The Edifice of Vasculature-On-Chips: A Focused Review on the Key Elements and Assembly of Angiogenesis Models.

The conception of vascularized organ-on-a-chip models provides researchers with the ability to supply controlled biological and physical cues that simulate the in vivo dynamic microphysiological environment of native blood vessels. The intention of this niche research area is to improve our understanding of the role of the vasculature in health or disease progression in vitro by allowing researchers to monitor angiogenic responses and cell-cell or cell-matrix interactions in real time. This review offers a comprehensive overview of the essential elements, including cells, biomaterials, microenvironmental factors, microfluidic chip design, and standard validation procedures that currently govern angiogenesis-on-a-chip assemblies. In addition, we emphasize the importance of incorporating a microvasculature component into organ-on-chip devices in critical biomedical research areas, such as tissue engineering, drug discovery, and disease modeling. Ultimately, advances in this area of research could provide innovative solutions and a personalized approach to ongoing medical challenges.

Boosting Upconversion Efficiency in Optically Inert Shelled Structures with Electroactive Membrane through Electron Donation.

This study innovatively addresses challenges in enhancing upconversion efficiency in lanthanide-based nanoparticles (UCNPs) by exploiting Shewanella oneidensis MR-1, a microorganism capable of extracellular electron transfer. Electroactive membranes, rich in c-type cytochromes, are extracted from bacteria and integrated into membrane-integrated liposomes (MILs), encapsulating core-shelled UCNPs with an optically inactive shell, forming UCNP@MIL constructs. The electroactive membrane, tailored to donate electrons through the inert shell, independently boosts upconversion emission under near-infrared excitation (980 nm or 1550 nm), bypassing ligand-sensitized UCNPs. The optically inactive shell restricts energy migration, emphasizing electroactive membrane electron donation. Density functional theory calculations elucidate efficient electron transfer due to the electroactive membrane hemes' highest occupied molecular orbital being higher than the valence band maximum of the optically inactive shell, crucial for enhancing energy transfer to emitter ions. The introduction of a SiO2 insulator coating diminishes light enhancement, underscoring the importance of unimpeded electron transfer. Luminescence enhancement remains resilient to variations in emitter or sensitizing ions, highlighting the robustness of the electron transfer-induced phenomenon. However, altering the inert shell material diminishes enhancement, emphasizing the role of electron transfer. This methodology holds significant promise for diverse biological applications. UCNP@MIL offers an advantage in cellular uptake, which proves beneficial for cell imaging. This article is protected by copyright. All rights reserved.

Neighborhood physical environments and change in cardiometabolic risk factors over 14 years in the study of Women's health across the nation.

BACKGROUND: Neighborhood physical environments may influence cardiometabolic health, but prior studies have been inconsistent, and few included long follow-up periods. METHODS: Changes in cardiometabolic risk factors were measured for up to 14 years in 2830 midlife women in the Study of Women's Health Across the Nation, a multi-ethnic/racial cohort of women from seven U.S. sites. Data on neighborhood food retail environments (modified Retail Food Environment Index) and walkability (National Walkability Index) were obtained for each woman's residence at each follow-up. Data on neighborhood access to green space, parks, and supermarkets were available for subsets (32-42%) of women. Models tested whether rates of change in cardiometabolic outcomes differed based on neighborhood characteristics, independent of sociodemographic and health-related covariates. RESULTS: Living in more (vs. less) walkable neighborhoods was associated with favorable changes in blood pressure outcomes (SBP: -0.27 mmHg/year, p = 0.002; DBP: -0.22 mmHg/year, p < 0.0001; hypertension status: ratio of ORs = 0.79, p < 0.0001), and small declines in waist circumference (-0.09 cm/year, p = 0.03). Small-magnitude associations were also observed between low park access and greater increases in blood pressure outcomes (SBP: 0.37 mmHg/year, p = 0.003; DBP: 0.15 mmHg/year, p = 0.04; hypertension status: ratio of ORs = 1.16, p = .04), though associations involving DBP and hypertension were only present after adjustment for sociodemographic variables. Other associations were statistically unreliable or contrary to hypotheses. CONCLUSION: Neighborhood walkability may have a meaningful influence on trajectories of blood pressure outcomes in women from midlife to early older adulthood, suggesting the need to better understand how individuals interact with their neighborhood environments in pursuit of cardiometabolic health.

Biomechanical analysis of plate versus K-wire fixation for metacarpal shaft fractures with wedge-shaped bone defects.

BACKGROUND: Metacarpal shaft fracture is a common type of hand fracture. Numerous studies have explored fixing transverse fractures in the midshaft of the metacarpal bone. However, this section of the metacarpal bone is often susceptible to high-energy injury, resulting in comminuted fracture or bone loss. In such cases, wedge-shaped bone defects can develop in the metacarpal shaft, increasing the difficulty of performing fracture fixation. Notably, the research on this type of fracture fixation is limited. This study compared the abilities of four fixation methods to fix metacarpal shaft fractures with wedge-shaped bone defects. METHODS: In total, 28 artificial metacarpal bones were used. To create wedge-shaped bone defects, an electric saw was used to create metacarpal shaft fractures at the midshaft of each bone. The artificial metacarpal bones were then divided into four groups for fixation. The bones in the first group were fixed with a dorsal locked plate (DP group), those in the second group were fixed with a volar locked plate (VP group), and those in the third group were fixed by combining dorsal and volar locked plates (DP + VP group), and those in the fourth group were fixed with two K-wires (2 K group). Cantilever bending tests were conducted using a material testing machine to measure yielding force and stiffness. The four groups' fixation capabilities were then assessed through analysis of variance and Tukey's test. RESULTS: The DP + VP group (164.1±44.0 N) achieved a significantly higher yielding force relative to the 2 K group (50.7 ± 8.9 N); the DP group (13.6 ± 3.0 N) and VP group (12.3 ± 1.0 N) did not differ significantly in terms of yielding force, with both achieving lower yielding forces relative to the DP + VP group and 2 K group. The DP + VP group (19.8±6.3 N/mm) achieved the highest level of stiffness, and the other three groups did not differ significantly in terms of stiffness (2 K group, 5.4 ± 1.1 N/mm; DP group, 4.0 ± 0.9 N/mm; VP group, 3.9 ± 1.9 N/mm). CONCLUSIONS: The fixation method involving the combined use of dorsal and volar locked plates (DP + VP group) resulted in optimal outcomes with respect to fixing metacarpal shaft fractures with volar wedge bone defects.

Enhanced Vascular-like Network Formation of Encapsulated HUVECs and ADSCs Coculture in Growth Factors Conjugated GelMA Hydrogels.

Tissue engineering primarily aimed to alleviate the insufficiency of organ donations worldwide. Nonetheless, the survival of the engineered tissue is often compromised due to the complexity of the natural organ architectures, especially the vascular system inside the organ, which allows food-waste transfer. Thus, vascularization within the engineered tissue is of paramount importance. A critical aspect of this endeavor is the ability to replicate the intricacies of the extracellular matrix and promote the formation of functional vascular networks within engineered constructs. In this study, human adipose-derived stem cells (hADSCs) and human umbilical vein endothelial cells (HUVECs) were cocultured in different types of gelatin methacrylate (GelMA). In brief, pro-angiogenic signaling growth factors (GFs), vascular endothelial growth factor (VEGF165) and basic fibroblast growth factor (bFGF), were conjugated onto GelMA via an EDC/NHS coupling reaction. The GelMA hydrogels conjugated with VEGF165 (GelMA@VEGF165) and bFGF (GelMA@bFGF) showed marginal changes in the chemical and physical characteristics of the GelMA hydrogels. Moreover, the conjugation of these growth factors demonstrated improved cell viability and cell proliferation within the hydrogel construct. Additionally, vascular-like network formation was observed predominantly on GelMA@GrowthFactor (GelMA@GF) hydrogels, particularly on GelMA@bFGF. This study suggests that growth factor-conjugated GelMA hydrogels would be a promising biomaterial for 3D vascular tissue engineering.

Rates of paclitaxel hypersensitivity reactions using a modified Markman's infusion protocol as primary prophylaxis.

PURPOSE: Markman's desensitisation protocol allows successful retreatment of patients who have had significant paclitaxel hypersensitivity reactions. We aimed to reduce the risk and severity of paclitaxel hypersensitivity reactions by introducing this protocol as primary prophylaxis. METHODS: We evaluated all patients with a gynaecological malignancy receiving paclitaxel before (December 2018 to September 2019) and after (October 2019 to July 2020) the implementation of a modified Markman's desensitisation protocol. The pre-implementation group received paclitaxel over a gradually up-titrated rate from 60 to 180 ml/h. The post-implementation group received paclitaxel via 3 fixed-dose infusion bags in the first 2 cycles. Rates and severity of paclitaxel hypersensitivity reactions were compared. RESULTS: A total of 426 paclitaxel infusions were administered to 78 patients. The median age was 64 years (range 34-81), and the most common diagnosis was ovarian, fallopian tube and primary peritoneal cancer (67%, n = 52/78). Paclitaxel hypersensitivity reaction rates were similar in the pre-implementation (8%, n = 16/195) and post-implementation groups (9%, n = 20/231; p = 0.87). Most paclitaxel hypersensitivity reactions occurred within 30 min (pre- vs. post-implementation, 88% [n = 14/16] vs. 75% [n = 15/20]; p = 0.45) and were grade 2 in severity (pre- vs. post-implementation, 81% [n = 13/16] vs. 75% [n = 15/20]; p = 0.37). There was one grade 3 paclitaxel hypersensitivity reaction in the pre-implementation group. All patients were successfully rechallenged in the post-implementation group compared to 81% (n = 13/16) in the pre-implementation group (p = 0.43). CONCLUSION: The modified Markman's desensitisation protocol as primary prophylaxis did not reduce the rate or severity of paclitaxel hypersensitivity reactions, although all patients could be successfully rechallenged.

Catalytic Nanoparticles in Biomedical Applications: Exploiting Advanced Nanozymes for Therapeutics and Diagnostics.

Catalytic nanoparticles (CNPs) as heterogeneous catalyst reveals superior activity due to their physio-chemical features, such as high surface-to-volume ratio and unique optical, electric, and magnetic properties. The CNPs, based on their physio-chemical nature, can either increase the reactive oxygen species (ROS) level for tumor and antibacterial therapy or eliminate the ROS for cytoprotection, anti-inflammation, and anti-aging. In addition, the catalytic activity of nanozymes could specifically trigger a specific reaction accompanied by the optical feature change, presenting the feasibility of biosensor and bioimaging applications. Undoubtedly, CNPs play a pivotal role in pushing the evolution of technologies in medical and clinical fields, and advanced strategies and nanomaterials rely on the input of chemical experts to develop. Herein, we present a systematic and comprehensive review of the challenges and recent development of catalytic NPs for biomedical applications from the viewpoint of advanced nanomaterial with unique catalytic activity and additional functions. Furthermore, we critically discuss the biosafety issue of applying biodegradable and non-biodegradable nanozymes and future perspectives to guide a promising direction in developing span-new nanozymes and more intelligent strategies for overcoming the current clinical limitations. This article is protected by copyright. All rights reserved.

S100A8/A9 predicts response to PIM kinase and PD-1/PD-L1 inhibition in triple-negative breast cancer mouse models.

BACKGROUND: Understanding why some triple-negative breast cancer (TNBC) patients respond poorly to existing therapies while others respond well remains a challenge. This study aims to understand the potential underlying mechanisms distinguishing early-stage TNBC tumors that respond to clinical intervention from non-responders, as well as to identify clinically viable therapeutic strategies, specifically for TNBC patients who may not benefit from existing therapies. METHODS: We conducted retrospective bioinformatics analysis of historical gene expression datasets to identify a group of genes whose expression levels in early-stage tumors predict poor clinical outcomes in TNBC. In vitro small-molecule screening, genetic manipulation, and drug treatment in syngeneic mouse models of TNBC were utilized to investigate potential therapeutic strategies and elucidate mechanisms of drug action. RESULTS: Our bioinformatics analysis reveals a robust association between increased expression of immunosuppressive cytokine S100A8/A9 in early-stage tumors and subsequent disease progression in TNBC. A targeted small-molecule screen identifies PIM kinase inhibitors as capable of decreasing S100A8/A9 expression in multiple cell types, including TNBC and immunosuppressive myeloid cells. Combining PIM inhibition and immune checkpoint blockade induces significant antitumor responses, especially in otherwise resistant S100A8/A9-high PD-1/PD-L1-positive tumors. Notably, serum S100A8/A9 levels mirror those of tumor S100A8/A9 in a syngeneic mouse model of TNBC. CONCLUSIONS: Our data propose S100A8/A9 as a potential predictive and pharmacodynamic biomarker in clinical trials evaluating combination therapy targeting PIM and immune checkpoints in TNBC. This work encourages the development of S100A8/A9-based liquid biopsy tests for treatment guidance.

Breast cancer is a complex disease, and not all patients respond well to existing treatments. In this study, we sought to understand why some patients with a specific type of breast cancer called triple-negative breast cancer respond poorly to current therapies. We also aimed to identify new treatments for these patients. We analyzed genetic data from breast cancer patients and identified a factor called S100A8/A9, which is linked to poor outcomes in early-stage cancer. We tested drugs that can reduce the levels of this factor in tumors and found promising results, especially when combined with another treatment called immunotherapy. Our findings suggest that S100A8/A9 could help predict how patients will respond to treatments, potentially leading to better therapies in the future.

Hidden in plain sight - Survival consequences of baseline symptom burden in women with recurrent ovarian cancer.

OBJECTIVE: To describe the baseline symptom burden(SB) experienced by patients(pts) with recurrent ovarian cancer(ROC) prior and associations with progression free survival (PFS) and overall survival (OS). METHODS: We analysed baseline SB reported by pts. with platinum resistant/refractory ROC (PRR-ROC) or potentially­platinum sensitive ROC receiving their third or greater line of chemotherapy (PPS-ROC≥3) enrolled in the Gynecologic Cancer InterGroup - Symptom Benefit Study (GCIG-SBS) using the Measure of Ovarian Symptoms and Treatment concerns (MOST). The severity of baseline symptoms was correlated with PFS and OS. RESULTS: The 948 pts. reported substantial baseline SB. Almost 80% reported mild to severe pain, and 75% abdominal symptoms. Shortness of breath was reported by 60% and 90% reported fatigue. About 50% reported moderate to severe anxiety, and 35% moderate to severe depression. Most (89%) reported 1 or more symptoms as moderate or severe, 59% scored 6 or more symptoms moderate or severe, and 46% scored 9 or more symptoms as moderate or severe. Higher SB was associated with significantly shortened PFS and OS; five symptoms had OS hazard ratios larger than 2 for both moderate and severe symptom cut-offs (trouble eating, vomiting, indigestion, loss of appetite, and nausea; p < 0.001). CONCLUSION: Pts with ROC reported high SB prior to starting palliative chemotherapy, similar among PRR-ROC and PPS-ROC≥3. High SB was strongly associated with early progression and death. SB should be actively managed and used to stratify patients in clinical trials. Clinical trials should measure and report symptom burden and the impact of treatment on symptom control.

Mucinous ovarian carcinoma: A survey of practice in Australia and New Zealand.

BACKGROUND: Mucinous ovarian carcinoma (MOC) is a rare ovarian cancer with limited evidence to support clinical care. AIMS: We undertook a clinician survey to better understand current practice in treating MOC in Australia and New Zealand, and to determine any features associated with variation in care. In addition, we aimed to understand future research priorities. METHODS: A RedCap survey was distributed to clinician members of the Australia New Zealand Gynaecological Oncology Group (ANZGOG). Questions included respondent demographics, three case studies and future research priorities. Clinicians were asked questions specific to their speciality. RESULTS: Respondents (n = 47) were commonly experienced gynae-oncology specialists, most often surgical (38%) or medical (30%) oncologists. There was good consensus for surgical approaches for stage I disease; however, variation in practice was noted for advanced or recurrent MOC. Variation was also observed for medical oncologists; in early-stage disease there was no clear consensus on whether to offer chemotherapy, or which regimen to recommend. For advanced and recurrent disease a wide range of chemotherapy options was considered, with a trend away from an ovarian-type toward gastrointestinal (GI)-type regimens in advanced MOC. This practice was reflected in future research priorities, with 'Is a GI chemotherapy regimen better than an ovarian regimen?' the most highly ranked option, followed by 'Should stage 1C patients receive chemotherapy?' CONCLUSIONS: Although the number of respondents limited the analyses, it was clear that chemotherapy selection was a key point of divergence for medical oncologists. Future research is needed to establish well-evidenced guidelines for clinical care of MOC.

Assessing Neurologic Complications in Thoracic Three-Column Osteotomy: A Clinical Application of a Novel MRI-Based Classification Approach.

STUDY DESIGN: Retrospective comparative study. OBJECTIVE: To investigate the occurrence of neurologic complications in patients undergoing thoracic three-column osteotomy (3CO) utilizing an MRI-based classification that assesses spinal cord shape and the presence of cerebrospinal fluid (CSF) at the curve apex, and evaluate its prognostic capacity for postoperative neurologic deficits. SUMMARY OF BACKGROUND DATA: Recent advancements in correction techniques have improved outcomes for severe spinal deformity patients undergoing 3CO. A novel MRI-based spinal cord classification system was introduced, but its validation and association with postoperative complications remain unexplored. MATERIALS AND METHODS: Between September 2012 and September 2018, a retrospective analysis was conducted on 158 adult patients with spinal deformities undergoing 3CO. Radiographic parameters were measured. T2-weighted axial MRI was employed to describe spinal cord morphology at the apex. Intraoperative neurophysiologic monitoring (INOM) alerts were recorded, and preoperative and postoperative neurologic functions were assessed using the Frankel score. Categorical data were compared using the Chi-Square or Fisher's exact test. The paired t-test was utilized to assess the mean difference between pre- and postoperative measurements, while the one-way ANOVA and independent t-test were employed for comparative analyses among the different spinal cord types. RESULTS: Patients were categorized into three groups: type 1, type 2, and type 3, consisting of 12, 85, and 61 patients. Patients with type 3 morphology exhibited larger Cobb angles of the main curve (P<.001). This disparity persisted both postoperatively and during follow-up (P<.05). IONM alerts were triggered in 32 patients (20.3%), with a distribution of one case in type 1, six cases in type 2, and 22 cases in type 3 morphologies (P<.001). New neurologic deficits were observed in 15 patients (9.5%), with one, three, and 11 cases in type 1, 2, and 3 morphologies, respectively. CONCLUSIONS: Patients with type 3 morphology exhibited greater spinal deformity severity, higher likelihood of preoperative neurologic deficits, and an elevated risk of postoperative neurologic complications. This underscores the utility of the classification as a tool for predicting postoperative neurologic complications in patients undergoing thoracic 3CO. LEVEL OF EVIDENCE: Level IV.

Mapping the Postpartum Experience Through Obstetric Patient Navigation for Low-Income Individuals.

Background: Although the postpartum period is an opportunity to address long-term health, fragmented care systems, inadequate attention to social needs, and a lack of structured transition to primary care threaten patient wellbeing, particularly for low-income individuals. Postpartum patient navigation is an emerging innovation to address these disparities. Methods: This mixed-methods analysis uses data from the first year of an ongoing randomized controlled trial to understand the needs of low-income postpartum individuals through 1 year of patient navigation. We designed standardized logs for navigators to record their services, tracking mode, content, intensity, and target of interactions. Navigators also completed semistructured interviews every 3 months regarding relationships with patients and care teams, care system gaps, and navigation process. Log data were categorized, quantified, and mapped temporally through 1 year postpartum. Qualitative data were analyzed using the constant comparative method. Results: Log data from 50 participants who received navigation revealed the most frequent needs related to health care access (45.4%), health and wellness (18.2%), patient-navigator relationship building (14.8%), parenting (13.6%), and social determinants of health (8.0%). Navigation activities included supporting physical and mental recovery, accomplishing health goals, connecting patients to primary and specialty care, preparing for health system utilization beyond navigation, and referring individuals to community resources. Participant needs fluctuated, yielding a dynamic timeline of the first postpartum year. Conclusion: Postpartum needs evolved throughout the year, requiring support from various teams. Navigation beyond the typical postpartum care window may be useful in mitigating health system barriers, and tracking patient needs may be useful in optimizing postpartum care. Clinical Trial Registration: Registered April 19, 2019, enrollment beginning January 21, 2020, NCT03922334, https://clinicaltrials.gov/ct2/show/NCT03922334.

Association of Antenatal Housing Instability with Perinatal Care Utilization and Outcomes.

Background: Social determinants of health are important contributors to maternal and child health outcomes. Limited existing research examines the relationship between housing instability during pregnancy and perinatal care utilization. Our objective was to evaluate whether antenatal housing instability is associated with differences in perinatal care utilization and outcomes. Materials and Methods: Participants who were surveyed during their postpartum hospitalization were considered to have experienced housing instability if they answered affirmatively to at least one of six screening items. The primary outcome was adequacy of prenatal care measured by the Adequacy of Prenatal Care Utilization index. Maternal, neonatal, and postpartum outcomes, including utilization and breastfeeding, were also collected as secondary outcomes. Multivariable logistic regression models were adjusted for sociodemographic and clinical covariates. Results: In this cohort (N = 490), 11.2% (N = 55) experienced housing instability during pregnancy. Participants with unstable housing were more likely to have inadequate prenatal care (17.3% vs. 3.9%; odds ratio [OR] 5.11, 95% confidence interval [CI] 2.15-12.14, p < 0.001), but findings were not significant after adjustment (aOR 1.72, 95% CI 0.55-5.41, p = 0.35). Similarly, postpartum visit attendance was lower for individuals with unstable housing (79.6% vs. 91.2%), but there was no difference in the odds of the postpartum visit attendance after adjustment (OR 0.69, 95% CI 0.29-1.66, p = 0.14). Conclusions: There were no statistically significant association with the maternal, neonatal, and other postpartum secondary outcomes. Housing instability appears to be a risk marker that is related to other social determinants of health. Given the range of housing instability experiences, future research must account for specific types and degrees of housing instability and their potential perinatal consequences.

Responses of Early Childhood Educators to Children's Interpersonal Sexual Behaviors.

There is a considerable amount of evidence in the literature that children engage in a wide range of sexual behaviors before puberty. How early childhood educators (ECEs) respond to children's interpersonal sexual behaviors (ISBs) is especially important during the early childhood stage not only due to their roles as educators, but also protector due to their legal obligation to report suspected cases of child sexual abuse. Considering the pivotal responsibilities ECEs have in addressing ISBs, it becomes imperative to gain a comprehensive understanding of the experiences they encounter in managing such behaviors. Surprisingly, the current body of research provides limited insights into how ECEs respond to children's ISBs. To address this gap, the present study aims to explore these topics by conducting a qualitative investigation to examine the experiences of Taiwanese ECEs who encountered ISBs among children and how they responded to these behaviors. Four themes emerged from an analysis of the stories shared by 36 ECEs: (1) being silent versus supporting children's healthy sexuality development, (2) protect yourself versus respect others, (3) punishments versus exploring strategies to address children's ISBs and (4) insensitivity to boundaries and bodily autonomy. This study provides guidelines for understanding the experiences of Taiwanese ECEs who encounter children's ISBs and contributes to the training needs of ECEs about children's sexuality development.

Nafion/Silver Nanoparticles as an Electrochemically Sensitive Interface for the Detection of Ractopamine in Pork Liver.

Many countries have allowed farmers to feed ß-adrenergic receptor agonists, such as ractopamine (Rac), to animals to improve the quality of their meat. However, Rac consumption can cause health problems for humans; thus, detecting Rac in meat before its packaging is essential. Consequently, this study developed a simple and sensitive electrochemical sensor by modifying a glassy carbon electrode (GCE) with Nafion/silver nanoparticles (Nafion/AgNPs). When this electrochemical sensor is used to detect Rac, electrostatic interaction occurs between Nafion and Rac, and the AgNPs oxidize Rac; thus, the accumulation and electrochemical sensing of Rac are achieved. Differential pulse voltammetry indicated that the as-prepared Nafion/AgNP-GCE sensor exhibited suitable electrochemical sensing ability under optimum conditions (6.0 µL of 0.10% Nafion/AgNPs in a Britton-Robertson buffer solution with a pH of 1.8, an accumulation potential of -0.2 V, and a Rac accumulation duration of 300 s). Moreover, this sensor has an extremely low limit of detection and high sensitivity (1.60 × 10-3 ppm and 2.14 µA/ppm, respectively) in the Rac concentration range 7.50 × 10-3-1.00 ppm. The as-prepared sensor also exhibits satisfactory reproducibility and storage stability, with the corresponding relative standard deviations (RSDs) being 4.27% (n = 5) and 1.56% (n = 10), respectively. The proposed electrochemical sensor was successfully used to determine the Rac content in pig liver samples, with spiked recoveries of 95.2-101.8% and RSDs of 0.55-4.83% being achieved.

Effect of intraoperative hand-grip position on surgical outcome of thumb carpometacarpal arthrodesis.

BACKGROUND: A variety of surgical techniques had been developed over the past few decades for treating thumb carpometacarpal joint (CMCJ) osteoarthritis (OA). However, there are currently no accepted consensus on the ideal treatment for thumb CMCJ OA. Arthrodesis was one of the widely popular treatment methods; however, studies have showed that non-union rates were as high as 50%, with higher complications such as osteoarthritis of neighbouring joints and higher revision surgeries required as compared to other surgical methods. Patients with arthrodesis were also reported to have decreased thumb range of motion and loss of opponens function. Currently, there are numerous intraoperative positioning techniques for arthrodesis which could be confusing for young surgeons. With recent developments of fixation plates and better understanding of the wrist anatomy, this retrospective review aimed to evaluate the efficacy of our intraoperative hand-grip positioning method for arthrodesis of thumb CMCJ OA. What are the postoperative functional outcomes of (1) T-hook plates and (2) our intraoperative hand-grip positioning method for Eaton III thumb CMCJ OA arthrodesis by evaluating pain visual analogue scale (VAS) score, Disabilities of the Arm, Shoulder and Hand questionnaires (DASH), Mayo Wrist scores, capability of thumb opposition (Kapandji score), and comparing pre- and postoperative grip and pinch strength? METHODS: Twenty patients with CMCJ OA underwent arthrodesis using our intraoperative hand-grip positioning method and T-hook plates and screws (Acumed, USA). Patients were evaluated preoperatively and at 1, 3, 6 and 12 months postoperatively. Radiologic assessment including fusion evaluation, evaluation of radial and palmar abduction angles was done on hand X-rays. RESULTS: Twenty patients with a minimum follow-up duration of 12 months were included in this study. 100% fusion rate was achieved with only 1 case of complication involving radial sensory nerve neuropathy which was resolved after removal of implant and neurolysis. Significant improvement in pain and Mayo Wrist scores were noted 3 months postoperatively, whilst DASH score exhibited significant improvements after 6 months of follow-up (p < 0.05). Even though there were no significant differences observed between preoperative and postoperative grip strength, pinch strength and Kapandji scores, positive recovery trends were noted for all parameters with these functions surpassing preoperative levels after 12 months of follow-up. Significant improvements on hand X-rays were also noted for both postoperative radial and palmar abduction angles. CONCLUSIONS: There is currently no consensus on the ideal treatment method for thumb CMCJ OA. In this study, we would like to propose a simple intraoperative hand-grip positioning method with T-hook plates for arthrodesis. As seen from our results, our technique was able to provide satisfactory and replicable postoperative results and thus we would like to propose our hand-grip positioning method with T-hook plates fixation for subsequent treatment of patients with Eaton stage III thumb CMCJ OA.

S100A8/A9 predicts triple-negative breast cancer response to PIM kinase and PD-1/PD-L1 inhibition.

It remains elusive why some triple-negative breast cancer (TNBC) patients respond poorly to existing therapies while others respond well. Our retrospective analysis of historical gene expression datasets reveals that increased expression of immunosuppressive cytokine S100A8/A9 in early-stage tumors is robustly associated with subsequent disease progression in TNBC. Although it has recently gained recognition as a potential anticancer target, S100A8/A9 has not been integrated into clinical study designs evaluating molecularly targeted therapies. Our small molecule screen has identified PIM kinase inhibitors as capable of decreasing S100A8/A9 expression in multiple cell types, including TNBC and immunosuppressive myeloid cells. Furthermore, combining PIM inhibition and immune checkpoint blockade induces significant antitumor responses, especially in otherwise resistant S100A8/A9-high PD-1/PD-L1-positive tumors. Importantly, serum S100A8/A9 levels mirror those of tumor S100A8/A9 in a syngeneic mouse model of TNBC. Thus, our data suggest that S100A8/A9 could be a predictive and pharmacodynamic biomarker in clinical trials evaluating combination therapy targeting PIM and immune checkpoints in TNBC and encourage the development of S100A8/A9-based liquid biopsy tests.

Pivotal Role of Slitrk1 in Adult Striatal Cholinergic Neurons in Mice: Implication in Tourette Syndrome.

OBJECTIVE: The SLIT and NTRK-like 1 (SLITRK1) gene mutation and striatal cholinergic interneurons (ChIs) loss are associated with Tourette syndrome (TS). ChIs comprise only 1 to 2% of striatal neurons but project widely throughout the stratum to impact various striatal neurotransmission, including TS-related dopaminergic transmission. Here, we link striatal Slitrk1, ChI function, and dopaminergic transmission and their associations with TS-like tic behaviors. METHODS: Slitrk1-KD mice were induced by bilaterally injecting Slitrk1 siRNA into their dorsal striatum. Control mice received scrambled siRNA injection. Their TS-like tic behaviors, prepulse inhibition, sensory-motor function and dopamine-related behaviors were compared. We also compared dopamine and ACh levels in microdialysates, Slitrk protein and dopamine transporter levels, and numbers of Slitrk-positive ChIs and activated ChIs in the striatum between two mouse groups, and electrophysiological properties between Slitrk-positive and Slitrk-negative striatal ChIs. RESULTS: Slitrk1-KD mice exhibit TS-like haloperidol-sensitive stereotypic tic behaviors, impaired prepulse inhibition, and delayed sensorimotor response compared with the control group. These TS-like characteristics correlate with lower striatal Slitrk1 protein levels, fewer Slitrk1-containing ChIs, and fewer activated ChIs in Slitrk1-KD mice. Based on their electrophysiological properties, Slitrk1-negative ChIs are less excitable than Slitrk1-positive ChIs. Slitrk1-KD mice have lower evoked acetylcholine and dopamine levels, higher tonic dopamine levels, and downregulated dopamine transporters in the striatum, increased apomorphine-induced climbing behaviors, and impaired methamphetamine-induced hyperlocomotion compared with controls. INTERPRETATION: Slitrk1 is pivotal in maintaining striatal ChIs activity and subsequent dopaminergic transmission for normal motor functioning. Furthermore, conditional striatal Slitrk1-KD mice may serve as a translational modality with aspects of TS phenomenology. ANN NEUROL 2023.

Beta Amyloid Oligomers with Higher Cytotoxicity have Higher Sidechain Dynamics.

The underlying biophysical principle governing the cytotoxicity of the oligomeric aggregates of ß-amyloid (Aß) peptides has long been an enigma. Here we show that the size of Aß40 oligomers can be actively controlled by incubating the peptides in reverse micelles. Our approach allowed for the first time a detailed comparison of the structures and dynamics of two Aß40 oligomers of different sizes, viz., 10 and 23 nm, by solid-state NMR. From the chemical shift data, we infer that the conformation and/or the chemical environments of the residues from K16 to K28 are different between the 10-nm and 23-nm oligomers. We find that the 10-nm oligomers are more cytotoxic, and the molecular motion of the sidechain of its charged residue K16 is more dynamic. Interestingly, the residue A21 exhibits unusually high structural rigidity. Our data raise an interesting possibility that the cytotoxicity of Aß40 oligomers could also be correlated to the motional dynamics of the sidechains.

Association of chemotherapy dose intensity and age with outcomes in patients with Ewing's family sarcoma.

BACKGROUND: Ewing's family sarcoma (EFS) is an aggressive malignancy with a peak incidence in adolescents. Multimodal treatment involves surgery and/or radiotherapy, and chemotherapy typically with VDC/IE (vincristine, doxorubicin, and cyclophosphamide alternating with ifosfamide and etoposide). There is a paucity of data for the treatment of adults, with protocols extrapolated from the pediatric setting. This study aimed to assess patterns of care, chemotherapy tolerability across age groups, and outcomes from four Australian sarcoma centers. METHODS: ANZSA ACCORD sarcoma database and medical records were used to identify and collect data of patients aged ≥ 10 years with EFS who received VDC/IE between 2010 and 2020. Survival outcomes were analyzed based on chemotherapy received dose intensity (RDI). Clinical predictors of RDI were explored using logistic regression. RESULTS: Of 146 patients with EFS, 76 received VDC/IE. The majority had localized disease (65%). Seventy-one percent completed scheduled chemotherapy, with some requiring dose reduction (29%), delay > 7 days (65%), or cycle omission (4%). Hematological toxicity was the main reason for dose reduction/delay. Fifty-seven percent patients achieved an acceptable RDI ≥85%. Compared to those aged 10-19, the odds ratio for acceptable RDI aged 40-59 was 0.20 (95% CI 0.04-0.86, p = 0.04). RDI was an independent prognostic factor for overall survival, after accounting for age, gender, Ewing's type, primary site, and stage (adjusted HR 0.25 [95% CI 0.10-0.63], p = 0.004). CONCLUSION: Survival outcomes in EFS were associated with chemotherapy RDI. Older adults more commonly required dose reduction or early cessation of treatment due to toxicity. VDC/IE chemotherapy should be carefully tailored in adults > 40 years.