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.

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.

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.

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.

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.

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.

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 non-sedating antischistosomal benzodiazepines.

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 1970's. Meclonazepam was not brought to market because of dose-limiting sedative side effects. However, the human target of meclonazepam that causes sedation (GABAARs) are 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.

Association of Residency Applicants' Hobbies and Subsequent Technical Proficiency Ratings as General Surgery Chief Residents: A Multi-Institutional Study.

OBJECTIVE: To determine whether participation in certain hobbies (e.g., participation in sports, playing musical instruments, or other hobbies requiring fine motor skills), preresidency, are associated with higher technical skills ratings at the time of residency graduation. DESIGN: Faculty members from 14 general surgery residency programs scored individual graduates from 2017 to 2020 on their technical skills using a 5-point Likert scale. Hobbies for these residents were collected from their Electronic Residency Application Service (ERAS) data. A single reviewer classified each ERAS hobby into predefined categories including musical instruments, sports requiring hand-eye coordination, team sports, and activities necessitating hand-eye coordination. Spearman correlation coefficients were calculated for the relationship between each category of hobby-as well as the total number of hobbies in each category-and the outcome of surgical faculty ratings of residents' technical surgical skills during their last year of residency. A proportional odds model including the above predictive variables was also fit to the data. SETTING: Fourteen general surgery residency programs. PARTICIPANTS: General surgery residency graduates from 14 different programs from 2017 to 2020. RESULTS: There were 296 residents across 14 institutions. The average ranking of residents' technical skills was 3.24 (SD 1.1). A total of 40% of residents played sports involving hand-eye coordination, 31% played team sports, 28% participated in nonsport hobbies that require eye-hand coordination, and 20% played musical instruments. Correlation coefficients were not statistically significant for any of the categories. In the proportional odds model, none of the variables were associated with statistically significant increased odds of a higher technical skills rating. CONCLUSIONS: There was no correlation between general surgery chief residents' technical skills as rated by faculty, and self-reported pre-residency hobbies on the ERAS application. These findings suggest such hobbies prior to residency are unlikely to predict future technical skills prowess.

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.

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.

New Imidazodiazepine Analogue, 5-(8-Bromo-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,5-a][1,4]diazepin-3-yl)oxazole, Provides a Simplified Synthetic Scheme, High Oral Plasma and Brain Exposures, and Produces Antiseizure Efficacy in Mice, and Antiepileptogenic Activity in Neural Networks in Brain Slices from a Patient with Mesial Temporal Lobe Epilepsy.

KRM-II-81 (1) is an imidazodiazepine GABAA receptor (GABAAR) potentiator with broad antiseizure efficacy and a low sedative burden. A brominated analogue, DS-II-73 (5), was synthesized and pharmacologically characterized as a potential backup compound as KRM-II-81 moves forward into development. The synthesis from 2-amino-5-bromophenyl)(pyridin-2yl)methanone (6) was processed in five steps with an overall yield of 38% and without the need for a palladium catalyst. GABAAR binding occurred with a Ki of 150 nM, and only 3 of 41 screened binding sites produced inhibition ≥50% at 10 µM, and the potency to induce cytotoxicity was ≥240 mM. DS-II-73 was selective for α2/3/5- over that of α1-containing GABAARs. Oral exposure of plasma and brain of rats was more than sufficient to functionally impact GABAARs. Tonic convulsions in mice and lethality induced by pentylenetetrazol were suppressed by DS-II-73 after oral administration and latencies to clonic and tonic seizures were prolonged. Cortical slice preparations from a patient with pharmacoresistant epilepsy (mesial temporal lobe) showed decreases in the frequency of local field potentials by DS-II-73. As with KRM-II-81, the motor-impairing effects of DS-II-73 were low compared to diazepam. Molecular docking studies of DS-II-73 with the α1ß3γ2L-configured GABAAR showed low interaction with α1His102 that is suggested as a potential molecular mechanism for its low sedative side effects. These findings support the viability of DS-II-73 as a backup molecule for its ethynyl analogue, KRM-II-81, with the human tissue data providing translational credibility.

KRM-II-81 suppresses epileptifom activity across the neural network of cortical tissue from a patient with pharmacoresistant epilepsy.

A clinical case of a 19-year-old male patient with pharmacoresistant seizures occurring following parieto-occipital tumor-resection at age 6 is described. Seizure surgery work-up included prolonged video EEG monitoring and head CT without contrast. Seizure focus was localized to the left temporal lobe, and we felt that the patient was an excellent candidate for seizure surgery. The patient underwent a left frontotemporal craniotomy for removal of the seizure focus with intraoperative electrocorticography (ECoG) conducted pre and post resection. ECoG recordings pre- and post-resection confirmed resolution of seizure generation. Imaging obtained immediately postoperatively showed complete resection of the residual tumor with no evidence of recurrence in follow-ups. A year after the surgery the patient is seizure-free but remains on seizure medication. With the patient's consent the excised epileptogenic tissue was used for ex-vivo research studies. The microelectrode recordings confirmed epileptiform activity in the excised tissue incubated in excitatory artificial cerebrospinal fluid. The epileptiform activity in the epileptogenic tissue was suppressed by addition of KRM-II-81, a novel α2/3 subtype preferring GABAA receptor (GABAAR) potentiator with previously demonstrated antiepileptic efficacy in multiple animal models of epilepsy and with reduced potential for CNS side-effects compared to classical benzodiazepine GABAAR potentiators. These findings support the proposition that KRM-II-81 might reduce seizure burden in pharmacoresistant patients.

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.

Characterizing Osteochondral Allograft Biomechanics for Optimizing Transplant Success: A Systematic Review.

Osteochondral allograft (OCA) transplantation has been largely successful in treating symptomatic articular cartilage lesions; however, treatment failures persist. While OCA biomechanics have been consistently cited as mechanisms of treatment failure, the relationships among mechanical and biological variables that contribute to success after OCA transplantation have yet to be fully characterized. The purpose of this systematic review was to synthesize the clinically relevant peer-reviewed evidence targeting the biomechanics of OCAs and the impact on graft integration and functional survival toward developing and implementing strategies for improving patient outcomes. The Cochrane Central Register of Controlled Trials, the Cochrane Database of Systematic Reviews, MEDLINE, PubMed, Cumulative Index to Nursing and Allied Health (CINAHL), Google Scholar, and EMBASE were searched to identify articles for systematic review. This review of relevant peer-reviewed literature provided evidence that the biomechanics related to OCA transplantation in the knee have direct and indirect effects on functional graft survival and patient outcomes. The evidence suggests that biomechanical variables can be optimized further to enhance benefits and mitigate detrimental effects. Each of these modifiable variables should be considered regarding indications, patient selection criteria, graft preservation methodology, graft preparation, transplantation, fixation techniques, and prescribed postoperative restriction and rehabilitation protocols. Criteria, methods, techniques, and protocols should target OCA quality (chondrocyte viability, extracellular matrix integrity, material properties), favorable patient and joint characteristics, rigid fixation with protected loading, and innovative ways to foster rapid and complete OCA cartilage and bone integration to optimize outcomes for OCA transplant patients.

Vascular effects of midazolam, flumazenil, and a novel imidazobenzodiazepine MP-III-058 on isolated rat aorta.

Hypotensive influences of benzodiazepines and other GABAA receptor ligands, recognized in clinical practice, seem to stem from the existence of "vascular" GABAA receptors in peripheral blood vessels, besides any mechanisms in the central and peripheral nervous systems. We aimed to further elucidate the vasodilatatory effects of ligands acting through GABAA receptors. Using immunohistochemistry, the rat aortic smooth muscle layer was found to express GABAA γ2 and α1-5 subunit proteins. To confirm the role of "vascular" GABAA receptors, we investigated the vascular effects of standard benzodiazepines, midazolam, and flumazenil, as well as the novel compound MP-III-058. Using two-electrode voltage clamp electrophysiology and radioligand binding assays, MP-III-058 was found to have modest binding but substantial functional selectivity for α5ß3γ2 over other αxß3γ2 GABAA receptors. Tissue bath assays revealed comparable vasodilatory effects of MP-III-058 and midazolam, both of which at 100 µmol/L concentrations had efficacy similar to prazosin. Flumazenil exhibited weak vasoactivity per se, but significantly prevented the relaxant effects of midazolam and MP-III-058. These studies indicate the existence of functional GABAA receptors in the rat aorta, where ligands exert vasodilatory effects by positive modulation of the benzodiazepine binding site, suggesting the potential for further quest for leads with optimized pharmacokinetic properties as prospective adjuvant vasodilators.

Short-Term Outcomes After Bipolar Osteochondral Allograft Transplantation (OCAT) in the Ankle.

Treatment options for symptomatic cartilage loss in the ankle are not consistently effective. This study documents initial outcomes for patients undergoing bipolar OCAT in the ankle after advances in tissue preservation, transplantation techniques, and patient management strategies were implemented. Patients were prospectively enrolled into a registry designed to follow outcomes after OCAT in the ankle. Fourteen patients were included for analyses (12 primary OCAT, 2 revision OCAT). Four patients underwent Bipolar OCAT (tibia, talus) and 10 Bipolar+ OCAT (tibia, talus, fibula). Short-term (median follow-up 43, range 13-73 months) success was documented for 13 patients. Radiographic assessments indicated OCA integration and maintenance of joint space in 12 patients. Statistically significant (p < .030) and clinically meaningful improvements in AAOS and VAS pain scores were noted at 3 months, 6 months, 1 year, and 2 years following OCA transplantation when compared to preoperative measures. For patients that were nonadherent to postoperative restriction and rehabilitation protocols, all 1-year postoperative PROs were significantly lower (p < .050) than for patients who were adherent. The successful outcomes documented in 13 of 14 patients in conjunction with significant and clinically meaningful improvements in patient-reported measures of pain and function support OCA transplantation as an appropriate treatment option in indicated patients. These improvements in outcomes were associated with advances in OCA preservation, preimplantation treatment, transplantation techniques, and patient management strategies, suggesting this shift in practice be considered for OCA transplantation in the ankle.

Transmission mode predicts coinfection patterns of insect-specific viruses in field populations of the Queensland fruit fly.

Insect-specific viruses (ISVs) can affect insect health and fitness, but can also interact with other insect-associated microorganisms. Despite this, ISVs are often studied in isolation from each other, in laboratory populations. Consequently, their diversity, prevalence and associations with other viruses in field populations are less known, yet these parameters are important to understanding virus epidemiology. To help address this knowledge gap, we assessed the diversity, prevalence and coinfections of three ISVs (horizontally transmitted cripavirus, biparentally transmitted sigmavirus and maternally transmitted iflavirus) in 29 field populations of Queensland fruit fly, Australia's most significant horticultural pest, in the context of their different transmission modes. We detected new virus variant diversity. In contrast to the very high virus prevalence in laboratory populations, 46.8% of 293 field flies carried one virus and 4.8% had two viruses. Cripavirus and sigmavirus occurred in all regions, while iflavirus was restricted to subtropical and tropical regions. Cripavirus was most prevalent (37.5%), followed by sigmavirus (13.7%) and iflavirus (4.4%). Cripavirus coinfected some flies with either one of the two vertically transmitted viruses. However, sigmavirus did not coinfect individuals with iflavirus. Three different modelling approaches detected negative association patterns between sigmavirus and iflavirus, consistent with the absence of such coinfections in laboratory populations. This may be linked with their maternal transmission and the ineffective paternal transmission of sigmavirus. Furthermore, we found that, unlike sigmavirus and iflavirus, cripavirus load was higher in laboratory than field flies. Laboratory and mass-rearing conditions may increase ISV prevalence and load due to increased transmission opportunities. We conclude that a combination of field and laboratory studies is needed to uncover ISV interactions and further our understanding of ISV epidemiology.