialization in the surgical treatment of IBD patients, with IBD-surgeons collaborating as a team with gastroenterologists to optimize the outcome of IBD-patients., Competing Interests: Die Autoren haben keine Interessenkonflikte., (© 2023 Aerzteverlag medinfo AG.)

The structural biopolymer spongin in the form of a 3D scaffold resembles in shape and size numerous species of industrially useful marine keratosan demosponges. Due to the large-scale aquaculture of these sponges worldwide, it represents a unique renewable source of biological material, which has already been successfully applied in biomedicine and bioinspired materials science. In the present study, spongin from the demosponge Hippospongia communis was used as a microporous template for the development of a new 3D composite containing goethite [α-FeO(OH)]. For this purpose, an extreme biomimetic technique using iron powder, crystalline iodine, and fibrous spongin was applied under laboratory conditions for the first time. The product was characterized using SEM and digital light microscopy, infrared and Raman spectroscopy, XRD, thermogravimetry (TG/DTG), and confocal micro X-ray fluorescence spectroscopy (CMXRF). A potential application of the obtained goethite-spongin composite in the electrochemical sensing of dopamine (DA) in human urine samples was investigated, with satisfactory recoveries (96% to 116%) being obtained.

Neurological disorders, including spinal cord injury, peripheral nerve injury, traumatic brain injury, and neurodegenerative diseases, pose significant challenges in terms of diagnosis, treatment, and understanding the underlying pathophysiological processes. Label-free multiphoton microscopy techniques, such as coherent Raman scattering, two-photon excited autofluorescence, and second and third harmonic generation microscopy, have emerged as powerful tools for visualizing nervous tissue with high resolution and without the need for exogenous labels. Coherent Raman scattering processes as well as third harmonic generation enable label-free visualization of myelin sheaths, while their combination with two-photon excited autofluorescence and second harmonic generation allows for a more comprehensive tissue visualization. They have shown promise in assessing the efficacy of therapeutic interventions and may have future applications in clinical diagnostics. In addition to multiphoton microscopy, vibrational spectroscopy methods such as infrared and Raman spectroscopy offer insights into the molecular signatures of injured nervous tissues and hold potential as diagnostic markers. This review summarizes the application of these label-free optical techniques in preclinical models and illustrates their potential in the diagnosis and treatment of neurological disorders with a special focus on injury, degeneration, and regeneration. Furthermore, it addresses current advancements and challenges for bridging the gap between research findings and their practical applications in a clinical setting., Competing Interests: Competing interestsThe authors declare no competing interests., (© The Author(s) 2023.)

Background: Surgical site infections (SSI) complicate up to 40% of surgical procedures, leading to increased patient morbidity and mortality. Previous research identified disparities in SSI prevention guidelines and clinical practices across different institutions. The study aims to identify variations in SSI prevention practices within and between specialties and financial systems and provide a representation of existing SSI preventative measures to help improve the standardization of SSI prevention practices., Methods: This collaborative cross-sectional survey will be aimed at pan-surgical specialties internationally. The study has been designed and will be reported in line with the CROSS and CHERRIES standards. An international study steering committee will design and internally validate the survey in multiple consensus-based rounds. This will be based on SSI prevention measures outlined in the CDC (2017), WHO (2018), NICE (2019), Wounds UK (2020) and the International Surgical Wound Complications Advisory Panel (ISWCAP) guidelines. The questionnaire will include demographics, SSI surveillance, preoperative, peri-operative and postoperative SSI prevention. Data will be collected on participants' surgical specialty, operative grade, of practice and financial healthcare system of practice. The online survey will be designed and disseminated using Qualtrics XM Platform™ through national and international surgical colleges and societies, in addition to social media and snowballing. Data collection will be open for 3 months with reminders, and raking will be used to ascertain the sample. Responses will be analyzed, and the chi-square test used to evaluate the impact of SSI prevention variables on responses., Discussion: Current SSI prevention practice in UK Vascular surgery varies considerably, with little consensus on many measures. Given the inconsistency in guidelines on how to prevent SSIs, there is a need for standardization. This survey will investigate the disparity in SSI preventative measures between different surgical fields and countries., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Heinz, Walshaw, Kwan, Long, Carradice, Totty, Kontouli, Lainas, Hitchman, Smith, Huo, Guadalajara, Garcia-Olmo, Sharma, Biyani, Tomlinson, Loubani, Galli, Lathan, Chetter and Yiasemidou.)

Introduction: A rectal prolapse is mainly a disease of the elderly population, occurring more frequently among women. The medical practitioner has an important role in the recognition and initiation of therapy for rectal prolapse. Appropriate therapy can have an important impact on symptom reduction and healthcare resources. Surgical therapy includes perineal or transabdominal surgery, with increasing use of minimally invasive techniques such as mesh rectopexy. This operation is indicated and feasible regardless of age. The management of the rectal prolapse in specialized pelvic floor centres with interdisciplinary expertise for diagnosis and therapy is recommended., Competing Interests: Es bestehen keine Interessenskonflikte., (© 2023 Aerzteverlag medinfo AG.)

Objectives: Single-visit testing and treatment for syphilis can reduce follow-up visits. The objectives of this study were to evaluate the performance and treatment outcomes of two dual syphilis/HIV point-of-care tests (POCTs)., Methods: Participants aged 16 years and older were offered concurrent syphilis/HIV POCTs with fingerstick blood sampling using two extremely rapid (<5 minutes) devices (MedMira Multiplo Rapid TP/HIV test and INSTI Multiplex HIV-1/HIV-2/Syphilis Antibody Test). Those with positive POCT results were offered same-day syphilis treatment and linkage to HIV care. Nurses performed testing at two emergency departments, a First Nations community, a correctional facility, and a sexually transmitted infection clinic. POCT results were compared with those of standard serological testing. Sensitivity and specificity were calculated., Results: Between August 2020 and February 2022, 1526 visits were completed. Both POCTs accurately identified participants with HIV (sensitivity, 100% [24 of 24]; 95% CI, 86.2-100%; specificity, 99.6% [1319 of 1324]; 95% CI, 99.1-99.8%), linking 24 HIV cases to care. Both tests were most sensitive with a rapid plasma reagin (RPR) of ≥1:8 dilutions (Multiplo: sensitivity, 98.3% [231 of 235]; 95% CI, 95.7-99.3%; specificity, 99.5% [871 of 875]; 95% CI, 98.8-99.8%; INSTI Multiplex: sensitivity, 97.9% [230 of 235]; 95% CI, 95.1-99.1%; specificity, 99.8% [873 of 875]; 95% CI, 99.2-99.9%) and least sensitive with non-reactive RPR (Multiplo: sensitivity, 54.1% [59 of 109]; 95% CI, 44.8-63.2%; specificity, 99.5% [871 of 875]; 95% CI, 98.8-99.8%; INSTI Multiplex: sensitivity, 28.4% [31 of 109]; 95% CI, 20.8-37.5%; specificity, 99.8% [873 of 875]; 95% CI, 99.2-99.9%). Eighty-five percent of participants with infectious syphilis were treated on the same day as the positive POCT result., Discussion: Two extremely rapid (<5 minutes) dual syphilis/HIV POCTs showed excellent sensitivity and specificity for the diagnosis of active syphilis (RPR, ≥1:8 dilutions) and HIV and confirmed the ability to offer single-visit testing and treatment for syphilis and linkage to HIV care in diverse clinical settings., (Crown Copyright © 2023. Published by Elsevier Ltd. All rights reserved.)

Purpose: Patient-derived cancer cell lines can be very useful to investigate genetic as well as epigenetic mechanisms of transformation and to test new drugs. In this multi-centric study, we performed genomic and transcriptomic characterization of a large set of patient-derived glioblastoma (GBM) stem-like cells (GSCs)., Methods: 94 (80 I surgery/14 II surgery) and 53 (42 I surgery/11 II surgery) GSCs lines underwent whole exome and trascriptome analysis, respectively., Results: Exome sequencing revealed TP53 as the main mutated gene (41/94 samples, 44%), followed by PTEN (33/94, 35%), RB1 (16/94, 17%) and NF1 (15/94, 16%), among other genes associated to brain tumors. One GSC sample bearing a BRAF p.V600E mutation showed sensitivity in vitro to a BRAF inhibitor. Gene Ontology and Reactome analysis uncovered several biological processes mostly associated to gliogenesis and glial cell differentiation, S - adenosylmethionine metabolic process, mismatch repair and methylation. Comparison of I and II surgery samples disclosed a similar distribution of mutated genes, with an overrepresentation of mutations in mismatch repair, cell cycle, p53 and methylation pathways in I surgery samples, and of mutations in receptor tyrosine kinase and MAPK signaling pathways in II surgery samples. Unsupervised hierarchical clustering of RNA-seq data produced 3 clusters characterized by distinctive sets of up-regulated genes and signaling pathways., Conclusion: The availability of a large set of fully molecularly characterized GCSs represents a valuable public resource to support the advancement of precision oncology for the treatment of GBM., (© 2023. The Author(s).)

As the state of resection margins is an important prognostic factor after extirpation of colorectal liver metastases, surgeons aim to obtain negative margins, sometimes elaborated by resections of the positive resection plane after intraoperative frozen sections. However, this is time consuming and results sometimes remain unclear during surgery. Label-free multimodal multiphoton microscopy (MPM) is an optical technique that retrieves morpho-chemical information avoiding all staining and that can potentially be performed in real-time. Here, we investigated colorectal liver metastases and hepatic tissue using a combination of three endogenous nonlinear signals, namely: coherent anti-Stokes Raman scattering (CARS) to visualize lipids, two-photon excited fluorescence (TPEF) to visualize cellular patterns, and second harmonic generation (SHG) to visualize collagen fibers. We acquired and analyzed over forty thousand MPM images of metastatic and normal liver tissue of 106 patients. The morphological information with biochemical specificity produced by MPM allowed discriminating normal liver from metastatic tissue and discerning the tumor borders on cryosections as well as formalin-fixed bulk tissue. Furthermore, automated tissue type classification with a correct rate close to 95% was possible using a simple approach based on discriminant analysis of texture parameters. Therefore, MPM has the potential to increase the precision of resection margins in hepatic surgery of metastases without prolonging surgical intervention., (© 2023. The Author(s).)

The in ovo sexing of chicken eggs is a current task and a prerequisite to overcome the mass killing of male day-old chicks from laying lines. Although various methods have been developed and tested in recent years, practicable methods for sex determination are still missing which can be applicated in poultry hatcheries before the chicken embryo is capable of nociception and pain sensation. Optical spectroscopic methods enable an early determination of the sex. In this study, a novel method based on two-wavelength in ovo fluorescence excitation is described. More than 1600 eggs were examined. In ovo fluorescence was sequentially excited at 532 nm and 785 nm. The fluorescence intensities of the spectral regions behave inversely with respect to sex. It is shown that the observed sex-related differences in the fluorescence intensities are based on the embryonic hemoglobin synthesis. The accuracy of sex determination is 96% for both sexes. The hatching rate is not reduced compared to an equivalent reference group., (© 2022. The Author(s).)

Timing of extubation on post-mandibular distraction osteogenesis (MDO) surgery is critical, given that at baseline these infants have difficult airways and failed extubation requires either re-intubation of an already complex airway with a fragile, recently osteotomized mandible, or adjunctive airway measures such as CPAP that may apply unwanted pressure to the surgical site. Thus, the goal is to plan extubation when the risk of failure is minimal. Currently, there is a void in the literature addressing the timing of extubation post-MDO and no objective sign of extubation readiness has been elucidated. This study describes a simple clinical pearl to assist in the evaluation of extubation readiness in these patients. Postoperatively, we obtain weekly radiographs to assess distractor stability and advancement, and to assess for the "Air Sign". The Air Sign describes a radiolucent space (air) visualized in the oropharynx on lateral radiographs, likely indicating that the tongue based airway obstruction has been relieved by mandibular advancement., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© 2021 The Author(s).)

Corneal cross-linking (CXL) with riboflavin and ultraviolet A light is a therapeutic procedure to restore the mechanical stability of corneal tissue. The treatment method is applied to pathological tissue, such as keratoconus and induces the formation of new cross-links. At present, the molecular mechanisms of induced cross-linking are still not known exactly. In this study, we investigated molecular alterations within porcine cornea tissue after treatment with riboflavin and ultraviolet A light by surface enhanced Raman spectroscopy (SERS). For that purpose, after CXL treatment a thin silver layer was vapor-deposited onto cornea flaps. To explore molecular alterations induced by the photochemical process hierarchical cluster analysis (HCA) was used. The detailed analysis of SERS spectra reveals that there is no general change in collagen secondary structure while modifications on amino acid side chains are the most dominant outcome. The formation of secondary and aromatic amine groups as well as methylene and carbonyl groups were observed. Even though successful cross-linking could not be registered in all treated samples, Raman signals of newly formed chemical groups are already present in riboflavin only treated corneas., Competing Interests: The authors declare no competing interests., (© 2023 The Authors.)

Glioblastoma (GBM) is a common and deadly form of brain tumor in adults. Dysregulated metabolism in GBM offers an opportunity to deploy metabolic interventions as precise therapeutic strategies. To identify the molecular drivers and the modalities by which different molecular subgroups of GBM exploit metabolic rewiring to sustain tumor progression, we interrogated the transcriptome, the metabolome, and the glycoproteome of human subgroup-specific GBM sphere-forming cells (GSC). L-fucose abundance and core fucosylation activation were elevated in mesenchymal (MES) compared with proneural GSCs; this pattern was retained in subgroup-specific xenografts and in subgroup-affiliated human patient samples. Genetic and pharmacological inhibition of core fucosylation significantly reduced tumor growth in MES GBM preclinical models. Liquid chromatography-mass spectrometry (LC-MS)-based glycoproteomic screening indicated that most MES-restricted core-fucosylated proteins are involved in therapeutically relevant GBM pathological processes, such as extracellular matrix interaction, cell adhesion, and integrin-mediated signaling. Selective L-fucose accumulation in MES GBMs was observed using preclinical minimally invasive PET, implicating this metabolite as a potential subgroup-restricted biomarker.Overall, these findings indicate that L-fucose pathway activation in MES GBM is a subgroup-specific dependency that could provide diagnostic markers and actionable therapeutic targets., Significance: Metabolic characterization of subgroup-specific glioblastoma (GBM) sphere-forming cells identifies the L-fucose pathway as a vulnerability restricted to mesenchymal GBM, disclosing a potential precision medicine strategy for targeting cancer metabolism., (©2022 American Association for Cancer Research.)

Raman spectroscopy is an optical technology that probes tissue composition and is envisioned for clinical applications in neurosurgery. Here, we provide an overview of basic and translational research addressing brain tumor delineation and diagnosis and identify potential scenarios for routine clinical use of Raman spectroscopy. Moreover, we discuss the practical technical requirements in the context of daily use as well as open questions regarding automated tissue assessment.

Purpose: Infrared (IR) spectroscopy has the potential for tumor delineation in neurosurgery. Previous research showed that IR spectra of brain tumors are generally characterized by reduced lipid-related and increased protein-related bands. Therefore, we propose the exploitation of these common spectral changes for brain tumor recognition., Methods: Attenuated total reflection IR spectroscopy was performed on fresh specimens of 790 patients within minutes after resection. Using principal component analysis and linear discriminant analysis, a classification model was developed on a subset of glioblastoma (n = 135) and non-neoplastic brain (n = 27) specimens, and then applied to classify the IR spectra of several types of brain tumors., Results: The model correctly classified 82% (517/628) of specimens as "tumor" or "non-tumor", respectively. While the sensitivity was limited for infiltrative glioma, this approach recognized GBM (86%), other types of primary brain tumors (92%) and brain metastases (92%) with high accuracy and all non-tumor samples were correctly identified., Conclusion: The concept of differentiation of brain tumors from non-tumor brain based on a common spectroscopic tumor signature will accelerate clinical translation of infrared spectroscopy and related technologies. The surgeon could use a single instrument to detect a variety of brain tumor types intraoperatively in future clinical settings. Our data suggests that this would be associated with some risk of missing infiltrative regions or tumors, but not with the risk of removing non-tumor brain., (© 2022. The Author(s).)

The occurrence of asymptomatic bacteriuria concomitant to urolithiasis is an issue for patients undergoing renal stone treatment. Disposing of a preoperative urine culture is essential to reduce the risk of septic events. The endpoint of the study is to report which characteristics of candidates for renal stone treatment are frequently associated with positive urine culture. 2605 patients were retrospectively enrolled from 14 centers; inclusion criteria were age > 18 and presence of a single renal stone 1-2 cm in size. The variables collected included age, gender, previous renal surgery, comorbidities, skin-to-stone distance, stone size, location, density, presence of hydronephrosis. After a descriptive analysis, the association between continuous and categorical variables and the presence of positive urine culture was assessed using a logistic regression model. Overall, 240/2605 patients (9%) had preoperative bacteriuria. Positive urine culture was more frequent in females, patients with previous renal interventions, chronic kidney disease, congenital anomalies, larger stones, increased density. Multivariate analysis demonstrated that previous renal interventions (OR 2.6; 95% CI 1.9-3.4; p < 0.001), renal-related comorbidities (OR 1.31; 95% CI 1.19-1.4; p < 0.001), higher stone size (OR 1.06; 95% CI 1.02-1.1; p = 0.01) and density (OR 1.00; 95% CI 1.0-1.00; p = 0.02) were associated with bacteriuria; male gender and lower caliceal location were inversely related to it. Beyond expected risk factors, such as female gender, other parameters are seemingly favoring the presence of positive urine culture. The awareness of variables associated with bacteriuria allows to assess which individuals are at increased risk of presenting bacteriuria and reduce the rate of septic complications., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

KBTBD13 variants cause nemaline myopathy type 6 (NEM6). The majority of NEM6 patients harbors the Dutch founder variant, c.1222C>T, p.Arg408Cys (KBTBD13 p.R408C). Although KBTBD13 is expressed in cardiac muscle, cardiac involvement in NEM6 is unknown. Here, we constructed pedigrees of three families with the KBTBD13 p.R408C variant. In 65 evaluated patients, 12% presented with left ventricle dilatation, 29% with left ventricular ejection fraction< 50%, 8% with atrial fibrillation, 9% with ventricular tachycardia, and 20% with repolarization abnormalities. Five patients received an implantable cardioverter defibrillator, three cases of sudden cardiac death were reported. Linkage analysis confirmed cosegregation of the KBTBD13 p.R408C variant with the cardiac phenotype. Mouse studies revealed that (1) mice harboring the Kbtbd13 p.R408C variant display mild diastolic dysfunction; (2) Kbtbd13-deficient mice have systolic dysfunction. Hence, (1) KBTBD13 is associated with cardiac dysfunction and cardiomyopathy; (2) KBTBD13 should be added to the cardiomyopathy gene panel; (3) NEM6 patients should be referred to the cardiologist., (© 2022 The Authors. Human Mutation published by Wiley Periodicals LLC.)

Recent advances in label-free histology promise a new era for real-time diagnosis in neurosurgery. Deep learning using autofluorescence is promising for tumor classification without histochemical staining process. The high image resolution and minimally invasive diagnostics with negligible tissue damage is of great importance. The state of the art is raster scanning endoscopes, but the distal lens optics limits the size. Lensless fiber bundle endoscopy offers both small diameters of a few 100 microns and the suitability as single-use probes, which is beneficial in sterilization. The problem is the inherent honeycomb artifacts of coherent fiber bundles (CFB). For the first time, we demonstrate an end-to-end lensless fiber imaging with exploiting the near-field. The framework includes resolution enhancement and classification networks that use single-shot CFB images to provide both high-resolution imaging and tumor diagnosis. The well-trained resolution enhancement network not only recovers high-resolution features beyond the physical limitations of CFB, but also helps improving tumor recognition rate. Especially for glioblastoma, the resolution enhancement network helps increasing the classification accuracy from 90.8 to 95.6%. The novel technique enables histological real-time imaging with lensless fiber endoscopy and is promising for a quick and minimally invasive intraoperative treatment and cancer diagnosis in neurosurgery., (© 2022. The Author(s).)

Purpose: Overall complication and leak rates in colorectal surgery showed only minor improvements over the last years and remain still high. While the introduction of the WHO Safer Surgery Checklist has shown a reduction of overall operative mortality and morbidity in general surgery, only minor attempts have been made to improve outcomes by standardizing perioperative processes in colorectal surgery. Nevertheless, a number of singular interventions have been found reducing postoperative complications in colorectal surgery. The aim of the present study is to combine nine of these measures to a catalogue called colorectal bundle (CB). This will help to standardize pre-, intra-, and post-operative processes and therefore eventually reduce complication rates after colorectal surgery., Methods: The study will be performed among nine contributing hospitals in the extended north-western part of Switzerland. In the 6-month lasting control period the patients will be treated according to the local standard of each contributing hospital. After a short implementation phase all patients will be treated according to the CB for another 6 months. Afterwards complication rates before and after the implementation of the CB will be compared., Discussion: The overall complication rate in colorectal surgery is still high. The fact that only little progress has been made in recent years underlines the relevance of the current project. It has been shown for other areas of surgery that standardization is an effective measure of reducing postoperative complication rates. We hypothesize that the combination of effective, individual components into the CB can reduce the complication rate., Trial Registration: Registered in ClinicalTrials.gov on 11/03/2020; NCT04550156., Highlights: Purpose: Overall complications in colorectal surgery remain still highStandardizing can reduce overall operative mortality and morbidityOnly minor attempts have been made to standardize perioperative processes in colorectal surgerySingular interventions have been found reducing postoperative complicationsThe aim is to combine nine of these measures to a colorectal bundle (CB)The CB will help to reduce complication rates after colorectal surgery Methods: The observational study will be performed among nine hospitals in SwitzerlandSix month the patients will be treated according to the local standardsAfterwards patients will be treated according to the CB for another six monthsComplication rates before and after the implementation of the CB will be compared Discussion: Only little progress has been made to reduce complication rate in colorectal surgeryStandardization is an effective measure of reducing complication ratesThe combination of effective, individual components into the CB can reduce the complication rate., Competing Interests: Author BW has received research support from freiwilliger akademischer Gesellschaft. Author MvS has received research support from Bangerter Stiftung and Waldmeier Wohlfahrtsfond. There are no non-financial interests., (Copyright: © 2022 The Author(s).)

Objectives: Fibromyalgia symptoms have a significant impact on the quality of life and respond poorly to medications. It has been hypothesized that the use of low-energy pulsed electromagnetic field (PEMF) induces neuroprotective effects that may interfere with pain perception. We explored the efficacy of PEMF in patients affected by fibromyalgia., Methods: Twenty-one females (median age 59 years, interquartile range [IQR] 16.5) affected by fibromyalgia were randomized to receive pulsed electromagnetic field-triple energy pain treatment (PEMF-TEPT) or placebo at T0 and at 4 weeks and 8 weeks. Fibromyalgia impact questionnaire (FIQ), widespread pain index (WPI), visual analog score (VAS) pain, symptom severity (SS) scale, and short form 36 (SF-36) health survey questionnaire have been evaluated., Results: Patients in the PEMF-TEPT group had a significantly higher reduction of WPI compared to placebo (mean difference -12.90 ± standard deviation [SD] 5.32 vs. -1.91 ± 4.55, difference in difference [DD] of -10.99; P < 0.001), of SS score (-4.10 ± 4.85 vs. -2.00 ± 2.32; DD = -2.1; P < 0.05), of VAS pain (-48 ± 30.75 vs. -16.82 ± 23.69; DD = -31.18; P < 0.01). They also reported a higher improvement of FIQ and SF-36, albeit not reaching statistical significance., Conclusion: In our pilot controlled study, PEMF-TEPT appeared to be safe and improved fibromyalgia symptoms., Competing Interests: Conflicts of Interest Stefano Rampoldi is employed at THS, which provided the device. The other authors certify that there is no conflict of interest with any financial organization regarding the material discussed in the manuscript., (© 2022 Massimo Giovale et al., published by Sciendo.)

The elucidation of biomechanics furthers our understanding of brain tumour biology. Brillouin spectroscopy is a new optical method that addresses viscoelastic properties down to subcellular resolution in a contact-free manner. Moreover, it can be combined with Raman spectroscopy to obtain co-localized biochemical information. Here, we applied co-registered Brillouin and Raman spectroscopy to U87-MG human glioblastoma cells in vitro . Using two-dimensional and three-dimensional cultures, we related biomechanical properties to local biochemical composition at the subcellular level, as well as the cell phenotype. Brillouin and Raman mapping of adherent cells showed that the nucleus and nucleoli are stiffer than the perinuclear region and the cytoplasm. The biomechanics of the cell cytoplasm is affected by culturing conditions, i.e. cells grown as spheroids are stiffer than adherent cells. Inside the spheroids, the presence of lipid droplets as assessed by Raman spectroscopy revealed higher Brillouin shifts that are not related to a local increase in stiffness, but are due to a higher refractive index combined with a lower mass density. This highlights the importance of locally defined biochemical reference data for a correct interpretation of the Brillouin shift of cells and tissues in future studies investigating the biomechanics of brain tumour models by Brillouin spectroscopy.

Actin is a fundamental member of an ancient superfamily of structural intracellular proteins and plays a crucial role in cytoskeleton dynamics, ciliogenesis, phagocytosis, and force generation in both prokaryotes and eukaryotes. It is shown that actin has another function in metazoans: patterning biosilica deposition, a role that has spanned over 500 million years. Species of glass sponges (Hexactinellida) and demosponges (Demospongiae), representatives of the first metazoans, with a broad diversity of skeletal structures with hierarchical architecture unchanged since the late Precambrian, are studied. By etching their skeletons, organic templates dominated by individual F-actin filaments, including branched fibers and the longest, thickest actin fiber bundles ever reported, are isolated. It is proposed that these actin-rich filaments are not the primary site of biosilicification, but this highly sophisticated and multi-scale form of biomineralization in metazoans is ptterned., (© 2022 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Widespread use of traditional packaging constitutes a serious ecological problem leading to a shift to biodegradable and compostable materials. The aim of this work is to study the ability of a new biopackaging (BP), based on biodegradable and compostable material, to preserve the quality of organic chicken meat for 14 days in comparison with a polyethylene terephthalate (PET) material. Results showed that the indices of Biogenic Amines (BAs) and the 18 monitored Volatile Organic Compounds (VOCs) have a similar trend in both packaged meats. For example, the total BAs concentration in meat increased from 390 to 961 mg Kg -1 in BP and from 393 to 800 mg Kg -1 in PET, as well as the microbiological counts. The new biopackaging (BP) showed similar properties of non-biodegradable material (PET) to preserve the shelf life of organic chicken meat and it could be used instead of plastic materials to promote a circular economy., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Recently, ferroelectric domain walls (DWs) have attracted considerable attention due to their intrinsic topological effects and their huge potential for optoelectronic applications. In contrast, many of the underlying physical properties and phenomena are not well characterized. In this regard, analyzing the vibrational properties, e.g. by Raman spectroscopy, provides direct access to the various local material properties, such as strains, defects or electric fields. While the optical phonon spectra of DWs have been widely investigated in the past, no reports on the acoustic phonon properties of DWs exist. In this work, we present a joint Raman and Brillouin visualization of ferroelectric DWs in the model ferroelectric lithium niobate. This is possible by using a combined Raman and virtually imaged phased array Brillouin setup. Here, we show that DWs can be visualized via frequency shifts observed in the acoustic phonons, as well. The observed contrast then is qualitatively explained by models adapted from Raman spectroscopy. This work, hence, provides a novel route to study ferroelectric DWs and their intrinsic mechanical properties.

T cell receptor (TCR)-based therapy has the potential to induce durable clinical responses in patients with cancer by targeting intracellular tumor antigens with high sensitivity and by promoting T cell survival. However, the need for TCRs specific for shared oncogenic antigens and the need for manufacturing protocols able to redirect T cell specificity while preserving T cell fitness remain limiting factors. By longitudinal monitoring of T cell functionality and dynamics in 15 healthy donors, we isolated 19 TCRs specific for Wilms' tumor antigen 1 (WT1), which is overexpressed by several tumor types. TCRs recognized several peptides restricted by common human leukocyte antigen (HLA) alleles and displayed a wide range of functional avidities. We selected five high-avidity HLA-A*02:01-restricted TCRs, three that were specific to the less explored immunodominant WT1 37-45 and two that were specific to the noncanonical WT1 -78-64 epitopes, both naturally processed by primary acute myeloid leukemia (AML) blasts. With CRISPR-Cas9 genome editing tools, we combined TCR-targeted integration into the TCR α constant ( TRAC ) locus with TCR β constant ( TRBC ) knockout, thus avoiding TCRαβ mispairing and maximizing TCR expression and function. The engineered lymphocytes were enriched in memory stem T cells. A unique WT1 37-45 -specific TCR showed antigen-specific responses and efficiently killed AML blasts, acute lymphoblastic leukemia blasts, and glioblastoma cells in vitro and in vivo in the absence of off-tumor toxicity. T cells engineered to express this receptor are being advanced into clinical development for AML immunotherapy and represent a candidate therapy for other WT1-expressing tumors.

Cephalopod mollusks are endowed with an impressive range of features that have captured the attention of scientists from different fields, the imaginations of artists, and the interests of the public. The ability to spontaneously regrow lost or damaged structures quickly and functionally is among one of the most notable peculiarities that cephalopods possess. Microscopical imaging techniques represent useful tools for investigating the regenerative processes in several species, from invertebrates to mammals. However, these techniques have had limited use in cephalopods mainly due to the paucity of specific and commercially available markers. In addition, the commonly used immunohistochemical staining methods provide data that are specific to the antigens studied. New microscopical methods were recently applied to vertebrates to investigate regenerative events. Among them, multiphoton microscopy appears promising. For instance, it does not depend on species-related epitopes, taking advantage of the specific characteristics of tissues and allowing for its use in a species-independent way. Here, we illustrate the results obtained by applying this label-free imaging technique to the injured arm of Octopus vulgaris , a complex structure often subject to injury in the wild. This approach allowed for the characterization of the entire tissue arm architecture (muscular layers, nerve component, connective tissues, etc.) and elements usually hardly detectable (such as vessels, hemocytes, and chromatophores). More importantly, it also provided morpho-chemical information which helped decipher the regenerative phases after damage, from healing to complete arm regrowth, thereby appearing promising for regenerative studies in cephalopods and other non-model species., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Imperadore, Galli, Winterhalder, Zumbusch and Uckermann.)

Background: The gold standard treatment for solitary medium-sized (1-2 cm) renal stones is not defined by recent guidelines, since management modalities including shockwave lithotripsy (SWL), retrograde intrarenal surgery (RIRS), and percutaneous nephrolithotomy (PNL) are recommended. Improved ability to predict patient outcomes would aid in patients' counseling and decision-making., Objective: To develop a nomogram predicting treatment failure, based on preoperative clinical variables, to be used in the preplanning setting., Design, Setting, and Participants: We recruited 2605 patients from 14 centers and carried out a multicenter retrospective analysis of 699 SWL, 1290 RIRS, and 616 PN L procedures performed as first-line treatment for 1-2-cm kidney stones. The variables evaluated included age, gender, previous renal surgery, body mass index, stone size, location, stone density, skin-to-stone distance, presence of urinary tract infections (UTIs), and hydronephrosis., Outcome Measurements and Statistical Analysis: Multivariate logistic regression was fitted to predict treatment failure, defined as the presence of residual fragments >4 mm. A nomogram was developed based on the coefficients of the logit function., Results and Limitations: A total of 2431 (93.3%) patients were stone free; 174 (6.7%) treatment failures were recorded and considered the event to be predicted. On univariate analysis, type of procedure, preoperative hydronephrosis, stone density, stone location, and laterality turned out to be statistically significant. Skin-to-stone distance, UTIs, and previous renal surgery were predictors of failure on multivariate analysis. Each variable was given a score based on statistical relevance. The main limitation of the current study is its retrospective nature., Conclusions: This nomogram provides a prediction of treatment failure and need of reintervention for medium-sized kidney stones. External validation is needed to determine its reproducibility and validity., Patient Summary: We developed a preoperative model of treatment outcomes for 1-2-cm kidney stones. Its application may assist urologists to counsel patients with regard to stone management modality., (Copyright © 2020. Published by Elsevier B.V.)

Medulloblastoma (MB), one of the most malignant brain tumors of childhood, comprises distinct molecular subgroups, with p53 mutant sonic hedgehog-activated (SHH-activated) MB patients having a very severe outcome that is associated with unfavorable histological large cell/anaplastic (LC/A) features. To identify the molecular underpinnings of this phenotype, we analyzed a large cohort of MB developing in p53-deficient Ptch+/- SHH mice that, unexpectedly, showed LC/A traits that correlated with mTORC1 hyperactivation. Mechanistically, mTORC1 hyperactivation was mediated by a decrease in the p53-dependent expression of mTORC1 negative regulator Tsc2. Ectopic mTORC1 activation in mouse MB cancer stem cells (CSCs) promoted the in vivo acquisition of LC/A features and increased malignancy; accordingly, mTORC1 inhibition in p53-mutant Ptch+/- SHH MB and CSC-derived MB resulted in reduced tumor burden and aggressiveness. Most remarkably, mTORC1 hyperactivation was detected only in p53-mutant SHH MB patient samples, and treatment with rapamycin of a human preclinical model phenocopying this subgroup decreased tumor growth and malignancy. Thus, mTORC1 may act as a specific druggable target for this subset of SHH MB, resulting in the implementation of a stringent risk stratification and in the potentially rapid translation of this precision medicine approach into the clinical setting.

The aim of this pilot, feasibility study was to assess health improvements in 16 institutionalized older people with Alzheimer's disease, after the Biodanza intervention, a nonpharmacological dance movement-based treatment. Biodanza significantly decreased agitated and neuropsychiatric behaviors. Effectiveness studies will be performed in order to assess the implication of such interventions., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

The design of new composite materials using extreme biomimetics is of crucial importance for bioinspired materials science. Further progress in research and application of these new materials is impossible without understanding the mechanisms of formation, as well as structural features at the molecular and nano-level. It presents a challenge to obtain a holistic understanding of the mechanisms underlying the interaction of organic and inorganic phases under conditions of harsh chemical reactions for biopolymers. Yet, an understanding of these mechanisms can lead to the development of unusual-but functional-hybrid materials. In this work, a key way of designing centimeter-scale macroporous 3D composites, using renewable marine biopolymer spongin and a model industrial solution that simulates the highly toxic copper-containing waste generated in the production of printed circuit boards worldwide, is proposed. A new spongin-atacamite composite material is developed and its structure is confirmed using neutron diffraction, X-ray diffraction, high-resolution transmission electron microscopy/selected-area electron diffraction, X-ray photoelectron spectroscopy, near-edge X-ray absorption fine structure spectroscopy, and electron paramagnetic resonance spectroscopy. The formation mechanism for this material is also proposed. This study provides experimental evidence suggesting multifunctional applicability of the designed composite in the development of 3D constructed sensors, catalysts, and antibacterial filter systems., (© 2021 The Authors. Advanced Materials published by Wiley-VCH GmbH.)

The poor transport of molecular and nanoscale agents through the blood-brain barrier together with tumour heterogeneity contribute to the dismal prognosis in patients with glioblastoma multiforme. Here, a biodegradable implant (μMESH) is engineered in the form of a micrometre-sized poly(lactic-co-glycolic acid) mesh laid over a water-soluble poly(vinyl alcohol) layer. Upon poly(vinyl alcohol) dissolution, the flexible poly(lactic-co-glycolic acid) mesh conforms to the resected tumour cavity as docetaxel-loaded nanomedicines and diclofenac molecules are continuously and directly released into the adjacent tumour bed. In orthotopic brain cancer models, generated with a conventional, reference cell line and patient-derived cells, a single μMESH application, carrying 0.75 mg kg -1 of docetaxel and diclofenac, abrogates disease recurrence up to eight months after tumour resection, with no appreciable adverse effects. Without tumour resection, the μMESH increases the median overall survival (∼30 d) as compared with the one-time intracranial deposition of docetaxel-loaded nanomedicines (15 d) or 10 cycles of systemically administered temozolomide (12 d). The μMESH modular structure, for the independent coloading of different molecules and nanomedicines, together with its mechanical flexibility, can be exploited to treat a variety of cancers, realizing patient-specific dosing and interventions., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Traumatic frontal fractures result from high force injuries and can result in significant morbidity and mortality. The purpose of the current study is to evaluate our Montreal General Hospital (MGH) experience with frontal bone fractures., Methods: A comprehensive review of our trauma database was performed. All adult patients (>18 years) presenting with a diagnosis of frontal sinus fracture were identified. A thorough retrospective electronic medical records search was performed and relevant data extracted. Specifically, all cases of ocular injury or sequelae were identified and an in-depth review was performed., Results: Between 2008 and 2014, 10,189 trauma patients presented to the MUHC Level 1 trauma center. A total of 1277 patients presented with a facial fracture and 140 had a frontal sinus fracture. The mean age was 43.5 years, 90% were male and the mean hospitalization time was 16.2 days. A significant proportion of patients suffered concomitant craniomaxillofacial fractures including orbital (79%), maxillary (66%), nasal (64%), zygomaticomaxillary complex (34%), nasoorbitoethmoid (31%), Lefort types I-III (18%), and mandibular (8%). Associated cervical spine injuries were documented in 16% of patients. Ocular injuries were present in 30% of subjects. 26% of patients had some form of permanent sequelae from their trauma, mainly neurological., Conclusions: Due to the intimate association of the frontal bones with the brain and the orbits, frontal sinus fractures demand a sophisticated multidisciplinary craniofacial surgical approach. Given the high rate of ocular injury of 30% as well as severe systemic injuries, the authors propose a modified treatment algorithm for these complex cases., Competing Interests: The authors report no conflicts of interest., (Copyright © 2020 by Mutaz B. Habal, MD.)

Glioblastoma (GBM) is a highly aggressive tumor of the brain. Despite the efforts, response to current therapies is poor and 2-years survival rate ranging from 6-12%. Here, we evaluated the preclinical efficacy of Metformin (MET) as add-on therapy to Temozolomide (TMZ) and the ability of [ 18 F]FLT (activity of thymidine kinase 1 related to cell proliferation) and [ 18 F]VC701 (translocator protein, TSPO) Positron Emission Tomography (PET) radiotracers to predict tumor response to therapy. Indeed, TSPO is expressed on the outer mitochondrial membrane of activated microglia/macrophages, tumor cells, astrocytes and endothelial cells. TMZ-sensitive (Gli36ΔEGFR-1 and L0627) or -resistant (Gli36ΔEGFR-2) GBM cell lines representative of classical molecular subtype were tested in vitro and in vivo in orthotopic mouse models. Our results indicate that in vitro , MET increased the efficacy of TMZ on TMZ-sensitive and on TMZ-resistant cells by deregulating the balance between pro-survival ( bcl2 ) and pro-apoptotic ( bax/bad ) Bcl-family members and promoting early apoptosis in both Gli36ΔEGFR-1 and Gli36ΔEGFR-2 cells. In vivo , MET add-on significantly extended the median survival of tumor-bearing mice compared to TMZ-treated ones and reduced the rate of recurrence in the TMZ-sensitive models. PET studies with the cell proliferation radiopharmaceutical [ 18 F]FLT performed at early time during treatment were able to distinguish responder from non-responder to TMZ but not to predict the duration of the effect. On the contrary, [ 18 F]VC701 uptake was reduced only in mice treated with MET plus TMZ and levels of uptake negatively correlated with animals' survival. Overall, our data showed that MET addition improved TMZ efficacy in GBM preclinical models representative of classical molecular subtype increasing survival time and reducing tumor relapsing rate. Finally, results from PET imaging suggest that the reduction of cell proliferation represents a common mechanism of TMZ and combined treatment, whereas only the last was able to reduce TSPO. This reduction was associated with the duration of treatment response. TSPO-ligand may be used as a complementary molecular imaging marker to predict tumor microenvironment related treatment effects., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Valtorta, Lo Dico, Raccagni, Martelli, Pieri, Rainone, Todde, Zinnhardt, De Bernardi, Coliva, Politi, Viel, Jacobs, Galli, Ottobrini, Vaira and Moresco.)

Glioblastoma (GBM) represents the most common and aggressive tumor of the brain. Despite the fact that several studies have recently addressed the molecular mechanisms underlying the disease, its etiology and pathogenesis are still poorly understood. GBM displays poor prognosis and its resistance to common therapeutic approaches makes it a highly recurrent tumor. Several studies have identified a subpopulation of tumor cells, known as GBM cancer stem cells (CSCs) characterized by the ability of self-renewal, tumor initiation and propagation. GBM CSCs have been shown to survive GBM chemotherapy and radiotherapy. Thus, targeting CSCs represents a promising approach to treat GBM. Recent evidence has shown that GBM is characterized by a dysregulated expression of microRNA (miRNAs). In this study we have investigated the difference between human GBM CSCs and their paired autologous differentiated tumor cells. Array-based profiling and quantitative Real-Time PCR (qRT-PCR) were performed to identify miRNAs differentially expressed in CSCs. The Cancer Genome Atlas (TCGA) data were also interrogated, and functional interpretation analysis was performed. We have identified 14 miRNAs significantly differentially expressed in GBM CSCs ( p < 0.005). MiR-21 and miR-95 were among the most significantly deregulated miRNAs, and their expression was also associated to patient survival. We believe that the data provided here carry important implications for future studies aiming at elucidating the molecular mechanisms underlying GBM.

The angiotensin receptor/neprilysin inhibitor Sacubitril/Valsartan (Sac/Val) has been shown to be beneficial in patients suffering from heart failure with reduced ejection fraction (HFrEF). However, the impact of Sac/Val in patients presenting with heart failure with preserved ejection fraction (HFpEF) is not yet clearly resolved. The present study aimed to reveal the influence of the drug on the functionality of the myocardium, the skeletal muscle, and the vasculature in a rat model of HFpEF. Female obese ZSF-1 rats received Sac/Val as a daily oral gavage for 12 weeks. Left ventricle (LV) function was assessed every four weeks using echocardiography. Prior to organ removal, invasive hemodynamic measurements were performed in both ventricles. Vascular function of the carotid artery and skeletal muscle function were monitored. Sac/Val treatment reduced E/é ratios, left ventricular end diastolic pressure (LVEDP) and myocardial stiffness as well as myocardial fibrosis and heart weight compared to the obese control group. Sac/Val slightly improved endothelial function in the carotid artery but had no impact on skeletal muscle function. Our results demonstrate striking effects of Sac/Val on the myocardial structure and function in a rat model of HFpEF. While vasodilation was slightly improved, functionality of the skeletal muscle remained unaffected.

Aortic valve sclerosis is characterized as the thickening of the aortic valve without obstruction of the left ventricular outflow. It has a prevalence of 30% in people over 65 years old. Aortic valve sclerosis represents a cardiovascular risk marker because it may progress to moderate or severe aortic valve stenosis. Thus, the early recognition and management of aortic valve sclerosis are of cardinal importance. We examined the aortic valve geometry and structure from healthy C57Bl6 wild type and age-matched hyperlipidemic ApoE -/- mice with aortic valve sclerosis using optical coherence tomography (OCT) and multiphoton microscopy (MPM) and compared results with histological analyses. Early fibrotic thickening, especially in the tip region of the native aortic valve leaflets from the ApoE -/- mice, was detectable in a precise spatial resolution using OCT. Evaluation of the second harmonic generation signal using MPM demonstrated that collagen content decreased in all aortic valve leaflet regions in the ApoE -/- mice. Lipid droplets and cholesterol crystals were detected using coherent anti-Stokes Raman scattering in the tissue from the ApoE -/- mice. Here, we demonstrated that OCT and MPM, which are fast and precise contactless imaging approaches, are suitable for defining early morphological and structural alterations of sclerotic murine aortic valves.

Purpose: The management of perforated diverticulitis with generalized peritonitis is still controversial and no preferred standardized therapeutic approach has been determined. We compared surgical outcomes between Hartmann's procedure (HP) and primary anastomosis (PA) in patients with Hinchey III and IV perforated diverticulitis., Methods: Multicenter retrospective analysis of 131 consecutive patients with Hinchey III and IV diverticulitis operated either with HP or PA from 2015 to 2018. Postoperative morbidity was compared after adjustment for known risk factors in a multivariate logistic regression., Results: Sixty-six patients underwent HP, while PA was carried out in 65 patients, 35.8% of those were defunctioned. HP was more performed in older patients (74.6 vs. 61.2 years, p < .001), with Hinchey IV diverticulitis (37% vs. 7%, p < .001) and in patients with worse prognostic scores (P-POSSUM Physiology Score, p < .001, Charlson Comorbidity Index p < .001). Major morbidity and mortality were higher in HP compared to PA (30.3% vs. 9.2%, p = .002 and 10.6% vs. 0%, p = .007, respectively) with lower stoma reversal rate (43.9% vs. 86.9%, p < .001). In a multivariate logistic regression, PA was independently associated with lower postoperative morbidity and mortality (OR 0.24, 95% CI 0.06-0.96, p = .044)., Conclusions: In comparison to PA, HP is associated with a higher morbidity, higher mortality, and a lower stoma reversal rate. Although a higher prevalence of risk factors in HP patients may explain these outcomes, a significant increase in morbidity and mortality persisted in a multivariate logistic regression analysis that was stratified for the identified risk factors.

Pancreatic cancer Abstract. Pancreatic cancer is the second most common cancer in the GI tract in Europe and North America and it is associated with a poor prognosis due to its aggressive tumor biology. Each year the number of deaths from pancreatic cancer is almost the same as the number of new cases diagnosed. Most of the pancreatic cancers develop from exocrine cells, while endocrine pancreatic cancers (i. e., neuroendocrine tumors or islet cell tumors) are uncommon. The term "pancreatic cancer" is typically used to refer to pancreatic adenocarcinoma, which will be the focus of this paper. Despite the introduction of multimodal therapy concepts, advanced surgical techniques, and increasing surgical specialization, overall survival in pancreatic cancer has not significantly improved. Early and complete surgical tumor resection remains the only curative option; however, this is rarely achieved, mainly due to the advanced stage at diagnosis. Adjuvant chemotherapy has become the gold standard after upfront resection. Neoadjuvant chemotherapy regimens, such as FOLFIRINOX, represent a valid option in order to achieve complete surgical tumor resection in more advanced cases. However, the overall uptake of this promising concept is very low.