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.

Initial Outcomes following Fresh Meniscus Allograft Transplantation in the Knee.

Based on recent evidence-based advances in meniscus allograft transplantation (MAT), fresh (viable) meniscus allografts have a potential for mitigating key risk factors associated with MAT failure, and preclinical and clinical data have verified the safety of fresh meniscus allografts as well as possible efficacy advantages compared to fresh-frozen meniscus allografts. The objective of this study was to prospectively assess clinical outcomes for the initial cohort of patients undergoing MAT using fresh meniscus allografts at our center. Patients who were prospectively enrolled in a dedicated registry were included for analyses when they had undergone primary MAT using a fresh meniscus allograft for treatment of medial and/or lateral meniscus deficiency with at least 1-year follow-up data recorded. Forty-five patients with a mean final follow-up of 47.8 months (range = 12-90) were analyzed. Mean patient age was 30.7 years (range = 15-60), mean BMI was 29.7 kg/m2 (range = 19-48), and 14 patients (31%) were female. In total, 28 medial, 13 lateral, and 4 combined medial and lateral MATs with 23 concurrent ligament reconstructions and 2 concurrent osteotomies were included. No local or systemic adverse events or complications related to MAT were reported for any patient in the study. Treatment success rate for all patients combined was 91.1% with 3 patients requiring MAT revision and 1 patient requiring arthroplasty. Treatment failures occurred 8 to 34 months after MAT and all involved the medial meniscus. None of the variables assessed were significantly different between treatment success versus treatment failure cohorts. Taken together, the data suggest that the use of fresh (viable) meniscus allografts can be considered a safe and effective option for medial and lateral meniscus allograft transplantation. When transplanted using double bone plug suspensory fixation with meniscotibial ligament reconstruction, fresh MATs were associated with a 91% success rate, absence of local or systemic adverse events or complications, and statistically significant and clinically meaningful improvements in patient-reported measures of pain and function at a mean of 4 years postoperatively.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.