Third and Fourth Vaccine Doses Broaden and Prolong Immunity to SARS-CoV-2 in Adult Patients with Immune-Mediated Inflammatory Diseases.

Previous studies have reported impaired humoral responses after SARS-CoV-2 mRNA vaccination in patients with immune-mediated inflammatory diseases (IMIDs), particularly those treated with anti-TNF biologics. We previously reported that IMID patients diagnosed with inflammatory bowel disease, psoriasis, psoriatic arthritis, ankylosing spondylitis, or rheumatoid arthritis exhibited greater waning of Ab and T cell responses than healthy control subjects after SARS-CoV-2 vaccine dose 2. Fewer data are available on the effects of third and fourth doses. This observational cohort study collected plasma and PBMCs from healthy control subjects and untreated or treated patients with IMIDs prevaccination and after one to four doses of SARS-CoV-2 mRNA vaccine (BNT162b2 or mRNA-1273). SARS-CoV-2-specific Ab levels, neutralization, and T cell cytokine release were measured against wild-type and Omicron BA.1 and BA.5 variants of concern. Third vaccine doses substantially restored and prolonged Ab and T cell responses in patients with IMIDs and broadened responses against variants of concern. Fourth-dose effects were subtle but also prolonged Ab responses. However, patients with IMIDs treated with anti-TNF, especially patients with inflammatory bowel disease, exhibited lower Ab responses even after the fourth dose. Although T cell IFN-γ responses were maximal after one dose, IL-2 and IL-4 production increased with successive doses, and early production of these cytokines was predictive of neutralization responses at 3-4 mo postvaccination. Our study demonstrates that third and fourth doses of the SARS-CoV-2 mRNA vaccines sustain and broaden immune responses to SARS-CoV-2, supporting the recommendation for three- and four-dose vaccination regimens in patients with IMIDs.

Residual Disease Activity in Canadian Patients With Psoriatic Arthritis Treated With Advanced Therapies: Results From a Multiregistry Analysis (UNISON-PsA).

OBJECTIVE: Although patient outcomes in psoriatic arthritis (PsA) have improved with the advent of advanced therapies, there remains a high unmet need to treat residual disease activity. The objective of the current study was to quantify residual disease activity and burden of disease in Canadian patients with PsA. METHODS: This was a multiregion, observational, retrospective analysis of patient data extracted from the Rhumadata and the International Psoriasis and Arthritis Research Team (IPART) registries, analyzing deidentified data from patients who had initiated advanced therapy for the treatment of PsA between January 2010 and December 2019. The primary endpoint was the proportion of patients failing to achieve minimal disease activity (MDA) within 6 months; secondary endpoints included clinical and patient-reported burden of disease. Descriptive statistics included summaries by region, treatment class, and number of prior advanced therapies. RESULTS: One thousand five hundred ninety-six patients were included. The proportions of patients who failed to achieve MDA within 6 months of an advanced therapy were 64.8% in Ontario, 68.3% in Western Canada, 74.8% in Quebec, and 75% in the Atlantic/East region. Failure to achieve MDA was higher among patients receiving an IL-17i compared with a TNFi in all regions except the Atlantic/East. Between 73.2% and 78.6% of patients reported pain at 6 months, and continuing functional impairment varied from 24% in the West to 83.3% in the Atlantic/East. CONCLUSION: There is substantial burden and unmet need for improved therapies for Canadians with PsA. There is a wide regional variation in outcomes that requires further assessment.

When Should I Get My Next COVID-19 Vaccine? Data From the Surveillance of Responses to COVID-19 Vaccines in Systemic Immune-Mediated Inflammatory Diseases (SUCCEED) Study.

OBJECTIVE: To determine how serologic responses to coronavirus disease 2019 (COVID-19) vaccination and infection in immune-mediated inflammatory disease (IMID) are affected by time since last vaccination and other factors. METHODS: Post-COVID-19 vaccination, data, and dried blood spots or sera were collected from adults with rheumatoid arthritis, inflammatory bowel disease, systemic lupus erythematosus, ankylosing spondylitis and spondylarthritis, and psoriasis and psoriatic arthritis. The first sample was collected at enrollment, then at 2 to 4 weeks and 3, 6, and 12 months after the latest vaccine dose. Multivariate generalized estimating equation regressions (including medications, demographics, and vaccination history) evaluated serologic response, based on log-transformed anti-receptor-binding domain (RBD) IgG titers; we also measured antinucleocapsid (anti-N) IgG. RESULTS: Positive associations for log-transformed anti-RBD titers were seen with female sex, number of doses, and self-reported COVID-19 infections in 2021 to 2023. Negative associations were seen with prednisone, anti-tumor necrosis factor agents, and rituximab. Over the 2021-2023 period, most (94%) of anti-N positivity was associated with a self-reported infection in the 3 months prior to testing. From March 2021 to February 2022, anti-N positivity was present in 5% to 15% of samples and was highest in the post-Omicron era, with antinucleocapsid positivity trending to 30% to 35% or higher as of March 2023. Anti-N positivity in IMID remained lower than Canada's general population seroprevalence (> 50% in 2022 and > 75% in 2023). Time since last vaccination was negatively associated with log-transformed anti-RBD titers, particularly after 210 days. CONCLUSION: Ours is the first pan-Canadian IMID assessment of how vaccine history and other factors affect serologic COVID-19 vaccine responses. These findings may help individuals personalize vaccination decisions, including consideration of additional vaccination when > 6 months has elapsed since last COVID-19 vaccination/infection.

Patients With Preexisting Anxiety and Mood Disorders Are More Likely to Develop Complex Regional Pain Syndrome After Fractures.

BACKGROUND: Complex regional pain syndrome (CRPS) is a multifactorial condition that may affect patients who sustain a fracture in the upper and lower extremities. Prior investigations have formed a foundation for exploring a possible association between psychiatric disorders and the development of CRPS; however, current studies are conflicted regarding the existence and temporality of a relationship between psychiatric disorders and the potential development of CRPS. QUESTIONS/PURPOSES: (1) Are patients with preexisting anxiety and mood disorders (AMDs) at increased risk of receiving a diagnosis of CRPS after upper or lower extremity fractures? (2) Are patients with preexisting AMDs at increased risk of being diagnosed with CRPS after surgical fixation of their fracture? METHODS: A large, retrospective cohort study was conducted using the TriNetX electronic medical record platform, which contains data from more than 100 million patients. This platform gathers data from healthcare organizations in the United States and Europe and collects comprehensive data over time that includes temporality rather than simply the binary presence or absence of conditions. The cohort included 760,595 patients older than 18 years with upper or lower extremity fractures between 2003 and 2022. Included patients had a minimum 1-year follow-up. We defined AMDs as any diagnosis of anxiety, depressive episode or disorder, a manic episode, or bipolar disorder. Patients with polytrauma or concurrent upper and lower extremity fractures were excluded to reduce confounders. CRPS I diagnosis was identified via International Classification of Diseases, Tenth Edition codes. Propensity score matching was performed to balance cohorts based on age, gender, and race. Hazard ratios and Aalen-Johansen cumulative incidence curves for the diagnosis of CRPS were calculated for patients with and without AMD diagnoses before sustaining a fracture. A subanalysis was performed in which we examined individuals in the upper and lower extremity fracture cohorts who underwent surgical treatment. RESULTS: Patients with preexisting AMDs were at a higher risk of experiencing CRPS I than patients without AMDs were (upper extremity: HR 1.8 [95% CI 1.7 to 1.9]; p < 0.01, lower extremity: HR 2.2 [95% CI 2.0 to 2.3]; p < 0.01). Similarly, patients with preexisting AMDs were at higher risk of experiencing CRPS I after fracture fixation than patients without AMDs were (upper extremity: HR 1.3 [95% CI 1.2 to 1.5]; p < 0.01, lower extremity: HR 2.3 [95% CI 2.1 to 2.5]; p < 0.01). CONCLUSION: Awareness of the relationship between AMDs and CRPS I will direct future research about the development of this condition and associated neurologic changes. Additionally, surgeons can address AMDs perioperatively and arrange for the treatment of these AMDs with psychiatrists, neurologists, or social work, as appropriate. Accordingly, patients with AMDs should also be made aware of the inherent risk of CRPS I after an upper or lower extremity fracture to comprehensively educate and care for this at-risk patient population. LEVEL OF EVIDENCE: Level III, therapeutic study.

Epidemiology of Pediatric Firearm Injuries in the United States: The Progression of Gunshot Injury Rates Through the Coronavirus Disease 2019 Pandemic.

OBJECTIVES: Ballistic injuries among pediatric populations have become a public health crisis in the United States. The surge in firearm injuries among children has outpaced other causes of death. This study aims to assess the trend in pediatric gunshot injuries (GSIs) over the last decade and investigate the impact, if any, of the pandemic on GSIs statistics. METHODS: A comprehensive retrospective analysis was conducted using a federated, real-time national database. A total of 15,267,921 children without GSIs and 6261 children with GSIs between 2017 and 2023 were identified. The study evaluated the incidence and annual proportions of GSIs among different demographics. In addition, the incidence proportions per 100,000 for accidental, nonaccidental, fracture-related, and fatal GSIs were analyzed. RESULTS: The incidence proportions per 100,000 for GSIs, accidental GSIs, nonaccidental GSIs, fatal GSIs, wheelchair-bound cases, and fracture-related GSIs increased significantly from 2017 to 2023, going from 9.7 to 22.8 (Relative Risk: 2.342, 95% CI: 2.041, 2.687, P < 0.001). The overall increase was mostly a result of accidental GSI when compared with nonaccidental (incidence proportion 25.8 vs 2.1; P < 0.001) in 2021 at the height of the pandemic. In patients with an accidental GSI, the incidence proportion per 100k between 2017 and 2023 increased from 8.81 to 21.11 (Relative Risk: 2.397, 95% CI: 2.076, 2.768, P < 0.001). CONCLUSION: The study supports the shift in the leading cause of death among children from motor vehicle accidents to GSIs, with the continued rise in rates despite the coronavirus disease 2019 pandemic. Accidental injuries constituted the majority of GSIs, indicating the need for enhanced gun safety measures, including requirements for gun storage, keeping firearms locked and unloaded, requiring child supervision in homes with guns, and enforcing stricter punishments as penalties. Comprehensive efforts are required to address this public health crisis. Pediatricians play a vital role in counseling and educating families on firearm safety. LEVEL OF EVIDENCE: Level III.

Risk Factors for Stiffness After Surgical Treatment of Pediatric Humeral Lateral Condyle Fractures: Results of a Multicenter Study.

INTRODUCTION: Pediatric humeral lateral condyle fractures are the second most common elbow fractures. Their treatment presents challenges due to physeal and intra-articular involvement. Postoperative stiffness is a common concern that can limit limb functionality. This study aims to identify risk factors for postoperative stiffness in a large cohort of these fractures across multiple institutions. METHODS: A large, multicenter retrospective review of medical records from 6 level I trauma centers was conducted. Data from children aged 1 to 12 years with lateral condyle fractures treated between 2005 and 2019 were collected. Elbow stiffness was defined in the present study as having a limited elbow ROM that led to requiring a physical or occupational therapy referral or needing surgical treatment to address stiffness. Relevant patient demographics, fracture characteristics, treatment approaches, and complications were analyzed. RESULTS: Six hundred sixty-five fractures were analyzed. The average patient age was 8.8 years with 21% experiencing stiffness. The stiffness group had older patients, a higher incidence of elbow dislocations, a higher rate of open reduction, and more severe fracture patterns. Multivariate regression analysis identified open reduction, increased age, and concurrent elbow dislocation as significant risk factors for stiffness. Patients with stiffness commonly utilized only physical or occupational therapy (96%), while a small percentage (4%) required surgical interventions. CONCLUSIONS: This study highlights the risk factors for postoperative stiffness in pediatric humeral lateral condyle fractures, namely increased age, concomitant elbow dislocation, and treatment with open reduction. Families of older patients or severe fracture patterns requiring open reduction and those with concurrent elbow instability should be counseled about their increased risk of stiffness. The authors recommend initially attempting a closed reduction in high-risk patients to help mitigate the risk of postoperative stiffness. Early initiation of range of motion exercises may also be beneficial for at-risk patients. LEVEL OF EVIDENCE: Level III: Therapeutic studies-Investigating the results of treatment.

Lumbopelvic fixation in the treatment of spinopelvic dissociation: union, complications, and neurologic outcomes of a multicenter case series.

PURPOSE: To review outcomes of spinopelvic dissociation treated with open lumbopelvic fixation. METHODS: We reviewed all cases of spinopelvic dissociation treated at three Level-I trauma centers with open lumbopelvic fixation, including those with adjunctive percutaneous fixation. We collected demographic data, associated injuries, pre- and postoperative neurologic status, pre- and postoperative kyphosis, and Roy-Camille classification. Outcomes included presence of union, reoperation rates, and complications involving hardware or wound. RESULTS: From an initial cohort of 260 patients with spinopelvic dissociation, forty patients fulfilled inclusion criteria with a median follow-up of 351 days. Ten patients (25%) had a combination of percutaneous iliosacral and open lumbopelvic repair. Average pre- and postoperative kyphosis was 30 degrees and 26 degrees, respectively. Twenty patients (50%) had neurologic deficit preoperatively, and eight (20%) were unknown or unable to be assessed. All patients presenting with bowel or bladder dysfunction (n = 12) underwent laminectomy at time of surgery, with 3 patients (25%) having continued dysfunction at final follow-up. Surgical site infection occurred in four cases (10%) and wound complications in two (5%). All cases (100%) went on to union and five patients (13%) required hardware removal. CONCLUSION: Open lumbopelvic fixation resulted in a high union rate in the treatment of spinopelvic dissociation. Approximately 1 in 6 patients had a wound complication, the majority of which were surgical site infections. Bowel and bladder dysfunction at presentation were common with the majority of cases resolving by final follow-up when spinopelvic dissociation had been treated with decompression and stable fixation.

One-Shot Resin 3D-Printed Stators for Low-Cost Fabrication of Magic-Angle Spinning NMR Probeheads.

Additive manufacturing such as three-dimensional (3D)-printing has revolutionized the fast and low-cost fabrication of otherwise expensive NMR parts. High-resolution solid-state NMR spectroscopy demands rotating the sample at a specific angle (54.74°) inside a pneumatic turbine, which must be designed to achieve stable and high spinning speeds without mechanical friction. Moreover, instability of the sample rotation often leads to crashes, resulting in costly repairs. Producing these intricate parts requires traditional machining, which is time-consuming, costly, and relies on specialized labor. Herein, we show that 3D-printing can be used to fabricate the sample holder housing (stator) in one shot, while the radiofrequency (RF) solenoid was constructed using conventional materials available in electronics stores. The 3D-printed stator, equipped with a homemade RF coil, showed remarkable spinning stability, yielding high-quality NMR data. At a cost below 5 €, the 3D-printed stator represents a cost reduction of over 99% compared to repaired commercial stators, illustrating the potential of 3D-printing for mass-producing affordable magic-angle spinning stators.

Capturing time-dependent activation of genes and stress-response pathways using transcriptomics in iPSC-derived renal proximal tubule cells.

Transcriptomic analysis is a powerful method in the utilization of New Approach Methods (NAMs) for identifying mechanisms of toxicity and application to hazard characterization. With this regard, mapping toxicological events to time of exposure would be helpful to characterize early events. Here, we investigated time-dependent changes in gene expression levels in iPSC-derived renal proximal tubular-like cells (PTL) treated with five diverse compounds using TempO-Seq transcriptomics with the aims to evaluate the application of PTL for toxicity prediction and to report on temporal effects for the activation of cellular stress response pathways. PTL were treated with either 50 µM amiodarone, 10 µM sodium arsenate, 5 nM rotenone, or 300 nM tunicamycin over a temporal time course between 1 and 24 h. The TGFß-type I receptor kinase inhibitor GW788388 (1 µM) was used as a negative control. Pathway analysis revealed the induction of key stress-response pathways, including Nrf2 oxidative stress response, unfolding protein response, and metal stress response. Early response genes per pathway were identified much earlier than 24 h and included HMOX1, ATF3, DDIT3, and several MT1 isotypes. GW788388 did not induce any genes within the stress response pathways above, but showed deregulation of genes involved in TGFß inhibition, including downregulation of CYP24A1 and SERPINE1 and upregulation of WT1. This study highlights the application of iPSC-derived renal cells for prediction of cellular toxicity and sheds new light on the temporal and early effects of key genes that are involved in cellular stress response pathways.

Novel SIRPα Antibodies That Induce Single-Agent Phagocytosis of Tumor Cells while Preserving T Cells.

The signal regulatory protein α (SIRPα)/CD47 axis has emerged as an important innate immune checkpoint that enables cancer cell escape from macrophage phagocytosis. SIRPα expression is limited to macrophages, dendritic cells, and neutrophils-cells enriched in the tumor microenvironment. In this study, we present novel anti-SIRP Abs, SIRP-1 and SIRP-2, as an approach to targeting the SIRPα/CD47 axis. Both SIRP-1 and SIRP-2 bind human macrophage SIRPα variants 1 and 2, the most common variants in the human population. SIRP-1 and SIRP-2 are differentiated among reported anti-SIRP Abs in that they induce phagocytosis of solid and hematologic tumor cell lines by human monocyte-derived macrophages as single agents. We demonstrate that SIRP-1 and SIRP-2 disrupt SIRPα/CD47 interaction by two distinct mechanisms: SIRP-1 directly blocks SIRPα/CD47 and induces internalization of SIRPα/Ab complexes that reduce macrophage SIRPα surface levels and SIRP-2 acts via disruption of higher-order SIRPα structures on macrophages. Both SIRP-1 and SIRP-2 engage FcγRII, which is required for single-agent phagocytic activity. Although SIRP-1 and SIRP-2 bind SIRPγ with varying affinity, they show no adverse effects on T cell proliferation. Finally, both Abs also enhance phagocytosis when combined with tumor-opsonizing Abs, including a highly differentiated anti-CD47 Ab, AO-176, currently being evaluated in phase 1 clinical trials, NCT03834948 and NCT04445701 SIRP-1 and SIRP-2 are novel, differentiated SIRP Abs that induce in vitro single-agent and combination phagocytosis and show no adverse effects on T cell functionality. These data support their future development, both as single agents and in combination with other anticancer drugs.

Recent assessment and characterization of Tuta absoluta resistance to cartap hydrochloride.

Tuta absoluta can cause 100% loss in tomato yield in Brazil and chemical control, which uses cartap hydrochloride (nereistoxin derivative), is still the most used tactic against T. absoluta populations. Despite the long use of cartap hydrochloride, the genetic and physiological bases underlying the resistance are not known. Resistance to cartap hydrochloride among field populations varied from very low (RR = 2.3 fold) to very high (RR = 537 fold). The Gameleira 2 (GML 2-Res) population was exposed to cartap hydrochloride (up to 500 mg L-1) for few rounds of selection to clean extrinsic factors before used in downstream experiments after 2.5 years without selection in laboratory. Resistance to cartap hydrochloride was autosomal, incompletely recessive, and polyfactorial. The effective dominance (dominance level of survival at a given insecticide dose) at 60 mg of cartap hydrochloride L-1 (which killed 100% of heterozygous individuals) discriminated resistant from susceptible phenotypes. Hydrolases and glutathione S-transferase appear to detoxify cartap hydrochloride as TPP and DEM synergized its toxicity, but CYP450-dependent monooxygenases are as well implicated. Cross-resistance was significant between cartap hydrochloride and methoxyfenozide (RR = 6.99 fold), deltamethrin (RR = 3.57 fold), chlorfenapyr (RR = 3.21 fold), or chlorantraniliprole (RR = 2.83 fold). The characterization of T. absoluta resistance to cartap hydrochloride provides valuable information to refine the management of resistance to insecticides (MRI) program in Brazil with cross resistance pattern very favorable to the rotation of active ingredients that will impair survival of this pest to that insecticide in the field.

SAR exploration of the non-imidazole histamine H3 receptor ligand ZEL-H16 reveals potent inverse agonism.

Histamine H3 receptor (H3 R) agonists without an imidazole moiety remain very scarce. Of these, ZEL-H16 (1) has been reported previously as a high-affinity non-imidazole H3 R (partial) agonist. Our structure-activity relationship analysis using derivatives of 1 identified both basic moieties as key interaction motifs and the distance of these from the central core as a determinant for H3 R affinity. However, in spite of the reported H3 R (partial) agonism, in our hands, 1 acts as an inverse agonist for Gαi signaling in a CRE-luciferase reporter gene assay and using an H3 R conformational sensor. Inverse agonism was also observed for all of the synthesized derivatives of 1. Docking studies and molecular dynamics simulations suggest ionic interactions/hydrogen bonds to H3 R residues D1143.32 and E2065.46 as essential interaction points.

Is There a Benefit to Rigid Fixation in Calcaneal Lengthening Osteotomy in Painful Pediatric Idiopathic Flatfoot Deformity? Comparing Results of Kirschner Wire Versus Plate Fixation.

INTRODUCTION: Flexible flatfoot (FF) is a common pediatric condition that is mostly asymptomatic, and surgical intervention is only considered when painful FF is refractory to conservative treatment. Calcaneal lengthening osteotomy (CLO) is one of the most commonly used procedures to address painful FF. Traditionally, Kirschner wires (K-wires) were used for fixation, but there has been a recent increase in the use of plates. We compared the clinical and radiographic outcomes of these 2 fixation methods. METHODS: This single-center retrospective study included children aged 8 to 18 years with symptomatic FF that received CLO using K-wire or plate fixation. Primary outcomes include weight-bearing radiographic measurements and complications after surgery. Secondary outcomes included patient-reported outcomes. Statistical significance was held at 0.05. RESULTS: Among 102 feet (65 patients), 42 feet (41.2%) underwent K-wire and 60 feet (58.8%) underwent plate fixation. No differences in casting duration ( P =0.525) and time-to-radiographic healing ( P =0.17) were noted. Total complications were higher in the plate cohort (12 vs. 2, P =0.04) due to a higher rate of reoperations (16.7%) for hardware-related pain [10 vs. 0; odds ratio 17.74, 95% CI (1.01, 310.54), P <0.05], and infection rates were similar. Both interventions significantly improved ( P ≤ 0.001) aneteroposterior (AP) Talo-first metatarsal and calcaneal pitch angles. Irrespective of intervention, CLO significantly improved pain at 6 months and mobility scores at 12 months. Neither modality demonstrated superior pain or mobility scores at final follow-up. CONCLUSION: Both K-wire and plate fixations lead to similar radiographic and functional outcomes after CLO in painful, pediatric flatfeet. Compared with K-wire fixation, plates cause a 17.7-fold increased risk of reoperations for painful hardware, with 16.7% of plated cases requiring reoperation. Noting this, along with the higher costs associated with using plates, our study advocates for K-wire fixation for children undergoing CLO. LEVEL OF EVIDENCE: Level III.

Displaced Tibia Fractures in Adolescents: Closed Reduction and Casting Versus Flexible Intramedullary Nails.

INTRODUCTION: Although there has been a recent trend towards the operative intervention of pediatric diaphyseal tibial fractures, there is sparse literature that supports this trend. This study compares the outcomes in children between 10 and 18 years of age with diaphyseal tibial fractures who undergo nonoperative treatment with closed reduction and casting (CRC) to those who undergo operative treatment with flexible intramedullary nailing. METHODS: A retrospective chart review was performed of all patients between 10 and 18 years of age who underwent treatment for tibia fractures at the authors home institution between 2005 and 2018. Radiographs and medical records were reviewed for the duration of immobilization, time to fracture healing and complications including delayed union, malunion, nonunion, and surgical site infection. All statistical analysis was performed using an αof 0.05. RESULTS: One hundred forty one patients (81.8% males) were included in the final analysis. Patients treated with flexible nailing took an average of 7 weeks ( P <0.001) longer than patients treated with CRC to achieve radiographic healing. The average time to full weight-bearing activities was longer by 1 week in the patients treated nonoperatively with CRC ( P =0.001). There was no statistically significant difference in the malunion rates between the 2 groups ( P =0.067), but delayed union and nonunion were exclusively seen in the flexible nailing group. There was a total of 40 complications among 33 (23.4%) patients, most of whom were in the CRC cohort (60.6%, n=20), but there was no statistically significant difference in complication rates between the 2 cohorts. DISCUSSION: Most adolescents presenting with closed diaphyseal tibial fractures of moderate severity can be successfully treated both nonoperatively with CRC and operatively with flexible intramedullary nailing. However, we recommend an initial attempt at nonoperative treatment be performed in these patients due to the association of more severe complications with flexible nailing. LEVEL OF EVIDENCE: Level III.

Prior Authorization in Total Joint Arthroplasty: A Survey of the American Association of Hip and Knee Surgeons Membership.

BACKGROUND: This study surveyed the impact that prior authorization has on the practices of total joint arthroplasty (TJA) members of the American Association of Hip and Knee Surgeons (AAHKS). METHODS: A 24-question survey was approved by the AAHKS Advocacy Committee and distributed to all 2,802 board-certified members of AAHKS. RESULTS: There were 353 survey responses (13%). Ninety-five percent of surgeons noted a 5-year increase in prior authorization. A majority (71%) of practices employ at least 1 staff member to exclusively work on prior authorization. Average time spent on prior authorization was 15 h/wk (range, 1 to 125) and average number of claims peer week was 18 (range, 1 to 250). Surgeries (99%) were the most common denial. These were denied because nonoperative treatment had not been tried (71%) or had not been attempted for enough time (67%). Most (57%) prior authorization processes rarely/never changed the treatment provided. Most (56%) indicated that prior authorization rarely/never followed evidence-based guidelines. A majority (93%) expressed high administrative burden as well as negative clinical outcomes (87%) due to prior authorization including delays to access care (96%) at least sometimes. DISCUSSION: Prior authorization has increased in the past 5 years resulting in high administrative burden. Prior authorizations were most common for TJA surgeries because certain nonoperative treatments were not attempted or not attempted for enough time. Surgeons indicated that prior authorization may be detrimental to high-value care and lead to potentially harmful delays in care without ultimately changing the management of the patient.

Evaluation of Smart Sensors for Subway Electric Motor Escalators through AHP-Gaussian Method.

This paper proposes the use of the AHP-Gaussian method to support the selection of a smart sensor installation for an electric motor used in an escalator in a subway station. The AHP-Gaussian methodology utilizes the Analytic Hierarchy Process (AHP) framework and is highlighted for its ability to save the decision maker's cognitive effort in assigning weights to criteria. Seven criteria were defined for the sensor selection: temperature range, vibration range, weight, communication distance, maximum electric power, data traffic speed, and acquisition cost. Four smart sensors were considered as alternatives. The results of the analysis showed that the most appropriate sensor was the ABB Ability smart sensor, which scored the highest in the AHP-Gaussian analysis. In addition, this sensor could detect any abnormalities in the equipment's operation, enabling timely maintenance and preventing potential failures. The proposed AHP-Gaussian method proved to be an effective approach for selecting a smart sensor for an electric motor used in an escalator in a subway station. The selected sensor was reliable, accurate, and cost-effective, contributing to the safe and efficient operation of the equipment.

Reliability of the Heartbeat Tracking Task to Assess Interoception.

Interoception refers to the competence in perceiving and interpreting internal sensations emerging from the body. The most common approach to assess interoception is through cardiac interoceptive tests like the heartbeat tracking task (HTT), which measures the accuracy on perceive and counting heartbeats during a period. However, the literature is scarce in providing adequate reliability evidence for this measure so that the interoception assessment may be threaten. In addition to HTT accuracy, it is possible to determine sensibility (self-reported confidence) and interoceptive awareness (correspondence between accuracy and sensibility). Thus, we measured the test-retest reliability of HTT and also investigated the behavior of HTT outcomes along the task. Therefore, 31 healthy adults (16 males) with 27.8 (9.4) years old performed two consecutive HTT interspersed by one day. Intraclass correlation coefficient (ICC), standard error of measurement (SEM) and minimal detectable difference (MD) analyzes showed 'Good' relative reliability for interoceptive accuracy (ICC = 0.880; SEM = 0.263; MD = 0.728; p < 0.001) and 'Moderate' for sensibility (ICC = 0.617; SEM = 0.648; MD = 1.797; p < 0.001) and awareness (ICC = 0.593; SEM = 0.227; MD = 0.628; p < 0.001). The absolute reliability shows low threshold values for observing true effects in HTT outcomes. The results also showed that reducing the number of HTT blocks did not impact the outcomes. The HTT showed to be reliable in determine the interoceptive competences in healthy adults.

Structural Integrity of Nucleolin Is Required to Suppress TDP-43-Mediated Cytotoxicity in Yeast and Human Cell Models.

The Transactivating response (TAR) element DNA-binding of 43 kDa (TDP-43) is mainly implicated in the regulation of gene expression, playing multiple roles in RNA metabolism. Pathologically, it is implicated in amyotrophic lateral sclerosis and in a class of neurodegenerative diseases broadly going under the name of frontotemporal lobar degeneration (FTLD). A common hallmark of most forms of such diseases is the presence of TDP-43 insoluble inclusions in the cell cytosol. The molecular mechanisms of TDP-43-related cell toxicity are still unclear, and the contribution to cell damage from either loss of normal TDP-43 function or acquired toxic properties of protein aggregates is yet to be established. Here, we investigate the effects on cell viability of FTLD-related TDP-43 mutations in both yeast and mammalian cell models. Moreover, we focus on nucleolin (NCL) gene, recently identified as a genetic suppressor of TDP-43 toxicity, through a thorough structure/function characterization aimed at understanding the role of NCL domains in rescuing TDP-43-induced cytotoxicity. Using functional and biochemical assays, our data demonstrate that the N-terminus of NCL is necessary, but not sufficient, to exert its antagonizing effects on TDP-43, and further support the relevance of the DNA/RNA binding central region of the protein. Concurrently, data suggest the importance of the NCL nuclear localization for TDP-43 trafficking, possibly related to both TDP-43 physiology and toxicity.

Resveratrol-Loaded Attalea funifera Oil Organogel Nanoparticles: A Potential Nanocarrier against A375 Human Melanoma Cells.

This study aimed to evaluate Attalea funifera seed oil with or without resveratrol entrapped in organogel nanoparticles in vitro against A375 human melanoma tumor cells. Organogel nanoparticles with seed oil (SON) or with resveratrol entrapped in the seed oil (RSON) formed functional organogel nanoparticles that showed a particle size <100 nm, polydispersity index <0.3, negative zeta potential, and maintenance of electrical conductivity. The resveratrol entrapment efficiency in RSON was 99 ± 1%. The seed oil and SON showed no cytotoxicity against human non-tumor cells or tumor cells. Resveratrol at 50 µg/mL was cytotoxic for non-tumor cells, and was cytotoxic for tumor cells at 25 µg/mL. Resveratrol entrapped in RSON showed a decrease in cytotoxicity against non-tumor cells and cytotoxic against tumor cells at 50 µg/mL. Thus, SON is a potential new platform for the delivery of resveratrol with selective cytotoxic activity in the treatment of melanoma.

Fragment Screening Yields a Small-Molecule Stabilizer of 14-3-3 Dimers That Modulates Client Protein Interactions.

The development of protein-protein interaction (PPI) inhibitors has been a successful strategy in drug development. However, the identification of PPI stabilizers has proven much more challenging. Here we report a fragment-based drug screening approach using the regulatory hub-protein 14-3-3 as a platform for identifying PPI stabilizers. A homogenous time-resolved FRET assay was used to monitor stabilization of 14-3-3/peptide binding using the known interaction partner estrogen receptor alpha. Screening of an in-house fragment library identified fragment 2 (VUF15640) as a putative PPI stabilizer capable of cooperatively stabilizing 14-3-3 PPIs in a cooperative fashion with Fusicoccin-A. Mechanistically, fragment 2 appears to enhance 14-3-3 dimerization leading to increased client-protein binding. Functionally, fragment 2 enhanced potency of 14-3-3 in a cell-free system inhibiting the enzyme activity of the nitrate reductase. In conclusion, we identified a general PPI stabilizer targeting 14-3-3, which could be used as a tool compound for investigating 14-3-3 client protein interactions.