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.

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

ABSTRACT: 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, although 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 1 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.

Development of non-sedating benzodiazepines with in vivo antischistosomal activity.

The neglected tropical disease schistosomiasis infects over 200 million people worldwide and is treated with just one broad-spectrum antiparasitic drug (praziquantel). Alternative drugs are needed in the event of emerging praziquantel resistance or treatment failure. One promising lead that has shown efficacy in animal models and a human clinical trial is the benzodiazepine meclonazepam, discovered by Roche in the 1970s. Meclonazepam was not brought to market because of dose-limiting sedative side effects. However, the human target of meclonazepam that causes sedation (GABAARs) is not orthologous to the parasite targets that cause worm death. Therefore, we were interested in whether the structure of meclonazepam could be modified to produce antiparasitic benzodiazepines that do not cause host sedation. We synthesized 18 meclonazepam derivatives with modifications at different positions on the benzodiazepine ring system and tested them for in vitro antiparasitic activity. This identified five compounds that progressed to in vivo screening in a murine model, two of which cured parasite infections with comparable potency to meclonazepam. When these two compounds were administered to mice that were run on the rotarod test, both were less sedating than meclonazepam. These findings demonstrate the proof of concept that meclonazepam analogs can be designed with an improved therapeutic index and point to the C3 position of the benzodiazepine ring system as a logical site for further structure-activity exploration to further optimize this chemical series.

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.

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.

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.

Addressing social determinants of health in orthopaedics: A systematic review of strategies and solutions.

BACKGROUND: Barriers stemming from Social Determinants of Health (SDOH) are known to contribute to higher rates of complications, poor patient adherence to treatment plans, and suboptimal outcomes following orthopaedic care. While SDOH's impact has been characterized, interventions to address SDOH-related inequities in orthopaedics have not yet been optimized. PURPOSE: The objective of the present systematic review was to identify and synthesize current peer-reviewed literature focused interventions to address SDOH-related inequities to develop optimal mitigation strategies that improve outcomes for orthopaedic patients. METHODS: A systematic search of PubMed, OVID, and CINAHL identified articles that referenced SDOH and an intervention to address inequities. RESULTS: After screening 419 studies, 19 met inclusion criteria. Studies commonly looked at the impact of insurance policy change on the rate of the population with active insurance and associated use of elective surgery. Nine studies found that policy changes generally increased the rate of insured patients, though inequities remained for younger and racial minority patients. The relative paucity of literature in conjunction with methodological differences among studies highlights the need for further development and validation of effective interventions to address SDOH-related inequities in orthopaedics. CONCLUSIONS: Insurance expansion was the focus of the majority of included articles, finding that expansion is associated with higher rates of insured patients undergoing elective and emergent procedures, however, gaps remain for young patients and racial minorities. Further research is needed to determine effective healthcare team, healthcare system, and policy-level interventions that overcome SDOH-related barriers to optimal care and outcomes for orthopaedic patients. LEVEL OF EVIDENCE: Level-II.

Mesenchymal stem cells in orthopaedics: A systematic review of applications to practice.

Background: Mesenchymal stem cells (MSCs) have alluring interest for clinical use in orthopaedics based on their therapeutic potential through directed pluripotent differentiation. While many studies and reviews have discussed the importance of this approach, few have reduced it to practice using reproducible criteria. This study was designed to systematically review and synthesize current evidence regarding clinical use of clearly defined MSCs in orthopaedics. Methods: Studies of any level of evidence and sample size, regardless of MSC source, orthopaedic pathology, and patient population, were reviewed. In vitro and animal studies, and articles written in a language other than English, were excluded. Studies were then screened for final inclusion based on documented MSC verification using testing of the therapeutic cellular population for at least one of the following phenotypic markers: CD 73, CD 90, and CD 105. In addition, therapeutic cellular populations could not have higher percentages of CD34, CD45, CD14, HLA-DR, CD11b, or CD19 markers compared to the aforementioned markers. From each studies' results, sample size, procedural methods, radiographic outcomes, clinical outcomes, patient-report outcomes (PROs), and adverse events were tabulated. Results: Overall, 43 studies were included. Twenty-three studies (53.5 %) derived their MSCs from iliac crest bone marrow while 12 (27.9 %) studied adipose-derived MSCs. Included studies explored MSC use in Osteoarthritis, Cartilage Defects, Osteonecrosis, Bone Defects and Nonunions, Spine, and Other. MSC use in all pathologies led to improvement of studied radiographic, clinical, and patient-reported outcomes. Conclusions: Mesenchymal stem cells have proven to have successful and safe uses in multiple orthopaedic applications, including treating chondral defects, osteoarthritis, and osteonecrosis. A stringent and reproducible process for evaluating obtained human stem cells using CD markers for clinical use is necessary to both evaluate previous studies and continue to evaluate for future uses. Level of evidence: Level V.

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.

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.

Accelerated versus Standard Rehabilitation after Meniscus Allograft Transplantation in the Knee.

Meniscus allograft transplantation (MAT) is a proven treatment option for patients with symptomatic irreparable meniscus deficiency. When patients are adherent to prescribed postoperative restriction and rehabilitation protocols, outcomes after MAT are considered good to excellent. However, nonadherence to standard protocols is common and can be associated with undesirable outcomes and patient dissatisfaction. Based on demonstrated safety for early weight-bearing following MAT in conjunction with significant advances in graft preservation and surgical techniques, our joint preservation center implemented a shift in practice toward accelerated weight-bearing following MAT and designed this study to test the hypothesis that accelerated rehabilitation would be associated with superior adherence, patient-reported outcomes, and patient satisfaction, without diminishing patient safety, when compared with standard rehabilitation. Patients were included for analyses when they had undergone fresh or fresh-frozen MAT using a double bone plug technique for treatment of medial or lateral meniscus deficiency and had at least 1-year treatment outcomes recorded. The results of this study revealed that patients who were prescribed accelerated rehabilitation after MAT were significantly more adherent than patients who were prescribed standard rehabilitation and reported statistically significant and clinically meaningful improvements in knee pain and function for at least 1-year following MAT, whereas those in the standard cohort did not. While not statistically different, treatment failure rate was lower in the accelerated rehabilitation cohort when compared with the standard rehabilitation cohort (11 vs. 29%). Importantly, initial outcomes for revision MAT were associated with short-term success in all the patients who opted for this option in the study population. These data suggest that accelerated weight-bearing after MAT is safe, promotes patient adherence, and is associated with statistically significant and clinically meaningful improvements in patient-reported knee pain and function at early and mid-term follow-up.

Functional trait mismatch between native and introduced bee pollinators servicing a global fruit crop.

BACKGROUND: Understanding connections between biodiversity and ecosystem services can be enhanced by shifting focus from species richness to functional trait-based approaches, that when paired with comparative phylogenetic methods can provide even deeper insights. We investigated the functional ecology and phylogenetic diversity of pollination services provided by hymenopteran insects visiting apple flowers in orchards surrounded by either 'natural' or 'disturbed' landscapes in New South Wales, Australia. We assessed whether morphological and behavioural traits (hairiness, body size, glossa length, pollen load purity, and probability of loose pollen) exhibited non-random phylogenetic patterns. Then, explored whether bees, the primary pollinators in this system, filled unique or overlapping functional entities (FEs). For each landscape, we calculated phylogenetic diversity and used FEs to assess functional richness, evenness, and diversion. RESULTS: A phylogenomic matrix based on ultraconserved elements (UCEs; 1,382,620 bp from 1,969 loci) was used to infer a fully-resolved and well-supported maximum likelihood phylogeny for 48 hymenopteran morphospecies. There was no significant difference in species richness between landscape categories. Pollinator communities at natural sites had higher phylogenetic complexity (X = 2.37) and functional divergence (x̄ = 0.74 ± 0.02 s.e.) than disturbed sites (X = 1.65 and x̄ = 0.6 ± 0.01 s.e.). Hairiness showed significant phylogenetic clustering (K = 0.94), whereas body size, glossa length, and loose pollen showed weaker non-random phylogenetic patterns (K between 0.3-0.5). Pollen load purity showed no association with phylogeny. The assemblage of 17 bee morphospecies comprised nine FEs: eight FEs consisted of native bees with three containing 65% of all native bee taxa. The introduced honey bee (Apis mellifera) occupied a unique FE, likely due to its different evolutionary history. Both landscape types supported six FEs each with three overlapping: two native bee FEs and the honey bee FE. CONCLUSIONS: Bee hairiness was the only functional trait to exhibit demonstrable phylogenetic signal. Despite differences in species richness, and functional and phylogenetic diversity between orchard landscape types, both maintained equal bee FE numbers. While no native bee taxon was analogous to the honey bee FE, four native bee FEs shared the same hairiness level as honey bees. Health threats to honey bee populations in Australia will likely disrupt pollination services to apple, and other pollination-dependent food crops, given the low level of functional redundancy within the investigated pollinator assemblages.

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.

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.

Treatment failures (revision or arthroplasty) after knee osteochondral allograft transplantation with minimum two-year follow-up.

BACKGROUND: Knee osteochondral allograft transplantation (OCAT) has been associated with good short- to mid-term outcomes, however, treatment failures occur more frequently than desired. This study used data from a lifelong outcomes registry to analyze knee OCAT treatment failure rates, variables associated with knee OCAT treatment failures, and outcomes after revision or arthroplasty surgery for knee OCAT treatment failures. METHODS: Patient outcomes were followed after knee OCAT performed using standard preservation (SP) or Missouri Osteochondral Preservation System (MOPS®) allografts. The study population consisted of patients undergoing primary OCAT with ≥ 2-year follow-up. For comparisons, the treatment failure population was defined by patients in the study population with documented treatment failure (revision or arthroplasty) with ≥ 2-year follow-up after failure. Functional graft survival was defined as no further need for revision surgery after primary or revision OCAT. RESULTS: A total of 262 patients (n = 136 males; 51.9%) were analyzed. SP grafts were used for 59 cases and MOPS grafts were used for 203 cases. Treatment failure was documented in 61 cases (23.3%). MOPS grafts were 3.3 times more likely to be associated with functional graft survival. SP grafts, older patient age, higher BMI, tibiofemoral bipolar OCAT and non-adherence to the postoperative rehabilitation protocol were significantly associated with treatment failure. CONCLUSIONS: Knee OCAT resulted in functional graft survival at short- to mid-term follow-up in the majority (70-88%) of cases. In addition, revision of primary OCAT resulted in functional graft survival for at least 2 years after revision surgery in the majority (66%) of patients. LEVEL OF EVIDENCE: 2, prospective cohort study.

Physical exercise to promote regeneration after peripheral nerve injury in animal models: A systematic review.

Peripheral nerve injuries are common injuries that often have a drastic effect on patient's activities of daily living and physical function. While techniques for the surgical repair of these injuries have improved over time, rehabilitation methods following these repairs have been non-standardized and under researched. Electronic searches were conducted in Ovid/Medline and SCOPUS to identify articles that discuss rehabilitation and exercise following peripheral nerve injury in animal models and its effects on peripheral nerve regeneration and recovery of function. Thirty-eight articles met inclusion criteria; all were prospective studies in animal models. This systematic review suggests that exercise is a useful tool in returning autonomy to the individual and has beneficial effects in the recovery from peripheral nerve injury. It is beneficial to use rehabilitation exercises following the repair of peripheral nerve injuries to promote regeneration, and timing of that exercise may be just as important as the exercise prescribed. However, further studies with standardized models and outcome measures need to be conducted before translation to clinical trials.

Beta-mannosidosis in a domestic cat associated with a missense variant in MANBA.

A 6-month-old cat of unknown ancestry presented for a neurologic evaluation due to progressive motor impairment. Complete physical and neurologic examinations suggested the disorder was likely to be hereditary, although the signs were not consistent with any previously described inherited disorders in cats. Due to the progression of disease signs including severely impaired motor function and cognitive decline, the cat was euthanized at approximately 10.5 months of age. Whole genome sequence analysis identified a homozygous missense variant c.2506G > A in MANBA that predicts a p.Gly836Arg alteration in the encoded lysosomal enzyme ß -mannosidase. This variant was not present in the whole genome or whole exome sequences of any of the 424 cats represented in the 99 Lives Cat Genome dataset. ß -Mannosidase enzyme activity was undetectable in brain tissue homogenates from the affected cat, whereas α-mannosidase enzyme activities were elevated compared to an unaffected cat. Postmortem examination of brain and retinal tissues revealed massive accumulations of vacuolar inclusions in most cells, similar to those reported in animals of other species with hereditary ß -mannosidosis. Based on these findings, the cat likely suffered from ß -mannosidosis due to the abolition of ß -mannosidase activity associated with the p.Gly836Arg amino acid substitution. p.Gly836 is located in the C-terminal region of the protein and was not previously known to be involved in modulating enzyme activity. In addition to the vacuolar inclusions, some cells in the brain of the affected cat contained inclusions that exhibited lipofuscin-like autofluorescence. Electron microscopic examinations suggested these inclusions formed via an autophagy-like process.

Extrasynaptic localization is essential for α5GABAA receptor modulation of dopamine system function.

Dopamine system dysfunction, observed in animal models with psychosis-like symptomatology, can be restored by targeting Gamma-Aminobutyric Acid type A receptors (GABAAR) containing the α5, but not α1, subunit in the ventral hippocampus (vHipp). The reason for this discrepancy in efficacy remains elusive; however, one key difference is that α1GABAARs are primarily located in the synapse, whereas α5GABAARs are mostly extrasynaptic. To test whether receptor location is responsible for this difference in efficacy, we injected a small interfering ribonucleic acid (siRNA) into the vHipp to knock down radixin, a scaffolding protein that holds α5GABAARs in the extrasynaptic space. We then administered GL-II-73, a positive allosteric modulator of α5GABAARs (α5-PAM) known to reverse shock-induced deficits in dopamine system function, to determine if shifting α5GABAARs from the extrasynaptic space to the synapse would prevent the effects of α5-PAM on dopamine system function. As expected, knockdown of radixin significantly decreased radixin-associated α5GABAARs and increased the proportion of synaptic α5GABAARs, without changing the overall expression of α5GABAARs. Importantly, GL-II-73 was no longer able to modulate dopamine neuron activity in radixin-knockdown rats, indicating that the extrasynaptic localization of α5GABAARs is critical for hippocampal modulation of the dopamine system. These results may have important implications for clinical use of GL-II-73, as periods of high hippocampal activity appear to favor synaptic α5GABAARs, thus efficacy may be diminished in conditions where aberrant hippocampal activity is present.Significance Statement Currently available treatments for psychosis, a debilitating symptom linked with several brain disorders, are inadequate. While they can help manage symptoms in some patients, they do so imperfectly. They are also associated with severe side effects that can cause discontinuation of medication. This study provides preclinical evidence that the drug, GL-II-73, possesses the ability to modulate dopamine activity, a key player in psychosis symptoms, and further provides some mechanistic details regarding these effects. Overall, this work contributes to the growing body of literature suggesting that GL-II-73 and similar compounds may possess antipsychotic efficacy.

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.

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.