Exploiting a key transcriptional dependency: ZMYND8 and IRF8 in AML.

In this issue of Molecular Cell, Cao et al. (2021) report that AML cells are specifically addicted to an IRF8-MEF2D gene expression network. Furthermore, they identify a chromatin reader, ZMYND8, as the upstream regulator of the IRF8-MEF2D program whose activity is critical for AML cell survival.

Developmental and biophysical determinants of grass leaf size worldwide.

One of the most notable ecological trends-described more than 2,300  years ago by Theophrastus-is the association of small leaves with dry and cold climates, which has recently been recognized for eudicotyledonous plants at a global scale1-3. For eudicotyledons, this pattern has been attributed to the fact that small leaves have a thinner boundary layer that helps to avoid extreme leaf temperatures4 and their leaf development results in vein traits that improve water transport under cold or dry climates5,6. However, the global distribution of leaf size and its adaptive basis have not been tested in the grasses, which represent a diverse lineage that is distinct in leaf morphology and that contributes 33% of terrestrial primary productivity (including the bulk of crop production)7. Here we demonstrate that grasses have shorter and narrower leaves under colder and drier climates worldwide. We show that small grass leaves have thermal advantages and vein development that contrast with those of eudicotyledons, but that also explain the abundance of small leaves in cold and dry climates. The worldwide distribution of leaf size in grasses exemplifies how biophysical and developmental processes result in convergence across major lineages in adaptation to climate globally, and highlights the importance of leaf size and venation architecture for grass performance in past, present and future ecosystems.

Dietary fructose improves intestinal cell survival and nutrient absorption.

Fructose consumption is linked to the rising incidence of obesity and cancer, which are two of the leading causes of morbidity and mortality globally1,2. Dietary fructose metabolism begins at the epithelium of the small intestine, where fructose is transported by glucose transporter type 5 (GLUT5; encoded by SLC2A5) and phosphorylated by ketohexokinase to form fructose 1-phosphate, which accumulates to high levels in the cell3,4. Although this pathway has been implicated in obesity and tumour promotion, the exact mechanism that drives these pathologies in the intestine remains unclear. Here we show that dietary fructose improves the survival of intestinal cells and increases intestinal villus length in several mouse models. The increase in villus length expands the surface area of the gut and increases nutrient absorption and adiposity in mice that are fed a high-fat diet. In hypoxic intestinal cells, fructose 1-phosphate inhibits the M2 isoform of pyruvate kinase to promote cell survival5-7. Genetic ablation of ketohexokinase or stimulation of pyruvate kinase prevents villus elongation and abolishes the nutrient absorption and tumour growth that are induced by feeding mice with high-fructose corn syrup. The ability of fructose to promote cell survival through an allosteric metabolite thus provides additional insights into the excess adiposity generated by a Western diet, and a compelling explanation for the promotion of tumour growth by high-fructose corn syrup.

Kinetic modeling identifies targets for engineering improved photosynthetic efficiency in potato (Solanum tuberosum cv. Solara).

Potato (Solanum tuberosum) is a significant non-grain food crop in terms of global production. However, its yield potential might be raised by identifying means to release bottlenecks within photosynthetic metabolism, from the capture of solar energy to the synthesis of carbohydrates. Recently, engineered increases in photosynthetic rates in other crops have been directly related to increased yield - how might such increases be achieved in potato? To answer this question, we derived the photosynthetic parameters Vcmax and Jmax to calibrate a kinetic model of leaf metabolism (e-Photosynthesis) for potato. This model was then used to simulate the impact of manipulating the expression of genes and their protein products on carbon assimilation rates in silico through optimizing resource investment among 23 photosynthetic enzymes, predicting increases in photosynthetic CO2 uptake of up to 67%. However, this number of manipulations would not be practical with current technologies. Given a limited practical number of manipulations, the optimization indicated that an increase in amounts of three enzymes - Rubisco, FBP aldolase, and SBPase - would increase net assimilation. Increasing these alone to the levels predicted necessary for optimization increased photosynthetic rate by 28% in potato.

The DNA dioxygenase Tet1 regulates H3K27 modification and embryonic stem cell biology independent of its catalytic activity.

Tet enzymes (Tet1/2/3) oxidize 5-methylcytosine to promote DNA demethylation and partner with chromatin modifiers to regulate gene expression. Tet1 is highly expressed in embryonic stem cells (ESCs), but its enzymatic and non-enzymatic roles in gene regulation are not dissected. We have generated Tet1 catalytically inactive (Tet1m/m) and knockout (Tet1-/-) ESCs and mice to study these functions. Loss of Tet1, but not loss of its catalytic activity, caused aberrant upregulation of bivalent (H3K4me3+; H3K27me3+) developmental genes, leading to defects in differentiation. Wild-type and catalytic-mutant Tet1 occupied similar genomic loci which overlapped with H3K27 tri-methyltransferase PRC2 and the deacetylase complex Sin3a at promoters of bivalent genes and with the helicase Chd4 at active genes. Loss of Tet1, but not loss of its catalytic activity, impaired enrichment of PRC2 and Sin3a at bivalent promoters leading to reduced H3K27 trimethylation and deacetylation, respectively, in absence of any changes in DNA methylation. Tet1-/-, but not Tet1m/m, embryos expressed higher levels of Gata6 and were developmentally delayed. Thus, the critical functions of Tet1 in ESCs and early development are mediated through its non-catalytic roles in regulating H3K27 modifications to silence developmental genes, and are more important than its catalytic functions in DNA demethylation.

ChatGPT-4 Performs Clinical Information Retrieval Tasks Utilizing Consistently More Trustworthy Resources Than Does Google Search for Queries Concerning the Latarjet Procedure.

PURPOSE: To assess the ability for ChatGPT-4, an automated Chatbot powered by artificial intelligence (AI), to answer common patient questions concerning the Latarjet procedure for patients with anterior shoulder instability and compare this performance to Google Search Engine. METHODS: Using previously validated methods, a Google search was first performed using the query "Latarjet." Subsequently, the top ten frequently asked questions (FAQs) and associated sources were extracted. ChatGPT-4 was then prompted to provide the top ten FAQs and answers concerning the procedure. This process was repeated to identify additional FAQs requiring discrete-numeric answers to allow for a comparison between ChatGPT-4 and Google. Discrete, numeric answers were subsequently assessed for accuracy based on the clinical judgement of two fellowship-trained sports medicine surgeons blinded to search platform. RESULTS: Mean (±standard deviation) accuracy to numeric-based answers were 2.9±0.9 for ChatGPT-4 versus 2.5±1.4 for Google (p=0.65). ChatGPT-4 derived information for answers only from academic sources, which was significantly different from Google Search Engine (p=0.003), which used only 30% academic sources and websites from individual surgeons (50%) and larger medical practices (20%). For general FAQs, 40% of FAQs were found to be identical when comparing ChatGPT-4 and Google Search Engine. In terms of sources used to answer these questions, ChatGPT-4 again used 100% academic resources, while Google Search Engine used 60% academic resources, 20% surgeon personal websites, and 20% medical practices (p=0.087). CONCLUSION: ChatGPT-4 demonstrated the ability to provide accurate and reliable information about the Latarjet procedure in response to patient queries, using multiple academic sources in all cases. This was in contrast to Google Search Engine, which more frequently used single surgeon and large medical practice websites. Despite differences in the resources accessed to perform information retrieval tasks, the clinical relevance and accuracy of information provided did not significantly differ between ChatGPT-4 and Google Search Engine.

Shoulder Arthroplasty in the Upper Extremity Weight-bearing Patient: A Systematic Review of Clinical Outcomes and Complications.

BACKGROUND: Patients who rely on their upper extremities for ambulation, or upper extremity ambulators (UEAs), place considerable stress on their shoulders through the use of assistive devices like walkers, crutches, canes, and wheelchairs. It has been postulated that UEAs may be at increased risk for complications following shoulder arthroplasty. This study aimed to systematically review the literature related to (1) patient-reported outcomes measures (PROMs), (2) functional outcomes, and (3) complications in UEAs who undergo shoulder arthroplasty. METHODS: A systematic review of the PubMed/MEDLINE, Embase, and Cochrane databases was performed to identify studies reporting clinical outcomes of shoulder arthroplasty in UEAs. Patient demographics, clinical characteristics, PROMs, radiographic outcomes, and postoperative range of motion were collected and compared to control patients (i.e. bipedal ambulators) from the constituent studies. RESULTS: A total of eight studies evaluating 248 UEA cases and 206 control cases were included for review. Ambulatory assistive devices utilized by UEAs included walkers (39%), wheelchairs (38%), canes (22%), and a crutch (<1%). Among UEA cases, 197 (79%) reverse total shoulder arthroplasty, 37 (15%) anatomic total shoulder arthroplasty, and 14 (6%) hemiarthroplasty were performed. Overall, patients exhibited significant improvements in mean American Shoulder and Elbow Surgeons (ASES) scores, Constant-Murley scores, Simple Shoulder Test (SST) scores, and Visual Analog Scale (VAS) scores postoperatively. Among 3 studies that included comparison with control groups of bipedal ambulators, no significant differences in outcomes were identified. The overall clinical complication rate was 17% for UEAs compared to 9.1% for controls. The rate of revision surgery was 7.7% for UEAs and 4.9% for bipedal ambulators. CONCLUSIONS: UEAs experience satisfactory pain relief, functional improvements, and good subjective outcomes following shoulder arthroplasty. However, complication and revision rates are higher compared to those for bipedal ambulators, and the majority of UEAs undergo reverse shoulder arthroplasty (RSA) compared to anatomic total shoulder arthroplasty (aTSA).

Outcomes after débridement, antibiotics, and implant retention for prosthetic joint infection in shoulder arthroplasty.

BACKGROUND: Patients who undergo total shoulder arthroplasty usually have excellent long-term outcomes. However, a subset of patients is diagnosed with a prosthetic joint infection (PJI) requiring revision procedures and prolonged recovery. The purpose of this study was to evaluate rates of recurrent shoulder PJI in patients undergoing débridement, antibiotics, and implant retention (DAIR), single-stage revision, and 2-stage revision. We also sought to compare outcomes and complications across procedures. METHODS: Retrospective chart review was conducted for patients diagnosed with PJI after primary shoulder arthroplasty between January 2010 and August 2021. Patients were included if they underwent treatment with DAIR, single-stage revision, or 2-stage revision. Demographic information, surgical details, complications, laboratory data, postoperative antibiotic regimen, and infectious pathogen were collected. Postoperative patient-reported outcomes were collected: American Shoulder and Elbow Surgeons Standardized Shoulder Assessment Form, Single Assessment Numeric Evaluation, Shoulder Activity Scale, and PROMIS Upper Extremity. Chi-square, t test, and 1-way analysis of variance were used as appropriate to evaluate each factor. RESULTS: Sixty-five patients were included in the study, 26% treated with DAIR, 9% treated with single-stage revision, and 65% treated with 2-stage revision. There were no significant differences in patient comorbidities. Patients undergoing DAIR were diagnosed significantly earlier than those undergoing single- and 2-stage revision procedures (12.6 ± 22.9 months vs. 49.6 ± 48.4 vs. 25.0 ± 26.6, P = .010). Recurrent PJI was noted in 23.1% of patients: 29.4% of DAIR patients, no single-stage patients, and 23.8% of 2-stage patients (P = .330). Patients undergoing 2-stage revision with treatment failure had a significantly higher Elixhauser Comorbidity Index (0.2 ± 3.7 vs. 3.7 ± 3.9, P = .027). There was no significant difference in patient-reported outcomes across groups. CONCLUSION: Patients undergoing treatment of shoulder PJI with DAIR did not have an increased rate of reinfection compared with single-stage and 2-stage revision procedures. Patients treated with DAIR were diagnosed with PJI significantly earlier than those undergoing single-stage and 2-stage revision procedures. There was no difference in complication rates between groups. This information adds to the body of work detailing outcomes after DAIR for shoulder PJI and provides encouraging data for use in this patient population. Future studies with a larger sample size may be conducted to further investigate specific pathogens, infection timelines, and antibiotic regimens that reduce the risk of treatment failure.

The proteasome regulates body weight and systemic nutrient metabolism during fasting.

The ubiquitin-proteasome system (UPS) and the autophagy-lysosome pathway are the primary means of degradation in mammalian tissues. We sought to determine the individual contribution of the UPS and autophagy to tissue catabolism during fasting. Mice were overnight fasted for 15 h before regaining food access ("Fed" group, n = 6) or continuing to fast ("Fast" group, n = 7) for 3 h. In addition, to investigate the effects of autophagy on systemic metabolism and tissue degradation, one group of mice was fasted for 18 h and treated with chloroquine ("Fast + CLQ" group, n = 7) and a fourth group of mice was treated with bortezomib ("Fast + Bort" group, n = 7) to assess the contribution of the UPS. Body weight, tissue weight, circulating hormones and metabolites, intracellular signaling pathways, and protein synthesis were investigated. Fasting induced the loss of body weight, liver mass, and white adipose tissue in the Fast and the Fast + CLQ group, whereas the Fast + Bort group maintained tissue and body weight. Fasting reduced glucose and increased ß hydroxybutyrate in the circulation of all mice. Both changes were most profound in the Fast + Bort group compared with the other fasting conditions. Molecular signaling indicated a successful inhibition of hepatic UPS with bortezomib and an upregulation of the PI3K/AKT/mTOR pathway. The latter was further supported by an increase in hepatic protein synthesis with bortezomib. Inhibition of the UPS through bortezomib blocks body weight loss and tissue catabolism during an acute overnight fast in mice. The effects were likely mediated through a combined effect of the drug on biomolecule degradation and synthesis.NEW & NOTEWORTHY Bortezomib treatment prevents tissue and body weight loss during fasting. The loss of proteasome activity with bortezomib exacerbates fasting-induced ketogenesis. During fasting, bortezomib increases AMPK and PI3K/AKT signaling in the liver, which promotes protein synthesis.

Elevated decision uncertainty and reduced avoidance drives in depression, anxiety and substance use disorders during approach-avoidance conflict: a replication study.

BACKGROUND: Decision-making under approach-avoidance conflict (AAC; e.g., sacrificing quality of life to avoid feared outcomes) may be affected in multiple psychiatric disorders. Recently, we used a computational (active inference) model to characterize information processing differences during AAC in individuals with depression, anxiety and/or substance use disorders. Individuals with psychiatric disorders exhibited increased decision uncertainty (DU) and reduced sensitivity to unpleasant stimuli. This preregistered study aimed to determine the replicability of this processing dysfunction. METHODS: A new sample of participants completed the AAC task. Individual-level computational parameter estimates, reflecting decision uncertainty and sensitivity to unpleasant stimuli ("emotion conflict"; EC), were obtained and compared between groups. Subsequent analyses combining the prior and current samples allowed assessment of narrower disorder categories. RESULTS: The sample in the present study included 480 participants: 97 healthy controls, 175 individuals with substance use disorders and 208 individuals with depression and/or anxiety disorders. Individuals with substance use disorders showed higher DU and lower EC values than healthy controls. The EC values were lower in females, but not males, with depression and/or anxiety disorders than in healthy controls. However, the previously observed difference in DU between participants with depression and/or anxiety disorders and healthy controls did not replicate. Analyses of specific disorders in the combined samples indicated that effects were common across different substance use disorders and affective disorders. LIMITATIONS: There were differences, although with small effect size, in age and baseline intellectual functioning between the previous and current sample, which may have affected replication of DU differences in participants with depression and/or anxiety disorders. CONCLUSION: The now robust evidence base for these clinical group differences motivates specific questions that should be addressed in future research: can DU and EC become behavioural treatment targets, and can we identify neural substrates of DU and EC that could be used to measure severity of dysfunction or as neuromodulatory treatment targets?

How accurate are positive preoperative aspiration culture results in shoulder periprosthetic joint infection? A concordance study.

BACKGROUND: The concordance between preoperative synovial fluid cultures and intraoperative tissue cultures for identifying pathogenic microorganisms in shoulder periprosthetic joint infection (PJI) remains poorly understood. The purpose of our study was to examine the diagnostic accuracy of positive synovial fluid culture results in early pathogen identification for shoulder PJI. METHODS: A total of 35 patients who met the Musculoskeletal Infection Society criteria for PJI following primary anatomic or reverse arthroplasty and the study inclusion criteria were identified retrospectively from a single institution (multiple surgeons) from January 2011 to June 2021. The inclusion criteria required a positive preoperative intra-articular synovial fluid sample within 90 days analyzed within the same institution and intraoperative tissue cultures at the time of arthrotomy. Concordance was determined when the organism(s) identified from the aspirate correlated with the intraoperative specimens. RESULTS: Overall concordance was identified in 28 of 35 patients (80%), with similar concordance for anatomic (21 of 24, 88%) and reverse (7 of 11, 64%) shoulder arthroplasties (P = .171). Culture discordance occurred in 7 of 35 patients (20%): of these, 5 (14%) had no corresponding intraoperative culture growth whereas 2 (6%) had polymicrobial intraoperative cultures. Monomicrobial Cutibacterium acnes PJI cases were the most common (24 of 35, 69%) and had an overall concordance rate of 79%. Of 5 discordant C acnes patients, 2 had polymicrobial intraoperative cultures and 3 had negative intraoperative culture results; all the patients with negative intraoperative culture results had received antibiotics between the time of aspiration and surgery. Considered separately, concordance in patients who had a positive aspirate finding for C acnes and did not receive antibiotics prior to surgery was 19 of 21 (90%), with a sensitivity of 100% (95% confidence interval, 82%-100%) and a corresponding positive predictive value of 0.91 (95% confidence interval, 58%-93%). CONCLUSION: Preoperative positive aspiration culture results demonstrated favorable sensitivity and specificity when compared with intraoperative tissue cultures in identifying pathogenic microorganisms in shoulder PJI patients. These findings are congruent with literature from hip and knee arthroplasty. Ultimately, confidence in the accuracy of positive preoperative aspiration culture results in shoulder PJI may facilitate the development of early, targeted treatment strategies while directing patient expectations and risk.

Shoulder arthroplasty device clearance: an ancestral network analysis.

BACKGROUND: The US Food and Drug Administration (FDA) oversees medical device regulation and oversight in the United States, and the majority of shoulder arthroplasty devices are cleared via the 510(k) pathway, in which a device demonstrates "substantial equivalence" to a previously cleared predicate. The purpose of this study was to determine an interconnected ancestral network of shoulder arthroplasty devices and determine equivalency ties to devices subsequently recalled by the FDA for design-related issues. METHODS: The FDA 510(k) database was used to identify all legally marketed shoulder arthroplasty devices from May 28, 1976, to July 1, 2021. Direct predicate information obtained via clearance summary documents associated with each device was used to generate an ancestral genealogy network for all shoulder arthroplasty devices cleared between July 1, 2020, and July 1, 2021. FDA design recalls were analyzed, and the number of descendant devices was calculated for each recalled device. RESULTS: An evaluation of all 476 510(k) premarket notification pathway-cleared shoulder devices since 1976 identified 0-313 descendant devices for each. Eighty of these devices (16.8%) have since been recalled, of which 10 recalls were directly related to implant design issues. Furthermore, among 29 of the most recently cleared devices (July 1, 2020-July 1, 2021), 16 (55.2%) claim predicates devices that have subsequently been withdrawn from the market because of design-related failures. CONCLUSIONS: Shoulder arthroplasty devices are linked together via an interconnected FDA 510(k) equivalency approval network dating back to 1976 despite substantive changes in material specifications and device design, many of which have since been recalled. Many of the cleared modern devices claim predicates based on subsequently recalled prostheses.

Artificial intelligence for automated identification of total shoulder arthroplasty implants.

BACKGROUND: Accurate and rapid identification of implant manufacturer and model is critical in the evaluation and management of patients requiring revision total shoulder arthroplasty (TSA). Failure to correctly identify implant designs in these circumstances may lead to delay in care, unexpected intraoperative challenges, increased morbidity, and excess health care costs. Deep learning (DL) permits automated image processing and holds the potential to mitigate such challenges while improving the value of care rendered. The purpose of this study was to develop an automated DL algorithm to identify shoulder arthroplasty implants from plain radiographs. METHODS: A total of 3060 postoperative images from patients who underwent TSA between 2011 and 2021 performed by 26 fellowship-trained surgeons at 2 independent tertiary academic hospitals in the Pacific Northwest and Mid-Atlantic Northeast were included. A DL algorithm was trained using transfer learning and data augmentation to classify 22 different reverse TSA and anatomic TSA prostheses from 8 implant manufacturers. Images were split into training and testing cohorts (2448 training and 612 testing images). Optimized model performance was assessed using standardized metrics including the multiclass area under the receiver operating characteristic curve (AUROC) and compared with a reference standard of implant data from operative reports. RESULTS: The algorithm classified implants at a mean speed of 0.079 seconds (±0.002 seconds) per image. The optimized model discriminated between 8 manufacturers (22 unique implants) with AUROCs of 0.994-1.000, accuracy of 97.1%, and sensitivities between 0.80 and 1.00 on the independent testing set. In the subset of single-institution implant predictions, a DL model identified 6 specific implants with AUROCs of 0.999-1.000, accuracy of 99.4%, and sensitivity >0.97 for all implants. Saliency maps revealed key differentiating features across implant manufacturers and designs recognized by the algorithm for classification. CONCLUSION: A DL model demonstrated excellent accuracy in identifying 22 unique TSA implants from 8 manufacturers. This algorithm may provide a clinically meaningful adjunct in assisting with preoperative planning for the failed TSA and allows for scalable expansion with additional radiographic data and validation efforts.

Factors associated with humeral stem revision in anatomic to reverse total shoulder arthroplasty revision.

BACKGROUND: Recent advances in implant technology have allowed for modular or platform humeral stem insertion during initial anatomic total shoulder arthroplasty (TSA). These systems allow for humeral stem retention during conversion to reverse TSA (RTSA). However, some patients still require humeral stem revision when undergoing revision to RTSA. The purpose of this study was to evaluate the association between patient-specific factors and radiographic parameters with humeral stem revision vs. retention during conversion from TSA to RTSA. METHODS: Retrospective chart review was conducted for patients who underwent a revision TSA to RTSA between January 2010 and May 2022 at a single institution. Patients were included if their prosthesis included a convertible humeral stem. Patient demographic information, surgical details, and postoperative outcomes and complications were collected. Radiographic parameters were measured by 2 graders on radiographs taken prior to the revision procedure. The need for humeral stem revision and American Shoulder and Elbow Surgeons Standardized Shoulder Assessment Form (ASES) scores (preoperative and 2 years) were also noted. Statistical analysis was performed using chi-square test for categorical variables and t test for continuous variables. RESULTS: One hundred seven patients were included, with 52 undergoing humeral stem revision. Patients were revised an average of 51.0 ± 54 months after primary TSA. Younger patient age (63.6 vs. 68.5 years, P = .017) and use of a lateralized glenosphere (1.6 mm vs. 0.4 mm, P < .001) were significantly associated with need for humeral stem revision. Glenoid to humeral head cut distance (28.3 mm vs. 26.3 mm, P = .076) approached significant association with the need for humeral stem revision. All other measurements were not associated with the need for humeral stem revision. Improvement of ASES scores at 2 years' follow-up was higher in the nonrevised group (increase of 33.4 points) than the revision group (23.3), but this did not reach significance (P = .149). Estimated blood loss and surgical time were significantly higher in the stem revision group than the non-revised group (P = .048 and P < .001, respectively). CONCLUSION: Younger patients and those receiving a lateralized glenosphere were more likely to undergo humeral stem revision during conversion from TSA to RTSA. Glenoid to the humeral head cut distance should be studied further as a potential indication for humeral stem revision, as it correlates with the space available for a revision implant. This information can guide surgeons with preoperative planning for a revision arthroplasty.

Disparity in peripheral and renal B-cell depletion with rituximab in systemic lupus erythematosus: an opportunity for obinutuzumab?

OBJECTIVES: To investigate key factors that may contribute to the variability of rituximab-mediated peripheral and renal B cell depletion (BCD) in SLE. METHODS: We analysed: (i) CD19+ B cell counts in patients with SLE before and 1, 2, 3 and 6 months after treatment with rituximab, comparing them with RA patients; (ii) the presence of B cells in renal biopsies after rituximab therapy; (iii) whether the duration of BCD correlated with patient demographics and B cell expression of CD20 and FcγRIIb; and (iv) the effect of B cell activation factor (BAFF) on the efficiency of rituximab and obinutuzumab at inducing BCD in whole blood assays, in vitro. RESULTS: In SLE (n = 71), the duration of BCD was shorter compared with RA (n = 27). B cells were detectable in renal biopsy samples (n = 6) after treatment with rituximab in all patients with poor response while peripheral blood B cells remained low or undetectable in the same patients. There were no significant relationships between peripheral BCD and patient age, disease duration, serum C3 levels or the level of expression of B cell surface proteins CD20 and FcγRIIb. Obinutuzumab was more efficient than rituximab at inducing BCD in whole blood assays, regardless of excess BAFF. CONCLUSIONS: BCD in SLE is less efficient than in RA. Renal B cell presence following rituximab treatment was associated with poor outcomes. No significant relationships between any measured B cell related, clinical or laboratory parameters and the efficiency of BCD by rituximab was found. Obinutuzumab was superior to rituximab at inducing BCD.

Phenotypic variation in photosynthetic traits in wheat grown under field versus glasshouse conditions.

Recognition of the untapped potential of photosynthesis to improve crop yields has spurred research to identify targets for breeding. The CO2-fixing enzyme Rubisco is characterized by a number of inefficiencies, and frequently limits carbon assimilation at the top of the canopy, representing a clear target for wheat improvement. Two bread wheat lines with similar genetic backgrounds and contrasting in vivo maximum carboxylation activity of Rubisco per unit leaf nitrogen (Vc,max,25/Narea) determined using high-throughput phenotyping methods were selected for detailed study from a panel of 80 spring wheat lines. Detailed phenotyping of photosynthetic traits in the two lines using glasshouse-grown plants showed no difference in Vc,max,25/Narea determined directly via in vivo and in vitro methods. Detailed phenotyping of glasshouse-grown plants of the 80 wheat lines also showed no correlation between photosynthetic traits measured via high-throughput phenotyping of field-grown plants. Our findings suggest that the complex interplay between traits determining crop productivity and the dynamic environments experienced by field-grown plants needs to be considered in designing strategies for effective wheat crop yield improvement when breeding for particular environments.

Runx1 promotes murine erythroid progenitor proliferation and inhibits differentiation by preventing Pu.1 downregulation.

Pu.1 is an ETS family transcription factor (TF) that plays critical roles in erythroid progenitors by promoting proliferation and blocking terminal differentiation. However, the mechanisms controlling expression and down-regulation of Pu.1 during early erythropoiesis have not been defined. In this study, we identify the actions of Runx1 and Pu.1 itself at the Pu.1 gene Upstream Regulatory Element (URE) as major regulators of Pu.1 expression in Burst-Forming Unit erythrocytes (BFUe). During early erythropoiesis, Runx1 and Pu.1 levels decline, and chromatin accessibility at the URE is lost. Ectopic expression of Runx1 or Pu.1, both of which bind the URE, prevents Pu.1 down-regulation and blocks terminal erythroid differentiation, resulting in extensive ex vivo proliferation and immortalization of erythroid progenitors. Ectopic expression of Runx1 in BFUe lacking a URE fails to block terminal erythroid differentiation. Thus, Runx1, acting at the URE, and Pu.1 itself directly regulate Pu.1 levels in erythroid cells, and loss of both factors is critical for Pu.1 down-regulation during terminal differentiation. The molecular mechanism of URE inactivation in erythroid cells through loss of TF binding represents a distinct pattern of Pu.1 regulation from those described in other hematopoietic cell types such as T cells which down-regulate Pu.1 through active repression. The importance of down-regulation of Runx1 and Pu.1 in erythropoiesis is further supported by genome-wide analyses showing that their DNA-binding motifs are highly overrepresented in regions that lose chromatin accessibility during early erythroid development.

Feasibility of a centralized specialty biologic medication management clinic at a VA hospital.

BACKGROUND: Given the cost and complexity of home subcutaneous biologic use, a centralized specialty medication management (CSMM) service was developed utilizing clinical pharmacist practitioners (CPPs). OBJECTIVE: To determine the implementation feasibility of the CSMM service. PRACTICE DESCRIPTION: The CSMM service was implemented in a Veterans Health Administration (VHA) hospital. The VHA does not use dedicated specialty pharmacies. PRACTICE INNOVATION: The CSMM service was developed utilizing CPPs who operated as an advance practice provider under a national VHA scope of practice. The CPP staffing the CSMM service performed patient education, screened for medication appropriateness, and monitored for safety and efficacy via videoconference or telephone. All patients newly starting a home subcutaneous biologic were offered the service from allergy, cardiology, dermatology, gastroenterology, and rheumatology clinics, as appropriate. EVALUATION METHODS: A retrospective chart review was completed through the first year the service was offered, which included the recruitment and retention of patients, number of follow-up appointments, and interventions made. RESULTS: Of the 68 patients offered clinic enrollment, 54 were enrolled in the service (79.4%). Of the 44 who had completed an initial appointment with the CPP, 42 had either received an initial follow-up or were scheduled for a follow-up (95.5%). A total of 161 clinical outcomes have been performed by the CSMM CPP including administrative assistance (33.5%), initial patient education (17.4%), technique correction (7.5%), and medication changes or discontinuations (6.8%). CONCLUSION: Given the high rate of enrollment and retention, the implementation of the CSMM service at a VA hospital was feasible. The service contributed to safe and effective medication use for enrolled patients and continues to grow in both patient enrollment and services offered.

The role of the long head of the biceps tendon in posterior shoulder stabilization during forward flexion.

BACKGROUND: The role of the long head of the biceps tendon (LHBT) in glenohumeral stability is not fully understood. Most objects are lifted in the sagittal plane with forward flexion, which stresses the posterior aspect of the unconstrained glenohumeral joint. Determining the mechanism by which the shoulder maintains stability with functional motions is important to understanding the pathoanatomy of degenerative shoulders. Our hypothesis was that the LHBT resists posterior translation of the humeral head (HH) during forward flexion by tensioning the posterior capsuloligamentous complex. METHODS: Ten fresh-frozen cadaveric shoulders were tested using an established shoulder simulator that loads the LHBT, rotator cuff, and deltoid tendons through a system of pulleys. A motion tracking system recorded glenohumeral translations with an accuracy of ±0.2 mm. In each subject, the scapula was fixed and the humerus was tested in 6 positions: 30° and 60° of glenohumeral forward flexion at (1) maximum internal rotation (IR), (2) neutral rotation, and (3) maximum external rotation (ER). The deltoid was loaded with 100 N, and the infraspinatus and subscapularis were loaded with 22 N each. The difference in glenohumeral translation was calculated at each position comparing the LHBT loaded with 45 N or unloaded. RESULTS: At 30° of glenohumeral forward flexion, unloading the LHBT increased HH posterior translation by 2.5 mm (±0.9 mm; P < .001), 1.7 mm (±1.0 mm; P < .001), and 1.0 mm (±0.9 mm; P = .01) at maximum ER, neutral rotation, and maximum IR, respectively. At 60° of glenohumeral forward flexion, unloading the LHBT increased HH posterior translation by 2.8 mm (±1.2 mm; P < .001), 2.4 mm (±1.6 mm; P < .001), and 1.7 mm (±1.4 mm; P < .001) at maximum ER, neutral rotation, and maximum IR, respectively. CONCLUSION: LHBT loading resists posterior translation of the HH during forward flexion. These data support the role of the LHBT as a posterior stabilizer of the shoulder, specifically when a person is carrying objects in front of them. Further work is needed to determine if unloading the LHBT, as is done with biceps tenotomy or tenodesis, may eventually lead to posterior labral pathology, or to the posterior glenoid wear commonly seen with osteoarthritis.

Outcomes of shoulder arthroplasty by year of index procedure: are we getting better?

BACKGROUND: The purpose of this study was to determine whether postoperative patient-reported outcomes improved over time following anatomic total shoulder arthroplasty (TSA) and reverse total shoulder arthroplasty (RTSA). METHODS: We performed a retrospective analysis of prospectively collected patient-reported outcomes from our institution's registry between 2008 and 2018 (N = 1899). American Shoulder and Elbow Surgeons (ASES) scores at a minimum of 2 years postoperatively were required. Univariable linear models were used to test the association between year of surgery and improvement in ASES scores at 2- and 5-year follow-up, as well as any association with age, sex, primary or revision surgery, hand dominance, American Society of Anesthesiologists classification, rotator cuff status, primary diagnosis, and Walch classification. Multivariable models were created to analyze ASES score improvement by index year while controlling for significant factors. RESULTS: In the univariable analysis, 5-year ASES difference scores increased each year by a mean of 1.65 (P < .001; 95% confidence interval [CI], 0.75-2.55) for TSA, 2.50 (P = .014; 95% CI, 0.52-4.49) for RTSA, and 1.64 (P < .001; 95% CI, 0.81-2.47) for the overall population. Patient sex, American Society of Anesthesiologists classification, rotator cuff status, primary diagnosis, Walch classification, and revision procedures were also significant factors affecting ASES scores. On multivariable analysis controlling for these factors, 5-year ASES difference scores were still significantly associated with year of surgery, increasing each year by a mean of 2.20 (P < .001; 95% CI, 0.91-3.50) for TSA, 4.83 (P < .001; 95% CI, 1.17-8.49) for RTSA, and 1.66 (P < .001; 95% CI, 0.81-2.51) for the entire population. CONCLUSION: Both anatomic TSA and RTSA patients reported increasing ASES difference scores at 5-year follow-up as time passed. These findings may indicate that advances in shoulder arthroplasty have resulted in better patient outcomes over time. Further research is needed to clarify which factors influence improvements in outcomes, particularly for revision procedures.