Tunnel Overlap Occurs 25% of the Time With Simultaneous Anterior Cruciate Ligament Reconstruction and Lateral Meniscal Root Repair.

Purpose: To assess the risk of socket-tunnel overlap for posterior medial or lateral meniscal root repair combined with anterior cruciate ligament reconstruction (ACLR) using artificial tibias and computed tomography scans for 3-dimensional modeling. Methods: Artificial tibias (n = 27; n = 3/subgroup) were allocated to groups based on inclination of socket-tunnels (55°, 60°, 65°) created for posterior root of the medial meniscus (MMPR) and lateral meniscus posterior root (LMPR) repair, and ACLR. Three standardized socket-tunnels were created: one for the ACL and one for each posterior meniscal root insertion. Computed tomography scans were performed and sequentially processed using computer software to produce 3-dimensional models for assessment of socket-tunnel overlap. Statistical analysis was performed with Kruskal-Wallis and Mann-Whitney U tests. Significance was set at P < .05. Results: The present study found no significant risk of tunnel overlap when drilling for combined ACLR and MMPR repair, whereas 7 cases of tunnel overlap occurred between ACL tunnels and LMPR (25.9% of cases). No subgroup or specific pattern of angulation consistently presented significantly safer distances than other subgroups for all distances measured. Conclusions: This study demonstrated 25.9% rate of overlap for combined LMPR repair and ACLR, compared with 0% for MMPR repair with ACLR. Lower ACL drilling angle (55 or 60°) combined with greater lateral meniscus drilling angle (65°) produced no socket-tunnel overlap. Clinical Relevance: Socket-tunnel overlap during meniscal root repair combined with ACLR may compromise graft integrity and lead to impaired fixation and treatment failure of either the ACL, the meniscus, or both. Despite this, risk for socket-tunnel overlap has not been well characterized.

Anti-PD-1 cancer immunotherapy induces central nervous system immune-related adverse events by microglia activation.

Cancer treatment with anti-PD-1 immunotherapy can cause central nervous system immune-related adverse events (CNS-irAEs). The role of microglia in anti-PD-1 immunotherapy-induced CNS-irAEs is unclear. We found that anti-PD-1 treatment of mice caused morphological signs of activation and major histocompatibility complex (MHC) class II up-regulation on microglia. Functionally, anti-PD-1 treatment induced neurocognitive deficits in mice, independent of T cells, B cells, and natural killer cells. Instead, we found that microglia mediated these CNS-irAEs. Single-cell RNA sequencing revealed major transcriptional changes in microglia upon anti-PD-1 treatment. The anti-PD-1 effects were mediated by anti-PD-1 antibodies interacting directly with microglia and were not secondary to peripheral T cell activation. Using a proteomics approach, we identified spleen tyrosine kinase (Syk) as a potential target in activated microglia upon anti-PD-1 treatment. Syk inhibition reduced microglia activation and improved neurocognitive function without impairing anti-melanoma effects. Moreover, we analyzed CNS tissue from a patient cohort that had received anti-PD-1 treatment. Imaging mass cytometry revealed that anti-PD-1 treatment of patients was associated with increased surface marker expression indicative of microglia activation. In summary, we identified a disease-promoting role for microglia in CNS-irAEs driven by Syk and provide an inhibitor-based approach to interfere with this complication after anti-PD-1 immunotherapy.

MR histology reveals tissue features beneath heterogeneous MRI signal in genetically engineered mouse models of sarcoma.

Purpose: To identify significant relationships between quantitative cytometric tissue features and quantitative MR (qMRI) intratumorally in preclinical undifferentiated pleomorphic sarcomas (UPS). Materials and methods: In a prospective study of genetically engineered mouse models of UPS, we registered imaging libraries consisting of matched multi-contrast in vivo MRI, three-dimensional (3D) multi-contrast high-resolution ex vivo MR histology (MRH), and two-dimensional (2D) tissue slides. From digitized histology we generated quantitative cytometric feature maps from whole-slide automated nuclear segmentation. We automatically segmented intratumoral regions of distinct qMRI values and measured corresponding cytometric features. Linear regression analysis was performed to compare intratumoral qMRI and tissue cytometric features, and results were corrected for multiple comparisons. Linear correlations between qMRI and cytometric features with p values of <0.05 after correction for multiple comparisons were considered significant. Results: Three features correlated with ex vivo apparent diffusion coefficient (ADC), and no features correlated with in vivo ADC. Six features demonstrated significant linear relationships with ex vivo T2*, and fifteen features correlated significantly with in vivo T2*. In both cases, nuclear Haralick texture features were the most prevalent type of feature correlated with T2*. A small group of nuclear topology features also correlated with one or both T2* contrasts, and positive trends were seen between T2* and nuclear size metrics. Conclusion: Registered multi-parametric imaging datasets can identify quantitative tissue features which contribute to UPS MR signal. T2* may provide quantitative information about nuclear morphology and pleomorphism, adding histological insights to radiological interpretation of UPS.

Optimizing Socket-Tunnel Position for Meniscal Allograft Transplantation Combined With ACL Reconstruction: A 3D Model Analysis.

Background: Socket-tunnel overlap during meniscal allograft transplantation (MAT) combined with anterior cruciate ligament reconstruction (ACLR) may compromise graft integrity and lead to impaired fixation and treatment failure. Purpose/Hypothesis: The purpose of this study was to determine optimal socket-tunnel drilling parameters for medial and lateral MAT with concurrent ACLR using artificial tibias and computed tomography (CT) scans for 3-dimensional (3D) modeling. It was hypothesized that clinically relevant socket tunnels could be created to allow for concurrent medial or lateral MAT and ACLR without significant risk for overlap at varying tunnel guide angles. Study Design: Descriptive laboratory study. Methods: A total of 27 artificial right tibias (3 per subgroup) were allocated to 9 experimental groups based on the inclination of the socket tunnels (55°, 60°, and 65°) created for simulating medial and lateral MAT and ACLR. Five standardized socket tunnels were created for each tibia using arthroscopic guides: one for the ACL tibial insertion and one for each meniscus root insertion. CT scans were performed for all specimens and sequentially processed using computer software to produce 3D models for quantitative assessment of socket-tunnel overlap risk. Statistical analysis was performed with Kruskal-Wallis and Mann-Whitney U tests. Results: No subgroup consistently presented significantly safer distances than other subgroups for all distances measured. Three cases (11%) and 24 cases (~90%) of tunnel overlap occurred between the ACL tunnel and tunnels for medial and lateral MAT, respectively. Most socket-tunnel overlap (25 of 27; 92.6%) occurred between sockets at depths ranging between 6.3 and 10 mm from the articular surface. For ACLR and posterior root of the lateral meniscus setting, the guide set at 65° increased socket-tunnel distances. Conclusion: When combined ACLR and MAT using socket tunnels for graft fixation is performed, the highest risk for tibial socket-tunnel overlap involves the ACLR tibial socket and the lateral meniscus anterior root socket at a depth of 6 to 10 mm from the tibial articular surface. Clinical Relevance: Setting tibial guides at 65° to the tibial articular surface with the tunnel entry point anteromedial and socket aperture location within the designated anatomic "footprint" will minimize the risk for socket-tunnel overlap.

The Impact of United States Medical Licensing Examination Step 1 Transitioning To Pass/Fail on Medical Student Perception of Research Needed to Match Into One's Preferred Specialty.

Purpose To evaluate how the transition of United States Medical Licensing Examination (USMLE) Step 1 to a pass/fail scoring influenced medical student perceptions of the importance of research required to match into their preferred residency specialty. Methods A 14-item survey was distributed by e-mail to medical students at one medical school in the southeastern United States in November of 2021. Responses were compared between medical students taking USMLE Step 1 pass/fail in the future and medical students taking USMLE Step 1 for a three-digit score. Results A total of 168 medical students responded to the survey with 98 respondents who planned on taking USMLE Step 1 pass/fail (45 first-year medical students (MS1) and 53 MS2) and 70 respondents who took USMLE Step 1 for a numerical score (37 MS3 and 33 MS4). There were no differences in how each cohort scored the level of importance of research in matching into their preferred residency specialty (p=0.10); however, those taking USMLE Step 1 pass/fail believe an average of 4.6 research experiences are necessary to match into their preferred residency, compared to only 3.4 research experiences for those who took it for a numerical score (p=0.04). Conclusion No statistically significant difference in the perceived importance of research in matching into one's preferred residency specialty was found between cohorts. However, the pass/fail cohort believes they will need more research experiences to match their chosen specialty than the numerical score cohort. Results could indicate that students participate in more research and extracurricular activities to be more competitive for residency applications.

Cell-Mediated Immune Responses May Play Roles in Osteochondral Allograft Transplantation Osteointegration Failures.

Prolonged and incomplete osteochondral allograft (OCA) osteointegration is consistently cited as a major mechanism for OCA treatment failure. Subrejection immune responses may play roles in this mode of failure. Preimplantation OCA preparation techniques, including subchondral bone drilling, thorough irrigation, and autogenous bone marrow aspirate concentrate saturation, may dampen immune responses and improve OCA osteointegration. This study sought to further characterize potential immune system contributions to OCA transplantation treatment failures by analyzing donor-recipient ABO and Rh-factor mismatches and histological and immunohistochemical assessments of transplanted OCA tissues recovered from revision surgeries. Using a dedicated registry, OCA transplant recipients with documented treatment failures who met inclusion criteria (n = 33) as well as age-, body mass index-, and joint-matched patients with successful outcomes (n = 70) were analyzed to compare matched cohorts of patients with successful versus failed OCA transplantation outcomes. Tissues recovered from 18 failed OCA transplants and portions of 7 nonimplanted OCA controls were further analyzed to provide contributing evidence for potential immune response mechanisms. For patients analyzed, no statistically significant differences in proportions for treatment success versus failure based on mismatches for ABO type, Rh factor, or both were noted. Further, no statistically significant differences in proportions for histological immune response presence or absence based on mismatches for ABO type, Rh factor, or both were noted. Twelve (67%) of the failed OCA tissues contained lymphocyte aggregations in the subchondral bone, which were comprised of combinations of CD3 + , CD4 + , CD8 + , and CD20+ lymphocytes. The mechanisms of failure for these 12 OCA transplants involved insufficient OCA osteointegration. Results of this study suggest that T- and B-cell-mediated subrejection immune responses may play roles in OCA transplant treatment failures independent of donor-recipient blood type mismatch effects.

Motive and Opportunity: MYC rearrangements in high-grade B-cell lymphoma with MYC and BCL2 rearrangements-an LLMPP study.

Rearrangements that place the oncogenes MYC, BCL2, or BCL6 adjacent to superenhancers are common in mature B-cell lymphomas. Lymphomas with diffuse large B-cell lymphoma (DLBCL) or high-grade morphology with both MYC and BCL2 rearrangements are classified as high-grade B-cell lymphoma with MYC and BCL2 rearrangements ("double hit": HGBCL-DH-BCL2) and are associated with aggressive disease and poor outcomes. Although it is established that MYC rearrangements involving immunoglobulin (IG) loci are associated with inferior outcomes relative to those involving other non-IG superenhancers, the frequency of, and mechanisms driving, IG vs non-IG MYC rearrangements have not been elucidated. Here we used custom targeted capture and/or whole genome sequencing to characterize oncogene rearrangements across 883 mature B-cell lymphomas including Burkitt lymphoma, follicular lymphoma, DLBCL, and HGBCL-DH-BCL2 tumors. We demonstrate that, while BCL2 rearrangement topology is consistent across entities, HGBCL-DH-BCL2 have distinct MYC rearrangement architecture relative to tumors with single MYC rearrangements or with both MYC and BCL6 rearrangements (HGBCL-DH-BCL6), including both a higher frequency of non-IG rearrangements and different architecture of MYC::IGH rearrangements. The distinct MYC rearrangement patterns in HGBCL-DH-BCL2 occur on the background of high levels of somatic hypermutation across MYC partner loci in HGBCL-DH-BCL2, creating more opportunity to form these rearrangements. Furthermore, because one IGH allele is already disrupted by the existing BCL2 rearrangement, the MYC rearrangement architecture in HGBCL-DH-BCL2 likely reflects selective pressure to preserve both BCL2 and B cell receptor expression. These data provide new mechanistic explanations for the distinct patterns of MYC rearrangements observed across different lymphoma entities.

Comparison of reamer irrigator aspirator (RIA) suspension versus bone marrow aspirate concentrate (BMC) for percutaneous treatment of long bone nonunions-A preclinical canine model.

OBJECTIVE: To compare the bone healing effects of percutaneously delivered bone marrow aspirate concentrate (BMC) versus reamer irrigator aspirator (RIA) suspension in a validated preclinical canine ulnar nonunion model. We hypothesized that BMC would be superior to RIA in inducing bone formation across a nonunion site after percutaneous application. The null hypothesis was that BMC and RIA would be equivalent. METHODS: A bilateral ulnar nonunion model (n= 6; 3 matched pairs) was created. Eight weeks after segmental ulnar ostectomy, RIA from the ipsilateral femur and BMC from the proximal humerus were harvested and percutaneously administered into either the left or right ulnar defect. The same volume (3 ml) of RIA suspension and BMC were applied on each side. Eight weeks after treatment, the dogs were euthanized, and the nonunions were evaluated using radiographic, biomechanical, and histologic assessments. RESULTS: All dogs survived for the intended study duration, formed radiographic nonunions 8 weeks after segmental ulnar ostectomy, and underwent the assigned percutaneous treatment. Radiographic and macroscopic assessments of bone healing at the defect sites revealed superior bridging-callous formation in BMC-treated nonunions. Histologic analyses revealed greater amount of bony bridging and callous formation in the BMC group. Biomechanical testing of the treated nonunions did not reveal any significant differences. CONCLUSION: Bone marrow aspirate concentrate (BMC) had important advantages over Reamer Irrigator Aspirator (RIA) suspension for percutaneous augmentation of bone healing in a validated preclinical canine ulnar nonunion model based on clinically relevant radiographic and histologic measures of bone formation.

Clonal hematopoiesis-derived therapy-related myeloid neoplasms after autologous hematopoietic stem cell transplant for lymphoid and non-lymphoid disorders.

Therapy-related myeloid neoplasms (tMN) are complications of cytotoxic therapies. Risk of tMN is high in recipients of autologous hematopoietic stem cell transplantation (aHSCT). Acquisition of genomic mutations represents a key pathogenic driver but the origins, timing and dynamics, particularly in the context of preexisting or emergent clonal hematopoiesis (CH), have not been sufficiently clarified. We studied a cohort of 1507 patients undergoing aHSCT and a cohort of 263 patients who developed tMN without aHSCT to determine clinico-molecular features unique to post-aHSCT tMN. We show that tMN occurs in up to 2.3% of patients at median of 2.6 years post-AHSCT. Age ≥ 60 years, male sex, radiotherapy, high treatment burden ( ≥ 3 lines of chemotherapy), and graft cellularity increased the risk of tMN. Time to evolution and overall survival were shorter in post-aHSCT tMN vs. other tMN, and the earlier group's mutational pattern was enriched in PPM1D and TP53 lesions. Preexisting CH increased the risk of adverse outcomes including post-aHSCT tMN. Particularly, antecedent lesions affecting PPM1D and TP53 predicted tMN evolution post-transplant. Notably, CH-derived tMN had worse outcomes than non CH-derived tMN. As such, screening for CH before aHSCT may inform individual patients' prognostic outcomes and influence their prospective treatment plans. Presented in part as an oral abstract at the 2022 American Society of Hematology Annual Meeting, New Orleans, LA, 2022.

Patients with Classic Hodgkin Lymphoma and Follicular Lymphoma Compared to Single Malignancy Controls.

Classic Hodgkin lymphoma (CHL) can arise in patients with low-grade B-cell lymphoma. The features of CHL arising in follicular lymphoma (FL) and its outcome are still unclear, mainly due to the very few cases reported. This study compares 17 patients with CHL and FL to 2 control groups: 1 of 26 patients with FL and a second of 60 patients older than 40 when diagnosed with CHL. Of the FL and CHL patients, 8 had simultaneous FL and CHL, while 9 had FL first, followed by CHL 4.7 years later on average. The age at the diagnosis of FL was 61 years for patients with synchronous FL and CHL and of 60 years for FL, followed by CHL at 65 years. Patients with FL only were, on average, 59 years old at presentation, while CHL patients were 61. FL was grade 1-2 in 75% of FL and CHL patients and 67% of FL first and CHL second patients, lower proportions than in the FL control group-92%. Epstein-Barr virus (EBV) was detected in a lower fraction (29%) of the FL and CHL group than in CHL-only controls (46%). BCL2 translocations were detected in 4 of the 7 cases with FL, but in positive cases, the rearrangement was also present in the CHL component, indicating a clonal relationship between FL and CHL. Patients with FL and CHL treated for CHL had an initial outcome more similar to FL than to CHL controls.

Antinociceptive effects of α2/α3-subtype selective GABAA receptor positive allosteric modulators KRM-II-81 and NS16085 in rats: behavioral specificity.

Recent studies suggest that amongst the GABAA receptor subtype heterogeneity, α2/α3 subunits of GABAA receptors mediate pain processing. Therefore, α2/α3-subtype selective GABAA receptor positive allosteric modulators (PAMs) may be candidate analgesics. Antinociceptive effects of α2/α3-subtype selective GABAA receptor PAMs have been reported, but the behavioral effects of these compounds have not been systematically evaluated. This study examined the behavioral effects of two α2/α3 subtype-selective GABAA receptor PAMs, KRM-II-81 and NS16085, in male rats. The antinociceptive effects of KRM-II-81 and NS16085 were examined using rat models of inflammatory (complete Freund's adjuvant) and neuropathic pain (chronic constriction injury). The effect of KRM-II-81 on affective pain was measured using the place escape/avoidance paradigm (PEAP). Rate-response of food-maintained operant responding, horizontal wire test, and the spontaneous alternation T-maze, were assessed to study the side-effect profiles of KRM-II-81 and NS16085. The benzodiazepine midazolam was used as a comparator in these studies. KRM-II-81 and NS16085 attenuated mechanical allodynia but not thermal hyperalgesia in both pain states, and their effects were attenuated by the benzodiazepine receptor antagonist flumazenil. KRM-II-81 attenuated affective pain-related behavior in the PEAP test. In the operant responding procedure and horizontal wire test, only midazolam produced significant effects at the dose that produced maximal antinociception. In the T-maze assay, only midazolam significantly decreased the percentage of alternation at an antinociceptive dose. Thus, KRM-II-81 and NS16085 but not midazolam selectively produced antinociceptive effects. Collectively, these data suggest that α2/α3-subtype selective GABAA PAMs could be a novel class of analgesics and warrant further investigation. Significance Statement This study demonstrates that α2/α3-subtype selective GABAA PAMs KRM-II-81 and NS16085 produce selective antinociceptive effects devoid of sedation, myorelaxation, cognitive impairment in two rat models of persistent pain. Unlikely classical benzodiazepines, this study supports the development of α2/α3-subtype selective GABAA PAMs as safe and novel analgesics for pain management.

Respiratory problems associated with liver disease in children.

Respiratory manifestations of chronic liver disease have a profound impact on patient clinical outcomes. Certain conditions within paediatric liver disease have an associated respiratory pathology. This overlap between liver and respiratory manifestations can result in complex challenges when managing patients and requires clinicians to be able to recognise when referral to specialists is required. While liver transplantation is at the centre of treatment, it opens up further potential for respiratory complications. It is established that these complications place patients at risk of longer stays in hospital and reduced survival. Additionally, late post-transplant complications can occur, including post-transplant lymphoproliferative disease and immunosuppression-induced interstitial lung disease. Although rare, it is important for clinicians to recognise these conditions to allow for prompt management. Finally, as liver disease progresses in children, respiratory complications can occur. Hepatopulmonary syndrome can occur in the context of portal hypertension, resulting in increased mortality and poorer quality of life for patients. Another consequence is portopulmonary hypertension, which can be associated with poor survival. Failure to recognise these complications in children may result in poorer outcomes and therefore it is vital that clinicians can establish when referral to a paediatric respiratory medicine specialist is required.

An Open Resource: MR and light sheet microscopy stereotaxic atlas of the mouse brain.

We have combined MR histology and light sheet microscopy (LSM) of five postmortem C57BL/6J mouse brains in a stereotaxic space based on micro-CT yielding a multimodal 3D atlas with the highest spatial and contrast resolution yet reported. Brains were imaged in situ with multi gradient echo (mGRE) and diffusion tensor imaging (DTI) at 15 µm resolution (∼ 2.4 million times that of clinical MRI). Scalar images derived from the average DTI and mGRE provide unprecedented contrast in 14 complementary 3D volumes, each highlighting distinct histologic features. The same tissues scanned with LSM and registered into the stereotaxic space provide 17 different molecular cell type stains. The common coordinate framework labels (CCFv3) complete the multimodal atlas. The atlas has been used to correct distortions in the Allen Brain Atlas and harmonize it with Franklin Paxinos. It provides a unique resource for stereotaxic labeling of mouse brain images from many sources.

Comparison of Outcomes After Primary Versus Salvage Osteochondral Allograft Transplantation for Femoral Condyle Osteochondritis Dissecans Lesions.

Background: Osteochondral allograft transplantation (OCAT) allows the restoration of femoral condyle osteochondritis dissecans (OCD) lesions using an osteochondral unit. When OCD lesions are irreparable, or treatments have failed, OCAT is an appropriate approach for revision or salvage surgery. Based on its relative availability, cost-effectiveness, lack of donor site morbidity, and advances in preservation methods, OCAT is also an attractive option for primary surgical treatment for femoral condyle OCD. Hypothesis: OCAT for large femoral condyle OCD lesions would be highly successful (>90%) based on significant improvements in knee pain and function, with no significant differences between primary and salvage procedure outcomes. Study Design: Cohort study; Level of evidence, 3. Methods: Patients were enrolled into a registry for assessing outcomes after OCAT. Those patients who underwent OCAT for femoral condyle OCD and had a minimum of 2-year follow-up were included. Reoperations, treatment failures, and patient-reported outcomes were compared between primary and salvage OCAT cohorts. Results: A total of 22 consecutive patients were included for analysis, with none lost to the 2-year follow-up (mean, 40.3 months; range, 24-82 months). OCD lesions of the medial femoral condyle (n = 17), lateral femoral condyle (n = 4), or both condyles (n = 1) were analyzed. The mean patient age was 25.3 years (range, 12-50 years), and the mean body mass index was 25.2 kg/m2 (range, 17-42 kg/m2). No statistically significant differences were observed between the primary (n = 11) and salvage (n = 11) OCAT cohorts in patient and surgical characteristics. Also, 91% of patients had successful outcomes at a mean of >3 years after OCAT with 1 revision in the primary OCAT cohort and 1 conversion to total knee arthroplasty in the salvage OCAT cohort. For both primary and salvage OCATs, patient-reported measures of pain and function significantly improved at the 1-year and final follow-up, and >90% of patients reported that they were satisfied and would choose OCAT again for treatment. Conclusion: Based on the low treatment failure rates in conjunction with statistically significant and clinically meaningful improvements in patient-reported outcomes, OCAT can be considered an appropriate option for both primary and salvage surgical treatment in patients with irreparable OCD lesions of the femoral condyles.

Outcomes following open acetabular labrum reconstruction: Comparing fresh-frozen tendon with fresh meniscus allograft transplantation.

Background: Symptomatic acetabular labral insufficiency in young, active patients is often treated with labral repair or reconstruction using fresh-frozen allografts. However, fresh-frozen tendon allografts do not have tissue or material properties that closely mimic acetabular labral fibrocartilage. Recent studies suggest meniscal allografts may be a better biomechanical, geometric, and material alternative for acetabular labrum reconstruction (ALR). Hypothesis: Patients undergoing open ALR using fresh meniscus allograft transplants (MAT) will have better outcomes than those using fresh-frozen tendon allografts transplants (TAT) when comparing initial treatment success, diagnostic imaging assessments, and patient-reported pain and function scores. Study design: Cohort Study. Methods: With IRB approval, patients undergoing ALR with either TAT or MAT were included when initial (>1-year) outcomes data related to treatment success, pain, and function were available. In addition, a subcohort of patients underwent magnetic resonance imaging at least 6-months after surgery to evaluate allograft healing. Results: Initial success rate, defined as no need for ALR revision or conversion to total hip arthroplasty (THA), was 88.9% for the entire group (n = 27, TAT = 5, MAT = 22) with 1 (20%) patient in the TAT cohort and 2 patients (9.9%) in the MAT cohort undergoing THA. In the MAT cohort, significant improvements were documented for physical function and pain scores at 1 year and final follow-up (FFU)(mean 26.8 months). Improvements in pain and function were noted at 1-year, but not at FFU (mean 59.6 months) in the TAT group. MRIs completed at least 6 months after labrum reconstruction showed improved allograft integrity and integration in the MAT cohort over the TAT cohort. Conclusion: For acetabular labrum reconstructions, MAT was associated with a higher initial success rate, superior patient reported outcomes, and subjectively better MRI findings when compared to TAT.

Activated nitinol compression staples are associated with favorable biomechanical properties for talonavicular arthrodesis.

Background: Nitinol compression staple use in foot and ankle arthrodesis procedures, including for the talonavicular joint, has gained acceptance. A previous study provided evidence for using nitinol compression staples in talonavicular arthrodesis (TNA) based on functional biomechanical testing comparisons to "gold standard" lag screw fixation. This study aimed to further compare the functional biomechanical properties of nitinol compression staple fixation to lag screw fixation for arthrodesis of the talonavicular joint. Body-temperature incubation and ankle inversion and eversion loading sequences were added to previously reported biomechanical testing. Methods: Robotic testing was performed on cadaveric feet (n = 10; 5 matched pairs) after TNA using either two nitinol compression staples or two fully threaded lag screws. TNA method was randomized, alternating between matched-pairs of left and right feet. After surgical stabilization, specimens were incubated at 38 °C for 24 h to simulate the initial postoperative period in a patient. After plantarflexion and dorsiflexion testing, the specimens underwent inversion and eversion testing, cycling from 20° inversion to 10° eversion for 10 cycles. Displacements were tracked using optical tracking markers. Significant (p < 0.05) differences between staple versus screw fixation cohorts were determined using paired t-Tests. Results: All specimens completed testing with none experiencing failure at the TNF. No statistically significant differences in functional biomechanical testing properties were noted between nitinol compression staple fixation and lag screw fixation for TNA. Conclusion: The study findings provide additional support for nitinol compression staple fixation as an option for talonavicular arthrodesis fixation. Taken together, the results of functional biomechanical testing studies have provided sufficient evidence for initiation of a prospective clinical outcomes study using nitinol compression staples for talonavicular arthrodesis fixation at our institution.

Development of a point-of-care colorimetric metabolomic sensor platform.

Metabolomics is the large-scale study of small molecule metabolites within a biological system. It has applications in measuring dietary intake, predicting heart disease risk, and diagnosing cancer. Metabolites are often measured using high-end analytical tools such as mass spectrometers or large spectrophotometers. However, due to their size, cost, and need for skilled operators, using such equipment at the bedside is not practical. To address this issue, we have developed a low-cost, portable, optical color sensor platform for metabolite detection. This platform includes LEDs, sensors, microcontrollers, a power source, and a Bluetooth chip enclosed within a 3D-printed light-tight case. We evaluated the color sensor's performance using both a range of dyed water samples as well as well-established colorimetric reactions for specific metabolite detection. The sensor accurately measured creatinine, L-carnitine, ascorbate, and succinate well within normal human urine levels with accuracy and sensitivity equal to or better than a standard laboratory spectrophotometer. Our color sensor offers a cost-effective, portable alternative for measuring metabolites via colorimetric assays, thereby enabling low-cost, point-of-care metabolite testing.

Genetic drivers of heterogeneity in type 2 diabetes pathophysiology.

Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes1,2 and molecular mechanisms that are often specific to cell type3,4. Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance (P < 5 × 10-8) that map to 611 loci, of which 145 loci are, to our knowledge, previously unreported. We define eight non-overlapping clusters of T2D signals that are characterized by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type-specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial cells and enteroendocrine cells. We build cluster-specific partitioned polygenic scores5 in a further 279,552 individuals of diverse ancestry, including 30,288 cases of T2D, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned polygenic scores are associated with coronary artery disease, peripheral artery disease and end-stage diabetic nephropathy across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings show the value of integrating multi-ancestry genome-wide association study data with single-cell epigenomics to disentangle the aetiological heterogeneity that drives the development and progression of T2D. This might offer a route to optimize global access to genetically informed diabetes care.