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During the last decades, effective pain reduction and early mobilization were identified as the central priorities in therapy of insufficiency fractures of the pelvis. For operative treatment minimally-invasive stabilization techniques are favored. While there is consensus on the significance of sufficient dorsal stabilization the role of additional fixation of the anterior fracture component stays under discussion. Within the present study we developed an internal ring fixator system (RingFix) with the question whether an in-itself-closed construct can improve stability of the entire ring structure. RingFix was evaluated on an osteoporotic bone model with a standardized FFP IIIc fracture within an established biomechanical setup regarding its primary stabilization potential. Further, it was compared to transiliac-transsacral screw fixation with and without stabilization of the anterior fracture component. The transiliac-transsacral fixation with separate screw fixation of the anterior fracture showed significantly higher stability than the RingFix and the transiliac-transsacral screw fixation without anterior stabilization. Our results show that stabilization of the anterior fracture component relevantly improves the stability of the entire ring construct. As a bridging stabilizer, RingFix shows biomechanical advantages over an isolated dorsal fracture fixation, but inferior results than direct stabilization of the single fracture components.

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Mammalian primordial germ cells (PGCs) migrate asynchronously through the embryonic hindgut and dorsal mesentery to reach the gonads. We previously found that interaction with different somatic niches regulates PGC proliferation along the migration route. To characterize transcriptional heterogeneity of migrating PGCs and their niches, we performed single-cell RNA sequencing of 13,262 mouse PGCs and 7,868 surrounding somatic cells during migration (E9.5, E10.5, E11.5) and in anterior versus posterior locations to enrich for leading and lagging migrants. Analysis of PGCs by position revealed dynamic gene expression changes between faster or earlier migrants in the anterior and slower or later migrants in the posterior at E9.5; these differences include migration-associated actin polymerization machinery and epigenetic reprogramming-associated genes. We furthermore identified changes in signaling with various somatic niches, notably strengthened interactions with hindgut epithelium via non-canonical WNT (ncWNT) in posterior PGCs compared to anterior. Reanalysis of a previously published dataset suggests that ncWNT signaling from the hindgut epithelium to early migratory PGCs is conserved in humans. Trajectory inference methods identified putative differentiation trajectories linking cell states across timepoints and from posterior to anterior in our mouse dataset. At E9.5, we mainly observed differences in cell adhesion and actin cytoskeletal dynamics between E9.5 posterior and anterior migrants. At E10.5, we observed divergent gene expression patterns between putative differentiation trajectories from posterior to anterior including Nodal signaling response genes Lefty1, Lefty2, and Pycr2 and reprogramming factors Dnmt1, Prc1, and Tet1. At E10.5, we experimentally validated anterior migrant-specific Lefty1/2 upregulation via whole-mount immunofluorescence staining for LEFTY1/2 proteins, suggesting that elevated autocrine Nodal signaling accompanies the late stages of PGC migration. Together, this positional and temporal atlas of mouse PGCs supports the idea that niche interactions along the migratory route elicit changes in proliferation, actin dynamics, pluripotency, and epigenetic reprogramming.

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Background/Objectives: The increasing numbers of already endemic hip fractures in the elderly taking anticoagulants is a growing concern for daily surgical practice. Ample evidence demonstrates decreased morbidity and mortality in the general population when surgery is performed at the earliest possibility. Direct anticoagulants are relatively new drugs that can cause increased perioperative bleeding. Current guidelines propose stopping the drug to allow for elimination before performing elective surgery. Optimal management in urgent hip surgery is presently based on expert opinion with arbitrary cut-offs. In this study, we investigated whether patients taking direct anticoagulants would benefit from early surgical treatment, regardless of the timing since last intake. Methods: A total of 340 patients were included in the analysis, of which 59 took direct anticoagulants. The primary outcomes were time to surgery, postoperative transfusion rate, postoperative hemoglobin decrease, length of postoperative in-hospital stay (LOPS), revision rate, and complication rate (medical and surgical). Results: Our findings showed that the anticoagulated group was fit for discharge earlier when operated on within 24 h (p = 0.0167). Postoperative transfusion and medical complication rate tended to be lower when the operation was performed earlier. Revision rate due to hematomas were higher in the direct anticoagulant group without a relationship to time to surgery. Simple linear regression could not determine a relationship between postoperative hemoglobin change and time to surgery. Conclusions: We suggest that directly anticoagulated patients needing hip fracture surgery must be considered for early surgery.

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Silk fibers constitute a class of protein building blocks capable of functionalization and reprocessing into various material formats. The properties of these fibers are typically affected by the intense thermal treatments needed to remove the sericin gum coating layer. Additionally, their mechanical characteristics are often misinterpreted by assuming the cross-sectional area is a perfect circle. The thermal treatments impact not only the mechanics of the fibers but also the structure of the resolubilized protein, thereby limiting the performance of the resulting silk-based materials. To mitigate these limitations, we explored varying alkali conditions at low temperatures for surface treatment, effectively removing the sericin gum layer while preserving the molecular structure of the fibroin protein, thus, maintaining the hierarchical integrity of the exposed fibroin microfiber core. The precise determination of the initial CSA of the asymmetrical silk fibers led to a comprehensive analysis of their mechanical properties. Our findings indicate that the alkali surface treatment raised the Young's modulus and tensile strength by increasing the fibers' crystallinity by approximately 40% and 50%, respectively, without compromising their strain. We have shown that this treatment facilitated further production of high-purity soluble silk with rheological and self-assembly characteristics comparable to those of native silk.

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PURPOSE: The clinical application of PD-L1 immunohistochemistry (IHC) testing is complicated by the availability of multiple IHC assays, scoring algorithms, and cutoffs. This study assessed the analytical comparability of three commercially available PD-L1 assays and two scoring algorithms used to assess PD-L1 status in gastric cancer (GC) samples. METHODS: Serial sections of 100 resected GC samples, with PD-L1 expression levels across the dynamic range, were stained with three in vitro diagnostic-grade PD-L1 assays (28-8, 22C3, and SP263). Three trained pathologists blindly and independently scored slides using combined positive score (CPS) and tumor area positivity (TAP) algorithms. Comprehensive statistical analyses were performed to evaluate analytical concordance. Digital image analysis (DIA) was used to objectively compare the technical performance of each assay by simulating CPS and TAP. RESULTS: Comparable staining patterns were observed with these three PD-L1 assays. Despite discernible variation in staining intensity, reproducible evaluations of PD-L1 positivity were observed. Inter- and intra-assay assessments of all three assays, using either CPS or TAP and the same PD-L1 cutoffs, demonstrated moderate to almost-perfect (interassay Cohen's kappa [κ] range, 0.47-0.83) and substantial to almost-perfect (intra-assay κ range, 0.77-1.00) agreement. Interpathologist assessment exhibited a significant level of concordance (intraclass correlation coefficient ≥0.92). No difference in technical performance was observed using DIA. CONCLUSION: This study highlights analytical concordance in PD-L1 testing between three major PD-L1 assays when TAP and CPS are applied. Comparability of the technical assay performance was further supported by independent DIA. These observations support cross-application flexibility of the different PD-L1 assays and scoring algorithms to characterize PD-L1 expression in GC.

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INTRODUCTION: Longer life expectancy is accompanied by a higher incidence of fragility fractures of the pelvis (FFP), which has repercussions on mortality and nursing home admissions. Given the paucity of data at French healthcare facilities, we carried out a retrospective study to (1) evaluate how surgical treatment of FFP with posterior displacement (type III and IV according to Rommens and Hofmann) affects a patient's pain, functional status and ability to stay at home and (2) evaluate the postoperative complications and mortality rate. HYPOTHESIS: Surgery for posteriorly displaced FFP will relieve pain and preserve the patient's independence. METHODS: All the patients over 65 years of age who were operated on for a posterior FFP between January 2015 and August 2020 were included in this prospective, single-center study. The demographics, fracture type, details of the surgical treatment, complications and mortality were analyzed. Pain (visual analog scale, VAS), functional status (Activity of Daily Living [ADL] and Instrumental Activity of Daily Living [IADL]), mobility (Parker score) and rates of nursing home admissions were compared before the fracture, after surgery and at a mean follow-up of 28 months (minimum follow-up of 1 year). RESULTS: Forty-eight patients with a mean age of 75 years were included. Twenty-four of these patients (50%) had at least two comorbidities. The FFPs were either type IV (31/48; 65%) or type III (17/48; 35%). The mean VAS for pain was significantly lower on the first day postoperative (3.5 versus 4.8; p=0.02). This significant reduction continued upon discharge from the hospital (1.95; p=0.003) and persisted at the mean follow-up of 28 months (2.2; p=0.64). The complication rate was 15% (7/48) and the mortality rate at the final review was 15% (7/48). Among the surviving patients, 81% (29/36) returned to living at home. The ADL (5.1 versus 5.8; p=0.09), IADL (5.9 versus 6.9; p=0.15) and Parker score (6.8 versus 8.2; p=0.08) at the final review were not significantly different from the values before the fracture. CONCLUSION: This is the first French study of patients operated on for an FPP. Fixation of posteriorly displaced fractures allows surviving patients to retain their mobility. Pain relief is achieved quickly and maintained during the follow-up period. Thus, our initial hypothesis is affirmed. The complication rate is not insignificant; given the complexity of this surgery, percutaneous treatment is preferable. LEVEL OF EVIDENCE: IV; retrospective study.

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As neuroendocrine tumors (NETs) often present as metastatic lesions, immunohistochemical assignment to a site of origin is one of the most important tasks in their pathologic assessment. Because a fraction of NETs eludes the typical expression profiles of their primary localization, additional sensitive and specific markers are required to improve diagnostic certainty. We investigated the expression of the transcription factor Pituitary Homeobox 2 (PITX2) in a large-scale cohort of 909 NET and 248 neuroendocrine carcinomas (NEC) according to the immunoreactive score (IRS) and correlated PITX2 expression groups with general tumor groups and primary localization. PITX2 expression (all expression groups) was highly sensitive (98.1%) for midgut-derived NET, but not perfectly specific, as non-midgut NET (especially pulmonary/duodenal) were quite frequently weak or moderately positive. The specificity rose to 99.5% for a midgut origin of NET if only a strong PITX2 expression was considered, which was found in only 0.5% (one pancreatic/one pulmonary) of non-midgut NET. In metastases of midgut-derived NET, PITX2 was expressed in all cases (87.5% strong, 12.5% moderate), whereas CDX2 was negative or only weakly expressed in 31.3% of the metastases. In NEC, a fraction of cases (14%) showed a weak or moderate PITX2 expression, which was not associated with a specific tumor localization. Our study independently validates PITX2 as a very sensitive and specific immunohistochemical marker of midgut-derived NET in a very large collective of neuroendocrine neoplasms. Therefore, our data argue toward implementation into diagnostic panels applied for NET as a firstline midgut marker.

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This study reports the first mitogenome from the antipatharian (black coral) genus Cirrhipathes (GenBank accession number ON653414). The 20,452 bp mitochondrial genome of Cirrhipathes cf. anguina LS-2022 consists of 13 protein-coding genes, two rRNA genes, and two tRNA genes (trnM and trnW). The mitogenome is typical of other antipatharian families, including an A + T biased (64.1%) base composition and cytochrome c oxidase subunit I (COX1) intron with embedded homing endonuclease gene (HEG). A phylogenetic tree based on complete mitogenome sequences of currently available antipatharians indicates Cirrhipathes cf. anguina LS-2022 is sister and closely related to Stichopathes sp. SCBUCN-8849. However, it seems unlikely that intergeneric taxa share 99.97% similarity across their complete mitogenomes, raising questions about the current taxonomy of this group. This study highlights the need for additional vouchered antipatharian species to be sequenced so phylogenetic relationships can be compared with accepted taxonomy.

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The field of developmental biology has declined in prominence in recent decades, with off-shoots from the field becoming more fashionable and highly funded. This has created inequity in discovery and opportunity, partly due to the perception that the field is antiquated or not cutting edge. A 'think tank' of scientists from multiple developmental biology-related disciplines came together to define specific challenges in the field that may have inhibited innovation, and to provide tangible solutions to some of the issues facing developmental biology. The community suggestions include a call to the community to help 'rebrand' the field, alongside proposals for additional funding apparatuses, frameworks for interdisciplinary innovative collaborations, pedagogical access, improved science communication, increased diversity and inclusion, and equity of resources to provide maximal impact to the community.

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Treatment of osteochondral lesions of the talus proves to be challenging given the unique anatomy of the intra-articular surface and associated complexity of larger lesions. Simple bone marrow-stimulating procedures for large complex lesions often lead to poor results with increased risk of lesion progression, refractory pain, and associated functional limitations. Other methods of osteochondral autografts or allografts often require osteotomies, bone windows, or fibrin glue, which are associated with donor pain and nonunion. Thus, for larger and cystic lesions, we report our experience using a modified low-flow arthroscopic sandwich technique consisting of autologous cancellous bone graft, followed by a viable cryopreserved cartilage fiber, cartilage allograft matrix putty.

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Hip fractures are common in the elderly, particularly due to an increased susceptibility to falls and greater bone frailty, especially in women. The consequences of such events are potentially serious. Early management (< 48 hours) significantly reduces the mortality and postoperative complications. Because of their comorbidities, older people are often on antiplatelet therapy, anticoagulant therapy, or both. However, there are no definitive recommendations for the perioperative management of antiplatelet and anticoagulant treatment in the early surgery of hip fractures. The purpose of this article is to review the management of these patients.

Les fractures de la hanche sont fréquentes chez les personnes âgées, notamment en raison d'une prédisposition accrue aux chutes et d'une plus grande fragilité des os, principalement chez les femmes. Les conséquences de tels événements sont potentiellement graves. Une prise en charge précoce (< 48 heures) diminue de manière significative la mortalité et les complications postopératoires. En raison de leurs comorbidités, les personnes âgées sont souvent sous traitement antiagrégant, anticoagulant ou les deux. Or il n'existe pas de recommandations définitives quant à la gestion périopératoire des traitements antiagrégants et anticoagulants de la chirurgie urgente de la fracture du fémur. Le but de cet article est de faire le point sur la prise en charge de ces patients.

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There is a growing understanding of the specific characteristics of insufficiency fractures of the pelvis and of general requirements for the treatment of affected patients with focus on early mobilization and effective pain reduction as the main goals of therapy. While there is consensus on the significance of achieving stability of the dorsal pelvic ring structures there is still an open discussion about the potential benefits of additional stabilization of an anterior fracture component. Within a biomechanical test setup, two established methods of dorsal fracture fixation were tested under axial loading (25-1200 N; 1000 test cycles) on an explicit osteoporotic bone model (n = 32) with a standardized FFP type IIIc fracture with and without additional fixation of the anterior fracture component. Dorsal fixation was performed with and long and a short 7.3 mm cannulated screw in S1 in one group (n = 16), and a trans sacral bar with an additional short 7.3 mm cannulated screw in S1 in the other group (n = 16). Half of the samples received a 7.3 mm cannulated retrograde transpubic screw for anterior fixation. The fixation with the trans sacral bar and the additional anterior screw fixation showed the highest rate of stability (p = 0.0014), followed by the double SI-screw fixation with stabilization of the anterior fracture (p = 0.0002). During testing, we observed the occurrence of new sacral fractures contralateral to the initial fracture in 22/32 samples. The results let us assume that stabilization of an additional anterior fracture component relevantly improves the stability of the entire ring construct and might prevent failure of the dorsal stabilization or further fracture progression.

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There is an expanding body of literature that describes the application of deep learning and other machine learning and artificial intelligence methods with potential relevance to neuroradiology practice. In this article, we performed a literature review to identify recent developments on the topics of artificial intelligence in neuroradiology, with particular emphasis on large datasets and large-scale algorithm assessments, such as those used in imaging AI competition challenges. Numerous applications relevant to ischemic stroke, intracranial hemorrhage, brain tumors, demyelinating disease, and neurodegenerative/neurocognitive disorders were discussed. The potential applications of these methods to spinal fractures, scoliosis grading, head and neck oncology, and vascular imaging were also reviewed. The AI applications examined perform a variety of tasks, including localization, segmentation, longitudinal monitoring, diagnostic classification, and prognostication. While research on this topic is ongoing, several applications have been cleared for clinical use and have the potential to augment the accuracy or efficiency of neuroradiologists.

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INTRODUCTION: Penicillin allergy is the most commonly reported drug allergy in the United States. Patients labeled with penicillin allergy are at risk of receiving broad-spectrum antibiotics for surgical site infection prophylaxis, which can lead to increased antibiotic resistance, higher morbidity, suboptimal antibiotic therapy, and higher medical costs. This study aimed to determine the true prevalence of penicillin allergy among surgical patients and to decrease the unnecessary use of broad-spectrum antibiotics. METHODS: A retrospective chart review was performed of patients who underwent urogynecologic surgery in 2017. In 2018, a quality initiative was started, and all patients reporting penicillin allergies were offered antibiotic allergy testing as part of their preoperative testing. RESULTS: In 2017, 15% of patients reported penicillin allergy and 52% of them received surgical prophylaxis with broad-spectrum antibiotics. In 2018, 463 patients underwent surgery, 55 of whom reported penicillin allergy and were offered penicillin allergy testing. 35 (64%) agreed to proceed with testing, and of those tested, 33 (94%) tested negative for penicillin allergy. CONCLUSIONS: 94% of patients with stated penicillin allergy who consented to allergy testing proved to have negative test. Penicillin allergy testing should be considered as part of preoperative management.

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Background and Objectives: Open fracture of the lower limb can lead to substantial bone and soft tissue damage, resulting in a challenging reconstructive scenarios, especially in presence of bone or periosteal loss, with a relevant risk of non-union. This work analyzes outcomes of using a double approach for orthoplastic reconstruction, adopting the free medial condyle flap to solve the bone defects, associated to a second free flap for specific soft tissue coverage. Indications, outcomes and reconstructive rationales are discussed. Materials and Methods: A retrospective investigation was performed on patients who underwent complex two-flap microsurgical reconstruction from January 2018 to January 2022. Inclusion criteria in this study were the use of a free femoral condyle periostal/bone flap together with a second skin-only flap. Only distal third lower limb reconstructions were included in order to help equalize our findings. Out of the total number of patients, only patients with complete pre- and post-operative follow-up (minimum 6 months) data were included in the study. Results: Seven patients were included in the study, with a total of 14 free flaps. The average age was 49. Among comorbidities, four patients were smokers and none suffered from diabetes. Etiology of the defect was acute trauma in four cases and septic non-union in three cases. No major complications occurred, and all flaps healed uneventfully with complete bone union. Conclusions: Combining a bone periosteal FMC to a second skin free flap for tailored defect coverage allowed achievement of bone union in all patients, despite the lack of initial bone vascularization or chronic infection. FMC is confirmed to be a versatile flap for small-to-medium bone defects, especially considering its use as a periosteal-only flap, with minimal donor site morbidity. Choosing a second flap for coverage allows for a higher inset freedom and tailored reconstruction, finally enhancing orthoplastic success.

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Signals from the surrounding niche drive proliferation and suppress differentiation of intestinal stem cells (ISCs) at the bottom of intestinal crypts. Among sub-epithelial support cells, deep sub-cryptal CD81+ PDGFRAlo trophocytes capably sustain ISC functions ex vivo. Here, we show that mRNA and chromatin profiles of abundant CD81- PDGFRAlo mouse stromal cells resemble those of trophocytes and that both populations provide crucial canonical Wnt ligands. Mesenchymal expression of key ISC-supportive factors extends along a spatial and molecular continuum from trophocytes into peri-cryptal CD81- CD55hi cells, which mimic trophocyte activity in organoid co-cultures. Graded expression of essential niche factors is not cell-autonomous but dictated by the distance from bone morphogenetic protein (BMP)-secreting PDGFRAhi myofibroblast aggregates. BMP signaling inhibits ISC-trophic genes in PDGFRAlo cells near high crypt tiers; that suppression is relieved in stromal cells near and below the crypt base, including trophocytes. Cell distances thus underlie a self-organized and polar ISC niche.

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We examined differences in HER2 expression between primary tumors and distant metastases, particularly within the HER2-negative primary breast cancer cohort (HER2-low and HER2-zero). The retrospective study included 191 consecutive paired samples of primary breast cancer and distant metastases diagnosed between 1995 and 2019. HER2-negative samples were divided into HER2-zero (immunohistochemistry [IHC] score 0) and HER2-low (IHC score 1+ or 2+/in situ hybridization [ISH]-negative). The main objective was to analyze the discordance rate between matched primary and metastatic samples, focusing on the site of distant metastasis, molecular subtype, and de novo metastatic breast cancer. The relationship was determined by cross-tabulation and calculation of Cohen's Kappa coefficient. The final study cohort included 148 paired samples. The largest proportion in the HER2-negative cohort was HER2-low [primary tumor 61.4% (n = 78), metastatic samples 73.5% (n = 86)]. The discordance rate between the HER2 status of primary tumors and corresponding distant metastases was 49.6% (n = 63) (Kappa -0.003, 95%CI -0.15-0.15). Development of a HER2-low phenotype occurred most frequently (n = 52, 40.9%), mostly with a switch from HER2-zero to HER2-low (n = 34, 26.8%). Relevant HER2 discordance rates were observed between different metastatic sites and molecular subtypes. Primary metastatic breast cancer had a significantly lower HER2 discordance rate than secondary metastatic breast cancer [30.2% (Kappa 0.48, 95%CI 0.27-0.69) versus 50.5% (Kappa 0.14, 95% CI -0.03-0.32)]. This highlights the importance of evaluating potentially therapy-relevant discordance rates between a primary tumor and corresponding distant metastases.

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Although it has long been known that the immune cell composition has a strong prognostic and predictive value in colorectal cancer (CRC), scoring systems such as the immunoscore (IS) or quantification of intraepithelial lymphocytes are only slowly being adopted into clinical routine use and have their limitations. To address this we established and evaluated a multistain deep learning model (MSDLM) utilizing artificial intelligence (AI) to determine the AImmunoscore (AIS) in more than 1,000 patients with CRC. Our model had high prognostic capabilities and outperformed other clinical, molecular and immune cell-based parameters. It could also be used to predict the response to neoadjuvant therapy in patients with rectal cancer. Using an explainable AI approach, we confirmed that the MSDLM's decisions were based on established cellular patterns of anti-tumor immunity. Hence, the AIS could provide clinicians with a valuable decision-making tool based on the tumor immune microenvironment.

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BACKGROUND: The optimal treatment for radiation-induced fragility fractures of the pelvis (RI-FFP) is not well evaluated due to the rarity of the condition. PURPOSE: The aim of this retrospective study was to assess the prevalence of RI-FFP, the radiological and clinical outcomes as well as the complications of patients treated with internal fixation. METHODS: A retrospective review of our database was performed to identify all surgically treated patients with RI-FFP. Surgical stabilization was recommended for patients with FFP type III and FFP type IV. Surgical stabilization was also recommended after 5-7 days for patients with FFP type II in case of unsuccessful conservative treatment. Demographic data, fracture patterns according to the FFP classification of Rommens and Hofmann, type of treatment and surgery-related complications including nonunion, hardware failure, fracture progression (secondary fracture) or infection were documented. RESULTS: Among 500 patients with FFP, the prevalence of patients with RI-FFP was 1% (5/500): 5 patients with a median age of 79 years (76-79). The median time interval from radiation to fracture was 18 months (18-24). All of them underwent internal fixation. Two patients experienced surgery-related complications, one due to hardware failure and one due to fracture progression. At median follow-up of 27 months, all fractures had healed. Patients reached a good level of mobility with a median Parker Mobility Score of 7 and suffered moderate pain with a median value of 2.5 on the numeric rating scale. CONCLUSION: RI-FFP remains a rare injury (1%). In our experience, patients, who underwent surgical treatment, obtained a high level of mobility and a moderate pain score after 2 years of follow-up. Internal fixation can be recommended in RI-FFP. Because bone healing may be impaired due to previous irradiation, highly stable constructs are required to avoid fracture progression or revision surgery. LEVEL OF EVIDENCE: III, retrospective study.

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