Development of SYK NanoBRET Cellular Target Engagement Assays for Gain-of-Function Variants.

Spleen tyrosine kinase (SYK) is a non-receptor tyrosine kinase that is activated by phosphorylation events downstream of FcR, B-cell and T-cell receptors, integrins, and C-type lectin receptors. When the tandem Src homology 2 (SH2) domains of SYK bind to phosphorylated immunoreceptor tyrosine-based activation motifs (pITAMs) contained within these immunoreceptors, or when SYK is phosphorylated in interdomain regions A and B, SYK is activated. SYK gain-of-function (GoF) variants were previously identified in six patients that had higher levels of phosphorylated SYK and phosphorylated downstream proteins JNK and ERK. Furthermore, the increased SYK activation resulted in the clinical manifestation of immune dysregulation, organ inflammation, and a predisposition for lymphoma. The knowledge that the SYK GoF variants have enhanced activity was leveraged to develop a SYK NanoBRET cellular target engagement assay in intact live cells with constructs for the SYK GoF variants. Herein, we developed a potent SYK-targeted NanoBRET tracer using a SYK donated chemical probe, MRL-SYKi, that enabled a NanoBRET cellular target engagement assay for SYK GoF variants, SYK(S550Y), SYK(S550F), and SYK(P342T). We determined that ATP-competitive SYK inhibitors bind potently to these SYK variants in intact live cells. Additionally, we demonstrated that MRL-SYKi can effectively reduce the catalytic activity of SYK variants, and the phosphorylation levels of SYK(S550Y) in an epithelial cell line (SW480) stably expressing SYK(S550Y).

Pathological Complete Response in Patients With Resected Pancreatic Adenocarcinoma After Preoperative Chemotherapy.

Importance: Preoperative chemo(radio)therapy is increasingly used in patients with localized pancreatic adenocarcinoma, leading to pathological complete response (pCR) in a small subset of patients. However, multicenter studies with in-depth data about pCR are lacking. Objective: To investigate the incidence, outcome, and risk factors of pCR after preoperative chemo(radio)therapy. Design, Setting, and Participants: This observational, international, multicenter cohort study assessed all consecutive patients with pathology-proven localized pancreatic adenocarcinoma who underwent resection after 2 or more cycles of chemotherapy (with or without radiotherapy) in 19 centers from 8 countries (January 1, 2010, to December 31, 2018). Data collection was performed from February 1, 2020, to April 30, 2022, and analyses from January 1, 2022, to December 31, 2023. Median follow-up was 19 months. Exposures: Preoperative chemotherapy (with or without radiotherapy) followed by resection. Main Outcomes and Measures: The incidence of pCR (defined as absence of vital tumor cells in the sampled pancreas specimen after resection), its association with OS from surgery, and factors associated with pCR. Factors associated with overall survival (OS) and pCR were investigated with Cox proportional hazards and logistic regression models, respectively. Results: Overall, 1758 patients (mean [SD] age, 64 [9] years; 879 [50.0%] male) were studied. The rate of pCR was 4.8% (n = 85), and pCR was associated with OS (hazard ratio, 0.46; 95% CI, 0.26-0.83). The 1-, 3-, and 5-year OS rates were 95%, 82%, and 63% in patients with pCR vs 80%, 46%, and 30% in patients without pCR, respectively (P < .001). Factors associated with pCR included preoperative multiagent chemotherapy other than (m)FOLFIRINOX ([modified] leucovorin calcium [folinic acid], fluorouracil, irinotecan hydrochloride, and oxaliplatin) (odds ratio [OR], 0.48; 95% CI, 0.26-0.87), preoperative conventional radiotherapy (OR, 2.03; 95% CI, 1.00-4.10), preoperative stereotactic body radiotherapy (OR, 8.91; 95% CI, 4.17-19.05), radiologic response (OR, 13.00; 95% CI, 7.02-24.08), and normal(ized) serum carbohydrate antigen 19-9 after preoperative therapy (OR, 3.76; 95% CI, 1.79-7.89). Conclusions and Relevance: This international, retrospective cohort study found that pCR occurred in 4.8% of patients with resected localized pancreatic adenocarcinoma after preoperative chemo(radio)therapy. Although pCR does not reflect cure, it is associated with improved OS, with a doubled 5-year OS of 63% compared with 30% in patients without pCR. Factors associated with pCR related to preoperative chemo(radio)therapy regimens and anatomical and biological disease response features may have implications for treatment strategies that require validation in prospective studies because they may not universally apply to all patients with pancreatic adenocarcinoma.

Factors predictive of recurrence, metastasis and death in node-negative penile squamous cell carcinoma: A retrospective multicentre cohort study.

BACKGROUND: Penile squamous cell carcinoma (PSCC) carries significant morbidity and mortality. Literature is limited regarding prognostic factors, especially prognostic factors for development of metastasis. OBJECTIVES: To identify independent prognostic factors associated with poor outcomes, defined as local recurrence (LR), metastasis and disease-specific death (DSD) in clinically node-negative PSCC undergoing local therapy. METHODS: Thirty-two-year Retrospective Multicenter Cohort Study of 265 patients with histologically diagnosed PSCC at three tertiary care centres. Predictive models based on patient or tumour characteristics were developed. RESULTS: Local recurrence occurred in 56 patients, metastasis in 52 patients and DSD in 40 patients. In multivariable models, the following five factors were independent prognostic factors based on subhazard ratio (SHR): history of balanitis (LR SHR: 2.3; 95% CI 1.2-4.2), poor differentiation (metastasis SHR 1.9; 95% CI 1.0-3.6), invasion into the corpora (metastasis SHR: 3.0; 95% CI 1.5-5.8 and DSD SHR: 4.5; 95% CI 1.7-12.1), perineural invasion (PNI) (metastasis SHR: 2.8; 95% CI 1.4-5.5 and DSD SHR: 3.5; 95% CI, 1.6-7.8) and a history of phimosis (DSD SHR: 2.5; 95% CI 1.2-5.3). The 5-year cumulative incidence of metastasis was higher for tumours with PNI [cumulative incidence function (CIF) = 55%, 95% CI 38-75 vs. CIF 15%, 95% CI 11-22], corporal invasion (CIF: 35%, 95% CI 26-47 vs. 12%, 95% CI 7-19) and poorly differentiated tumours (CIF = 46%, 95% CI 31-64 vs. CIF 15%, 95% CI 11-22). CONCLUSIONS: History of balanitis, history of phimosis, PNI, corporal invasion and poor differentiation are independent risk factors associated with poor outcomes. Since poor differentiation and PNI currently constitute only T1b disease, prognostic staging can likely be improved.

Malic enzyme 1 knockout has no deleterious phenotype and is favored in the male germline under standard laboratory conditions.

Malic Enzyme 1 (ME1) plays an integral role in fatty acid synthesis and cellular energetics through its production of NADPH and pyruvate. As such, it has been identified as a gene of interest in obesity, type 2 diabetes, and an array of epithelial cancers, with most work being performed in vitro. The current standard model for ME1 loss in vivo is the spontaneous Mod-1 null allele, which produces a canonically inactive form of ME1. Herein, we describe two new genetically engineered mouse models exhibiting ME1 loss at dynamic timepoints. Using murine embryonic stem cells and Flp/FRT and Cre/loxP class switch recombination, we established a germline Me1 knockout model (Me1 KO) and an inducible conditional knockout model (Me1 cKO), activated upon tamoxifen treatment in adulthood. Collectively, neither the Me1 KO nor Me1 cKO models exhibited deleterious phenotype under standard laboratory conditions. Knockout of ME1 was validated by immunohistochemistry and genotype confirmed by PCR. Transmission patterns favor Me1 loss in Me1 KO mice when maternally transmitted to male progeny. Hematological examination of these models through complete blood count and serum chemistry panels revealed no discrepancy with their wild-type counterparts. Orthotopic pancreatic tumors in Me1 cKO mice grow similarly to Me1 expressing mice. Similarly, no behavioral phenotype was observed in Me1 cKO mice when aged for 52 weeks. Histological analysis of several tissues revealed no pathological phenotype. These models provide a more modern approach to ME1 knockout in vivo while opening the door for further study into the role of ME1 loss under more biologically relevant, stressful conditions.

Low smoking exposure and development and prognosis of COPD over four decades: A population-based cohort study.

A diagnosis of chronic obstructive pulmonary disease (COPD) is mainly considered in individuals with more than 10 pack-years of smoking. We tested the hypothesis that low smoking exposure, below the critical threshold of 10 pack-years, increases risk of COPD and leads to poor prognosis.We followed non-obstructive adult smokers from the Copenhagen City Heart Study for COPD, defined as forced expiratory volume in one second [FEV1]/forced vital capacity [FVC]<0.70 and FEV1<80% predicted, and for related clinical outcomes. First, we followed individuals for 5years according to baseline smoking for risk of developing COPD, and hereafter for up to four decades for severe exacerbations and death.In 6098 non-obstructive smokers, 1781(29%) developed COPD after 5 years follow-up; 23% in individuals with <10pack-years of smoking at baseline, 26% in those with 10-19.9pack-years, 30% in those with 20-39.9pack-years, and 39% in those with ≥40pack-years. During four decades follow-up, we recorded 620 exacerbations and 5573 deaths. Compared to individuals without COPD with <10pack-years of smoking, multivariable adjusted hazard ratios (HRs) for exacerbations were 1.94(95% confidence interval:1.36-2.77) in those without COPD with ≥10pack-years, 2.83(1.72-4.66) in those with COPD with <10pack-years, 4.34(2.93-6.43) in COPD with 10-19.9pack-years, 4.39(2.98-6.47) in COPD with 20-39.9pack-years, and 4.98(3.11-7.97) in COPD with ≥40pack-years. Corresponding HRs for all-cause mortality were 1.20(1.10-1.32), 1.33(1.14-1.56), 1.59(1.40-1.80),1.81(1.62-2.03), and 1.81(1.55-2.10), respectively.Low smoking exposure below the critical threshold of 10 pack-years increases risk of COPD in middle-aged adults within 5 years, and these individuals have increased risk of severe exacerbation and early death over four decades.

Most Major Hospitals Fail to Comply With Federal Price Transparency Regulations.

PURPOSE: To present hospital compliance with federal price transparency regulations for sports medicine procedures. METHODS: Online price estimator and machine-readable files were recovered for U.S. News and World Report's top 100 orthopaedic hospitals. From June to November 2023, compliance and monetary values were recorded for each of Centers for Medicare and Medicaid Services price transparency regulations. Price estimator data were assessed on the basis of hospital placement in the bottom and top 50 of the 100 institutions under review, as well as by region (Northeast, South, Midwest, West). Statistical analyses included 2-sample t tests and Kruskal-Wallis tests. RESULTS: In total, 95% of hospitals had a price estimator tool for both subacromial decompression (Current Procedural Terminology [CPT] code 29826) and meniscectomy (CPT code 29881). Only 38% were compliant with all regulations for subacromial decompression and 39% for meniscectomy; the remaining did not list minimum or maximum procedure charges. Higher-ranked hospitals were significantly more likely to charge a greater cash price for subacromial decompression and meniscectomy (P = .040 and P = .009, respectively). Compliance with machine-readable file reporting was poor, with less than 20% meeting requirements for each CPT code. Reported prices varied greatly by hospital. CONCLUSIONS: This study demonstrates that U.S. News and World Report's top 100 orthopaedic hospitals exhibit poor overall compliance with federal price transparency regulations for sports medicine procedures. Most often they lack full compliance by not reporting minimum or maximum charges as part of their price estimator tool or do not report procedure prices in their machine-readable files. Hospitals also exhibit wide variation in prices reported for specific procedures. CLINICAL RELEVANCE: Consumer price transparency continues to be an important goal in health care, as it allows patients to make informed decisions when selecting appropriate treatment options and providers. To realize the full benefits of price transparency, hospitals should address areas of improvement.

Timing-dependent synergies between motor cortex and posterior spinal stimulation in humans.

Volitional movement requires descending input from the motor cortex and sensory feedback through the spinal cord. We previously developed a paired brain and spinal electrical stimulation approach in rats that relies on convergence of the descending motor and spinal sensory stimuli in the cervical cord. This approach strengthened sensorimotor circuits and improved volitional movement through associative plasticity. In humans, it is not known whether posterior epidural spinal cord stimulation targeted at the sensorimotor interface or anterior epidural spinal cord stimulation targeted within the motor system is effective at facilitating brain evoked responses. In 59 individuals undergoing elective cervical spine decompression surgery, the motor cortex was stimulated with scalp electrodes and the spinal cord was stimulated with epidural electrodes, with muscle responses being recorded in arm and leg muscles. Spinal electrodes were placed either posteriorly or anteriorly, and the interval between cortex and spinal cord stimulation was varied. Pairing stimulation between the motor cortex and spinal sensory (posterior) but not spinal motor (anterior) stimulation produced motor evoked potentials that were over five times larger than brain stimulation alone. This strong augmentation occurred only when descending motor and spinal afferent stimuli were timed to converge in the spinal cord. Paired stimulation also increased the selectivity of muscle responses relative to unpaired brain or spinal cord stimulation. Finally, clinical signs suggest that facilitation was observed in both injured and uninjured segments of the spinal cord. The large effect size of this paired stimulation makes it a promising candidate for therapeutic neuromodulation. KEY POINTS: Pairs of stimuli designed to alter nervous system function typically target the motor system, or one targets the sensory system and the other targets the motor system for convergence in cortex. In humans undergoing clinically indicated surgery, we tested paired brain and spinal cord stimulation that we developed in rats aiming to target sensorimotor convergence in the cervical cord. Arm and hand muscle responses to paired sensorimotor stimulation were more than five times larger than brain or spinal cord stimulation alone when applied to the posterior but not anterior spinal cord. Arm and hand muscle responses to paired stimulation were more selective for targeted muscles than the brain- or spinal-only conditions, especially at latencies that produced the strongest effects of paired stimulation. Measures of clinical evidence of compression were only weakly related to the paired stimulation effect, suggesting that it could be applied as therapy in people affected by disorders of the central nervous system.

Effect of BMI on Complications Following Total Shoulder Arthroplasty: A Population-Wide Analysis.

BACKGROUND: Evidence regarding the effect of body mass index (BMI) on complications following anatomic shoulder arthroplasty (aTSA) and reverse shoulder arthroplasty (rTSA) remains controversial. This high-powered study examines the effect of BMI on surgical and medical complications following anatomic shoulder arthroplasty (aTSA) and reverse shoulder arthroplasty (rTSA). METHODS: This retrospective cohort study was conducted using the Premier Healthcare Database (PHD) to query all adult patients who underwent primary, elective TSA (aTSA, rTSA) from 2016 to 2020. Patients eligible for inclusion were identified using ICD-10 and CPT codes for primary TSA. Patients were stratified into three subgroups based on BMI (BMI <30 kg/m2, BMI 30-35 kg/m2, BMI > 35 kg/m2). The primary endpoints assessed were 90-day risks of postoperative complications, revisions, and readmissions among the three BMI groups undergoing primary TSA. RESULTS: A total of 32,645 patients were analyzed; 10,951 patients underwent aTSA and 21,694 patients underwent rTSA. Patient populations for aTSA and rTSA differed significantly across all BMI categories in terms of age, sex, cost of care, and insurance status. After multivariate regression analysis, there was no increased risk of surgical complications in the aTSA and rTSA cohorts with BMI 30-35 kg/m2 and BMI > 35 kg/m2. In the aTSA cohort, rates of acute respiratory failure (adjusted Odds Ratio (aOR) 2.65) was all significantly higher in the BMI > 35 kg/m2 group. As for rTSA cohort, acute respiratory failure (aOR 1.67) and acute renal failure (aOR 1.53) were significantly higher in the BMI > 35 kg/m2 group. CONCLUSION: While we found no increased risk of immediate postoperative surgical risks, patients with a BMI > 35 kg/m2 demonstrated greater risk of medical complications after rTSA. Given this trend, providers should exercise caution in patient selection for TSA and counsel obese patients as to these increased risks. Future studies should aim to provide a more comprehensive picture of the effect of BMI on functional outcomes after TSA.

Results of Randomized Controlled Trials of Platelet-Rich Plasma in Lower-Extremity Tendinopathy Are Not Influenced by Industry Sponsorship.

PURPOSE: To determine whether industry affiliation influences the results of randomized controlled trials (RCTs) studying the use of platelet-rich plasma (PRP) for the treatment of patellar or Achilles tendinopathy. METHODS: The PubMed, Scopus, Cochrane, and MEDLINE databases were searched in July 2023 for RCTs investigating PRP for the treatment of patellar or Achilles tendinopathy published between 2009 and July 2023. Industry affiliation was determined by analyzing each study's funding or conflict-of-interest section. Author disclosures were searched in the American Academy of Orthopaedic Surgeons disclosure database and the Centers for Medicare & Medicaid Services open payments database. An industry-affiliated (IA) designation was given if an author had a relevant disclosure or if the company that funded the study manufactured PRP. Otherwise, a non-industry-affiliated (NIA) designation was given. Fisher exact analysis was used to determine whether PRP had a favorable effect, no significant effect, or an unfavorable effect on outcome. RESULTS: Analysis was performed on 22 studies (10 IA and 12 NIA), with 17 studies (77.3%) reporting a conflict of interest or funding for the research, 4 (18.2%) reporting no conflict of interest, and 1 (4.5%) with no reporting. Of the 22 included studies, 8 (36.4%) reported favorable outcomes regarding PRP use and 14 (63.6%) reported no significant effect. Favorable outcomes were found in 4 of the 10 IA studies (40.0%), whereas no significant effect was reported in 6 (60.0%). The 12 NIA studies included 4 (33.3%) with favorable results and 8 (66.7%) with no significant effect. The comparison between industry affiliation and results reported was not statistically significant (P > .999). CONCLUSIONS: The results of RCTs evaluating the use of PRP in lower-extremity tendinopathy were not influenced by industry sponsorship. CLINICAL RELEVANCE: Most biomedical research is funded through industry sponsorship. Although this relation is necessary as technologies are developed, it is important to scrutinize studies for evidence of industry bias to understand how this bias may be affecting study results published in the literature.

Perioperative intravenous dexamethasone use is not associated with periprosthetic joint infection or wound healing complications following shoulder arthroplasty.

BACKGROUND: Perioperative intravenous (IV) dexamethasone is commonly used in lower extremity total joint arthroplasty to manage postoperative pain and nausea/vomiting, and recent studies have demonstrated that its use may lower rates of acute postoperative medical complications. However, there is limited information regarding the safety and efficacy of IV dexamethasone in patients undergoing total shoulder arthroplasty (TSA). Additionally, there is concern surrounding corticosteroid use prior to surgery as preoperative corticosteroid injections have been associated with adverse outcomes after TSA, including periprosthetic joint infection (PJI) and revision surgery. Thus, the purpose of this study was to evaluate the effect of perioperative IV dexamethasone on 90-day rates of PJI, wound complications, and medical complications after TSA. METHODS: The Premiere national hospital database was used to identify adult patients undergoing elective TSA between 2016 and 2020; patients were excluded if they were under 18 years old, were undergoing revision TSA, or had a prior proximal humerus open reduction internal fixation procedure. Patients who did and did not receive perioperative IV dexamethasone were then compared in both univariate and multivariate analyses. A Bonferroni correction was utilized to adjust for multiple comparisons. The primary end point was risk of acute infectious complications within 90 days of surgery, including PJI and wound infection/dehiscence. Secondary end points included acute pulmonary, renal, and thromboembolic complications. RESULTS: A total of 135,333 patients underwent TSA during the study period; 61.2% underwent reverse total shoulder arthroplasty, 33.8% underwent anatomic total shoulder arthroplasty, and 5.0% underwent hemiarthroplasty. From 2016 to 2020, perioperative IV dexamethasone use increased by 135%. Multivariate analysis revealed that patients who received perioperative IV dexamethasone did not have increased odds of PJI, superficial wound infection, or wound dehiscence (P = .15-.47) but did have decreased odds of sepsis (odds ratio [OR] 0.67, 95% confidence interval [CI] 0.55-0.81) and other medical complications such as urinary tract infection and acute kidney injury. Additionally, there was a trend towards decreased 90-day hospital readmission (OR 0.88, 95% CI 0.81-0.96, P = .003). CONCLUSIONS: Perioperative IV dexamethasone was not associated with increased risk of acute infectious and wound healing complications. Moreover, patients who received perioperative IV dexamethasone had decreased odds of medical complications and trended toward lower rates of 90-day hospital readmission. The results of this study support the safety of perioperative IV dexamethasone use in patients undergoing elective TSA.

Foundations of the Diagnosis and Management of Idiopathic Intracranial Hypertension and Pulsatile Tinnitus.

Venous sinus stenosis has garnered increasing academic attention as a potential etiology of idiopathic intracranial hypertension (IIH) and pulsatile tinnitus (PT). The complex anatomy of the cerebral venous sinuses and veins plays a crucial role in the pathophysiology of these conditions. Venous sinus stenosis, often found in the superior sagittal or transverse sinus, can lead to elevated intracranial pressure (ICP) and characteristic IIH symptoms. Stenosis, variations in dural venous anatomy, and flow dominance patterns contribute to aberrant flow and subsequent PT. Accurate imaging plays a vital role in diagnosis, and magnetic resonance (MR) venography is particularly useful for detecting stenosis. Management strategies for IIH and PT focus on treating the underlying disease, weight management, medical interventions, and, in severe cases, surgical or endovascular procedures. Recently, venous sinus stenting has gained interest as a minimally invasive treatment option for IIH and PT. Stenting addresses venous sinus stenosis, breaking the feedback loop between elevated ICP and stenosis, thus reducing ICP and promoting cerebrospinal fluid outflow. The correction and resolution of flow aberrances can also mitigate or resolve PT symptoms. While venous sinus stenting remains an emerging field, initial results are promising. Further research is needed to refine patient selection criteria and evaluate the long-term efficacy of stenting as compared to traditional treatments.

Challenges in the use of Venous Sinus Stenting in the Treatment of Idiopathic Intracranial Hypertension and Pulsatile Tinnitus.

Although numerous case series and meta-analyses have shown the efficacy of venous sinus stenting (VSS) in the treatment of idiopathic intracranial hypertension and idiopathic intracranial hypertension-associated pulsatile tinnitus, there remain numerous challenges to be resolved. There is no widespread agreement on candidacy; pressure gradient and failed medical treatment are common indications, but not all clinicians require medical refractoriness as a criterion. Venous manometry, venography, and cerebral angiography are essential tools for patient assessment, but again disagreements exist regarding the best, or most appropriate, diagnostic imaging choice. Challenges with the VSS technique also exist, such as stent choice and deployment. There are considerations regarding postprocedural balloon angioplasty and pharmacologic treatment, but there is insufficient evidence to formalize postoperative decision making. Although complications of VSS are relatively rare, they include in-stent stenosis, hemorrhage, and subdural hematoma, and the learning curve for VSS presents specific challenges in navigating venous anatomy, emphasizing the need for wider availability of high-quality training. Recurrence of symptoms, particularly stent-adjacent stenosis, poses challenges, and although restenting and cerebrospinal fluid-diverting procedures are options, there is a need for clearer criteria for retreatment strategies. Despite these challenges, when comparing VSS with traditional cerebrospinal fluid-diverting procedures, VSS emerges as a favorable option, with strong clinical outcomes, lower complication rates, and cost-effectiveness. Further research is necessary to refine techniques and indications and address specific aspects of VSS to overcome these challenges.

Future Directions and Innovations in Venous Sinus Stenting.

This review explores the future role of venous sinus stenting (VSS) in the management of idiopathic intracranial hypertension and pulsatile tinnitus. Despite its favorable safety profile and clinical outcomes compared with traditional treatments, VSS is not yet the standard of care for these conditions, lacking high-level evidence data and guidelines for patient selection and indications. Current and recently completed clinical trials are expected to provide data to support the adoption of VSS as a primary treatment option. Additionally, VSS shows potential in treating other conditions, such as dural arteriovenous fistula and cerebral venous sinus thrombosis, and it is likely that the procedure will continue to see an expansion of its approved indications. The current lack of dedicated venous stenting technology is being addressed with promising advancements, which may improve procedural ease and patient outcomes. VSS also offers potential for expansion into modulation of brain electrophysiology via endovascular routes, offering exciting possibilities for neurodiagnostics and treatment of neurodegenerative disorders.

Comparing posterior cervical foraminotomy with anterior cervical discectomy and fusion in radiculopathic patients: an analysis from the Quality Outcomes Database.

OBJECTIVE: The objective of this study was to compare clinical and patient-reported outcomes (PROs) between posterior foraminotomy and anterior cervical discectomy and fusion (ACDF) in patients presenting with cervical radiculopathy. METHODS: The Quality Outcomes Database was queried for patients who had undergone ACDF or posterior foraminotomy for radiculopathy. To create two highly homogeneous groups, optimal individual matching was performed at a 5:1 ratio between the two groups on 29 baseline variables (including demographic characteristics, comorbidities, symptoms, patient-reported scores, underlying pathologies, and levels treated). Outcomes of interest were length of stay, reoperations, patient-reported satisfaction, increase in EQ-5D score, and decrease in Neck Disability Index (NDI) scores for arm and neck pain as long as 1 year after surgery. Noninferiority analysis of achieving patient satisfaction and minimal clinically important difference (MCID) in PROs was performed with an accepted risk difference of 5%. RESULTS: A total of 7805 eligible patients were identified: 216 of these underwent posterior foraminotomy and were matched to 1080 patients who underwent ACDF. The patients who underwent ACDF had more underlying pathologies, lower EQ-5D scores, and higher NDI and neck pain scores at baseline. Posterior foraminotomy was associated with shorter hospitalization (0.5 vs 0.9 days, p < 0.001). Reoperations within 12 months were significantly more common among the posterior foraminotomy group (4.2% vs 1.9%, p = 0.04). The two groups performed similarly in PROs, with posterior foraminotomy being noninferior to ACDF in achieving MCID in EQ-5D and neck pain scores but also having lower rates of maximal satisfaction at 12 months (North American Spine Society score of 1 achieved by 65.2% posterior foraminotomy patients vs 74.6% of ACDF patients, p = 0.02). CONCLUSIONS: The two procedures were found to be offered to different populations, with ACDF being selected for patients with more complicated pathologies and symptoms. After individual matching, posterior foraminotomy was associated with a higher reoperation risk within 1 year after surgery compared to ACDF (4.2% vs 1.9%). In terms of 12-month PROs, posterior foraminotomy was noninferior to ACDF in improving quality of life and neck pain. The two procedures also performed similarly in improving NDI scores and arm pain, but ACDF patients had higher maximal satisfaction rates.

Multilineage involvement in KMT2A-rearranged B acute lymphoblastic leukaemia: cell-of-origin, biology, and clinical implications.

AIMS: B lymphoblastic leukaemia/lymphoma (B-ALL) is thought to originate from Pro/Pre-B cells and the genetic aberrations largely reside in lymphoid-committed cells. A recent study demonstrated that a proportion of paediatric B-ALL patients have BCR::ABL1 fusion in myeloid cells, suggesting a chronic myeloid leukaemia (CML)-like biology in this peculiar subset of B-ALL, although it is not entirely clear if the CD19-negative precursor compartment is a source of the myeloid cells. Moreover, the observation has not yet been extended to other fusion-driven B-ALLs. METHODS AND RESULTS: In this study we investigated a cohort of KMT2A-rearranged B-ALL patients with a comparison to BCR::ABL1-rearranged B-ALL by performing cell sorting via flow cytometry followed by FISH (fluorescence in situ hybridization) analysis on each of the sorted populations. In addition, RNA sequencing was performed on one of the sorted populations. These analyses showed that (1) multilineage involvement was present in 53% of BCR::ABL1 and 36% of KMT2A-rearranged B-ALL regardless of age, (2) multilineage involvement created pitfalls for residual disease monitoring, and (3) HSPC transcriptome signatures were upregulated in KMT2A-rearranged B-ALL with multilineage involvement. CONCLUSIONS: In summary, multilineage involvement is common in both BCR::ABL1-rearranged and KMT2A-rearranged B-ALL, which should be taken into consideration when interpreting the disease burden during the clinical course.

Illumination of understudied ciliary kinases.

Cilia are cellular signaling hubs. Given that human kinases are central regulators of signaling, it is not surprising that kinases are key players in cilia biology. In fact, many kinases modulate ciliogenesis, which is the generation of cilia, and distinct ciliary pathways. Several of these kinases are understudied with few publications dedicated to the interrogation of their function. Recent efforts to develop chemical probes for members of the cyclin-dependent kinase like (CDKL), never in mitosis gene A (NIMA) related kinase (NEK), and tau tubulin kinase (TTBK) families either have delivered or are working toward delivery of high-quality chemical tools to characterize the roles that specific kinases play in ciliary processes. A better understanding of ciliary kinases may shed light on whether modulation of these targets will slow or halt disease onset or progression. For example, both understudied human kinases and some that are more well-studied play important ciliary roles in neurons and have been implicated in neurodevelopmental, neurodegenerative, and other neurological diseases. Similarly, subsets of human ciliary kinases are associated with cancer and oncological pathways. Finally, a group of genetic disorders characterized by defects in cilia called ciliopathies have associated gene mutations that impact kinase activity and function. This review highlights both progress related to the understanding of ciliary kinases as well as in chemical inhibitor development for a subset of these kinases. We emphasize known roles of ciliary kinases in diseases of the brain and malignancies and focus on a subset of poorly characterized kinases that regulate ciliary biology.

Randomized controlled trials in the shoulder arthroplasty literature rarely include key demographic and socioeconomic patient data.

BACKGROUND: It is well known that socioeconomic and demographic variables can greatly affect health outcomes. Previous studies across medical and surgical subspecialties have demonstrated that these variables are frequently under-reported in randomized controlled trials (RCTs). No such study currently exists that examines rates of reporting of sociodemographic variables in shoulder arthroplasty RCTs. This study aims to present these rates and explore the impact of failing to report socioeconomic variables in shoulder arthroplasty RCTs. METHODS: The PubMed database was queried for the term shoulder arthroplasty. Sixty-five RCTs from the past 10 years were identified for inclusion from 5 high-impact orthopedic surgery journals. Each RCT was analyzed for patient age and sex or gender as well as the following sociodemographic variables: race, ethnicity, insurance status, income, work status, and education. It was also noted whether each of the above variable was mentioned in the results section of the article. Data were presented in a descriptive fashion as well as analyzed using χ2 and Fisher exact tests where appropriate. RESULTS: From 2014 to 2023, the 65 shoulder arthroplasty RCTs published reported age in 40 of 65 (61.5%) in their results sections and 61 of 65 (93.8%) in any section. Sex or gender was reported in 27 of 65 (41.5%) in their results sections and 61 of 65 (93.8%) in any section. No articles included any sociodemographic variables in the results section. Reporting rates for sociodemographic variables in any section were as follows: race, 6 of 65 (9.2%); ethnicity, 5 of 65 (7.7%); work status, 4 of 65 (6.2%); and insurance status, 1 of 65 (1.5%). No studies included income or education of the enrolled patients. There was no difference in reporting sociodemographic variables by journal (P = .45) or by year of publication (P = .57). However, no study prior to 2020 included any sociodemographic variable (0 of 27, 0%), whereas from 2020 onward 6 studies included at least 1 (6 of 38, 15.8%). Sociodemographic variables were reported significantly less frequently than age and sex or gender (P = .001). DISCUSSION: Our study found sociodemographic variables are rarely reported in shoulder arthroplasty RCTs, whereas age and sex or gender are reported with great frequency. In order to understand the results of shoulder arthroplasty RCTs, apply their findings to the care of our patients, and address health disparities, we must ensure these studies include patient sociodemographic data.

Cervical spondylotic myelopathy and driving abilities: defining the prevalence and long-term postoperative outcomes using the Quality Outcomes Database.

OBJECTIVE: Cervical spondylotic myelopathy (CSM) can cause significant difficulty with driving and a subsequent reduction in an individual's quality of life due to neurological deterioration. The positive impact of surgery on postoperative patient-reported driving capabilities has been seldom explored. METHODS: The CSM module of the Quality Outcomes Database was utilized. Patient-reported driving ability was assessed via the driving section of the Neck Disability Index (NDI) questionnaire. This is an ordinal scale in which 0 represents the absence of symptoms while driving and 5 represents a complete inability to drive due to symptoms. Patients were considered to have an impairment in their driving ability if they reported an NDI driving score of 3 or higher (signifying impairment in driving duration due to symptoms). Multivariable logistic regression models were fitted to evaluate mediators of baseline impairment and improvement at 24 months after surgery, which was defined as an NDI driving score < 3. RESULTS: A total of 1128 patients who underwent surgical intervention for CSM were included, of whom 354 (31.4%) had baseline driving impairment due to CSM. Moderate (OR 2.3) and severe (OR 6.3) neck pain, severe arm pain (OR 1.6), mild-moderate (OR 2.1) and severe (OR 2.5) impairment in hand/arm dexterity, severe impairment in leg use/walking (OR 1.9), and severe impairment of urinary function (OR 1.8) were associated with impaired driving ability at baseline. Of the 291 patients with baseline impairment and available 24-month follow-up data, 209 (71.8%) reported postoperative improvement in their driving ability. This improvement seemed to be mediated particularly through the achievement of the minimal clinically important difference (MCID) in neck pain and improvement in leg function/walking. Patients with improved driving at 24 months noted higher postoperative satisfaction (88.5% vs 62.2%, p < 0.01) and were more likely to achieve a clinically significant improvement in their quality of life (50.7% vs 37.8%, p < 0.01). CONCLUSIONS: Nearly one-third of patients with CSM report impaired driving ability at presentation. Seventy-two percent of these patients reported improvements in their driving ability within 24 months of surgery. Surgical management of CSM can significantly improve patients' driving abilities at 24 months and hence patients' quality of life.

Improved Clinical Staging System for Localized Pancreatic Cancer Using the ABC Factors: A TAPS Consortium Study.

PURPOSE: Previous studies suggest that besides anatomy (A: resectable, borderline resectable [BR], or locally advanced [LA]) also biologic (B: carbohydrate antigen 19-9 [CA 19-9]) and conditional (C: performance status) factors should be considered when staging patients with localized pancreatic ductal adenocarcinoma (PDAC). The prognostic value of the combined ABC factors has not been quantitatively validated. METHODS: In this retrospective cohort study, we evaluated patients with localized PDAC treated with initial (modified) fluorouracil with leucovorin, irinotecan, and oxaliplatin ([m]FOLFIRINOX) at five high-volume pancreatic cancer centers in the United States and the Netherlands (2012-2019). Multivariable Cox proportional hazards analysis was used to investigate the impact of the ABC factors for overall survival (OS). RESULTS: Overall, 1,835 patients with localized PDAC were included. Tumor stage at diagnosis was potentially resectable in 346 (18.9%), BR in 531 (28.9%), and LA in 958 (52.2%) patients. The baseline CA 19-9 was >500 U/mL in 559 patients (32.5%). Performance status was ≥1 in 1,110 patients (60.7%). Independent poor prognostic factors for OS were BR disease (hazard ratio [HR], 1.26 [95% CI, 1.06 to 1.50]), LA disease (HR, 1.71 [95% CI, 1.45 to 2.02]), CA 19-9 >500 U/mL (HR, 1.36 [95% CI, 1.21 to 1.52]), and WHO performance status ≥1 (HR, 1.31 [95% CI, 1.16 to 1.47]). Patients were assigned 1 point for each poor ABC factor and 2 points for LA disease. The median OS for patients with score 0-4 was 49.7, 29.9, 22.0, 19.1, and 14.9 months with corresponding 5-year OS rates of 47.0%, 28.9%, 19.2%, 9.3%, and 4.8%, respectively. CONCLUSION: The ABC factors of tumor anatomy, CA 19-9, and performance status at diagnosis were independent prognostic factors for OS in patients with localized PDAC treated with initial (m)FOLFIRINOX. Staging of patients with localized PDAC at diagnosis should be based on anatomy, CA 19-9, and performance status.